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Electrical stimulation has been used clinically as an adjunct therapy to accelerate the healing of bone defects, and its mechanism requires further investigations. The complexity of the physiological microenvironment makes it challenging to study the effect of electrical signal on cells alone. Therefore, an artificial system mimicking cell microenvironment in vitrowas developed to address this issue. In this work, a novel electrical stimulation system was constructed based on polypyrrole nanowires (ppyNWs) with a high aspect ratio. Synthesized ppyNWs formed a conductive network in the composited hydrogel which contained modified gelatin with methacrylate, providing a conductive cell culture matrix for bone marrow mesenchymal stem cells. The dual-network conductive hydrogel had improved mechanical, electrical, and hydrophilic properties. It was able to imitate the three-dimensional structure of the cell microenvironment and allowed adjustable electrical stimulations in the following system. This hydrogel was integrated with cell culture plates, platinum electrodes, copper wires, and external power sources to construct the artificial electrical stimulation system. The optimum voltage of the electrical stimulation system was determined to be 2 V, which exhibited remarkable biocompatibility. Moreover, this system had significant promotion in cell spreading, osteogenic makers, and bone-related gene expression of stem cells. RNA-seq analysis revealed that osteogenesis was correlated to Notch, BMP/Smad, and calcium signal pathways. It was proven that this biomimetic system could regulate the osteogenesis procedure, and it provided further information about how the electrical signal regulates osteogenic differentiations.

Malignant hyperthermia (MH) is a fatal hyperthermia with a high mortality, which usually occurs during induction of general anesthesia. Dantrolene sodium is a wonder drug currently used for treating malignant hyperthermia. However, preparing, storing, and maintaining dantrolene sodium are crucially expensive, thus making it financially unsatisfactory and difficult for clinicians to acquire in time. Monitoring patients’ condition closely and intervening promptly when early signs of malignant hyperthermia occur can effectively prevent the condition from worsening and win over time for the arrival of dantraline sodium. This article is to report a case in which we successfully rescued a child occurring malignant hyperthermia without using dantrolene sodium.

BackgroundPrimary adrenal insufficiency (PAI) is a rare but life-threatening condition. Differential diagnosis of numerous causes of PAI requires a thorough understanding of the condition.MethodsTo describe the genetic composition and presentations of PAI. The following data were collected retrospectively from 111 patients with non-21OHD with defined genetic diagnoses: demographic information, onset age, clinical manifestations, laboratory findings and genetic results. Patients were divided into four groups based on the underlying pathogenesis: (1) impaired steroidogenesis, (2) adrenal hypoplasia, (3) resistance to adrenocorticotropic hormone (ACTH) and (4) adrenal destruction. The age of onset was compared within the groups.ResultsMutations in the following genes were identified: NR0B1(n=39), STAR(n=33), CYP11B1(n=12), ABCD1(n=8), CYP17A1(n=5), HSD3B2(n=4), POR(n=4), MRAP(n=2), MC2R(n=1), CYP11A1(n=1), LIPA(n=1) and SAMD9(n=1). Frequent clinical manifestations included hyperpigmentation (73.0%), dehydration (49.5%), vomiting (37.8%) and abnormal external genitalia (23.4%). Patients with adrenal hypoplasia typically presented manifestations earlier than those with adrenal destruction but later than those with impaired steroidogenesis (both p<0.01). The elevated ACTH (92.6%) and decreased cortisol (73.5%) were the most common laboratory findings. We generated a differential diagnosis flowchart for PAI using the following clinical features: 17-hydroxyprogesterone, very-long-chain fatty acid, external genitalia, hypertension and skeletal malformation. This flowchart identified 84.8% of patients with PAI before next-generation DNA sequencing.ConclusionsSTARand NR0B1were the most frequently mutated genes in patients with non-21OHD PAI. Age of onset and clinical characteristics were dependent on aetiology. Combining clinical features and molecular tests facilitates accurate diagnosis.

BackgroundMethylmalonic acidemia (MMA), which results from defects in methylmalonyl-CoA mutase (muttype) or its cofactor, is the most common inherited organic acid metabolic disease in China. This study aimed to investigate the phenotype and genotype of mut-type MMA in Chinese patients.MethodsWe recruited 365 patients with mut-type MMA; investigated their disease onset, newborn screening (NBS) status, biochemical metabolite levels, gene variations and prognosis; and explored the relationship between phenotype and genotype.ResultsThere were 152 patients diagnosed by tandem mass spectrometry (MS/MS) expanded NBS, 209 patients diagnosed because of disease onset without NBS and 4 cases diagnosed because of sibling diagnosis. The median age of onset was 15 days old, with a variety of symptoms without specificity. Urinary levels of methylmalonic acid and methylcitric acid (MCA) decreased after treatment. Regarding the prognosis, among the 152 patients with NBS, 50.6% were healthy, 30.3% had neurocognitive impairment and/or movement disorders and 13.8% died. Among the 209 patients without NBS, 15.3% were healthy, 45.9% had neurocognitive impairment and/or movement disorders and 33.0% died. In total, 179 variants were detected in the MMUTgene, including 52 novel variations. c.729_730insTT, c.1106G>A, c.323G>A, c.914T>C and c.1663G>A were the five most frequent variations. The c.1663G>A variation led to a milder phenotype and better prognosis.ConclusionThere is a wide spectrum of variations in the MMUTgene with several common variations. Although the overall prognosis of mut-type MMA was poor, participation in MS/MS expanded NBS, vitamin B12responsive and late onset are favourable factors for the prognosis.

A donor-acceptor covalent organic framework (COF), TB-COF, constructed from an electron-rich building unit (donor) and an electron-deficient building unit (acceptor), was developed as a promising photothermal agent for photothermal therapy (PTT). Upon laser irradiation, significant photoinduced electron transfer (PET) occurs between the donor and acceptor in TB-COF, converting the absorbed optical energy to thermal energy and resulting in the ablation of tumor. TB-COF possessed satisfying photothermal conversion efficiency, reaching 43.65%, similar to materials commonly used for PTT. Moreover, hyaluronic acid (HA) was coated on TB-COF to improve its biocompatibility and achieve tumor targeting. Furthermore, in vitroand in vivoexperiments confirmed satisfying photothermal anticancer efficacy of TB-COF-HA.

Background: Isolated methylmalonic acidemia, an autosomal recessive disorder of propionate metabolism, is usually caused by mutations in the methylmalonyl-CoA mutase gene (mut-type). Because no universal consensus was made on whether mut-type methylmalonic acidemia should be included in newborn screening (NBS), we aimed to compare the outcome of this disorder detected by NBS with that detected clinically and investigate the influence of NBS on the disease course. Design & methods: In this study, 168 patients with mut-type methylmalonic acidemia diagnosed by NBS were compared to 210 patients diagnosed after disease onset while NBS was not performed. Clinical data of these patients from 7 metabolic centers in China were analyzed retrospectively, including initial manifestations, biochemical metabolites, the responsiveness of vitamin B12 therapy, and gene variation, to explore different factors on the long-term outcome. Results: By comparison of the clinically-diagnosed patients, NBS-detected patients showed younger age at diagnosis, less incidence of disease onset, better responsiveness of vitamin B12, younger age at start of treatment, lower levels of biochemical features before and after treatment, and better long-term prognosis (P&lt; 0.01). Onset of disease, blood C3/C2 ratio and unresponsiveness of vitamin B12 were more positively associated with poor outcomes of patients whether identified by NBS. Moreover, the factors above as well as older age at start of treatment were positively associated with mortality. Conclusions: This research highly demonstrated NBS could prevent major disease-related events and allow an earlier treatment initiation. As a key prognostic factor, NBS is beneficial for improving the overall survival of infants with mut-type methylmalonic acidemia.

Malignant glioma remains one of the most aggressive intracranial tumors with devastating clinical outcomes despite the great advances in conventional treatment approaches, including surgery and chemotherapy. Spatio-temporally controllable approaches to glioma are now being actively investigated due to the preponderance, including spatio-temporal adjustability, minimally invasive, repetitive properties, etc. External stimuli can be readily controlled by adjusting the site and density of stimuli to exert the cytotoxic on glioma tissue and avoid undesired injury to normal tissues. It is worth noting that the removability of external stimuli allows for on-demand treatment, which effectively reduces the occurrence of side effects. In this review, we highlight recent advancements in drug delivery systems for spatio-temporally controllable treatments of glioma, focusing on the mechanisms and design principles of sensitizers utilized in these controllable therapies. Moreover, the potential challenges regarding spatio-temporally controllable therapy for glioma are also described, aiming to provide insights into future advancements in this field and their potential clinical applications.

The physical and chemical properties of sodium lauryl glutamate were systematically investigated in this work. To determine the critical micelle concentration (CMC) of sodium lauryl glutamate, the surface tension was measured using the Wilhelmy plate method. The Krafft point was determined using the ultraviolet/visible spectrophotometer. The effect of pH on the solute in the solution was studied using potentiometric titration. The critical packing parameter (CPP) and Gibbs free energy (ΔG) of micelle formation were calculated using the corresponding parameters. The temperature-concentration phase diagram of sodium lauryl glutamate was constructed using the dynamic light scattering system (DLS) and polarised optical microscopy (POM). The calculated theoretical data were combined with the actual observed data from the phase diagram. Finally, the phase behaviour of sodium lauryl glutamate was determined.

Rare genetic variants in the PURAgene cause the PURA-related neurodevelopmental disorder (PURA-NDD), characterized by neonatal abnormalities and developmental delay. Using genome-wide DNA methylation analysis on patients with PURAvariants, we aim to establish a PURA-NDD-specific methylation profile and provide further insights on the molecular basis of the PURA-NDD.

A facile and one-step colorimetric assay is described for the determination of glutathione (GSH). It is based on the use of manganese dioxide-decorated magnetic (Fe3O4@MnO2) nanocomposite that was prepared by an in-situ redox reaction. It exhibits oxidase-mimicking activity and can catalyze the oxidation of 3,3’,5,5’-tetramethylbenzidine (TMB) without H2O2to form a blue colored product (oxTMB) with an absorption maximum at 651 nm. Once GSH is introduced, the component of MnO2can be rapidly reduced to Mn2+ions, which leads to inhibit the formation of oxTMB. Based on these findings, a one-step colorimetric assay was developed for the detection GSH in the range of 0.2 to 25 μM with a low detection limit of 0.2 μM without using any procedures of separation and washing. Importantly, the proposed approach is also used to accurately evaluate the intracellular GSH levels. In our perception, the assay is rapid, sensitive and specific.

Long continuous stretches of homozygosity (LCSH) are associated with risk of recessive disorders. Though LCSH can be detected by SNP microarrays, additional testing is necessary to clarify the clinical significance. This study is to assess the yield of additional exome sequencing (ES) after LCSH detection and inform the likelihood of eventual diagnosis. In 2226 patients referred to SNP microarrays, 35 patients met the criteria of indicative LCSH. These patients were recruited and went through additional ES. The diagnostic yield was analyzed, and the LCSH pattern was compared between eventually diagnosed cases and those undiagnosed. The results showed additional ES attained a diagnostic yield of 31.4% (11/35), but only one-third of the yield (11.4%, 4/35) was relevant to LCSH. In contrast, two-thirds of the diagnostic variants (20%, 7/35) were de novo or dominantly inherited, irrelevant to the original LCSH finding. No particular LCSH pattern, including the chromosomal coverage or LCSH size, was found to associate with the diagnostic outcome. We concluded that additional ES after LCSH detection could reveal diagnostic variants, but it is strongly recommended to consider all possible inheritance mode, as the diagnostic variants may be irrelevant to the original LCSH finding.

Tumor metastasis is extremely deadly for cancer patients and developing effective treatments for deep metastatic tumors remains a major challenge. In this study, we demonstrated a dual-catalytic nanoreactor for tumor metastasis suppression by synergistic Fenton reaction activated chemodynamic therapy (CDT) and glucose oxidase (GOx) initiated starvation therapy. GOx on the surface of hollow mesoporous silica nanoparticles can catalyze the decomposition of intratumoral glucose to generate gluconic acid and H2O2, while Fe3O4nanoparticles as a Fenton reaction catalyst can in situcatalyze H2O2to produce highly toxic hydroxyl radicals (OH). The oxygen-carrying perfluorohexane (PFC) in the hole of the hollow structures can alleviate the hypoxic environment and promote dual-catalytic reactions. After being disguised by the cancer cell membrane, the delivery efficiency and biological safety of the nanoreactor were effectively improved. The nanoreactor can realize sequential glucose depletion and OH aggregation, which effectively suppress tumor metastasis with negligible side effects.

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A diastereo- and enantioselective construction of biologically important chiral 1,3-dioxolochroman frameworks has been established via chiral phosphoric acid (CPA)-catalyzed asymmetric [4+2] cycloaddition of ortho-quinone methides with 3-methyl-2-vinylindoles. By using this approach, a series of indole-based chiral 1,3-dioxolochromans were synthesized with structural diversity in generally good yields, excellent diastereoselectivities and high enantioselectivities (up to 98% yields, >95:5 dr, 97% ee). The evaluation on the cytotoxic activity of some selected products indicated that this class of chiral 1,3-dioxolochroman derivatives had some extent of anti-cancer activity. This reaction not only provides an efficient synthetic method for accessing chiral 1,3-dioxolochroman derivatives with structural diversity and optical purity but also will enrich the research contents of catalytic asymmetric [4+2] cycloadditions involving ortho-quinone methides. In addition, the bioassay of these compounds will cast a light on discovering useful bioactivities of chiral 1,3-dioxolochroman derivatives, which will be helpful for finding lead compounds.

Gaucher disease (GD) is a lysosomal storage disease caused by the deficiency of glucocerebrosidase characterized by a broad spectrum of clinical manifestations including hepatosplenomegaly, bone infiltration, and cytopenia, and even central nervous system involvement. Bone manifestations are typical of the GD-I and partially responded to mainstay therapy. Ambroxol (ABX), an approved cough-suppressant, was identified as an enzyme-enhancement agent of the residual activity of glucocerebrosidase mutants derived from different misfolding-mutations in the GBAgene. Here, we describe the early beneficial effects of ABX on skeletal and hematological manifestations of a child suffering with progressive GD-I.

The reliability of irrigated area (IA) information dominates the performance of irrigation water use and crop modeling accuracy. IA is typically mapped using Food and Agriculture Organization (FAO) agricultural census and remote sensing indices. Recent advances in machine learning and sampling techniques further improve IA mapping. However, the relative performances of different IA mapping approaches and their capability in capturing long‐term IA temporal variability remain unknown. Here, 1861 county‐level IA information from Government Censored Data (GCD) during 2000–2021 are collected, cross‐validated, and employed to evaluate commonly used gridded IA data sets. Results show that IA data sets based on the direct interpolation of FAO agricultural census can accurately capture the spatial distribution of IA. However, FAO statistics are only available in a particular year, which cannot capture inter‐annual irrigation variations. In contrast, IA products solely based on vegetation indices are prone to positive biases over humid regions due to the lack of contrast in vegetation dynamics. Overall, the latest GCD‐based machine learning IA data sets are relatively more accurate, but they are also problematic in estimating IA trends due to the use of temporally static training samples. Such biases are tightly related to agricultural suitability (AS calculated using precipitation and potential evapotranspiration). This suggests that AS should be employed as an endogenous variable in future machine learning based IA mapping algorithms. Understanding how much land is irrigated (Irrigated Area or IA) is crucial for accurate water use and crop modeling. Traditional IA maps are developed using data from the Food and Agriculture Organization (FAO) and remote sensing indices. Recent improvements, like machine learning, have enhanced IA mapping. However, the relative performances of these methods and their reliability in capturing long‐term changes in irrigated areas remain unknown. This study collects government‐censored county‐level IA data from 2000 to 2021, which is subsequently used for evaluating commonly used IA data sets. Results show that data sets directly using FAO data can reasonability capture the spatial distribution of IA but may miss year‐to‐year changes. On the other hand, data sets relying only on vegetation data tend to overestimate irrigated areas in humid regions. The latest machine learning‐based IA data sets are relatively more accurate but still contain significant uncertainties in IA trends. These biases are closely linked to agricultural suitability (calculated using precipitation and potential evapotranspiration), which may be useful for enhancing future IA mapping algorithms. Remote sensing vegetation index is insufficient for identifying irrigated area over humid regionsMachine learning based irrigated area is sensitive to the quality of training sampleAll the irrigated area data sets are biased in representing the temporal dynamics of irrigated area Remote sensing vegetation index is insufficient for identifying irrigated area over humid regions Machine learning based irrigated area is sensitive to the quality of training sample All the irrigated area data sets are biased in representing the temporal dynamics of irrigated area

Long-term infiltration of chronic inflammation plays a crucial role in tumorigenesis and progression. Chronic inflammation can create a hypoxic microenvironment, stimulate inflammatory mediator expression, induce immunosuppression, and influence tumorigenesis through intricate signaling pathways. Revealing the intricate interplay between inflammation and tumor development holds paramount promise for novel therapeutic strategies in oncology research. The impact of tumor-associated inflammation on tumor development can be observed across various physiological levels, encompassing diverse inflammatory pathways, factors, and cells. All these elements hold potential as therapeutic targets in the pursuit of novel treatment agents. Currently, a variety of pharmacological agents have demonstrated significant efficacy in regulating chronic inflammation and inhibiting tumorigenesis and progression, many of which have gained widespread clinical utilization. Furthermore, nano-based drug delivery systems (NDDS) serve as a promising platform that can enhance the efficacy and safety of therapeutic drugs in regulating tumor-associated inflammation. They possess the advantages of targeted delivery and specific release, thereby playing a pivotal role in tumor therapy. Herein, this review initially discusses the intricate interplay among inflammation, tumor and immunity, providing an overview of key aspects related to tumor-associated inflammation such as pathways, factors, and cells. Additionally, a comprehensive summary is provided on therapeutic agents and their application in nano-based drug delivery systems for modulating tumor-associated inflammation.

Objective Angiogenesis is essential for growth and recurrence of uterine leiomyomas, and angiogenesis is mediated by vascular endothelial growth factor C (VEGF-C) and prostaglandin E2 (PGE2). This study investigated whether spinal anesthesia (SA) with continuous postoperative epidural analgesia attenuates postoperative changes in these angiogenic factors compared with general anesthesia (GA) with patient-controlled intravenous analgesia.Methods Forty-four women with uterine leiomyomas undergoing abdominal myomectomy were randomized to receive either standard SA or GA. Blood samples were taken before anesthesia and at 48 hours after surgery for measuring serum VEGF-C and PGE2levels, which were analyzed by using enzyme-linked immunosorbent assays. Visual analog scale pain scores were used to evaluate postoperative pain.Results Serum VEGF-C and PGE2levels were not significantly different preoperatively between the SA and GA groups, but they were decreased in each group at 48 hours after surgery compared with preoperatively. The change in pre- and postoperative VEGF-C levels was smaller in the GA group than in the SA group.Conclusions Removal of uterine leiomyomas by surgery can reduce serum VEGF-C and PGE2levels. The anesthetic technique affects serum VEGF-C levels, which are associated with angiogenesis in surgery for leiomyomas.

Hydrogen gas has been successfully produced from cultivated microalgae biomass by supercritical water gasification (SCWG). This paper describes SCWG of natural cyanobacterial biomass for hydrogen production at low temperatures (<500 °C). Natural decomposition of cyanobacteria biomass was first studied to achieve prospective H2production. Transformation of carbon, nitrogen, and phosphorus and the degradation of microcystins were also clarified for the nature and safety assessment of SCWG products. Cyanobacteria would remain an ideal SCWG feedstock for H2production such as cultivated microalgae biomass, and it could be gasified as 2.92 mol/kg of H2yield without any catalyst addition at 500 °C. Liquid products with above 2800 mg/L ammonia-nitrogen and 100% removed microcystins had great potential for producing high-quality liquid fertilizers. C (50.50%) was concentrated into a solid residue as char and tar. The percentage of P combined with Ca2+and turned into authigenic apatite was as high as 72.25%. The synergistic effects of ash, N element, or proteins, and fixed carbon content make cyanobacteria a more optimistic feedstock for H2production than some other types of organic wastes. The SCWG technology provides an effective method of gasification of waste cyanobacteria for high-value energy utilization.

SID1 transmembrane family member 2 (Sidt2) is an integral lysosomal membrane protein. To investigate its explicit function, we generated a global Sidt2knockout mouse model (Sidt2−/−). Compared with the littermate controls, Sidt2−/−mice exhibited a remarkable accumulation of lipid droplets in liver. First, it was observed that food consumption, hepatocyte fatty acid uptake and de novo lipogenesis, hepatocyte lipolysis, and TG secretion in the form of very low density lipoprotein were comparable between Sidt2−/−and WT mice. However, the hepatic β-oxidation of fatty acids decreased significantly as revealed by a low level of serum β-hydroxybutyrate in the Sidt2−/−mice along with normal mRNA expression of genes involved in fatty acid oxidation. In addition, the classical autophagy pathway marker proteins, p62 and LC3-II, increased in liver, along with compromised autophagic flux in primary hepatocytes, indicating a block of autophagosome maturation due to Sidt2 deficiency, which was also supported by electron microscopy image analysis both in livers and in primary hepatocytes from Sidt2−/−mice. It was concluded that Sidt2 plays an important role in mouse hepatic lipid homeostasis by regulating autophagy at the terminal stage.

Gaucher disease (GD) is an inherited metabolic disorder that involves accumulation of glycolipid glucocerebroside in monocyte–macrophage cells, which can result in multiple organ damage. Enzyme replacement and substrate reduction therapies have improved the potential for early diagnosis and treatment. Determining the true incidence of this rare disease is critical for relevant policy establishment. Newborn screening allows for early diagnosis and an comparatively accurate incidence of GD. A fluorometric method to detect acid β-glucocerebrosidase (GBA) activity on a dried blood spot punch was developed. Validity and feasibility of the fluorometric method was demonstrated by examining 116 healthy controls, 19 confirmed GD patients and 19 obligate carriers. GBA activity was measured on dried blood spots of 80 855 newborns. Samples from positively screened newborns were reanalyzed by a leukocyte GBA activity test and GBAgene analysis. Plasma glucosylsphingosine level was determined as a biomarker of the pathophysiology of GD. GD patients were distinguished from healthy controls and obligate carriers using the fluorometric method. Mean GBA activity in newborn screening specimens was 145.69±44.76 μmol l−1h−1(n=80 844). Three children had low GBA activity, of which one child had low GBA activity on the second dried blood spot specimen. Leukocyte, genetic and biomarker analysis confirmed the diagnosis and indicated that this child was in the early stages of GD. In conclusion, the incidence of GD in Shanghai of China is approximately 1 in 80 855. Screening for GD by fluorometric analysis of GBA activity is an efficient and feasible technology in newborns.

Phenylalanine hydroxylase (PAH) deficiency or phenylketonuria (PKU) is the most common cause of hyperphenylalaninemia (HPA), and approximately 5% of patients remain genetically unsolved. Identifying deep intronic PAHvariants may help improve their molecular diagnostic rate. Next-generation sequencing was utilized to detect the whole PAHgene in 96 patients with genetically unsolved HPA from 2013 to 2022. The effects of deep intronic variants on pre-mRNA splicing were investigated by minigene-based assay. The allelic phenotype values of recurrent deep intronic variants were calculated. Twelve deep intronic PAHvariants, located in intron 5 (c.509+434C>T), intron 6 (c.706+288T>G, c.706+519T>C, c.706+531T>C, c.706+535G>T, c.706+600A>C, c.706+603T>G, and c.706+608A>C), intron 10 (c.1065+241C>A and c.1065+258C>A), and intron 11 (c.1199+502A>T and c.1199+745T>A) were identified in 80.2% (77/96) patients. Ten of the 12 variants were novel, and they all generated pseudoexons in mRNA, leading to frameshift or lengthened proteins. The most prevalent deep intronic variant was c.1199+502A>T, followed by c.1065+241C>A, c.1065+258C>A, and c.706+531T>C. The metabolic phenotypes of the four variants were assigned as classic PKU, mild HPA, mild HPA, and mild PKU, respectively. The results suggest that deep intronic PAHvariants improved the diagnostic rate from 95.3% to 99.3% in the overall patients with HPA. Our data demonstrate the importance of assessing noncoding variants in genetic diseases. Pseudoexon inclusion caused by deep intronic variants could represent a recurrent mechanism.

Lysosomal storage disorders (LSDs) are a group of >50 different types of inherited metabolic disorders that result from defects in the lysosome. The aim of this study was to investigate the distribution and demographic characteristics of the different subtypes of LSDs in Eastern China. From 2006 to 2012, 376 out of 1331 clinically suspected patients were diagnosed with 17 different subtypes of LSDs at our hospital. Mucopolysaccharidoses (MPS) were the most common group of LSDs (50.5%), followed by sphingolipidoses (25.4%) and Pompe disease (19.8%). Mucolipidosis type II/III accounted for the remaining 4% of diagnosed LSDs. MPS II was the most common form of MPS, comprising 47.4% of all MPS cases diagnosed, followed by MPS IVA (26.8%) and MPS I (16.3%). Gaucher disease and Niemann–Pick disease type A/B were the two most common forms of sphingolipidoses. There was a large variation in the time between disease onset and eventual diagnosis, from 0.3 years in infantile-onset Pompe disease to 30 years in Fabry disease, highlighting timely and accurate diagnosis of LSDs as the main challenge in China.

In this study, the degradation behaviour of phospholipid 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) during hydrothermal conversion (HC) and the effect of alkali additives on phosphorus forms during HC of phospholipids and different phosphorus-containing wastes were investigated. The mechanism of phosphate-alkali-directed regulation and transformation was discussed and analysed with batch hydrothermal treatment experiments and characterizations such as XRD and SEM. The obtained results showed that DOPC degradation was divided into two periods, i.e., the initial accumulation of phosphorus-containing precursors with increasing temperature, followed by complete degradation to H3PO4as treatment continued. In addition, compared with the activation of P by NaOH, Ca(OH)2is more favourable for the stabilization of P and the migration of non-apatite inorganic phosphorus (NAIP) to apatite inorganic phosphorus (AP). The pH and appropriate feed Ca/P molar ratio during HC determine the degree to which total phosphorus is converted to Ca-bound P. The findings reveal the mechanism of phosphate-alkali-directed regulation and transformation and provide a theoretical reference for the efficient treatment of phosphorus-containing waste and the alkali-directed production of high-phosphorus bioavailability products.

Molecular diagnosis of genetic bone dysplasia is challenging for non-expert. A targeted next-generation sequencing technology was applied to identify the underlying molecular mechanism of bone dysplasia and evaluate the contribution of these genes to patients with bone dysplasia encountered in pediatric endocrinology. A group of unrelated patients (n=82), characterized by short stature, dysmorphology and X-ray abnormalities, of which mucopolysacharidoses, GM1 gangliosidosis, mucolipidosis type II/III and achondroplasia owing to FGFR3 G380R mutation had been excluded, were recruited in this study. Probes were designed to 61 genes selected according to the nosology and classification of genetic skeletal disorders of 2010 by Illumina’s online DesignStudio software. DNA was hybridized with probes and then a library was established following the standard Illumina protocols. Amplicon library was sequenced on a MiSeq sequencing system and the data were analyzed by MiSeq Reporter. Mutations of 13 different genes were found in 44 of the 82 patients (54%). Mutations of COL2A1 gene and PHEX gene were found in nine patients, respectively (9/44=20%), followed by COMP gene in 8 (18%), TRPV4 gene in 4 (9%), FBN1 gene in 4 (9%), COL1A1 gene in 3 (6%) and COL11A1, TRAPPC2, MATN3, ARSE, TRPS1, SMARCAL1, ENPP1 gene mutations in one patient each (2% each). In conclusion, mutations of COL2A1, PHEX and COMP gene are common for short stature due to bone dysplasia in outpatient clinics in pediatric endocrinology. Targeted next-generation sequencing is an efficient way to identify the underlying molecular mechanism of genetic bone dysplasia.

Acid sphingomyelinase (ASMase)-deficient Niemann-Pick disease (NPD) is caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, resulting in accumulation of sphingomyelin in the lysosomes and secondary changes in cholesterol metabolism. We hypothesized that the oxidation product of cholesterol, 7-ketocholesterol (7-KC), might increase in the plasma of patients with ASMase-deficient NPD. In this study, a rapid and nonderivatized method of measurement of plasma 7-KC by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. Plasma samples from healthy subjects, patients with ASMase-deficient NPD, nonaffected ASMase-deficient NPD heterozygotes, Niemann-Pick type C (NPC) disease, glycogen storage disorder type II (GSDII), Gaucher disease (GD), mucopolysaccharidosis type II (MPSII), Krabbe disease (KD), and metachromatic leukodystrophy (MLD) were tested retrospectively. Markedly elevated 7-KC was found in patients with ASMase-deficient NPD and NPC disease that showed significant differences from ASMase-deficient NPD heterozygotes; patients with GSDII, GD, MPSII, KD, and MLD; and normal controls. The analysis of plasma 7-KC by LC-MS/MS offers the first simple, quantitative, and highly sensitive method for detection of ASMase-deficient NPD and could be useful in the diagnosis of both ASMase-deficient NPD and NPC disease.

AbstractBackground:Maple syrup urine disease (MSUD) is an inherited disorder caused by a deficiency of the mitochondrial branched-chain keto acid dehydrogenase complex. We investigated whether liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a more reliable and accurate method than MS/MS in the diagnosis and management of patients with MSUD in a Chinese population.Methods:A total of 370 dried blood spots (DBS) from healthy neonates, 44 DBS specimens from phenylketonuria neonates, and 38 DBS samples from 10 MSUD patients were retrospectively tested using the LC-MS/MS method. The results were compared with those obtained by the MS/MS method.Results:The reference intervals of branched-chain amino acids (BCAAs) and alloiosleucine (Allo-Ile) were estimated for both sexes. In classic MSUD patients, Allo-Ile was markedly elevated (average of 136 μmol/L, which was significantly higher than the normal value, <5 μmol/L). The averages of BCAAs were also markedly elevated continually during the treatment.Conclusions:The application of the LC-MS/MS method in the measurement of Allo-Ile and BCAAs in DBS is more useful for diagnosing and managing classic MSUD than the MS/MS method.

Phenylketonuria (PKU) is characterized by a high concentration of phenylalanine, which can lead to mental retardation. One of the characteristic pathologic changes in untreated phenylketonuria patients is a reduction in the number of axons, dendrites, and synapses in the brain. This is thought to be due to the toxic effects of phenylalanine and/or its metabolites, however, the underlying mechanism remains unclear. In this study, we observed that phenylalanine reduced the number of dendrites and dendritic spines in cultured neurons. We further demonstrated that phenylalanine down-regulated Rac1, Cdc42, and RhoA mRNA and protein expression. Pull-down assays indicated that phenylalanine caused a decrease in Rac1/Cdc42 activity but increased RhoA activity. Expression of a dominant negative RhoA or treatment with a Rho-associated kinase specific inhibitor, Y-27632, partly inhibited the phenylalanine-induced decrease in dendrite numbers. In conclusion, we have demonstrated that phenylalanine affects the expression and activity of Rac1, Cdc42, and RhoA. Furthermore, RhoA signaling is involved in the inhibitory effect of phenylalanine on dendritic branching. These results may provide an important insight into the molecular mechanism underlying phenylalanine-induced abnormalities of dendrites, specifically in phenylketonuria neuronal injury.

Phenylketonuria (PKU) is characterized by a high concentration of phenylalanine, which can lead to mental retardation. One of the characteristic pathologic changes in untreated phenylketonuria patients is a reduction in the number of axons, dendrites, and synapses in the brain. This is thought to be due to the toxic effects of phenylalanine and/or its metabolites, however, the underlying mechanism remains unclear. In this study, we observed that phenylalanine reduced the number of dendrites and dendritic spines in cultured neurons. We further demonstrated that phenylalanine down-regulated Rac1, Cdc42, and RhoA mRNA and protein expression. Pull-down assays indicated that phenylalanine caused a decrease in Rac1/Cdc42 activity but increased RhoA activity. Expression of a dominant negative RhoA or treatment with a Rho-associated kinase specific inhibitor, Y-27632, partly inhibited the phenylalanine-induced decrease in dendrite numbers. In conclusion, we have demonstrated that phenylalanine affects the expression and activity of Rac1, Cdc42, and RhoA. Furthermore, RhoA signaling is involved in the inhibitory effect of phenylalanine on dendritic branching. These results may provide an important insight into the molecular mechanism underlying phenylalanine-induced abnormalities of dendrites, specifically in phenylketonuria neuronal injury.

This paper examines China's fertilizer conservation in 1978–2017. The provincial data displays a positive reversal shift consistent to the Environmental Kuznets Curve (EKC) hypothesis in fertilizer application. The occurrences of applying less fertilizer but achieving higher farming output, is a positive signal for fertilizer conservation. Then we select Hubei as a case study for more county-specific examinations. To examine Hubei's 80 county-level areas in 2000–2017, we define an ecological impact index of fertilizer use as the local fertilizer application divided by the agricultural gross product. After passing the unit root tests, the panel regressions indicate the N-shaped EKC shift: Hubei's annual county-specific fertilizer-impact indexes rose first with the rural household income, and then declined before they started increasing again, while time effect also existed significantly in the samples. We advise local agricultural policy implementers keep multi-scalar measures and circular economy to conserve fertilizer-use, with more stakeholders engaging fertilizer conservation in rural areas.

Capillary electrophoresis (CE) was used to study the polydispersity of TX-100/SDS and C12E8/SDS micelle systems. Compared with other techniques, CE provides more specific and graphically detailed information on the compositional polydispersity of such micellar systems. Clear evidence of the coexistence of micelles rich in either nonionic or anionic component has been obtained. This coexistence is explained by considering that the stability of mixed micelles is affected by several factors, including counterion binding, and steric shielding of the electrostatic repulsive interaction among the headgroups of SDS by the bulky EO groups of TX-100. Due to these two factors, micelles with different compositions may be energetically equivalent, leading to a broad distribution of micelle size and composition. In this study, we observe how the pattern of the distribution changes with the mole fraction of SDS. Electrophoretographic patterns also showed that broader compositional distribution of the original components produces a wider distribution of mobilities.

The biggest obstacles of putting lithium–sulfur batteries into practice are the sluggish redox kinetics of polysulfides and serious “shuttle effect” under high sulfur mass loading and lean-electrolyte conditions. Herein, Fe3C/Fe3N@nitrogen-doped carbon nanotubes (NCNTs) as multifunctional sulfur hosts are designed to realize high-areal-capacity Li–S batteries. The Fe3N and Fe3C particles attached to NCNT can promote the conversion of polysulfides. Besides, NCNT can not only enhance the chemisorption of polysulfides but also increase the special surface area and electrical conductivity by constructing a three-dimensional skeleton network. Integrating the merits of high electrical conductivity, high catalytic activity, and strong chemical binding interaction with lithium polysulfides (LiPSs) to achieve in situ anchoring conversion, the Fe3C/Fe3N@NCNT multifunctional hosts realize high sulfur mass loading and accelerate redox kinetics. The novel Fe3C/Fe3N@NCNT/S composite cathode exhibits steady cycle ability and a high areal capacity of 9.10 mAh cm–2with a sulfur loading of 13.12 mg cm–2at 2.20 mA cm–2after 50 cycles.

The present study aimed to determine the diagnostic value of prenatal chromosomal microarray analysis (CMA) for fetuses with several indications of being at high risk for various conditions.

Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1or RUNX1—master regulators of carbohydrate metabolic subtypes—modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility.

Protein ubiquitination is a dynamic and reversible process of adding single ubiquitin molecules or various ubiquitin chains to target proteins. Here, using multidimensional omic data of 9,125 tumor samples across 33 cancer types from The Cancer Genome Atlas, we perform comprehensive molecular characterization of 929 ubiquitin-related genes and 95 deubiquitinase genes. Among them, we systematically identify top somatic driver candidates, including mutated FBXW7with cancer-type-specific patterns and amplified MDM2showing a mutually exclusive pattern with BRAFmutations. Ubiquitin pathway genes tend to be upregulated in cancer mediated by diverse mechanisms. By integrating pan-cancer multiomic data, we identify a group of tumor samples that exhibit worse prognosis. These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERTamplification, and APC/PTENdeletion. Our analysis highlights the importance of the ubiquitin pathway in cancer development and lays a foundation for developing relevant therapeutic strategies.