The present invention provides refillable drug delivery systems, as well as methods of refilling the systems, and methods of using them to treat diseases.

The described invention provides compositions and methods for treating a fibrotic condition in a subject. The methods include administering a therapeutic amount of a pharmaceutical composition comprising synthetic extracellular vesicles (EVs) and a pharmaceutically acceptable carrier.

The present disclosure relates, according to some embodiments, to compositions, methods, systems, and kits for programmable endonucleolytic cleavage of DNA (e.g., ds DNA). For example, the in vitro activity of an Argonaute (e.g., a mesophilic Argonaute CbAgo from Clostridium butyricum) may be synchronized with DNA strand unwinding activity of a helicase (e.g., a nuclease deficient RecB.sup.exo-C DNA helicase from E. coli) for a rapid and efficient cleavage of double-stranded DNA targets. Enzymatic properties of CbAgo and different aspects of ds DNA cleavage were thoroughly explored by adapting high-throughput capillary electrophoreses technique for monitoring CbAgo cleavage activity in concurrence with RecB.sup.exo-C. The present disclosure shows that in the presence of RecB.sup.exo-C, CbAgo can be programmed with guides to cleave any site of interest localized at up to 10 kb distance from the end of linear ds DNA at 37° C. temperature. CbAgo/RecB.sup.exo-C can be programmed to generate DNA fragments flanked with unique single-stranded extensions suitable for seamless ligation with compatible DNA fragments. The present disclosure relates further the compositions, methods, systems, and kits for PRC-free assembly of linear DNA molecules by using CbAgo/RecB.sup.exo-C programmable DNA endonuclease. The results presented here demonstrate that the combination of CbAgo and RecB.sup.exo-C is currently an efficient mesophilic DNA-guided DNA-cleaving programmable endonuclease which can be used to prepare synthetic biology tools that require or benefit from sequence-specific nicking/cleavage of natural DNA at otherwise inaccessible locations.

Provided herein are methods for the treatment of polycystic kidney disease, including autosomal dominant polycystic kidney disease, using modified oligonucleotides targeted to miR-17.

Described herein are methods of prolonging or reactivating organogenesis in a subject in need thereof (e.g., a subject that has impaired organ function such as a prematurely born infant). The methods comprise increasing the expression or activity of Lin28A or Lin28B proteins, inhibiting the expression or activity of let-7 family microRNAs, and/or inhibiting the expression or activity of Dis3L2 exonuclease.

The application relates to methods for compositions for identifying lncRNA loci associated with target genotypes or phenotypes, including desirable plant genotypes or phenotype. The application also relates to regulatory regions and genes associated with drug resistance, such as resistance to BRAF-inhibitors. Such regulatory regions and genes form the basis for methods for identifying resistance to BRAF-inhibitors, which is useful for improving disease prognosis, treatment, and likely outcomes. The regulatory regions and genes are also suitable targets for therapy in melanoma that is resistant to BRAF-inhibitors.

The present invention includes methods for detecting and reducing or inhibiting ischemic stroke in a mammal, the method comprising: (a) selecting microRNAs to downregulate selected from the group consisting of hsa-miR-96-5p, hsa-miR-99a-5p, hsa-miR-122-5p, hsa-miR-186-5p, hsa-miR-211-5p, hsa-mir-760, PC-3p-57664, or PC-5p-12969, (b) selecting microRNAs to upregulate selected from the group consisting of ggo-miR-139, hsa-miR-30d-5p, hsa-miR-22-3p, hsa-miR-23a-3p, mmu-miR-5124a, mmu-mir-6240-5p, PC-3p-32463, or PC-5p-211, and combinations thereof, and (c) administering an agent that: downregulates that targets in (a), upregulates the targets in (b), or both, to the subject in an amount sufficient to reduce or inhibit ischemic stroke in the mammal. The present invention also includes the detection of the markers for use with stroke patients.

Provided herein are aptamers for binding lipoproteins, systems for binding lipoproteins, and methods of detecting lipoproteins in a sample. The aptamers are useful for detecting the levels of lipoproteins in a biological sample and selectively detecting LDL particles in the presence of HDL particles. The aptamers can also be used as therapeutic agents against various diseases.

The disclosure is directed to inhibitory agents that hybridize to a GAPLINC RNA and inhibit or reduce the expression of the GAPLINC RNA. The GAPLINC RNA is a long non-coding RNA (lncRNA) located on chromosome 18 between the protein-coding genes Tgif and Dlgap1. The disclosure also features pharmaceutical compositions including the inhibitory agents and methods of using the inhibitory agents to treat an inflammatory disease, such as sepsis.

Provided are a precursor miRNA and application thereof in a tumor treatment. The precursor miRNA from the 5′ end to 3′ end has a structure presented as formula I:

##STR00001##

B1 is anti-miRNA-214-5p; B2 is an essentially complementary sequence or a totally complementary sequence to B1, and B2 and C are not complementary; C is a sequence having a stem-loop structure; A1 and A2 are respectively RNA sequences having no or 4-5 bases freely selected bases respectively; the precursor miRNA shown can be processed to form anti-miRNA-214 in a host, and only anti-miRNA-214-5p but not anti-miRNA-214-3p is expressed in the anti-miRNA-214.