The efficient delivery of biopharmaceutical drugs such as proteins and peptides into the cytosol of target cells poses substantial challenges owing to their large size and susceptibility to degradation. Current protein delivery vehicles have limitations such as the need for protein modification, insufficient delivery of large-size proteins or small peptides, and loss of protein function after the delivery. Here, we adopted a rational approach to design a polymer with robust efficacy for intracellular protein and peptide delivery. The polymer is composed of a dendrimer scaffold, a hydrophobic membrane-disruptive region, and a multivalent protein binding surface. It allows efficient protein/peptide binding, endocytosis, and endosomal disruption and is capable of efficiently delivering various biomacromolecules including bovine serum albumin, R-phycoerythrin, p53, saporin, β-galactosidase, and peptides into the cytosol of living cells. Transduction of apoptotic proteins and peptides successfully induces apoptosis in cancer cells, suggesting that the activities of proteins and peptides are maintained during the delivery. This technology represents an efficient and useful tool for intracellular protein and peptide delivery and has broad applicability for basic research and clinical applications.

Cytosolic delivery is the major challenge that limits the clinical translation of siRNA-based therapeutics. Although thousands of polymers have been developed for siRNA delivery, the efficiency–toxicity correlation is unsatisfactory. Here, we report a facile strategy to fabricate core–shell-structured nanoparticles with robust siRNA delivery efficiency. The nanoparticle is prepared by entropy-driven complexation of siRNA with a green tea catechin to yield a negatively charged core, followed by coating low-molecular-weight polymers to form the shell. This supramolecular strategy facilitates the polymers condensing siRNA into uniform nanoparticles. The nanoparticle specifically down-regulates target genes in vitro and in vivo, and efficiently attenuates chronic intestinal inflammation in an inflammatory bowel disease model. Notably, the highly efficient nanoparticles are applicable for various polymers with different topologies and chemical compositions, providing a versatile technique to break down the efficiency–toxicity correlation of cationic polymers. The proposed strategy in this study permits the development of a promising platform for polymer-mediated siRNA delivery.

We studied admission and dynamic demographic, hematological and biochemical co-variates in 1449 hospitalized subjects with coronavirus infectious disease-2019 (COVID-19) in five hospitals in Wuhan, Hubei province, China. We identified two admission co-variates: age (Odds Ratio [OR] = 1.18, 95% Confidence Interval [CI] [1.02, 1.36]; P = 0.026) and baseline D-dimer (OR = 3.18 [1.48, 6.82]; P = 0.003) correlated with an increased risk of death in persons with COVID-19. We also found dynamic changes in four co-variates, Δ fibrinogen (OR = 6. 45 [1.31, 31.69]; P = 0.022), Δ platelets (OR = 0.95 [0.90-0.99]; P = 0.029), Δ C-reactive protein (CRP) (OR = 1.09 [1.01, 1.18]; P = 0.037), and Δ lactate dehydrogenase (LDH) (OR = 1.03 [1.01, 1.06]; P = 0.007) correlated with an increased risk of death. The potential risk factors of old age, high baseline D-dimer, and dynamic co-variates of fibrinogen, platelets, CRP, and LDH could help clinicians to identify and treat subjects with poor prognosis. data of hematological abnormalities in persons with . We studied hematological co-variates in 1449 hospitalized persons with COVID-19 in five hospitals in Wuhan, China, interrogating correlations of admission parameters with COVID-19 outcomes. Methods Study design and subjectsWe studied subjects in seven centers of five hospitals of

The advancement of miniaturized electronic devices requires the development of high-performance microsupercapacitors. The low areal energy density of microsupercapacitors with the interdigitated architecture is the major challenge hindering the application. Here, a simple method for the scalable fabrication of all-solid-state, flexible microsupercapacitors is demonstrated by direct graphene-carbon nanotube composite ink writing technology. The microsupercapacitors demonstrate good electrochemical performance with a high areal energy density of 1.36 µWh cm -2 and power density of 0.25 mW cm -2 , good cycling stability, and excellent mechanical flexibility. The method developed here sheds light on the simple method of preparing high-performance, all-solid-state, flexible microsupercapacitors in a straightforward and scalable process.

SUMMARY The ubiquitin-proteasome and autophagy-lysosome systems are major proteolytic pathways, whereas function of the Ub-independent proteasome pathway is yet to be clarified. Here, we investigated roles of the Ub-independent REGγ-proteasome proteolytic system in regulating metabolism. We demonstrate that mice deficient for the proteasome activator REGγ exhibit dramatic autophagy induction and are protected against high-fat diet (HFD)-induced liver steatosis through autophagy. Molecularly, prevention of steatosis in the absence of REGγ entails elevated SirT1, a deacetylase regulating autophagy and metabolism. REGγ physically binds to SirT1, promotes its Ub-independent degradation and inhibits its activity to deacetylate autophagy-related proteins, thereby inhibiting autophagy under normal conditions. Moreover, REGγ and SirT1 dissociate from each other through a phosphorylation-dependent mechanism under energy-deprived conditions, unleashing SirT1 to stimulate autophagy. These observations provide a function of the REGγ proteasome in autophagy and hepatosteatosis, underscoring mechanistically a cross-talk between the proteasome and autophagy degradation system in the regulation of lipid homeostasis.