On the atomic structure of cocaine in solution

Cocaine is an amphiphilic drug which has the ability to cross the blood–brain barrier (BBB). Here, a combination of neutron diffraction and computation has been used to investigate the atomic scale structure of cocaine in aqueous solutions. Both the observed conformation and hydration of cocaine appear to contribute to its ability to cross hydrophobic layers afforded by the BBB, as the average conformation yields a structure which might allow cocaine to shield its hydrophilic regions from a lipophilic environment. Specifically, the carbonyl oxygens and amine group on cocaine, on average, form ~5 bonds with the water molecules in the surrounding solvent, and the top 30% of water molecules within 4 Å of cocaine are localized in the cavity formed by an internal hydrogen bond within the cocaine molecule. This water mediated internal hydrogen bonding suggests a mechanism of interaction between cocaine and the BBB that negates the need for deprotonation prior to interaction with the lipophilic portions of this barrier. This finding also has important implications for understanding how neurologically active molecules are able to interact with both the blood stream and BBB and emphasizes the use of structural measurements in solution in order to understand important biological function.Peer ReviewedPostprint (author's final draft

Deciphering the relative roles of matrix metalloproteinase‐ and plasmin‐mediated matrix degradation during capillary morphogenesis using engineered hydrogels

Extracellular matrix (ECM) remodeling is essential for the process of capillary morphogenesis. Here we employed synthetic poly(ethylene glycol) (PEG) hydrogels engineered with proteolytic specificity to either matrix metalloproteinases (MMPs), plasmin, or both to investigate the relative contributions of MMP‐ and plasmin‐mediated ECM remodeling to vessel formation in a 3D‐model of capillary self‐assembly analogous to vasculogenesis. We first demonstrated a role for both MMP‐ and plasmin‐mediated mechanisms of ECM remodeling in an endothelial‐fibroblast co‐culture model of vasculogenesis in fibrin hydrogels using inhibitors of MMPs and plasmin. When this co‐culture model was employed in engineered PEG hydrogels with selective protease sensitivity, we observed robust capillary morphogenesis only in MMP‐sensitive matrices. Fibroblast spreading in plasmin‐selective hydrogels confirmed this difference was due to protease preference by endothelial cells, not due to limitations of the matrix itself. In hydrogels engineered with crosslinks that were dually susceptible to MMPs and plasmin, capillary morphogenesis was unchanged. These findings highlight the critical importance of MMP‐mediated degradation during vasculogenesis and provide strong evidence to justify the preferential selection of MMP‐degradable peptide crosslinkers in synthetic hydrogels used to study vascular morphogenesis and promote vascularization. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2507–2516, 2019.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151850/1/jbmb34341_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151850/2/jbmb34341.pd

Minimal Informationally Complete Measurements for Pure States

We consider measurements, described by a positive-operator-valued measure (POVM), whose outcome probabilities determine an arbitrary pure state of a D-dimensional quantum system. We call such a measurement a pure-state informationally complete (PSI-complete) POVM. We show that a measurement with 2D-1 outcomes cannot be PSI-complete, and then we construct a POVM with 2D outcomes that suffices, thus showing that a minimal PSI-complete POVM has 2D outcomes. We also consider PSI-complete POVMs that have only rank-one POVM elements and construct an example with 3D-2 outcomes, which is a generalization of the tetrahedral measurement for a qubit. The question of the minimal number of elements in a rank-one PSI-complete POVM is left open.Comment: 2 figures, submitted for the Asher Peres festschrif

Effects of resistance training on depression and cardiovascular disease risk in black men: Protocol for a randomized controlled trial

Background Depression is severely undertreated in Black men. This is primarily because Black men are less likely to seek traditional psychiatric treatment, have less access and more barriers to treatment, and perceive more stigma associated with treatment. Depression contributes to cardiovascular disease (CVD), and Black men have the highest rate of mortality from CVD. Resistance training (RT) can have beneficial effects on both depression and CVD. This study will be the first randomized controlled trial to test the effects of RT on depression and cardiovascular health in a sample of depressed Black men. Method Fifty Black men with clinically significant symptoms of depression will be randomized to either (a) a 12-week RT or (b) an attention control group. Behavioral Activation techniques will be used to support adherence to home-based RT goals. Both groups will meet on-site twice/week during the 12-week program, and follow-up assessments will occur at the end-of-treatment and 3 months post-treatment. Qualitative interviews will be conducted after the 3-month follow-up. The objectives of this study are (1) to assess the feasibility and acceptability of recruitment, retention, and intervention procedures, (2) to obtain preliminary evidence of efficacy, and (3) to explore potential mediators of the effects of RT on depression. Discussion This study will advance the field of minority men\u27s health by producing new data on the effects of RT for depression, the potential mechanisms of action that may support its use, and its effects on markers of CVD risk in Black men

The differential effect of instructions on dysphoric and nondysphoric persons

The experimenters investigated whether dysphoric and nondysphoric persons differentially exhibited the traditional instruction-induced schedule-insensitivity effect (rule-governed behavior). Dysphoric and nondysphoric participants were given instructions to perform a matching-to-sample task (four blocks, 40 trials each). The instructions in the first half of the study were correct and in the second half, incorrect. Participants were assigned to one of two instructional control conditions in which they read the instruction either privately (tracking condition) or out loud to the experimenter (pliance condition). Dysphoric individuals demonstrated greater schedule sensitivity (less rule-governed behavior) than did nondysphoric persons. No other differences were found. Results indicate that deficits in rule-governed behavior may contribute to depression; however, this experiment did not incorporate procedures to directly test the role of rule-governed experiential avoidance

In the dedicated pursuit of dedicated capital: restoring an indigenous investment ethic to British capitalism

Tony Blair’s landslide electoral victory on May 1 (New Labour Day?) presents the party in power with a rare, perhaps even unprecedented, opportunity to revitalise and modernise Britain’s ailing and antiquated manufacturing economy.* If it is to do so, it must remain true to its long-standing (indeed, historic) commitment to restore an indigenous investment ethic to British capitalism. In this paper we argue that this in turn requires that the party reject the very neo-liberal orthodoxies which it offered to the electorate as evidence of its competence, moderation and ‘modernisation’, which is has internalised, and which it apparently now views as circumscribing the parameters of the politically and economically possible

Obstructive Sleep Apnea and Weight Loss Treatment Outcome Among Adults With Metabolic Syndrome

OBJECTIVE: The purpose of this study was to examine whether adults with obesity and metabolic syndrome who screen as high risk for obstructive sleep apnea (OSA) lose less weight as part of a weight loss intervention than those who screen as low risk. METHOD: We conducted a secondary analysis of a randomized trial comparing 2 weight loss interventions consisting of dietary counseling for adults with obesity and metabolic syndrome. Participants were screened for sleep apnea using a validated screening questionnaire. Percent weight loss was calculated from weight measured at baseline and intervention end (12 months). Weight loss of 5% or greater was considered clinically significant. Multivariate linear and logistic regression models estimated the association between OSA screening status (high vs. low risk) and percent weight loss and clinically significant weight loss, adjusting for relevant covariates including body mass index and sleep duration. RESULTS: Nearly half of participants (45.8%) screened as high risk for OSA. Participants who screened as high risk for OSA lost less weight (1.2% +/- 4.2% vs. 4.2% +/- 5.3%) and were less likely to lose 5% or greater (24.4% vs. 75.6%) than participants without OSA. CONCLUSION: Among adults with obesity and metabolic syndrome, those at high risk for OSA lost less weight in response to a dietary counseling intervention than adults with low risk of OSA. Routine OSA screening should be considered as part of weight loss treatment programs. Additional research is needed to determine how to tailor weight loss treatment for those with high risk for OSA. (PsycINFO Database Recor

Tumor Blood Flow Differs between Mouse Strains: Consequences for Vasoresponse to Photodynamic Therapy

Fluctuations in tumor blood flow are common and attributed to factors such as vasomotion or local vascular structure, yet, because vessel structure and physiology are host-derived, animal strain of tumor propagation may further determine blood flow characteristics. In the present report, baseline and stress-altered tumor hemodynamics as a function of murine strain were studied using radiation-induced fibrosacomas (RIF) grown in C3H or nude mice. Fluctuations in tumor blood flow during one hour of baseline monitoring or during vascular stress induced by photodynamic therapy (PDT) were measured by diffuse correlation spectroscopy. Baseline monitoring revealed fluctuating tumor blood flow highly correlated with heart rate and with similar median periods (i.e., ∼9 and 14 min in C3H and nudes, respectively). However, tumor blood flow in C3H animals was more sensitive to physiologic or stress-induced perturbations. Specifically, PDT-induced vascular insults produced greater decreases in blood flow in the tumors of C3H versus nude mice; similarly, during baseline monitoring, fluctuations in blood flow were more regular and more prevalent within the tumors of C3H mice versus nude mice; finally, the vasoconstrictor L-NNA reduced tumor blood flow in C3H mice but did not affect tumor blood flow in nudes. Underlying differences in vascular structure, such as smaller tumor blood vessels in C3H versus nude animals, may contribute to strain-dependent variation in vascular function. These data thus identify clear effects of mouse strain on tumor hemodynamics with consequences to PDT and potentially other vascular-mediated therapies

De novo design of protein logic gates

The design of modular protein logic for regulating protein function at the posttranscriptional level is a challenge for synthetic biology. Here, we describe the design of two-input AND, OR, NAND, NOR, XNOR, and NOT gates built from de novo–designed proteins. These gates regulate the association of arbitrary protein units ranging from split enzymes to transcriptional machinery in vitro, in yeast and in primary human T cells, where they control the expression of the TIM3 gene related to T cell exhaustion. Designed binding interaction cooperativity, confirmed by native mass spectrometry, makes the gates largely insensitive to stoichiometric imbalances in the inputs, and the modularity of the approach enables ready extension to three-input OR, AND, and disjunctive normal form gates. The modularity and cooperativity of the control elements, coupled with the ability to de novo design an essentially unlimited number of protein components, should enable the design of sophisticated posttranslational control logic over a wide range of biological functions

PRL3-DDX21 transcriptional control of endolysosomal genes restricts melanocyte stem cell differentiation

Melanocytes, replenished throughout life by melanocyte stem cells (MSCs), play a critical role in pigmentation and melanoma. Here, we reveal a function for the metastasis-associated phosphatase of regenerating liver 3 (PRL3) in MSC regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at master transcription factor (MITF)-regulated endolysosomal vesicle genes. In zebrafish, this mechanism controls premature melanoblast expansion and differentiation from MSCs. In melanoma patients, restricted transcription of this endolysosomal vesicle pathway is a hallmark of PRL3-high melanomas. Our work presents the conceptual advance that PRL3-mediated control of transcriptional elongation is a differentiation checkpoint mechanism for activated MSCs and has clinical relevance for the activity of PRL3 in regenerating tissue and cancer