Prostate-specific membrane antigen (PSMA)-mediated laminin proteolysis generates a pro-angiogenic peptide

Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis. The previous research determined that PSMA cleavage of small peptides generated via matrix metalloprotease-mediated proteolysis of the extracellular matrix protein laminin potently activated endothelial cells, integrin signaling and angiogenesis, although the specific peptide substrates were not identified. Herein, using enzymatic analyses and LC/MS, we unequivocally demonstrate that several laminin-derived peptides containing carboxy-terminal glutamate moieties (LQE, IEE, LNE) are bona fide substrates for PSMA. Subsequently, the peptide products were tested for their effects on angiogenesis in various models. We report that LQ, the dipeptide product of PSMA cleavage of LQE, efficiently activates endothelial cells in vitro and enhances angiogenesis in vivo. Importantly, LQE is not cleaved by an inactive PSMA enzyme containing an active site mutation (E424S). Endothelial cell activation by LQ was dependent on integrin beta-1-induced activation of focal adhesion kinase. These results characterize a novel PSMA substrate, provide a functional rationale for the upregulation of PSMA in cancer cells and tumor vasculature and suggest that inhibition of PSMA could lead to the development of new angiogenic therapies.     

Factor Structure of Repetitive Behaviors Across Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder

Journal of Autism and Developmental Disorders - Restricted interests and repetitive behaviors (RRBs) are core symptoms of autism spectrum disorder (ASD), and commonly occur in...     

Changes in functional connectivity after theta-burst transcranial magnetic stimulation for post-traumatic stress disorder: a machine-learning study

European Archives of Psychiatry and Clinical Neuroscience - Intermittent theta burst stimulation (iTBS) is a novel treatment approach for post-traumatic stress disorder (PTSD), and recent...     

Horseshoe adrenal gland: a rare congenital anomaly

A solitary adrenal gland spanning the midline has been alternatively described as “Horseshoe” or “Butterfly” and is a rare congenital abnormality almost exclusively associated with neonates. There have been 65 reported cases in fetuses and infants, based on ultrasound and autopsy findings. Horseshoe adrenal gland is associated with several congenital anomalies, such as asplenia (52 %), neural tube defects (37 %), renal abnormalities (29 %), and diaphragmatic defects (1 %). Recently, Feldman and colleagues [2] reported the first case of an adult male with horseshoe adrenal gland and posterior midline diaphragmatic anomaly found incidentally with CT imaging. We present a second case of asymptomatic adult horseshoe adrenal gland with posterior midline diaphragmatic hernia in a 51-year-old woman discovered on CT imaging. In our patient these abnormalities were also associated with a 9th thoracic butterfly vertebrae and a unilateral region of underdevelopment of the paraspinal musculature at the level of the diaphragmatic defect. To our knowledge, this is the first time this abnormality has been documented with MRI.     

Structural integrity of extracted teeth restored using three different post-and-core systems: An in vitro comparative study

AimThe objective of the study was to assess the in vitro fracture resistance of endodontically treated teeth restored using different post-and-core materials.Materials and methodsExtracted human mandibular premolars (n = 36) were extracted teeth and equally distributed into four (4) treatment groups: cast metal post-and-core, milled zirconia post-and-core, pre-fabricated post with composite resin core and control group. These samples were then each subjected to the load to fracture test using a universal testing machine. Fracture resistance data were compared among groups by analysis of variance and Fisher’s exact test.ResultsThe highest mean fracture resistance value was observed in the zirconia post-and-core treatment group (1567.26 ± 317.66 N), followed by the cast metal (1355.92 ± 621.56 N) and lastly the pre-fabricated post with composite resin core (725.67 ± 251.05 N) treatment group. Differences among groups were not statistically significantly different (P = 3.77).ConclusionEndodontically treated mandibular premolars with a zirconia post-and-core system exhibited the highest robustness against structural failure based on its mean fracture resistance value. In addition, extracted teeth restored with cast post-and-core resisted a greater stress load than those restored with fiber-reinforced posts. Zirconia showed a more favorable fracture mode than the other restorations.     

The Strategic Use of Noise in Pragmatic Reasoning

We combine two recent probabilistic approaches to natural language understanding, exploring the formal pragmatics of communication on a noisy channel. We first extend a model of rational communication between a speaker and listener, to allow for the possibility that messages are corrupted by noise. In this model, common knowledge of a noisy channel leads to the use and correct understanding of sentence fragments. A further extension of the model, which allows the speaker to intentionally reduce the noise rate on a word, is used to model prosodic emphasis. We show that the model derives several well-known changes in meaning associated with prosodic emphasis. Our results show that nominal amounts of actual noise can be leveraged for communicative purposes.