Adult mammalian brains have largely lost neuroregeneration capability except for a few niches. Previous studies have converted glial cells into neurons, but the total number of neurons generated is ...limited and the therapeutic potential is unclear. Here, we demonstrate that NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. Specifically, using NeuroD1 adeno-associated virus (AAV)-based gene therapy, we were able to regenerate one third of the total lost neurons caused by ischemic injury and simultaneously protect another one third of injured neurons, leading to a significant neuronal recovery. RNA sequencing and immunostaining confirmed neuronal recovery after cell conversion at both the mRNA level and protein level. Brain slice recordings found that the astrocyte-converted neurons showed robust action potentials and synaptic responses at 2 months after NeuroD1 expression. Anterograde and retrograde tracing revealed long-range axonal projections from astrocyte-converted neurons to their target regions in a time-dependent manner. Behavioral analyses showed a significant improvement of both motor and cognitive functions after cell conversion. Together, these results demonstrate that in vivo cell conversion technology through NeuroD1-based gene therapy can regenerate a large number of functional new neurons to restore lost neuronal functions after injury.
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After ischemic brain injury, many neurons die but surviving astrocytes become activated and proliferative. Using NeuroD1 AAV-based gene therapy, Chen and colleagues demonstrate robust neuroregeneration through direct astrocyte-to-neuron conversion and significantly improved functional recovery. This study provides a new paradigm for brain repair using in vivo cell conversion technology.
Breast cancer is now the most frequently diagnosed malignancy, and metastasis remains the leading cause of death in breast cancer. However, little is known about the dynamic changes during the ...evolvement of dissemination. In this study, 65 968 cells from four patients with breast cancer and paired metastatic axillary lymph nodes are profiled using single‐cell RNA sequencing (scRNA‐seq) and spatial transcriptomics. A disseminated cancer cell cluster with high levels of oxidative phosphorylation (OXPHOS), including the upregulation of cytochrome C oxidase subunit 6C and dehydrogenase/reductase 2, is identified. The transition between glycolysis and OXPHOS when dissemination initiates is noticed. Furthermore, this distinct cell cluster is distributed along the tumor's leading edge. The findings here are verified in three different cohorts of breast cancer patients and an external scRNA‐seq dataset, which includes eight patients with breast cancer and paired metastatic axillary lymph nodes. This work describes the dynamic metabolic evolvement of early disseminated breast cancer and reveals a switch between glycolysis and OXPHOS in breast cancer cells as the early event during lymph node metastasis.
By single‐cell RNA sequencing and spatial transcriptomics, the early early‐disseminated breast cancer cells are found to travel from the border of primary tumor to axillary lymph nodes. During this metastasis, a switch between glycolysis and oxidative phosphorylation occurs in early disseminated breast cancer cells, indicating an interesting dynamic metabolic evolvement.
Metabolic associated fatty liver disease (MAFLD) is a new definition for liver disease associated with known metabolic dysfunction. Based on new diagnostic criteria, we aimed to investigate its ...prevalence and risk factors in Chinese population.
We conducted this study in a health examination population who underwent abdominal ultrasonography in China. The diagnosis of MAFLD was based on the new diagnostic criteria. The characteristics of the MAFLD population, as well as the associations between MAFLD and metabolic abnormalities, were explored. Mann-Whitney U test and chi-square test were performed to compare different variables. Binary logistic regression was used to determine the risk factors for MAFLD.
Among 139,170 subjects, the prevalence of MAFLD was 26.1% (males: 35.4%; females: 14.1%). The prevalence based on female menopausal status, that is, premenopausal, perimenopausal, and postmenopausal, was 6.1%, 16.8%, and 30.2%, respectively. In different BMI groups (underweight, normal, overweight and obese), the prevalence was 0.1%, 4.0%, 27.4% and 59.8%, respectively. The proportions of abnormal metabolic features in the MAFLD group were significantly higher than those in the non-MAFLD group, as was the proportion of elevated alanine aminotransferase (ALT) (42.5% vs. 11%, P < 0.001). In nonobese individuals with MAFLD, the proportions of abnormal metabolic features were also all significantly higher than those in nonobese individuals without MAFLD. The prevalence of metabolic syndrome (MS), dyslipidaemia, and hyperuricaemia, respectively, in the MAFLD group (53.2%, 80.0%, and 45.0%) was significantly higher than that in the non-MAFLD group (10.1%, 41.7%, and 16.8%). Logistic regression revealed that age, BMI, waist circumference, ALT, triglycerides, fasting glucose, uric acid and platelet count were associated with MAFLD.
MAFLD is prevalent in China and varies considerably among different age, sex, BMI, and female menopausal status groups. MAFLD is related to metabolic disorders, especially obesity, while metabolic disorders also play important roles in the occurrence of MAFLD in nonobese individuals. MAFLD patients exhibit a high prevalence of MS, dyslipidaemia, hyperuricaemia, and elevated liver enzymes. MAFLD tends to coexist with systemic metabolic disorders, and a deep inner relationship may exist between MAFLD and MS. Metabolic disorders should be considered to improve the management of MAFLD.
Reliable and noninvasive biomarkers for the early diagnosis of non‐small‐cell lung cancer (NSCLC) are an unmet need. This study aimed to screen and validate potential urinary biomarkers for the early ...diagnosis of NSCLC. Using protein mass spectrometry, urinary MDH2 was found to be abundant both in patients with lung cancer and lung cancer model mice compared with controls. Urine samples obtained as retrospective and prospective cohorts including 1091 NSCLC patients and 736 healthy controls were measured using ELISA. Patients with stage I NSCLC had higher urinary MDH2 compared with healthy controls. The area under the receiver‐operating characteristic curve (AUC) for the urinary MDH2 was 0.7679 and 0.7234 in retrospective and prospective cohorts to distinguish stage I cases from controls. Urinary MDH2 levels correlated with gender and smoking history. MDH2 expression levels were elevated in lung cancer tissues. MDH2 knockdown using shRNA inhibited the proliferation of lung cancer cells. Our study demonstrated that urinary MDH2 concentration was higher in early‐stage NSCLC patients compared with that in controls and that MDH2 could serve as a potential biomarker for early detection of NSCLC.
Malate dehydrogenase 2 was significantly elevated both in urine and in cancer tissues of NSCLC patients. The level of MDH2 in urine could serve as an assistant biomarker for the early diagnosis of NSCLC.
New synthetic routes were devised for total synthesis of Fe3+‐bound (ferri−) salmycin B (Sal B) (1), glycan‐based Sal analogues 2–5 and their Fe3+‐unbound (desferri−) counterparts 1′–5′ for the ...structure to activity relationship (SAR) study. The results of SAR study reveal the effective structure of 1 and its desferri‐counterpart 1′ that are responsible for the observed inhibitory activity against Staphylococcus aureus (S. aureus). Among the analogues 2–5 and 2′–5′, glucose‐based analogue 2 and its desferri‐counterpart 2′ exhibited inhibitory potency comparable to 1 and 1′. Chemical modification of 2′ for further antibacterial study enabled us to discover desferri‐Sal analogue 7′ that endowed with a simpler pharmacophore structure but significantly higher antibacterial potency against methicillin‐sensitive and resistant S. aureus than the natural product 1′ and even the clinical vancomycin. Together with a better hydrolytic stability and shorter synthetic route, the analogue 7′ represents an attractive antibiotic lead for further exploration.
Microbe‐mediated mineralization is ubiquitous in nature, involving bacteria, fungi, viruses, and algae. These mineralization processes comprise calcification, silicification, and iron mineralization. ...The mechanisms for mineral formation include extracellular and intracellular biomineralization. The mineral precipitating capability of microbes is often harnessed for green synthesis of metal nanoparticles, which are relatively less toxic compared with those synthesized through physical or chemical methods. Microbe‐mediated mineralization has important applications ranging from pollutant removal and nonreactive carriers, to other industrial and biomedical applications. Herein, the different types of microbe‐mediated biomineralization that occur in nature, their mechanisms, as well as their applications are elucidated to create a backdrop for future research.
Different types of biomineralization, including calcification, silicification, iron, carbon, nitrogen, and phosphorus mineralization, which are mediated by algae, bacteria, fungi, and viruses, are summarized. The mechanisms of extracellular and intracellular microbe‐mediated mineralization, as well as their environmental, industrial, and biotechnological applications are discussed in depth.
Although 5-methylcytosine (m
C) is a widespread modification in RNAs, its regulation and biological role in pathological conditions (such as cancer) remain unknown. Here, we provide the ...single-nucleotide resolution landscape of messenger RNA m
C modifications in human urothelial carcinoma of the bladder (UCB). We identify numerous oncogene RNAs with hypermethylated m
C sites causally linked to their upregulation in UCBs and further demonstrate YBX1 as an m
C 'reader' recognizing m
C-modified mRNAs through the indole ring of W65 in its cold-shock domain. YBX1 maintains the stability of its target mRNA by recruiting ELAVL1. Moreover, NSUN2 and YBX1 are demonstrated to drive UCB pathogenesis by targeting the m
C methylation site in the HDGF 3' untranslated region. Clinically, a high coexpression of NUSN2, YBX1 and HDGF predicts the poorest survival. Our findings reveal an unprecedented mechanism of RNA m
C-regulated oncogene activation, providing a potential therapeutic strategy for UCB.
Abstract
Context
Thyroid function variation within the thyroxine reference range has negative metabolic effects. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a recently proposed ...definition.
Objective
We aim to explore the effects of thyroid function status on prevalence and mortality of MAFLD.
Methods
Data of 10 666 participants from the Third National Health and Nutrition Examination Survey (NHANES III) were used. MAFLD was diagnosed based on the new definition. Thyroid function variation within the thyroxine reference range was defined based on thyroid-stimulating hormone (TSH) levels: subclinical hyperthyroidism, <0.39 mIU/L; strict-normal thyroid function, 0.39-2.5 mIU/L; and low thyroid function, >2.5 mIU/L, which comprised low-normal thyroid function (2.5-4.5 mIU/L) and subclinical hypothyroidism (> 4.5 mIU/L). Logistic and Cox regression were used in multivariate analysis.
Results
Low thyroid function is independently associated with MAFLD (odds ratio: 1.27). Compared with strict-normal thyroid function, subclinical hypothyroidism was significantly associated with increased risk for all-cause and cardiovascular mortality in the total population (hazard ratio HR for all-cause: 1.23; cardiovascular: 1.65) and MAFLD population (HR for all-cause: 1.32; cardiovascular: 1.99); meanwhile, in the low-normal thyroid function group, an increasing trend in mortality risk was observed. Furthermore, low thyroid function also showed significant negative impact on mortality in the total and MAFLD population. Among thyroid function spectrum, mild subclinical hypothyroidism showed the highest HRs on mortality.
Conclusions
Low thyroid function is independent risk factor of MAFLD and is associated with increased risk for all-cause and cardiovascular mortality in the MAFLD population. Reevaluation of TSH reference range should be considered.
This study establishes the first organocatalytic enantioselective synthesis of axially chiral N,N′‐bisindoles via chiral phosphoric acid‐catalyzed formal (3+2) cycloadditions of indole‐based ...enaminones as novel platform molecules with 2,3‐diketoesters, where de novo indole‐ring formation is involved. Using this new strategy, various axially chiral N,N′‐bisindoles were synthesized in good yields and with excellent enantioselectivities (up to 87 % yield and 96 % ee). More importantly, this class of axially chiral N,N′‐bisindoles exhibited some degree of cytotoxicity toward cancer cells and was derived into axially chiral phosphine ligands with high catalytic activity. This study provides a new strategy for enantioselective synthesis of axially chiral N,N′‐bisindoles using asymmetric organocatalysis and is the first to realize the applications of such scaffolds in medicinal chemistry and asymmetric catalysis.
An organocatalytic enantioselective synthesis of axially chiral N,N′‐bisindoles has been established via chiral phosphoric acid‐catalyzed formal (3+2) cycloaddition of indole‐based enaminones with 2,3‐diketoesters. This study provides a new strategy for the highly selective synthesis of axially chiral N,N′‐bisindoles and shows the successful application of such skeletons in medicinal and synthetic chemistry.
We propose a novel method to compute multi-loop master integrals by constructing and numerically solving a system of ordinary differential equations, with almost trivial boundary conditions. Thus it ...can be systematically applied to problems with arbitrary kinematic configurations. Numerical tests show that our method can not only achieve results with high precision, but also be much faster than the only existing systematic method sector decomposition. As a by product, we find a new strategy to compute scalar one-loop integrals without reducing them to master integrals.
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