PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide-isomerase A3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein (CRP) level and disease activity score 28 (DAS28). Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor (TCR) signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing Th1 and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.

Proteomic profiling of TBC1 domain family member 21-null sperms reveals the critical roles of TEKT 1 in their tail defects.

BACKGROUND: Approximately 7% of the males exhibit reduced fertility; however, the regulatory genes and pathways involved remain largely unknown. TBC1 domain family member 21 (TBC1D21) contains a conserved RabGAP catalytic domain that induces GDP/GTP exchange to inactivate Rabs by interacting with microtubules. We previously reported that Tbc1d21-null mice exhibit severe sperm tail defects with a disrupted axoneme, and that TBC1D21 interacts with RAB10. However, the pathological mechanisms underlying the Tbc1d21 loss-induced sperm tail defects remain unknown. RESULTS: Murine sperm from wild-type and Tbc1d21-null mice were comparatively analyzed using proteomic assays. Over 1600 proteins were identified, of which 15 were significantly up-regulated in Tbc1d21-null sperm. Notably, several tektin (TEKT) family proteins, belonging to a type of intermediate filament critical for stabilizing the microtubular structure of cilia and flagella, were significantly up-regulated in Tbc1d21-/- sperm. We also found that TBC1D21 interacts with TEKT1. In addition, TEKT1 co-localized with RAB10 during sperm tail formation. Finally, we found Tbc1d21-null sperm exhibited abnormal accumulation of TEKT1 in the midpiece region, accompanied by disrupted axonemal structures. CONCLUSIONS: These results reveal that TBC1D21 modulates TEKTs protein localization in the axonemal transport system during sperm tail formation.

Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Ethylene-responsive VviERF003 modulates glycosylated monoterpenoid synthesis by upregulating VviGT14 in grapes.

Terpenoids are important contributors to the aroma of grapes and wines. Grapes contain terpenoids in both volatile free form and non-volatile glycosidic form, with the latter being more abundant. Glycosylated terpenoids are deemed as latent aromatic potentials for their essential role in adding to the flowery and fruity bouquet of wines. However, the transcriptional regulatory mechanism underlying glycosylated terpenoid biosynthesis remains poorly understood. Our prior study identified an AP2/ERF transcription factor, VviERF003, through DNA pull-down screening using the promoter of terpenoid glycosyltransferase VviGT14 gene. This study demonstrated that both genes were co-expressed and synchronized with the accumulation of glycosylated monoterpenoids during grape maturation. VviERF003 can bind to the VviGT14 promoter and promote its activity according to yeast one-hybrid and dual-luciferase assays. VviERF003 upregulated VviGT14 expression in vivo, leading to increased production of glycosylated monoterpenoids based on the evidence from overexpression or RNA interference in leaves, berry skins, and calli of grapes, as well as tomato fruits. Additionally, VviERF003 and VviGT14 expressions and glycosylated monoterpenoid levels were induced by ethylene in grapes. The findings suggest that VviERF003 is ethylene-responsive and stimulates glycosylated monoterpenoid biosynthesis through upregulating VviGT14 expression.

Gossypol acetic acid regulates leukemia stem cells by degrading LRPPRC via inhibiting IL-6/JAK1/STAT3 signaling or resulting mitochondrial dysfunction.

BACKGROUND: Leukemia stem cells (LSCs) are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia (AML), as they are protected by the bone marrow microenvironment (BMM) against conventional therapies. Gossypol acetic acid (GAA), which is extracted from the seeds of cotton plants, exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2. AIM: To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism. METHODS: In this study, LSCs were magnetically sorted from AML cell lines and the CD34+CD38- population was obtained. The expression of leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) and forkhead box M1 (FOXM1) was evaluated in LSCs, and the effects of GAA on malignancies and mitochondrial function were measured. RESULTS: LRPPRC was found to be upregulated, and GAA inhibited cell proliferation by degrading LRPPRC. GAA induced LRPPRC degradation and inhibited the activation of interleukin 6 (IL-6)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 3 signaling, enhancing chemosensitivity in LSCs against conventional chemotherapies, including L-Asparaginase, Dexamethasone, and cytarabine. GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC. Furthermore, GAA induced reactive oxygen species accumulation, disturbed mitochondrial homeostasis, and caused mitochondrial dysfunction. By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC, GAA resulted in the elimination of LSCs. Meanwhile, GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage. CONCLUSION: Taken together, the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.

Identification of common genes and pathways between type 2 diabetes and COVID-19.

Background: Numerous studies have reported a high incidence and risk of severe illness due to coronavirus disease 2019 (COVID-19) in patients with type 2 diabetes (T2DM). COVID-19 patients may experience elevated or decreased blood sugar levels and may even develop diabetes. However, the molecular mechanisms linking these two diseases remain unclear. This study aimed to identify the common genes and pathways between T2DM and COVID-19. Methods: Two public datasets from the Gene Expression Omnibus (GEO) database (GSE95849 and GSE164805) were analyzed to identify differentially expressed genes (DEGs) in blood between people with and without T2DM and COVID-19. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the common DEGs. A protein-protein interaction (PPI) network was constructed to identify common genes, and their diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analysis. Validation was performed on the GSE213313 and GSE15932 datasets. A gene co-expression network was constructed using the GeneMANIA database to explore interactions among core DEGs and their co-expressed genes. Finally, a microRNA (miRNA)-transcription factor (TF)-messenger RNA (mRNA) regulatory network was constructed based on the common feature genes. Results: In the GSE95849 and GSE164805 datasets, 81 upregulated genes and 140 downregulated genes were identified. GO and KEGG enrichment analyses revealed that these DEGs were closely related to the negative regulation of phosphate metabolic processes, the positive regulation of mitotic nuclear division, T-cell co-stimulation, and lymphocyte co-stimulation. Four upregulated common genes (DHX15, USP14, COPS3, TYK2) and one downregulated common feature gene (RIOK2) were identified and showed good diagnostic accuracy for T2DM and COVID-19. The AUC values of DHX15, USP14, COPS3, TYK2, and RIOK2 in T2DM diagnosis were 0.931, 0.917, 0.986, 0.903, and 0.917, respectively. In COVID-19 diagnosis, the AUC values were 0.960, 0.860, 1.0, 0.9, and 0.90, respectively. Validation in the GSE213313 and GSE15932 datasets confirmed these results. The miRNA-TF-mRNA regulatory network showed that TYH2 was targeted by PITX1, PITX2, CRX, NFYA, SREBF1, RELB, NR1L2, and CEBP, whereas miR-124-3p regulates THK2, RIOK2, and USP14. Conclusion: We identified five common feature genes (DHX15, USP14, COPS3, TYK2, and RIOK2) and their co-regulatory pathways between T2DM and COVID-19, which may provide new insights for further molecular mechanism studies.

Analysis of fungal diversity in the gut feces of wild takin (Budorcas taxicolor).

Introduction: The composition of the intestinal microbiome correlates significantly with an animal's health status. Hence, this indicator is highly important and sensitive for protecting endangered animals. However, data regarding the fungal diversity of the wild Budorcas taxicolor (takin) gut remain scarce. Therefore, this study analyzes the fungal diversity, community structure, and pathogen composition in the feces of wild B. taxicolor. Methods: To ensure comprehensive data analyses, we collected 82 fecal samples from five geographical sites. Amplicon sequencing of the internal transcribed spacer (ITS) rRNA was used to assess fecal core microbiota and potential pathogens to determine whether the microflora composition is related to geographical location or diet. We further validated the ITS rRNA sequencing results via amplicon metagenomic sequencing and culturing of fecal fungi. Results and discussion: The fungal diversity in the feces of wild Budorcas taxicolor primarily comprised three phyla (99.69%): Ascomycota (82.19%), Fungi_unclassified (10.37%), and Basidiomycota (7.13%). At the genus level, the predominant fungi included Thelebolus (30.93%), Functional_unclassified (15.35%), and Ascomycota_unclassified (10.37%). Within these genera, certain strains exhibit pathogenic properties, such as Thelebolus, Cryptococcus, Trichosporon, Candida, Zopfiella, and Podospora. Collectively, this study offers valuable information for evaluating the health status of B. taxicolor and formulating protective strategies.

Hidden delta degradation due to fluvial sediment decline and intensified marine storms.

Deltas are threatened by erosion due to climate change and reduced sediment supply, but their response to these changes remains poorly quantified. We investigate the abandoned Yellow River delta that has transitioned from rapid growth to ongoing deterioration due to a river avulsion removing the sediment supply. Integrating bathymetric data, process observations, and sediment transport modeling, we find that while the subaerial delta was stabilized by engineering measures, the subaqueous delta continued to erode due to intensified storms, losing 39% of its mass deposited before the avulsion. Long-term observations show that winter storms initiate scouring of the subaqueous delta, contributing up to 70% of seabed erosion. We then analyze 108 global deltas to assess subaqueous delta erosion risks and identify 17 deltas facing similar situations of sediment decline and storm intensification during the past 40 years. Our findings suggest that subaqueous delta erosion must be integrated into delta sustainability evaluations.

Magnetic resonance imaging-based prediction models for differentiating intraspinal schwannomas from meningiomas: classification and regression tree and random forest analysis.

Background: Due to the variations in surgical approaches and prognosis between intraspinal schwannomas and meningiomas, it is crucial to accurately differentiate between the two prior to surgery. Currently, there is limited research exploring the implementation of machine learning (ML) methods for distinguishing between these two types of tumors. This study aimed to establish a classification and regression tree (CART) model and a random forest (RF) model for distinguishing schwannomas from meningiomas. Methods: We retrospectively collected 88 schwannomas (52 males and 36 females) and 51 meningiomas (10 males and 41 females) who underwent magnetic resonance imaging (MRI) examinations prior to the surgery. Simple clinical data and MRI imaging features, including age, sex, tumor location and size, T1-weighted images (T1WI) and T2-weighted images (T2WI) signal characteristics, degree and pattern of enhancement, dural tail sign, ginkgo leaf sign, and intervertebral foramen widening (IFW), were reviewed. Finally, a CART model and RF model were established based on the aforementioned features to evaluate their effectiveness in differentiating between the two types of tumors. Meanwhile, we also compared the performance of the ML models to the radiologists. The receiver operating characteristic (ROC) curve, accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were used to evaluate the models and clinicians' discrimination performance. Results: Our investigation reveals significant variations in ten out of 11 variables in the training group and five out of 11 variables in the test group when comparing schwannomas and meningiomas (P<0.05). Ultimately, the CART model incorporated five variables: enhancement pattern, the presence of IFW, tumor location, maximum diameter, and T2WI signal intensity (SI). The RF model combined all 11 variables. The CART model, RF model, radiologist 1, and radiologist 2 achieved an area under the curve (AUC) of 0.890, 0.956, 0.681, and 0.723 in the training group, and 0.838, 0.922, 0.580, and 0.659 in the test group, respectively. Conclusions: The RF prediction model exhibits more exceptional performance than an experienced radiologist in discriminating intraspinal schwannomas from meningiomas. The RF model seems to be better in discriminating the two tumors than the CART model.

Polyhydroxy structure orchestrates the intrinsic antibacterial property of acrylamide hydrogel as a versatile wound-healing dressing.

Hydrogel is considered as a promising candidate for wound dressing due to its tissue-like flexibility, good mechanical properties and biocompatibility. However, traditional hydrogel dressings often fail to fulfill satisfied mechanical, antibacterial, and biocompatibility properties simultaneously, due to the insufficient intrinsic bactericidal efficacy and the addition of external antimicrobial agents. In this paper, hydroxyl-contained acrylamide monomers, N-Methylolacrylamide (NMA) and N-[Tris (hydroxymethyl)methyl] acrylamide (THMA), are employed to prepare a series of polyacrylamide hydrogel dressings xNMA-yTHMA, where x and y represent the mass fractions of NMA and THMA in the hydrogels. We have elucidated that the abundance of hydroxyl groups determines the antibacterial effect of the hydrogels. Particularly, hydrogel 35NMA-5THMA exhibits excellent mechanical properties, with high tensile strength of 259 kPa and large tensile strain of 1737%. Furthermore, the hydrogel dressing 35NMA-5THMA demonstrates remarkable inherent antibacterial without exogenous antimicrobial agents owing to the existence of abundant hydroxyl groups. Besides, hydrogel dressing 35NMA-5THMA possesses excellent biocompatibility, in view of marginal cytotoxicity, low hemolysis ratio, and negligible inflammatory response and organ toxicity to mice during treatment. Encouragingly, hydrogel 35NMA-5THMA drastically promote the healing of bacteria-infected wound in mice. This study has revealed the importance of polyhydroxyl in the antibacterial efficiency of hydrogels and provided a simplified strategy to design wound healing dressings with translational potential.

Catalysts with Trimetallic Sites on Graphene-like C2N for Electrocatalytic Nitrogen Reduction Reaction: A Theoretical Investigation.

Electrocatalytic nitrogen reduction reaction (NRR) is a green and highly efficient way to replace the industrial Haber-Bosch process. Herein, clusters consisting of three transition metal atoms loaded on C2N as NRR electrocatalysts are investigated using density functional theory (DFT). Meanwhile, Ca was introduced as a promoter and the role of Ca in NRR was investigated. It was found that Ca anchored to the catalyst can act as an electron donor and effectively promote the activation of N2 on M3. In both M3@C2N and M3Ca@C2N (M = Fe, Co, Ni), the limiting potential (UL) is less negative than that of the Ru(0001) surface and has the ability to suppress the competitive hydrogen evolution reaction (HER). Among them, Fe3@C2N is suggested to be the most promising candidate for NRR with high thermal stability, strong N2 adsorption ability, low limiting potential, and good NRR selectivity. The concepts of trimetallic sites and alkaline earth metal promoters in this work provide theoretical guidance for the rational design of atomically active sites in electrocatalytic NRR.

A novel pathogenic mitochondrial DNA variant m.4344T>C in tRNAGln causes developmental delay.

Mitochondrial diseases are a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA. However, the genetic spectrum of this disease is not yet complete. In this study, we identified a novel variant m.4344T>C in mitochondrial tRNAGln from a patient with developmental delay. The mutant loads of m.4344T>C were 95% and 89% in the patient's blood and oral epithelial cells, respectively. Multialignment analysis showed high evolutionary conservation of this nucleotide. TrRosettaRNA predicted that m.4344T>C variant would introduce an additional hydrogen bond and alter the conformation of the T-loop. The transmitochondrial cybrid-based study demonstrated that m.4344T>C variant impaired the steady-state level of mitochondrial tRNAGln and decreased the contents of mitochondrial OXPHOS complexes I, III, and IV, resulting in defective mitochondrial respiration, elevated mitochondrial ROS production, reduced mitochondrial membrane potential and decreased mitochondrial ATP levels. Altogether, this is the first report in patient carrying the m.4344T>C variant. Our data uncover the pathogenesis of the m.4344T>C variant and expand the genetic mutation spectrum of mitochondrial diseases, thus contributing to the clinical diagnosis of mitochondrial tRNAGln gene variants-associated mitochondrial diseases.

Enhancing Hydride Transfer in Catalytic Hydrogenation via σ-Electron-Induced Polarization of Imines.

In this study, we investigated the role of aluminum cations in facilitating hydride transfer during the hydrogenation of imines within the context of Noyori-type metal-ligand cooperative catalysis. We propose a novel model involving aluminum cations directly coordinated with imines to induce activation from the lone pair electron site, a phenomenon termed σ-induced activation. The aluminum metal-hydride amidate complex ("HMn-NAl") exhibits a higher ability of hydride transfer in the hydrogenation of imines compared to its lithium counterpart ("HMn-NLi"). Density functional theory (DFT) calculations uncover that the aluminum cation efficiently polarizes unsaturated bonds through σ-electron-induced activation in the transition state of hydride transfer, thereby enhancing substrate electrophilicity more efficiently. Additionally, upon substrate coordination, aluminum's coordination saturation improves the hydride nucleophilicity of the HMn-NAl complex via the breakage of the Al-H coordination bond.

Construction and regulation of high active sites in montmorillonite composite catalyst for the removal of ofloxacin via persulfate activation.

In this study, ionic liquids (ILs) were used as organic modifiers by introducing montmorillonite nanolayers containing potential C and N active sites between the montmorillonite nanolayers. Organically modified montmorillonite (ILs-Mt-p) was further prepared by high-temperature pyrolysis under N2 and used for the removal of ofloxacin (OFL) by activated peroxymonosulfate (PMS). Combined with XPS and other characterization analyses, it was found that the catalyst materials prepared from different organic modifiers had similar surface functional groups and graphitized structures, but contained differences in the types and numbers of C and N active sites. The catalyst (3CPC-Mt-p) obtained after pyrolysis of montmorillonite modified with cetylpyridinium chloride (CPC) had optimal catalytic performance, in which graphitic C, graphitic N, and carbonyl group (C[bond, double bond]O) could synergistically promote the activation of PMS by electron transfer, and 77.3 % of OFL could be removed within 60 min. The effects of OFL concentration, initial pH, and anions on the effects of OFL removal by the 3CPC-Mt-p/PMS system were further investigated. Satisfactory degradation results were obtained over a wide pH range. Cl- promoted the system to degrade OFL, while the presence of SO42-, H2PO4- and HA showed some inhibition, but overall the 3CPC-Mt-p catalysts had a strong anti-interference ability, showing good application prospects. The quenching experiments and EPR tests showed that O2-- and 1O2 in the 3CPC-Mt-p/PMS system were the main reactive oxygen species for the degradation of OFL, and •OH was also involved in the reaction. This study provides ideas for the construction and modulation of active sites in mineral materials such as montmorillonite and broadens the application of montmorillonite composite catalysts in advanced oxidation processes for the treatment of antibiotic wastewater.

Development and validation of LCMM prediction algorithms to estimate recovery pattern of postoperative AKI in type A aortic dissection: a retrospective study.

Background: Postoperative acute kidney injury (PO-AKI) is a prevalent complication among patients with acute type A aortic dissection (aTAAD) for which unrecognized trajectories of renal function recovery, and their heterogeneity, may underpin poor success in identifying effective therapies. Methods: This was a retrospective, single-center cohort study in a regional Great Vessel Center including patients undergoing aortic dissection surgery. Estimated glomerular filtration rate (eGFR) recovery trajectories of PO-AKI were defined through the unsupervised latent class mixture modeling (LCMM), with an assessment of patient and procedural characteristics, complications, and early-term survival. Internal validation was performed by resampling. Results: A total of 1,295 aTAAD patients underwent surgery and 645 (49.8%) developed PO-AKI. Among the PO-AKI cohort, the LCMM identified two distinct eGFR trajectories: early recovery (ER-AKI, 51.8% of patients) and late or no recovery (LNR-AKI, 48.2% of patients). Binary logistic regression identified five critical determinants regarding poor renal recovery, including chronic kidney disease (CKD) history, renal hypoperfusion, circulation arrest time, intraoperative urine, and myoglobin. LNR-AKI was associated with increased mortality, continuous renal replacement therapies, mechanical ventilation, ICU stay, and hospital stay. The assessment of the predictive model was good, with an area under the curve (AUC) of 0.73 (95% CI: 0.69-0.76), sensitivity of 61.74%, and specificity of 75.15%. The internal validation derived a consistent average AUC of 0.73. The nomogram was constructed for clinicians' convenience. Conclusion: Our study explored the PO-AKI recovery patterns among surgical aTAAD patients and identified critical determinants that help to predict individuals at risk of poor recovery of renal function.

Effects of Connectivity Isomerization on Electron Transport Through Thiophene Heterocyclic Molecular Junction.

Connectivity isomerization of the same aromatic molecular core with different substitution positions profoundly affects electron transport pathways and single-molecule conductance. Herein, we designed and synthesized all connectivity isomers of a thiophene (TP) aromatic ring substituted by two dihydrobenzo[b]thiophene (BT) groups with ethynyl spacers (m,n-TP-BT, (m,n = 2,3; 2,4; 2,5; 3,4)), to systematically probe how connectivity contributes to single-molecule conductance. Single-molecule conductance measurements using a scanning tunneling microscopy break junction (STM-BJ) technique show ∼12-fold change in conductance values, which follow an order of 10-4.83 G0 (2,4-TP-BT) < 10-4.78 G0 (3,4-TP-BT) < 10-4.06 G0 (2,3-TP-BT) < 10-3.75 G0 (2,5-TP-BT). Electronic structure analysis and theoretical simulations show that the connectivity isomerization significantly changes electron delocalization and HOMO-LUMO energy gaps. Moreover, the connectivity-dependent molecular structures lead to different quantum interference (QI) effects in electron transport, e.g., a strong destructive QI near E = EF leads the smallest conductance value for 2,4-TP-BT. This work proves a clear relationship between the connectivity isomerization and single-molecule conductance of thiophene heterocyclic molecular junctions for the future design of molecular devices.

Recent advances in total synthesis of protoberberine and chiral tetrahydroberberine alkaloids.

Covering: Up to 2024Due to the widespread distribution of protoberberine alkaloids (PBs) and tetrahydroberberine alkaloids (THPBs) in nature, coupled with their myriad unique physiological activities, they have garnered considerable attention from medical practitioners. Over the past few decades, synthetic chemists have devised various total synthesis methods to attain these structures, continually expanding reaction pathways to achieve more efficient synthetic strategies. Simultaneously, the chiral construction of THPBs has become a focal point. In this comprehensive review, we categorically summarized the developmental trajectory of the total synthesis of these alkaloids based on the core closure strategies of protoberberine and tetrahydroberberine.

A case report of secondary B-cell acute lymphoblastic leukemia treated with a combination of FLT3 inhibitor and decitabine.

Secondary acute lymphoblastic leukemia (s-ALL) refers to acute lymphoblastic leukemia that occurs after a previous malignant tumor, including therapy-related acute lymphoblastic leukemia (t-ALL) and prior malignant tumor acute lymphoblastic leukemia (pm-ALL). We report a case of a 51-year-old female patient who developed acute lymphoblastic leukemia 14 years after being diagnosed with diffuse large B-cell lymphoma (DLBCL). The patient was unresponsive to conventional chemotherapy for acute lymphoblastic leukemia (ALL) and achieved remission with a combination of sorafenib and decitabine based on the molecular biology characteristics of her B-ALL.

Comparing generative and retrieval-based chatbots in answering patient questions regarding age-related macular degeneration and diabetic retinopathy.

BACKGROUND/AIMS: To compare the performance of generative versus retrieval-based chatbots in answering patient inquiries regarding age-related macular degeneration (AMD) and diabetic retinopathy (DR). METHODS: We evaluated four chatbots: generative models (ChatGPT-4, ChatGPT-3.5 and Google Bard) and a retrieval-based model (OcularBERT) in a cross-sectional study. Their response accuracy to 45 questions (15 AMD, 15 DR and 15 others) was evaluated and compared. Three masked retinal specialists graded the responses using a three-point Likert scale: either 2 (good, error-free), 1 (borderline) or 0 (poor with significant inaccuracies). The scores were aggregated, ranging from 0 to 6. Based on majority consensus among the graders, the responses were also classified as 'Good', 'Borderline' or 'Poor' quality. RESULTS: Overall, ChatGPT-4 and ChatGPT-3.5 outperformed the other chatbots, both achieving median scores (IQR) of 6 (1), compared with 4.5 (2) in Google Bard, and 2 (1) in OcularBERT (all p ≤8.4×10-3). Based on the consensus approach, 83.3% of ChatGPT-4's responses and 86.7% of ChatGPT-3.5's were rated as 'Good', surpassing Google Bard (50%) and OcularBERT (10%) (all p ≤1.4×10-2). ChatGPT-4 and ChatGPT-3.5 had no 'Poor' rated responses. Google Bard produced 6.7% Poor responses, and OcularBERT produced 20%. Across question types, ChatGPT-4 outperformed Google Bard only for AMD, and ChatGPT-3.5 outperformed Google Bard for DR and others. CONCLUSION: ChatGPT-4 and ChatGPT-3.5 demonstrated superior performance, followed by Google Bard and OcularBERT. Generative chatbots are potentially capable of answering domain-specific questions outside their original training. Further validation studies are still required prior to real-world implementation.

Loss-of-function mutation in DDX53 associated with hereditary spastic paraplegia-like disorder.

DEAD-box helicase 53 (DDX53) is a member of the DEAD-box protein family of RNA helicases. Unlike other family members that are responsible for RNA metabolism, the biological function of DDX53 and its impact on the human condition are unclear. Herein, we found a full-length DDX53 deletion mutation in a hereditary spastic paraplegia-like (HSP-like) patient with lower extremity spasticity, walking disorder, visual impairment, and lateral ventricular white matter lesions. Bioinformatic analysis revealed that DDX53 was mainly expressed in the cerebellar cortex and may function as a tissue-specific RNA helicase. Transcriptome analysis showed that the expression of multiple brain-associated genes involved in synapse organization, neuron function, and neuromuscular junctions was affected by DDX53 depletion. Moreover, RNA immunoprecipitation sequencing (RIP-seq) analysis showed that DDX53 interacted with 176 genes, and 96 of these genes were associated with the execution of neurofunction, particularly in the regulation of cell projection organization and nervous system development. Collectively, although a more specified cell or animal model is required to fully understand the functional role of DDX53 in the human brain, we report for the first time that the patient with DDX53 defects exhibits HSP-like symptoms and that DDX53 is essential for maintaining neuronal function, with loss-of-function mutation in DDX53 potentially leading to HSP due to impaired RNA metabolism in the nervous system. KEY MESSAGES: DDX53 deficiency was first reported to be associated with HSP disorder. DDX53 exhibited minimal impact on mitochondrial function. DDX53 impaired RNA metabolism in the nervous system.