CAT Interruption as a Protective Factor in Chinese Patients with Spinocerebellar Ataxia Type 1.

Spinocerebellar ataxia type 1 (SCA1) is the third most common type of spinocerebellar ataxias in China. CAT interruptions in the pathogenic alleles of SCA1 patients had only been reported by limited documents and there was a lack of data based on the Chinese population. In this study, we detected CAT interrupted pathogenic alleles in SCA1 patients from 4 out of 79 (5.1%) Chinese families. Their total CAG repeats were larger (median 58 vs. 47, p < 0.001) but ages at onset were later (median 46 vs. 38, p = 0.020). The longest uninterrupted CAG repeats could explain 65.4% of the AAO variance, making an increase of 28.0% compared to the total CAG repeats. The interruption pattern was greatly different between Chinese cohort and Caucasian cohort, indicating the effect of race.

Selective inhibition of glycolysis in hepatic stellate cells and suppression of liver fibrogenesis with vitamin A-derivative decorated camptothecin micelles.

The persistent transformation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (MFs) and the excessive proliferation of MF-HSCs in the liver contribute to the pathogenesis of liver fibrosis, cirrhosis, and liver cancer. Glycolysis inhibition of MF-HSCs can reverse their MF phenotype and suppress their abnormal expansion. Here, we have developed vitamin A-derivative (VA) decorated PEG-PCL polymeric micelles to encapsulate the labile and hydrophobic camptothecin (CPT) and direct its active attack on HSCs, selectively inhibiting of HIF-1α and cellular glycolysis, ultimately repressing hepatic fibrogenesis. The obtained micelles exhibited a good stability, biocompatibility, pH sensitivity, and exceptional HSC-targetability, allowing an efficient accumulation of their carried CPT in acutely and chronically injured livers. On their intracellular release of CPT specifically in MF-HSCs, these CPT micelles nicely inhibited the HIF-1α and a series of glycolytic players in MF-HSCs and prominently suppressed their proliferation and MF phenotypic characteristics. Accordingly, on in vitro administration to the mice challenged by CCl4 or subjected to bile duct ligation, these VA-decorated CPT micelles ameliorated the pathological symptoms of the livers, as evidenced by the significant reduction in serum levels of ALT and AST, infiltration of inflammatory cells, and collagen accumulation, the drastic down-regulation of multiple fibrotic genes, and the good recovery of attenuated hepatocyte CYP2E1 and lipogenesis regulator PPARγ. Overall, the CPT carried by VA-decorated PEG-PCL polymeric micelles can selectively inhibit the glycolysis and expansion of HSCs and thus suppress fibrogenesis, providing an original and effective approach for anti-fibrotic therapy. STATEMENT OF SIGNIFICANCE: Our work introduces an innovative antifibrotic drug system that is developed upon the active targeting of CPT and aims for the fate reversal of HSCs. Through HSC-targeted delivery achieved by PEG-PCL polymeric micelles decorated with vitamin A-derivatives, CPT significantly suppressed the expressions of HIF-1α and glycolytic enzymes in MF-HSCs, as well as their pathologic expansion in mouse livers. It effectively ameliorated chronic liver fibrosis in mice induced by CCl4 injection or BDL and restored the damaged liver structure and function. These compelling findings demonstrate the therapeutic potential of glycolytic HSC-targeting in combating fibrosis and related disorders and thus provide new promise for future clinical management of such prevalent and life-threatening conditions.

Confining Co-Based Nanocatalysts by Ultrathin Nanotubes for Efficient Transfer Hydrogenation of Biomass Derivatives.

Catalytic transfer hydrogenation (CTH) based on non-noble-metal catalysts has emerged as an environmentally friendly way for the utilization of biomass resources. However, the development of efficient and stable non-noble-metal catalysts is crucially challenging due to their inherent inactivity. Herein, a metal-organic framework (MOF)-transformed CoAl nanotube catalyst (CoAl NT160-H) with unique confinement effect was developed via a "MOF transformation and reduction" strategy, which exhibited excellent catalytic activity for the CTH reaction of levulinic acid (LA) to γ-valerolactone (GVL) with isopropanol (2-PrOH) as the H donor. Comprehensive characterizations and experimental investigations uncovered that the confined effect of the ultrathin amorphous Al2O3 nanotubes could modulate the electronic structure and enhance the Lewis acidity of Co nanoparticles (NPs), thus contributing to the adsorption and activation of LA and 2-PrOH. The synergy between the electropositive Co NPs and Lewis acid-base sites of the CoAl NT160-H catalyst facilitated the transfer of α-H in 2-PrOH to the C atom of carbonyl in LA during the CTH process via a Meerwein-Ponndorf-Verley mechanism. Moreover, the confined Co NPs embedded on am-Al2O3 nanotubes endowed the CoAl NT160-H catalyst with superior stability and the catalytic activity was nearly unchanged for at least ten cycles, far surpassing that of the Co/am-Al2O3 catalyst prepared by the traditional impregnation method.

Nutrients and rheumatoid arthritis: From the perspective of neutrophils.

Neutrophils are considered as core immune cells involve in the early stage of rheumatoid arthritis (RA) and participate in the disease progression. The underlining mechanisms include the elevated chemotaxis and infiltration of neutrophils, the increase in the reactive oxygen species and the promotion of neutrophil extracellular traps formation. Accumulating studies demonstrated the important role of nutrients intake played in the initiation and progression of RA. This study summarized the effects of several macronutrients and micronutrients on regulating RA through the modulation of activated neutrophils and appealed for a healthy diet in RA-risk individuals as well as RA patients.

Folate Decoration Supports the Targeting of Camptothecin Micelles against Activated Hepatic Stellate Cells and the Suppression of Fibrogenesis.

As the central cellular player in fibrogenesis, activated hepatic stellate cells (aHSCs) are the major target of antifibrotic nanomedicines. Based on our finding that activated HSCs increase the expression of folate receptor alpha (FRα), we tried to apply folic acid (FA) decoration to generate an active drug-targeting at aHSCs and suppress hepato-fibrogenesis. FA-conjugated poly(ethylene glycol)-poly(ε-caprolactone) copolymers (PEG-PCL) were synthesized and self-assembled into the spherical micelles that owned a uniform size distribution averaging at 60 nm, excellent hemo- and cyto-compatibility, and pH-sensitive stability. These FA-modified micelles were preferentially ingested by aHSCs as expected and accumulated more in acutely CCl4 injured mouse livers compared to nondecorated counterparts. Such an aHSC targetability facilitated the loaded medicinal camptothecin (CPT) to achieve a greater therapeutic efficacy and inhibition of MF phenotypic genes in aHSCs. Encouragingly, though free CPT and nontargeting CPT micelles produced negligible curative outcomes, FA-decorated CPT micelles yielded effectively remedial effects in chronically CCl4-induced fibrotic mice, as represented by a significant shrinkage of aHSC population, suppression of fibrogenesis, and recovery of liver structure and function, clearly indicating the success of the folate decoration-supported aHSC-targeted strategy for antifibrotic nanomedicines in fibrosis resolution.

Responsive shape-shifting nanoarchitectonics and its application in tumor diagnosis and therapy.

Nanodrug delivery system has a great application in the treatment of solid tumors by virtue of EPR effect, though its success in clinics is still limited by its poor extravasation, small intratumoral accumulation, and weak tumor penetration. The shape of nanoparticles (NPs) greatly affects their circulation time, flow behavior, intratumoral amassing, cell internalization as well as tumor tissue penetration. Generally, short nanorods and 100-200 nm spherical nanocarriers possess nice circulation behaviors, nanorods and nanofibers with a large aspect ratio (AR) cumulate well at tumor sites, and tiny nanospheres/disks (< 50 nm) and short nanorods with a low AR achieve a favorable tumor tissue penetration. The AR and surface evenness of NPs also tune their cell contact, cell ingestion, and drug accumulation at tumor sites. Therefore, adopting stimulus-responsive shape-switching (namely, shape-shifting nanoarchitectonics) can not only ensure a good circulation and extravasation for NPs, but also and more importantly, promote their amassing, retention, and penetration in tumor tissues to maximize therapeutic efficacy. Here we review the recently developed shape-switching nanoarchitectonics of antitumoral NPs based on stimulus-responsiveness, demonstrate how successful they are in tumor shrinking and elimination, and provide new ideas for the optimization of anticancer nanotherapeutics.

In Situ Construction of a Co/ZnO@C Heterojunction Catalyst for Efficient Hydrogenation of Biomass Derivative under Mild Conditions.

The efficient hydrogenation of biomass-derived levulinic acid (LA) to value-added γ-valerolactone (GVL) based on nonprecious metal catalysts under mild conditions is crucial challenge because of the intrinsic inactivity and instability of these catalysts. Herein, a series of highly active and stable carbon-encapsulated Co/ZnO@C-X (where X = 0.1, 0.3, 0.5, the molar ratios of Zn/(Co+Zn)) heterojunction catalysts were obtained by in situ pyrolysis of bimetal CoZn MOF-74. The optimal Co/ZnO@C-0.3 catalyst could achieve 100% conversion of LA and 98.35% selectivity to GVL under mild conditions (100 °C, 5 bar, 3 h), which outperformed most of the state-of-the-art catalysts reported so far. Detailed characterizations, experimental investigations, and theoretical calculations revealed that the interfacial interaction between Co and ZnO nanoparticles (NPs) could promote the dispersibility and air stability of the active Co0 for the activation of H2. Moreover, the strong Co-ZnO interaction also enhanced the Lewis acidity of the Co/ZnO interface, contributing to the adsorption of LA and the esterification of intermediates. The synergy between the hydrogenation sites and the Lewis acid sites at the Co/ZnO interface enabled the conversion of LA to GVL with high efficiency. In addition, benefiting from the Co-ZnO interfacial interaction as well as the unique carbon-encapsulated structure of the heterojunction catalyst, the recyclability was also greatly improved and the yield of GVL was nearly unchanged even after six cycles.

Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias.

BACKGROUND: Although many causative genes have been uncovered in recent years, genetic diagnosis is still missing for approximately 50% of autosomal recessive cerebellar ataxia (ARCA) patients. Few studies have been performed to determine the genetic spectrum and clinical profile of ARCA patients in the Chinese population. METHODS: Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing (WES) and copy number variation (CNV) calling with ExomeDepth. Likely causal CNV predictions were validated by CNVseq. RESULTS: Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, of which four most common genes were SACS, SYNE1, ADCK3 and SETX, which accounted for 76.0% (19/25) of the positive cases. The de novo microdeletion in SACS was reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Clinical features of the patients carrying SACS, SYNE1 and ADCK3 mutations were summarized. CONCLUSIONS: Our results expand the genetic spectrum and clinical profiles of ARCA patients, demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.

Association of the Level of Neurofilament Light With Disease Severity in Patients With Spinocerebellar Ataxia Type 2.

BACKGROUND AND OBJECTIVES: Few biochemical markers have been identified in spinocerebellar ataxia type 2 (SCA2). This study aimed to determine the levels of neurofilament light (NfL) in patients with SCA2 and to identify whether they are associated with disease severity. METHODS: Participants were recruited from 1 medical center in China, and individuals with SCA2 were genetically diagnosed. NfL levels were assessed with the single molecule array method. Disease severity was evaluated with the Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and the Inventory of Non-Ataxia Symptoms (INAS). Cerebellum and brainstem volumes were calculated from neuroimaging measurements. We used the Pearson correlation and partial correlation for correlation analyses. RESULTS: Forty-nine patients with manifest SCA2, 10 preclinical individuals with SCA2, and 92 controls were enrolled. A high consistency was identified between serum and CSF NfL (r = 0.868, p < 0.0001). In individuals with SCA2, levels of serum NfL were associated with disease severity (SARA: r = 0.425, p = 0.003; ICARS: r = 0.383, p = 0.009; INAS:, r = 0.390, p = 0.007; cerebellum volume: r = -0.393, p = 0.024) after adjustment for age. NfL levels were higher close to the expected age at onset in preclinical individuals with SCA2 (R 2 = 0.43, p = 0.04). DISCUSSION: Levels of serum NfL were correlated with disease intensity in individuals with SCA2 and were higher close to the estimated age at onset in preclinical SCA2. Therefore, NfL is a potential serum biomarker of disease severity in SCA2. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that elevated NfL levels are associated with disease severity in individuals with SCA2.

Mitochondrial dysfunction and mitochondrion-targeted therapeutics in liver diseases.

The liver is a vital metabolic and detoxifying organ and suffers diverse endogenous or exogenous damage. Hepatocyte mitochondria experience various structural and functional defects from liver injury, bearing oxidative stress, metabolic dysregulation, and the disturbance of mitochondrial quality control (MQC) mechanisms. Mitochondrial malfunction initiates the mitochondria-mediated apoptotic pathways and the release of damage signals, aggravating liver damage and disease progression via inflammation and reparative fibrogenesis. Removal of mitochondrial impairment or the improvement of MQC mechanisms restore mitochondrial homeostasis and benefit liver health. This review discusses the association of mitochondrial disorders with hepatic pathophysiological processes and the resultant potential of mitochondrion-targeting therapeutics for hepatic disorders. The recent advances in the MQC mechanisms and the mitochondrial-derived damage-associated molecular patterns (DAMPs) in the pathology and treatment of liver disease are particularly focussed.

Encapsulation of Ultrafine Metal-Organic Framework Nanoparticles within Multichamber Carbon Spheres by a Two-Step Double-Solvent Strategy for High-Performance Catalysts.

Carbon-encapsulated metal-organic framework (MOF) composite is one kind of emerging new catalyst with high efficiency and has gained much attention. However, for this kind of composite catalyst, the key to improving its catalytic activity and durability is to realize the effective dispersion of MOF nanoparticles (NPs) and enhance the interaction between MOF NPs and the carbon matrix, which remain a significant challenge. Herein, ultrafine MOF NPs within multichamber carbon spheres (MOF@MCCS), for the first time, have been rationally synthesized by a two-step double-solvent strategy for high-performance catalysts. The precise loading of guest MOFs can be achieved by adjusting the multichamber structure and calcination extent of the multichamber polymer (MCP), and the particle size of MOFs can be as low as 13.2 nm. Due to the formation of abundant carbon defects in the pyrolysis process of MCPs, the special structure and synergistic effect make the material exhibit higher catalytic activity and durability. More importantly, this method is universal and can be extended to different MOF systems. The two-step double-solvent strategy not only prepares a unique structure of MOF@MCCS-type host-guest-encapsulated catalysts but also provides a new idea for the design of high-efficiency catalysts with better performance and higher durability.

Genotype-phenotype correlation in 667 Chinese families with spinocerebellar ataxia type 3.

INTRODUCTION: Due to diverse symptoms of spinocerebellar ataxia type 3 (SCA3) and the high prevalence of SCA3 in China, a more in-depth study of Chinese SCA3 patients in a large cohort is well merited. METHODS: During the last 10 years, 730 patients and 133 premanifest individuals from 667 SCA3 families genetically confirmed to have SCA3 were enrolled from three leading academic hospitals in China. The clinical profile and genotype-phenotype correlation were analyzed. RESULTS: A quadratic equation best explained the relationship between the logarithmically transformed age at onset (AAO) and expanded CAG repeats (expCAGs) (r2 = 0.634, p < 0.001). The expCAG and AAO in Asian populations and western populations were compared with the Chinese population. SCA3 individuals had shorter normal CAG repeats (norCAGs) than healthy controls (Mann-Whitney, p < 0.0001). Most (92.1%) SCA3 patients had gait-ataxia onset. Their AAO and expCAGs were not significantly different from SCA3 patients with non-gait-ataxia onset. Limb ataxia and pyramidal impairment occurred less in patients with disease duration >10 years. Intriguingly, onset after parturition happened in 10 female patients with the AAO of 26.7 ± 4.3 years and the expCAG of 77.4 ± 1.4 repeats. Five out of 12 patients with subtype V and larger expCAGs (78.8 ± 4.8 repeats) suffered from spastic gait initially, and 10 out of 12 showed no limb ataxia. Nystagmus happened most frequently (10.5%) in premanifest individuals. CONCLUSION: We demonstrated the genotype-phenotype correlation in the largest cohort of SCA3 individuals to date, and interestingly found some new phenomena in Chinese SCA3 individuals.

Preparation and application of novel MIL-101(Cr) composite in liquid chromatographic separation of aromatic compounds: experimental and computational insights.

A novel composite material of SiO2@dSiO2@MIL-101(Cr) was synthesized via SiO2@dSiO2 as the core and MIL-101(Cr) as the shell to separate aromatic compounds. The laboratory prepared column gave rise to the baseline separation of xylene, dichlorobenzene isomers, phthalate esters, nitrobenzene, and acetophenone with high column efficiency (e.g., 109,050 plates m-1 for methyl phthalate) and good precision (e.g., 0.02-0.05%, 0.24-0.34%, 0.14-0.18%, and 0.11-0.13% corresponding to the relative standard deviation of retention time, peak area, peak height, and half peak width for xylene isomers, respectively). The calculation of thermodynamic parameters demonstrated that the separation of o-xylene, nitrobenzene, acetophenone, and p-dichlorobenzene was controlled by positive ∆H and ∆S. Although the separation of aromatic compounds by a MOF packed column has been reported in many studies, the knowledge regarding their separation mechanism at atomic level is still very limited. In this study, we integrate fully atomistic molecular dynamics simulation and binding free energy calculation to investigate the separation mechanism of aromatic compounds by MIL-101(Cr). The investigation provides a base for separation of more and other compounds in the future. Graphical abstract.

Factors Associated with Intergenerational Instability of ATXN3 CAG Repeat and Genetic Anticipation in Chinese Patients with Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3 (SCA3) is caused by unstable expanded CAG repeats (expCAGs) in ATXN3. Factors associated with intergenerational instability (delta-expCAG) and genetic anticipation in SCA3 have never been reported in Chinese mainland. Here, we demonstrated that unstable transmissions occurred more often in sons than in daughters (91% vs 72%, Fisher's exact test, p = 0.012). The extended delta-expCAG of father-son transmissions was greater than that of mother-son transmissions (3.8 ± 2.3 repeats vs 1.6 ± 1.0 repeats, Mann-Whitney U, p = 0.001). Genetic anticipation was frequently observed between generations but not affected by the delta-expCAG.

Crucial Breakthrough of Functional Persistent Luminescence Materials for Biomedical and Information Technological Applications.

Persistent luminescence is a phenomenon in which luminescence is maintained for minutes to hours without an excitation source. Owing to their unique optical properties, various kinds of persistent luminescence materials (PLMs) have been developed and widely employed in numerous areas, such as bioimaging, phototherapy, data-storage, and security technologies. Due to the complete separation of two processes, -excitation and emission-, minimal tissue absorption, and negligible autofluorescence can be obtained during biomedical fluorescence imaging using PLMs. Rechargeable PLMs with super long afterglow life provide novel approaches for long-term phototherapy. Moreover, owing to the exclusion of external excitation and the optical rechargeable features, multicolor PLMs, which have higher decoding signal-to-noise ratios and high storage capability, exhibited an enormous application potential in information technology. Therefore, PLMs have significantly promoted the application of optics in the fields of multimodal bioimaging, theranostics, and information technology. In this review, we focus on the recently developed PLMs, including inorganic, organic and inorganic-organic hybrid PLMs to demonstrate their superior applications potential in biomedicine and information technology.