Structural basis of the dehydratase module (hDH) of human fatty acid synthase.

The human fatty acid synthase (hFASN) produces fatty acids for cellar membrane construction, energy storage, biomolecule modifications and signal transduction. Abnormal expression and functions of hFASN highly associate with numerous human diseases such as obesity, diabetes, and cancers, and thereby it has been considered as a valuable potential drug target. So far, the structural and catalytic mechanisms of most of the hFASN enzymatic modules have been extensively studied, except the key dehydratase module (hDH). Here we presented the enzymatic characterization and the high-resolution crystal structure of hDH. We demonstrated that the hDH preferentially catalyzes the acyl substrates with short lengths between 4 to 8-carbons, and exhibits much lower enzymatic activity on longer substrates. Subsequent structural study showed that hDH displays a pseudo-dimeric organization with a single L-shaped composite hydrophobic catalytic tunnel as well as an atypical ACP binding site nearby, indicating that hDH achieves distinct substrate recognition and dehydration mechanisms compared to the conventional bacterial fatty acid dehydratases identified. Our findings laid the foundation for understanding the biological and pathogenic functions of hFASN, and may facilitate therapeutical drug development against diseases with abnormal functionality of hFASN.

The landscape of N1-methyladenosine (m1A) modification in mRNA of the decidua in severe preeclampsia.

Recent discoveries in mRNA modification have highlighted N1-methyladenosine (m1A), but its role in preeclampsia (PE) pathogenesis remains unclear. In this study, we utilized methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) to identify m1A peaks and the expression profile of mRNA in the decidua of humans with early-onset PE (EPE), late-onset PE (LPE), and normal pregnancy (NP). We assessed the m1A modification patterns in preeclamptic decidua using 10 m1A modulators. Our bioinformatic analysis focused on differentially methylated mRNAs (DMGs) and differentially expressed mRNAs (DEGs) in pairwise comparisons of EPE vs. NP, LPE vs. NP, and EPE vs. LPE, as well as m1A-related DEGs. The comparisons of EPE vs. NP, LPE vs. NP, and EPE vs. LPE identified 3110, 2801, and 2818 DMGs, respectively. We discerned three different m1A modification patterns from this data. Further analysis revealed that key PE-related DMGs and m1A-related DEGs predominantly influence signaling pathways critical for decidualization, including cAMP, MAPK, PI3K-Akt, Notch, and TGF-ß pathways. Additionally, these modifications impact pathways related to vascular smooth muscle contraction, estrogen signaling, and relaxin signaling, contributing to vascular dysfunction. Our findings demonstrate that preeclamptic decidua exhibits unique mRNA m1A modification patterns and gene expression profiles that significantly alter signaling pathways essential for both decidualization and vascular dysfunction. These differences in m1A modification patterns provide valuable insights into the molecular mechanisms influencing the decidualization process and vascular function in the pathogenesis of PE. These m1A modification regulators could potentially serve as potent biomarkers or therapeutic targets for PE, warranting further investigation.

Breakthrough of Hypoxia Limitation by Tumor-Targeting Photothermal Therapy-Enhanced Radiation Therapy.

Purpose: To address the problem of suboptimal reactive oxygen species (ROS) production in Radiation therapy (RT) which was resulted from exacerbated tumor hypoxia and the heterogeneous distribution of radiation sensitizers. Materials and Methods: In this work, a novel nanomedicine, designated as PLGA@IR780-Bi-DTPA (PIBD), was engineered by loading the radiation sensitizer Bi-DTPA and the photothermal agent IR780 onto poly(lactic-co-glycolic acid) (PLGA). This design leverages the tumor-targeting ability of IR780 to ensure selective accumulation of the nanoparticles in tumor cells, particularly within the mitochondria. The effect of the photothermal therapy-enhanced radiation therapy was also examined to assess the alleviation of hypoxia and the enhancement of radiation sensitivity. Results: The PIBD nanoparticles exhibited strong capacity in mitochondrial targeting and selective tumor accumulation. Upon activation by 808 nm laser irradiation, the nanoparticles effectively alleviated local hypoxia by photothermal effect enhanced blood supplying to improve oxygen content, thereby enhancing the ROS production for effective RT. Comparative studies revealed that PIBD-induced RT significantly outperformed conventional RT in treating hypoxic tumors. Conclusion: This design of tumor-targeting photothermal therapy-enhanced radiation therapy nanomedicine would advance the development of targeted drug delivery system for effective RT regardless of hypoxic microenvironment.

Recent advancement of sonogenetics: A promising noninvasive cellular manipulation by ultrasound.

Recent advancements in biomedical research have underscored the importance of noninvasive cellular manipulation techniques. Sonogenetics, a method that uses genetic engineering to produce ultrasound-sensitive proteins in target cells, is gaining prominence along with optogenetics, electrogenetics, and magnetogenetics. Upon stimulation with ultrasound, these proteins trigger a cascade of cellular activities and functions. Unlike traditional ultrasound modalities, sonogenetics offers enhanced spatial selectivity, improving precision and safety in disease treatment. This technology broadens the scope of non-surgical interventions across a wide range of clinical research and therapeutic applications, including neuromodulation, oncologic treatments, stem cell therapy, and beyond. Although current literature predominantly emphasizes ultrasonic neuromodulation, this review offers a comprehensive exploration of sonogenetics. We discuss ultrasound properties, the specific ultrasound-sensitive proteins employed in sonogenetics, and the technique's potential in managing conditions such as neurological disorders, cancer, and ophthalmic diseases, and in stem cell therapies. Our objective is to stimulate fresh perspectives for further research in this promising field.

Enhancing efficiency of protein language models with minimal wet-lab data through few-shot learning.

Accurately modeling the protein fitness landscapes holds great importance for protein engineering. Pre-trained protein language models have achieved state-of-the-art performance in predicting protein fitness without wet-lab experimental data, but their accuracy and interpretability remain limited. On the other hand, traditional supervised deep learning models require abundant labeled training examples for performance improvements, posing a practical barrier. In this work, we introduce FSFP, a training strategy that can effectively optimize protein language models under extreme data scarcity for fitness prediction. By combining meta-transfer learning, learning to rank, and parameter-efficient fine-tuning, FSFP can significantly boost the performance of various protein language models using merely tens of labeled single-site mutants from the target protein. In silico benchmarks across 87 deep mutational scanning datasets demonstrate FSFP's superiority over both unsupervised and supervised baselines. Furthermore, we successfully apply FSFP to engineer the Phi29 DNA polymerase through wet-lab experiments, achieving a 25% increase in the positive rate. These results underscore the potential of our approach in aiding AI-guided protein engineering.

Chitosan-modified molybdenum selenide mediated efficient killing of Helicobacter pylori and treatment of gastric cancer.

Helicobacter pylori (H. pylori) is one of the major causes of gastrointestinal diseases, including gastric cancer. However, the acidic environment of the stomach and H. pylori resistance severely impair the antimicrobial efficacy of oral drugs. Here, a biocompatible chitosan-modified molybdenum selenide (MoSe2@CS) was designed for the simultaneous photothermal treatment of H. pylori infection and gastric cancer. MoSe2@CS showed a photothermal conversion efficiency was as high as 45.7 %. In the H. pylori-infected mice model, MoSe2@CS displayed a high bacteriostasis ratio of 99.9 % upon near-infrared irradiation. The antimicrobial functionality was also proved by transcriptomic sequencing study, which showed that MoSe2@CS combined with NIR laser irradiation modulated the gene expression of a variety of H. pylori bioprocesses, including cell proliferation and inflammation-related pathways. Further gut flora analysis results indicated that MoSe2@CS mediated PTT of H. pylori did not affect the homeostasis of gut flora, which highlights its advantages over traditional antibiotic therapy. In addition, MoSe2@CS exhibited a good photothermal ablation effect and significantly inhibited gastric tumor growth in vitro and in vivo. The comprehensive application of MoSe2@CS in the PTT of H. pylori infection and gastric cancer provides a new avenue for the clinical treatment of H. pylori infection and related diseases.

Non B Cell-Derived Immunoglobulin, A Brighter Horizon for the Future.

The canonical theory of immunology stating that "Immunoglobulin (Ig) is produced by B lymphocytes and exerts antibody activity" has been established since the 1970s. However, the discovery of non B cell-derived Igs (non B-Igs), which can exert multiple biological activities in addition to their antibody activities, necessitates a reevaluation of the classic concept of Ig. This has been documented with a number of characteristics related to their structure, modification, genetic regulation as well as the functions associated with clinical conditions, particularly multiple cancers. The discovery of non B-Ig provides us with a new perspective to better understand not only basic immunology, but also various Ig-related clinical manifestations including autoimmune diseases, chronic inflammation, and anaphylaxis. Notably, non B-Ig can directly promote the occurrence of malignant tumours.

Parameter estimation of the hyperbolic frequency-modulated bat calls using hyperbolic scale transform.

Echolocating bats are known to vary their waveforms at the phases of searching, approaching, and capturing the prey. It is meaningful to estimate the parameters of the calls for bat species identification and the technological improvements of the synthetic systems, such as radar and sonar. The type of bat calls is species-related, and many calls can be modeled as hyperbolic frequency- modulated (HFM) signals. To obtain the parameters of the HFM-modeled bat calls, a reversible integral transform, i.e., hyperbolic scale transform (HST), is proposed to transform a call into two-dimensional peaks in the "delay-scale" domain, based on which harmonic separation and parameter estimation are realized. Compared with the methods based on time-frequency analysis, the HST-based method does not need to extract the instantaneous frequency of the bat calls, only searching for peaks. The verification results show that the HST is suitable for analyzing the HFM-modeled bat calls containing multiple harmonics with a large energy difference, and the estimated parameters imply that the use of the waveforms from the searching phase to the capturing phase is beneficial to reduce the ranging bias, and the trends in parameters may be useful for bat species identification.

Clinical implications of persistent joint pain after gout flare.

OBJECTIVES: A subset of gout patients developed persistent joint pain after flares. Analysis of this clinical phenomenon may shed further light on the factors related to worsening gout and even provide clues to its pathogenesis. METHODS: We analyzed the clinical, laboratory, and ultrasound data of gout patients to explore the associations of these data with persistent joint pain after gout flares. RESULTS: A total of 1029 gout patients were included: 182 (17.7%) patients with persistent joint pain and 847 (82.3%) patients with nonpersistent joint pain. Patients with persistent joint pain had more total involved joints, more gout flares in the past year, and more joints with simultaneous gout flares (P<0.01). Among the ultrasound-detected lesions, patients with persistent joint pain had a higher incidence of tophus (36.4% vs. 21.1%) and bone erosion (18.6% vs. 8.6%) (P<0.05). Higher UA and lower TBil were found in patients with persistent joint pain (P<0.001). Hypertension (54.9% vs. 38.7%) and metabolic syndrome (58.8% vs. 46.4%) were both more frequent in patients with persistent joint pain (P<0.05). TBil was negatively correlated with the incidence of persistent joint pain (P<0.001, r=-0.190), UA values (P<0.001, r=-0.125), and metabolic syndrome scores (P<0.001, r=-0.192). A correlation curve was fitted using LOESS (locally weighted region). CONCLUSION: Persistent joint pain after gout flares is a marker of increased disease burden in gout. The significance of the level of total bilirubin for the exacerbation of gout deserves further study.

Ultrasound -Induced Thermal Effect Enhances the Efficacy of Chemotherapy and Immunotherapy in Tumor Treatment.

Background: The inadequate perfusion, frequently resulting from abnormal vascular configuration, gives rise to tumor hypoxia. The presence of this condition hinders the effective delivery of therapeutic drugs and the infiltration of immune cells into the tumor, thereby compromising the efficacy of treatments against tumors. The objective of this study is to exploit the thermal effect of ultrasound (US) in order to induce localized temperature elevation within the tumor, thereby facilitating vasodilation, augmenting drug delivery, and enhancing immune cell infiltration. Methods: The selection of US parameters was based on intratumor temperature elevation and their impact on cell viability. Vasodilation and hypoxia improvement were investigated using enzyme-linked immunosorbent assay (ELISA) and immunofluorescence examination. The distribution and accumulation of commercial pegylated liposomal doxorubicin (PLD) and PD-L1 antibody (anti-PD-L1) in the tumor were analyzed through frozen section analysis, ELISA, and in vivo fluorescence imaging. The evaluation of tumor immune microenvironment was conducted using flow cytometry (FCM). The efficacy of US-enhanced chemotherapy in combination with immunotherapy was investigated by monitoring tumor growth and survival rate after various treatments. Results: The US irradiation condition of 0.8 W/cm2 for 10 min effectively elevated the tumor temperature to approximately 40 °C without causing any cellular or tissue damage, and sufficiently induced vasodilation, thereby enhancing the distribution and delivery of PLD and anti-PD-L1 in US-treated tumors. Moreover, it effectively mitigated tumor hypoxia while significantly increasing M1-phenotype tumor-associated macrophages (TAMs) and CD8+ T cells, as well as decreasing M2-phenotype TAMs. By incorporating US irradiation, the therapeutic efficacy of PLD and anti-PD-L1 was substantially boosted, leading to effective suppression of tumor growth and prolonged survival in mice. Conclusion: The application of US (0.8 W/cm2 for 10 min) can effectively induce vasodilation and enhance the delivery of PLD and anti-PD-L1 into tumors, thereby reshaping the immunosuppressive tumor microenvironment and optimizing therapeutic outcomes.

The expression and clinical significance of CFAP65 in colon cancer.

BACKGROUND: CFAP65 (cilia and flagella associated protein 65) is a fundamental protein in the development and formation of ciliated flagella, but few studies have focused on its role in cancer. This study aimed to investigate the prognostic significance of CFAP65 in colon cancer. METHODS: The functionally enriched genes related to CFAP65 were analyzed through the Gene Ontology (GO) database. Subsequently, CFAP65 expression levels in colon cancer were evaluated by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) and immunoblotting in 20 pairs of frozen samples, including tumors and their matched paratumor tissue. Furthermore, protein expression of CFAP65 in 189 colon cancer patients were assessed via immunohistochemical staining. The correlations between CFAP65 expression and clinical features as well as long-term survival were statistically analyzed. RESULTS: CFAP65-related genes are significantly enriched on cellular processes of cell motility, ion channels, and GTPase-associated signaling. The expression of CFAP65 was significantly higher in colon cancer tissue compared to paratumor tissue. The proportion of high expression and low expression of CFAP65 in the clinical samples of colon cancer were 61.9% and 38.1%, respectively, and its expression level was not associated with the clinical parameters including gender, age, tumor location, histological differentiation, tumor stage, vascular invasion and mismatch repair deficiency. The five-year disease-free survival rate of the patients with CFAP65 low expression tumors was significantly lower than that those with high expression tumors (56.9% vs. 72.6%, P = 0.03), but the overall survival rate has no significant difference (69% vs. 78.6%, P = 0.171). The cox hazard regression analysis model showed that CFAP65 expression, tumor stage and tumor location were independent prognostic factors. CONCLUSIONS: In conclusion, we demonstrate CFAP65 is a potential predictive marker for tumor progression in colon cancer.

Conductive/Insulating Bioinks with Multitechnology Compatibility and Adjustable Performance.

Conducting/insulating inks have received significant attention for the fabrication of a wide range of additive manufacturing technology. However, current inks often demonstrate poor biocompatibility and face trade-offs between conductivity and mechanical stiffness under physiological conditions. Here, conductive/insulating bioinks based on two-dimensional materials are proposed. The conductive bioink, graphene (GR)-poly(lactic-co-glycolic acid) (PLGA), is prepared by introducing conductive GR into a degradable polymer matrix, PLGA, while the insulating bioink, boron nitride (BN)-PLGA, is synthesized by adding insulating BN. By optimizing the material ratios, this work achieves precise control of the electromechanical properties of the bioinks, thereby enabling the flexible construction of conductive networks according to specific requirements. Furthermore, these bioinks are compatible with a variety of manufacturing technologies such as 3D printing, electrospinning, spin coating, and injection molding, expanding their application range in the biomedical field. Overall, the results suggest that these conducting/insulating bioinks offer improved mechanical, electronic, and biological properties for various emerging biomedical applications.

LinearAlifold: Linear-time consensus structure prediction for RNA alignments.

Predicting the consensus structure of a set of aligned RNA homologs is a convenient method to find conserved structures in an RNA genome, which has many applications including viral diagnostics and therapeutics. However, the most commonly used tool for this task, RNAalifold, is prohibitively slow for long sequences, due to a cubic scaling with the sequence length, taking over a day on 400 SARS-CoV-2 and SARS-related genomes (∼30,000nt). We present LinearAlifold, a much faster alternative that scales linearly with both the sequence length and the number of sequences, based on our work LinearFold that folds a single RNA in linear time. Our work is orders of magnitude faster than RNAalifold (0.7 h on the above 400 genomes, or ∼36× speedup) and achieves higher accuracies when compared to a database of known structures. More interestingly, LinearAlifold's prediction on SARS-CoV-2 correlates well with experimentally determined structures, substantially outperforming RNAalifold. Finally, LinearAlifold supports two energy models (Vienna and BL*) and four modes: minimum free energy (MFE), maximum expected accuracy (MEA), ThreshKnot, and stochastic sampling, each of which takes under an hour for hundreds of SARS-CoV variants. Our resource is at: https://github.com/LinearFold/LinearAlifold (code) and http://linearfold.org/linear-alifold (server).

A novel polymer platform for endoscopic tattooing with high efficacy and safety.

Endoscopic tattooing plays a pivotal role in modern endoscopic localization of gastrointestinal lesions, facilitating further surgical intervention and aiding in the postoperative identification and repositioning of lesions. However, traditional endoscopic tattoo dyes often suffer from drawbacks such as side effects, short tattoo duration, and high overall costs. In this study, we developed polyvinylpyrrolidone (PVP)-modified polypyrrole (PPy) nanoparticles by oxidizing pyrrole in a PVP aqueous solution to create a PPy/PVP nanoparticle solution. This innovation aims to enhance endoscopic tattooing efficiency and mitigate the limitations associated with current tattooing methods. Both in vitro and in vivo evaluations confirmed the biosafety of PPy/PVP nanoparticles. Endoscopic tattooing experiments conducted in a pig model demonstrated the dye's stability within the digestive tract. Similarly, subcutaneous tissue tattooing experiments performed in a mouse model revealed the sustained stability of the PPy/PVP tattoo dye for at least 180 days. With its robust stability, safety, and longevity, PPy/PVP nanoparticles hold promise as novel tattoo dyes for marking intestinal lesion sites. This advancement has the potential to enhance the accuracy of lesion localization and long-term tracking.

The impact of V-flow on preoperative diagnosis of thyroid tumors: individually and as part of multimodal sonographic imaging.

V-flow is a dynamic ultrasound technique that visualizes perfusion patterns by displaying dynamic arrows that change in response to the flow of erythrocytes. Furthermore, it provides quantitative values for the maximum and mean velocity of blood flow as well as a percentage value for turbulence. The aim was to enhance the preoperative diagnostic accuracy of thyroid lesions by combining V-flow with established ultrasound modes.B-mode, CCDS, elastography, CEUS, and V-flow were performed on 101 patients. After the ultrasound examination, every nodule was confirmed as benign or malignant via histopathology. The Kruskal-Wallis test, ROC curve, and binary logistic regression were used for the statistical analysis.93 benign regressive thyroid nodules and 8 carcinomas were included in this study. The average mean velocity value for benign lesions was measured at 19.5 cm/s and at 10.7 cm/s for malignant lesions (p = 0.039). The average turbulence percentage was 26.1% for benign nodules and 46.7% for carcinomas (p = 0.016). Carcinomas exhibited a slower and more turbulent perfusion pattern compared to benign tumors. A V-flow-centered system achieves a sensitivity of 100.0% and a specificity of 84.9% in predicting malignancy. This system could have reduced the number of unnecessary thyroid surgeries for benign lesions in our patient group by 70%.The capillary perfusion of thyroid nodules represents a significant indicator of its status. By analyzing the velocity and turbulence level of microvascular blood flow, V-flow offers promising prospects for accurately distinguishing between benign and malignant thyroid lesions. When integrated into a comprehensive multimodal sonographic imaging approach, V-flow further enhances diagnostic accuracy. · V-flow allows for qualitative and quantitative analysis of microvascular perfusion. · Malignant tumors are associated with slower and more turbulent microvascular hemodynamics. · Combining V-flow with other ultrasound modes eases the diagnosis of thyroid carcinomas. · Brandenstein MK, Zhang L, Scharf G et al. The impact of V-flow on preoperative diagnosis of thyroid tumors: individually and as part of multimodal sonographic imaging. Fortschr Röntgenstr 2024; DOI 10.1055/a-2350-0107.

Exploring the Health Benefits of Boletus aereus Polysaccharides: Extraction, Structural Characterization, and Antiproliferative Properties against Non-Hodgkin's Lymphomas (NHLs).

Boletus aereus Fr. ex Bull. stands out as a delectable edible mushroom with high nutritional and medicinal values, featuring polysaccharides as its primary nutrient composition. In our continuous exploration of its beneficial substances, a novel polysaccharide (BAPN-1) with a molecular weight of 2279 kDa was prepared. It was identified as a glucan with a backbone composed of the residues →4)-α-Glcp-(1→ and →4,6)-α-Glcp-(1→ connected in a proportion of 5:1 and a ß-Glcp-(1→ side residue attached at C6 of the →4,6)-α-Glcp-(1→ residue. Biologically, BAPN-1 exhibited broad-spectrum antiproliferative activities against various NHL cells, including HuT-78, OCI-LY1, OCI-LY18, Jurkat, RL, and Karpas-299, with IC50 values of 0.73, 1.21, 3.18, 1.52, 3.34, and 4.25 mg/mL, respectively. Additionally, BAPN-1 significantly induced cell cycle arrest in the G2/M phase and caused apoptosis of NHL cells. Mechanistically, bulk RNA sequencing and Western blot analysis revealed that BAPN-1 could upregulate cyclin B1 and enhance cleaved caspase-9 expression through the inhibition of FGFR3 and RAF-MEK-ERK signaling pathways. This work supports the improved utilization of B. aereus in high-value health products.

[Chemical composition and pharmacological effects of Cinnamomum camphora chvar. borneol essential oil: a review].

Cinnamomum camphora chvar. borneol, a rare camphor tree variant recently identified in China, is distinguished by its high concentration of D-borneol, also known as " plant gold" due to its significant value. The essential oil extracted from this variant,rich in monoterpenes and sesquiterpenes, demonstrates a broad spectrum of pharmacological activities, including analgesic, antiinflammatory, antioxidant, cognition-enhancing, anti-bacterial, and insecticidal effects. These properties, underscored by extensive research, highlight the oil's potential in the biomedical, chemical, and food sectors as a valuable commodity. Nonetheless, the safety profile of this valuable oil remains poorly characterized, with its chemical composition and therapeutic efficacy subject to variations in the factors like geographic origin, harvesting timing, part used for extraction, and processing techniques. Such variability poses challenges to its clinical application and hampers the efficient exploitation of this resource. This review synthesizes current studies on C. camphora chvar. borneol essential oil and provides a detailed examination of its chemical and pharmacological profiles. In this study, we discuss existing research gaps and propose strategies for advancing its clinical use and industrial application, aiming to provide a foundational reference for future investigations and the resolution of its commercial and therapeutic challenges.

The phosphatidylethanolamine-binding proteins OsMFT1 and OsMFT2 regulate seed dormancy in rice.

Seed dormancy is crucial for optimal plant life-cycle timing. However, domestication has largely diminished seed dormancy in modern cereal cultivars, leading to challenges such as pre-harvest sprouting (PHS) and subsequent declines in yield and quality. Therefore, it is imperative to unravel the molecular mechanisms governing seed dormancy for the development of PHS-resistant varieties. In this study, we screened a mutant of BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTOR4 (OsbHLH004) with decreased seed dormancy and revealed that OsbHLH004 directly regulates the expression of 9-CIS-EPOXYCAROTENOID DIOXYGENASE3 (OsNCED3) and GIBBERELLIN 2-OXIDASE6 (OsGA2ox6) in rice (Oryza sativa). Additionally, we determined that two phosphatidylethanolamine-binding proteins, MOTHER OF FT AND TFL1 and 2 (OsMFT1 and OsMFT2; hereafter OsMFT1/2) interact with OsbHLH004 and Ideal Plant Architecture 1 (IPA1) to regulate their binding capacities on OsNCED3 and OsGA2ox6, thereby promoting seed dormancy. Intriguingly, FT-INTERACTING PROTEIN1 (OsFTIP1) interacts with OsMFT1/2 and affects their nucleocytoplasmic translocation into the nucleus, where OsMFT1/2-OsbHLH004 and OsMFT1/2-IPA1 antagonistically modulate the expression of OsNCED3 and OsGA2ox6. Our findings reveal that OsFTIP1-mediated inhibition of nuclear translocation of OsMFT1/2 and the dynamic transcriptional modulation of OsNCED3 and OsGA2ox6 by OsMFT1/2-OsbHLH004 and OsMFT1/2-IPA1 complexes in seed dormancy in rice.

The combination of temozolomide and perifosine synergistically inhibit glioblastoma by impeding DNA repair and inducing apoptosis.

Temozolomide (TMZ) is widely utilized as the primary chemotherapeutic intervention for glioblastoma. However, the clinical use of TMZ is limited by its various side effects and resistance to chemotherapy. The present study revealed the synergistic inhibition of glioblastoma through the combined administration of TMZ and perifosine. This combination therapy markedly diminished BRCA1 expression, resulting in the suppression of DNA repair mechanisms. Furthermore, the combination of TMZ and perifosine elicited caspase-dependent apoptosis, decreasing glioblastoma cell viability and proliferation. The observed synergistic effect of this combination therapy on glioblastoma was validated in vivo, as evidenced by the substantial reduction in glioblastoma xenograft growth following combined treatment with TMZ and perifosine. In recurrent glioma patients, higher BRCA1 expression is associated with worse prognosis, especially the ones that received TMZ-treated. These findings underscore the potent antitumor activity of the AKT inhibitor perifosine when combined with TMZ and suggest that this approach is a promising strategy for clinical glioblastoma treatment.

Effect of transcranial direct current stimulation with concurrent cognitive performance targeting posterior parietal cortex vs prefrontal cortex on working memory in schizophrenia: a randomized clinical trial.

Working memory deficits are linked to irregularities in the dorsolateral prefrontal cortex (DLPFC) and the posterior parietal cortex (PPC) in schizophrenia, effective intervention strategies are lacking. We evaluated the differential efficacy and underlying neuromechanisms of targeting transcranial direct current stimulation (tDCS) at the DLPFC and the PPC with concurrent cognitive performance for working memory in schizophrenia. In a randomized and double-blind clinical trial, sixty clinically stable schizophrenic patients with below-average working memory were randomly assigned to active DLPFC, active PPC, and sham tDCS groups. Two sessions of tDCS during N-back task were delivered daily for five days. The primary outcome was changes in spatial span test scores from baseline to week 1. The secondary outcomes included changes in scores of color delay-estimation task, other cognitive tasks, and mismatch negativity (biomarker of N-methyl-d-aspartate receptor functioning). Compared with the active DLPFC group, the active PPC group demonstrated significantly greater improvement in spatial span test scores (p = 0.008, d = 0.94) and an augmentation in color delay-estimation task capacity at week 1; the latter sustained to week 2. Compared with the sham tDCS group, the active PPC group did not show a significant improvement in spatial span test scores at week 1 and 2; however, significant enhancement was observed in their color delay-estimation task capacity at week 2. Additionally, mismatch negativity amplitude was enhanced, and changes in theta band measures were positively correlated with working memory improvement in the active PPC group, while no such correlations were observed in the active DLPFC group or the sham tDCS group. Our results suggest that tDCS targeting the PPC relative to the DLPFC during concurrent cognitive performance may improve working memory in schizophrenia, meriting further investigation. The improvement in working memory appears to be linked to enhanced N-methyl-d-aspartate receptor functioning.