A novel type of cellular-uptake-shielding multifunctional envelope-type mesoporous silica nanoparticle (MEMSN) was designed for tumor-triggered targeting drug delivery to cancerous cells. β-Cyclodextrin (β-CD) was anchored on the surface of mesoporous silica nanoparticles via disulfide linking for glutathione-induced intracellular drug release. Then a peptide sequence containing Arg-Gly-Asp (RGD) motif and matrix metalloproteinase (MMP) substrate peptide Pro-Leu-Gly-Val-Arg (PLGVR) was introduced onto the surface of the nanoparticles via host-guest interaction. To protect the targeting ligand and prevent the nanoparticles from being uptaken by normal cells, the nanoparticles were further decorated with poly(aspartic acid) (PASP) to obtain MEMSN. In vitro study demonstrated that MEMSN was shielded against normal cells. After reaching the tumor cells, the targeting property could be switched on by removing the PASP protection layer via hydrolyzation of PLGVR at the MMP-rich tumor cells, which enabled the easy uptake of drug-loaded nanoparticles by tumor cells and subsequent glutathione-induced drug release intracellularly.

Damage induced in the DNA after exposure of cells to ionizing radiation activates checkpoint pathways that inhibit progression of cells through the G1 and G2 phases and induce a transient delay in the progression through S phase. Checkpoints together with repair and apoptosis are integrated in a circuitry that determines the ultimate response of a cell to DNA damage. Checkpoint activation typically requires sensors and mediators of DNA damage, signal transducers and effectors. Here, we review the current state of knowledge regarding mechanisms of checkpoint activation and proteins involved in the different steps of the process. Emphasis is placed on the role of ATM and ATR, as well on CHK1 and CHK2 kinases in checkpoint response. The roles of downstream effectors, such as P53 and the CDC25 family of proteins, are also described, and connections between repair and checkpoint activation are attempted. The role of checkpoints in genomic stability and the potential of improving the treatment of cancer by DNA damage inducing agents through checkpoint abrogation are also briefly outlined.

Soaring cases of coronavirus disease (COVID-19) are pummeling the global health system. Overwhelmed health facilities have endeavored to mitigate the pandemic, but mortality of COVID-19 continues to increase. Here, we present a mortality risk prediction model for COVID-19 (MRPMC) that uses patients’ clinical data on admission to stratify patients by mortality risk, which enables prediction of physiological deterioration and death up to 20 days in advance. This ensemble model is built using four machine learning methods including Logistic Regression, Support Vector Machine, Gradient Boosted Decision Tree, and Neural Network. We validate MRPMC in an internal validation cohort and two external validation cohorts, where it achieves an AUC of 0.9621 (95% CI: 0.9464–0.9778), 0.9760 (0.9613–0.9906), and 0.9246 (0.8763–0.9729), respectively. This model enables expeditious and accurate mortality risk stratification of patients with COVID-19, and potentially facilitates more responsive health systems that are conducive to high risk COVID-19 patients.

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IL-10/TGF-␤-modified macrophages, a subset of activated macrophages, produce anti-inflammatory cytokines, suggesting that they may protect against inflammation-mediated injury. Here, macrophages modified ex vivo by IL-10/TGF-␤ (IL-10/TGF-␤ ⌴2) significantly attenuated renal inflammation, structural injury, and functional decline in murine adriamycin nephrosis (AN). These cells deactivated effector macrophages and inhibited CD4 ϩ T cell proliferation. IL-10/TGF-␤ ⌴2 expressed high levels of the regulatory co-stimulatory molecule B7-H4, induced regulatory T cells from CD4 cells in vitro,and increased the number of regulatory T cells in lymph nodes draining the kidneys in AN. The phenotype of IL-10/TGF-␤ ⌴2 did not switch to that of effector macrophages in the inflamed kidney, and these cells did not promote fibrosis. Taken together, these data demonstrate that IL-10/TGF-␤-modified macrophages effectively protect against renal injury in AN and may become part of a therapeutic strategy for chronic inflammatory disease.

SUMMARY DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved carboxyl-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction but not dNTPase-inactive SAMHD1 fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity and prevents disease, including cancer.

BackgroundRadiotherapy kills tumor-cells by inducing DNA double strand breaks (DSBs). However, the efficient repair of tumors frequently prevents successful treatment. Therefore, identifying new practical sensitizers is an essential step towards successful radiotherapy. In this study, we tested the new hypothesis: identifying the miRNAs to target DNA DSB repair genes could be a new way for sensitizing tumors to ionizing radiation.Principal FindingsHere, we chose two genes: DNA-PKcs (an essential factor for non-homologous end-joining repair) and ATM (an important checkpoint regulator for promoting homologous recombination repair) as the targets to search their regulating miRNAs. By combining the database search and the bench work, we picked out miR-101. We identified that miR-101 could efficiently target DNA-PKcs and ATM via binding to the 3′- UTR of DNA-PKcs or ATM mRNA. Up-regulating miR-101 efficiently reduced the protein levels of DNA-PKcs and ATM in these tumor cells and most importantly, sensitized the tumor cells to radiation in vitro and in vivo.ConclusionsThese data demonstrate for the first time that miRNAs could be used to target DNA repair genes and thus sensitize tumors to radiation. These results provide a new way for improving tumor radiotherapy.

Although various two-dimensional (2D) nanomaterials have been explored as promising capacitive materials due to their unique layered structure, their natural restacking tendency impedes electrolyte transport and significantly restricts their practical applications. Herein, we synthesize all-carbon layer-by-layer motif architectures by introducing 2D ordered mesoporous carbons (OMC) within the interlayer space of 2D nanomaterials. As a proof of concept, MXenes are selected as 2D hosts to design 2D–2D heterostructures. Further removing the metal elements from MXenes leads to the formation of all-carbon 2D–2D heterostructures consisting of alternating layers of MXene-derived carbon (MDC) and OMC. The OMC layers intercalated with the MDC layers not only prevent restacking but also facilitate ion diffusion and electron transfer. The performance of the obtained hybrid carbons as supercapacitor electrodes demonstrates their potential for upcoming electronic devices. This method allows to overcome the restacking and blocking of 2D nanomaterials by constructing ion-accessible OMC within the 2D host material.