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STAT3 activates transcription of genes that regulate cell growth, differentiation, and survival of mammalian cells. Genetic deletion of Stat3 in T cells has been shown to abrogate Th17 differentiation, suggesting that STAT3 is a potential therapeutic target for Th17-mediated diseases. However, a major impediment to therapeutic targeting of intracellular proteins such as STAT3 is the lack of efficient methods for delivering STAT3 inhibitors into cells. In this study, we developed a novel antibody (SBT-100) comprised of the variable (V) region of a STAT3-specific heavy chain molecule and demonstrate that this 15 kDa STAT3-specific nanobody enters human and mouse cells, and induced suppression of STAT3 activation and lymphocyte proliferation in a concentration-dependent manner. To investigate whether SBT-100 would be effective in suppressing inflammation in vivo, we induced experimental autoimmune uveitis (EAU) in C57BL/6J mice by active immunization with peptide from the ocular autoantigen, interphotoreceptor retinoid binding protein (IRBP651-670). Analysis of the retina by fundoscopy, histological examination, or optical coherence tomography showed that treatment of the mice with SBT-100 suppressed uveitis by inhibiting expansion of pathogenic Th17 cells that mediate EAU. Electroretinographic (ERG) recordings of dark and light adapted a- and b-waves showed that SBT-100 treatment rescued mice from developing significant visual impairment observed in untreated EAU mice. Adoptive transfer of activated IRBP-specific T cells from untreated EAU mice induced EAU, while EAU was significantly attenuated in mice that received IRBP-specific T cells from SBT-100 treated mice. Taken together, these results demonstrate efficacy of SBT-100 in mice and suggests its therapeutic potential for human autoimmune diseases.

Interleukin-27 is constitutively secreted by microglia in the retina or brain, and upregulation of IL-27 during neuroinflammation suppresses encephalomyelitis and autoimmune uveitis. However, while IL-35 is structurally and functionally similar to IL-27, the intrinsic roles of IL-35 in CNS tissues are unknown. Thus, we generated IL-35/YFP-knock-in reporter mice (p35-KI) and demonstrated that photoreceptor neurons constitutively secrete IL-35, which might protect the retina from persistent low-grade inflammation that can impair photoreceptor functions. Furthermore, the p35-KI mouse, which is hemizygous at the il12a locus, develops more severe uveitis because of reduced IL-35 expression. Interestingly, onset and exacerbation of uveitis in p35-KI mice caused by extravasation of proinflammatory Th1/Th17 lymphocytes into the retina were preceded by a dramatic decrease of IL-35, attributable to massive death of photoreceptor cells. Thus, while inflammation-induced death of photoreceptors and loss of protective effects of IL-35 exacerbated uveitis, our data also suggest that constitutive production of IL-35 in the retina might have housekeeping functions that promote sterilization immunity in the neuroretina and maintain ocular immune privilege.

Purpose: We investigated the pathogenesis of idiopathic nephrotic syndrome (INS) by measuring the effects two specific miRNAs on Th2 cells in children with this disease.Methods: After informed consent, we enrolled 20 children with active INS before steroid initiation, 20 children with INS in remission after steroid therapy, and 20 age-matched healthy controls. Flow cytometry was used to measure the levels of Th2 cells and a cytometric bead array was used to measure the levels of IgE, interleukin (IL)−4, and IL-13. RT-PCR was used to measure the levels of miR-24 and miR-27 in CD4+TCD25− cells. PBMCs were isolated using Ficoll density gradient centrifugation, and transfected with different mimic or inhibitor miRNAs. RT-PCR was used to measure the expression of different RNAs, and flow cytometry was used to determine the percentage of Th2 cells.Results: Relative to healthy controls, children with active INS had higher percentages of Th2 cells (P < 0.05), but there was no significant difference in controls and children in remission. The plasma levels of IgE, IL-4, and IL-13 were significantly increased in children with active INS (P < 0.05). There were lower levels of miR-24 and miR-27 in children with active non-atopic INS (P < 0.05). Transfection experiments indicated that upregulation of each miRNA decreased the percentage of Th2 cells and the level of IL-4 (P < 0.05), and down-regulation of each miRNA had the opposite effects (P < 0.05).Conclusion: Children with active INS, with or without atopy, had higher levels of IgE, possibly related to their higher levels of IL-13 and IL-4 due to a drift toward Th2 cells. miR-24 and miR-27 suppressed the expression of Th2 cells and have a critical function regulating Th2 cell expression in INS.

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.

Exploration of new electron‐withdrawing building blocks plays a key role in the development of n‐type organic semiconductors. Herein, a strong electron‐withdrawing building block, dipyridyl‐fused quinoxalineimide (DPQI), was successfully designed and synthesized. Single‐crystal structure reveals that DPQI molecule possesses a completely planar backbone, which is beneficial for charge transport. For comparison, dibenzo‐fused quinoxalineimide (DBQI) was also synthesized. The frontier molecular orbital (FMO) energy levels downshift with the incorporation of nitrogen atoms onto the π‐conjugated backbone of quinoxalineimide. Two acceptor‐acceptor (or all‐acceptor) polymers P(BTI‐DBQI) and P(BTI‐DPQI) based on DBQI and DPQI were synthesized, respectively. Two polymers exhibit deep lowest‐unoccupied molecular orbital (LUMO) levels (~−3.5 eV). Additionally, P(BTI‐DPQI) exhibits unipolar n‐type charge transport with μe of 1.4×10−4 cm2 V−1 s−1 in the organic field‐effect transistors (OFET), which render them highly attractive for developing n‐type semiconductors device. This work demonstrates that DPQI is a promising building block for constructing n‐type polymer semiconductors. [ABSTRACT FROM AUTHOR]

To investigate the differences in visual perception between children with autism spectrum disorder (ASD) and typically developing (TD) children when watching different intention videos, and to explore the feasibility of machine learning algorithms in objectively distinguishing between ASD children and TD children. Methods A total of 58 children with ASD and 50 TD children were enrolled and were asked to watch the videos containing joint intention and non-joint intention, and the gaze duration and frequency in different areas of interest were used as original indicators to construct classifier-based models. The models were evaluated in terms of the indicators such as accuracy, sensitivity, and specificity. Results When using eight common classifiers, including support vector machine, linear discriminant analysis, decision tree, random forest, and K-nearest neighbors (with K values of 1, 3, 5, and 7), based on the original feature indicators, the highest classification accuracy achieved was 81.90%. A feature reconstruction approach with a decision tree classifier was used to further improve the accuracy of classification, and then the model showed the accuracy of 91.43%, the specificity of 89.80%, and the sensitivity of 92.86%, with an area under the receiver operating characteristic curve of 0.909 (P<0.001). Conclusions The machine learning model based on eye-tracking data can accurately distinguish ASD children from TD children, which provides a scientific basis for developing rapid and objective ASD screening tools. [ABSTRACT FROM AUTHOR]

Objective: A systematic review and meta‐analysis were conducted to evaluate the efficacy and safety of ablative laser combined with pulsed dye laser to treat pathological scars. Methods: A systematic literature review was conducted to identify all blind, randomized, controlled trials of ablative laser and pulsed dye laser for treating pathological scars. The databases PubMed, Embase, and Cochrane were used. All research on ablative laser combined with PDL in treating pathological scars with ablative laser or no treatment as controls were included in the meta‐analysis. The retrieved studies' reference lists were thoroughly examined. Results: POSAS and VSS were used as evaluation criteria in seven studies involving 189 patients. Effect of combined laser group therapy (−1.259 95% confidence interval, −1.515 to −1.003; p < 0.0001). The difference between the combined treatment and control groups was (−1.375; 95% CI, −1.727 to −1.023; p < 0.0001) and (−1.150; 95% CI, −1.523 to −0.777; p < 0.0001). Conclusions: Ablative laser combined with PDL is more effective and safer than ablative laser or PDL alone in the treatment of pathological scars. [ABSTRACT FROM AUTHOR]

Background: Striae Distensae (SD) is a common dermatological lesion. The mechanism of formation is unclear, the prevailing theory is mechanical pulling of the skin and hormonal changes. Traditional SD treatment methods include topical drugs, photoelectric therapy, stripping and others, but each has limitations. Stromal vascular fraction gel (SVF‐gel) is a filler physically prepared from granular fat, enriched with adipose‐derived stem cells (ADSCs) and extracellular matrix (ECM). A good effect in the treatment of neck lines, wounds, acne, and other aspects. SD formation and treatment goals are comparable to those of neck lines. In this study, SVF‐gel filling will be used to treat mature SD, and its effectiveness and safety will be discussed in detail. Methods: From December 2019 to June 2022, recruit patients who want to treat SD caused by obesity or pregnancy among those who have "autologous fat aspiration" to change their body shape. Preoperatively, the area to be treated for SD was marked, autologous fat aspiration was performed, and the aspirated fat was prepared as SVF‐gel and filled into the preoperatively marked SD. All patients had preoperative and postoperative follow‐up with planar photographs and VISIA skin analyzer photographs to assess surgical results and safety from subjective and objective perspectives. Results: A total of 36 patients were enrolled, with 31 of them successfully followed up on. The mean Global Aesthetic Improvement Scale (GAIS) score six months after surgery was 1.87 ± 0.03. At six months postoperatively, the overall patient satisfaction rate was 90%. The depth, area, and color of SD improved six months after surgery, and no serious complications occurred in any of the patients. Conclusions: SVF‐gel is a safe and effective method of improving mature SD and can be used as a clinical treatment option. [ABSTRACT FROM AUTHOR]

Deconstruction is an essential step of conversion of polysaccharides, and polysaccharide-degrading enzymes play a key role in this process. Although there is recent progress in the identification of these enzymes, the diversity and phylogenetic distribution of these enzymes in marine microorganisms remain largely unknown, hindering our understanding of the ecological roles of marine microorganisms in the ocean carbon cycle. Here, we studied the phylogenetic distribution of nine types of polysaccharide-degrading enzymes in marine bacterial genomes. First, we manually compiled a reference sequence database containing 961 experimentally verified enzymes. With this reference database, we annotated 9,335 enzyme sequences from 2,182 high-quality marine bacterial genomes, revealing extended distribution for six enzymes at the phylum level and for all nine enzymes at lower taxonomic levels. Next, phylogenetic analyses revealed intra-clade diversity in the encoding potentials and phylogenetic conservation of a few enzymes at the genus level. Lastly, our analyses revealed correlations between enzymes, with alginate lyases demonstrating the most extensive correlations with others. Intriguingly, chitinases showed negative correlations with cellulases, alginate lyases, and agarases in a few genera. This result suggested that intra-genus lifestyle differentiation occurred many times in marine bacteria and that the utilization of polysaccharides may act as an important driver in the recent ecological differentiation of a few lineages. This study expanded our knowledge of the phylogenetic distribution of polysaccharide enzymes and provided insights into the ecological differentiation of marine bacteria.

Chromosome replication is an essential process for cell division. The mode of chromosome replication has important impacts on the structure of the chromosome and replication speed.

We developed and evaluated an intervention that teaches reading comprehension via expository text structure training to second graders in urban public schools at risk for academic failure. Fifty lessons on 5 basic text structures (sequence, comparison, causation, description, and problem-solution) were embedded in a social studies curriculum that focused on U.S. historical communities. Second-grade classrooms were randomly assigned to 1 of 3 experimental conditions: the intervention, a comparison program that focused on the social studies content and did not include text structure training, and a no-instruction control. Sixteen classrooms (N = 258) completed the study. The performance of the intervention group was higher than that of the other 2 groups on reading comprehension measures based on written summaries, demonstrating the effectiveness of the intervention. On social studies content measures, the intervention and the content groups showed higher performance than the control group, indicating that embedding the text-structure training did not lessen the amount of social studies content acquired. The study confirms previous findings and extends our earlier work by showing that all 5 basic text structures can be taught to second graders effectively within the academic year. Robust transfer effects were found on typical reading comprehension tasks (sentence completion, questions) when the text continued to be well structured, and there was also evidence of transfer to authentic (ill-structured) text.