Upregulation of KDM6B in the anterior cingulate cortex contributes to neonatal maternal deprivation-induced chronic visceral pain in mice.

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disease characterized by chronic visceral pain with a complex etiology and challenging treatment. Although accumulating evidence supports the involvement of central nervous system sensitization in the development of visceral pain, the precise molecular mechanisms remain incompletely understood. In this study, we highlight the critical regulatory role of lysine-specific demethylase 6B (KDM6B) in the anterior cingulate cortex (ACC) in chronic visceral pain. To simulate clinical IBS conditions, we utilized the neonatal maternal deprivation (NMD) mouse model. Our results demonstrated that NMD induced chronic visceral pain and anxiety-like behaviors in mice. Notably, the protein expression level of KDM6B significantly increased in the ACC of NMD mice, leading to a reduction in the expression level of H32K7me3. Immunofluorescence staining revealed that KDM6B primarily co-localizes with neurons in the ACC, with minimal presence in microglia and astrocytes. Injecting GSK-J4 (a KDM6B-specific inhibitor) into ACC of NMD mice, resulted in a significant alleviation in chronic visceral pain and anxiety-like behaviors, as well as a remarkable reduction in NR2B expression level. ChIP assay further indicated that KDM6B regulates NR2B expression by influencing the demethylation of H3K27me3. In summary, our findings underscore the critical role of KDM6B in regulating chronic visceral pain and anxiety-like behaviors in NMD mice. These insights provide a basis for further understanding the molecular pathways involved in IBS and may pave the way for targeted therapeutic interventions.

Integrating high-throughput phenotyping and genome-wide association studies for enhanced drought resistance and yield prediction in wheat.

Drought, especially terminal drought, severely limits wheat growth and yield. Understanding the complex mechanisms behind the drought response in wheat is essential for developing drought-resistant varieties. This study aimed to dissect the genetic architecture and high-yielding wheat ideotypes under terminal drought. An automated high-throughput phenotyping platform was used to examine 28 392 image-based digital traits (i-traits) under different drought conditions during the flowering stage of a natural wheat population. Of the i-traits examined, 17 073 were identified as drought-related. A genome-wide association study (GWAS) identified 5320 drought-related significant single-nucleotide polymorphisms (SNPs) and 27 SNP clusters. A notable hotspot region controlling wheat drought tolerance was discovered, in which TaPP2C6 was shown to be an important negative regulator of the drought response. The tapp2c6 knockout lines exhibited enhanced drought resistance without a yield penalty. A haplotype analysis revealed a favored allele of TaPP2C6 that was significantly correlated with drought resistance, affirming its potential value in wheat breeding programs. We developed an advanced prediction model for wheat yield and drought resistance using 24 i-traits analyzed by machine learning. In summary, this study provides comprehensive insights into the high-yielding ideotype and an approach for the rapid breeding of drought-resistant wheat.

Efficient polarization-insensitive quasi-BIC modulation by VO2 thin films.

Bound states in the continuum (BIC) offer great design freedom for realizing high-quality factor metasurfaces. By deliberately disrupting the inherent symmetries, BIC can degenerate into quasi-BIC exhibiting sharp spectra with strong light confinement. This transformation has been exploited to develop cutting-edge sensors and modulators. However, most proposed quasi-BICs in metasurfaces are composed of unit cells with Cs symmetry that may experience performance degradation due to polarization deviation, posing challenges in practical applications. Addressing this critical issue, our research introduces an innovative approach by incorporating metasurfaces with C4v unit cell symmetry to eliminate polarization response sensitivity. Vanadium Dioxide (VO2) is a phase-change material with a relatively low transition temperature and reversibility. Here, we theoretically investigate the polarization-insensitive quasi-BIC modulation in Si-VO2 hybrid metasurfaces. By introducing defects into metasurfaces with Cs, C4, and C4v symmetries, we enable the emergence of quasi-BICs characterized by strong Fano resonance in their transmission spectra. Via numerically calculating the multipole decomposition, distinct dominant multipoles for different quasi-BICs are identified. A comprehensive investigation into the polarization responses of these structures under varying directions of linearly polarized light reveals the superior polarization-independent characteristics of metasurfaces with C4 and C4v symmetries, a feature that ensures the maintenance of maximum resonance peaks irrespective of polarization direction. Utilizing the polarization-insensitive quasi-BIC, we thus designed two different Si-VO2 hybrid metasurfaces with C4v symmetry. Each configuration presents complementary benefits, leveraging the VO2 phase transition's loss change to facilitate efficient modulation. Our quantitative calculation indicates notable achievements in modulation depth, with a maximum relative modulation depth reaching up to 342%. For the first time, our research demonstrates efficient modulation using polarization-insensitive quasi-BICs in designed Si-VO2 hybrid metasurfaces, achieving identical polarization responses for quasi-BIC-based applications. Our work paves the way for designing polarization-independent quasi-BICs in metasurfaces and marks a notable advancement in the field of tunable integrated devices.

3D hUC-MSC spheroids exhibit superior resistance to autophagy and apoptosis of granulosa cells in POF rat model.

In brief: This study reveals that orthotopic transplantation of 3D hUC-MSC spheroids is more effective than monolayer-cultured hUC-MSCs in improving POF and distinctly reducing oxidative stress through the paracrine effect, thereby preventing apoptosis and autophagy of GCs. Abstract: Premature ovarian failure (POF) is a common reproductive disease in women younger than 40 years old, and studies have demonstrated that the application of human umbilical cord mesenchymal stem cells (hUC-MSCs) is a promising therapy strategy for POF. Given the previously established therapeutic advantages of 3D MSC spheroids, and to evaluate their effectiveness, both 3D hUC-MSC spheroids and monolayer-cultured hUC-MSCs were employed to treat a cyclophosphamide-induced POF rat model through orthotopic transplantation. The effects of these two forms on POF were subsequently assessed by examining apoptosis, autophagy, and oxidative damage in ovarian granulosa cells (GCs). The results indicated that hUC-MSC spheroids exhibited superior treatment effects on resisting autophagy, apoptosis, and oxidative damage in GCs compared to monolayer-cultured hUC-MSCs. To further elucidate the impact of hUC-MSC spheroids in vitro, a H2O2-induced KGN cells model was established and co-cultured with both forms of hUC-MSCs. As expected, the hUC-MSC spheroids also exhibited superior effects in resisting apoptosis and autophagy caused by oxidative damage. Therefore, this study demonstrates that 3D hUC-MSC spheroids have potential advantages in POF therapy; however, the detailed mechanisms need to be further investigated. Furthermore, this study will provide a reference for the clinical treatment strategy of POF.

Risk factors for self-reported medication adherence in community-dwelling older patients with multimorbidity and polypharmacy: a multicenter cross-sectional study.

BACKGROUND: Medication nonadherence is a significant public health problem as it contributes to poor clinical outcomes and increased healthcare costs. Older patients with multimorbidity and polypharmacy often have low medication adherence. These patients also have a high prevalence of potentially inappropriate medication (PIM) use. AIM: To explore risk factors related to medication nonadherence in older patients with multimorbidity and polypharmacy and examine the association between medication nonadherence and PIM use. METHOD: A multicenter cross-sectional study was conducted from May to December 2019 in 16 tertiary hospitals from 12 provinces and cities in China. Data were collected from outpatients 65 years or older with multimorbidity and polypharmacy. The PIMs were evaluated using the 2019 Beers Criteria. Self-reported medication adherence was assessed using the Visual Analog Scale (VAS). RESULTS: A total of 773 outpatients were recruited. The prevalence of medication nonadherence was 31.8%. In the univariate analysis, nonadherence was significantly associated with sex, cognitive impairment, stroke, visiting the same physicians, self-administration of medication, the percentage of drug costs ≥ 10% of the medical expenses, and PIMs for the alimentary tract and metabolism. In the multivariate analysis, the results almost paralleled those of the univariate associations. Notably, the use of PIM was significantly associated with medication adherence. CONCLUSION: Several factors that influence medication adherence were identified. Targeted interventions can be implemented to improve medication adherence, such as encouraging self-administering medications and reducing medication expenses.

Abnormal electrocardiogram and poor prognosis in heart failure with preserved ejection fraction.

PURPOSE: Electrocardiogram (ECG) is generally performed in patients with heart failure with preserved ejection fraction (HFpEF), but the prognostic value of abnormal ECG is not fully understood. We aim to explore the prognostic value of abnormal ECG at baseline in HFpEF using data from the TOPCAT trial. METHODS: A total of 1736 patients from TOPCAT-Americas were included and divided into normal versus abnormal ECG groups. Survival analyses were performed for the following outcomes: the primary endpoint [a composite of cardiovascular death, heart failure (HF) hospitalization, and aborted cardiac arrest], all-cause death, cardiovascular death, and HF hospitalization. RESULTS: Abnormal ECG was significantly associated with higher risks of the primary endpoint [hazard ratio (HR): 1.480, P = 0.001] and HF hospitalization (HR: 1.400, P = 0.015), and borderline significantly with cardiovascular death (HR: 1.453, P = 0.052) in patients with HFpEF after multivariate adjustment. As for specific ECG abnormalities, bundle branch block was associated with the primary endpoint (HR: 1.278, P = 0.020) and HF hospitalization (HR: 1.333, P = 0.016), whereas atrial fibrillation/flutter was associated with all-cause death (HR: 1.345, P = 0.051) and cardiovascular death (HR: 1.570, P = 0.023), but ventricular paced rhythm, pathological Q waves, and left ventricular hypertrophy were not of prognostic significance. Besides, other unspecific abnormalities together were associated with the primary endpoint (HR: 1.213, P = 0.032). CONCLUSION: Abnormal ECG at baseline could be associated with poor prognosis in patients with HFpEF. Physicians are encouraged to pay more attention to HFpEF patients who present an abnormal ECG instead of ignoring those obscure abnormalities. Key messages What is already known on this topic Electrocardiogram (ECG) is a basic and easily accessible examination for patients with heart failure with preserved ejection fraction (HFpEF). Some findings from ECG such as frontal QRS-T angle, QTc interval, and the Cornell product have been shown to be associated with the prognosis of HFpEF but these results are from studies with relatively small sample sizes. What this study adds Using data from TOPCAT-Americas, this study found that an overall estimation of abnormal ECG significantly predicted poor prognosis in patients with HFpEF. As for specific abnormalities in ECG, bundle branch block mainly predicted heart failure hospitalization and atrial fibrillation mainly predicted death. How this study might affect research, practice, or policy This study reminds physicians to pay more attention to HFpEF patients who present an abnormal ECG.

Activation of the p62-Keap1-Nrf2 pathway protects against oxidative stress and excessive autophagy in ovarian granulosa cells to attenuate DEHP-induced ovarian impairment in mice.

Di-(2-ethylhexyl) phthalate (DEHP) is widely used in various plastics but has been demonstrated to cause female reproductive toxicity. However, the exact mechanism underlying the ovarian damage induced by DEHP remains unclear. In this study, DEHP was administered orally to 5-week-old female mice for 30 days at doses of 0, 250, 500, and 1000 mg/kg/day. The findings demonstrated that DEHP exposure disrupted ovarian function and follicular development as well as induced oxidative stress and autophagy in ovarian granulosa cells (GCs). Further, 200 µM mono-(2-ethylhexyl) phthalate (MEHP), the primary metabolite of DEHP in vivo, induced autophagy in both human ovarian granulosa cells line (KGN) and mouse primary GCs within 24 h in vitro. However, it did not affect the p62-dependent autophagy flux. Furthermore, MEHP-induced autophagy was inhibited by the autophagy inhibitor 3-MA and exacerbated by the autophagy activator rapamycin, indicating that MEHP induces excessive autophagy in GCs. Subsequently, we found that MEHP-induced autophagic cell death was primarily attributed to oxidative damage from elevated intracellular ROS levels. Meanwhile, MEHP exposure induced nuclear translocation of erythroid-derived factor 2-related factor (Nrf2), a key regulator of antioxidant activity resulting in activating antioxidant effects. Interestingly, we also found that MEHP-induced increase in p62 competitively binds Keap1, thereby facilitating nuclear translocation of Nrf2 and establishing a positive feedback loop in antioxidant regulation. Therefore, this study demonstrated that inhibition of Nrf2 could aggravate oxidative damage and enhance excessive autophagy caused by MEHP, while activation of Nrf2 could reverse the trend. These findings have also been reinforced in studies of cultured ovaries in vitro. Our study suggests that the p62-Keap1-Nrf2 pathway may serve as a potential protective mechanism against DEHP-induced oxidative stress and excessive autophagy in mouse GCs.

Integrated fecal microbiome and metabolome analysis explore the link between polystyrene nanoplastics exposure and male reproductive toxicity in mice.

Microplastics (MPs) and nanoplastics (NPs) are novel environmental pollutants that are ubiquitous in the environment and everyday life. NPs can easily enter the tissues and have more significant potential health risks due to their smaller diameter. Previous studies have shown that NPs can induce male reproductive toxicity, but the detailed mechanisms remain uncertain. In this study, intragastric administration treated mice with polystyrene NPs (PS-NPs, 50, and 90 nm) at 3 and 15 mg/mL/day doses for 30 days. Then, the fresh fecal samples were collected from those mice that the exposure doses of 50 nm PS-NPs at 3 mg/mL/day and 90 nm at 15 mg/mL/day for subsequent investigations of 16S rRNA and metabolomics according to significant toxicological effects (Sperm number, viability, abnormality, and testosterone level). The conjoint analysis findings indicated that PS-NPs disrupted the homeostasis of the gut microbiota, metabolism, and male reproduction, suggesting that abnormal gut microbiota-metabolite pathways may be important in PS-NPs-induced male reproductive toxicity. Meanwhile, the common differential metabolites such as 4-deoxy-Erythronic acid, 8-iso-15-keto-PGE2, apo-10'-violaxanthin, beta-D-glucosamine, isokobusone, oleamide, oxoadipic acid, sphingosine induced by 50 and 90 nm PS-NPs might be used as biomarkers to explore PS-NPs-induced male reproductive toxicity. In addition, this study systematically demonstrated that nano-scale PS-NPs induced male reproductive toxicity via the crosstalk of gut microbiota and metabolites. It also provided valuable insights into the toxicity of PS-NPs, which was conducive to reproductive health risk assessment for public health prevention and treatment.

[Analysis of lysosomal enzyme activity and genetic variants in a child with late-onset Pompe disease].

OBJECTIVE: To explore the clinical features, lysosomal enzymatic [acid α-glucosidase (GAA)] activities and genetic variants in a child with late-onset Pompe disease (LOPD). METHODS: Clinical data of a child who had presented at the Genetic Counseling Clinic of West China Second University Hospital in August 2020 was retrospectively analyzed. Blood samples were collected from the patient and her parents for the isolation of leukocytes and lymphocytes as well as DNA extraction. The activity of lysosomal enzyme GAA in leukocytes and lymphocytes was analyzed with or without addition of inhibitor of GAA isozyme. Potential variants in genes associated with neuromuscular disorders were analyzed, in addition with conservation of the variant sites and protein structure. The remaining samples from 20 individuals undergoing peripheral blood lymphocyte chromosomal karyotyping were mixed and used as the normal reference for the enzymatic activities. RESULTS: The child, a 9-year-old female, had featured delayed language and motor development from 2 years and 11 months. Physical examination revealed unstable walking, difficulty in going upstairs and obvious scoliosis. Her serum creatine kinase was significantly increased, along with abnormal electromyography, whilst no abnormality was found by cardiac ultrasound. Genetic testing revealed that she has harbored compound heterozygous variants of the GAA gene, namely c.1996dupG (p.A666Gfs*71) (maternal) and c.701C>T (p.T234M) (paternal). Based on the guidelines from the American College of Medical Genetics and Genomics, the c.1996dupG (p.A666Gfs*71) was rated as pathogenic (PVS1+PM2_Supporting+PM3), whilst the c.701C>T (p.T234M) was rated as likely pathogenic (PM1+PM2_Supporting+PM3+PM5+PP3). The GAA in the leukocytes from the patient, her father and mother were respectively 76.1%, 91.3% and 95.6% of the normal value without the inhibitor, and 70.8%, 112.9% and 128.2% of the normal value with the inhibitor, whilst the activity of GAA in their leukocytes had decreased by 6 ~ 9 times after adding the inhibitor. GAA in lymphocytes of the patient, her father and mother were 68.3%, 59.0% and 59.5% of the normal value without the inhibitor, and 41.0%, 89.5% and 57.7% of the normal value with the inhibitor, the activity of GAA in lymphocytes has decreased by 2 ~ 5 times after adding the inhibitor. CONCLUSION: The child was diagnosed with LOPD due to the c.1996dupG and c.701C>T compound heterozygous variants of the GAA gene. The residual activity of GAA among LOPD patients can range widely and the changes may be atypical. The diagnosis of LOPD should not be based solely on the results of enzymatic activity but combined clinical manifestation, genetic testing and measurement of enzymatic activity.

The treatment of Qibai Pingfei Capsule on chronic obstructive pulmonary disease may be mediated by Th17/Treg balance and gut-lung axis microbiota.

BACKGROUND: Chronic obstructive pulmonary disease (COPD), a prevalent, progressive respiratory disease, has become the third leading cause of death globally. Increasing evidence suggests that intestinal and pulmonary microbiota dysbiosis is associated with COPD. Researchers have shown that T helper (Th) 17/regulatory T (Treg) imbalance is involved in COPD. Qibai Pingfei Capsule (QBPF) is a traditional Chinese medicine used to treat COPD clinically in China. However, the effects of QBPF intervention on the Th17/Treg balance and microbiota in the gut and lung are still poorly understood. METHODS: This study divided the rats into three groups (n = 8): control, model, and QBPF group. After establishing the model of COPD for four weeks and administering of QBPF for two weeks, Th17 cells, Treg cells, their associated cytokines, transcription factors, and intestinal and pulmonary microbiota of rats were analyzed. Furthermore, the correlations between intestinal and pulmonary microbiota and between bacterial genera and pulmonary function and immune function were measured. RESULTS: The results revealed that QBPF could improve pulmonary function and contribute to the new balance of Th17/Treg in COPD rats. Meanwhile, QBPF treatment could regulate the composition of intestinal and pulmonary microbiota and improve community structure in COPD rats, suppressing the relative abundance of Coprococcus_2, Prevotella_9, and Blautia in the gut and Mycoplasma in the lung, but accumulating the relative abundance of Prevotellaceae_UCG_003 in the gut and Rikenellaceae_RC9_gut_group in the lung. Additionally, gut-lung axis was confirmed by the significant correlations between the intestinal and pulmonary microbiota. Functional analysis of microbiota showed amino acid metabolism was altered in COPD rats in the gut and lung. Spearman correlation analysis further enriched the relationship between the microbiota in the gut and lung and pulmonary function and immune function in COPD model rats. CONCLUSIONS: Our study indicated that the therapeutic effects of QBPF may be achieved by maintaining the immune cell balance and regulating the gut-lung axis microbiota, providing references to explore the potential biomarkers of COPD and the possible mechanism of QBPF to treat COPD.

Broadband nanostructured fiber mode convertors enabled by inverse design.

Nanostructured fiber devices enabling mode conversion between arbitrary fiber modes are proposed and numerically validated. The intra-fiber nanostructures are optimized by the inverse design algorithm. We demonstrate a set of designs of nanophotonic fibers that can facilitate high-purity conversion from the fundamental mode to higher-order modes up to 3 orders for both LP and OAM modes inside the fibers. The purity values of the output modes can reach 98% with an ultra-wide operation band exceeding 400 nm around the telecom wavelengths. These devices can be fabricated by technique of thermal drawing of assembled preforms, making them suitable for mass production.

Emerging role of m6A modification in osteogenesis of stem cells.

The differentiation of stem cells into osteoblasts is a key link in the treatment of bone defects and other orthopedic diseases. N6-methyladenosine (m6A) modification, an important post-transcriptional modification, is a methylation that occurs at the N6 site of RNA adenylate. The modification plays a regulatory role in the growth and development of biological individuals, the directional differentiation of stem cells and the occurrence of diseases. It is involved in various processes of the fate decision of stem cells. And it regulates the development and constant renewal of bone and keeps bone homeostasis by controlling and maintaining the balance between osteogenesis and adipogenesis. Meanwhile, it also affects the progress of orthopedic-associated diseases such as degenerative osteoporosis and bone tumor. In this review, we mainly summarize the new findings of three key molecules including Writers, Erasers and Readers which regulate m6A modification, and the emerging role of m6A modification in determining the fate and directed differentiation potential of stem cells, especially highlight the regulatory mechanism of osteogenic differentiation, the balance between osteogenesis and adipogenesis and the occurrence and development of bone-related diseases. It may provide some important ideas about finding new strategies to recover from bone defect and degenerative bone disease.

Rapamycin attenuated podocyte apoptosis via upregulation of nestin in Ang II-induced podocyte injury.

BACKGROUND: Angiotensin II (Ang II) contributes to the progression of glomerulosclerosis, mainly by inducing podocyte injury. Convincing evidence indicates that the mTOR inhibitor rapamycin could play a fundamental role in protection against podocyte injury. Nestin, a major cytoskeletal protein, is stably expressed in podocytes and correlates with podocyte damage. The purpose of this study was to investigate the effect of rapamycin on podocyte injury induced by Ang II and to clarify the role and mechanism of nestin in the protective effect of rapamycin of podocyte injury. METHODS AND RESULTS: We established an Ang II perfusion animal model, and the effects of rapamycin treatment on podocytes were investigated in vivo. In vitro, podocytes were stimulated with Ang II and rapamycin to observe podocyte injury, and nestin-siRNA was transfected to investigate the underlying mechanisms. We observed that Ang II induced podocyte injury both in vivo and in vitro, whereas rapamycin treatment relieved Ang II-induced podocyte injury. We further found that nestin co-localized with p-mTOR in glomeruli, and the protective effect of rapamycin was reduced by nestin-siRNA in podocytes. Moreover, co-IP indicated the interaction between nestin and p-mTOR, and nestin could affect podocyte injury via the mTOR/P70S6K signaling pathway. CONCLUSION: We demonstrated that rapamycin attenuated podocyte apoptosis via upregulation of nestin expression through the mTOR/P70S6K signaling pathway in an Ang II-induced podocyte injury.

Compound heterozygous variations in IARS1 cause recurrent liver failure and growth retardation in a Chinese patient: a case report.

BACKGROUND: Aminoacyl-tRNA synthetases (ARSs) are enzymes responsible for attaching amino acids to tRNA, which enables protein synthesis. Mutations in isoleucyl-tRNA synthetase (IARS1) have recently been reported to be a genetic cause for growth retardation, intellectual disability, muscular hypotonia, and infantile hepatopathy (GRIDHH). CASE PRESENTATION: In this study, we reported an additional case of compound heterozygous missense variations c.701 T > C (p.L234P) and c.1555C > T (p.R519C) in IARS1, which were identified using medical exome sequencing; c.701 T > C (p.L234P) was a novel variant, and c.1555C > T (p.R519C) was found in GnomAD. Unlike other reported patients, this individual presented prominently with recurrent liver failure, which led to her death at an early age of 19 months. She also had significant growth retardation, muscular hypotonia, chubby and flabby face, recurrent loose stools, and abnormal brain computed tomography (CT), while zinc deficiency and hearing loss were not present. Studies in zebrafish embryo modeling recapitulated some of the key phenotypic traits in embryo development, neurodevelopment, liver development, and myogenesis, demonstrating that these variations caused a loss of gene function in IARS1. CONCLUSIONS: We have found a novel mutation point c.701 T > C (p.L234P) in IARS1. Compound heterozygous mutations of c.701 T > C (p.L234P) and c.1555C > T (p.R519C) in IARS1 are pathogenic, which can cause GRIDHH in child.

[Lysosomal enzyme analysis of mucolipidosis type II α/ß and type III α/ß in two Chinese pedigrees].

OBJECTIVE: To analyze the characteristics of lysosomal enzymes in mucolipidosis (ML) type II α/ß and type III α/ß for the choice of enzyme evaluating indicators. METHODS: Multiple lysosomal enzymes including α-iduronidase (IDUA), α -N-acetylglucosaminidase (NAGLU), ß-galactosidase-1 (GLB1), ß-glucuronidase (GUSB), α-galactosidase A (GLA), glucocerebrosidase (GBA) and arylsulphatase A (ASA) in plasma and leukocyte of two Chinese pedigrees with ML type II α/ß and type III α/ß and healthy controls were determined. Previous publications on ML type II α/ß and type III α/ß during the last five years were retrieved from PubMed, CNKI and WanFang databases by using "mucolipidosis" as key word. RESULTS: The activities of several lysosomal enzymes were increased in the plasma of both patients: ASA, IDUA (20-fold) > GUSB (10-fold) > GLB1, GLA (5-fold) > NAGLU (2-fold), whilst there was no significant change in GBA. The activities of several lysosomal enzymes in the leukocyte of the two patients were normal. 15 lysosomal enzymes have been used in 22 previous studies, the most frequently used were hexosaminidase A and B (Hex A+B) (12 papers), α-mannosidase (α-man) (11 papers) and GUSB (10 papers). The degree of Hex A+B and α-man elevation was most obvious (24.4-fold and 24.7-fold on average respectively), followed by ASA (22.4-fold on average), GUSB is 18.8-fold on average. CONCLUSION: Based on the lysosomal enzyme analysis of the two cases and literature review, ASA, GUSB, Hex A+B and α-man are recommended as the evaluating indicators for lysosomal enzyme analysis of ML type II α/ß and type III α/ß.

Guided mode meta-optics: metasurface-dressed waveguides for arbitrary mode couplers and on-chip OAM emitters with a configurable topological charge.

Metasurface has achieved fruitful results in tailoring optical fields in free space. However, a systematic investigation on applying meta-optics to completely control waveguide modes is still elusive. Here we present a comprehensive catalog to selectively and exclusively couple free space light into arbitrary high-order waveguide modes of interest, leveraging silicon metasurface-patterned silicon nitride waveguides. By simultaneously engineering the matched phase gradient of the nanoantennas and the vectorial spatial modal overlap between the antenna near-field and target waveguide mode profile, either single or multiple high-order modes are successfully launched with high purity reaching 98%. Moreover, on-chip twisted light generators are theoretically proposed with configurable OAM topological charge ℓ from -3 to +2. This work may serve as a comprehensive framework for guided mode meta-optics and motivates further applications such as versatile integrated couplers, multiplexers, and mode-division multiplexing-based communication systems.

Hollow polydopamine nanoparticles loading with peptide RL-QN15: a new pro-regenerative therapeutic agent for skin wounds.

BACKGROUND: Although the treatments of skin wounds have greatly improved with the increase in therapeutic methods and agents, available interventions still cannot meet the current clinical needs. Therefore, the development of new pro-regenerative therapies remains urgent. Owing to their unique characteristics, both nanomaterials and peptides have provided novel clues for the development of pro-regenerative agents, however, more efforts were still be awaited and anticipated. RESULTS: In the current research, Hollow polydopamine (HPDA) nanoparticles were synthesized and HPDA nanoparticles loading with RL-QN15 (HPDAlR) that was an amphibian-derived peptide with obvious prohealing activities were prepared successfully. The characterization, biodistribution and clearance of both HPDA nanoparticles and HPDAlR were evaluated, the loading efficiency of HPDA against RL-QN15 and the slow-releasing rate of RL-QN15 from HPDAlR were also determined. Our results showed that both HPDA nanoparticles and HPDAlR exerted no obvious toxicity against keratinocyte, macrophage and mice, and HPDA nanoparticles showed no prohealing potency in vivo and in vitro. Interestingly, HPDAlR significantly enhanced the ability of RL-QN15 to accelerate the healing of scratch of keratinocytes and selectively modulate the release of healing-involved cytokines from macrophages. More importantly, in comparison with RL-QN15, by evaluating on animal models of full-thickness injured skin wounds in mice and oral ulcers in rats, HPDAlR showed significant increasing in the pro-regenerative potency of 50 and 10 times, respectively. Moreover, HPDAlR also enhanced the prohealing efficiency of peptide RL-QN15 against skin scald in mice and full-thickness injured wounds in swine. CONCLUSIONS: HPDA obviously enhanced the pro-regenerative potency of RL-QN15 in vitro and in vivo, hence HPDAlR exhibited great potential in the development of therapeutics for skin wound healing.

The Link between Circadian Clock Genes and Autophagy in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD), a progressive respiratory disease, is characterized by the alveolar epithelium injury and persistent airway inflammation. It is documented that oscillation and dysregulated expression of circadian clock genes, like Bmal1, Per1, and Per2, involved in COPD pathogenies, including chronic inflammation and imbalanced autophagy level, and targeting the associations of circadian rhythm and autophagy is promising strategies in the management and treatment of COPD. Herein, we reviewed the mechanisms of the circadian clock and the unbalance of the autophagic level in COPD, as well as the link between the two, so as to provide further theoretical bases for the study on the pathogenesis of COPD.

CircRNAs and LncRNAs in Osteoporosis.

Osteoporosis is a systemic bone disease with bone fragility and increased fracture risk. The non-coding RNAs (ncRNAs) have appeared as important regulators of cellular signaling and pertinent human diseases. Studies have demonstrated that circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) are involved in the progression of osteoporosis through a variety of pathways, and are considered as targets for the prophylaxis and treatment of osteoporosis. Based on an in-depth understanding of their roles and mechanisms in osteoporosis, we summarize the functions and molecular mechanisms of circRNAs and lncRNAs involved in the progression of osteoporosis and provide some new insights for the prognosis, diagnosis and treatment of osteoporosis.

Investigation on chronic tinnitus efficacy of combination of non-repetitive preferred music and educational counseling: a preliminary study.

PURPOSE: To improve the efficacy of music therapy on tinnitus relief, specific music that was not repetitively played and satisfies individualized preference was developed. The aim of this study was to investigate effects of combination of the specific music and educational counseling on tinnitus relief in short term. METHODS: Sixty patients suffering from chronic tinnitus were included. The non-randomized controlled study was designed with two intervention groups: educational counseling (EC, which included a 1-h individualized instruction) and preferred music therapy [PMT, which included EC plus 15, 30-min preferred music sessions (PMS)]. Three assessments-the Chinese-Mandarin version of Tinnitus Handicap Inventory (THI-CM), Tinnitus Evaluation Questionnaire (TEQ), and Visual Analogue Scale (VAS) were administered before and 1, 2, 3 weeks after initiation of treatment to evaluate the efficacy. RESULTS: Twenty-six patients in PMT group attained a clinically meaningful improvement in THI compared to 15 in the EC group, though both groups achieved a statistically relevant reduction in the 3 assessments. CONCLUSION: The PMT had a positive impact on chronic tinnitus and related distress in a short term. It outperformed the separate EC, which is an appropriate treatment option in clinic. Therefore, it presents a possible complement to the therapeutic spectrum in chronic tinnitus. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900022624. Registered on 19 April 2019.