Leopard subspecies conservation under climate and land-use change.

Predicting the effects of global environmental changes on species distribution is a top conservation priority, particularly for large carnivores, that contribute to regulating and maintaining ecosystems. As the most widespread and adaptable large felid, ranging across Africa and Asia, leopards are crucial to many ecosystems as both keystone and umbrella species, yet they are threatened across their ranges. We used intraspecific species distribution models (SDMs) to predict changes in range suitability for leopards under future climate and land-use change and identify conservation gaps and opportunities. We generated intraspecific SDMs for the three western leopard subspecies, the African, Panthera pardus pardus; Arabian, Panthera pardus nimr; and Persian, Panthera pardus tulliana, leopards, and overlapped predictions with protected areas (PAs) coverage. We show that leopard subspecies differ in their environmental associations and vulnerability to future changes. The African and Arabian leopards are predicted to lose ~25% and ~14% of their currently suitable range, respectively, while the Persian leopard is predicted to experience ~12% range gains. We found that most areas predicted to be suitable were not protected, with only 4%-16% of the subspecies' ranges falling inside PAs, and that these proportions will decrease in the future. The highly variable responses we found between leopard subspecies highlight the importance of considering intraspecific variation when modelling vulnerability to climate and land-use changes. The predicted decrease in proportion of suitable ranges falling inside PAs threatens global capacity to effectively conserve leopards because survival rates are substantially lower outside PAs due to persecution. Hence, it is important to work with local communities to address negative human-wildlife interactions and to restore habitats to retain landscape connectivity where PA coverage is low. On the other hand, the predicted increase in range suitability across southern Europe presents opportunities for expansion outside of their contemporary range, capitalising on European rewilding schemes.

Online disease management of diabetes: engaging and motivating patients online with enhanced resources-diabetes (EMPOWER-D), a randomized controlled trial.

OBJECTIVE: To evaluate an online disease management system supporting patients with uncontrolled type 2 diabetes. MATERIALS AND METHODS: Engaging and Motivating Patients Online With Enhanced Resources for Diabetes was a 12-month parallel randomized controlled trial of 415 patients with type 2 diabetes with baseline glycosylated hemoglobin (A1C) values ≥7.5% from primary care sites sharing an electronic health record. The intervention included: (1) wirelessly uploaded home glucometer readings with graphical feedback; (2) comprehensive patient-specific diabetes summary status report; (3) nutrition and exercise logs; (4) insulin record; (5) online messaging with the patient's health team; (6) nurse care manager and dietitian providing advice and medication management; and (7) personalized text and video educational 'nuggets' dispensed electronically by the care team. A1C was the primary outcome variable. RESULTS: Compared with usual care (UC, n=189), patients in the intervention (INT, n=193) group had significantly reduced A1C at 6 months (-1.32% INT vs -0.66% UC; p<0.001). At 12 months, the differences were not significant (-1.14% INT vs -0.95% UC; p=0.133). In post hoc analysis, significantly more INT patients had improved diabetes control (>0.5% reduction in A1C) than UC patients at 12 months (69.9 (95% CI 63.2 to 76.5) vs 55.4 (95% CI 48.4 to 62.5); p=0.006). CONCLUSIONS: A nurse-led, multidisciplinary health team can manage a population of diabetic patients in an online disease management program. INT patients achieved greater decreases in A1C at 6 months than UC patients, but the differences were not sustained at 12 months. More INT than UC patients achieved improvement in A1C (>0.5% decrease). Trial registered in clinical trials.gov: #NCT00542204.

IFN-γ acts on the airway epithelium to inhibit local and systemic pathology in allergic airway disease.

Inhibiting allergic airway inflammation is the goal of therapy in persistent asthma. Administration of medication via the airways delivers drug directly to the site of inflammation and avoids systemic side effects but often fails to modulate systemic features of asthma. We have shown that Th1 cells, through production of IFN-γ, inhibit many Th2-induced effector functions that promote disease. Using a newly generated mouse that expresses IFN-γR only on airway epithelial cells, we show that the airway epithelium controls a range of pathological responses in asthma. IFN-γ acting only through the airway epithelium inhibits mucus, chitinases, and eosinophilia, independent of Th2 cell activation. IFN-γ signaling through the airway epithelium inhibits eosinophil generation in the bone marrow, indicating that signals on the airway mucosal surface can regulate distant functions to inhibit disease. IFN-γ actions through the airway epithelium will limit airway obstruction and inflammation and may be therapeutic in refractory asthma.

Solvent-free aromatic C-H functionalisation/halogenation reactions.

The solvent-free, palladium-catalysed reaction of anilides with CuCl(2) in the presence or absence of copper acetate yields ortho-chlorinated anilides in good to excellent yields, even on a large scale (100 mmol). By contrast, the equivalent reactions with copper bromide, either solvent free or in 1,2-dichloroethane, in the presence or absence of palladium, under air or inert conditions, gave the products of simple electrophilic bromination. Mechanistic studies highlighted the involvement of palladacyclic intermediates, one of which was characterised crystallographically, which undergo subsequent reaction with copper(II) chloride to yield the chlorinated anilide products.

Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR.

Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.

Solvent free catalytic C-H functionalisation.

Solvent-free reaction conditions facilitate a range of aromatic C-H functionalisations that traditionally require acidic or disfavoured solvents. These reactions include selective ortho- and meta-arylation of aryl carbamates and anilides and selective halogenation reactions.

Palladium-catalysed ortho-arylation of carbamate-protected phenols.

The carbamate (-O2CNR2) function is an excellent directing group for palladium-catalysed direct arylation reactions giving both protected or free mono- or di-substituted phenols, as well as an example of a dibenzopyranone, depending on coupling partners (aryl iodides or diaryliodonium salts) and conditions.

Pyrazolopyridines as a novel structural class of potent and selective PDE4 inhibitors.

Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.

Design and synthesis of orally active pyrrolidin-2-one-based factor Xa inhibitors.

A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.

PAMFOnline: integrating EHealth with an electronic medical record system.

The Institute of Medicine stressed the need for continuous healing relationships, yet the delivery of health care has traditionally been confined to the physician office or hospital. We implemented an eHealth application tightly integrated with our electronic medical record system that provides patients with a convenient, continuously available communication channel to their physician's office. Patients can view summary data from their medical record, including the results of diagnostic tests, and request medical advice, prescription renewals, appointments, or updates to their demographic information. We have found that patients embrace this new communication channel and are using the service appropriately. Patients especially value electronic messaging with their physicians and timely access to their test results. While initially concerned about an increase in work, physicians have found that use of electronic messaging can be an efficient method for handling non-urgent communication with their patients. Online tools for patients, when integrated with an electronic medical record, can provide patients with better access to health information, improve patient satisfaction, and improve operational efficiency.