Functional interactions underlying visuospatial orthographic processes in Chinese reading.

As a logographic writing system, Chinese reading involves the processing of visuospatial orthographic (ORT) properties. However, this aspect has received relatively less attention in neuroimaging research, which has tended to emphasize phonological (PHO) and semantic (SEM) aspects in processing Chinese characters. Here, we compared the functional correlates supporting all these three processes in a functional MRI single-character reading study, in which 35 native Chinese adults were asked to make ORT, PHO, and SEM judgments in separate task-specific activation blocks. Our findings revealed increased involvement of the right hemisphere in processing Chinese visuospatial orthography, particularly evident in the right ventral occipito-temporal cortex (vOTC). Additionally, time course analysis revealed that the left superior parietal gyrus (SPG) was initially involved in SEM processing but contributed to the visuospatial processing of words in a later time window. Finally, ORT processing demonstrated stronger recruitment of left vOTC-SPG-middle frontal gyrus (MFG) functional connectivity compared to SEM processing. This functional coupling correlated with reduced regional engagement of the left vOTC and MFG, highlighting that visuospatial ORT processes in reading Chinese rely on functional interactions among key regions rather than local regional processes. In conclusion, these findings underscore visuospatial ORT processes as a distinctive feature of reading logographic characters.

HDAC2-miR183-5p Epigenetic Circuit Contributes to the Growth of Philadelphia Chromosome-Positive B-cell Acute Lymphoblastic Leukemia via PTEN/AKT and c-MYC Signaling Pathway.

Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph(+)B-ALL) is a hematological malignancy with a poor prognosis. Epigenetic abnormalities, especially abnormal histone acetylation and microRNAs (miRNAs) dysregulation, are a group of epigenetic patterns that contribute to leukemia progression. However, their regulatory mechanisms in Ph(+)B-ALL have not been fully elucidated. In this study, we identified that miR-183-5p is significantly downregulated in Ph(+)B-ALL and associated with poor prognosis. Moreover, we found that the BCR-ABL fusion gene is a key target gene of miR-183-5p. MiR-183-5p directly targets BCR-ABL gene and induces cell apoptosis via PTEN/AKT and c-MYC signaling pathways. In addition, histone deacetylase inhibitor (HADCi) could mitigate the suppressive effects of HDAC2 on miR-183-5p by promoting promoter acetylation, thereby enhancing cell apoptosis. In conclusion, our results indicate that miR-183-5p is a potential biomarker and suggest that a novel "HDAC2-miR-183-5p epigenetic circuitry regulation" may be involved in the pathogenesis of Ph(+)B-ALL. Taken together, These findings provide new insights into the design of promising molecular-targeted drugs for Ph(+)B-ALL.

O-GlcNAcylation of SERCA protects skeletal muscle in hibernating Spermophilus dauricus from disuse atrophy.

Long-term inactivity of skeletal muscle results in muscular disuse atrophy; however, hibernating animals do not experience muscular disuse atrophy during the hibernation period. The molecular mechanism underlining the anti-atrophy effect in these animals is unclear. O-linked N acetyl-ß-D-glucosaminylation (O-GlcNAcylation) and its effect on cell signaling pathways are important mechanisms underlying muscular disuse atrophy; thus, in this study, we investigated O-GlcNAcylation changes during hibernation in Spermophilus dauricus to explore the role of O-GlcNAcylation in the muscle disuse atrophy resistance of hibernating animals. The results showed that during hibernation, the muscle fiber cross-sectional area and ratio of muscle fiber did not change, and the morphological structure of the muscle remained intact, with normal contractile function. The level of O-GlcNAcylation decreased during hibernation, but quickly returned to normal in the periodic arousal stage. The O-GlcNAcylation level of sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (SERCA1) decreased, whereas its activity increased. The decrease in O-GlcNAcylation of SERCA could result in the decreased binding of phospholamban to SERCA1, thus decreasing its inhibition to SERCA1 activity. This in turn can inhibit muscle cell calcium overload, maintain muscle cell calcium homeostasis, and stabilize the calpain proteolytic pathway, ultimately inhibiting skeletal muscle atrophy. Our results demonstrate that periodic arousal along with returning O-GlcNAcylation level to normal are important mechanisms in preventing disuse atrophy of skeletal muscle during hibernation.

The causal relationship between androgenetic alopecia and serum uric acid: A bidirectional Mendelian randomization analysis.

BACKGROUND: Despite numerous studies investigating the association between androgenetic alopecia (AGA) and serum uric acid (SUA), the causal relationship between AGA and SUA remains unknown. METHODS: We utilized bidirectional Mendelian randomization (MR) to explore the causality between AGA and SUA. Our study chose single nucleotide polymorphisms associated with genome-wide significance (p < 5×10-8) for the exposure and showing low linkage disequilibrium (R2 < 0.001) as IVs. Various MR methods were employed to evaluate causality, including inverse-variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode and Simple Mode. Sensitivity analyses were performed to test the robustness of the results. RESULTS: Using the IVW method, we did not find a significant causal relationship between AGA and SUA (OR = 1.00, 95% CI 0.99-1.01; p = 0.451). Similarly, the IVW method did not reveal evidence of causality between SUA and AGA (OR = 0.97, 95% CI = 0.91-1.03; p = 0.301). The results from other methods were consistent with those of the IVW approach. CONCLUSION: The study did not identify a causal relationship between AGA and SUA. Future research should involve larger cohorts and advanced methods to validate the findings and explore the complex interactions between AGA and SUA levels in different populations.

Targeting eukaryotic elongation factor 2 kinase (eEF2K) with small-molecule inhibitors for cancer therapy.

Eukaryotic elongation factor 2 kinase (eEF2K) is a member of the α-kinase family that is activated by calcium/calmodulin. Of note, eEF2K is crucial for regulating translation and is often highly overexpressed in malignant cells. Therefore in this review, we summarize the molecular structure of eEF2K and its oncogenic roles in cancer. Moreover, we further discuss the inhibition of eEF2K with small-molecule inhibitors and other new emerging therapeutic strategies in cancer therapy. Taken together, these inspiring findings provide new insights into a promising strategy for inhibiting eEF2K to greatly improve future cancer therapy.

A- and B-type wheat starch granules: The multiscale structural evolution during digestion and the distinct digestion mechanisms.

The digestive characteristics of wheat starch are closely related to human health. However, the digestive mechanisms of distinct wheat starch granules are not well understood. To address this problem, A- and B-type wheat starch granules (AWS and BWS, respectively) were digested in vitro and the structural evolution of the digestive remnants was compared. After stomach-intestinal digestion of AWS, its crystallinity decreased from 12.75 % to 6.65 %, its fractal dimension decreased from 3.12 to 2.35, and the median particle size decreased from 20.613 to 10.135 µm. Additionally, the number of short chains (polymerization degree<14) and thermodynamic stability decreased after digestion. For BWS, Fourier transform infrared ratio of 1047/1022 cm-1 and 995/1022 cm-1 increased from 0.665 and 0.725 to 0.990 and 0.800, respectively. The median particle size decreased from 5.480 to 4.769 µm. An enzyme-resistant scattering peak was observed in the 1.35 nm-1 lamellar structure. Additionally, the number of B2 and B3 chains and the thermodynamic stability increased after digestion. Our study confirmed that BWS is more likely than AWS to form enzyme-resistant structures during digestion. These findings provide insights into the distinct digestion mechanisms of AWS and BWS, and serve as a foundation for modifying wheat starch to increase its nutritional value.

IGF-1 and myostatin-mediated co-regulation in skeletal muscle and bone of Daurian ground squirrels (Spermophilus dauricus) during different hibernation stages.

Muscle and bone are cooperatively preserved in Daurian ground squirrels (Spermophilus dauricus) during hibernation. As such, we hypothesized that IGF-1 and myostatin may contribute to musculoskeletal maintenance during this period. Thus, we systematically assessed changes in the protein expression levels of IGF-1 and myostatin, as well as their corresponding downstream targets, in the vastus medialis (VM) muscle and femur in Daurian ground squirrels during different stages. Group differences were determined using one-way analysis of variance (ANOVA). Results indicated that the co-localization levels of IGF-1 and its receptor (IGF-1R) increased by 50% during the pre-hibernation period (PRE) and by 35% during re-entry into torpor (RET) compared to the summer active period (SA). The phosphorylation level of FOXO1 in the VM muscle increased by 50% in the torpor (TOR) group and by 82% in the inter-bout arousal (IBA) group compared to the PRE group. The phosphorylation level of SGK-1 increased by 54% in the IBA group and by 62% in the RET group compared to the SA group. In contrast, the protein expression of IGF-1 and phosphorylation levels of PI3K, Akt, mTOR, and GSK3ß in the VM muscle showed no obvious differences among the different groups. ß-catenin protein expression was up-regulated by 84% in the RET group compared to the SA group, while the content of IGF-1 protein, correlation coefficients of IGF-1 and IGF-1R, and phosphorylation levels of PI3K, Akt, and GSK3ß in the femur showed no significant differences among groups. Regarding myostatin and its downstream targets, myostatin protein expression decreased by 70% in the RET group compared to the SA group, whereas ActRIIB protein expression and Smad2/3 phosphorylation in the VM muscle showed no obvious differences among groups. Furthermore, Smad2/3 phosphorylation decreased by 58% in the TOR group and 53% in the RET group compared to the SA group, whereas ActRIIB protein expression in the femur showed no obvious differences among groups. Overall, the observed changes in IGF-1 and myostatin expression and their downstream targets may be involved in musculoskeletal preservation during hibernation in Daurian ground squirrels.

In Situ Construction of Specific SEI Layer Affords Effective Prelithiation.

Silicon-based anodes have been attracting attention due to their high theoretical specific capacity, but their low initial Coulombic efficiency (ICE) seriously hinders their commercial application. Direct contact prelithiation is considered to be one of the effective means of solving this problem. By means of prelithiation, a specific solid electrolyte interphase (SEI) was constructed, which inhibited the volume expansion of the SiO/C composite anode during prelithiation and reduced the local current generated when the lithium source was in contact with the anode. On the one hand, it can reduce the side reactions derived from the decomposition of electrolytes in the prelithiation process, and on the other hand, it can slow down the prelithiation process and inhibit the volume expansion of the SiO/C composite anode in the prelithiation process. The results of XPS, TOF-SIMS, and other tests show that the use of an electrolyte whose main component is LiTFSI can construct SEI film whose main component is LiF, which to a certain extent can slow down the rate of prelithiation, reduce the local current generated when the lithium source is in contact with the negative electrode, minimize the occurrence of side reactions, and inhibit the volume expansion of the negative electrode material. The full battery assembled with NCM111 positive electrode still exhibits 83.5% capacity retention after 500 cycles at 1 C current density. These studies provide some ideas to enhance the performance of silicon-based materials.

Predictive model for CAR-T cell therapy success in patients with relapsed/refractory B-cell acute lymphoblastic leukaemia.

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable efficacy in treating relapsed/refractory acute B-cell lymphoblastic leukaemia (R/R B-ALL). However, a subset of patients does not benefit from CAR-T therapy. Our study aims to identify predictive indicators and establish a model to evaluate the feasibility of CAR-T therapy. Fifty-five R/R B-ALL patients and 22 healthy donors were enrolled. Peripheral blood lymphocyte subsets were analysed using flow cytometry. Sensitivity, specificity, accuracy, positive and negative predictive values and receiver operating characteristic (ROC) areas under the curve (AUC) were determined to evaluate the predictive values of the indicators. We identified B lymphocyte, regulatory T cell (Treg) and peripheral blood minimal residual leukaemia cells (B-MRD) as indicators for predicting the success of CAR-T cell preparation with AUC 0.936, 0.857 and 0.914. Furthermore, a model based on CD3+ T count, CD4+ T/CD8+ T ratio, Treg and extramedullary diseases (EMD) was used to predict the response to CAR-T therapy with AUC of 0.938. Notably, a model based on CD4+ T/CD8+ T ratio, B, Treg and EMD were used in predicting the success of CAR-T therapy with AUC 0.966 [0.908-1.000], with specificity (92.59%) and sensitivity (91.67%). In the validated group, the predictive model predicted the success of CAR-T therapy with specificity (90.91%) and sensitivity (100%). We have identified several predictive indicators for CAR-T cell therapy success and a model has demonstrated robust predictive capacity for the success of CAR-T therapy. These results show great potential for guiding informed clinical decisions in the field of CAR-T cell therapy.

Efficacy and safety of topical minocycline foam (FMX101 4%) in treatment of Chinese subjects with moderate-to-severe facial acne vulgaris: A phase 3, multi-centre, randomized, double-blind, vehicle-controlled study.

BACKGROUND: FMX101 4%, as a topical foam formulation of minocycline, has been approved by US Food and Drug Administration for the treatment of moderate-to-severe acne vulgaris (AV). OBJECTIVE: To evaluate the efficacy and safety of FMX101 4% in treating Chinese subjects with moderate-to-severe facial AV. METHODS: This was a multi-centre, randomized, double-blind, vehicle-controlled phase 3 study in Chinese subjects with moderate-to-severe AV. Eligible subjects were randomized 2:1 to receive either FMX101 4% or vehicle foam treatment for 12 weeks. The primary efficacy endpoint was the change in inflammation lesion count (ILC) from baseline at week 12. The key secondary endpoint was the treatment success rate according to Investigator's Global Assessment (IGA) at week 12. RESULTS: In total, 372 subjects were randomized into two groups (FMX101 4% group, n = 248; vehicle group, n = 124). After 12 weeks treatment, the reduction in ILC from baseline was statistically significant in favour of FMX101 4%, compared with vehicle foam (-21.0 [0.08] vs. -12.3 [1.14]; LSM [SE] difference, -8.7 [1.34]; 95% CI [-11.3, -6.0]; p < 0.001). FMX101 4% treatment yielded significantly higher IGA treatment success rate at week 12 as compared to the control treatment (8.06% vs. 0%). Applying FMX101 4% also resulted in significant reduction in noninflammatory lesion count (nILC) versus vehicle foam at week 12 (-19.4 [1.03] vs. -14.9 [1.47]; LSM [SE] difference, -4.5 [1.74]; 95% CI [-8.0, -1.1]; p = 0.009). Most treatment-emergent adverse events (TEAEs) were mild-to-moderate in severity, and no treatment-related treatment-emergent serious adverse event (TESAE) occurred. Thus, FMX101 4% was considered to be a safe and well-tolerated product during the 12-week treatment period. CONCLUSION: FMX101 4% treatment for 12 weeks could lead to significantly reduced ILC and nILC, and improved IGA treatment success rate in Chinese subjects with moderate-to-severe facial AV. It also showed a well acceptable safe and tolerability profile.

Chromodomain Y-like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis.

Acute kidney injury (AKI) is a common disease, but lacking effective drug treatments. Chromodomain Y-like (CDYL) is a kind of chromodomain protein that has been implicated in transcription regulation of autosomal dominant polycystic kidney disease. Benzo[d]oxazol-2(3H)-one derivative (compound D03) is the first potent and selective small-molecule inhibitor of CDYL (KD = 0.5 µM). In this study, we investigated the expression of CDYL in three different models of cisplatin (Cis)-, lipopolysaccharide (LPS)- and ischemia/reperfusion injury (IRI)-induced AKI mice. By conducting RNA sequencing and difference analysis of kidney samples, we found that tubular CDYL was abnormally and highly expressed in injured kidneys of AKI patients and mice. Overexpression of CDYL in cisplatin-induced AKI mice aggravated tubular injury and pyroptosis via regulating fatty acid binding protein 4 (FABP4)-mediated reactive oxygen species production. Treatment of cisplatin-induced AKI mice with compound D03 (2.5 mg·kg-1·d-1, i.p.) effectively attenuated the kidney dysfunction, pathological damages and tubular pyroptosis without side effects on liver or kidney function and other tissue injuries. Collectively, this study has, for the first time, explored a novel aspect of CDYL for tubular epithelial cell pyroptosis in kidney injury, and confirmed that inhibition of CDYL might be a promising therapeutic strategy against AKI.

A Retrospective Cohort Study on the Comorbidity in 19,264 Chinese Patients of Different Ages with Urticaria.

To examine the prevalence of comorbidities in Chinese urticaria patients and assess medication use patterns across different ages (6-11 years, 12-17 years, above 18 years), a retrospective cohort study was performed in 192,647 urticaria patients within the Health Database. After 1:1 propensity score matching, 166,921 people were divided into the urticaria group and the control group, and the follow-up data were collected within 2 years. During the 12-month and 24-month follow-up period, significant comorbidities identified included allergic rhinitis and asthma, with distinct patterns observed across age groups. Chronic urticaria patients often have complications, such as allergic rhinitis, upper respiratory infection, oropharyngeal infection, and dental caries. The study underscores the need for age-specific treatment strategies in urticaria management.

Deciphering three predominant biopsy-proven phenotypes of IgG4-associated kidney disease: a retrospective study.

Background: IgG4-associated kidney disease (IgG4-RKD) encompasses a spectrum of disorders, predominantly featuring tubulointerstitial nephritis (TIN) and membranous glomerulonephropathy (MGN). The limited understanding of the co-occurrence of IgG4-RD-TIN with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) poses a diagnostic and therapeutic challenge. Methods: We examined 49 cases, comprising 21 cases of IgG4-RD-TIN (group A), 10 cases of IgG4-RD-TIN accompanied with MGN (group B), and 18 cases of IgG4-RD-TIN concurrent with AAV (group C), at the First Affiliated Hospital of Zhejiang University, China, from June 2015 to December 2022. Results: The mean age and gender of the three IgG4-RKD subtypes were not statistically significant. IgG4-RD-TIN exhibited higher serum creatinine and a higher incidence of hypocomplementemia (group A 47.6%, group B 30%, group C 16.7%). IgG4-RD-TIN-MGN was characterized by proteinuria (group A 0.3 g/d, group B 4.0 g/d, group C 0.8 g/d, P < 0.001) and hypoalbuminemia. IgG4-RD-TIN-AAV exhibited hypohemoglobinemia (group A 103.45 g/l, group B 119.60 g/l, group C 87.94 g/l, P < 0.001) and a high level of urine erythrocytes. The primary treatment for IgG4-RD-TIN was steroids alone, whereas IgG4-RD-TIN-MGN and IgG4-RD-TIN-AAV necessitated combination therapy. Group A experienced two relapses, whereas groups B and C had no relapses. There was no significant difference in patient survival among the three groups, and only two cases in group C suffered sudden death. Conclusions: This study provides valuable insights into clinical manifestations, auxiliary examination features, pathological characteristics, and prognosis of IgG4-RD-TIN, IgG4-RD-TIN-MGN, and IgG4-RD-TIN concurrent AAV. Large-scale studies are required to validate these findings.

Comorbidities among adult patients with psoriasis in Tianjin: a cross-sectional analysis of the Health Database study.

OBJECTIVES: This study aims to examine the prevalence of comorbidities in adult patients with psoriasis and compare them with those in control subjects without psoriasis in Tianjin, China. DESIGN: The study is a cross-sectionalanalysis. PARTICIPANTS: The participants were established by identifying all patients (age ≥18 years) who visited hospitals and clinics in Tianjin between 1 January 2016 and 31 October 2019. SETTING: The study group consisted of 20 678 adult patients with psoriasis, and a comparison group was created after 1:1 propensity score matching. Logistic regression analyses were conducted to examine the risk of 22 comorbidities for these two groups. RESULTS: Patients with psoriasis had a significantly higher prevalence of 11 comorbidities and a lower prevalence of 2 comorbidities within 12 months of follow-up. Our results also showed that the proportion of psoriatic arthritis might account for approximately 2% of all patients with psoriasis. This psoriatic arthritis group had a higher average age and CCI (Charlson Comorbidity Index) index score (2.27 >1.62, p <0.001) than the non-arthritis group. CONCLUSIONS: This study showed that psoriasis in Tianjin is associated with various comorbidities. It also emphasises the importance of clinical treatment in improving therapeutic effects and reducing the burden of psoriasis in China.

A novel seasonal grey prediction model with fractional order accumulation for energy forecasting.

To accurately predict sequence data with seasonal characteristics, we combine data restart technology and fractional order accumulation into a novel seasonal grey model (FSGM (1,1, α)). The particle swarm optimization (PSO) algorithm is used to solve the fractional order and background value coefficients of the model, and the effectiveness of FSGM (1,1, α) is verified using three cases. Finally, we use FSGM (1,1, α) to predict quarterly electricity generation in Beijing and Henan Province and quarterly petroleum coke production in China from 2023 to 2027. The research results indicate that, first, FSGM (1,1, α) is reasonable and effective and has the ability to accurately capture the dynamic trend of seasonal data. Second, compared with the grey model (GM (1,1)), seasonal grey model (SGM (1,1)), data grouping grey model (DGGM (1,1)), data grouping seasonal model (DGSM (1,1)), and data grouping seasonal time model (DGSTM (1,1)), which have seasonal characteristics, FSGM (1,1, α) can better fit the original data, achieve higher prediction accuracy, and perform better. Third, from 2023 to 2027, it is predicted that there will be no significant change in Beijing's electricity generation, and the current stable trend will be maintained. Both the power generation in Henan Province and the petroleum coke production in China will steadily increase to a certain extent, with obvious seasonal cyclical fluctuations. Notably, the power generation and petroleum coke production in Henan Province in the fourth quarter of 2027 will increase by 11.50 % and 10.93 %, respectively, compared to those in the fourth quarter of 2023.

The roles of adenosine signaling in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multiple etiological factors. Immune disorder contributes to SLE development and is an important clinical manifestation of SLE patients. Immune dysfunction is characterized by abnormal of B cells, T cells, monocyte-macrophages and dendritic cells (DCs), in both quantity and quality. Adenosine is a critical factor for human immune homeostasis, which acts as an immunosuppressive signal and can prevent the hyperactivity of human immune system. Adenosine levels are significant decreased in serum from SLE patients. Adenosine level is regulated by the CD39, CD73 and adenosine deaminase (ADA). CD39/CD73/ADA catalyzed the cascade enzymatic reaction, which contained the adenosine generation and degradation. Adenosine affects the function of various immune cells via bind to the adenosine receptors, which are expressed on the cell surface. This review aims to export the changes of immune cells and adenosine signal pathway in SLE, as well as the effect of adenosine signal pathway in SLE development.

DNT cells mediate resistance to CAR-T cells therapy in a pediatric patient with relapsed and refractory B-ALL.

Chimeric antigen receptor T (CAR-T) cells therapy is a milestone achievement in the immunotherapy of relapsed and refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL). However, some patients treated with CAR-T cells do not achieve complete remission, the mechanisms of which have not been elucidated. In the present study, we report a 9-year-old pediatric patient with refractory B-ALL received a triple infusion of autologous CD19 CAR-T cells therapy after the second relapse. CAR-T cells expanded in the peripheral blood and bone marrow. However, the patient did not achieve complete remission, indicating a lack of response to CAR-T cells therapy. Analysis of etiological factors revealed that the number of CD4 and CD8 double-negative T (DNT) cells was significantly upregulated in the peripheral blood, bone marrow, and autologous CAR-T cells products. In conclusiont, these findings indicate that DNT cells mediated resistance to CAR-T cells therapy in this pediatric patient with R/R B-ALL.