Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines.

Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins.

Fecal dysbiosis and inflammation in intestinal-specific Cftr knockout mice on regimens preventing intestinal obstruction.

Chronic intestinal inflammation is a poorly understood manifestation of cystic fibrosis (CF), which may be refractory to ion channel CF transmembrane conductance regulator (CFTR) modulator therapy. People with CF exhibit intestinal dysbiosis, which has the potential for stimulating intestinal and systemic inflammation. CFTR is expressed in organ epithelia, leukocytes, and other tissues.

Fecal Dysbiosis and Inflammation in Intestinal-Specific Cftr Knockout Mice on Regimens Preventing Intestinal Obstruction.

Unlabelled: Chronic intestinal inflammation is a poorly understood manifestation of Cystic Fibrosis (CF), which may be refractory to ion channel CFTR modulator therapy. People with CF exhibit intestinal dysbiosis which has potential for stimulating intestinal and systemic inflammation. CFTR is expressed in organ epithelia and in the leukocyte population.

Goblet cell hyperplasia is not epithelial-autonomous in the Cftr knockout intestine.

Goblet cell hyperplasia is an important manifestation of cystic fibrosis (CF) disease in epithelial-lined organs. Explants of CF airway epithelium show normalization of goblet cell numbers; therefore, we hypothesized that small intestinal enteroids from Cftr knockout (KO) mice would not exhibit goblet cell hyperplasia. Toll-like receptors 2 and 4 (Tlr2 and Tlr4) were investigated as markers of inflammation and influence on goblet cell differentiation.

A comparison of impulse response modification techniques for time reversal with application to crack detection.

Time reversal (TR) focusing used for nonlinear detection of cracks relies on the ability of the TR process to provide spatially localized, high-amplitude excitation. The high amplitude improves the ability to detect nonlinear features that are a signature of the motion of closed cracks. It follows that a higher peak focal amplitude than what can be generated with the traditional TR process will improve the detection capability.

Nonlinearity from stress corrosion cracking as a function of chloride exposure time using the time reversed elastic nonlinearity diagnostic.

The Time Reversed Elastic Nonlinearity Diagnostic (TREND) has a long history of successful nondestructive detection of cracks in solids using nonlinear indicators. Recent research implemented TREND to find stress corrosion cracking (SCC) in the heat-affected zone adjacent to welds in stainless steel. SCC development around welds is likely to occur due to the temperature and chemical exposure of steel canisters housing spent nuclear fuel.

Time reversal focusing of high amplitude sound in a reverberation chamber.

Time reversal (TR) is a signal processing technique that can be used for intentional sound focusing. While it has been studied in room acoustics, the application of TR to produce a high amplitude focus of sound in a room has not yet been explored. The purpose of this study is to create a virtual source of spherical waves with TR that are of sufficient intensity to study nonlinear acoustic propagation.

Time reversal focusing of elastic waves in plates for an educational demonstration.

The purpose of this research is to develop a visual demonstration of time reversal focusing of vibrations in a thin plate. Various plate materials are tested to provide optimal conditions for time reversal focusing. Specifically, the reverberation time in each plate and the vibration coupling efficiency from a shaker to the plate are quantified to illustrate why a given plate provides the best spatially confined focus as well as the highest focal amplitude possible.

Stretch regulates expression and binding of chymotrypsin-like elastase 1 in the postnatal lung.

Lung stretch is critical for normal lung development and for compensatory lung growth after pneumonectomy (PNX), but the mechanisms by which strain induces matrix remodeling are unclear. Our prior work demonstrated an association of chymotrypsin-like elastase 1 (Cela1) with lung elastin remodeling, and that strain triggered a near-instantaneous elastin-remodeling response. We sought to determine whether stretch regulates Cela1 expression and Cela1 binding to lung elastin.

Outdoor measurements of spherical acoustic shock decay.

Prior anechoic measurements of a small acetylene-oxygen balloon explosion were used to study spherical weak-shock decay over short ranges [Muhlestein et al., J. Acoust.

Localization and stretch-dependence of lung elastase activity in development and compensatory growth.

Synthesis and remodeling of the lung matrix is necessary for primary and compensatory lung growth. Because cyclic negative force is applied to developing lung tissue during the respiratory cycle, we hypothesized that stretch is a critical regulator of lung matrix remodeling. By using quantitative image analysis of whole-lung and whole-lobe elastin in situ zymography images, we demonstrated that elastase activity increased twofold during the alveolar stage of postnatal lung morphogenesis in the mouse.

Dynamic expression of chymotrypsin-like elastase 1 over the course of murine lung development.

Postnatal lung development requires coordination of three processes (surface area expansion, microvascular growth, and matrix remodeling). Because normal elastin structure is important for lung morphogenesis, because physiological remodeling of lung elastin has never been defined, and because elastin remodeling is angiogenic, we sought to test the hypothesis that, during lung development, elastin is remodeled in a defined temporal-spatial pattern, that a novel protease is associated with this remodeling, and that angiogenesis is associated with elastin remodeling. By elastin in situ zymography, lung elastin remodeling increased 24-fold between embryonic day (E) 15.

JNK suppresses pulmonary fibroblast elastogenesis during alveolar development.

Background: The formation of discrete elastin bands at the tips of secondary alveolar septa is important for normal alveolar development, but the mechanisms regulating the lung elastogenic program are incompletely understood. JNK suppress elastin synthesis in the aorta and is important in a host of developmental processes. We sought to determine whether JNK suppresses pulmonary fibroblast elastogenesis during lung development.

A study of fragmentation of protonated amides of some acylated amino acids by tandem mass spectrometry: observation of an unusual nitrilium ion.

A tandem mass spectrometric study of a series of secondary amides of acetylglycine and hippuric acid utilizing electrospray ionization (ESI) was conducted. Among the fragment ions observed was an unusual one, which we have determined to be a nitrilium ion having the structure CH3-C≡N⊕-Ph or Ph-C≡N⊕-Ph by loss of the full mass of glycine as a neutral fragment. A mechanism that we propose involves an initial protonation of the oxygen atom at the N-terminus, followed by cyclization to a five-membered imidazolium ring, and its subsequent collapse to the nitrilium ion.