Structure-activity study of novel tricyclic benzazepine arginine vasopressin antagonists

Novel tricyclic benzazepine derivatives were synthesized as arginine vasopressin (AVP) antagonists. Several tricyclic compounds showed potent antagonistic activity in rat AVP receptors V(1a) and V(2). Derivatives containing pyrrolo-tricyclic amines, 13i-k, 30, and 31 also showed selectivity for the V(2) receptor.     

(4-Substituted-phenyl)-(5H-10,11-dihydro-pyrrolo [2,1-c][1,4] benzodiazepin-10-yl)-methanone derivatives as vasopressin receptor modulators

Synthesis and structure-activity relationships (SAR) of arginine vasopressin (AVP) receptor modulators are described. Potent and selective compounds are prepared when the amide linkage connecting rings A and B of VPA-985 is replaced with a bond, CO, -O-, -S-, or -SO2- bond.     

Two‐Year Changes in Child Weight Status,Diet, and Activity by Neighborhood Nutrition and Physical Activity Environment

Objective

The aim of this study was to examine 2‐year changes in weight status and behaviors among children living in neighborhoods differing on nutrition and activity environments.

Methods

A prospective observational study, the Neighborhood Impact on Kids study, was conducted in King County, Washington, and San Diego County, California. Children 6 to 12 years old and a parent or caregiver completed Time 1 (n = 681) and Time 2 (n = 618) assessments. Children lived in neighborhoods characterized as “high/favorable” or “low/unfavorable” in nutrition and activity environments, respectively (four neighborhood types). Child BMI z score and overweight or obesity status were primary outcomes, with diet and activity behaviors as behavioral outcomes.

Results

After adjusting for sociodemographics and Time 1 values, children living in two of the three less environmentally supportive neighborhoods had significantly less favorable BMI z score changes (+0.11, 95% CI: 0.01‐0.21; + 0.12, 95% CI: 0.03‐0.21), and all three less supportive neighborhoods had higher overweight or obesity (relative risks, 1.41‐1.49; 95% CI: 1.13‐1.80) compared with children in the most environmentally supportive neighborhoods. Changes in daily energy intake and sedentary behavior by neighborhood type were consistent with observed weight status changes, with unexpected findings for physical activity.

Conclusions

More walkable and recreation‐supportive environments with better nutrition access were associated with better child weight outcomes and related behavior changes.     

Evidence‐based restoration in the Anthropocene—from acting with purpose to acting for impact

The recognition that we are in the distinct new epoch of the Anthropocene suggests the necessity for ecological restoration to play a substantial role in repairing the Earth's damaged ecosystems. Moreover, the precious yet limited resources devoted to restoration need to be used wisely. To do so, we call for the ecological restoration community to embrace the concept of evidence‐based restoration. Evidence‐based restoration involves the use of rigorous, repeatable, and transparent methods (i.e. systematic reviews) to identify and amass relevant knowledge sources, critically evaluate the science, and synthesize the credible science to yield robust policy and/or management advice needed to restore the Earth's ecosystems. There are now several examples of restoration‐relevant systematic reviews that have identified instances where restoration is entirely ineffective. Systematic reviews also serve as a tool to identify the knowledge gaps and the type of science needed (e.g. repeatable, appropriate replication, use of controls) to improve the evidence base. The restoration community, including both scientists and practitioners, needs to make evidence‐based restoration a reality so that we can move from best intentions and acting with so‐called “purpose” to acting for meaningful impact. Doing so has the potential to serve as a rallying point for reframing the Anthropocene as a so‐called “good” epoch.     

Rapid murine mixed lymphocyte cultures assessed by emergence of T-cell insulin receptors

Murine T lymphocytes incubated in a mixed lymphocyte culture with allogeneic lymphocytes incompatible for theH-2 region or subregions thereof rapidly develop insulin receptors. In contrast, T cells cultured with syngeneic orH-2- andMlslocus compatible cells do not develop insulin-binding sites. The emergence of insulin receptors is probably an early premitotic event.     

Altered immune function during long-term host-tumor interactions can be modulated to retard autochthonous neoplastic growth

Ag-specific and generalized forms of immunosuppression have been documented in animal tumor models. However, much of our knowledge on tumor-induced immunosuppression was acquired using tumor implant models, which do not reiterate the protracted nature of host-tumor interactions. Therefore, a transgenic mouse model of autochthonous mammary tumor development and progression was chosen to investigate the long-term consequences of neoplastic growth on the immune system. In vitro proliferation of unfractionated splenocytes from tumor-bearing mice, as assessed by [(3)H]thymidine uptake, was inhibited by the presence of suppressor cells within these splenocyte preparations, because purifying the T cells restored their biological activity. However, the level of inhibition did not correlate with either tumor load or the percentage of myeloid-derived CD11b+Gr1+ cells. To evaluate tumor-specific immune dysfunction, transgenic mice were challenged with autologous tumor cells. Mice with extensive, but not minimal autochthonous tumor burdens demonstrated a significantly enhanced rate of autologous tumor growth compared with age-matched controls. In contrast, an allogeneic tumor challenge was efficiently rejected from both groups of transgenic mice. It was also noted that allogeneic tumor challenge of mice with minimal disease significantly inhibited autochthonous primary tumor growth. We therefore demonstrated that 1) a generalized form of immunosuppression occurred, but not as a result of permanent alterations to T cell function, because purified T cell subsets retained normal biological activity following polyclonal or allostimulation; and 2) tumor-specific immunosuppression emerged as a consequence of tumor progression, but could be modulated to enhance antitumor responses against autochthonous primary neoplastic growth.     

Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance

Insulin resistance occurs in 20%-25% of the human population, and the condition is a chief component of type 2 diabetes mellitus and a risk factor for cardiovascular disease and certain forms of cancer. Herein, we demonstrate that the sphingolipid ceramide is a common molecular intermediate linking several different pathological metabolic stresses (i.e., glucocorticoids and saturated fats, but not unsaturated fats) to the induction of insulin resistance. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. Collectively, these data have two important implications. First, they indicate that different fatty acids induce insulin resistance by distinct mechanisms discerned by their reliance on sphingolipid synthesis. Second, they identify enzymes required for ceramide synthesis as therapeutic targets for combating insulin resistance caused by nutrient excess or glucocorticoid therapy.