Developmental ECM Sculpting: Laying It Down and Cutting It Up

In mammals, proteolytic remodeling of the embryonic extracellular matrix (ECM) controls morphogenesis, but the key players remain elusive. Two recent reports identify new roles for metalloproteinases belonging to the MT-MMP and ADAMTS families in branching morphogenesis and interdigital web regression

Psychosocial Effects of a Holistic Ayurvedic Approach to Well-being in Health and Wellness Courses.

BackgroundAs individuals are increasingly attending health and wellness courses outside of the conventional medical system, there is a need to obtain objective data on the effects of those programs on well-being.MethodsIn total, 154 men and women (mean age 54.7 years; range 25-83) participated in 3 different holistic wellness programs based on Ayurvedic Medicine principles (Seduction of Spirit, Journey into Healing, and Perfect Health) or a vacation control group. Psychosocial outcomes included spirituality (Delaney Spirituality Scale), mindful awareness (Mindful Attention Awareness Scale), psychological flexibility (Acceptance and Action Questionnaire), mood (Center for Epidemiology Studies-Depression), and anxiety (Patient-Reported Outcomes Measurement System Anxiety Scale).ResultsParticipants in the Seduction of Spirit (P < .004), Journey into Healing (P < .05), and Perfect Health (P < .004) courses showed significant increases in spirituality as compared to vacation controls. Participants in Seduction of Spirit (P < .007) also showed significant increases in mindfulness as compared to vacation controls. Participants in the Seduction of Spirit (P < .001) and Journey into Healing (P < .05) courses showed significant decreases in depressed mood as compared to those in the Perfect Health and vacation control groups. All study participants showed similar increases in psychological flexibility (P < .01) and decreases in anxiety (P < .01).ConclusionParticipation in wellness courses that incorporate a mind-body-spirit approach to health improves multiple domains of psychosocial well-being, which persists even after course participation

The Right to Treatment - Alternative Rationales [Note]

That which is most clear in any debate over proper care for the mentally ill is the need for an immediate solution. Understaffed and poorly maintained hospitals with doctor-patient ratios as high as one to 950 are no less than a national shame. To ask where the blame lies is a waste of time. The important concern is what must be done

Complex collective states in a one-dimensional two-atom system

We consider a pair of identical two-level atoms interacting with a scalar field in one dimension, separated by a distance $x_{21}$. We restrict our attention to states where one atom is excited and the other is in the ground state, in symmetric or anti-symmetric combinations. We obtain exact collective decaying states, belonging to a complex spectral representation of the Hamiltonian. The imaginary parts of the eigenvalues give the decay rates, and the real parts give the average energy of the collective states. In one dimension there is strong interference between the fields emitted by the atoms, leading to long-range cooperative effects. The decay rates and the energy oscillate with the distance $x_{21}$. Depending on $x_{21}$, the decay rates will either decrease, vanish or increase as compared with the one-atom decay rate. We have sub- and super-radiance at periodic intervals. Our model may be used to study two-cavity electron wave-guides. The vanishing of the collective decay rates then suggests the possibility of obtaining stable configurations, where an electron is trapped inside the two cavities.Comment: 14 pages, 14 figures, submitted to Phys. Rev.

How Do the Lives of Participants in a Housing Mobility Program Change After They Move? A Case Study of the Mobility Connection Program

SPI Research Brief No. 20-01. This brief outlines the results of an assessment of Mobility Connection, a housing mobility program in St. Louis, Missouri. Mobility Connection is administered through Ascend STL and this assessment was conducted in partnership with the Social Policy Institute at Washington University in St. Louis. Our research focused on answering the following questions: How do Mobility Connection participants report their lives changing since moving to a High Opportunity Area? How do participants feel about the quality of the Mobility Connection program? To answer these questions, researchers administered a novel survey to 20 Mobility Connection participants who had completed a move with support from the program

Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib.

BackgroundEarly detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics.MethodsA nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death.ResultsPlasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (P=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk.ConclusionsHeretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264

Three-Dimensional Spheroid Cell Model of In Vitro Adipocyte Inflammation

To improve treatment of obesity, a contributing factor to multiple systemic and metabolic diseases, a better understanding of metabolic state and environmental stress at the cellular level is essential. This work presents development of a three-dimensional (3D) in vitro model of adipose tissue displaying induced lipid accumulation as a function of fatty acid supplementation that, subsequently, investigates cellular responses to a pro-inflammatory stimulus, thereby recapitulating key stages of obesity progression. Three-dimensional spheroid organization of adipose cells was induced by culturing 3T3-L1 mouse preadipocytes on an elastin-like polypeptide-polyethyleneimine (ELP-PEI)-coated surface. Results indicate a more differentiated phenotype in 3D spheroid cultures relative to two-dimensional (2D) monolayer analogues based on triglyceride accumulation, CD36 and CD40 protein expression, and peroxisome proliferator-activated receptor-? (PPAR-?) and adiponectin mRNA expression. The 3T3-L1 adipocyte spheroid model was then used to test the effects of a pro-inflammatory microenvironment, namely maturation in the presence of elevated fatty acid levels followed by acute exposure to tumor necrosis factor alpha (TNF-α). Under these conditions, we demonstrate that metabolic function was reduced across all cultures exposed to TNF-α, especially so when pre-exposed to linoleic acid. Further, in response to TNF-α, enhanced lipolysis, monitored as increased extracellular glycerol and fatty acids levels, was observed in adipocytes cultured in the presence of exogenous fatty acids. Taken together, our 3D spheroid model showed enhanced adipogenic differentiation and presents a platform for elucidating the key phenotypic responses that occur in pro-inflammatory microenvironments that characterize obesogenic states.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140235/1/ten.tea.2014.0531.pd

Membrane-Type-3 Matrix Metalloproteinase (MT3-MMP) Functions as a Matrix Composition-Dependent Effector of Melanoma Cell Invasion

Peer reviewe

Total Synthesis of the Bovine Pancreatic Trypsin Inhibitor (BPTI) and the Protein Diastereomer [Gly37D-Ala]BPTI using Boc Chemistry Solid Phase Peptide Synthesis

Bovine pancreatic trypsin inhibitor (BPTI) is a well‐studied model for investigation of protein folding and stability. Here, we report the synthesis and characterization of wild‐type BPTI and a diastereomeric protein analogue [Gly37D‐Ala]BPTI. Each 58‐residue polypeptide chain was made by native chemical ligation of two peptide segments, BPTI[1‐29]‐αthioester and the appropriate version of the Cys30‐58 BPTI peptide segment. Boc chemistry in situ neutralization solid phase synthesis was used to prepare the peptide segment reactants. The resulting full‐length polypeptide chains were folded in a cysteine/cystine redox buffer to give synthetic protein molecules containing three disulfide bonds. The diastereomeric analogue [Gly37D‐Ala]BPTI folded as efficiently as the native protein. Synthetic proteins were characterized by analytical LCMS and by natural‐abundance 1H‐15N HSQC NMR fingerprinting. These results illustrate the power of Boc chemistry peptide synthesis and its utility for the total chemical synthesis of protein molecules