GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy.

Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient low-density lipoprotein receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use of structure-guided rational design in a series of mouse and non-human primate studies to optimize a GalNAc-Lipid nanoparticle that allows for low-density lipoprotein receptor independent delivery.

The combination of structure and material distribution ensures functionality of the honeybee wing-coupling mechanism.

Fore- and hindwings of honeybees are coupled and synchronized to flap by means of a forewing posterior recurved margin (PRM) and hindwing hamuli which constitute a hook-furrow coupling. Morphological analysis shows that the PRM is composed of a thickened and sclerotized membrane with the Archimedean spiral configuration and hamuli are a set of tiny, sclerotized hooks with flexible bases. By developing a theoretical PRM model, the influence of cuticle sclerotization and membrane-thickening on a deforming pattern and maximal coupling force was comparatively simulated, indicating that the real PRM is capable of bearing the highest coupling force and the membrane thickening makes more contribution than cuticle sclerotization on augmenting the maximal coupling force that the PRM can resist.

In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates.

Gene-editing technologies, which include the CRISPR-Cas nucleases and CRISPR base editors, have the potential to permanently modify disease-causing genes in patients. The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys (Macaca fascicularis).

Onset of the Mach Reflection of Zel'dovich-von Neumann-Döring Detonations.

The present study investigates the similarity problem associated with the onset of the Mach reflection of Zel'dovich-von Neumann-Döring (ZND) detonations in the near field. The results reveal that the self-similarity in the frozen-limit regime is strictly valid only within a small scale, i.e.

Towards Further Understanding the Secondary Fracture during Spaghetti Bent Break.

When a brittle thin rod, such as a dry spaghetti stick, is bent beyond its flexural limit, it often breaks into more than two pieces, typically three or more. This phenomenon and puzzle has aroused widespread interest and discussion since its first proposal by Feynman. Previous work has partly explained the inevitability of the secondary fracture, but without any adjustable time parameter.

Effect of Internal Microstructure Distribution on Quasi-Static Compression Behavior and Energy Absorption of Hollow Truss Structures.

In this work, hollow truss structures with different internal microstructure distributions, i.e., basic hollow truss structure (specimen HT), hollow truss structure with internal microstructure at joints (specimen HTSJ), and hollow truss structure with internal microstructure on tube walls (specimen HTSW), were designed and manufactured using a selective laser melting technique.

Structure, properties and functions of the forewing-hindwing coupling of honeybees.

Worker honeybees (Apis mellifera) are morphologically four-winged, but are functionally dipterous insects. During flight, their fore- and hindwings are coupled by means of the forewing posterior rolled margin (PRM) and hindwing hamuli. Morphological analysis shows that the PRM can be connected to the hamuli, so that the fore- and hindwing are firmly hinged, and can rotate with respect to each other.

Phage-derived protein-mediated targeted chemotherapy of pancreatic cancer.

Pancreatic cancer has been a life-threatening illness associated with high incidence and mortality rates. Paclitaxel (PCT) that causes mitotic arrest in cancer cells disrupting microtubule function is used for pancreatic cancer treatment. Nausea, anorexia and abdominal pain are some of the typical dose-limiting toxicity associated gastrointestinal side effects of the drug.

Investigation of span-chordwise bending anisotropy of honeybee forewings.

In this study, the spanwise and chordwise bending stiffness of honeybee forewings were measured by a cantilevered bending test. The test results indicate that the spanwise of the forewing is two orders of magnitude larger than the chordwise Three structural aspects result in this span-chordwise bending anisotropy: the distribution of resilin patches, the corrugation along the span and the leading edge vein of the venation. It was found that flexion lines formed by resilin patches revealed through fluorescence microscopy promoted the chordwise bending of the forewing during flapping flight.

Combination therapy targeting both cancer stem-like cells and bulk tumor cells for improved efficacy of breast cancer treatment.

Many types of tumors are organized in a hierarchy of heterogeneous cell populations. The cancer stem-like cells (CSCs) hypothesis suggests that tumor development and metastasis are driven by a minority population of cells, which are responsible for tumor initiation, growth and recurrences. The inability to efficiently eliminate CSCs during chemotherapy, together with CSCs being highly tumorigenic and invasive, may result in treatment failure due to cancer relapse and metastases.

[T cell immunity analysis in children with obstructive sleep apnea syndrome].

Objective: To probe into the possible impact on T cell immunity in children with obstructive sleep apnea syndrome (OSAS).

Method: Lymphocytes in peripheral blood vessel of children with OSAS vs normal controls were checked by APAAP method and analyzed statistically.

Result: The comparison with the controls showed that CD3+ had no significant difference (P>0.