Synthesis of electroneutralized amphiphilic copolymers with peptide dendrons for intramuscular gene delivery

Intramuscular gene delivery materials are of great importance in plasmid-based gene therapy system, but there is limited information so far on how to design and synthesize them. A previous study showed that the peptide dendron-based triblock copolymer with its components arranged in a reversed biomembrane architecture could significantly increase intramuscular gene delivery and expression. Herein, we wonder whether copolymers with biomembrane-mimicking arrangement may have similar function on intramuscular gene delivery. Meanwhile, it is of great significance to uncover the influence of electric charge and molecular structure on the function of the copolymers. To address the issues, amphiphilic triblock copolymers arranged in hydrophilic-hydrophobic-hydrophilic structure were constructed despite the paradoxical characteristics and difficulties in synthesizing such hydrophilic but electroneutral molecules. The as-prepared two copolymers, dendronG2(l-lysine-OH)-poly propylene glycol2k(PPG2k)-dendronG2(l-lysine-OH) (rL2PL2) and dendronG3(l-lysine-OH)-PPG2k-dendronG3(l-lysine-OH) (rL3PL3), were in similar structure but had different hydrophilic components and surface charges, thus leading to different capabilities in gene delivery and expression in skeletal muscle. rL2PL2 was more efficient than Pluronic L64 and rL3PL3 when mediating luciferase, β-galactosidase, and fluorescent protein expressions. Furthermore, rL2PL2-mediated growth-hormone-releasing hormone expression could significantly induce mouse body weight increase in the first 21 days after injection. In addition, both rL2PL2 and rL3PL3 showed good in vivo biosafety in local and systemic administration. Altogether, rL2PL2-mediated gene expression in skeletal muscle exhibited applicable potential for gene therapy. The study revealed that the molecular structure and electric charge were critical factors governing the function of the copolymers for intramuscular gene delivery. It can be concluded that, combined with the previous study, both structural arrangements either reverse or similar to the biomembrane are effective in designing such copolymers. It also provides an innovative way in designing and synthesizing new electroneutralized triblock copolymers, which could be used safely and efficiently for intramuscular gene delivery

Oscillation-specific nodal alterations in early to middle stages Parkinsons disease.

Background: Different oscillations of brain networks could carry different dimensions of brain integration. We aimed to investigate oscillation-specific nodal alterations in patients with Parkinsons disease (PD) across early stage to middle stage by using graph theory-based analysis. Methods: Eighty-eight PD patients including 39 PD patients in the early stage (EPD) and 49 patients in the middle stage (MPD) and 36 controls were recruited in the present study. Graph theory-based network analyses from three oscillation frequencies (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz; slow-3: 0.073-0.198 Hz) were analyzed. Nodal metrics (e.g. nodal degree centrality, betweenness centrality and nodal efficiency) were calculated. Results: Our results showed that (1) a divergent effect of oscillation frequencies on nodal metrics, especially on nodal degree centrality and nodal efficiency, that the anteroventral neocortex and subcortex had high nodal metrics within low oscillation frequencies while the posterolateral neocortex had high values within the relative high oscillation frequency was observed, which visually showed that network was perturbed in PD; (2) PD patients in early stage relatively preserved nodal properties while MPD patients showed widespread abnormalities, which was consistently detected within all three oscillation frequencies; (3) the involvement of basal ganglia could be specifically observed within slow-5 oscillation frequency in MPD patients; (4) logistic regression and receiver operating characteristic curve analyses demonstrated that some of those oscillation-specific nodal alterations had the ability to well discriminate PD patients from controls or MPD from EPD patients at the individual level; (5) occipital disruption within high frequency (slow-3) made a significant influence on motor impairment which was dominated by akinesia and rigidity. Conclusions: Coupling various oscillations could provide potentially useful information for large-scale network and progressive oscillation-specific nodal alterations were observed in PD patients across early to middle stages

Recent Advances: Decoding Alzheimer’s Disease With Stem Cells

Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder that destroys cognitive functions. Recently, a number of high-profile clinical trials based on the amyloid cascade hypothesis have encountered disappointing results. The failure of these trials indicates the necessity for novel therapeutic strategies and disease models. In this review, we will describe how recent advances in stem cell technology have shed light on a novel treatment strategy and revolutionized the mechanistic investigation of AD pathogenesis. Current advances in promoting endogenous neurogenesis and transplanting exogenous stem cells from both bench research and clinical translation perspectives will be thoroughly summarized. In addition, reprogramming technology-based disease modeling, which has shown improved efficacy in recapitulating pathological features in human patients, will be discussed

Magnetic Field Sensing Based on Magnetic-Fluid-Clad Multimode-Singlemode-Multimode Fiber Structures

Magnetic field sensing based on magnetic-fluid-clad multimode-singlemode- multimode fiber structures is proposed and experimentalized. The structures are fabricated out using fiber fusion splicing techniques. The sensing principle is based on the interference between the core mode and cladding modes. Two interference dips are observed in our spectral range. Experimental results indicate that the magnetic field sensing sensitivities of 215 pm/mT and 0.5742 dB/mT are obtained for interference dip around 1595 nm. For interference dip around 1565 nm, the sensitivities are 60.5 pm/mT and 0.4821 dB/mT. The response of temperature is also investigated. The temperature sensitivity for the dip around 1595 nm is obtained to be 9.93 pm/°C

Physiological and Pathological Functions of Neuronal Hemoglobin: A Key Underappreciated Protein in Parkinson’s Disease

The expression of Hemoglobin (Hb) is not restricted to erythrocytes but is also present in neurons. Hb is selectively enriched in vulnerable mesencephalic dopaminergic neurons of Parkinson’s disease (PD) instead of resistant neurons. Controversial results of neuronal Hb levels have been reported in postmortem brains of PD patients: although neuronal Hb levels may decline in PD patients, elderly men with higher Hb levels have an increased risk of developing PD. α-synuclein, a key protein involved in PD pathology, interacts directly with Hb protein and forms complexes in erythrocytes and brains of monkeys and humans. These complexes increase in erythrocytes and striatal cytoplasm, while they decrease in striatal mitochondria with aging. Besides, the colocalization of serine 129-phosphorylated (Pser129) α-synuclein and Hb β chains have been found in the brains of PD patients. Several underlying molecular mechanisms involving mitochondrial homeostasis, α-synuclein accumulation, iron metabolism, and hormone-regulated signaling pathways have been investigated to assess the relationship between neuronal Hb and PD development. The formation of fibrils with neuronal Hb in various neurodegenerative diseases may indicate a common fibrillization pathway and a widespread target that could be applied in neurodegeneration therapy