N-Alkoxyphthalimides as Nitrogen Electrophiles to Construct C-N Bonds via Reductive Cross-Coupling.

N-Alkoxyphthalimides, one kind of phthalimide derivative, have great importance in synthesis, mainly used as free radical precursors. While the phthalimide unit, for a long time, was treated as part of the waste stream. Construction of C-N bonds has always been a hot spot, especially in reductive cross-coupling. Herein, a nickel-catalyzed reductive cross-coupling reaction of N-methoxyphthalimides with alkyl halides is described, where N-methoxyphthalimides serve as nitrogen electrophiles. This tactic provides a new approach to construct C-N bonds under mild neutral conditions. Alkyl chlorides, bromides, iodides, and sulfonates are all fit to this transformation. Moreover, the reaction could tolerate a broad substrate scope, especially base-sensitive functional groups (boron or silicon groups), as well as competitive nucleophilic groups (phenols and amides), which are incompatible with traditional Gabriel synthesis under basic conditions, demonstrating a complementary role of this work to Gabriel synthesis.

Manganese-promoted reductive cross-coupling of disulfides with dialkyl carbonates.

Manganese is a cheap and environmentally friendly metal on Earth. Herein, we report a manganese-promoted reductive cross-coupling using easily available and odorless disulfides as thiolating agents in an excellent 100% sulfur atom economy. The protocol featured a broad substrate scope, including various alkyl disulfides and excellent functional group compatibility, constructing diverse thioethers under simple conditions. Ultimately, thioethers can be prepared in gram-scale reactions and further transformed into structurally complex molecules.

Potential differentiation of successive SARS-CoV-2 mutations by RNA: DNA hybrid analyses.

The constant mutation of SARS-CoV-2 has triggered a new round of public health crises and has had a huge impact on existing vaccines and diagnostic tools. It is essential to develop a new flexible method to distinguish mutations to prevent the spread of the virus. In this work, we used the combination of density functional theory (DFT) and non-equilibrium Green's function formulation with decoherence, to theoretically study the effect of viral mutation on charge transport properties of viral nucleic acid molecules. We found that all mutation of SARS-CoV-2 on spike protein was accompanied by the change of gene sequence conductance, this is attributed to the change of nucleic acid molecular energy level caused by mutation. Among them, the mutations L18F, P26S, and T1027I caused the largest conductance change after mutation. This provides a theoretical possibility for detecting virus mutation based on the change of molecular conductance of virus nucleic acid.

Electrical modulation properties of DNA drug molecules.

DNA drug molecules are not only widely used in gene therapy, but also play an important role in controlling the electrical properties of molecular electronics. Covalent binding, groove binding and intercalation are all important forms of drug-DNA interaction. But its applications are limited due to a lack of understanding of the electron transport mechanisms after different drug-DNA interaction modes. Here, we used a combination of density functional theory calculations and nonequilibrium Green's function formulation with decoherence to study the effect of drug molecules on the charge transport property of DNA under three different binding modes. Conductance of DNA is found to decrease from 2.35E-5 G0 to 1.95E-6 G0 upon doxorubicin intercalation due to modifications of the density of states in the near-highest occupied molecular orbital region, δG = 1105.13%. Additionally, the conductance of DNA after cis-[Pt(NH3)2(py)Cl]+ covalent binding increases from 1.02E-6 G0 to 5.25E-5 G0, δG = 5047.06%. However, in the case of pentamidine groove binding, because there is no direct change in DNA molecular structure during drug binding, the conductance changes before and after drug binding is much smaller than in the two above cases, δG = 90.43%. Our theoretical calculations suggest that the conductance of DNA can be regulated by different drug molecules or switching the interaction modes between small molecules and DNA. This regulation opens new possibilities for their potential applications in controllable modulation of the electron transport property of DNA.

Charge transport properties of SARS-CoV-2 Delta variant (B.1.617.2).

The B.1.617.2 (Delta) variant of concern is causing a new wave of infections in many countries. In order to better understand the changes of the SARS-CoV-2 mutation at the genetic level, we selected six mutations in the S region of the Delta variant compared with the native SARS-CoV-2 and get the conductance information of these six short RNA oligonucleotides groups by construct RNA: DNA hybrids. The electronic characteristics are investigated by the combination of density functional theory and non-equilibrium Green's function formulation with decoherence. We found that conductance is very sensitive to small changes in virus sequence. Among the 6 mutations in the Delta S region, D950N shows the largest change in relative conductance, reaching a surprising 4104.75%. These results provide new insights into the Delta variant from the perspective of its electrical properties. This may be a new method to distinguish virus variation and possess great research prospects.

An ischemia-homing bioengineered nano-scavenger for specifically alleviating multiple pathogeneses in ischemic stroke.

BACKGROUND: Ischemic stroke is one of the most serious global public health problems. However, the performance of current therapeutic regimens is limited due to their poor target specificity, narrow therapeutic time window, and compromised therapeutic effect. To overcome these barriers, we designed an ischemia-homing bioengineered nano-scavenger by camouflaging a catalase (CAT)-loaded self-assembled tannic acid (TA) nanoparticle with a M2-type microglia membrane (TPC@M2 NPs) for ischemic stroke treatment. RESULTS: The TPC@M2 NPs can on-demand release TA molecules to chelate excessive Fe2+, while acid-responsively liberating CAT to synergistically scavenge multiple ROS (·OH, ·O2-, and H2O2). Besides, the M2 microglia membrane not only can be served as bioinspired therapeutic agents to repolarize M1 microglia into M2 phenotype but also endows the nano-scavenger with ischemia-homing and BBB-crossing capabilities. CONCLUSIONS: The nano-scavenger for specific clearance of multiple pathogenic elements to alleviate inflammation and protect neurons holds great promise for combating ischemic stroke and other inflammation-related diseases.

Induced Pluripotent Stem Cells for Ischemic Stroke Treatment.

Ischemic stroke is one of the main central nervous system diseases and is associated with high disability and mortality rates. Recombinant tissue plasminogen activator (rt-PA) and mechanical thrombectomy are the optimal therapies available currently to restore blood flow in patients with stroke; however, their limitations are well recognized. Therefore, new treatments are urgently required to overcome these shortcomings. Recently, stem cell transplantation technology, involving the transplantation of induced pluripotent stem cells (iPSCs), has drawn the interest of neuroscientists and is considered to be a promising alternative for ischemic stroke treatment. iPSCs are a class of cells produced by introducing specific transcription factors into somatic cells, and are similar to embryonic stem cells in biological function. Here, we have reviewed the current applications of stem cells with a focus on iPSC therapy in ischemic stroke, including the neuroprotective mechanisms, development constraints, major challenges to overcome, and clinical prospects. Based on the current state of research, we believe that stem cells, especially iPSCs, will pave the way for future stroke treatment.

NLRP3 in the Cerebrospinal Fluid as a Potential Biomarker for the Diagnosis and Prognosis of Community-Acquired Bacterial Meningitis in Adults.

OBJECTIVE: To discover the levels of NLR family pyrin domain-containing 3 (NLRP3) in the cerebrospinal fluid (CSF) from adult patients with community-acquired bacterial meningitis (CABM). METHODS: We enrolled 34 patients with CABM, 20 patients with viral meningitis (VM), and 25 patients with non-inflammatory neurological disease. Data on standard clinical parameters, scores, and outcomes were obtained from clinical records, and inflammasome levels in the CSF were measured by an enzyme-linked immunosorbent assay. The area under the receiver operating characteristic curve (AUROC) was used to quantify the diagnostic and prognostic performance of CSF NLRP3 as a biomarker of CABM. RESULTS: The levels of NLRP3 were elevated in the CSF of patients with CABM, but levels for ASC, caspase-1, or other inflammasomes did not vary significantly. CSF NLRP3 was positively correlated with clinical severity and with the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte count, albumin quotient (Qalb), and immunoglobulin G quotient (QIgG). Patients with unfavorable outcomes had higher levels of NLRP3 in the CSF, which were correlated with several blood indicators, including NLR, PLR, and lymphocyte and monocyte counts. CONCLUSIONS: Our results suggested that the level of CSF NLRP3 could represent the severity of CABM in adults. CSF NLRP3 may be a good biomarker for the diagnosis of CABM and for the discrimination between CABM and VM. It may also be a better biomarker for predicting the prognosis of adult patients with CABM when compared to the NLR or the lymphocyte and monocyte counts.