Treatment algorithms of relapsing multiple sclerosis: an exploration based on the available disease-modifying therapies in China.

Multiple sclerosis (MS) was defined as a rare disease in China due to its low prevalence. For a long time, interferon ß was the only approved disease-modifying therapy (DMT). Since the first oral DMT was approved in 2018, DMT approval accelerated, and seven DMTs were approved within 5 years. With an increasing number of DMTs being prescribed in clinical practice, it is necessary to discuss the standardized MS treatment algorithms depending on the disease activity and DMT availability. In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country.

Treatment algorithms of relapsing multiple sclerosis in China In this review paper, more than 20 Chinese experts in MS have reviewed the therapeutic progress of MS in China and worldwide and discussed algorithms for treating relapsing MS (RMS) based on the available DMTs in China, providing insights for establishing the standardized RMS treatment algorithms in this country: 1) CIS and RRMS account for more than 90% of the MS patients and most of them are mild to moderate; 2) MS patients should initiate DMT treatments as soon as the disease has been diagnosed in order to reduce the risk of disease progression; 3) Patients who have been diagnosed with MS should start treatment with fundamental DMTs unless the disease course has been highly active; 4) MAGNIMS score may be a suitable and simplified assessment tool for measuring treatment response to DMTs; 5) Patients treated with corticosteroids and NSIS should be switched to the standardized DMT treatment during remission in accordance with disease activity.

Mutations and intron polymorphisms in voltage-gated sodium channel genes of different geographic populations of Culex pipiens pallens/Culex pipiens quinquefasciatus in China.

BACKGROUND: Culex pipiens pallens and Culex pipiens quinquefasciatus are the dominant species of Culex mosquitoes in China and important disease vectors. Long-term use of insecticides can cause mutations in the voltage-gated sodium channel (vgsc) gene of mosquitoes, but little is known about the current status and evolutionary origins of vgsc gene in different geographic populations. Therefore, this study aimed to determine the current status of vgsc genes in Cx. p. pallens and Cx. p. quinquefasciatus in China and to investigate the evolutionary inheritance of neighboring downstream introns of the vgsc gene to determine the impact of insecticides on long-term evolution. METHODS: Sampling was conducted from July to September 2021 in representative habitats of 22 provincial-level administrative divisions in China. Genomic DNA was extracted from 1308 mosquitoes, the IIS6 fragment of the vgsc gene on the nerve cell membrane was amplified using polymerase chain reaction, and the sequence was used to evaluate allele frequency and knockdown resistance (kdr) frequency. MEGA 11 was used to construct neighbor-joining (NJ) tree. PopART was used to build a TCS network. RESULTS: There were 6 alleles and 6 genotypes at the L1014 locus, which included the wild-type alleles TTA/L and CTA/L and the mutant alleles TTT/F, TTC/F, TCT/S and TCA/S. The geographic populations with a kdr frequency less than 20.00% were mainly concentrated in the regions north of 38° N, and the geographic populations with a kdr frequency greater than 80.00% were concentrated in the regions south of 30° N. kdr frequency increased with decreasing latitude. And within the same latitude, the frequency of kdr in large cities is relatively high. Mutations were correlated with the number of introns. The mutant allele TCA/S has only one intron, the mutant allele TTT/F has three introns, and the wild-type allele TTA/L has 17 introns. CONCLUSIONS: Cx. p. pallens and Cx. p. quinquefasciatus have developed resistance to insecticides in most regions of China. The neighboring downstream introns of the vgsc gene gradually decreased to one intron with the mutation of the vgsc gene. Mutations may originate from multiple mutation events rather than from a single origin, and populations lacking mutations may be genetically isolated.

ZmMAPK6, a mitogenactivated protein kinase, regulates maize kernel weight.

Kernel weight is a critical agronomic trait in maize production. Many genes are related to it, but only a few of them have been applied to maize breeding and cultivation. Here, we identify a novel function of maize mitogenactivated protein kinase 6 (ZmMPK6) in the regulation of maize kernel weight. The kernel weight reduced in zmmpk6 mutants, while enhanced in ZmMPK6 overexpression lines. In addition, starch granules, starch content, protein content, and grainfilling characteristics are also affected. ZmMAPK6 is mainly localized in the nucleus and cytoplasm, widely distributed across various tissues, and expresses during kernel development, which is consistent with its role in kernel weight. Thus, these results denote new insights into the role of ZmMAPK6, a MAPK, in maize kernel weight, and could be applied to further molecular breeding for kernel quality and yield in maize.

The OsWRKY72-OsAAT30/OsGSTU26 module mediates reactive oxygen species scavenging to drive heterosis for salt tolerance in hybrid rice.

Hybrid rice (Oryza sativa) generally outperforms its inbred parents in yield and stress tolerance, a phenomenon termed heterosis, but the underlying mechanism is not completely understood. Here, we combined transcriptome, proteome, physiological, and heterosis analyses to examine the salt response of super hybrid rice Chaoyou1000 (CY1000). In addition to surpassing the mean values for its two parents (mid-parent heterosis), CY1000 exhibited a higher reactive oxygen species scavenging ability than both its parents (over-parent heterosis or heterobeltiosis). Nonadditive expression and allele-specific gene expression assays showed that the glutathione S-transferase gene OsGSTU26 and the amino acid transporter gene OsAAT30 may have major roles in heterosis for salt tolerance, acting in an overdominant fashion in CY1000. Furthermore, we identified OsWRKY72 as a common transcription factor that binds and regulates OsGSTU26 and OsAAT30. The salt-sensitive phenotypes were associated with the OsWRKY72paternal genotype or the OsAAT30maternal genotype in core rice germplasm varieties. OsWRKY72paternal specifically repressed the expression of OsGSTU26 under salt stress, leading to salinity sensitivity, while OsWRKY72maternal specifically repressed OsAAT30, resulting in salinity tolerance. These results suggest that the OsWRKY72-OsAAT30/OsGSTU26 module may play an important role in heterosis for salt tolerance in an overdominant fashion in CY1000 hybrid rice, providing valuable clues to elucidate the mechanism of heterosis for salinity tolerance in hybrid rice.

Tailoring Charge Separation in ZnIn2S4@CdS Hollow Nanocages for Simultaneous Alcohol Oxidation and CO2 Reduction under Visible Light.

Artificial photosynthesis provides a sustainable strategy for producing usable fuels and fine chemicals and attracts broad research interest. However, conventional approaches suffer from low reactivity or low selectivity. Herein, we demonstrate that photocatalytic reduction of CO2 coupled with selective oxidation of aromatic alcohol into corresponding syngas and aromatic aldehydes can be processed efficiently and fantastically over the designed S-scheme ZnIn2S4@CdS core-shell hollow nanocage under visible light. In the ZnIn2S4@CdS heterostructure, the photoexcited electrons and holes with weak redox capacities are eliminated, while the photoexcited electrons and holes with powder redox capacities are separated spatially and preserved on the desired active sites. Therefore, even if there are no cocatalysts and no vacancies, ZnIn2S4@CdS exhibits high reactivity. For instance, the CO production of ZnIn2S4@CdS is about 3.2 and 3.4 times higher than that of pure CdS and ZnIn2S4, respectively. More importantly, ZnIn2S4@CdS exhibits general applicability and high photocatalytic stability. Trapping agent experiments, 13CO2 isotopic tracing, in situ characterizations, and theoretical calculations reveal the photocatalytic mechanism. This study provides a new strategy to design efficient and selective photocatalysts for dual-function redox reactions by tailoring the active sites and regulating vector separation of photoexcited charge carriers.

Batoclimab vs Placebo for Generalized Myasthenia Gravis: A Randomized Clinical Trial.

Importance: Myasthenia gravis (MG) is caused by autoantibodies that disrupt the neuromuscular junction. The neonatal fragment crystallizable receptor (FcRn) antagonists, efgartigimod and rozanolixizumab, reduce immunoglobulin G (IgG) level in the circulation and alleviate symptoms in patients with generalized MG. Objective: To examine the efficacy and safety profile of batoclimab, a monoclonal IgG1 antibody, in patients with generalized MG. Design, Setting, and Participants: This was a multicenter randomized clinical trial conducted from September 15, 2021, to June 29, 2022, at 27 centers in China. Adult patients 18 years or older with generalized MG were screened, and those who were antibody positive were enrolled. Intervention: Eligible patients received batoclimab or matching placebo in addition to standard of care. Each treatment cycle consisted of 6 weekly subcutaneous injections of batoclimab, 680 mg, or matching placebo followed by 4 weeks of observation. A second treatment cycle was conducted in patients who required continuing treatment. Main Outcome and Measure: The primary outcome was sustained improvement, as defined by a 3-point or greater reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score from baseline for 4 or more consecutive weeks in the first cycle in individuals who were positive for acetylcholine receptor or muscle-specific kinase antibodies. Results: A total of 178 adult patients with generalized MG were screened, 132 were randomly assigned, 131 tested positive for antibodies, and 1 tested negative for antibodies. A total of 132 patients (mean [SE] age, 43.8 [13.6] years; 88 women [67.2%]) were enrolled. The rate of sustained MG-ADL improvement in the first cycle in antibody-positive patients was 31.3% (20 of 64) in the placebo group vs 58.2% (39 of 67) in the batoclimab group (odds ratio, 3.45; 95% CI, 1.62-7.35; P = .001). The MG-ADL score diverged between the 2 groups as early as week 2. The mean (SE) maximum difference in MG-ADL score reduction occurred 1 week after the last dose (day 43, 1.7 [0.3] in the placebo group vs 3.6 [0.3] in the batoclimab group; group difference, -1.9; 95% CI, -2.8 to -1.0; nominal P < .001). The rates of treatment-related and severe treatment-emergent adverse events in patients were 36.9% (24 of 65) and 7.7% (5 of 65) in the placebo group vs 70.1% (47 of 67) and 3.0% (2 of 67) in the batoclimab group, respectively. Conclusions and Relevance: Batoclimab increased the rate of sustained MG-ADL improvement and was well tolerated in adult patients with generalized MG. Clinical effects and the extent of IgG reduction were similar to those previously reported for efgartigimod and rozanolixizumab. Future studies of large sample size are needed to further understand the safety profile of batoclimab. Trial Registration: ClinicalTrials.gov Identifier: NCT05039190.

The relative and combined ability of stress hyperglycemia ratio and N-terminal pro-B-type natriuretic peptide to predict all-cause mortality in diabetic patients with multivessel coronary artery disease.

BACKGROUND: Stress hyperglycemia ratio (SHR) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are independently associated with increased mortality risk in diabetic patients with coronary artery disease (CAD). However, the role of these biomarkers in patients with diabetes and multivessel disease (MVD) remains unknown. The present study aimed to assess the relative and combined abilities of these biomarkers to predict all-cause mortality in patients with diabetes and MVD. METHODS: This study included 1148 diabetic patients with MVD who underwent coronary angiography at Tianjin Chest Hospital between January 2016 and December 2016. The patients were divided into four groups according to their SHR (SHR-L and SHR-H) and NT-proBNP (NT-proBNP-L and NT-proBNP-H) levels. The primary outcome was all-cause mortality. Multivariate Cox regression analyses were performed to evaluate the association of SHR and NT-proBNP levels with all-cause mortality. RESULTS: During a mean 4.2 year follow-up, 138 patients died. Multivariate analysis showed that SHR and NT-proBNP were strong independent predictors of all-cause mortality in diabetic patients with MVD (SHR: HR hazard ratio [2.171; 95%CI 1.566-3.008; P < 0.001; NT-proBNP: HR: 1.005; 95%CI 1.001-1.009; P = 0.009). Compared to patients in the first (SHR-L and NT-proBNP-L) group, patients in the fourth (SHR-H and NT-proBNP-H) group had the highest mortality risk (HR: 12.244; 95%CI 5.828-25.721; P < 0.001). The areas under the curve were 0.615(SHR) and 0.699(NT-proBNP) for all-cause mortality. Adding either marker to the original models significantly improved the C-statistic and integrated discrimination improvement values (all P < 0.05). Moreover, combining SHR and NT-proBNP levels into the original model provided maximal prognostic information. CONCLUSIONS: SHR and NT-proBNP independently and jointly predicted all-cause mortality in diabetic patients with MVD, suggesting that strategies to improve risk stratification in these patients should incorporate SHR and NT-porBNP into risk algorithms.

Enhanced detection of monoiodoacetic acid at ng/L level by ion chromatography with novel derivatization-free pretreatment.

Concerns have recently arisen regarding the formation of carcinogenic and genotoxic iodinated haloacetic acids (HAAs), such as monoiodoacetic acid (MIAA), during the disinfection of iodine-containing water with chloramine. Existing detection methods for MIAA rely on either labor-intensive derivatization operations or expensive instruments, making analysis challenging. To bypass these issues, this study proposed a novel two-step liquid-liquid extraction strategy to enrich MIAA and then pioneered the integration of common ion chromatography (IC) with an ultraviolet detector to measure trace MIAA precisely. This novel approach achieved a remarkable 155.6-fold enrichment of MIAA and significantly reduced the need for water and chemicals, hence enhancing its efficiency and environmental friendliness. Besides, this method effectively removed coexisting anions and separated MIAA from other interferents by adjusting IC column and eluent conditions. The method detection limit of MIAA is an impressive 21.44 ng/L, and the recoveries in synthetic and real water samples ranged from 85 to 113%, with maximum deviations of 7.59%. We validated the reliability of our approach by comparing it with the USEPA 552.3 method. In conclusion, this IC-based method proves to be a robust and environment-benign solution for detecting trace MIAA in complex water components.

Unlocking Antibacterial Potential: Key-Site-Based Regulation of Antibacterial Spectrum of Peptides.

In the pursuit of combating multidrug-resistant bacteria, antimicrobial peptides (AMPs) have emerged as promising agents; however, their application in clinical settings still presents challenges. Specifically, the exploration of crucial structural parameters that influence the antibacterial spectrum of AMPs and the subsequent development of tailored variants with either broad- or narrow-spectrum characteristics to address diverse clinical therapeutic needs has been overlooked. This study focused on investigating the effects of amino acid sites and hydrophobicity on the peptide's antibacterial spectrum through Ala scanning and fixed-point hydrophobic amino acid substitution techniques. The findings revealed that specific amino acid sites played a pivotal role in determining the antibacterial spectrum of AMPs and confirmed that broadening the spectrum could be achieved only by increasing hydrophobicity at certain positions. In conclusion, this research provided a theoretical basis for future precise regulation of an antimicrobial peptide's spectrum by emphasizing the intricate balance between amino acid sites and hydrophobicity.

Phase I study of the Syk inhibitor sovleplenib in relapsed or refractory mature B-cell tumors.

Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with antitumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/refractory mature Bcell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase 2 dose (RP2D). Overall, 134 Chinese patients were enrolled (dose escalation, n=27; dose expansion, n=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (≤65 kg) q.d. The primary efficacy end point of independent review committee-assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% CI, 37.5-64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, 0%). The most common (≥10% patients) grade ≥3 treatment-related adverse events in the doseexpansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased doseproportionally with ascending dose levels from 200-800 mg, without observed saturation. Sovleplenib showed antitumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.

Genetic variation in ZmKW1 contributes to kernel weight and size in dent corn and popcorn.

Kernel weight is a critical factor that essentially affects maize (Zea mays) yield. In natural inbred lines, popcorn kernels exhibit overtly smaller sizes compared to dent corn kernels, and kernel weight, which is controlled by multiple genetic loci, varies widely. Here, we characterized a major quantitative trait locus on chromosome 1, responsible for controlling kernel weight (qKW1) and size. The qKW1 locus encodes a protein containing a seven in absentia domain with E3 ubiquitin ligase activity, expressed prominently from the top to the middle region of the endosperm. The presence and function of qKW1 were confirmed through ZmKW1 gene editing, where the mutations in ZmKW1 within dent corn significantly increased kernel weight, consistent with alterations in kernel size, while overexpression of ZmKW1 had the opposite effect. ZmKW1 acts as a negative regulator of kernel weight and size by reducing both the number and size of the endosperm cells and impacting endosperm filling. Notably, the popcorn allele qKW1N and the dent corn allele qKW1D encode identical proteins; however, the differences in promoter activity arise due to the insertion of an Indel-1346 sequence in the qKW1N promoter, resulting in higher expression levels compared to qKW1D , thus contributing to the variation in kernel weight and size between popcorn and dent corn kernels. Linkage disequilibrium analysis of the 2.8 kb promoter region of ZmKW1 in a dataset comprising 111 maize association panels identified two distinct haplotypes. Our results provide insight into the mechanisms underlying kernel development and yield regulation in dent corn and popcorn, with a specific focus on the role of the ubiquitination system.

Impact of digital finance on urban ecological resilience: evidence from the Yangtze River Economic Belt in China.

From the emergence of the new coronavirus pandemic to extreme climatic catastrophes, the development and enhancement of urban ecological resilience has evolved into a critical and strategic imperative. Investigating the capacity of digital finance to promote urban ecological resilience bears substantial relevance to the sustainable advancement of urban centers. This study examines the influence of digital finance on urban ecological resilience by applying a benchmark regression model on data from 107 prefecture-level cities within the Yangtze River Economic Belt across 2011-2020. Additionally, this study delves into its mechanism and spatial spillover impacts via a mediating effect model and a spatial effect model. The findings revealed that (1) digital finance strengthens the ecological resilience of the locale and beneficially impacts the surrounding regions; (2) digital finance enhances urban ecological resilience by fostering technological innovation and reducing energy intensity; and (3) in the lower reaches of the Yangtze River, digital finance plays a greater role in improving urban ecological resilience. Cities with high level of traditional financial development, high level of economic development and high intensity of environmental regulation have a more obvious role in promoting urban ecological resilience. Within the paradigm of ecological civilization, it is advisable for governmental bodies to fortify inter-regional digital financial collaboration, refine the green financial infrastructure, and advocate for sustainable, low-carbon, high-quality urban development.

Generation of a new therapeutic D-peptide that induces the differentiation of acute myeloid leukemia cells through A TLR-2 signaling pathway.

Acute myeloid leukemia (AML) is caused by clonal disorders of hematopoietic stem cells. Differentiation therapy is emerging as an important treatment modality for leukemia, given its less toxicity and wider applicable population, but the arsenal of differentiation-inducing agents is still very limited. In this study, we adapted a competitive peptide phage display platform to search for candidate peptides that could functionally induce human leukemia cell differentiation. A monoclonal phage (P6) and the corresponding peptide (pep-P6) were identified. Both L- and D-chirality of pep-P6 showed potent efficiency in inducing AML cell line differentiation, driving their morphologic maturation and upregulating the expression of macrophage markers and cytokines, including CD11b, CD14, IL-6, IL-1ß, and TNF-α. In the THP-1 xenograft animal model, administration of D-pep-P6 was effective in inhibiting disease progression. Importantly, exposure to D-pep-P6 induced the differentiation of primary human leukemia cells isolated AML patients in a similar manner to the AML cell lines. Further mechanism study suggested that D-pep-P6 induced human leukemia cell differentiation by directly activating a TLR-2 signaling pathway. These findings identify a novel D-peptide that may promote leukemia differentiation therapy.

Discovery of Unique Bis-Substituted Aromatic Amide Derivatives as Novel Highly Potent Antibiotics for Combating Methicillin-Resistant Staphylococcus aureus (MRSA).

Due to the increasing antibiotic resistance, developing novel antimicrobials to fight infections caused by resistant bacteria is imperative. Herein, a series of novel bis-substituted aromatic amides were designed and synthesized through modifying the hit compound 1, and their antimicrobial activities were evaluated. Among them, compound 4t, as the most potent lead, exhibited excellent antimicrobial activities against Gram-positive bacteria, including clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates, while keeping weak hemolytic and mammalian cytotoxic activities. Furthermore, compound 4t displayed rapid bactericidal capabilities, low tendency to produce resistance, and favorable capacities to destroy bacterial biofilms. Further explorations indicated that compound 4t induces bacterial death by binding to cardiolipin (CL) on the bacterial membrane, disrupting the cell membrane, and facilitating the accumulation of reactive oxygen species (ROS). Additionally, compound 4t showed remarkable anti-MRSA activity in vivo, demonstrating compound 4t could be developed as a potential candidate to combat MRSA infections.

Study on function evolution and coupling coordination degree of "Three Lives Space" in the upper reaches of Yangtze River in China.

Analyzing the functional evolution characteristics and coupling coordination of the "Three Lives Space" in the upper reaches of Yangtze River (URYR) is crucial for achieving high-quality, coordinated development and ecological protection in the region. Based on the panel data of the production function, living function, and ecological function of 31 cities in the URYR from 2010 to 2020, this study establishes the evaluation index system of the "Three Lives Space" function and analyzes its spatio-temporal evolution characteristics and spatial correlation by utilizing the coupling coordination degree model and spatial autocorrelation test. The results indicate that (1) the functional coupling coordination of 31 cities in the URYR exhibits a steady upward trend as a whole, which can be characterized by a sequence of stages, including the disordering decline in disorder, barely coordination, primary coordination, and intermediate coordination. (2) The 31 cities in the URYR have significant spatial agglomeration characteristics. Among them, most cities in Sichuan Province and Chongqing City have high-high gathering effects, and most cities in Guizhou Province and Yunnan Province have low-low gathering effects. Therefore, it is imperative to scientifically and rationally organize the production, living, and ecological space, collectively safeguard the crucial ecological barrier of the URYR, and promote its integrated development.

Identification and Verification of Hub Mitochondrial Dysfunction Genes in Osteoarthritis Based on Bioinformatics Analysis.

Objective: Age-related mitochondrial dysfunction and associated oxidative stress may contribute to the development of osteoarthritis. The aim of this study was to identify hub genes associated with mitochondrial dysfunction in osteoarthritis (OA) patients, helping predict the risk of OA, and revealing the mechanism of OA progression. Methods: OA expression data and mitochondrial dysfunction genes were downloaded from GEO (GSE55235, GSE82107, and GSE114007) and GeneCard databases. The differentially expressed mitochondrial dysfunction genes (DEMDFGs) between OA and control samples were screened. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes pathways were analyzed for DEMDFGs. The hub genes were determined by WGCNA and LASSO regression analysis. ROC curves manifested the diagnostic efficacy of each hub gene. A nomogram model was constructed and validated to predict OA risk. The expression of hub genes in OA and normal chondrocytes was verified by external datasets, qRT-PCR and western blotting. Results: A total of 31 DEMDFGs were identified, with 15 genes upregulated and 16 genes downregulated. GO functional enrichment analysis revealed that DEMDFGs were enriched in biological processes related to energy metabolism and cellular respiration. By employing weighted gene coexpression network analysis, we identified four distinct coexpression modules, among which the blue module exhibited the strongest correlation with OA. The intersection between DEMDFGs and this module yielded eight candidate genes. After LASSO analysis of the data, four hub genes (ACADL, CYBA, SLC19A2, and UCP2) were identified as potential biomarkers for OA. The expression levels of these four genes were externally validated in the GSE114007 dataset. And the biologically differential expression of these four genes has been verified in OA and normal chondrocytes. Moreover, the four hub genes had good sensitivity and specificity by ROC curve analysis, and the risk model constructed with these four genes showed promising performance. In conclusion, our study may provide novel mitochondrial dysfunction hub genes with potential clinical applications for understanding the pathology, diagnosis, and treatment of OA.

Recent advances of partial anammox by controlling nitrite supply in mainstream wastewater treatment through step-feed mode.

At present, the step-feed process is a very active branch in practical application of mainstream wastewater treatment, and the anammox technology empowers the sustainable development and in-depth research of step-feed process. This review provides a systematically inspection of the realization and application of partial anammox process through step-feed mode, with a particular focus on controlling nitrite supply for anammox. The characteristics and advantages of step-feed mode in traditional management are reviewed. The unique organics utilization strategy by step-feed and indispensable intermittent aeration mode creates advantages for achieving nitritation (NH4+ â†’ NO2-) and denitratation (NO3- â†’ NO2-), providing flexible combination possibility with anammox. Additionally, the lab- or pilot-scale control strategies with different forms of anammox, including nitritation/anammox, denitratation/anammox, and double-anammox (combined nitritation/anammox and denitratation/anammox), are summarized. Finally, future directions and application perspectives on leveraging the relationship between flocs and biofilm, nitritation and denitratation, and different strains to maximize the anammox proportion in N-removal are proposed.

Development of IL-17A inhibitor-induced atopic dermatitis-like rash in psoriasis patients: Insights into immune shift.

Cases of atopic dermatitis (AD)-like rash induced by IL-17A inhibitor secukinumab treatment (SI-AD) have been recently reported in psoriasis patients. To identify immune and inflammatory factors expression in SI-AD. A panel of 15 immune and inflammatory factors in peripheral blood samples from various groups, including patients with patients with SI-AD, psoriasis with secukinumab (S-stable), advanced psoriasis patients (Advanced) and healthy controls (HC). Interleukin-10 (IL-10), IL-4 and IL-17A were detected in skin tissue biopsy samples by immunohistochemistry and real-time quantitative polymerase chain reaction. The immunoglobulin E levels in the SI-AD patients exceeded normal values. The IL-10 levels in SI-AD patients were higher than those in S-stable patients, advanced patients and HC. The IL-4 levels in SI-AD patients were higher than that in S-stable patients and HC. The IL-17A levels in SI-AD patients were higher than those in advanced psoriasis patients and HC, but no significant differences were observed between SI-AD patients and S-stable patients. IL-10 and IL-4 levels were higher in AD-like rashes than in healthy skin, while IL-17A did not differ significantly between the two. Upon discontinuing secukinumab, and switching to oral cyclosporine, antihistamines, Janus kinase 1 inhibitor and topical glucocorticoids, SI-AD patients experienced significant improvement in their skin lesions. Upon reexamination, all 15 immune and inflammatory factors returned to normal levels. Immune shift from Th17 towards Th2 may occur in SI-AD, as indicated by abnormal expression of multiple immune and inflammatory factors observed in peripheral blood and skin tissues.

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study.

BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.