Retinoic acid-regulated nuclear matrix-associated protein (RAMP) is a WD40 repeat-containing protein that is involved in various biological functions, but little is known about its role in human cancer. This study aims to delineate the oncogenic role of RAMP in gastric carcinogenesis.

Caspase-3 is the best known executioner caspase in apoptosis. We generated caspase-3 knockout (C3KO) and knockdown human colorectal cancer cells, and found that they are unexpectedly sensitized to DNA-damaging agents including 5-fluorouracil (5-FU), etoposide, and camptothecin. C3KO xenograft tumors also displayed enhanced therapeutic response and cell death to 5-FU. C3KO cells showed intact apoptosis and activation of caspase-7 and -9, impaired processing of caspase-8, and induction of necrosis in response to DNA-damaging agents. This form of necrosis is associated with HMGB1 release and ROS production, and suppressed by genetic or pharmacological inhibition of RIP1, MLKL1, or caspase-8, but not inhibitors of pan-caspases or RIP3. 5-FU treatment led to the formation of a z-VAD-resistant pro-caspase-8/RIP1/FADD complex, which was strongly stabilized by caspase-3 KO. These data demonstrate a key role of caspase-3 in caspase-8 processing and suppression of DNA damage-induced necrosis, and provide a potentially novel way to chemosensitize cancer cells.

Genome-wide association studies (GWAS) of adolescents and adults are transforming our understanding of how genetic variants impact brain structure and psychiatric risk, but cannot address the reality that psychiatric disorders are unfolding developmental processes with origins in fetal life. To investigate how genetic variation impacts prenatal brain development, we conducted a GWAS of global brain tissue volumes in 561 infants. An intronic single-nucleotide polymorphism (SNP) in IGFBP7 (rs114518130) achieved genome-wide significance for gray matter volume (P=4.15 × 10-10). An intronic SNP in WWOX (rs10514437) neared genome-wide significance for white matter volume (P=1.56 × 10-8). Additional loci with small P-values included psychiatric GWAS associations and transcription factors expressed in developing brain. Genetic predisposition scores for schizophrenia and ASD, and the number of genes impacted by rare copy number variants (CNV burden) did not predict global brain tissue volumes. Integration of these results with large-scale neuroimaging GWAS in adolescents (PNC) and adults (ENIGMA2) suggests minimal overlap between common variants impacting brain volumes at different ages. Ultimately, by identifying genes contributing to adverse developmental phenotypes, it may be possible to adjust adverse trajectories, preventing or ameliorating psychiatric and developmental disorders.

Colorectal cancer (CRC), the second leading cause of cancer-related deaths in the US, has been treated with targeted therapies. However, the mechanisms of differential responses and resistance of CRCs to targeted therapies are not well understood. In this study, we found that genetic alterations of FBW7, an E3 ubiquitin ligase and a tumor suppressor frequently mutated in CRCs, contribute to resistance to targeted therapies. CRC cells containing FBW7-inactivating mutations are insensitive to clinically used multi-kinase inhibitors of RAS/RAF/MEK/ERK signaling, including regorafenib and sorafenib. In contrast, sensitivity to these agents is not affected by oncogenic mutations in KRAS, BRAF, PIK3CA or p53. These cells are defective in apoptosis owing to blocked degradation of Mcl-1, a pro-survival Bcl-2 family protein. Deleting FBW7 in FBW7-wild-type CRC cells abolishes Mcl-1 degradation and recapitulates the in vitro and in vivo drug-resistance phenotypes of FBW7-mutant cells. CRC cells selected for regorafenib resistance have progressive enrichment of pre-existing FBW7 hotspot mutations, and are cross-resistant to other targeted drugs that induce Mcl-1 degradation. Furthermore, a selective Mcl-1 inhibitor restores regorafenib sensitivity in CRC cells with intrinsic or acquired resistance. Together, our results demonstrate FBW7 mutational status as a key genetic determinant of CRC response to targeted therapies, and Mcl-1 as an attractive therapeutic target.

The hind wings of beetles are deployable and play an essential role in flight. In the Asian ladybird Harmonia axyridis (Coleoptera: Coccinellidae), the pterostigma (pst) is found in the middle of the hind wing instead of at the tip of the hind wing. This paper investigates the effect of the pst on the vibrational characteristics during the flight of H. axyridis. Based on cross sections of the pst and veins as well as the morphology and nanomechanical properties of the hind wing, including the wing membrane and veins, three three-dimensional coupling models, Models I-III, of hind wings with/without pst structures and veins with varying or uniform reduced moduli are established. Modal analysis results for these three models show that the vibrational characteristics and deformation tendencies change the flight performance of the hind wing models with pst structures compared with that of the other models. The results in this paper reveal that the pst structure has an important influence on vibrational characteristics and deformation tendencies and, hence, on flight performance; the relationships between the body mass and the area of the hind wing, which have significant implications for the design of biomimetic deployable wing structures for micro air vehicles (MAVs), are also analyzed.

To explore the effects of protein factor Oncostatin M (OSM), a member of the Interleukin-6 (IL-6) family on cell proliferation, osteogenic differentiation and mineralization.

Spinal cord injury (SCI) initiates a cascade of processes that ultimately form a nonpermissive environment for axonal regeneration. Emerging evidence suggests that regenerative failure may be due in part to inhibitory factors expressed by reactive spinal cord glial cells and meningeal fibroblasts, such as the Eph receptor protein-tyrosine kinases and their corresponding ligands (ephrins). Here we sought to assess the role of ephrin B2, an inhibitory axonal guidance molecule, as an inhibitor of the recovery process following SCI. To determine the extent of ephrin B2 involvement in axonal regenerative failure, a SCI model was performed on a conditional ephrin B2 knockout mouse strain (ephrin B2(-/-)), in which the ephrin B2 gene was deleted under the GFAP promoter . The expression of ephrin B2 was significantly decreased in astrocytes of injured and uninjured ephrin B2(-/-) mice compared to wild-type mice. Notably, in the ephrin B2(-/-) mice, the deletion of ephrin B2 reduced astrogliosis, and accelerated motor function recovery after SCI. Anterograde axonal tracing on a hemisection model of SCI further showed that ephrin B2(-/-) mice exhibited increased regeneration of injured corticospinal axons and a reduced glial scar, when compared to littermate controls exposed to similar injury. These results were confirmed by an in vitro neurite outgrowth assay and ephrin B2 functional blockage, which showed that ephrin B2 expressed on astrocytes inhibited axonal growth. Combined these findings suggest that ephrin B2 ligands expressed by reactive astrocytes impede the recovery process following SCI.

Initial sensitivity to psychostimulants can predict subsequent use and abuse in humans. Acute locomotor activation in response to psychostimulants is commonly used as an animal model of initial drug sensitivity and has been shown to have a substantial genetic component. Identifying the specific genetic differences that lead to phenotypic differences in initial drug sensitivity can advance our understanding of the processes that lead to addiction. Phenotyping inbred mouse strain panels are frequently used as a first step for studying the genetic architecture of complex traits. We assessed locomotor activation following a single, acute 20 mg/kg dose of cocaine (COC) in males from 45 inbred mouse strains and observed significant phenotypic variation across strains indicating a substantial genetic component. We also measured levels of COC, the active metabolite, norcocaine and the major inactive metabolite, benzoylecgonine, in plasma and brain in the same set of inbred strains. Pharmacokinetic (PK) and behavioral data were significantly correlated, but at a level that indicates that PK alone does not account for the behavioral differences observed across strains. Phenotypic data from this reference population of inbred strains can be utilized in studies aimed at examining the role of psychostimulant-induced locomotor activation on drug reward and reinforcement and to test theories about addiction processes. Moreover, these data serve as a starting point for identifying genes that alter sensitivity to the locomotor stimulatory effects of COC.

There is great interest in identifying a glucagon-like peptide-1 (GLP-1)-based combination therapy that will more effectively promote weight loss in patients with type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a compelling yet previously unexplored drug candidate to combine with GLP-1 due to its thermogenic and insulin-sensitizing effects. Here, we describe the development of a biologic that fuses GLP-1 to FGF21 with an elastin-like polypeptide linker that acts as a sustained release module with zero-order drug release. We show that once-weekly dual-agonist treatment of diabetic mice results in potent weight-reducing effects and enhanced glycemic control that are not observed with either agonist alone. Furthermore, the dual-agonist formulation has superior efficacy compared to a GLP-1/FGF21 mixture, demonstrating the utility of combining two structurally distinct peptides into one multifunctional molecule. We anticipate that these results will spur further investigation into GLP-1/FGF21 multiagonism for the treatment of metabolic disease.