Polymersomes in Drug Delivery─From Experiment to Computational Modeling.

Polymersomes, composed of amphiphilic block copolymers, are self-assembled vesicles that have gained attention as potential drug delivery systems due to their good biocompatibility, stability, and versatility. Various experimental techniques have been employed to characterize the self-assembly behaviors and properties of polymersomes. However, they have limitations in revealing molecular details and underlying mechanisms. Computational modeling techniques have emerged as powerful tools to complement experimental studies and enabled researchers to examine drug delivery mechanisms at molecular resolution. This review aims to provide a comprehensive overview of the state of the art in the field of polymersome-based drug delivery systems, with an emphasis on insights gained from both experimental and computational studies. Specifically, we focus on polymersome morphologies, self-assembly kinetics, fusion and fission, behaviors in flow, as well as drug encapsulation and release mechanisms. Furthermore, we also identify existing challenges and limitations in this rapidly evolving field and suggest possible directions for future research.

Relationship between dry skin and pressure injury in older patients: A multicentre cross-sectional survey in China.

Dry skin and pressure injuries in older persons have become global health care problems. This was a multicentre, prospective cross-sectional study in 44 hospitals and 8 long term care institutions from 20 provinces, autonomous regions and municipalities in China and aimed to explore the relationship between the two skin problems in older patients. We mainly found 11 602 cases with dry skin and 1076 cases with pressure injuries in a total of 33 769 valid participants. The overall prevalence of dry skin and pressure injuries was 34.4% (95% confidence interval [CI] 33.9-34.9) and 3.1% (95% CI 2.9-3.3). Stage 2+ pressure injuries were the most (32.9%), followed by stage 1 (32.4%). The patients with dry skin had more pressure injuries than ones without dry skin (50.0% vs 33.9%). The patients with very severe and severe dry skin had more pressure injury risk (OR 2.22 and 1.90) and more stage 2+ pressure injury risk (OR 2.83 and 1.63). Other nine predictors associated with overall pressure injuries and stage 2+ pressure injuries. The area under receiver operating characteristic (ROC) curve of the predictive models of overall pressure injuries and stage 2+ pressure injuries were 0.89 (95% CI 0.88-0.90) and 0.91 (95% CI 0.90-0.92), respectively.

Enhancing lactose recognition of a key enzyme in 2'-fucosyllactose synthesis: α-1,2-fucosyltransferase.

BACKGROUND: 2'-Fucosyllactose, a representative oligosaccharide in human milk, is an emerging and promising food and pharmaceutical ingredient due to its powerful health benefits, such as participating in immune regulation, regulation of intestinal flora, etc. To enable economically viable production of 2'-fucosyllactose, different biosynthesis strategies using precursors and pathway enzymes have been developed. The α-1,2-fucosyltransferases are an essential part involved in these strategies, but their strict substrate selectivity and unsatisfactory substrate tolerance are one of the key roadblocks limiting biosynthesis. RESULTS: To tackle this issue, a semi-rational manipulation combining computer-aided designing and screening with biochemical experiments were adopted. The mutant had a 100-fold increase in catalytic efficiency compared to the wild-type. The highest 2'-fucosyllactose yield was up to 0.65 mol mol-1 lactose with a productivity of 2.56 g mL-1  h-1 performed by enzymatic catalysis in vitro. Further analysis revealed that the interactions between the mutant and substrates were reduced. The crucial contributions of wild-type and mutant to substrate recognition ability were closely related to their distinct phylotypes in terms of amino acid preference. CONCLUSION: It is envisioned that the engineered α-1,2-fucosyltransferase could be harnessed to relieve constraints imposed on the bioproduction of 2'-fucosyllactose and lay a theoretical foundation for elucidating the substrate recognition mechanisms of fucosyltransferases. © 2022 Society of Chemical Industry.

A crosstalk between circular RNA, microRNA, and messenger RNA in the development of various brain cognitive disorders.

Patients with Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI), stroke, and postoperative neurocognitive disorder (POND) are commonly faced with neurocognitive disorders with limited therapeutic options. Some non-coding ribonucleic acids (ncRNAs) are involved in the development of various brain cognitive disorders. Circular RNAs (circRNAs), a typical group of ncRNAs, can function as competitive endogenous RNAs (ceRNAs) to dysregulate shared microRNAs (miRNAs) at post-transcription level, inhibiting regulation of miRNAs on their targeted messenger RNAs (mRNAs). circRNAs are abundant in central nervous system (CNS) diseases and cause brain disorders, but the exact roles of circRNAs are unclear. The crosstalk between circRNA, miRNA, and mRNA plays an important role in the pathogenesis of these neurocognitive dysfunction diseases and abnormal conditions including AD, PD, stroke, TBI, and POND. In this review, we summarized the participation of circRNA in neuroglial damage and inflammation. Finally, we aimed to highlight the regulatory mechanisms of circRNA-miRNA-mRNA networks in the development of various brain cognitive disorders and provide new insights into the therapeutics of these diseases.

Effect of Early Exercise Rehabilitation on Cardiopulmonary Function and Quality of Life in Patients after Coronary Artery Bypass Grafting.

The purpose of this study was to analyze the effect of early exercise rehabilitation on cardiopulmonary function and quality of life in patients after coronary artery bypass grafting (CABG). Eighty patients with coronary heart disease who underwent CABG from April 2020 to April 2022 were divided into the study group (n = 40) and control group (n = 40). The control group was given conventional treatment and routine care after CABG, and the study group received early exercise rehabilitation according to the control group. The cardiac function indexes, 6-minute walking test (6MWT), and cardiopulmonary function indexes and quality of life of the two groups were compared before and after the intervention, and the length of hospitalization and hospital costs as well as the occurrence of pulmonary complications in both groups were recorded. Left ventricular ejection fraction (LVEF) was significantly higher (P < 0.05), and left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic diameter (LVESD) were significantly lower (P < 0.05) in the study group than in the control group after the intervention; 6MWT, maximal oxygen consumption (VO2max), and anaerobic threshold (AT) were significantly higher (P < 0.05) in the study group than in the control group after the intervention; physical function (PF), role physical (RP), general health (GH), and role emotional (RE) dimension scores were significantly higher (P < 0.05) in the study group compared with the control group after the intervention The differences in the scores of the remaining dimensions were not statistically significant (P > 0.05); the total hospitalization time in the test group was significantly shorter than that in the control group (P < 0.05), the hospitalization cost was significantly less than that in the control group (P < 0.05), and the total incidence of pulmonary infection and hypoxemia was significantly lower than that in the control group (P < 0.05). Early exercise rehabilitation can effectively improve cardiopulmonary function and exercise tolerance and improve the quality of life of patients after CABG.

ECG Utilization Patterns of Patients With Arrhythmias During COVID-19 Epidemic and Post-SARS-CoV-2 Eras in Shanghai, China.

Background: The COVID-19 pandemic has led to concerns around its subsequent impact on global health. Objective: To investigate the health-seeking behavior, reflected by ECG utilization patterns, of patients with non-COVID-19 diseases during and after COVID-19 epidemic. Methods: Taking advantage of the remote ECG system covering 278 medical institutions throughout Shanghai, the numbers of medical visits with ECG examinations during the lockdown (between January 23 and April 7, 2020), post-lockdown (between April 8 and December 31, 2020) and post-SARS-CoV-2 (between January 23 and April 7, 2021) periods were analyzed and compared against those during the same periods of the preceding years (2018 and 2019). Results: Compared with the same period during pre-COVID years, the number of medical visits decreased during the lockdown (a 38% reduction), followed by a rebound post-lockdown (a 17% increase) and a fall to the baseline level in post-SARS-CoV-2 period. The number of new COVID-19 cases announced on a given day significantly correlated negatively with the numbers of medical visits during the following 7 days. Medical visit dynamics differed for various arrhythmias. Whereas medical visits for sinus bradycardia exhibited a typical decrease-rebound-fallback pattern, medical visits for atrial fibrillation did not fall during the lockdown but did exhibit a subsequent increase during the post-lockdown period. By comparison, the volume for ventricular tachycardia remained constant throughout this entire period. Conclusion: The ECG utilization patterns of patients with arrhythmias exhibited a decrease-rebound-fallback pattern following the COVID-19 lockdowns. Medical visits for diseases with more severe symptoms were less influenced by the lockdowns, showing a resilient demand for healthcare.

Epidemiology of Atrial Fibrillation and Related Myocardial Ischemia or Arrhythmia Events in Chinese Community Population in 2019.

Background: Atrial fibrillation (AF) is the most common arrhythmia, and the incidence increases rapidly all over the world. The global prevalence of AF (age-adjusted) is 0.60% for men and 0.37% for women and the prevalence of AF in China is 0.65%. It is expected that the number of patients with AF will continue to rise in the future worldwide due to population aging. Objective: To explore the prevalence of AF in Chinese community population in 2019 and clarify the prevalence of AF complicated with other arrhythmias and myocardial ischemia (MI) events. Methods: The remote electrocardiogram (ECG) diagnosis system of Xinhua Hospital was assessed to the screen participants with ECG evidence of AF between January 1 and December 31, 2019. The prevalence rates of AF and its association with other arrhythmias and MI events were analyzed and subgroup analysis was performed between different sexes and age groups. Results: A total of 22,016 AF cases were identified out of all ECGs derived from the remote ECG diagnosis system in 2019. It is estimated that AF was presented in nearly 10.15 million people in China (age-adjusted standardized rate 0.72%, 95% CI 0.20-1.25%) in 2019 and 62% of the AF cases (6.27 million) affected people aged 65 years and above (age-adjusted standardized rate 3.56%, 95% CI 3.28-3.85%). The prevalence rate of AF in males was higher than that in females (p < 0.001), and the ventricular rate of AF patients was faster in females (p < 0.001) and younger patients (p < 0.001). AF patients with lower ventricular rate (under 60 beats per min) were associated with increased prevalence of ventricular escape/escape rhythm [p < 0.001, odds ratio (OR) 5.14] and third-degree atrioventricular block (p < 0.001, OR 32.05). Conclusion: The prevalence of AF is higher in the Chinese community population than that was previously reported. AF patients complicated with ECG patterns suggesting myocardial infarction is common in men, and stricter measures should be taken to control the common risk factors of AF and coronary heart disease. It is also important that more attention should be paid to recognize fatal arrhythmias, especially in elderly male patients with AF.

A Four-Step Enzymatic Cascade for Efficient Production of L-Phenylglycine from Biobased L-Phenylalanine.

Enantiopure amino acids are of particular interest in the agrochemical and pharmaceutical industries. Here, we report a multi-enzyme cascade for efficient production of L-phenylglycine (L-Phg) from biobased L-phenylalanine (L-Phe). We first attempted to engineer Escherichia coli for expressing L-amino acid deaminase (LAAD) from Proteus mirabilis, hydroxymandelate synthase (HmaS) from Amycolatopsis orientalis, (S)-mandelate dehydrogenase (SMDH) from Pseudomonas putida, the endogenous aminotransferase (AT) encoded by ilvE and L-glutamate dehydrogenase (GluDH) from E. coli. However, 10 mM L-Phe only afforded the synthesis of 7.21±0.15 mM L-Phg. The accumulation of benzoylformic acid suggested that the transamination step might be rate-limiting. We next used leucine dehydrogenase (LeuDH) from Bacillus cereus to bypass the use of L-glutamate as amine donor, and 40 mM L-Phe gave 39.97±3.84 mM (6.04±0.58 g/L) L-Phg, reaching 99.9 % conversion. In summary, this work demonstrates a concise four-step enzymatic cascade for L-Phg synthesis from biobased L-Phe, with a potential for future industrial applications.

Stable immobilization of uranium in iron containing environments with microbial consortia enriched via two steps accumulation method.

The stable stabilization of uranium (U) in iron (Fe) containing environments is restricted by the reoxidation of UO2. In the current study, based on air reoxidation tests, we propose a novel two steps accumulation method to enrich microbial consortia from paddy soil. The constructed microbial consortia, denoted as the Fe-U bacteria, can co-precipitate U and Fe to form stable Fe-U solids. Column experiments running for 4 months demonstrated the production of U(IV)-O-Fe(II) precipitates containing maximum of 39.51% uranium in the presence of Fe-U bacteria. The reoxidation experiments revealed the U(IV)-O-Fe(II) precipitates were more stable than UO2. 16S rDNA high throughput sequencing analysis demonstrated that Acinetobacter and Stenotrophomonas were responsible for Fe and U precipitation, while, Caulobacteraceae and Aminobacter were crucial for the formation of U(VI)-PO4 chemicals. The proposed two steps accumulation method has an extraordinary application potential in stable immobilization of uranium in iron containing environments.

Constructing new Fe3O4@MnOx with 3D hollow structure for efficient recovery of uranium from simulated seawater.

Enrichment of uranium from seawater is a promising method for addressing the energy crisis. Current technologies are generally not effective for enriching uranium from seawater because its concentration in seawater is low. In this study, new Fe3O4@MnOx with 3D hollow structure, which is capable of enriching low concentration uranium, was prepared via a novel redox etching method. The physicochemical characteristics of Fe3O4@MnOx were studied with TEM, HRTEM, SEAD, FTIR, XRD, and N2 adsorption-desorption analysis. Dynamic kinetic studies of different initial U(VI) concentrations revealed that the pseudo-second-order model fit the sorption process better, and the sorption rates of Fe3O4@MnOx in 1, 10, and 25 mg/L U(VI) solution were 0.0124, 0.00298, and 0.000867 g/mg·min, respectively. Isothermal studies showed that the maximum sorption amounts were 50.09, 56.27, and 64.62 mg/g for 1, 10, and 25 mg/L U(VI), respectively, at pH 5.0 and 313 K, suggesting that Fe3O4@MnOx could effectively enrich low concentration U(VI) from water. The sorption amount of U(VI) did not significantly decrease in the presence of Na+, Mg2+, and Ca2+. HRTEM, FTIR, and XPS results demonstrated that Fe(II) and Mn/Fe-O-H active sites in Fe3O4@MnOx were accounted for the high and specific enrichment efficiency. A column experiment was conducted to evaluate the U(VI) sorption efficiency of Fe3O4@MnOx in simulated seawater. The U(VI) sorption efficiency remained above 80% in 28 days run. Our findings demonstrate that Fe3O4@MnOx has extraordinary potential for the enrichment of uranium from simulated seawater.

Serum creatinine as a biomarker for dystrophinopathy: a cross-sectional and longitudinal study.

BACKGROUND: Dystrophinopathy, a common neuromuscular disorder, includes Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Many researches are currently ongoing to develop curative approaches, which results in an urgent need for biomarkers of disease progression and treatment response. This study investigated whether the serum creatinine (SCRN) level can be used as a biomarker of disease progression in dystrophinopathy. METHODS: We enrolled 377 male patients with dystrophinopathy and 520 male non-dystrophinopathy controls in a cross-sectional study. From this cohort, 113 follow-up patients were enrolled in a longitudinal study. Patients' demographic information, motor function, muscle fatty infiltration, and muscle dystrophin levels were evaluated. We investigated correlations between these parameters and SCRN levels, and determined changes in SCRN levels with maturation and with motor function changes. RESULTS: Our results showed SCRN levels correlated with motor function (FDR < 0.001) and timed test results (FDR between < 0.001-0.012), as well as with muscle fatty infiltration (FDR < 0.001) and dystrophin levels (FDR = 0.015 and 0.001). SCRN levels increased with maturation in control individuals; it slowly increased with maturation in patients with BMD but decreased generally with maturation in patients with DMD. The longitudinal study further demonstrated that SCRN levels were associated with motor function. CONCLUSIONS: These findings indicated that the SCRN level is a promising biomarker for assessing disease progression in dystrophinopathy and could be used as a potential outcome measure in clinical trials.

Noncoding RNAs: Novel Insights into Postoperative Neurocognitive Disorders.

Postoperative recovery for patients (particularly elderly) will be commonly encountered for postoperative neurocognitive disorders. Although effort has been undertaken to better understand and prevent these disorders, little improvement has been observed, due to largely unknown mechanisms. Emerging evidence indicates that noncoding RNAs including microRNA(s), long noncoding RNA(s), and circular RNA(s) are promising biomarkers for diagnosis, prognosis, and novel pathways to reveal mechanisms of postoperative neurocognitive disorders. However, there has been little crosstalk between noncoding RNA biology and development of postoperative neurocognitive disorders. We discuss the major noncoding RNAs in mechanisms, diagnosis, risk-stratification, prognosis, and treatment in postoperative neurocognitive disorders in a novel approach.

In vivo genome editing in mouse restores dystrophin expression in Duchenne muscular dystrophy patient muscle fibers.

BACKGROUND: Mutations in the DMD gene encoding dystrophin-a critical structural element in muscle cells-cause Duchenne muscular dystrophy (DMD), which is the most common fatal genetic disease. Clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene editing is a promising strategy for permanently curing DMD. METHODS: In this study, we developed a novel strategy for reframing DMD mutations via CRISPR-mediated large-scale excision of exons 46-54. We compared this approach with other DMD rescue strategies by using DMD patient-derived primary muscle-derived stem cells (DMD-MDSCs). Furthermore, a patient-derived xenograft (PDX) DMD mouse model was established by transplanting DMD-MDSCs into immunodeficient mice. CRISPR gene editing components were intramuscularly delivered into the mouse model by adeno-associated virus vectors. RESULTS: Results demonstrated that the large-scale excision of mutant DMD exons showed high efficiency in restoring dystrophin protein expression. We also confirmed that CRISPR from Prevotella and Francisella 1(Cas12a)-mediated genome editing could correct DMD mutation with the same efficiency as CRISPR-associated protein 9 (Cas9). In addition, more than 10% human DMD muscle fibers expressed dystrophin in the PDX DMD mouse model after treated by the large-scale excision strategies. The restored dystrophin in vivo was functional as demonstrated by the expression of the dystrophin glycoprotein complex member ß-dystroglycan. CONCLUSIONS: We demonstrated that the clinically relevant CRISPR/Cas9 could restore dystrophin in human muscle cells in vivo in the PDX DMD mouse model. This study demonstrated an approach for the application of gene therapy to other genetic diseases.

Construction of Core-Shell MOFs@COF Hybrids as a Platform for the Removal of UO22+ and Eu3+ Ions from Solution.

The binary nanocomposites of metal/covalent-organic frameworks (NH2-MIL-125(Ti)@TpPa-1) were constructed by solvothermal method, which was developed as a multifunctional platform with adsorption and photocatalysis for radionuclides removal. The batch experiments and physicochemical property (FT-IR, XRD, SEM, TEM, XPS, etc.) corroborated: (i) core-shell NH2-MIL-125(Ti)@TpPa-1 had a more stable, multilayer pore structure and abundant active functional groups; (ii) NH2-MIL-125(Ti)@TpPa-1 had fast a removal rate, as well as a high adsorption capacity of 536.73 mg (UO22+)/g and 593.97 mg (Eu3+)/g; (iii) the pseudo-second-order and Langmuir model provided a more reasonable description, indicating the immobilization process was endothermic, spontaneous chemisorption; (iv) the adsorption mechanism was chelation and electrostatic attraction, ascribed to the nitrogen/oxygen-containing functional groups. These results illustrated that NH2-MIL-125(Ti)@TpPa-1 was a prospective adsorbent for the remediation polluted by radionuclides. In addition, the research provided the theoretical basis for further investigation on the UO22+(VI) photoreduction.

Insight into efficient removal of Cr(VI) by magnetite immobilized with Lysinibacillus sp. JLT12: Mechanism and performance.

In this work, Lysinibacillus sp. JLT12 was used to remove the Cr(VI)-induced passive layer on the magnetite. Mechanism study via dynamic kinetics, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy analyses revealed that Lysinibacillus sp. JLT12 could remove the passive layer (lepidocrocite and goethite) to facilitate the further Cr(VI) reduction by magnetite. For large-scale applications, porous ceramsite (PC) was prepared with magnetite, kaolin, and fallen leaves. Lysinibacillus sp. was then immobilized on the holes in PC. Slow-released nutrients were added to immobilized porous ceramsite (IM-PC) at a ratio of 1.5:10 (g/g) to supply carbon, nitrogen, and phosphorus to Lysinibacillus sp. JLT12 with low secondary pollution. The performance of IM-PC was evaluated via a column experiment. The results indicate that, in the presence of Lysinibacillus, the break-through time and maximum adsorption ability of IM-PC were 11.67 h and 121.47 mg/g, respectively. These values are higher than those of PC. Additionally, break-through curves detected at 5, 10, and 15 days demonstrated that the usage life of IM-PC was significantly longer than that of PC.

Shikonin ameliorates lipoteichoic acid­induced acute lung injury via promotion of neutrophil apoptosis.

Shikonin is the major active component in Lithospermum erythrorhizon and has pharmacological effects including reducing inflammation, aiding resistance to bacteria and promoting wound healing. However, the effect of shikonin on lipoteichoic acid (LTA)­induced acute lung injury (ALI) remains to be elucidated. ALI is a serious illness resulting from significant pulmonary inflammation caused by various diseases, such as sepsis, acid aspiration and trauma. The present study found that shikonin significantly attenuated LTA­induced ALI. Following shikonin treatment, the accumulation of pulmonary neutrophils and expression of TNFα, IL­1ß and IL­6 were decreased in mice with LTA­induced ALI. Furthermore, Shikonin promoted neutrophil apoptosis by increasing the activation of caspase­3 and reducing the expression of the antiapoptotic myeloid cell leukemia­1 (Mcl­1) protein. However, shikonin treatment did not influence the expression of B­cell lymphoma­2. The findings of the present study demonstrated that shikonin protected against LTA­induced ALI by promoting caspase-3 and Mcl­1­related neutrophil apoptosis, suggesting that shikonin is a potential agent that can be used in the treatment of sepsis­mediated lung injury.

Genetic Modifiers of Duchenne Muscular Dystrophy in Chinese Patients.

Background: Duchenne muscular dystrophy (DMD) is a fatal, X-linked recessive muscle disorder characterized by heterogeneous progression and severity. We aimed to study the effects of single nucleotide polymorphisms (SNPs) in SPP1 and LTBP4 on DMD progression in Chinese patients. Methods: We genotyped LTBP4 haplotypes and the SPP1 promoter SNPs rs28357094, rs11730582, and rs17524488 in 326 patients registered in the neuromuscular database of The First Affiliated Hospital of Sun Yat-sen University. Kaplan-Meier curves and log-rank tests were used to estimate and compare median age at loss of ambulation, while Cox proportional hazard regression models were used as to analyze the effects of glucocorticoids treatments, DMD genotype, and SPP1/LTBP4 SNPs on loss of ambulation. Results: The CC/CT genotype at rs11730582 was associated with a 1.33-year delay in ambulation loss (p = 0.006), with hazard ratio 0.63 (p = 0.008), in patients with truncated DMD genotype and undergoing steroid treatment. On the other hand, rs17524488 in SPP1 and the IAAM/IAAM haplotype in LTBP4 were not associated with time to ambulation loss. Conclusions: SPP1 rs11730582 is a genetic modifier of the long-term effects of steroid treatment in Chinese DMD patients. Thus, any future clinical study in DMD should adjust for glucocorticoids use, DMD genotype, and SPP1 polymorphisms.

Engraftment of human induced pluripotent stem cell-derived myogenic progenitors restores dystrophin in mice with duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a devastating genetic muscular disorder with no effective treatment that is caused by the loss of dystrophin. Human induced pluripotent stem cells (hiPSCs) offer a promising unlimited resource for cell-based therapies of muscular dystrophy. However, their clinical applications are hindered by inefficient myogenic differentiation, and moreover, the engraftment of non-transgene hiPSC-derived myogenic progenitors has not been examined in the mdx mouse model of DMD. METHODS: We investigated the muscle regenerative potential of myogenic progenitors derived from hiPSCs in mdx mice. The hiPSCs were transfected with enhanced green fluorescent protein (EGFP) vector and defined as EGFP hiPSCs. Myogenic differentiation was performed on EGFP hiPSCs with supplementary of basic fibroblast growth factor, forskolin, 6-bromoindirubin-3'-oxime as well as horse serum. EGFP hiPSCs-derived myogenic progenitors were engrafted into mdx mice via both intramuscular and intravenous injection. The restoration of dystrophin expression, the ratio of central nuclear myofibers, and the transplanted cells-derived satellite cells were accessed after intramuscular and systemic transplantation. RESULTS: We report that abundant myogenic progenitors can be generated from hiPSCs after treatment with these three small molecules, with consequent terminal differentiation giving rise to mature myotubes in vitro. Upon intramuscular or systemic transplantation into mdx mice, these myogenic progenitors engrafted and contributed to human-derived myofiber regeneration in host muscles, restored dystrophin expression, ameliorated pathological lesions, and seeded the satellite cell compartment in dystrophic muscles. CONCLUSIONS: This study demonstrates the muscle regeneration potential of myogenic progenitors derived from hiPSCs using non-transgenic induction methods. Engraftment of hiPSC-derived myogenic progenitors could be a potential future therapeutic strategy to treat DMD in a clinical setting.

Homozygous NOTCH3 p.R587C mutation in Chinese patients with CADASIL: a case report.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations in NOTCH3 gene with remarkable phenotypic heterogeneity. Cases of CADASIL associated with homozygous NOTCH3 mutations are rare and subsequently understudied. In this study, we investigate the genetic and phenotypic features within patients of CADASIL with homozygous NOTCH3 mutations. CASE PRESENTATION: We recruited two affected individuals with CADASIL from a mainland Chinese family. The proband (Patient 1), a 60-year-old male, presented with slow progressive gait instability, severe cognitive impairment, and emotional disorder for more than 2 years with a history of ischemic stroke and hypertension. His younger brother (Patient 2) presented with apparent gait difficulties, dysarthria as well as cognitive decline at 59 years old. Brain magnetic resonance imaging (MRI) showed diffused white matter lesions involving bilateral periventricular white matter, semioval center region, and anterior temporal lobes. Molecular genetic testing identified a homozygous variant, c.1759C > T (p.R587C), in NOTCH3 gene in both patients. Pathological analysis revealed granular osmiophilic material (GOM) deposits in small arterial walls of skin from the proband. The diagnosis of CADASIL was confirmed. CONCLUSIONS: Our cases of CADASIL with homozygous mutation c.1759C > T (p.R587C) in NOTCH3 share similar manifestation to the patients with heterozygous same mutation reported previously. Other than genetic factors, vascular risk factors or environmental factors might contribute to the phenotypic variation of CADASIL.

One-Pot Cascade Biotransformation for Efficient Synthesis of Benzyl Alcohol and Its Analogs.

Benzyl alcohol is a naturally occurring aromatic alcohol and has been widely used in the cosmetics and flavor/fragrance industries. The whole-cell biotransformation for synthesis of benzyl alcohol directly from bio-based L-phenylalanine (L-Phe) was herein explored using an artificial enzyme cascade in Escherichia coli. Benzaldehyde was first produced from L-Phe via four heterologous enzymatic steps that comprises L-amino acid deaminase (LAAD), hydroxymandelate synthase (HmaS), (S)-mandelate dehydrogenase (SMDH) and benzoylformate decarboxylase (BFD). The subsequent reduction of benzaldehyde to benzyl alcohol was achieved by a broad substrate specificity phenylacetaldehyde reductase (PAR) from Solanum lycopersicum. We found the designed enzyme cascade could efficiently convert L-Phe into benzyl alcohol with conversion above 99%. In addition, we also examined L-tyrosine (L-Tyr) and m-fluoro-phenylalanine (m-f-Phe) as substrates, the cascade biotransformation could also efficiently produce p-hydroxybenzyl alcohol and m-fluoro-benzyl alcohol. In summary, the developed biocatalytic pathway has great potential to produce various high-valued fine chemicals.