In vitro and in vivo antiproliferative activity on lung cancer of two acylhydrazone based zinc(II) complexes.

Two acylhydrazone based zinc(II) complexes [Zn(HL)2Cl2(CH3OH)2] (Zn1) and [ZnL(AC)]2 (Zn2) were synthesized from 3-(1-(salicyloylhydrazono)ethyl) pyridine (HL). Single crystal X-ray structure analyses showed that complexes Zn1 and Zn2 have a zero-dimensional monomer or dimer structure. Antiproliferative activity studies revealed that Zn1 and Zn2 are both more effective against A549 cells than cisplatin. The results of the reactive oxygen species (ROS) generation assay on A549 cells showed that both Zn1 and Zn2 induced apoptosis through ROS accumulation. The apoptosis-inducing and cell cycle arrest effects of Zn1 and Zn2 on A549 cells indicated that the antitumor effect was achieved through apoptosis induction and inhibition of DNA synthesis by blocking the G0/G1 phase of the cell cycle. What's more, the results of wound-healing assay showed that Zn1 and Zn2 could inhibit the migration of A549 cells. Western blot analysis further demonstrated that Zn1 and Zn2 induced cell apoptosis through the mitochondrial pathway, in which process, the expression level of cytochrome C, cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 9 proteins increased while pro-caspase 3 and pro-caspase 9 expression decreased. In vivo anticancer evaluation demonstrated that both Zn1 and Zn2 complexes effectively inhibited tumor growth without causing significant toxicity in systemic organs.

Genome-wide profiling of angiogenic cis-regulatory elements unravels cis-regulatory SNPs for vascular abnormality.

Angiogenesis is extensively involved in embryonic development and requires complex regulation networks, whose defects can cause a variety of vascular abnormalities. Cis-regulatory elements control gene expression at all developmental stages, but they have not been studied or profiled in angiogenesis yet. In this study, we exploited public DNase-seq and RNA-seq datasets from a VEGFA-stimulated in vitro angiogenic model, and carried out an integrated analysis of the transcriptome and chromatin accessibility across the entire process. Totally, we generated a bank of 47,125 angiogenic cis-regulatory elements with promoter (marker by H3K4me3) and/or enhancer (marker by H3K27ac) activities. Motif enrichment analysis revealed that these angiogenic cis-regulatory elements interacted preferentially with ETS family TFs. With this tool, we performed an association study using our WES data of TAPVC and identified rs199530718 as a cis-regulatory SNP associated with disease risk. Altogether, this study generated a genome-wide bank of angiogenic cis-regulatory elements and illustrated its utility in identifying novel cis-regulatory SNPs for TAPVC, expanding new horizons of angiogenesis as well as vascular abnormality genetics.

Integrated Transcriptomic and Proteomic Study of the Mechanism of Action of the Novel Small-Molecule Positive Allosteric Modulator 1 in Targeting PAC1-R for the Treatment of D-Gal-Induced Aging Mice.

Small-molecule positive allosteric modulator 1 (SPAM1), which targets pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R), has been found to have a neuroprotective effect, and the underlying mechanism was explored in this study. First, using a D-galactose (D-gal)-induced aging mouse model, we confirmed that SPAM1 improves the structure of the hippocampal dentate gyrus and restores the number of neurons. Compared with D-gal model mice, SPAM1-treated mice showed up-regulated expression of Sirtuin 6 (SIRT6) and Lamin B1 and down-regulated expression of YinYang 1 (YY1) and p16. A similar tendency was observed in senescent RGC-5 cells induced by long-term culture, indicating that SPAM1 exhibits significant in vitro and in vivo anti-senescence activity in neurons. Then, using whole-transcriptome sequencing and proteomic analysis, we further explored the mechanism behind SPAM1's neuroprotective effects and found that SPAM is involved in the longevity-regulating pathway. Finally, the up-regulation of neurofilament light and medium polypeptides indicated by the proteomics results was further confirmed by Western blotting. These results help to lay a pharmacological network foundation for the use of SPAM1 as a potent anti-aging therapeutic drug to combat neurodegeneration with anti-senescence, neuroprotective, and nerve regeneration activity.

Dapagliflozin promotes browning of white adipose tissue through the FGFR1-LKB1-AMPK signaling pathway.

BACKGROUND: Obesity is associated with a wide variety of metabolic disorders that impose significant burdens on patients and society. The "browning" phenomenon in white adipose tissue (WAT) has emerged as a promising therapeutic strategy to combat metabolic disturbances. However, though the anti-diabetic drug dapagliflozin (DAPA) is thought to promote "browning," the specific mechanism of this was previously unclear. METHODS: In this study, C57BL/6 J male mice were used to establish an obesity model by high-fat diet feeding, and 3T3-L1 cells were used to induce mature adipocytes and to explore the role and mechanism of DAPA in "browning" through a combination of in vitro and in vivo experiments. RESULTS: The results show that DAPA promotes WAT "browning" and improves metabolic disorders. Furthermore, we discovered that DAPA activated "browning" through the fibroblast growth factor receptors 1-liver kinase B1-adenosine monophosphate-activated protein kinase signaling pathway. CONCLUSION: These findings provide a rational basis for the use of DAPA in treating obesity by promoting the browning of white adipose tissue.

CeCR: Cross-entropy contrastive replay for online class-incremental continual learning.

Aiming at the realization of learning continually from an online data stream, replay-based methods have shown superior potential. The main challenge of replay-based methods is the selection of representative samples which are stored in the buffer and replayed. In this paper, we propose the Cross-entropy Contrastive Replay (CeCR) method in the online class-incremental setting. First, we present the Class-focused Memory Retrieval method that proceeds the class-level sampling without replacement. Second, we put forward the class-mean approximation memory update method that selectively replaces the mistakenly classified training samples with samples of current input batch. In addition, the Cross-entropy Contrastive Loss is proposed to implement the model training with obtaining more solid knowledge to achieve effective learning. Experiments show that the CeCR method has comparable or improved performance in two benchmark datasets in comparison with the state-of-the-art methods.

Ion imprinted differential modulation system based on enhanced optic-fiber evanescent wave for sensitive and label-free detection of trace nickel ions.

An optical system with low cost monitoring, high sensitivity, strong selectivity and much lower nickel ion (Ni2+) content in tap water than the World Health Organization (WHO) standard (1.19 µM) has been prepared by a simple strategy. This proposed ion-imprinted differential modulation system is based on the Bragg grating (FBG) and microfiber interferometer structure, and the interferometer sensing surface is coated with a polydopamine (PDA)/graphene oxide (GO) film to enhance its sensitivity. Combined with the ion imprinting technique, the microfiber interferometer sensor sensitivity can reach 0.32 nm/nM with the detection limit of 0.66 nM in the low concentration range (Ni2+ concentration range is 0 nM-100 nM). The experiment not only studies the principle of microfiber interferometer and FBG and their refractive index and temperature performance, but also shows that the FBG power change has a good fitting relationship with wavelength change. In addition, this system performance by the amount of power difference rather than the amount of wavelength shift, which significantly saves on the high cost weight, and size associated with the use of spectral analyzers in traditional inspection systems. This study provides a novel and easy method to develop new sensors with higher comprehensive performance.

Chemically tailored molecular surface modification of bamboo pulp fibers for manipulating the electret performance of electret filter media.

The surface chemical composition of materials is essential for regulating their charge trapping and storage capabilities, which directly affect their electret performance. Although chemical modification of materials to alter electret performance has been investigated, the mechanism through which electret properties are regulated more systematically via chemical customization has not been elucidated in detail. Herein, p-phenylenediamine, benzidine and 4,4'-diaminotriphenyl, which have different conjugated strength functional groups, were selected to chemically tailor the surface of bamboo pulp fibers to regulate the electret properties and elucidate the regulatory mechanism more systematically. The results showed that the charge trapping and storage properties of materials could be regulated by introducing functional groups with different conjugated strengths to their surfaces, realizing the regulation of the electret properties. Moreover, the charge trapping and storage ability could be tailored more specifically by regulating the number of functional groups. By chemical customization to provide electrostatic effects to the materials, the purification time was reduced by approximately 45 %-52 %. More importantly, a relatively systematic mechanism was proposed to elucidate the effect of the conjugate group strength on the charge trapping and charge storage properties of the material. These findings will provide guidance for the investigation of chemical modifications to regulate the electret performance of materials.

Research progress on classical traditional Chinese medicine formula Baihe Zhimu (Lilium lancifolium bulb and Anemarrhena asphodeloides rhizome) decoction in the treatment of depression.

Depression is considered to be an "emotional disease" in ancient books of traditional Chinese medicine. Its clinical features are similar to those of "Lily disease" in the ancient Chinese medicine book Synopsis of the Golden Chamber written by Zhang Zhongjing in the Han Dynasty. Baihe Zhimu (Lilium lancifolium bulb and Anemarrhena asphodeloides rhizome) decoction (LBRAD) is the first prescription of "Lily Disease" in this book. It is also a special remedy for "Lily disease" after sweating. The classic recipe LBRAD consists of two herbs, fresh lily bulbs and dried Rhizoma Anemarrhena slice. It has the effect of supplementing nutrition and clearing heat, nourishing Yin and moistening. After more than two thousand years of clinical practice, it has been currently widely used in clinical treatment of depression. In this paper, the relationship between LBRAD and depression was systematically reviewed from both clinical and experimental studies, as well as the preparation, the clinical application, the pharmacological mechanism and the effective material basis for the treating depression of LBRAD. The core targets and biological processes of the depression treatment were explored through network pharmacological analysis, so as to speculate its potential mechanism. Finally, the association between LBRAD and post-COVID-19 depression was discussed. We concluded with a summary and future prospects. This review may provide a theoretical basis for the expansion of the clinical application of LBRAD and the development of new drugs for the treatment of depression, as well as new ideas for the secondary development of classical prescriptions.

Clinical, genetic profile and therapy evaluation of 11 Chinese pediatric patients with Fanconi-Bickel syndrome.

BACKGROUND: Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction. METHODS: Clinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed. RESULTS: Hepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3-) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3- and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from - 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient. CONCLUSIONS: Early diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.

Rheological and radioactive decontamination properties of ethyl cellulose sols in green solvents at a temperature below 0 °C.

Strippable film decontamination has been considered one of the best prospects for radioactive surface decontamination due to its high decontamination effect and less secondary pollution. However, research into strippable films has until now focused on radioactive decontamination at room temperature. Therefore, it is vital to seek a suitable degradable material for preparing strippable films in removing contaminants in an extremely cold region, as it will face the problem of the freezing of the detergent. Ethyl cellulose (EC) is a kind of degradable biopolymer which is easily dissolved in volatile green organic solvents to form a sol below 0 °C which is advantageous for forming a film. Therefore, it would be the best choice for preparing a strippable film detergent. In this study, EC sols were obtained by placing EC powder into the green solvents anhydrous ethanol and ethyl acetate. The steady and dynamic rheological behavior of EC sols was investigated with a rotary rheometer with the temperature ranging from -10 °C to 0 °C to disclose their spraying performance. Moreover, the radioactive decontamination effect of EC sols and the mechanism were also investigated. The results showed that the EC sols were pseudoplastic fluids which obeyed the Ostwald-de Waele power law below 0 °C. Furthermore, the viscosity of EC sols could be reduced by stirring, which is convenient for large-area spraying during decontamination below 0 °C. At -10 °C, the comprehensive decontamination rates of all plates were over 85%. Therefore, EC sols could be used as a basic material for strippable film decontamination below 0 °C.

Screening of 1.17 million newborns for inborn errors of metabolism using tandem mass spectrometry in Shanghai, China: A 19-year report.

BACKGROUND: Inborn errors of metabolism (IEMs) frequently result in progressive and irreversible clinical consequences if not be diagnosed or treated timely. The tandem mass spectrometry (MS/MS)-based newborn screening (NBS) facilitates early diagnosis and treatment of IEMs. The aim of this study was to determine the characteristics of IEMs and the successful deployment and application of MS/MS screening over a 19-year time period in Shanghai, China, to inform national NBS policy. METHODS: The amino acids and acylcarnitines in dried blood spots from 1,176,073 newborns were assessed for IEMs by MS/MS. The diagnosis of IEMs was made through a comprehensive consideration of clinical features, biochemical performance and genetic testing results. The levels of MS/MS testing parameters were compared between various IEM subtypes and genotypes. RESULTS: A total of 392 newborns were diagnosed with IEMs from January 2003 to June 2022. There were 196 newborns with amino acid disorders (50.00%, 1: 5910), 115 newborns with organic acid disorders (29.59%, 1: 10,139), and 81 newborns with fatty acid oxidation disorders (20.41%; 1:14,701). Phenylalanine hydroxylase deficiency, methylmalonic acidemia and primary carnitine deficiency were the three most common disorders. Some hotspot variations in eight IEM genes (PAH, SLC22A5, MMACHC, MMUT, MAT1A, MCCC2, ACADM, ACAD8), 35 novel variants and some genotype-biochemical phenotype associations were identified. CONCLUSIONS: A total of 28 types of IEMs were identified, with an overall incidence of 1: 3000 in Shanghai, China. Our study offered clinical guidance for the implementation of MS/MS-based NBS and genetic counseling for IEMs in this city.

Verteporfin regulates corneal neovascularization through inhibition of YAP protein activation.

Corneal neovascularization (CNV) is a vision-threatening disease that is becoming a growing public health concern. While Yes-associated protein (YAP) plays a critical role in neovascular disease and allow for the sprouting angiogenesis. Verteporfin (VP) is a classical inhibitor of the YAP-TEAD complex, which is used for clinical treatment of neovascular macular degeneration through photodynamic therapy. The purpose of this study is to explore the effect of verteporfin (VP) on the inhibition of CNV and its potential mechanism. Rat CNV model were established by suturing in the central cornea and randomly divided into three groups (control, CNV and VP group). Neovascularization was observed by slit lamp to extend along the corneal limbus to the suture line. RNA-sequencing was used to reveal the related pathways on the CNV and the results revealed the vasculature development process and genes related with angiogenesis in CNV. In CNV group, we detected the nuclear translocation of YAP and the expression of CD31 in corneal neovascular endothelial cells through immunofluorescence. After the application of VP, the proliferation, migration and the tube formation of HUVECs were significantly inhibited. Furthermore, VP showed the CNV inhibition by tail vein injection without photoactivation. Then we found that the expression of phosphorylated YAP significantly decreased, and its downstream target protein connective tissue growth factor (CTGF) increased in the CNV group, while the expression was just opposite in other groups. Besides, both the expression of vascular endothelial growth factor receptor 2 (VEGFR2) and cofilin significantly increased in CNV group, and decreased after VP treatment. Therefore, we conclude that Verteporfin could significantly inhibited the CNV without photoactivation by regulating the activation of YAP.

Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort.

BACKGROUND: The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene (MMACHC) c.482G > A mutation in 195 Chinese cases with CblC disease. METHODS: We carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months. RESULTS: Among 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower (P < 0.05) than those in the non-c.482G > A group, while the concentration of urinary methylmalonic acid was slightly lower (P > 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels (P < 0.05). In patients carrying the c.482G > A variant compared with the non-c.428G > A group, there were markedly lower rates of mortality (0.5% vs. 2.0%) and developmental delay (20.5% vs. 65.5%). When compared with individuals diagnosed due to disease onset, those identified through NBS in either group exhibited a reduced proportion of disease onset (6.7% vs. 100% in the c.482G > A group, 54.4% vs. 100% in the non-c.482G > A group), lower mortality (0.0% vs. 1.7% in the c.482G > A group, 0.0% vs. 3.6% in the non-c.482G > A group), and had a higher percentage of patients exhibiting normal psychomotor and language development (99.3% vs. 33.3% in the c.482G > A group, 58.9% vs. 10.9% in the non-c.482G > A group). CONCLUSIONS: The c.482G > A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease. Patients with this mutation tend to have a relatively better response to hydroxocobalamin, better metabolic control, and more favorable neurological outcomes. NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis, resulting in favorable clinical outcomes. Video Abstract (MP4 136794 kb).

The chemical recognition of hydrogen fluoride via B24N24 nanocage: quantum chemical approach.

CONTEXT: Ab initio calculations were employed in this investigation to scrutinize the adsorption characteristics of a linear chain (HF)n on a BN nanocage (B24N24), wherein the chain lengths varied (n = 1, 2, 3, and 4). The overarching aim was to assess the efficiency of this setup in detecting and adhering to (HF)n under both liquid and gaseous scenarios. This study encompassed an array of aspects, encompassing adsorption energy, optimal configuration determination, work function analysis, and charge exchange assessment. Furthermore, an exploration was conducted into the impact of HF linear chain dimensions on electrical attributes and adsorption energy. According to the values of adsorption energy, the dimer form of HF adsorbed onto BN nanocages displayed the highest stability. METHODS: This scrutiny was undertaken utilizing density functional theory (DFT), employing the B3LYP functional and the 6-31 + + G(d,p) basis set. Notably, the choice of the 6-31 + + G(d,p) basis set is particularly apt for delving into nanostructure analyses. The HOMO-LUMO energy gap was significantly reduced by (HF)n upon adsorption onto the nanocage, falling from 6.48 to 5.43 eV and enhancing electrical conductivity as a result. Additionally, BN nanocages may be used as sensors to find (HF)n among other environmental pollutants.

[Analysis of disease spectrum for abnormal 3-hydroxyisovalerylcarnitine metabolism identified through newborn screening and clinical diagnosis].

OBJECTIVE: To explore the disease spectrum for abnormal 3-hydroxyisovalerylcarnitine (C5OH) metabolism identified through newborn screening and clinical diagnosis patients and the key points for differential diagnosis so as to raise the awareness of pediatricians for such diseases. METHODS: Clinical data of 85 neonates with abnormal C5OH metabolism identified from February 2004 to January 2022 at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were collected. Their clinical manifestations and results of tandem mass spectrometry (MS/MS), gas chromatography mass spectrometry (GC-MS) and genetic testing were retrospectively analyzed. RESULTS: Among the 85 cases, 46 (54.1%) were identified by neonate screening, whilst 39 (45.9%) were clinically diagnosed patients. Five diseases were diagnosed, including 28 cases with multiple carboxylase deficiency (MCD, 32.9%), 29 cases with 3-methylcrotonyl-coenzymeAcarboxylasedeficiency (MCCD, 34.1%), 4 cases with 3-methylglutaconic acid (3-MGA, 4.7%), 7 cases with 3-hydroxy-3-methylglutaric acid (3-HMG, 8.2%), and 17 cases with beta-ketothiolase deficiency (BKD, 20.0%). The disorders were characterized by sudden onset, anorexia, vomiting, diarrhea, abnormal breathing, consciousness disorder, spasm and developmental delay. CONCLUSION: Among newborns with abnormal C5OH metabolism, MCCD is the most common disorder, which was followed by BKD and MCD. For patients with abnormal C5OH metabolism, MCD is the most common, followed by BKD and 3-HMG. C5OH related diseases have great heterogeneity. Combination of blood acylcarnitine levels, urinary organic acid levels and genetic testing based on clinical characteristics can help to attain the diagnosis.

Clinical profile, genetic spectrum and therapy evaluation of 19 Chinese pediatric patients with lipoprotein lipase deficiency.

BACKGROUND: Lipoprotein lipase (LPL) deficiency, the most common familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disease characterized by chylomicronemia and severe hypertriglyceridemia (HTG), with limited clinical and genetic characterization. OBJECTIVE: To describe the manifestations and management of 19 pediatric patients with LPL-FCS. METHODS: LPL-FCS patients from 2014 to 2022 were divided into low-fat (LF), very-low-fat (VLF) and medium-chain-triglyceride (MCT) groups. Their clinical data were evaluated to investigate the effect of different diets. The genotype-phenotype relationship was assessed. Linear regression comparing long-chain triglyceride (LCT) intake and TG levels was analyzed. RESULTS: Nine novel LPL variants were identified in 19 LPL-FCS pediatric patients. At baseline, eruptive xanthomas occurred in 3/19 patients, acute pancreatitis in 2/19, splenomegaly in 6/19 and hepatomegaly in 3/19. The median triglyceride (TG) level (30.3 mmol/L) was markedly increased. The MCT group and VLF group with LCT intakes <20 en% (energy percentage) had considerably lower TG levels than the LF group (both p<0.05). The LF group presented with severe HTG and significantly decreased TG levels after restricting LCT intakes to <20 en% (p<0.05). Six infants decreased TG levels to <10 mmol/L by keeping LCT intake <10 en%. TG levels and LCT intake were positively correlated in both patients under 2 years (r=0.84) and those aged 2-9 years (r=0.89). No genotype-phenotype relationship was observed. CONCLUSIONS: This study broadens the clinical and genetic spectra of LPL-FCS. The primary therapy for LPL-FCS pediatric patients is restricting dietary LCTs to <10 en% or <20 en% depending on different ages. MCTs potentially provide extra energy.

Late-onset cblC defect: clinical, biochemical and molecular analysis.

BACKGROUND: cblC defect is the most common type of methylmalonic acidemia in China. Patients with late-onset form (>1 year) are often misdiagnosed due to heterogeneous symptoms. This study aimed to describe clinical characteristics and evaluate long-term outcomes of Chinese patients with late-onset cblC defect. METHODS: A total of 85 patients with late-onset cblC defect were enrolled. Clinical data, including manifestations, metabolites, molecular diagnosis, treatment and outcome, were summarized and analyzed. RESULTS: The age of onset ranged from 2 to 32.8 years old (median age 8.6 years, mean age 9.4 years). The time between first symptoms and diagnosis ranged from a few days to 20 years (median time 2 months, mean time 20.7 months). Neuropsychiatric symptoms were presented as first symptoms in 68.2% of cases, which were observed frequently in schoolchildren or adolescents. Renal involvement and cardiovascular disease were observed in 20% and 8.2% of cases, respectively, which occurred with the highest prevalence in preschool children. Besides the initial symptoms, the disease progressed in most patients and cognitive decline became the most frequent symptom overall. The levels of propionylcarnitine, propionylcarnitine / acetylcarnitine ratio, methylmalonic acid, methylcitric acid and homocysteine, were decreased remarkably after treatment (P<0.001). Twenty-four different mutations of MMACHC were identified in 78 patients, two of which were novel. The c.482G>A variant was the most frequent mutated allele in this cohort (25%). Except for 16 patients who recovered completely, the remaining patients were still left with varying degrees of sequelae in a long-term follow-up. The available data from 76 cases were analyzed by univariate analysis and multivariate logistic regression analysis, and the results showed that the time from onset to diagnosis (OR = 1.025, P = 0. 024) was independent risk factors for poor outcomes. CONCLUSIONS: The diagnosis of late-onset cblC defect is often delayed due to poor awareness of its various and nonspecific symptoms, thus having an adverse effect on the prognosis. It should be considered in patients with unexplained neuropsychiatric and other conditions such as renal involvement, cardiovascular diseases or even multiple organ damage. The c.482G>A variant shows the highest frequency in these patients. Prompt treatment appears to be beneficial.

Mild Photothermal Therapy Prevents Posterior Capsule Opacification through Cytoskeletal Remodeling.

Cataract is the first leading cause of blindness in the world and posterior capsule opacification (PCO) is the most common long-term complication after surgery. The primary pathogenic processes contributing to PCO are the proliferation and migration of residual lens epithelial cells (LECs). This study aimed to explore the mild photothermal effect on LECs. Interestingly, this work finds that the mild photothermal effect significantly inhibited the proliferation and migration of LECs. The live cell fluorescence imaging reveals that the remodeling of the actin cytoskeleton and cell morphology attributed to the inhibition effect. Further mechanistic studies at molecular level suggest that the mild photothermal effect can regulate the phosphorylation of ERM, YAP, and Cofilin and thereby affect the proliferation and migration of LECs. In order to explore the potential clinical application of mild photothermal therapy for PCO prevention, PDA/PVA gel rings with photothermal effect is prepared by the repeated freeze-thaw method and conducted experiments in vivo, which achieved favorable PCO prevention effect. Overall, this study shows that the mild photothermal effect can regulate the proliferation and migration of LECs through cytoskeletal remodeling and the results of experiments in vivo demonstrate that mild photothermal effect is a promising approach for PCO prevention.