Exploring the genetic and socioeconomic interplay between ADHD and anxiety disorders using Mendelian randomization.

Background: ADHD and anxiety disorders often co-occur, sharing symptoms and dysfunctions, yet the underlying mechanisms remain elusive. Methods: To explore the shared and distinct genetic variations between ADHD and anxiety disorders, we applied Mendelian randomization (MR) analysis to ADHD, anxiety disorders, and three socioeconomic factors: income, educational attainment (EA), and intelligence. MR analysis utilized genome-wide association study summary datasets (anxiety disorder: 7,016 cases and 14,745 controls; ADHD: 38,691 cases and 275,986 controls; EA: 766,345 participants; intelligence: 146,808 participants; household income: 392,422 participants), with inverse-variance weighting as the primary method. Results: Our MR analysis revealed no discernible genetic-level causal effect between ADHD and anxiety disorders (p > 0.77). Additionally, the independent variables for ADHD (25 SNPs) and anxiety disorders (18 SNPs) did not overlap, highlighting the genetic distinction between the two conditions. Higher income (p < 0.002) and EA (p < 0.005) were found to serve as protective factors for both ADHD and anxiety disorders. Genetic predisposition to higher income (86 SNPs) and EA (457 SNPs) were identified as a potential common protective factors for both conditions. Lastly, genetic predisposition to higher intelligence was found to potentially guard against ADHD (p < 0.001) but not against anxiety disorders (p > 0.55). Conclusion: Our findings indicate that the shared symptoms observed between ADHD and anxiety disorders are more likely influenced by genetic predispositions related to socioeconomic factors rather than by the genetic predispositions specific to the disorders themselves.

Adverse childhood experiences and cognitive function in later life: the sequential mediating roles of education level and adult loneliness.

Background: This study assesses the impact of adverse childhood experiences (ACEs) on the cognitive function of older adults. Furthermore, it examines the potential underlying mechanism involving education level and the subjective "feeling of loneliness" (FOL). Methods: Analyzing a population-based cohort sample from the China Health and Retirement Longitudinal Study database, 8,365 subjects aged 45 or older were interviewed in 2018. Ten ACEs indicators were measured using life history questionnaires assessed at 2014. FOL was assessed using a single item from 10-item Center for Epidemiological Studies Depression Scale (CESD-10). Cognitive function was assessed using a structured questionnaire comprising four dimensions: memory, orientation, computation, and visuospatial abilities. Results: In the fully adjusted model, which accounted for age, gender, marital status, smoke, drink, rural residence, and education levels of both mothers and fathers, the linear regression analysis indicated that ACEs were inversely associated the lower education level (B = -0.058, 95% CI = -0.090, -0.026, p < 0.001), and ACEs were found to be linked to an elevated risk of FOL (B = 0.072, 95% CI = 0.056, 0.089, p < 0.001). In addition, ACEs was not significantly associated with cognitive function (B = -0.047, 95% CI = -0.108, 0.015, p = 0.136), but FOL was significantly associated with cognitive function (B = -0.483, 95% CI = -0.561, -0.404, p < 0.001). Mediation analysis revealed that education level and FOL sequentially and partially mediated the association between ACEs and the total cognitive score, with a proportion mediated of 52.58%. Limitations: The evaluation of ACEs exposure was based on binary response options. This method limited our ability to explore various dimensions of adversity, such as ages of occurrence, severity, frequency, duration, and the extent of psychological effects at the time. Furthermore, the assessment of loneliness relied on a single item from the CESD-10, introducing a potential source of measurement error. Conclusion: Our study unveils a substantial association between ACEs and education level, as well as with FOL and cognitive function in the older adults. Moreover, education level and FOL serve as sequential mediating factors in the relationship between ACEs and cognitive function.

Revealing the Complete Bispecific Phosphatase Genes (DUSPs) across the Genome and Investigating the Expression Patterns of GH_A11G3500 Resistance against Verticillium wilt.

DUSPs, a diverse group of protein phosphatases, play a pivotal role in orchestrating cellular growth and development through intricate signaling pathways. Notably, they actively participate in the MAPK pathway, which governs crucial aspects of plant physiology, including growth regulation, disease resistance, pest resistance, and stress response. DUSP is a key enzyme, and it is the enzyme that limits the rate of cell metabolism. At present, complete understanding of the DUSP gene family in cotton and its specific roles in resistance to Verticillium wilt (VW) remains elusive. To address this knowledge gap, we conducted a comprehensive identification and analysis of four key cotton species: Gossypium arboreum, Gossypium barbadense, Gossypium hirsutum, and Gossypium raimondii. The results revealed the identification of a total of 120 DUSP genes in the four cotton varieties, which were categorized into six subgroups and randomly distributed at both ends of 26 chromosomes, predominantly localized within the nucleus. Our analysis demonstrated that closely related DUSP genes exhibited similarities in terms of the conserved motif composition and gene structure. A promoter analysis performed on the GhDUSP gene promoter revealed the presence of several cis-acting elements, which are associated with abiotic and biotic stress responses, as well as hormone signaling. A tissue expression pattern analysis demonstrated significant variations in GhDUSP gene expression under different stress conditions, with roots exhibiting the highest levels, followed by stems and leaves. In terms of tissue-specific detection, petals, leaves, stems, stamens, and receptacles exhibited higher expression levels of the GhDUSP gene. The gene expression analysis results for GhDUSPs under stress suggest that DUSP genes may have a crucial role in the cotton response to stress in cotton. Through Virus-Induced Gene Silencing (VIGS) experiments, the silencing of the target gene significantly reduced the resistance efficiency of disease-resistant varieties against Verticillium wilt (VW). Consequently, we conclude that GH_A11G3500-mediated bispecific phosphorylated genes may serve as key regulators in the resistance of G. hirsutum to Verticillium wilt (VW). This study presents a comprehensive structure designed to provide an in-depth understanding of the potential biological functions of cotton, providing a strong foundation for further research into molecular breeding and resistance to plant pathogens.

Hemophagocytic lymphohistiocytosis associated with brucellosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune disorder categorized as familial HLH or secondary HLH. Our case report describes a 63-year-old woman with epilepsy whose clinical signs were unremitting fever and altered consciousness. Primary abnormalities consisted of fever, splenomegaly, cytopenia, hypertriglyceridemia, hyperferritinemia and hemophagocytosis in the bone marrow. Results of blood next generation sequencing and blood culture confirmed Brucella infection. This report illustrates a sHLH case caused by Brucella melitensis infection. Here, we review the classification, clinical features, diagnostic methods, treatment regimens, differential diagnosis, and prognosis of HLH and brucellosis.

Lactic acid bacteria modulate the CncC pathway to enhance resistance to ß-cypermethrin in the oriental fruit fly.

The gut microbiota of insects has been shown to regulate host detoxification enzymes. However, the potential regulatory mechanisms involved remain unknown. Here, we report that gut bacteria increase insecticide resistance by activating the cap "n" collar isoform-C (CncC) pathway through enzymatically generated reactive oxygen species (ROS) in Bactrocera dorsalis. We demonstrated that Enterococcus casseliflavus and Lactococcus lactis, two lactic acid-producing bacteria, increase the resistance of B. dorsalis to ß-cypermethrin by regulating cytochrome P450 (P450) enzymes and α-glutathione S-transferase (GST) activities. These gut symbionts also induced the expression of CncC and muscle aponeurosis fibromatosis. BdCncC knockdown led to a decrease in resistance caused by gut bacteria. Ingestion of the ROS scavenger vitamin C in resistant strain affected the expression of BdCncC/BdKeap1/BdMafK, resulting in reduced P450 and GST activity. Furthermore, feeding with E. casseliflavus or L. lactis showed that BdNOX5 increased ROS production, and BdNOX5 knockdown affected the expression of the BdCncC/BdMafK pathway and detoxification genes. Moreover, lactic acid feeding activated the ROS-associated regulation of P450 and GST activity. Collectively, our findings indicate that symbiotic gut bacteria modulate intestinal detoxification pathways by affecting physiological biochemistry, thus providing new insights into the involvement of insect gut microbes in the development of insecticide resistance.

Abscisic acid root-to-shoot translocation by transporter AtABCG25 mediates stomatal movements in Arabidopsis.

The phytohormone abscisic acid (ABA) plays a central role in regulating stomatal movements under drought conditions. The root-derived peptide CLAVATA3/EMBRYO SURROUNDING REGION-RELATED 25 (CLE25) moves from the root to shoot for activating ABA biosynthesis under drought conditions. However, the root-to-shoot translocation of root-derived ABA and its regulation of stomatal movements in the shoot remain to be clarified. Here, we reveal that the ABA transporter ATP-binding cassette subfamily G member 25 (AtABCG25) mediates root-to-shoot translocation of ABA and ABA-glucosyl ester (ABA-GE) in Arabidopsis (Arabidopsis thaliana). Isotope-labeled ABA tracer experiments and hormone quantification in xylem sap showed that the root-to-shoot translocation of ABA and ABA-GE was substantially impaired in the atabcg25 mutant under nondrought and drought conditions. However, the contents of ABA and ABA-GE in the leaves were lower in the atabcg25 mutant than in the wild type (WT) under nondrought but similar under drought conditions. Consistently, the stomatal closure was suppressed in the atabcg25 mutant under nondrought but not under drought conditions. The transporter activity assays showed that AtABCG25 directly exported ABA and ABA-GE in planta and in yeast (Saccharomyces cerevisiae) cells. Thus, we proposed a working model in which root-derived ABA transported by AtABCG25 via xylem mediates stomatal movements in the shoot under nondrought conditions but might exhibit little effect on stomatal movements under drought conditions. These findings extend the functions of AtABCG25 and provide insights into the long-distance translocation of ABA and its role in stomatal movements.

Sunflower-like missing-linker covalent organic framework for efficient extraction of non-steroidal anti-inflammatory drugs.

As excellent crystalline materials, covalent organic frameworks (COFs) are widely used in drug adsorption. In this work, a defective engineering strategy was proposed for designing and preparing the functionalized end-capping monomer and missing-linker COFs. The missing-linker COF 2,4,6-trihydroxybenzene-1,3,5-tricarbaldehyde compound with glycidyltrimethyl ammonium chloride modified benzene-1,4-diamine (TpPa-GTA) was synthesized through Schiff base reaction with wide pore size distribution for adsorption of four nonsteroidal anti-inflammatory drugs (NSAIDs). The adsorption process follows pseudo-second-order kinetics, and the four drugs reached adsorption equilibrium within 10 min. The sunflower-like structure helps to promote intraparticle diffusion during the adsorption process, thereby realizing the rapid adsorption of TpPa-GTA. The equilibrium isotherms fit well with both the Freundlich and Langmuir models, with a maximum adsorption capacity of 83.3-315 mg g-1 calculated from the Langmuir model. Based on the detection results of Zeta potential and XPS, the adsorption mechanism was inferred, and the rapid capture of NSAIDs in the wide pH range of 4.0 to 7.5 was realized under electrostatic interaction, hydrogen bonding, and π-π interaction. The detection of lake and river samples using the missing adapter TpPa-GTA has a recovery rate of 84.2-117%, which provides a new approach to the adsorption of pollutants with COFs.

Maintaining Toll signaling in Drosophila brain is required to sustain autophagy for dopamine neuron survival.

Macroautophagy/autophagy is a conserved process in eukaryotic cells to degrade and recycle damaged intracellular components. Higher level of autophagy in the brain has been observed, and autophagy dysfunction has an impact on neuronal health, but the molecular mechanism is unclear. In this study, we showed that overexpression of Toll-1 and Toll-7 receptors, as well as active Spätzle proteins in Drosophila S2 cells enhanced autophagy, and Toll-1/Toll-7 activated autophagy was dependent on Tube-Pelle-PP2A. Interestingly, Toll-1 but not Toll-7 mediated autophagy was dMyd88 dependent. Importantly, we observed that loss of functions in Toll-1 and Toll-7 receptors and PP2A activity in flies decreased autophagy level, resulting in the loss of dopamine (DA) neurons and reduced fly motion. Our results indicated that proper activation of Toll-1 and Toll-7 pathways and PP2A activity in the brain are necessary to sustain autophagy level for DA neuron survival.

SHMT2 Mediates Small-Molecule-Induced Alleviation of Alzheimer Pathology Via the 5'UTR-dependent ADAM10 Translation Initiation.

It is long been suggested that one-carbon metabolism (OCM) is associated with Alzheimer's disease (AD), whereas the potential mechanisms remain poorly understood. Taking advantage of chemical biology, that mitochondrial serine hydroxymethyltransferase (SHMT2) directly regulated the translation of ADAM metallopeptidase domain 10 (ADAM10), a therapeutic target for AD is reported. That the small-molecule kenpaullone (KEN) promoted ADAM10 translation via the 5' untranslated region (5'UTR) and improved cognitive functions in APP/PS1 mice is found. SHMT2, which is identified as a target gene of KEN and the 5'UTR-interacting RNA binding protein (RBP), mediated KEN-induced ADAM10 translation in vitro and in vivo. SHMT2 controls AD signaling pathways through binding to a large number of RNAs and enhances the 5'UTR activity of ADAM10 by direct interaction with GAGGG motif, whereas this motif affected ribosomal scanning of eukaryotic initiation factor 2 (eIF2) in the 5'UTR. Together, KEN exhibits therapeutic potential for AD by linking OCM with RNA processing, in which the metabolic enzyme SHMT2 "moonlighted" as RBP by binding to GAGGG motif and promoting the 5'UTR-dependent ADAM10 translation initiation.

Optimizing the therapeutic window of sirolimus by monitoring blood concentration for the treatment of immune thrombocytopenia.

Previous studies have demonstrated that sirolimus (SRL) is an effective agent for the treatment of refractory/relapsed (R/R) ITP. However, the therapeutic window of sirolimus in the treatment of ITP has not been established. As the toxicity of sirolimus increases with higher blood concentrations, it is crucial to determine the optimal therapeutic concentration of SRL for the treatment of ITP. Thus, in this study, we used a retrospective cohort of ITP patients treated with sirolimus to propose the therapeutic dosage window for sirolimus. A total of 275 laboratory results of SRL blood concentration from 63 ITP patients treated with SRL were analyzed retrospectively. The ITP patients were divided into five groups based on their SRL blood concentration: 0-4 ng/ml, 4-8 ng/ml, 8-12 ng/ml, 12-16 ng/ml and ≥16 ng/ml. In addition to the SRL blood concentration, platelet counts and adverse events that occurred during the first 6 weeks of SRL treatment were analyzed. These findings were then used to establish the decision matrix tables and ROC curves, which helped identify the therapeutic window of SRL. Based on the values and trends of true-positive rate (TPR) and false-positive rate (FPR) in the ROC curve, patients who achieved a SRL blood concentration of 4-12 ng/ml displayed a higher response rate compared to those with a SRL concentration of 0-4 ng/ml or ≥16ng/ml. Additionally, the response rate was better for patients with a SRL concentration of 8-12 ng/ml compared to 4-8 ng/ml. Adverse events were related to the concentration of SRL; however, there was no significant difference in the incidence of adverse events between the concentrations of 4-8 ng/ml and 8-12 ng/ml (P > .05). Regression analysis suggested that the concentration of SRL correlated with the patient's age, PLT count at the start of SRL administration, and the dose of SRL. It is suggested that the optimal blood concentration of SRL monotherapy for managing ITP is 8-12 ng/ml. This range may achieve a favorable balance between clinical efficacy and the severity of adverse events.

Although sirolimus (SRL) has been proven to be an effective alternative agent for refractory/relapsed immune thrombocytopenia (R/R ITP), there is currently no recommended optimal blood concentration during its administration. We collected data on SRL drug concentration, platelet response, and drug side effects in ITP patients, constructed ROC curves to evaluate the relationship between the SRL concentration and both efficacy and side effects, and finally suggested a most appropriate SRL blood concentration (8­12ng/ml). This concentration window ensured optimal efficacy of SRL in the treatment of ITP while maintaining tolerable side effects. Additionally, we conducted a multivariate analysis to explore factors that may influence SRL blood concentration. The present study made an important contribution to the precision therapy of ITP with sirolimus by clarifying the optimal blood concentration range.

Myeloid/Lymphoid Neoplasms with ETV6::PDGFRB Fusion Gene: A Rare Case of Poor Response to Imatinib and Possible Transformation Mechanisms from Myeloid Neoplasms of Bone Marrow to T-Cell Lymphoblastic Lymphoma Invasion in Lymph Nodes.

The ETV6::PDGFRB fusion gene is commonly reported in chronic myelomonocytic leukemia with eosinophilia, yet patients with ETV6::PDGFRB presenting myeloid and lymphoid neoplasms successively have not been reported. Here, we report the first case of a 35-year-old man with myeloid and lymphoid neoplasms harboring an ETV6::PDGFRB fusion gene who demonstrated poor response to imatinib. The patient was diagnosed with an ETV6::PDGFRB fusion gene myeloid neoplasm on initial diagnosis at our hospital. After 5 months of treatment with imatinib, he was diagnosed with T-cell lymphoblastic lymphoma. ETV6::PDGFRB turned negative after increasing the dose of imatinib, but enlarged superficial lymph nodes reappeared the following year. Notably, the patient exhibited a worse response to imatinib treatment. This study describes this rare case and speculates on a possible mechanism.

GBSOT4 Enhances the Resistance of Gossypium barbadense to Fusarium oxysporum f. sp. vasinfectum (FOV) by Regulating the Content of Flavonoid.

Sulfotransferases (SOTs) (EC 2.8.2.-) are sulfate regulatory proteins in a variety of organisms that have been previously shown to be involved in regulating a variety of physiological and biological processes, such as growth, development, adaptation to land, stomatal closure, drought tolerance, and response to pathogen infection. However, there is a lack of comprehensive identification and systematic analysis of SOT in cotton, especially in G. barbadense. In this study, we used bioinformatics methods to analyze the structural characteristics, phylogenetic relationships, gene structure, expression patterns, evolutionary relationships, selection pressure and stress response of SOT gene family members in G. barbadense. In this study, a total of 241 SOT genes were identified in four cotton species, among which 74 SOT gene members were found in G. barbadense. According to the phylogenetic tree, 241 SOT protein sequences were divided into five distinct subfamilies. We also mapped the physical locations of these genes on chromosomes and visualized the structural information of SOT genes in G. barbadense. We also predicted the cis-acting elements of the SOT gene in G. barbadense, and we identified the repetitive types and collinearity analysis of SOT genes in four cotton species. We calculated the Ka/Ks ratio between homologous gene pairs to elucidate the selective pressure between SOT genes. Transcriptome data were used to explore the expression patterns of SOT genes, and then qRT-PCR was used to detect the expression patterns of GBSOT4, GBSOT17 and GBSOT33 under FOV stress. WGCNA (weighted gene co-expression network analysis) showed that GB_A01G0479 (GBSOT4) belonged to the MEblue module, which may regulate the resistance mechanism of G. barbadense to FOV through plant hormones, signal transduction and glutathione metabolism. In addition, we conducted a VIGS (virus-induced gene silencing) experiment on GBSOT4, and the results showed that after FOV inoculation, the plants with a silenced target gene had more serious leaf wilting, drying and cracking than the control group, and the disease index of the plants with the silenced target gene was significantly higher than that of the control group. This suggests that GBSOT4 may be involved in protecting the production of G. barbadense from FOV infection. Subsequent metabolomics analysis showed that some flavonoid metabolites, such as Eupatorin-5-methylether (3'-hydroxy-5,6,7,4'-tetramethoxyflavone, were accumulated in cotton plants in response to FOV infection.

Genetic Channelization Mechanism of Four Chalcone Isomerase Homologous Genes for Synergistic Resistance to Fusarium wilt in Gossypium barbadense L.

Duplication events occur very frequently during plant evolution. The genes in the duplicated pathway or network can evolve new functions through neofunctionalization and subfunctionalization. Flavonoids are secondary metabolites involved in plant development and defense. Our previous transcriptomic analysis of F6 recombinant inbred lines (RILs) and the parent lines after Fusarium oxysporum f. sp. vasinfectum (Fov) infection showed that CHI genes have important functions in cotton. However, there are few reports on the possible neofunctionalization differences of CHI family paralogous genes involved in Fusarium wilt resistance in cotton. In this study, the resistance to Fusarium wilt, expression of metabolic pathway-related genes, metabolite content, endogenous hormone content, reactive oxygen species (ROS) content and subcellular localization of four paralogous CHI family genes in cotton were investigated. The results show that the four paralogous CHI family genes may play a synergistic role in Fusarium wilt resistance. These results revealed a genetic channelization mechanism that can regulate the metabolic flux homeostasis of flavonoids under the mediation of endogenous salicylic acid (SA) and methyl jasmonate (MeJA) via the four paralogous CHI genes, thereby achieving disease resistance. Our study provides a theoretical basis for studying the evolutionary patterns of homologous plant genes and using homologous genes for molecular breeding.

Significance of PPARA as a Treatment Target for Chronic Lymphocytic Leukemia.

Peroxisome proliferator-activated receptor alpha (PPARA) has been suggested as a therapeutic target for chronic lymphocytic leukemia (CLL). However, the underlying molecular mechanism remains largely unclear. In this study, we analyzed DNA next-generation sequencing (NGS) data and clinical information from 86 CLL patients to identify gene markers related to treatment-free survival (TFS) length. We then constructed a genetic network that includes CLL promoters, treatment targets, and TFS-related marker genes. To assess the significance of PPARA within the network, we utilized degree centrality (DC) and pathway enrichment score (EScore). Clinical and NGS data revealed 10 TFS length-related gene markers, including RPS15, FOXO1, FBXW7, KMT2A, NOTCH1, GNA12, EGR2, GNA13, KDM6A, and ATM. Through literature data mining, 83 genes were identified as CLL upstream promoters and treatment targets. Among them, PPARA exhibited a stronger connection to CLL and TFS-related gene markers, as evidenced by its ranking at No. 13 based on DC, compared to most of the other promoters (>84%). Additionally, PPARA co-functions with 70 out of 92 in-network genes in various functional pathways/gene groups related to CLL pathology, such as regulation of cell adhesion, inflammation, reactive oxygen species, and cell differentiation. Based on our findings, PPARA is considered one of the critical genes within a large genetic network that influences the prognosis and TFS of CLL through multiple pathogenic pathways.

Development of a blood proteins-based model for bronchopulmonary dysplasia prediction in premature infants.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common chronic pulmonary disease in premature infants. Blood proteins may be early predictors of the development of this disease. METHODS: In this study, protein expression profiles (blood samples during their first week of life) and clinical data of the GSE121097 was downloaded from the Gene Expression Omnibus. Weighted gene co-expression network analysis (WGCNA) and differential protein analysis were carried out for variable dimensionality reduction and feature selection. Least absolute shrinkage and selection operator (LASSO) were conducted for BPD prediction model development. The performance of the model was evaluated by the receiver operating characteristic (ROC) curve, calibration curve, and decision curve. RESULTS: The results showed that black module, magenta module and turquoise module, which included 270 proteins, were significantly correlated with the occurrence of BPD. 59 proteins overlapped between differential analysis results and above three modules. These proteins were significantly enriched in 253 GO terms and 11 KEGG signaling pathways. Then, 59 proteins were reduced to 8 proteins by LASSO analysis in the training cohort. The proteins model showed good BPD predictive performance, with an AUC of 1.00 (95% CI 0.99-1.00) and 0.96 (95% CI 0.90-1.00) in training cohort and test cohort, respectively. CONCLUSION: Our study established a reliable blood-protein based model for early prediction of BPD in premature infants. This may help elucidate pathways to target in lessening the burden or severity of BPD.

Efficacy and toxicity of CLAG combined with pegylated liposomal doxorubicin in the treatment of refractory or relapsed acute myeloid leukemia.

BACKGROUND: Refractory and relapsed acute myeloid leukemia (r/rAML) is associated with a difficult prognosis; clinical trials are typically suggested despite lack of a recognized standard of care. Combinatorial chemotherapy regimens utilized for r/rAML salvage play a crucial role in battling this invasive phase. Although it is characterized by a low response rate, CLAG is a traditional regimen used in r/rAML. We aimed to compare the efficacy and toxicity of CLAG+PLD to explore whether there was any improvement with the addition of pegylated liposomal doxorubicin (PLD) to CLAG METHODS: A total of 110 r/rAML patients were retrospectively analyzed from February 2017 to June 2020 at the Medical Center of Hematology, XinQiao Hospital, the 303rd Hospital of the Chinese People's Liberation Army, and Central Hospital of Chang Sha, Hunan Province. The response, overall survival (OS), disease-free survival (DFS), and side effects in 110 r/rAML patients were evaluated retrospectively. Of these, 55 patients were administered CLAG+PLD, while 55 patients received CLAG alone as salvage therapy. RESULTS: In the CLAG+PLD group, there were 27 (49.1%) cases of complete response (CR) with no measurable residual disease (MRD-), 12 (21.8%) cases of CR with positive MRD (MRD+), 5 (9.1%) cases of partial response (PR), 11 (20%) cases of no response (NR), and no cases of death during the cycles. The response rates in the CLAG group were lower: CR was reached in 24 (46.6%) patients with MRD-, 6 (10.9%) patients with MRD+, 10 (18.2%) patients with PR, 13 (23.6%) patients with NR, and 2 (3.6%) patients who passed away, one from infection and the other from cerebral hemorrhage. The median OS and DFS were not attained in the CLAG+PLD group during the 2-year OS and DFS follow-up, while both values were 10 months in the CLAG group (p = 0.023 and p = 0.045, respectively). The results of the Cox regression analysis for the CLAG+PLD group were strongly illustrative of the importance of hematopoietic stem cell transplantation (HSCT) following salvage therapy. No increased toxicity was observed in the CLAG+PLD group. CONCLUSION: CLAG+PLD is a potential salvage regimen for r/r AML that has a similar toxicity profile to CLAG and that improves response rates, 2-year OS, and DFS relative to CLAG.

ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation.

Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferentially inhibiting BACE1 translation via the 5' untranslated region (5'UTR) and rescued cognitive decline in an animal model of APP/PS1 mice. ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1) was then found to mediate the effect of CNP on BACE1 translation, amyloidogenesis, glial activation, and cognitive function. Through analysis of the 5'UTR-targetd RNA-binding proteins by RNA pulldown combined with LC-MS/MS, we found that FMR1 autosomal homolog 1 (FXR1) interacted with ARL6IP1 and mediated CNP-induced reduction of BACE1 by regulating the 5'UTR activity. Without altering the protein levels of ARL6IP1 and FXR1, CNP treatment promoted ARL6IP1 interaction with FXR1 and inhibited FXR1 binding to the 5'UTR both in vitro and in vivo. Collectively, CNP exhibited a therapeutic potential for AD via ARL6IP1. Through pharmacological manipulation, we uncovered a dynamic interaction between FXR1 and the 5'UTR in translational control of BACE1, adding to the understanding of the pathophysiology of AD.

Development and identification of molecular markers of GhHSP70-26 related to heat tolerance in cotton.

Heat stress significantly affect plant growth and development, which is an important factor contributing to crop yield loss. However, heat shock proteins (HSPs) in plants can effectively alleviate cell damage caused by heat stress. In order to rapidly and accurately cultivate heat-tolerant cotton varieties, this study conducted correlation analysis between heat tolerance index and insertion/deletion (In/Del) sites of GhHSP70-26 promoter in 39 cotton materials, so as to find markers related to heat tolerance function of cotton, which can be used in molecular marker-assisted breeding. The results showed the natural variation allele (Del22 bp) type at -1590 bp upstream of GhHSP70-26 promoter (haplotype2, Hap2) in cotton (Gossypium spp.) promoted GhHSP70-26 expression under heat stress. The relative expression level of GhHSP70-26 of M-1590-Del22 cotton materials were significantly higher than that of M-1590-In type cotton materials under heat stress (40 ℃). Also, M-1590-Del22 material had lower conductivity and less cell damage after heat stress, indicating that it is a heat resistant cotton material. The Hap1 (M-1590-In) promoter was mutated into Hap1del22, and Hap1 and Hap1del22 were fused with GUS to transform Arabidopsis thaliana. Furthermore, Hap1del22 promoter had higher induction activity than Hap1 under heat stress and abscisic acid (ABA) treatment in transgenic Arabidopsis thaliana. Further analysis confirmed that M-1590-Del22 was the dominant heat-resistant allele. In summary, these results identify a key and previously unknown natural variation in GhHSP70-26 with respect to heat tolerance, providing a valuable functional molecular marker for genetic breeding of cotton and other crops with heat tolerance.

Two new species of Antrodia (Polyporales, Basidiomycota) in western China.

Two new species of Antrodia, A. aridula and A. variispora, are described from western China. Phylogeny based on a six-gene dataset (ITS + nLSU + nSSU + mtSSU + TEF1 + RPB2) demonstrates that samples of the two species form two independent lineages within the clade of Antrodia s.s. and are different in morphology from the existing species of Antrodia. Antrodia aridula is characterized by its annual and resupinate basidiocarps with angular to irregular pores of 2-3 mm each and oblong ellipsoid to cylindrical basidiospores measuring 9-12 × 4.2-5.3 µm, growing on gymnosperm wood in a dry environment. Antrodia variispora is characterized by its annual and resupinate basidiocarps with sinuous or dentate pores with a size of 1-1.5 mm each and oblong ellipsoid, fusiform, pyriform, or cylindrical basidiospores measuring 11.5-16 × 4.5-5.5 µm, growing on the wood of Picea. The differences between the new species and morphologically similar species are discussed in this article.

Weighted Gene Co-Expression Network Analysis Reveals Hub Genes for Fuzz Development in Gossypium hirsutum.

Fuzzless Gossypium hirsutum mutants are ideal materials for investigating cotton fiber initiation and development. In this study, we used the fuzzless G. hirsutum mutant Xinluzao 50 FLM as the research material and combined it with other fuzzless materials for verification by RNA sequencing to explore the gene expression patterns and differences between genes in upland cotton during the fuzz period. A gene ontology (GO) enrichment analysis showed that differentially expressed genes (DEGs) were mainly enriched in the metabolic process, microtubule binding, and other pathways. A weighted gene co-expression network analysis (WGCNA) showed that two modules of Xinluzao 50 and Xinluzao 50 FLM and four modules of CSS386 and Sicala V-2 were highly correlated with fuzz. We selected the hub gene with the highest KME value among the six modules and constructed an interaction network. In addition, we selected some genes with high KME values from the six modules that were highly associated with fuzz in the four materials and found 19 common differential genes produced by the four materials. These 19 genes are likely involved in the formation of fuzz in upland cotton. Several hub genes belong to the arabinogalactan protein and GDSL lipase, which play important roles in fiber development. According to the differences in expression level, 4 genes were selected from the 19 genes and tested for their expression level in some fuzzless materials. The modules, hub genes, and common genes identified in this study can provide new insights into the formation of fiber and fuzz, and provide a reference for molecular design breeding for the genetic improvement of cotton fiber.