OsCSN2 orchestrates Oryza sativa L. growth and development through modulation of the GA and BR pathways.

The COP9 signalosome (CSN) is a conserved protein complex found in higher eukaryotes, consisting of eight subunits, and it plays a crucial role in regulating various processes of plant growth and development. Among these subunits, CSN2 is one of the most conserved components within the COP9 signalosome complex. Despite its prior identification in other species, its specific function in Oryza sativa L. (Rice) has remained poorly understood. In this study, we investigated the role of CSN2 in rice using gene editing CRISPR/Cas9 technology and overexpression techniques. We created two types of mutants: the oscsn2 mutant and the OsCSN2-OE mutant, both in the background of rice, and also generated point mutants of OsCSN2 (OsCSN2K64E, OsCSN2K67E, OsCSN2K71E and OsCSN2K104E) to further explore the regulatory function of OsCSN2. Phenotypic observation and gene expression analysis were conducted on plants from the generated mutants, tracking their growth from the seedling to the heading stages. The results showed that the loss and modification of OsCSN2 had limited effects on plant growth and development during the early stages of both the wild-type and mutant plants. However, as the plants grew to 60 days, significant differences emerged. The OsCSN2 point mutants exhibited increased tillering compared to the OsCSN2-OE mutant plants, which were already at the tillering stage. On the other hand, the OsCSN2 point mutant had already progressed to the heading and flowering stages, with the shorter plants. These results, along with functional predictions of the OsCSN2 protein, indicated that changes in the 64th, 67th, 71st, and 104th amino acids of OsCSN2 affected its ubiquitination site, influencing the ubiquitination function of CSN and consequently impacting the degradation of the DELLA protein SLR1. Taken together, it can be speculated that OsCSN2 plays a key role in GA and BR pathways by influencing the functional regulation of the transcription factor SLR1 in CSN, thereby affecting the growth and development of rice and the number of tillers.

Upadacitinib in Rheumatoid Arthritis and Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs: Efficacy and Safety Through 5 Years (SELECT-NEXT).

OBJECTIVE: To report 5-year efficacy and safety of upadacitinib (UPA) in rheumatoid arthritis (RA) from the phase III long-term extension (LTE) of SELECT-NEXT. METHODS: Patients on stable conventional synthetic disease-modifying antirheumatic drugs were randomized to UPA 15 mg once daily (QD), UPA 30 mg QD, or placebo for 12 weeks. Following this, placebo-randomized patients were switched to UPA 15 mg QD or UPA 30 mg QD in the LTE; UPA-randomized patients continued their original dose. Blinding remained until dose switching from UPA 30 mg QD to UPA 15 mg QD because of approval of UPA 15 mg QD; the earliest switch occurred at week 168. Efficacy (as observed) and treatment-emergent adverse events (TEAEs) are reported through 5 years. RESULTS: Overall, 611 (92%) randomized patients entered the LTE; 271 (44%) discontinued the study drug by 5 years, primarily because of adverse events (16%). Clinical outcomes improved or were maintained at 5 years; 51% and 43% of patients achieved Clinical Disease Activity Index remission and 75% and 66% achieved Disease Activity Score in 28 joints based on C-reactive protein < 2.6 among those initially randomized to UPA 15 mg QD and UPA 30 mg QD, respectively. Proportions of patients achieving ≥ 20%/50%/70% improvement in American College of Rheumatology criteria responses increased from week 60 through 5 years. Results were similar regardless of initial randomization to UPA or placebo. TEAEs, including TEAEs of special interest, were consistent with earlier analyses and other SELECT studies. Malignancies (excluding nonmelanoma skin cancer), major adverse cardiovascular events, and venous thromboembolic events were reported infrequently. No new safety signals were observed. CONCLUSION: The 5-year benefit-risk profile for UPA in RA remains favorable. (SELECT-NEXT; ClinicalTrials.gov: NCT02675426).

[Type â £ Hiatal Hernia With Severe Anemia as the Main Clinical Manifestation:Report of One Case].

Type Ⅳ hiatal hernia with a high risk usually presents sudden or suddenly worsening epigastric pain,vomiting,and dysphagia.It is not conducive to early diagnosis and treatment when symptoms are atypical.Type Ⅳ hiatal hernia with severe anemia is rare.This article reports an atypical case of type Ⅳ hiatal hernia with melena and severe anemia as the main manifestations,aiming to improve clinicians' identification of the atypical clinical presentations of type Ⅳ hiatal hernia.

School bullying and self-efficacy in adolescence: A meta-analysis.

INTRODUCTION: Given that literature has examined the relation between school bullying and self-efficacy, findings have been mixed. This meta-analysis aimed to clarify whether school bullying is associated with adolescents' self-efficacy, a key component of social information processing essential for the evaluation of potential behavioral responses. We further examined moderators associated with heterogeneity in the above relation, including participant roles, types of school bullying, types of self-efficacy, and demographic factors (e.g., age, gender, and cultural background). METHOD: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement for searching, identifying, and screening eligible articles. A total of 53 articles (N = 71,661; Mage = 12.69 years) were included (50 in English and 3 in Chinese). Articles were coded by two graduate-level coders independently with a high inter-rater reliability (97.12%). RESULTS: The results showed that (1) school bullying was negatively associated with self-efficacy (r = -.07, p < .001) among adolescents, and (2) the above relation varied by participant role (e.g., bullies, victims, bully-victims, and defenders), types of school bullying (e.g., traditional bullying, cyberbullying, and both), and types of self-efficacy (e.g., general and domain-specific self-efficacy). FINDINGS: The findings highlight that school bullying is associated with disruptive cognitive processing in adolescence, low self-efficacy in particular, and the heterogeneity should be considered to fully understand the association between school bullying and self-efficacy among adolescents.

The Development of Internalizing and Externalizing Problems in Primary School: Contributions of Executive Function and Social Competence.

This study sought to elucidate the contributions of inferior executive function and social competence to the development of internalizing and externalizing problems in primary school. Children (N = 1,115), on average 5.36 years old in first grade, were followed across primary school with measures of multi-method and multi-informant. Results of growth modeling demonstrated that poor executive function in first grade predicted high levels of both problems and a low rate of decline in externalizing problems over time, independent of the co-occurrence of both problems. Moreover, the impact of poor executive function on behavioral problems may be dependent on its association with disruptive social competence. Findings highlighted the interrelations of risk factors to understanding the development of behavioral problems in primary school.

Aspergillus fumigatus Induces the Release of IL-8 and MCP-1 by Activating Nuclear Transcription Through Dectin-1 and CR3 Receptors in Alveolar Epithelial Cells.

Invasive pulmonary aspergillosis induced by the pathogenic fungus Aspergillus fumigatus is one of the common fatal complications in immunocompromised patients. Lung epithelial cells play an important role in host immune defense against A. fumigatus. However, the interaction between lung epithelial cells and A. fumigatus conidia is not fully understood. In this study, we used the swollen conidia of A. fumigatus to stimulate the type II lung epithelial A549 cells. Results showed that swollen conidia could significantly increase RNA transcription and protein expression of interleukin 8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1), but not TNF-α in A549 cells in a time-dependent manner. Moreover, serum opsonization was able to improve the release of inflammatory factors induced by swollen conidia. Blocking of the dectin-1 or CR3 receptors, or both simultaneously, in the A549 cells could decrease the release of IL-8 and MCP-1. Additionally, blocking dectin-1 or CR3 could inhibit the transcription of nuclear factor NF-κB that was activated by swollen conidia. Here we reported for the first time that dectin-1 and CR3 receptors in A549 cells mediate the release of pro-inflammatory factors IL-8 and MCP-1 induced by A. fumigatus.

Bivariate genome-wide association study of the growth plasticity of Staphylococcus aureus in coculture with Escherichia coli.

Phenotypic plasticity is the capacity to change the phenotype in response to different environments without alteration of the genotype. Despite sufficient evidence that microorganisms have a major role in the fitness and sickness of eukaryotes, there has been little research regarding microbial phenotypic plasticity. In this study, 45 strains of Staphylococcus aureus were grown for 12 days in both monoculture and in coculture with the same strain of Escherichia coli to create a competitive environment. Cell abundance was determined by quantitative PCR every 24 h, and growth curves of each S. aureus strain under the two sets of conditions were generated. Combined with whole-genome resequencing data, bivariate genome-wide association study (GWAS) was performed to analyze the growth plasticity of S. aureus in coculture. Finally, 20 significant single-nucleotide polymorphisms (eight annotated, seven unannotated, and five non-coding regions) were obtained, which may affect the competitive growth of S. aureus. This study advances genome-wide bacterial growth plasticity research and demonstrates the potential of bivariate GWAS for bacterial phenotypic plasticity research. KEY POINTS: • Growth plasticity of S. aureus was analyzed by bivariate GWAS. • Twenty significant SNPs may affect the growth plasticity of S. aureus.

Improved mitochondrial targeting effect of HPMA copolymer by SS20 peptide mediation and nonendocytosis pathway.

Mitochondrion plays an important role in executing cell programmed death pathway. Therefore, drugs designed to target mitochondria are supposed to make superior contributions to cancer therapy. However, the problem that drugs or drug delivery systems being sequestrated in endosomes/lysosomes needs to be solved for effective drug delivery. Here, mitochondrial targeting and nonendocytic cell entry peptide SS20 modified HPMA copolymer (P-FITC-SS20) was synthesized. With SS20 peptide modification, the uptake behavior of HPMA copolymers changed remarkably compared with unmodified ones. The internalization of P-FITC-SS20 was not influenced by endocytic inhibitors and temperature. Further, the internalized copolymers were not trapped in endosomes/lysosomes. Although cellular uptake of HPMA copolymer was decreased after SS20 peptide modification, SS20 peptide significantly improved mitochondrial accumulation of HPMA copolymers due to its outstanding mitochondrial targeting ability. Moreover, owing to lower susceptibility to macrophagocyte in blood, P-SS20-Cy5 showed longer blood circulation time and enhanced tumor accumulation. The current study validated that SS20 peptide modification is a promising strategy for mitochondrial targeting drug delivery systems and can be further applied to mitochondria associated diseases to improve therapeutic efficacy.

Gliotoxin destructs the pulmonary epithelium barrier function by reducing cofilin oligomer formation to promote the dissolution of actin stress fibers.

The destruction of pulmonary epithelium is a major feature of lung diseases caused by the fungal pathogen Aspergillus fumigatus (A. fumigatus). Gliotoxin, a major mycotoxin of A. fumigatus, is widely postulated to be associated with the tissue invasion. However, the mechanism is unclear. In this study, we first discovered that cofilin, a regulator of actin dynamics in the pulmonary epithelial cells, existed mainly in the form of oligomer, which kept it unable to depolymerize actin filaments. Gliotoxin could reduce the formation of cofilin oligomer and promote the release of active cofilin monomer by regulating cofilin phosphorylation balance. Then, the active cofilin induced the dissolution of actin stress fibers to result in the disruption of pulmonary epithelium barrier function. Collectively, our study revealed a novel mechanism of gliotoxin destructing lung epithelium barrier function and for the first time indicated the role of cofilin oligomer in this process.

The effects of sclerostin antibody plus parathyroid hormone (1-34) on bone formation in ovariectomized rats.

Previous studies have demonstrated the effects of sclerostin antibody (Scl-Ab) and parathyroid hormone (1-34, PTH) on healing in osteoporosis; however, reports about the combined effects of Scl-Ab plus PTH on osteoporosis are limited. This study was designed to investigate the impact of combined treatment with Scl-Ab and PTH on osteoporosis healing in ovariectomized (OVX) rats. After bilateral ovariectomy, 12 weeks were allowed to pass for the establishment of standard conditions for osteoporosis in animal models. The rats then randomly received a vehicle (control), Scl-Ab (25 mg/kg body weight, twice weekly), PTH (60 µg/kg, three times per week) or PTH plus Scl-Ab until death at 12 weeks. The blood and distal femurs of the rats were harvested for evaluation. The results of treatment for osteoporosis were evaluated by serum analysis, histology, microcomputed tomography (micro-CT) and biomechanical tests. Results from this study indicated that PTH + Scl-Ab had stronger effects on the prevention and treatment of osteoporosis than either of the monotherapies in OVX rats. The PTH + Scl-Ab produced the strongest effects on bone volume fraction (BV/TV), bone trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular spacing (Tb.Sp), bone mineral density (BMD) and strength of distal femurs and increased the levels of procollagen type I N­terminal propeptide (PINP) and osteocalcin. In contrast, monotherapy with PTH or Scl-Ab showed no differences between treated groups in the assessment of the metaphysis of contralateral femurs by histology, serum, biomechanical tests and micro-CT. These results seem to indicate that Scl-Ab plus PTH has an additive effect on osteoporosis in OVX rats.

Representation of Maximally Regular Textures in Human Visual Cortex.

Naturalistic textures with an intermediate degree of statistical regularity can capture key structural features of natural images (Freeman and Simoncelli, 2011). V2 and later visual areas are sensitive to these features, while primary visual cortex is not (Freeman et al., 2013). Here we expand on this work by investigating a class of textures that have maximal formal regularity, the 17 crystallographic wallpaper groups (Fedorov, 1891). We used texture stimuli from four of the groups that differ in the maximum order of rotation symmetry they contain, and measured neural responses in human participants using functional MRI and high-density EEG. We found that cortical area V3 has a parametric representation of the rotation symmetries in the textures that is not present in either V1 or V2, the first discovery of a stimulus property that differentiates processing in V3 from that of lower-level areas. Parametric responses were also seen in higher-order ventral stream areas V4, VO1, and lateral occipital complex (LOC), but not in dorsal stream areas. The parametric response pattern was replicated in the EEG data, and source localization indicated that responses in V3 and V4 lead responses in LOC, which is consistent with a feedforward mechanism. Finally, we presented our stimuli to four well developed feedforward models and found that none of them were able to account for our results. Our results highlight structural regularity as an important stimulus dimension for distinguishing the early stages of visual processing, and suggest a previously unrecognized role for V3 in the visual form-processing hierarchy. Significance statement: Hierarchical processing is a fundamental organizing principle in visual neuroscience, with each successive processing stage being sensitive to increasingly complex stimulus properties. Here, we probe the encoding hierarchy in human visual cortex using a class of visual textures--wallpaper patterns--that are maximally regular. Through a combination of fMRI and EEG source imaging, we find specific responses to texture regularity that depend parametrically on the maximum order of rotation symmetry in the textures. These parametric responses are seen in several areas of the ventral visual processing stream, as well as in area V3, but not in V1 or V2. This is the first demonstration of a stimulus property that differentiates processing in V3 from that of lower-level visual areas.

Dynamics of microbial community during the extremely long-term fermentation process of a traditional soy sauce.

BACKGROUND: Soy sauce produced by long-term natural fermentation is a traditional specialty in Asia, with a reputation for superior quality and rich flavour. In this study, both culture-dependent and culture-independent approaches were used to investigate the microbial diversity and community dynamics during an extremely long-term (up to 4 years) natural fermentation of Xianshi Soy Sauce, a national intangible cultural heritage. RESULTS: Genera of Bacillus, Aspergillus and Cladosporium were detected by both methods above. The relative abundance of the genera Bacillus and Weissella was significantly higher in the late stage than in the early one, while the genera Klebsiella and Shimwellia were opposite (P < 0.05). For microbial community structure, subsequent analyses showed that obvious changes occurred with fermentation time, while there was a fair homogeneousness among samples of the same year, especially during the late fermentation stage. CONCLUSIONS: The clustering analysis tended to separate the fermented mashes of the 4th year from the earlier stages, suggesting the necessity of the long fermentation period for developing distinctive microbiota and characteristic quality-related compounds. This is the first report to explore the temporal changes in microbial dynamics over a period of 4 years in traditional fermentation of soy sauce, and this work illustrated the importance of isolation of appropriate strains to be used as starter cultures in brewing processes. © 2016 Society of Chemical Industry.

Direct Cytoplasmic Delivery and Nuclear Targeting Delivery of HPMA-MT Conjugates in a Microtubules Dependent Fashion.

As the hearts of tumor cells, the nucleus is the ultimate target of many chemotherapeutic agents and genes. However, nuclear drug delivery is always hampered by multiple intracellular obstacles, such as low efficiency of lysosome escape and insufficient nuclear trafficking. Herein, an N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-based drug delivery system was designed, which could achieve direct cytoplasmic delivery by a nonendocytic pathway and transport into the nucleus in a microtubules dependent fashion. A special targeting peptide (MT), derived from an endogenic parathyroid hormone-related protein, was conjugated to the polymer backbone, which could accumulate into the nucleus a by microtubule-mediated pathway. The in vitro studies found that low temperature and NaN3 could not influence the cell internalization of the conjugates. Besides, no obvious overlay of the conjugates with lysosome demonstrated that the polymer conjugates could enter the tumor cell cytoplasm by a nonendocytic pathway, thus avoiding the drug degradation in the lysosome. Furthermore, after suppression of the microtubule dynamics with microtubule stabilizing docetaxel (DTX) and destabilizing nocodazole (Noc), the nuclear accumulation of polymeric conjugates was significantly inhibited. Living cells fluorescence recovery after photobleaching study found that the nuclear import rate of conjugates was 2-fold faster compared with the DTX and Noc treated groups. These results demonstrated that the conjugates transported into the nucleus in a microtubules dependent way. Therefore, in addition to direct cytoplasmic delivery, our peptide conjugated polymeric platform could simultaneously mediate nuclear drug accumulation, which may open a new path for further intracellular genes/peptides delivery.

Association of C-reactive protein, tumor necrosis factor-alpha, and interleukin-6 with chronic kidney disease.

BACKGROUND: We studied the association of inflammatory biomarkers including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) with chronic kidney disease (CKD). METHODS: We conducted a case-control study among 201 CKD patients and 201 community-based controls in the greater New Orleans area. CKD was defined as estimated-glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) or albuminuria ≥30 mg/24-h. Serum CRP, TNF-α, and IL-6 were measured using standard methods. Multivariable regression models were used to examine associations between the inflammatory biomarkers and CKD adjusting for important CKD risk factors, history of cardiovascular disease, and use of antihypertensive, antidiabetic, and lipid-lowering agents and aspirin. RESULTS: The multivariable-adjusted medians (interquartile-range) were 2.91 (1.47, 5.24) mg/L in patients with CKD vs. 1.91 (0.99, 3.79) mg/L in controls without CKD (p = 0.39 for group difference) for CRP; 1.86 (1.51, 2.63) pg/mL vs. 1.26 (1.01, 1.98) pg/mL (p < 0.0001) for TNF-α; and 2.53 (1.49, 4.42) pg/mL vs. 1.39 (0.95, 2.15) pg/mL (p = 0.04) for IL-6, respectively. Compared to the lowest tertile, the highest tertile of TNF-α (OR 7.1, 95% CI 3.2 to 15.5) and IL-6 (OR 2.5, 95% CI 1.1 to 5.5) were significantly associated with higher odds of CKD in multivariable-adjusted models. Additionally, higher TNF-α and IL-6 were independently and significantly associated with lower eGFR and higher albuminuria. CONCLUSIONS: Our data suggest that TNF-α and IL-6, but not CRP, are associated with the prevalence and severity of CKD, independent from established CKD risk factors, history of cardiovascular disease, and use of antihypertensive, antidiabetic, and lipid-lowering agents and aspirin.

Effects of low-carbohydrate and low-fat diets: a randomized trial.

BACKGROUND: Low-carbohydrate diets are popular for weight loss, but their cardiovascular effects have not been well-studied, particularly in diverse populations. OBJECTIVE: To examine the effects of a low-carbohydrate diet compared with a low-fat diet on body weight and cardiovascular risk factors. DESIGN: A randomized, parallel-group trial. (ClinicalTrials.gov: NCT00609271). SETTING: A large academic medical center. PARTICIPANTS: 148 men and women without clinical cardiovascular disease and diabetes. INTERVENTION: A low-carbohydrate (<40 g/d) or low-fat (<30% of daily energy intake from total fat [<7% saturated fat]) diet. Both groups received dietary counseling at regular intervals throughout the trial. MEASUREMENTS: Data on weight, cardiovascular risk factors, and dietary composition were collected at 0, 3, 6, and 12 months. RESULTS: Sixty participants (82%) in the low-fat group and 59 (79%) in the low-carbohydrate group completed the intervention. At 12 months, participants on the low-carbohydrate diet had greater decreases in weight (mean difference in change, -3.5 kg [95% CI, -5.6 to -1.4 kg]; P = 0.002), fat mass (mean difference in change, -1.5% [CI, -2.6% to -0.4%]; P = 0.011), ratio of total-high-density lipoprotein (HDL) cholesterol (mean difference in change, -0.44 [CI, -0.71 to -0.16]; P = 0.002), and triglyceride level (mean difference in change, -0.16 mmol/L [-14.1 mg/dL] [CI, -0.31 to -0.01 mmol/L {-27.4 to -0.8 mg/dL}]; P = 0.038) and greater increases in HDL cholesterol level (mean difference in change, 0.18 mmol/L [7.0 mg/dL] [CI, 0.08 to 0.28 mmol/L {3.0 to 11.0 mg/dL}]; P < 0.001) than those on the low-fat diet. LIMITATION: Lack of clinical cardiovascular disease end points. CONCLUSION: The low-carbohydrate diet was more effective for weight loss and cardiovascular risk factor reduction than the low-fat diet. Restricting carbohydrate may be an option for persons seeking to lose weight and reduce cardiovascular risk factors. PRIMARY FUNDING SOURCE: National Institutes of Health.

Exposure image correction of electrical equipment nameplate based on the LMPEC algorithm.

An optimization algorithm based on the LMPEC algorithm is proposed to rectify the nameplate image to address the problem that overexposure and underexposure of the nameplate image of electrical equipment will make subsequent nameplate recognition difficult. In the network structure, the PS-UNet++ network is based on the sub-pixel convolution upsampling module, and the UNet++ network is constructed as the feature extraction sub-network of the optimization algorithm to extract more detailed information from the model. Smooth L1 loss is substituted for L1 loss in the loss function to prevent model oscillation. In addition, to increase the robustness of the model, an improved method built on the multi-scale training method is applied. The experimental results indicate that, among all comparison algorithms, the optimized algorithm performs the best on the data set of electrical equipment nameplate exposure the experimenter generated. Compared to the original LMPEC algorithm, the SSIM, PSNR, and PI image evaluation indices are enhanced by 5.6%, 5.1%, and 7.96%, respectively.

Safety and Efficacy of Upadacitinib in Patients with Rheumatoid Arthritis Refractory to Biologic DMARDs: Results Through Week 216 from the SELECT-CHOICE Study.

INTRODUCTION: The safety and efficacy of upadacitinib 15 mg (UPA15) through week 216 was evaluated in patients with rheumatoid arthritis (RA) from the long-term extension (LTE) of the phase 3 SELECT-CHOICE study. METHODS: Patients with RA refractory to biologic disease-modifying antirheumatic drugs (bDMARDs) were randomized to UPA15 or abatacept (ABA) for 24 weeks. During the open-label LTE, patients on ABA switched to UPA15 at week 24, and those on UPA15 continued treatment. The safety and efficacy of continuous UPA15, and ABA to UPA15, are summarized through week 216. RESULTS: The LTE was comprised of 91.4% (n = 277/303) of patients that initially received UPA15, and 89.6% (n = 277/309) that initially received ABA. Of patients on UPA15 in the LTE (n = 547), 28.3% (n = 155/547) discontinued the study drug by week 216. Relative to other adverse events of special interest, and largely consistent with previous findings at week 24, higher rates of serious infection, COVID-19, herpes zoster, and elevated creatine phosphokinase were reported, while rates of malignancy excluding nonmelanoma skin cancer (NMSC), NMSC, major adverse cardiovascular event (MACE), and venous thromboembolism (VTE) were low. Long-term safety data with UPA through week 216 aligned with previous observations and no new safety risks were identified, including in patients who switched from ABA to UPA15. Proportions of patients achieving 28-joint disease activity score based on C-reactive protein (DAS28[CRP]) < 2.6/ ≤ 3.2, clinical disease activity index (CDAI) and simple disease activity index (SDAI) low disease activity/remission, ≥ 20%/50%/70% improvement in the American College of Rheumatology (ACR20/50/70) response criteria, and Boolean remission were maintained or improved with UPA15 through week 216. Improvements in the Health Assessment Questionnaire-Disability Index (HAQ-DI), patient's assessment of pain, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were also maintained or improved with UPA15 through week 216. Across all efficacy endpoints, similar results were observed in patients who switched from ABA to UPA15 versus continuous UPA15. Patients with an inadequate response to ≥ 1 prior tumor necrosis factor (TNF) inhibitor (UPA15: n = 263/303, 86.8%; ABA to UPA15: n = 273/309, 88.3%) showed similar responses to the total population. CONCLUSIONS: The long-term safety profile of UPA was consistent with previous findings and the broader RA clinical program. Compared to the primary analyses at week 24, efficacy responses were maintained or further improved with UPA15 through week 216 in patients with RA. Trial registration, ClinicalTrials.gov identifier: NCT03086343.

A long-term study looked at a drug named upadacitinib to treat people with rheumatoid arthritis (RA), a disease that causes joint pain and damage. The study included patients whose RA was not improved by other injectable medicines. The study compared upadacitinib with another drug called abatacept. After 24 weeks, patients who were taking abatacept switched to upadacitinib, and patients taking upadacitinib continued on upadacitinib treatment for over 4 years. The researchers looked at how well the treatments worked over the long-term and if there were any side effects. The side effects with upadacitinib treatment in this long-term study were similar to side effects reported in previous studies with upadacitinib. The researchers also found that upadacitinib helped to lessen the symptoms of RA over time and helped patients complete their daily activities and reduced their pain and tiredness. This was true for patients who switched from abatacept to upadacitinib after 24 weeks and for patients who took upadacitinib from the start of the study. Patients who had not responded to other medicines also had similar improvements with upadacitinib. In conclusion, upadacitinib can help people with RA over the long term and no new safety risks were found.

Cloning of the Arabidopsis SMAP2 promoter and analysis of its expression activity.

The SMALL ACIDIC PROTEIN (SMAP) gene is evolutionarily indispensable for organisms. There are two copies of the SMAP gene in the Arabidopsis thaliana genome, namely, SMAP1 and SMAP2. The function of SMAP2 is similar to that of SMAP1, and both can mediate 2,4-D responses in the root of Arabidopsis. This study cloned the AtSMAP2 genetic promoter sequence. Two promoter fragments of different lengths were designed according to the distribution of their cis-acting elements, and the corresponding ß- glucuronidase (GUS) expression vector was constructed. The expression activity of promoters of two lengths, 1993 bp and 997 bp, was studied by the genetic transformation in Arabidopsis. The prediction results of cis-acting elements in the promoter show that there are many hormone response elements in 997 bp, such as three abscisic acid response elements ABRE, gibberellin response elements P-box and GARE-motif and auxin response element AuxRR-core. Through GUS histochemical staining and qRT‒PCR analysis, it was found that the higher promoter activity of PAtSMAP2-997, compared to PAtSMAP2-1993, drove the expression of GUS genes at higher levels in Arabidopsis, especially in the root system. The results provide an important basis for subsequent studies on the regulation of AtSMAP2 gene expression and biological functions.

Distinguishing schizophrenia and bipolar disorder through a Multiclass Classification model based on multimodal neuroimaging data.

This study aimed to identify neural biomarkers for schizophrenia (SZ) and bipolar disorder (BP) by analyzing multimodal neuroimaging. Utilizing data from structural magnetic resonance imaging (sMRI), diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI), multiclass classification models were created for SZ, BP, and healthy controls (HC). A total of 113 participants (BP: 31, SZ: 39, and HC: 43) were recruited under strict enrollment control, from which 272, 200, and 1875 features were extracted from sMRI, DTI, and rs-fMRI data, respectively. A support vector machine (SVM) with recursive feature elimination (RFE) was employed to build the models using a one-against-one approach and leave-one-out cross-validation, achieving a classification accuracy of 70.8%. The most discriminative features were primarily from rs-fMRI, along with significant findings in sMRI and DTI. Key biomarkers identified included the increased thickness of the left cuneus cortex and decreased regional functional connectivity strength (rFCS) in the left supramarginal gyrus as shared indicators for BP and SZ. Additionally, decreased fractional anisotropy in the left superior fronto-occipital fasciculus was suggested as specific to BP, while decreased rFCS in the left inferior parietal area might serve as a specific biomarker for SZ. These findings underscore the potential of multimodal neuroimaging in distinguishing between BP and SZ and contribute to the understanding of their neural underpinnings.

Image-Based Stability Quantification.

Quantitative evaluation of human stability using foot pressure/force measurement hardware and motion capture (mocap) technology is expensive, time consuming, and restricted to the laboratory. We propose a novel image-based method to estimate three key components for stability computation: Center of Mass (CoM), Base of Support (BoS), and Center of Pressure (CoP). Furthermore, we quantitatively validate our image-based methods for computing two classic stability measures, CoMtoCoP and CoMtoBoS distances, against values generated directly from laboratory-based sensor output (ground truth) using a publicly available, multi-modality (mocap, foot pressure, two-view videos), ten-subject human motion dataset. Using Leave One Subject Out (LOSO) cross-validation, experimental results show: 1) our image-based CoM estimation method (CoMNet) consistently outperforms state-of-the-art inertial sensor-based CoM estimation techniques; 2) stability computed by our image-based method combined with insole foot pressure sensor data produces consistent, strong, and statistically significant correlation with ground truth stability measures (CoMtoCoP r = 0.79 p < 0.001, CoMtoBoS r = 0.75 p < 0.001); 3) our fully image-based estimation of stability produces consistent, positive, and statistically significant correlation on the two stability metrics (CoMtoCoP r = 0.31 p < 0.001, CoMtoBoS r = 0.22 p < 0.043). Our study provides promising quantitative evidence for the feasibility of image-based stability evaluation in natural environments.