Human umbilical cord blood mesenchymal stem cells mediate microglia activation and improve anxiety-like behavior in MIA-induced offspring of schizophrenic rats.

Current treatments for schizophrenia (SCZ) remain largely ineffective in one-third of patients. Recent studies using stem cell therapy show a close relationship between stem cell immunomodulatory function and neuroinflammation in SCZ. To better investigate the efficacy of stem cell therapy for SCZ, human umbilical cord blood mesenchymal stem cells (hUC-MSC) with powerful immunomodulatory effects were administered to rats via the tail vein (once a week for 5 consecutive weeks starting from the weaning period) using a maternal immune activation (MIA) rodent model. Open field, PPI, Western blotting, Q-PCR, and immunofluorescence were used to assess the biological effects of repeated tail vein injections of hUC-MSC in offspring rats following the MIA model of SCZ. The results indicated that offspring of MIA rats exhibited schizophrenia-like (SCZ-like) anxiety behavior, with observed microglial activation triggering neuroinflammation. Furthermore, levels of IBA1, HMGB1, and PSD95 were significantly up-regulated, while SYP was significantly down-regulated. It is suggested that hUCB-MSCs may act through HMGB1, Iba1, PSD95, and related pathway molecules to alleviate neuroinflammation and repair synaptic damage by regulating the activity state of microglia. Consequently, this could improve the abnormal behavior observed in MIA offspring rats.

Investigating amplitude of low-frequency fluctuation and possible links with cognitive impairment in childhood and adolescence onset schizophrenia: a correlation study.

Background: Cognitive impairment (CI) is a distinctive characteristic of schizophrenia, with evidence suggesting that childhood and adolescence onset schizophrenia (CAOS), representing severe but rare forms of schizophrenia, share continuity with adult-onset conditions. While relationships between altered brain function and CI have been identified in adults with schizophrenia, the extent of brain function abnormalities in CAOS remains largely unknown. In this study, we employed resting-state functional magnetic resonance imaging (rs-fMRI) to investigate functional alterations in brain areas among patients with CAOS. To assess CI across multiple cognitive domains, we utilized the Stroop Color and Word Tests (SCWT) and MATRICS Consensus Cognitive Battery (MCCB) tests. Our objective was to explore the associations between functional CI and the amplitude of low-frequency fluctuation (ALFF) levels in these patients. Methods: We enrolled 50 patients diagnosed with CAOS and 33 healthy controls (HCs) matched for sex and age. Cognitive functions were assessed using the MCCB and SCWT methods. Rs-fMRI data were acquired using gradient-echo echo-planar imaging sequences. Voxel-based ALFF group maps were compared through two-sample t-tests in SPM8. Subsequently, correlation analyses were conducted to identify associations between ALFF levels and cognitive scores. Results: In comparison to HCs, patients exhibited significantly increased ALFF levels in the right fusiform gyrus, frontal lobe, and caudate, as well as the left frontal lobe and caudate. Conversely, reduced ALFF levels were observed in the temporal and left medial frontal lobes. Significant differences were identified between HCs and patients in terms of total cognitive scores, ALFF levels, and domain scores. All test scores were decreased, except for TMA. Correlation analyses between ALFF levels and cognitive functions in patients with CAOS differed from those in HCs. Pearson correlation analyses revealed positive associations between Brief Visuospatial Memory Test - Revised (BVMT-R) scores and ALFF levels in the left medial frontal gyrus. Digital Span Test (DST) scores were negatively correlated with ALFF levels in the right caudate, and Maze Test values were negatively correlated with levels in the left caudate. However, Pearson correlation analyses in HCs indicated that color and Hopkins Verbal Learning Test (HVLT-R) scores positively correlated with ALFF levels in the left frontal lobe, while color-word and symbol coding scores negatively correlated with levels in the right caudate. Conclusions: Altered ALFF levels in the brain may be linked to cognitive impairment (CI) in patients with CAOS. We highlighted the pathophysiology of schizophrenia and provide imaging evidence that could potentially aid in the diagnosis of CAOS.

Bicyclic Amidine-Triggered Cyclization of o-Alkynylisocyanobenzenes: Synthesis of Lactam-Derived Quinolines.

Efficient access to the synthesis of lactam-derived quinoline through a bicyclic amidine-triggered cyclization reaction from readily prepared o-alkynylisocyanobenzenes has been developed. The reaction was initiated by nucleophilic attack of the bicyclic amidines to o-alkynylisocyanobenzenes, subsequently with intramolecular cyclization to produce a DBU-quinoline-based amidinium salt, followed by hydrolysis to afford the lactam-derived quinoline in moderate to good yields.

Facile access to 2-hydroxy-2-substituted indole-3-ones via a copper-catalyzed oxidative cyclization of 2-arylethynylanilines.

This paper reports a practical and versatile oxidative cyclization of 2-arylethynylanilines towards 2-hydroxy-2-substituted indol-3-ones via a copper-catalyzed radical approach in the presence of O2. The transformation of 2-hydroxy-2-arylindol-3-ones to 3-hydroxy-3-arylindol-2-ones proceeds well with good yields and highlights the practicability and utility of this catalytic system. Mechanistic investigations showed that the acetyl substituent on 2-arylaethynylanilines played an important role in the formation of the cyclic products and the reaction proceeded via an N-center radical-based 5-endo-dig aza-cyclization pathway.

Abnormalities of Regional Brain Activity in Patients With Schizophrenia: A Longitudinal Resting-State fMRI Study.

BACKGROUND: Evidence from functional and structural research suggests that abnormal brain activity plays an important role in the pathophysiology of schizophrenia (SZ). However, limited studies have focused on post-treatment changes, and current conclusions are inconsistent. STUDY DESIGN: We recruited 104 SZ patients to have resting-state functional magnetic resonance imaging scans at baseline and 8 weeks of treatment with second-generation antipsychotics, along with baseline scanning of 86 healthy controls (HCs) for comparison purposes. Individual regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF), and degree centrality values were calculated to evaluate the functional activity. The Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery were applied to measure psychiatric symptoms and cognitive impairment in SZ patients. RESULTS: Compared with HCs at baseline, SZ patients had higher ALFF and ReHo values in the bilateral inferior temporal gyrus, inferior frontal gyrus, and lower ALFF and ReHo values in fusiform gyrus and precuneus. Following 8 weeks of treatment, ReHo was increased in right medial region of the superior frontal gyrus (SFGmed) and decreased in the left middle occipital gyrus and the left postcentral gyrus. Meanwhile, ReHo of the right SFGmed was increased after treatment in the response group (the reduction rate of PANSS ≥50%). Enhanced ALFF in the dorsolateral of SFG correlated with improvement in depressive factor score. CONCLUSIONS: These findings provide novel evidence for the abnormal functional activity hypothesis of SZ, suggesting that abnormality of right SFGmed can be used as a biomarker of treatment response in SZ.

Rh(III)-catalyzed redox-neutral C-H alkenylation of benzamides with gem-difluorohomoallylic silyl ethers via ß-H elimination.

Fluorinated molecules are widely used in pharmaceutical and agrochemical industries. Herein we report the synthesis of 2-(3,3-difluoro-4-(silyloxy)but-1-en-1-yl)benzamides from the unprecedented rhodium(III)-catalyzed alkenylation of various benzamides with difluorohomoallylic silyl ethers. The practicability of this protocol is demonstrated by its broad substrate compatibility, good functional group tolerance, ready scalability and high regioselectivity. The oxygen in difluorohomoallylic silyl ethers makes ß-H elimination feasible, which suppresses both the ß-F elimination and dialkenylation of benzamides. This redox-neutral reaction proceeds efficiently via N-O bond cleavage without external oxidants and thus provides new opportunities for the synthesis of elaborate difluorinated compounds from readily available fluorinated synthons.

Bibliometric Analysis of the Top 100 Cited Articles in Pediatric Ophthalmology.

PURPOSE: To determine and analyze the 100 most cited articles in pediatric ophthalmology. METHODS: A literature search was conducted using the ISI Web of Science database on the top 100 most cited articles in pediatric ophthalmology. RESULTS: The 100 most cited articles were published between 1941 and 2018, with the greatest number published in both 2005 and 2012. A total of 29,731 citations were generated during the study period. There has been a significant increase in citations annually since 1941, with a peak number of citations in 2021 with 2,629 citations. Myopia, retinopathy of prematurity, and other forms of refractive error were the topics most studied and cited in these articles. Most of the articles were classified as either large cohort prospective/retrospective studies (34) or randomized clinical trials (19), with case reports/series being the least frequent (7). Investigative Ophthalmology & Visual Science (23), JAMA Ophthalmology (22), and Ophthalmology (22) published the majority of the articles. Institutions that conducted the majority of the studies presented include the National Eye Institute (10), the Ohio State University College of Optometry (9), and the Oregon Health & Science University (6). CONCLUSIONS: This bibliometric analysis provides a unique historical perspective of the literature in the field of pediatric ophthalmology that has not been studied before. The research in the field of pediatric ophthalmology is advancing quickly, with most articles and citations occurring within the past 15 years. The strong focus on prospective cohort studies and clinical trials reveals the importance of advancing the treatment of critical disease within the field of pediatric ophthalmology. [J Pediatr Ophthalmol Strabismus. 2023;60(5):330-336.].

Preparation and application of a specific single-chain variable fragment against artemether.

Artemether, an artemisinin derivative, is a component of the commonly used artemisinin-based combination therapy, artemether-lumefantrine. In this study, we cloned the VH and VL genes of a cell line (mAb 2G12E1) producing a monoclonal antibody specific to artemether, and used to construct a recombinant DNA of single-chain variable fragment (scFv). The scFv was constructed into prokaryotic expression vectors pET32a (+), pET22b (+), pGEX-2T, and pMAL-p5x, respectively. However, only the pMAL-p5x/scFv could be induced to express soluble scFv with comparable sensitivity and specificity to that of mAb 2G12E1. Based on the anti-artemether scFv, an indirect competitive enzyme-linked immunosorbent assay (icELISA) was developed. The 50% of inhibition concentration (IC50) value and the working range based on IC20 to IC80 were 4.33 ng mL-1 and 1.05-22.65 ng mL-1, respectively. The artemether content in different drugs were determined by the developed icELISA, and the results were consistent to those determined by ultra performance liquid chromatography (UPLC). The anti-artemether scFv prepared in the current study could be a valuable genetically engineered antibody applied for artemether monitoring and specific binding mechanism studying.

Cycloplegic Autorefraction as a Substitute for Cycloplegic Retinoscopy in the Pediatric Population.

PURPOSE: To evaluate whether cycloplegic autorefraction can provide similar results as cycloplegic retinoscopy, allowing more comprehensive ophthalmologists to be comfortable in managing pediatric refractive error and refractive amblyopia. METHODS: This retrospective chart review was performed to determine the mean difference in sphere, cylinder, and axis between cycloplegic autorefraction and retinoscopy, both of which were obtained on the same eye at least 30 minutes after cycloplegia and dilation with a mixed solution of tropicamide, cyclopentolate, and phenylephrine. RESULTS: A total of 34 eyes (18 right, 16 left) from 18 patients were included in the analysis. Mean sphere difference between cycloplegic autorefraction and retinoscopy was 0.044 ± 0.278 diopters (D) (95% CI: -1.275 to 1.363 D), mean cylinder difference was -0.081 ± 0.236 D (95% CI: -0.706 to 0.544 D), and mean axis difference was 7.059 ± 19.676 degrees (95% CI: -32.527 to 38.878 degrees). Mean differences in sphere, cylinder, and axis were not statistically significant (P = .362, .0541, and .377, respectively). CONCLUSIONS: In this small sample population, cycloplegic autorefraction was comparable to cycloplegic retinoscopy. Recognition of amblyopia should still prompt evaluation by a pediatric ophthalmologist. Further research is necessary to confirm whether uncomplicated refractive error in children may be sufficiently detected and managed by a comprehensive ophthalmologist. [J Pediatr Ophthalmol Strabismus. 2022:59(6):422-427.].

Generation of a homozygous ARHGAP11B knockout hiPSC line by CRISPR/Cas9 system.

The human specific gene ARHGAP11B is preferentially expressed in neural progenitors of fetal neocortex and plays a key role in the evolutionary expansion of the neocortex. Here, we generated a homozygous ARHGAP11B knockout human induced pluripotent stem cell (hiPSC) line through CRISPR/Cas9 gene editing system. ARHGAP11B deficient cell line maintained a normal karyotype (46, XX), expressed pluripotency markers, and showed the capability to spontaneously differentiate into all three germ layers in vivo. The ARHGAP11B knockout cell line can provide a new cell model for studying the evolution of human neocortex.

Force of lifelong crystalline lens growth: chronic traumatic mechanical insult to the choroid.

PURPOSE: To calculate the forces applied to the uvea and retina as a result of lifelong crystalline lens growth. DESIGN: Retrospective study. SETTING: MRI Research, Inc., Middleburg Heights, Ohio; Institute of Ophthalmology and Visual Science UMDNJ-New Jersey Medical School, Newark, New Jersey; USC Psychology University of Southern California, Los Angeles. METHODS: Magnetic resonance images were acquired from 15 phakic/pseudophakic eye pairs in patients with cataract (ages 46 to 83 years). Choroidal lengths were measured. The forces required to produce differences between phakic/pseudophakic choroidal lengths were calculated. RESULTS: The length of the choroid is greater in the phakic eye compared with the corresponding pseudophakic eye (n = 15), and this difference increases with age (P = .00006; power = 0.99). The corresponding choroidal strain also increases with age (P = .00003, power = 0.99) as do the forces required to produce such a change in choroidal length (P = .000008, power = 0.99). CONCLUSIONS: The authors theorize that lifelong crystalline lens growth applies a chronic, traumatic, mechanical insult to the uvea and retina. This previously unknown, ever-increasing, force appears to stretch the choroidal tissue and may be an intraocular pressure-independent modifiable risk factor for retinal disease. Implications exist for understanding the pathophysiology of retinal diseases in the aging eye that are often comorbid with cataracts, for example, glaucoma, macular degeneration, and diabetic retinopathy.

Children and Adolescents' Psychological Well-Being Became Worse in Heavily Hit Chinese Provinces during the COVID-19 Epidemic.

In light of the novel coronavirus's (COVID-19's) threat to public health worldwide, we sought to elucidate COVID-19's impacts on the mental health of children and adolescents in China. Through online self-report questionnaires, we aimed to discover the psychological effects of the pandemic and its associated risk factors for developing mental health symptoms in young people. We disseminated a mental health survey through online social media, WeChat, and QQ in the five Chinese provinces with the most confirmed cases of COVID-19 during the late stage of the country-wide lockdown. We used a self-made questionnaire that queried children and adolescents aged 6 to 18 on demographic information, psychological status, and other lifestyle and COVID-related variables. A total of 17,740 children and adolescents with valid survey data participated in the study. 10,022 (56.5%), 11,611 (65.5%), 10,697 (60.3%), 6868 (38.7%), and 6225 (35.1%) participants presented, respectively, more depressive, anxious, compulsive, inattentive, and sleep-related problems compared to before the outbreak of COVID-19. High school students reported a greater change in depression and anxiety than did middle school and primary school students. Despite the fact that very few children (0.1%) or their family members (0.1%) contracted the virus in this study, the psychological impact of the pandemic was clearly profound. Fathers' anxiety appeared to have the strongest influence on a children's psychological symptoms, explaining about 33% of variation in the child's overall symptoms. Other factors only explained less than 2% of the variance in symptoms once parents' anxiety was accounted for. The spread of COVID-19 significantly influenced the psychological state of children and adolescents in participants' view. It is clear that children and adolescents, particularly older adolescents, need mental health support during the pandemic. The risk factors we uncovered suggest that reducing fathers' anxiety is particularly critical to addressing young people's mental health disorders in this time.

Genome-wide association study followed by trans-ancestry meta-analysis identify 17 new risk loci for schizophrenia.

BACKGROUND: Over 200 schizophrenia risk loci have been identified by genome-wide association studies (GWASs). However, the majority of risk loci were identified in populations of European ancestry (EUR), potentially missing important biological insights. It is important to perform 5 GWASs in non-European populations. METHODS: To identify novel schizophrenia risk loci, we conducted a GWAS in Han Chinese population (3493 cases and 4709 controls). We then performed a large-scale meta-analysis (a total of 143,438 subjects) through combining our results with previous GWASs conducted in EAS and EUR. In addition, we also carried out comprehensive post-GWAS analysis, including heritability partitioning, enrichment of schizophrenia associations in tissues and cell types, trancscriptome-wide association study (TWAS), expression quantitative trait loci (eQTL) and differential expression analysis. RESULTS: We identified two new schizophrenia risk loci, including associations in SHISA9 (rs7192086, P = 4.92 × 10-08) and PES1 (rs57016637, P = 2.33 × 10-11) in Han Chinese population. A fixed-effect meta-analysis (a total of 143,438 subjects) with summary statistics from EAS and EUR identifies 15 novel genome-wide significant risk loci. Heritability partitioning with linkage disequilibrium score regression (LDSC) reveals a significant enrichment of schizophrenia heritability in conserved genomic regions, promoters, and enhancers. Tissue and cell-type enrichment analyses show that schizophrenia associations are significantly enriched in human brain tissues and several types of neurons, including cerebellum neurons, telencephalon inhibitory, and excitatory neurons. Polygenic risk score profiling reveals that GWAS summary statistics from trans-ancestry meta-analysis (EAS + EUR) improves prediction performance in predicting the case/control status of our sample. Finally, transcriptome-wide association study (TWAS) identifies risk genes whose cis-regulated expression change may have a role in schizophrenia. CONCLUSIONS: Our study identifies 17 novel schizophrenia risk loci and highlights the importance and necessity of conducting genetic study in different populations. These findings not only provide new insights into genetic etiology of schizophrenia, but also facilitate to delineate the pathophysiology of schizophrenia and develop new therapeutic targets.

Genome wide association study identifies four loci for early onset schizophrenia.

Early onset schizophrenia (EOS, defined as first onset of schizophrenia before age 18) is a rare form of schizophrenia (SCZ). Though genome-wide association studies (GWASs) have identified multiple risk variants for SCZ, most of the cases included in these GWASs were not stratified according to their first age at onset. To date, the genetic architecture of EOS remains largely unknown. To identify the risk variants and to uncover the genetic basis of EOS, we conducted a two-stage GWAS of EOS in populations of Han Chinese ancestry in this study. We first performed a GWAS using 1,256 EOS cases and 2,661 healthy controls (referred as discovery stage). The genetic variants with a P < 1.0 × 10-04 in discovery stage were replicated in an independent sample (903 EOS cases and 3,900 controls). We identified four genome-wide significant risk loci for EOS in the combined samples (2,159 EOS cases and 6,561 controls), including 1p36.22 (rs1801133, Pmeta = 4.03 × 10-15), 1p31.1 (rs1281571, Pmeta = 4.14 × 10-08), 3p21.31 (rs7626288, Pmeta = 1.57 × 10-09), and 9q33.3 (rs592927, Pmeta = 4.01 × 10-11). Polygenic risk scoring (PRS) analysis revealed substantial genetic overlap between EOS and SCZ. These discoveries shed light on the genetic basis of EOS. Further functional characterization of the identified risk variants and genes will help provide potential targets for therapeutics and diagnostics.

Inclusive Finance, Environmental Regulation, and Public Health in China: Lessons for the COVID-19 Pandemic.

The slow-down of the Chinese economy and the depression in the global economy during the COVID-19 show that governments should provide stimulus packages. These policies should be inclusive in terms of financial gains. Using the panel data of 30 regions in China from 2006 to 2016, this paper uses the Poisson Pseudo-Maximum Likelihood (PPML) estimator to analyze the impact of inclusive finance on public health. The results show that inclusive finance has a significant positive effect on public health. The performance of the eastern region is significantly better than that of the central and western regions. When we consider the combined effect of environmental regulation, the improvement effect of inclusive finance on public health is still significant, and the coefficient increases in the eastern region. Similarly, there is also a significant improvement effect in the central and western regions. Our findings reveal that environmental regulation promotes the beneficial effect of inclusive finance. Therefore, it is important to improve the inclusive financial development mechanism and enhance environmental regulation intensity for solving public health issues. Lessons related to the COVID-19 pandemic are also discussed.

Update on the Use of Anti-VEGF Drugs in the Treatment of Retinopathy of Prematurity.

Retinopathy of prematurity (ROP) is one of the many significant consequences of premature birth and remains one of the leading causes of visual impairment in infants. Originally, cryotherapy was used to prevent the complications of vitreous hemorrhage and retinal detachment. Subsequently, laser photocoagulation, which is at least as effective and possibly safer than cryoretinopexy, was adopted as the primary treatment for type 1 ROP (stage 2 or 3 disease in zone II with plus disease or any stage disease in zone I with plus disease or stage 3 disease in zone I without plus disease). Laser therapy has been proven effective, and has a degree of permanence that is yet to be matched by alternative treatments, but can be associated with significant ocular side effects such as myopia. Treatment of type 1 ROP with anti-vascular endothelial growth factor (VEGF) agents seems to have fewer ocular side effects than laser ablation of the retina, particularly if used to treat type 1 ROP in zone I. However, ROP recurrence is a real threat after anti-VEGF therapy and long-term systemic side effects of this therapy remain under evaluation. This review focuses on the ophthalmic and systemic benefits and risks of anti-VEGF therapies for ROP as compared to retinal photocoagulation. Anti-VEGF therapies have dramatically altered the management of ROP and have also been shown to be beneficial with regard to the visual prognosis of patients with ROP, but patients so treated require frequent short- and long-term follow-up to detect and manage potential complications associated with this form of treatment. Such information also will allow clinicians to characterize the efficacy, side effect profile, and utility of intravitreal anti-VEGF agents for this condition. Prospective studies are needed to identify the optimum anti-VEGF drug and dose. [J Pediatr Ophthalmol Strabismus. 2020;57(6):351-362.].