Ligand sensitivity in dimeric associations of the serotonin 5HT2c receptor

G-protein-coupled receptors (GPCRs) respond to external stimuli by activating heterotrimeric G proteins inside the cell. There is increasing evidence that many GPCRs exist as dimers or higher oligomers, but the biochemical nature of such dimers and what roles they have, if any, in signal transduction remains unclear. We conducted a comprehensive study of dimerization of the 5HT2c serotonin receptor using disulphide-trapping experiments. We found a dimer interface between transmembrane (TM) helices IV and V that is markedly sensitive to the state of receptor activation. This dimer seems to be quasisymmetrical in interfacial geometry and asymmetrical in its association with its cognate Gα protein. We also found a second interface at TM I helices, which is insensitive to the state of activation

Efficacy of personalized cognitive counseling in men of color who have sex with men: secondary data analysis from a controlled intervention trial.

In a previous report, we demonstrated the efficacy of a cognitively based counseling intervention compared to standard counseling at reducing episodes of unprotected anal intercourse (UAI) among men who have sex with men (MSM) seeking HIV testing. Given the limited number of efficacious prevention interventions for MSM of color (MOC) available, we analyzed the data stratified into MOC and whites. The sample included 196 white MSM and 109 MOC (23 African Americans, 36 Latinos, 22 Asians, eight Alaskan Natives/Native Americans/Hawaiian/Pacific Islander, and 20 of mixed or other unspecified race). Among MOC in the intervention group, the mean number of episodes of UAI declined from 5.1 to 1.6 at six months and was stable at 12 months (1.8). Among the MOC receiving standard counseling, the mean number of UAI episodes was 4.2 at baseline, 3.9 at six months and 2.1 at 12 months. There was a significant treatment effect overall (relative risk 0.59, 95% confidence interval 0.35-0.998). These results suggest that the intervention is effective in MOC

Mohs math – where the error hides

BACKGROUND: Mohs surgical technique allows a full view of surgical margins and has a reported cure rate approaching 100%. METHOD: A survey amongst Mohs surgeons was performed to assess operator technique. In addition, an animated clay model was constructed to identify and quantify tissue movement seen during the processing of Mohs surgical specimens. RESULTS: There is variability in technique used in Mohs surgery in regards to the thickness of layers, and the number of blocks layers are cut into. A mathematical model is described which assesses the clinical impact of this variability. CONCLUSION: Our mathematical model identifies key aspects of technique that may contribute to error. To keep the inherent error rate at a minimum, we advocate minimal division and minimal physical thickness of Mohs specimens

A Functional Architecture of Optic Flow in the Inferior Parietal Lobule of the Behaving Monkey

The representation of navigational optic flow across the inferior parietal lobule was assessed using optical imaging of intrinsic signals in behaving monkeys. The exposed cortex, corresponding to the dorsal-most portion of areas 7a and dorsal prelunate (DP), was imaged in two hemispheres of two rhesus monkeys. The monkeys actively attended to changes in motion stimuli while fixating. Radial expansion and contraction, and rotation clockwise and counter-clockwise optic flow stimuli were presented concentric to the fixation point at two angles of gaze to assess the interrelationship between the eye position and optic flow signal. The cortical response depended upon the type of flow and was modulated by eye position. The optic flow selectivity was embedded in a patchy architecture within the gain field architecture. All four optic flow stimuli tested were represented in areas 7a and DP. The location of the patches varied across days. However the spatial periodicity of the patches remained constant across days at ∼950 and 1100 µm for the two animals examined. These optical recordings agree with previous electrophysiological studies of area 7a, and provide new evidence for flow selectivity in DP and a fine scale description of its cortical topography. That the functional architectures for optic flow can change over time was unexpected. These and earlier results also from inferior parietal lobule support the inclusion of both static and dynamic functional architectures that define association cortical areas and ultimately support complex cognitive function

Business-friendly contracting : how simplification and visualization can help bring it to practice

One thesis of this book is that the legal function within businesses will shift from a paradigm of security to one of opportunity. This chapter embraces that likelihood in the context of business contracting, where voices calling for a major shift are starting to surface. It explores how contracts can be used to reach better outcomes and relationships, not just safer ones. It introduces the concept of business-friendly contracting, highlighting the need for contracts to be seen as business tools rather than exclusively as legal tools, and working as business enablers rather than obstacles. By changing the design of contracts and the ways in which those contracts are communicated—through simplification and visualization, for example—legal and business operations can be better integrated. Contracts can then be more useful to business, and contract provisions can actually become more secure by becoming easier to negotiate and implement.fi=vertaisarvioitu|en=peerReviewed

Fracture-fill calcite as a record of microbial methanogenesis and fluid migration: a case study from the Devonian Antrim Shale, Michigan Basin

The Devonian Antrim Shale is an organic-rich, naturally fractured black shale in the Michigan Basin that serves as both a source and reservoir for natural gas. A well-developed network of major, through-going vertical fractures controls reservoir-scale permeability in the Antrim Shale. Many fractures are open, but some are partially sealed by calcite cements that retain isotopic evidence of widespread microbial methanogenesis. Fracture filling calcite displays an unusually broad spectrum of δ 13 C values (+34 to −41‰ PDB), suggesting that both aerobic and anaerobic bacterial processes were active in the reservoir. Calcites with high δ 13 C values (>+15‰) record cementation of fractures from dissolved inorganic carbon (DIC) generated during bacterial methanogenesis. Calcites with low δ 13 C values (<−32‰) are solely associated with outcrop samples and record methane oxidation during cement precipitation. Fracture-fill calcite with δ 13 C values between −10 and −30‰ can be attributed to variable organic matter oxidation pathways, methane oxidation, and carbonate rock buffering. Identification of 13 C-rich calcite provides unambiguous evidence of biogenic methane generation and may be used to identify gas deposits in other sedimentary basins. It is likely that repeated glacial advances and retreats exposed the Antrim Shale at the basin margin, enhanced meteoric recharge into the shallow part of the fractured reservoir, and initiated multiple episodes of bacterial methanogenesis and methanotrophic activity that were recorded in fracture-fill cements. The δ 18 O values in both formation waters and calcite cements increase with depth in the basin (−12 to −4‰ SMOW, and +21 to +27‰ PDB, respectively). Most fracture-fill cements from outcrop samples have δ 13 C values between −41 and −15‰ PDB. In contrast, most cement in cores have δ 13 C values between +15 and +34‰ PDB. Radiocarbon and 230 Th dating of fracture-fill calcite indicates that the calcite formed between 33 and 390 ka, well within the Pleistocene Epoch.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75720/1/j.1468-8123.2002.00036.x.pd

Activation and Inhibition of Transglutaminase 2 in Mice

Transglutaminase 2 (TG2) is an allosterically regulated enzyme with transamidating, deamidating and cell signaling activities. It is thought to catalyze sequence-specific deamidation of dietary gluten peptides in the small intestines of celiac disease patients. Because this modification has profound consequences for disease pathogenesis, there is considerable interest in the design of small molecule TG2 inhibitors. Although many classes of TG2 inhibitors have been reported, thus far an animal model for screening them to identify promising celiac drug candidates has remained elusive. Using intraperitoneal administration of the toll-like receptor 3 (TLR3) ligand, polyinosinic-polycytidylic acid (poly(I∶C)), we induced rapid TG2 activation in the mouse small intestine. Dose dependence was observed in the activation of TG2 as well as the associated villous atrophy, gross clinical response, and rise in serum concentration of the IL-15/IL-15R complex. TG2 activity was most pronounced in the upper small intestine. No evidence of TG2 activation was observed in the lung mucosa, nor were TLR7/8 ligands able to elicit an analogous response. Introduction of ERW1041E, a small molecule TG2 inhibitor, in this mouse model resulted in TG2 inhibition in the small intestine. TG2 inhibition had no effect on villous atrophy, suggesting that activation of this enzyme is a consequence, rather than a cause, of poly(I∶C) induced enteropathy. Consistent with this finding, administration of poly(I∶C) to TG2 knockout mice also induced villous atrophy. Our findings pave the way for pharmacological evaluation of small molecule TG2 inhibitors as drug candidates for celiac disease