Molecular Engineering of Plasma Membrane and Mitochondria Dual-Targeted NIR-II AIE Photosensitizer Evoking Synergetic Pyroptosis and Apoptosis.

Phototherapy provides a noninvasive and spatiotemporal controllable paradigm to inhibit the evasion of the programmed cell death (PCD) of tumors. However, conventional photosensitizers (PSs) often induce a single PCD process, resulting in insufficient photodamage and severely impeding their application scopes. In this study, molecular engineering is conducted by adjusting electron donors to develop an aggregation-induced NIR-II emissive PS (DPITQ) for plasma membrane and mitochondria dual-targeted tumor therapy by evoking synergetic pyroptosis and apoptosis. DPITQ displays boosted type I and II reactive oxygen species generation as well as a high photothermal conversion efficacy (43%) after laser irradiation of 635 nm. The excellent biocompatibility and appropriate lipophilicity help the DPITQ to specifically anchor in the plasma membrane and mitochondria of cancer cells. Furthermore, the photosensitized DPITQ can disrupt the intact plasma membrane and cause mitochondrial dysfunction, ultimately causing concurrent pyroptosis and apoptosis to suppress cancer cell proliferation even under hypoxia. It is noteworthy that the DPITQ nanoparticles (NPs) present clear NIR-II fluorescence imaging capability on the venous vessels of nude mice. Notably, the DPITQ NPs exert efficient NIR-II fluorescence imaging-guided phototherapy both in multicellular tumor spheroids and in vivo, causing maximum destruction to tumors but minimum adverse effects to normal tissue.

New endoscopic closure technique, "internal traction-assisted suspended closure," for GI defect closure: a pilot study (with video).

BACKGROUND AND AIMS: After endoscopic full-thickness resection (EFTR), reliable closure of the perforation is critical. However, it is technically difficult to close some defects by using metal clips alone or by purse-string suturing, which may lead to unreliable closure. Inspired by the process of pulling up the 2 ends of the incision in the surgical suture, we developed a new endoscopic closure technique, the "internal traction-assisted suspended closure" technique. This pilot study was performed as an initial evaluation of the feasibility and safety of this new endoscopic closure technique. METHODS: Data from patients in whom this suspended closure technique was used to close full-thickness defects after EFTR were retrospectively reviewed. The primary outcome was successful closure rate. Secondary outcomes were closure time, length of postprocedural hospital stay, and incidence of postprocedural adverse events. Defect size and tumor characteristics were also analyzed. RESULTS: Eight patients who underwent the suspended closure technique after EFTR were included. All patients were successfully treated with the suspended closure technique, and no patient developed serious adverse events. The median length of the defect was 3.25 cm (range, 2.5-9.0) and the median width was 2.8 cm (range, 1.8-6.0). The median closing time was 13 minutes (range, 6-24). CONCLUSIONS: The internal traction-assisted suspended closure technique is a simple, reliable, and easy-to-use technique for large full-thickness defects after endoscopic resection.

De Novo Synthesis of Poly(3-hydroxybutyrate-co-3-hydroxypropionate) from Oil by Engineered Cupriavidus necator.

Poly(3-hydroxybutyrate-co-3-hydroxypropionate) [P(3HB-co-3HP)] is a biodegradable and biocompatible polyester with improved and expanded material properties compared with poly(3-hydroxybutyrate) (PHB). This study engineered a robust malonyl-CoA pathway in Cupriavidus necator for the efficient supply of a 3HP monomer, and could achieve the production of [P(3HB-co-3HP)] from variable oil substrates. Flask level experiments followed by product purification and characterization found the optimal fermentation condition (soybean oil as carbon source, 0.5 g/L arabinose as induction level) in general consideration of the PHA content, PHA titer and 3HP molar fraction. A 5 L fed-batch fermentation (72 h) further increased the dry cell weight (DCW) to 6.08 g/L, the titer of [P(3HB-co-3HP)] to 3.11 g/L and the 3HP molar fraction to 32.25%. Further improving the 3HP molar fraction by increasing arabinose induction failed as the engineered malonyl-CoA pathway was not properly expressed under the high-level induction condition. With several promising advantages (broader range of economic oil substrates, no need for expensive supplementations such as alanine and VB12), this study indicated a candidate route for the industrial level production of [P(3HB-co-3HP)]. For future prospects, further studies are needed to further improve the strain and the fermentation process and expand the range of relative products.

Rare tandem repeat expansions associate with genes involved in synaptic and neuronal signaling functions in schizophrenia.

Tandem repeat expansions (TREs) are associated with over 60 monogenic disorders and have recently been implicated in complex disorders such as cancer and autism spectrum disorder. The role of TREs in schizophrenia is now emerging. In this study, we have performed a genome-wide investigation of TREs in schizophrenia. Using genome sequence data from 1154 Swedish schizophrenia cases and 934 ancestry-matched population controls, we have detected genome-wide rare (<0.1% population frequency) TREs that have motifs with a length of 2-20 base pairs. We find that the proportion of individuals carrying rare TREs is significantly higher in the schizophrenia group. There is a significantly higher burden of rare TREs in schizophrenia cases than in controls in genic regions, particularly in postsynaptic genes, in genes overlapping brain expression quantitative trait loci, and in brain-expressed genes that are differentially expressed between schizophrenia cases and controls. We demonstrate that TRE-associated genes are more constrained and primarily impact synaptic and neuronal signaling functions. These results have been replicated in an independent Canadian sample that consisted of 252 schizophrenia cases of European ancestry and 222 ancestry-matched controls. Our results support the involvement of rare TREs in schizophrenia etiology.