Identification of a Novel Homozygous Mutation in MTMR2 Gene Causes Very Rare Charcot-Marie-Tooth Disease Type 4B1.

Background: Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders involving peripheral nervous system. Charcot-Marie-Tooth disease 4B1 (CMT4B1) is a rare subtype of CMT. CMT4B1 is an axonal demyelinating polyneuropathy with an autosomal recessive mode of inheritance. Patients with CMT4B1 usually manifested with dysfunction of the motor and sensory systems which leads to gradual and progressive muscular weakness and atrophy, starting from the peroneal muscles and finally affecting the distal muscles. Germline mutations in MTMR2 gene causes CMT4B1. Material and Methods: In this study, we investigated a 4-year-old Chinese boy with gradual and progressive weakness and atrophy of both proximal and distal muscles. The proband's parents did not show any abnormalities. Whole-exome sequencing and Sanger sequencing were performed. Results: Whole-exome sequencing identified a novel homozygous nonsense mutation (c.118A>T; p.Lys40*) in exon 2 of MTMR2 gene in the proband. This novel mutation leads to the formation of a truncated MTMR2 protein of 39 amino acids instead of the wild- type MTMR2 protein of 643 amino acids. This mutation is predicted to cause the complete loss of the PH-GRAM domain, phosphatase domain, coiled-coil domain, and PDZ-binding motif of the MTMR2 protein. Sanger sequencing revealed that the proband's parents carried the mutation in a heterozygous state. This mutation was absent in 100 healthy control individuals. Conclusion: This study reports the first mutation in MTMR2 associated with CMT4B1 in a Chinese population. Our study also showed the importance of whole-exome sequencing in identifying candidate genes and disease-causing variants in patients with CMT4B1.

Omni-polarized Faraday isolator based on non-Hermitian Faraday system.

Non-Hermitian systems have recently attracted significant attention in photonics due to the realization that the interplay between gain and loss can lead to entirely new and unexpected features. Here, we propose and demonstrate a non-Hermitian Faraday system capable of non-reciprocal omni-polarizer action at the exceptional point. Notably, both forward and backward propagating light with arbitrary polarization converge to the same polarization state. Leveraging the robustness and non-reciprocity of the non-Hermitian Faraday system, we realize an omni-polarized Faraday isolator that can effectively isolate any polarized light without the need for a polarizer at the incident port of backward propagation. Remarkably, under the given parameter configuration, the isolator achieves a maximum isolation ratio of approximately 100 dB and a minimum isolation ratio of around 45 dB for various polarized light, accompanied by near-zero insertion loss. Furthermore, our research reveals the remarkable tolerance of the non-Hermitian Faraday isolator to nonlinear effects. This unique characteristic allows us to harness nonlinear effects to achieve various optical functions, all while maintaining excellent isolation performance. The proposed non-Hermitian Faraday system paves the way for the realization of magnetically or optically switchable non-reciprocal devices.

Leakage Retardation of Static Seals via Surface Roughness and Wettability Modification.

In this paper, the effects of surface roughness and wettability on the leakage performance of static seals were highlighted. The results show that the leakage rate is negatively correlated with the contact pressure and positively correlated with surface roughness. Surface wettability affects leakage performance. Leakage retardation is achieved by modifying the roughness and wettability at the interface. The seal interface consists of two oleophobicity surfaces and exhibits an excellent seal performance, of which the leakage reduction is approximately 64%. A theoretical model based on wettability is established to predict the leakage rates under varying wettability conditions, and its validity is confirmed. This research result is expected to be applied in the field of seals and predict the leakage performance of interfaces with different wettabilities to minimize and reduce the leakage of oil in static sealing systems.

Inflammatory microenvironment regulation and osteogenesis promotion by bone-targeting calcium and magnesium repletion nanoplatform for osteoporosis therapy.

Osteoporosis is the most common bone metabolic disease that affects the health of middle-aged and elderly people, which is hallmarked by imbalanced bone remodeling and a deteriorating immune microenvironment. Magnesium and calcium are pivotal matrix components that participate in the bone formation process, especially in the immune microenvironment regulation and bone remodeling stages. Nevertheless, how to potently deliver magnesium and calcium to bone tissue remains a challenge. Here, we have constructed a multifunctional nanoplatform composed of calcium-based upconversion nanoparticles and magnesium organic frameworks (CM-NH2-PAA-Ald, denoted as CMPA), which features bone-targeting and pH-responsive properties, effectively regulating the inflammatory microenvironment and promoting the coordination of osteogenic functions for treating osteoporosis. The nanoplatform can efficaciously target bone tissue and gradually degrade in response to the acidic microenvironment of osteoporosis to release magnesium and calcium ions. This study validates that CMPA possessing favorable biocompatibility can suppress inflammation and facilitate osteogenesis to treat osteoporosis. Importantly, high-throughput sequencing results demonstrate that the nanoplatform exerts a good inflammatory regulation effect through inhibition of the nuclear factor kappa-B signaling pathway, thereby normalizing the osteoporotic microenvironment. This collaborative therapeutic strategy that focuses on improving bone microenvironment and promoting osteogenesis provides new insight for the treatment of metabolic diseases such as osteoporosis.

Enhancing angiogenesis and inhibiting apoptosis: evaluating the therapeutic efficacy of bone marrow mesenchymal stem cell-derived exosomes in a DHEA-induced PCOS mouse model.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a widespread endocrine disorder among women, characterized by symptoms like ovarian cysts, hormonal imbalance, and metabolic issues. This research evaluates the therapeutic potential of Bone Marrow Mesenchymal Stem Cell-derived exosomes (BMSC-Exo) in treating PCOS symptoms within a mouse model. METHODS: BMSC-Exo were isolated from NMRI mice, characterized using Transmission Electron Microscopy (TEM) and Nanoparticle Tracking Analysis (NTA), and administered to a PCOS mouse model induced by dehydroepiandrosterone (DHEA). The efficacy of BMSC-Exo was assessed in three groups of mice: a control group, a PCOS group, and a PCOS group treated with intravenous BMSC-Exo. Morphological changes in ovarian tissue were examined by Hematoxylin and Eosin (H&E) staining, apoptosis was determined using the TUNEL assay, and CD31 expression was analyzed through immunofluorescent staining to assess angiogenic activity. RESULTS: The existence of BMSCs-Exo was confirmed via TEM and NTA, revealing their distinct cup-shaped morphology and a size range of 30 to 150 nanometers. H&E staining revealed that BMSCs-Exo treatment improved ovarian morphology in PCOS models, increasing corpora lutea and revitalizing granulosa cell layers, suggesting a reversal of PCOS-induced damage. TUNEL assays showed that BMSCs-Exo treatment significantly reduced apoptosis in PCOS-affected ovarian cells to levels comparable with the control group, highlighting its role in mitigating PCOS-induced cellular apoptosis. Immunofluorescence for CD31 indicated that BMSCs-Exo treatment normalized endothelial marker expression and angiogenic activity in PCOS models, suggesting its effectiveness in modulating the vascular irregularities of PCOS. Collectively, these findings demonstrate the therapeutic potential of BMSCs-Exo in addressing ovarian dysfunction, cellular apoptosis, and aberrant angiogenesis associated with PCOS. CONCLUSION: The study substantiates the role of BMSC-Exo in mitigating the deleterious effects of PCOS on ovarian tissue, with implications for enhanced follicular development and reduced cellular stress. The modulation of CD31 by BMSC-Exo further highlights their potential in normalizing PCOS-induced vascular anomalies. These findings propel the need for clinical investigations to explore BMSC-Exo as a promising therapeutic avenue for PCOS management.

Lactobacillus reuteri compared with placebo as an adjuvant in Helicobacter pylori eradication therapy: a meta-analysis of randomized controlled trials.

Background: Given the growing problem of antibiotic resistance, it is crucial to improve Helicobacter pylori (H. pylori) treatment interventions or provide adjunctive therapy. The objective of this meta-analysis was to evaluate whether Lactobacillus reuteri (L. reuteri) could improve H. pylori eradication rate, reduce the incidence of adverse events (AEs), and alleviate gastrointestinal symptoms. Design: A meta-analysis of randomized controlled trials (RCTs) comparing L. reuteri supplementation therapy with placebo was conducted. Sources and methods: We retrieved relevant studies from PubMed, Embase, and the Cochrane Library. The primary outcome was H. pylori eradication rate, and the scores on the Gastrointestinal Symptom Rating Scale and AEs were secondary outcomes. Results: Eight RCTs including 1087 patients were included in this analysis. The L. reuteri supplementation group showed significantly higher H. pylori eradication rates in both intention-to-treat (ITT) and per-protocol (PP) analysis [ITT: 80.0% versus 72.6%; p = 0.005, relative risk (RR): 1.10; 95% confidence interval (CI): 1.03-1.17; number needed to treat (NNT) = 14; PP: 81.8% versus 75.0%; p = 0.006, RR: 1.09; 95% CI: 1.03-1.16; NNT = 15]. Patients treated with L. reuteri showed greater improvements in gastrointestinal symptoms (pooled mean difference: -2.43, 95% CI: -4.56 to -0.29, p = 0.03). The incidence of AEs was significantly reduced in the L. reuteri supplementation group based on ITT and PP analysis (ITT: p < 0.00001, RR: 0.72, 95% CI: 0.67-0.78; PP: p < 0.00001, RR: 0.70, 95% CI: 0.65-0.77). Conclusion: The present meta-analysis demonstrated that supplementation with L. reuteri was beneficial for improving the eradication rate of H. pylori, reducing the overall incidence of side effects, and relieving gastrointestinal symptoms in patients during treatment. The findings provide new insights into clinical decision-making. Trial registration PROSPERO: CRD42023424052.

Lactobacillus reuteri compared with placebo as an adjuvant in Helicobacter pylori eradication therapy: a meta-analysis of randomized controlled trials Given the growing problem of antibiotic resistance, it is crucial to improve Helicobacter pylori (H. pylori) treatment interventions or provide adjunctive therapy. Eight randomized controlled trials (RCTs) including 1087 patients were included in this analysis. The present meta-analysis demonstrated that supplementing with L. reuteri tends to increase the eradication rate of H. pylori, reduce the overall incidence of antibiotic-related side effects, and alleviate gastrointestinal symptoms in patients during treatment, providing new insights for clinical decision-making.

IDEAL-IQ measurement can distinguish dysplastic nodule from early hepatocellular carcinoma: a case-control study.

Background: Previous studies have confirmed that malignant transformation of dysplastic nodule (DN) into hepatocellular carcinoma (HCC) is accompanied by reduction of iron content in nodules. This pathological abnormality can serve as the basis for magnetic resonance imaging (MRI). This study was designed to identify the feasibility of iterative decomposition of water and fat with echo asymmetry and least squares estimation-iron quantitative (IDEAL-IQ) measurement to distinguish early hepatocellular carcinoma (eHCC) from DN. Methods: We reviewed MRI studies of 35 eHCC and 23 DN lesions (46 participants with 58 lesions total, 37 males, 9 females, 31-80 years old). The exams include IDEAL-IQ sequence and 3.0T MR conventional scan [including T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and Gadopentic acid (Gd-GDPA)-enhanced]. Then, 3 readers independently diagnosed eHCC, DN, or were unable to distinguish eHCC from DN using conventional MRI (CMRI), and then assessed R2* value of nodules [R2* value represents the nodule iron content (NIC)] and R2* value of liver background [R2* value represents the liver background iron content (LBIC)] with IDEAL-IQ. Statistical analysis was conducted using the t-test for comparison of means, the Mann-Whitney test for comparison of medians, the chi-square test for comparison of frequencies, and diagnostic efficacy was evaluated by using receiver operating characteristic (ROC) curve. Results: This study evaluated 35 eHCC participants (17 males, 6 females, 34-81 years old, nodule size: 10.5-27.6 mm, median 18.0 mm) and 23 DN participants (20 males, 3 females, 31-76 years old, nodule size: 16.30±4.095 mm). The NIC and ratio of NIC to LIBC (NIC/LBIC) of the eHCC group (35.926±12.806 sec-1, 0.327±0.107) was lower than that of the DN group (176.635±87.686 sec-1, 1.799±0.629) (P<0.001). Using NIC and NIC/LBIC to distinguish eHCC from DN, the true positive/false positive rates were 91.3%/94.3% and 87.0%/97.1%, respectively. The rates of CMRI, NIC and NIC/LBIC in diagnosis of eHCC were 77.1%, and 94.3%, 97.1%, respectively, and those of DN were 65.2%, 91.3%, and 87.0%, respectively. The diagnosis rate of eHCC and DN by CMRI was lower than that of NIC and NIC/LBIC (eHCC: P=0.03, 0.04, DN: P=0.02, 0.04). Conclusions: Using IDEAL-IQ measurement can distinguish DN from eHCC.

Mir-204-5p alleviates mitochondrial dysfunction by targeting IGFBP5 in diabetic cataract.

BACKGROUND: Cataract contributes to visual impairment worldwide, and diabetes mellitus accelerates the formation and progression of cataract. Here we found that the expression level of miR-204-5p was diminished in the lens epithelium with anterior lens capsule of cataract patients compared to normal donors, and decreased more obviously in those of diabetic cataract (DC) patients. However, the contribution and mechanism of miR-204-5p during DC development remain elusive. METHODS AND RESULT: The mitochondrial membrane potential (MMP) was reduced in the lens epithelium with anterior lens capsule of DC patients and the H2O2-induced human lens epithelial cell (HLEC) cataract model, suggesting impaired mitochondrial functional capacity. Consistently, miR-204-5p knockdown by the specific inhibitor also attenuated the MMP in HLECs. Using bioinformatics and a luciferase assay, further by immunofluorescence staining and Western blot, we identified IGFBP5, an insulin-like growth factor binding protein, as a direct target of miR-204-5p in HLECs. IGFBP5 expression was upregulated in the lens epithelium with anterior lens capsule of DC patients and in the HLEC cataract model, and IGFBP5 knockdown could reverse the mitochondrial dysfunction in the HLEC cataract model. CONCLUSIONS: Our results demonstrate that miR-204-5p maintains mitochondrial functional integrity through repressing IGFBP5, and reveal IGFBP5 may be a new therapeutic target and prognostic factor for DC.

Reactive oxide species and ultrasound dual-responsive bilayer microneedle array for in-situ sequential therapy of acute myocardial infarction.

Acute myocardial infarction (AMI) resulting from coronary artery occlusion stands as the predominant cause of cardiovascular disability and mortality worldwide. An all-encompassing treatment strategy targeting pathological processes of oxidative stress, inflammation, proliferation and fibrotic remodeling post-AMI is anticipated to enhance therapeutic outcomes. Herein, an up-down-structured bilayer microneedle (Ce-CLMs-BMN) with reactive oxygen species (ROS) and ultrasound (US) dual-responsiveness is proposed for AMI in-situ sequential therapy. The upper-layer microneedle is formulated by crosslinking ROS-sensitive linker with polyvinyl alcohol loaded with cerium dioxide nanoparticles (CeNPs) featuring versatile enzyme-mimetic activities. During AMI acute phase, prompted by ischemia-induced microenvironmental redox imbalance, this layer swiftly releases CeNPs, which aid in eliminating excessive ROS and catalyzing oxygen gas (O2) production through multiple enzymatic pathways, thereby alleviating oxidative stress-induced damage and modulating inflammation. In AMI chronic repair phase, micro-nano reactors (CLMs) situated in the lower-layer microneedle undergo cascade reactions with the assistance of US irradiation to generate nitric oxide (NO). As a bioactive molecule with pro-angiogenic and anti-fibrotic effects, NO expedites cardiac repair while attenuating adverse remodeling. Additionally, its antiplatelet-aggregating properties contribute to thromboprophylaxis. In-vitro and in-vivo results substantiate the efficacy of this integrated healing approach in AMI management, showcasing promising prospects for advancing infarcted heart repair.

Transcranial magnetic stimulation in the assessment of acupuncture effect on exercise-induced fatigue.

BACKGROUND: Acupuncture as a traditional Chinese medicine therapy relies on unique theories to alleviate fatigue. The aim of this study is to evaluate the effect of acupuncture on exercise-induced fatigue utilizing transcranial magnetic stimulation (TMS). METHODS: A total of 20 participants with regular exercise habits were recruited for this study. All participants were randomly assigned to receive either acupuncture or sham acupuncture intervention for exercise-induced fatigue. TMS and a heart rate monitor were used to measure the amplitude and latency of motor evoked potential (MEP) as well as heart rate every 5 min over a 30-min period. The blood lactic acid (BLA) levels were measured using Lactate Scout+ at baseline, 0 min, and 30 min after fatigue. Two-way repeated measures analysis of variance was utilized to compare the differences between the effects of acupuncture method and time. Bonferroni post hoc tests were conducted to compare specific differences. Statistical significance was set at p < .05. RESULTS: Interaction effect was observed between acupuncture method and time effect in terms of amplitude (F(1, 38) = 5.40, p < .001, η2 = 0.12) and latency (F(1, 38) = 3.78, p = .008, η2 = .09) of MEP. The application of acupuncture can promote the recovery of heart rate especially at 30 min (p < .05), but which seem insufficient to generate significant difference in BLA (F(1, 38) = 0.067, p = .797, η2 = 0.002). CONCLUSIONS: Acupuncture can promote the increase of MEP amplitude, shorten MEP latency, and restore heart rate. Preliminary findings provide novel insights for individuals with exercise habits to alleviate fatigue and enhance sports performance.

Organic radicals driving polycyclic aromatic hydrocarbon polymerization with peracetic acid activation in soil.

The use of peracetic acid (PAA) in advanced oxidation processes has gained significant attention recently, but the knowledge of activating PAA to degrade polycyclic aromatic hydrocarbons (PAHs) is limited due to the variety and selectivity of reactive substances in PAA oxidation system. This paper presented the first systemically study on the degradation of PAHs by PAA activation in soil. It was found that heat-activated peracetic acid (heat/PAA) was capable of degrading phenanthrene (PHE) efficiently with degradation efficiency > 90 % within 30 min. Experimental results demonstrated that a series of reactive oxygen species (ROS) including organic radicals (RO•), hydroxyl radicals (HO•) and singlet oxygen (1O2) were generated, while acetylperoxyl (CH3C(O)OO•) and acetyloxyl (CH3C(O)O•) radicals were primarily responsible for PHE degradation in soil. Further analysis shows that polymerization products such as diphenic acid, 2'-formyl-2-biphenylcarboxylic acid and other macromolecules were dominant products of PHE degradation, suggesting polymerization driving PHE degradation instead of the conventional mineralization process. Toxicity analysis shows that most of the polymerization products had less toxicity than that of PHE. These results indicate that PAA activation was a highly effective remediation method for PAHs contaminated soil, which also provided a novel mechanism for pollutant degradation with the PAA activation process for environmental remediation.

A reconfigurable integrated smart device for real-time monitoring and synergistic treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a global autoimmune disease that requires long-term management. Ambulatory monitoring and treatment of RA favors remission and rehabilitation. Here, we developed a wearable reconfigurable integrated smart device (ISD) for real-time inflammatory monitoring and synergistic therapy of RA. The device establishes an electrical-coupling and substance delivery interfaces with the skin through template-free conductive polymer microneedles that exhibit high capacitance, low impedance, and appropriate mechanical properties. The reconfigurable electronics drive the microneedle-skin interfaces to monitor tissue impedance and on-demand drug delivery. Studies in vitro demonstrated the anti-inflammatory effect of electrical stimulation on macrophages and revealed the molecular mechanism. In a rodent model, impedance sensing was validated to hint inflammation condition and facilitate diagnosis through machine learning model. The outcome of subsequent synergistic therapy showed notable relief of symptoms, elimination of synovial inflammation, and avoidance of bone destruction.

Curcumin Equipped Nanozyme-Like Metal-Organic Framework Platform for the Targeted Atherosclerosis Treatment with Lipid Regulation and Enhanced Magnetic Resonance Imaging Capability.

Atherosclerotic cardiovascular disease (ASCVD) has become the leading cause of death worldwide, and early diagnosis and treatment of atherosclerosis (AS) are crucial for reducing the occurrence of acute cardiovascular events. However, early diagnosis of AS is challenging, and oral anti-AS drugs suffer from limitations like imprecise targeting and low bioavailability. To overcome the aforementioned shortcomings, Cur/MOF@DS is developed, a nanoplatform integrating diagnosis and treatment by loading curcumin (Cur) into metal-organic frameworks with nanozymes and magnetic resonance imaging (MRI) properties. In addition, the surface-modification of dextran sulfate (DS) enables PCN-222(Mn) effectively target scavenger receptor class A in macrophages or foam cells within the plaque region. This nanoplatform employs mechanisms that effectively scavenge excessive reactive oxygen species in the plaque microenvironment, promote macrophage autophagy and regulate macrophage polarization to realize lipid regulation. In vivo and in vitro experiments confirm that this nanoplatform has outstanding MRI performance and anti-AS effects, which may provide a new option for early diagnosis and treatment of AS.

Extent of surgery for unilateral papillary thyroid cancer with nonsuspicious contralateral nodules by ultrasound.

BACKGROUND: The discussion about surgical treatment of patients with papillary thyroid cancer(PTC) has been an ongoing issue, which is mainly focused on characteristics of tumor, but rarely on nonsuspicious contralateral nodules. We aimed to compare recurrence-free survival(RFS)/progression-free survival(PFS) of unilateral PTC patients with nonsuspicious contralateral nodules after different extents of surgery. METHODS: Unilateral PTC patients with nonsuspicious contralateral nodules underwent surgery from 2015 to 2017 were enrolled. The association between surgical extent and RFS/PFS was analyzed by Kaplan-Meier method and Cox proportional hazards model. RESULTS: A total of 1293 PTC patients (595[46.0%]TT,523[40.4%]lobectomy+nodule enucleation(LNE),175[13.5%]lobectomy) were analyzed. Patients with a greater surgical extent were more likely to be older, have a greater multifocality of the tumor and contralateral nodules, larger contralateral nodules and primary tumors, and more micro extrathyroidal extension (P < 0.05). After a median follow-up of 45 months, significant growth(>3 mm) was identified in 24 (4.6%) and 19 (10.9%) patients in the LNE and lobectomy group, 7 (1.2%), 14 (2.7%) and 11 (6.3%) structural recurrences and 7 (1.2%), 11 (2.1%) and 7 (4.0%) progression in disease were identified in the TT, LNE and lobectomy groups, respectively. Unadjusted and adjusted RFS/PFS were significantly worse for patients treated with lobectomy than for those who underwent LNE or TT(3-year RFS, 95.5%, 98.2% vs. 99.0%; 3-year PFS, 97.9%, 98.9% vs. 99.0%, P < 0.05), but difference in PFS between LNE and TT lost statistical significance (unadjusted P = 0.226, adjusted P = 0.150). CONCLUSIONS: Due to subtle changes in nodules and acceptable prognosis, lobectomy is a considerable option for unilateral PTC patients with nonsuspicious nodules, when a similar prognosis to TT is expected, LNE may be an effective alternative to optimize quality of life.

Infliximab modifies CD74-mediated lymphatic abnormalities and adipose tissue alterations in creeping fat of Crohn's disease.

BACKGROUND: Lymphatic abnormalities are essential for pathophysiologic changes of creeping fat (CrF) in Crohn's disease (CD). Anti-tumor necrosis factor (TNF) therapy has been proved to alleviate CrF lesions, however, whether it achieves these by remodeling lymphatics is unknown. METHODS: CD74 expression was detected in CrF and uninvolved mesentery of CD patients. Lymphatic functions in vitro were evaluated and lymphatic endothelium barrier were checked by transendothelial electrical resistance (TEER) and FITC-Dextran permeability. Protein level of tight junction and signaling pathways were detected by western blotting. RESULTS: CD74 was upregulated in LECs of CrF and positively correlated with TNF-α synthesis. This was suppressed by IFX administration. In vitro, TNF-α stimulated LECs to express CD74 through NF-κB signaling pathway, and this was rescued by IFX. CD74 downregulation suppressed the abilities of LECs in proliferation, migration and tube formation. Interaction of CD74-MIF impaired LECs' barrier via reducing tight junction proteins in an ERK1/2-dependent manner, which was reversed by CD74 downregulation. Consistently, the CD patients receiving IFX therapy displayed decreased lymphangiogenesis and improved mesenteric lymphatic endothelium barrier, companied with reduced adipocyte size and adipokine levels in CrF. CONCLUSIONS: Anti-TNF therapy could modify pathological changes in CrF by alleviating CD74-mediated lymphatic abnormalities.

Association Between Exposure to Multiple Toxic Metals in Follicular Fluid and the Risk of PCOS Among Infertile Women: The Mediating Effect of Metabolic Markers.

Polycystic ovary syndrome (PCOS) severely affects women's fertility and accompanies serious metabolic disturbances, affecting 5%-20% of women of reproductive age globally. We previously found that exposure to toxic metals in the blood raised the risk of PCOS, but the association between exposure to toxic metals and the risk of PCOS in the follicular fluid, the microenvironment for oocyte growth and development in females, and its effect on metabolism has not been reported. This study aimed to evaluate the associations between the concentrations of cadmium (Cd), mercury (Hg), barium (Ba) and arsenic (As) in FF and the risk of PCOS, and to explore the mediating effect of metabolic markers in FF on the above relationship. We conducted a case-control study, including 557 women with PCOS and 651 controls. Ba, Cd, Hg and As levels in FF were measured by ICP-MS, metabolites levels in FF was measured by LC-MS/MS among 168 participants randomly selected from all the participants. Logistic regression models were used to assess the association of a single metal level with the PCOS risk, and linear regression models were used to assess the relationships of a single metal level with clinical phenotype parameters and metabolites levels. Combined effect of metals mixture levels on the risk of PCOS were assessed via weighted quantile sum (WQS) regression and bayesian kernel machine regression (BKMR). Medication analysis was performed to explore the role of metabolic markers on the relationship of toxic metals levels with the risk of PCOS. The exposure levels of Cd, Hg, Ba and As in FF were all positively and significantly associated with the PCOS risk (with respect to the highest vs. lowest tertile group: OR = 1.57, 95% CI = 1.17 ~ 2.12 for Cd, OR = 1.69, 95% CI = 1.22 ~ 2.34 for Hg, OR = 1.76, 95% CI = 1.32 ~ 2.34 for Ba, OR = 1.42, 95% CI = 1.05 ~ 1.91 for As). In addition, levels of metal mixture also significantly correlated with the risk of PCOS, Cd level contributed most to it. Moreover, we observed significant positive relationships between Cd level and LH (ß = 0.048, 95% CI = 0.002 ~ 0.094), T (ß = 0.077, 95% CI = 0.029 ~ 0.125) and HOMA-IR value (ß = 0.060, 95% CI = 0.012 ~ 0.107), as well as Hg level with LH, FSH/LH ratio and TC. Furthermore, we revealed that estrone sulfate, LysoPE 22:6 and N-Undecanoylglycine were significantly and positively mediating the association between Cd level and the risk of PCOS (with mediated proportion of 0.39, 0.24 and 0.35, respectively), and between Hg level and the risk of PCOS (with mediated proportion of 0.29, 0.20 and 0.46, respectively). These highly expressed metabolites significantly enriched in the fatty acid oxidation, steroid hormone biosynthesis and glycerophospholipids metabolism, which may explain the reason why the levels of Cd and Hg in FF associated with the phenotype of PCOS. Ba and As in FF was not found the above phenomenon. Our results suggested that exposure to multiple toxic metals (Cd, Hg, Ba and As) in FF associated with the increased risk of PCOS, Cd was a major contributor. Levels of Cd and Hg in FF significantly associated with the phenotype of PCOS. The above association may result from that Cd and Hg in FF related with the disturbance of fatty acid oxidation, steroid hormone biosynthesis and the glycerophospholipids metabolism.

Intranasal Delivery of Near-Infrared and Magnetic Dual-Response Nanospheres to Rapidly Produce Antidepressant-Like and Cognitive Enhancement Effects.

Restricted by synaptic plasticity, dopamine receptor (DR) upregulation takes a long time to work. Moreover, the impact of the blood-brain barrier (BBB) on delivery efficiency restricts the development of drugs. Taking inspiration from snuff bottles, a convenient, fast-acting, and nonaddictive nasal drug delivery system has been developed to rapidly reshape the balance of synaptic transmitters. This optical and magnetic response system called CFs@DP, comprised of carbonized MIL-100 (Fe) frameworks (CFs) and domperidone (DP), which can enter the brain via nasal administration. Under dual stimulation of near-infrared (NIR) irradiation and catecholamine-induced complexation, CFs@DP disintegrates to release iron ions and DP, causing upregulation of the dopamine type 1 (D1), type 2 (D2) receptors, and brain-derived neurotrophic factor (BDNF) to achieve a therapeutic effect. In vivo experiments demonstrate that the DR density of mice (postnatal day 50-60) increased in the prefrontal cortex (PFC) and the hippocampus (HPC) after 10 days of therapy, resulting in antidepressant-like and cognitive enhancement effects. Interestingly, the cognitive enhancement effect of CFs@DP is even working in noniron deficiency (normal fed) mice, making it a promising candidate for application in enhancing learning ability.

Synergy of nodal factors in predicting recurrence after treatment of N1b papillary thyroid carcinoma.

BACKGROUND: Nodal factors are important predictors of prognosis for papillary thyroid carcinoma (PTC), but their synergy effect is not well understood. We aimed to explore their synergy effect in predicting recurrence of clinical N1b PTC. METHODS: Patients who underwent surgery for cN1b PTC from 2013 to 2017 were enrolled. The association between nodal factors and recurrence was assessed using Cox proportional hazards regression models. Interaction and stratified analyses were conducted according to significant nodal factors. RESULTS: Of 1067 cN1b PTC patients included, all nodal factors (bilateral metastasis, largest dimension>3cm, micro and gross extranodal extension (mENE, gENE), No. of metastatic lymph nodes (MLN), lymph node yield (LNY) and ratio (LNR)) were significantly associated with all site and nodal recurrence in the univariate analysis (all P<0.05). Multivariate analyses revealed largest dimension>3cm, gENE and LNR>0.21 were associated with elevated both all site (HR [95%CI], 2.58 [1.67-4.00], 1.87[1.26-3.01], 1.68[1.11-2.42], all P<0.01) and nodal recurrences (HR[95%CI], 2.63[1.67-4.13], 1.90[1.15-3.12], 1.76[1.17-2.66], all P<0.01). LNR and gENE had interactive effect (all site recurrence: P for interaction = 0.009; nodal recurrence: P for interaction = 0.02). LNR was significantly associated with recurrence in patients without gENE (HR[95% CI], all site recurrence: 2.41[1.50-3.87]; nodal recurrence: 2.51[1.52-4.14], all P< 0.001), while when gENE appeared, LNR was no longer associated with recurrence (HR [95% CI], all site recurrence: 0.81[0.43-1.54], P=0.53; nodal recurrence: 0.85[0.43-1.67], P=0.64). CONCLUSIONS: Nodal factors have synergy effect in predicting recurrence in cN1b PTC patients. Increasing lymph nodes harvest may only decrease recurrence in patients without gENE, while not in gENE patients.

Synthesis of 1,2-Disubstituted C-Aryl Glycosides via Palladium/Norbornene Cooperative Catalysis.

The Catellani reaction offers an opportunity to address multiple chemical bonds in a single pot. However, it is still quite a challenge to construct fully substituted olefins via this strategy, especially in electron-rich, unstable, and highly functionalized glycals. Herein we report the first palladium-catalyzed Catellani reaction for the direct preparation of 1,2-disubstituted C-aryl glycosides from easily available 2-iodoglycals, bromoaryl, and alkene/alkyne substrates. This transformation exhibits a wide substrate scope, accommodating diverse functional groups and intricate molecular frameworks. This innovative reactivity offers an efficient pathway to valuable 1,2-disubstituted carbohydrate analogues and molecular building blocks, facilitating novel strategic bond disconnections and broadening the reactivity landscape of palladium catalysis.

The Role of SLIT3-ROBO4 Signaling in Endoplasmic Reticulum Stress-Induced Delayed Corneal Epithelial and Nerve Regeneration.

Purpose: In the present study, we aim to elucidate the underlying molecular mechanism of endoplasmic reticulum (ER) stress induced delayed corneal epithelial wound healing and nerve regeneration. Methods: Human limbal epithelial cells (HLECs) were treated with thapsigargin to induce excessive ER stress and then RNA sequencing was performed. Immunofluorescence, qPCR, Western blot, and ELISA were used to detect the expression changes of SLIT3 and its receptors ROBO1-4. The role of recombinant SLIT3 protein in corneal epithelial proliferation and migration were assessed by CCK8 and cell scratch assay, respectively. Thapsigargin, exogenous SLIT3 protein, SLIT3-specific siRNA, and ROBO4-specific siRNA was injected subconjunctivally to evaluate the effects of different intervention on corneal epithelial and nerve regeneration. In addition, Ki67 staining was performed to evaluate the proliferation ability of epithelial cells. Results: Thapsigargin suppressed normal corneal epithelial and nerve regeneration significantly. RNA sequencing genes related to development and regeneration revealed that thapsigargin induced ER stress significantly upregulated the expression of SLIT3 and ROBO4 in corneal epithelial cells. Exogenous SLIT3 inhibited normal corneal epithelial injury repair and nerve regeneration, and significantly suppressed the proliferation and migration ability of cultured mouse corneal epithelial cells. SLIT3 siRNA inhibited ROBO4 expression and promoted epithelial wound healing under thapsigargin treatment. ROBO4 siRNA significantly attenuated the delayed corneal epithelial injury repair and nerve regeneration induced by SLIT3 treatment or thapsigargin treatment. Conclusions: ER stress inhibits corneal epithelial injury repair and nerve regeneration may be related with the upregulation of SLIT3-ROBO4 pathway.