The spark of synchronization in heterogeneous networks of chaotic maps.

We investigate the emergence of synchronization in heterogeneous networks of chaotic maps. Our findings reveal that a small cluster of highly connected maps is responsible for triggering the spark of synchronization. After the spark, the synchronized cluster grows in size and progressively moves to less connected maps, eventually reaching a cluster that may remain synchronized over time. We explore how the shape of the network degree distribution affects the onset of synchronization and derive an expression based on the network construction that determines the expected time for a network to synchronize. Understanding how the network design affects the spark of synchronization is particularly important for the control and design of more robust systems that require some level of coherence between a subset of units for better functioning. Numerical simulations in finite-sized networks are consistent with this analysis.

Emergence of chaotic cluster synchronization in heterogeneous networks.

Many real-world complex systems rely on cluster synchronization to function properly. A cluster of nodes exhibits synchronous behavior, while others behave erratically. Predicting the emergence of these clusters and understanding the mechanism behind their structure and variation in response to a parameter change is a daunting task in networks that lack symmetry. We unravel the mechanism for the emergence of cluster synchronization in heterogeneous random networks. We develop heterogeneous mean-field approximation together with a self-consistent theory to determine the onset and stability of the cluster. Our analysis shows that cluster synchronization occurs in a wide variety of heterogeneous networks, node dynamics, and coupling functions. The results could lead to a new understanding of the dynamical behavior of networks ranging from neural to social.

Herd immunity under individual variation and reinfection.

We study a susceptible-exposed-infected-recovered (SEIR) model considered by Aguas et al. (In: Herd immunity thresholds for SARS-CoV-2 estimated from unfolding epidemics, 2021), Gomes et al. (In: J Theor Biol. 540:111063, 2022) where individuals are assumed to differ in their susceptibility or exposure to infection. Under this heterogeneity assumption, epidemic growth is effectively suppressed when the percentage of the population having acquired immunity surpasses a critical level - the herd immunity threshold - that is lower than in homogeneous populations. We derive explicit formulas to calculate herd immunity thresholds and stable configurations, especially when susceptibility or exposure are gamma distributed, and explore extensions of the model.

Sex versus asex: An analysis of the role of variance conversion.

The question as to why most complex organisms reproduce sexually remains a very active research area in evolutionary biology. Theories dating back to Weismann have suggested that the key may lie in the creation of increased variability in offspring, causing enhanced response to selection. Under appropriate conditions, selection is known to result in the generation of negative linkage disequilibrium, with the effect of recombination then being to increase genetic variance by reducing these negative associations between alleles. It has therefore been a matter of significant interest to understand precisely those conditions resulting in negative linkage disequilibrium, and to recognise also the conditions in which the corresponding increase in genetic variation will be advantageous. Here, we prove rigorous results for the multi-locus case, detailing the build up of negative linkage disequilibrium, and describing the long term effect on population fitness for models with and without bounds on fitness contributions from individual alleles. Under the assumption of large but finite bounds on fitness contributions from alleles, the non-linear nature of the effect of recombination on a population presents serious obstacles in finding the genetic composition of populations at equilibrium, and in establishing convergence to those equilibria. We describe techniques for analysing the long term behaviour of sexual and asexual populations for such models, and use these techniques to establish conditions resulting in higher fitnesses for sexually reproducing populations.

Optimization of alpha-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric site.

We have optimized a novel series of potent p38 MAP kinase inhibitors based on an alpha-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME, in vivo PK and efficacy studies show these compounds to have drug-like characteristics and have resulted in the nomination of a development candidate which is currently in phase II clinical trials for the oral treatment of inflammatory conditions.

'Reverse' alpha-ketoamide-based p38 MAP kinase inhibitors.

We have identified a second series of potent p38 inhibitors. As with our first generation series, these compounds are based on an alpha-ketoamide scaffold. The reversal of the ketoamide order, however, introduces more chemical flexibility and in addition results in improve potencies against p38.

The design and synthesis of novel alpha-ketoamide-based p38 MAP kinase inhibitors.

We have identified a novel series of potent p38 MAP kinase inhibitors through structure-based design which due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME and in vivo PK studies show these compounds to have drug-like characteristics which could result in the development of an oral treatment for inflammatory conditions.

Discovery of 2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy)acetate (Ralinepag): An Orally Active Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension.

The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration-time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development for the treatment of PAH.

Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor.

APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure.

Rice sequences of relations.

We propose a framework to study the computational complexity of definable relations on a structure. Many of the notions we discuss are old, but the viewpoint is new. We believe that all the pieces fit together smoothly under this new point of view. We also survey related results in the area. More concretely, we study the space of sequences of relations over a given structure. On this space, we develop notions of c.e.-ness, reducibility, join and jump. These notions are equivalent to other notions studied in other settings. We explain the equivalences and differences between these notions.

Isolated osteochondral fracture of the patella without patellar dislocation.

Chondral fractures of the patella are associated with acute dislocation of the patella. Osteochondral fracture in patellar dislocation is located in the medial facet of the patella. This article presents a case of a 15-year-old female ballerina with isolated displaced osteochondral fracture of the patella without patellar dislocation. She had no history of trauma. A Merchant's view of both knees showed mild subluxation of the patella, a small fragment on the lateral aspect of the knee, and a small defect of the centromedial patella. Axial magnetic resonance imaging (MRI) revealed an osteochondral fragment measuring 13 mm medial to the patella. However, the medial patellofemoral ligament and medial retinaculum were intact. An effusion on the medial side of the patella consistent with hemarthrosis was observed. An absence of a contusion or bone bruise on the lateral femoral condyle was shown. The loose body was removed arthroscopically. Intraoperative findings included a 1.5×2 cm osteochondral fragment. It is unusual that the osteochondral patellar defect site in this patient was in the inferior and central areas of the patella. Patellar chondral fractures without dislocation or patella fracture are rare. Therefore, the possibility of a trivial trauma leading to an osteochondral fracture should be kept in mind in adolescent and young adults who present with knee pain and hemarthrosis.

Early complications of medial opening wedge high tibial osteotomy using autologous tricortical iliac bone graft and T-plate fixation.

Despite several advantages of medial opening wedge high tibial osteotomy, this procedure has been noted to have a high rate of complications especially with the use of a spacer plate for fixation. We retrospectively evaluated the early complications of 138 medial opening wedge high tibial osteotomies done using autologous tricortical iliac bone graft and T-plate fixation(AO locking compression T-plate, Ti/3H 4.5-5.0 mm, Synthes, Switzerland, Model No. 440.131 in 30 and low-profile locking T-plate and low-profile locking T-plate in 128 patients. At a mean follow-up of 36.8 months (13 to 78), 26 knees (18.8%) developed complications. Complications varied from osteotomy site infection, loss of correction, broken screws and lateral tibial plateau fracture to joint fluid leakage, pseudoaneurysm and iliac bone fractures. Using the "safe zone" technique and penetrating the lateral cortex with Steinmann pins may help to avoid complications such as loss of correction and lateral tibial plateau fractures. The results of this study indicate that medial opening wedge high tibial osteotomy using autologous tricortical iliac bone graft and T-plate fixation may be a technically demanding procedure associated with a moderate rate of complications. However, these complications could be minimized with proper planning, adequate intra-operative precautions and few modifications to avoid technical error.

KR-003048, a potent, orally active inhibitor of p38 mitogen-activated protein kinase.

The tumor necrosis factor-alpha (TNF-alpha) cytokine, secreted by activated monocytes/macrophages and T lymphocytes, is implicated in several diseases, including rheumatoid arthritis, chronic obstructive pulmonary disease, inflammatory bowel disease, and osteoporosis. Monocyte/macrophage production of TNF-alpha is largely driven by p38alpha mitogen-activated protein kinase (MAP kinase), an intracellular soluble serine-threonine kinase. p38alpha MAP kinase is activated by growth factors, cellular stresses, and cytokines such as TNF-alpha and interleukin-l (IL-I). The primary contribution of p38alpha activation to excess TNF-alpha in settings of both chronic and acute inflammation has instigated efforts to find inhibitors of this enzyme as possible therapies for associated disease states. Analogue design, synthesis, and structure-activity studies led to the identification of 5-tert-butyl-N-cyclopropyl-2-methoxy-3-{2-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-2-oxo-acetylamino}-benzamide (KR-003048) as a potent inhibitor of the p38 MAP kinase signaling pathway in vitro and in vivo. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide (LPS)-induced p38 activation and subsequent TNF-alpha release is described. KR-00348 was demonstrated to be a potent inhibitor of inflammatory cytokine production ex vivo in rat and human whole blood, and showed good oral bioavailability. Additionally, efficacy in mouse and rat models of acute and chronic inflammation was obtained. KR-003048 possessed therapeutic activity in acute models, demonstrating substantial inhibition of carrageenan-induced paw edema and in vivo LPS-induced TNF release at 30mg/kg p.o. Collagen-induced arthritis in mice was significantly inhibited by 10 and 30mg/kg doses of KR-003048. Evidence for disease-modifying activity in this model was indicated by histological evaluation of joints.

Peripherally metalated secoporphyrazines: a new generation of photoactive pigments.

Base-catalyzed cross condensation of dipropylmaleonitrile 1 with bis(dimethylamino)maleonitrile 2 in an equimolar ratio afforded the porphyrazines 3a, 4a, 5a, 6a and 7a. Subsequent demetalation of 5a with TFA followed by remetalation with Zn(OAc)(2) gave ligand 5c in good yield. Compound 5c was, in turn, selectively oxidized and further peripherally functionalized using Pt(PhCN)(2)Cl(2) and PdCl(2) to yield the novel seco solitaire porphyrazines 10a and 10b. The photophysical profiles of the seco solitaire porphyrazines 10a and 10b were evaluated by means of absorption, emission, and transient absorption spectroscopy. The new pigments 10a and 10b were found to be photochemically more stable than the solitaire complexes 3d and 3e and mediated the generation of singlet oxygen with quantum yields of 0.59 and 0.45, respectively.

Synthesis and reactions of aminoporphyrazines with annulated five- and seven-membered rings.

The novel five- and seven-membered ring appended aminoporphyrazines 3 and 12 have been prepared via mixed Linstead macrocyclization. The structures of both have been unequivocally established by X-ray crystallographic studies. Reductive deselenation of selenadiazole 3 in the presence of 9,10-phenanthrenequinone or 2,3-butanedione results in the formation of pyrazines 6a,b, whereas oxidation of porphyrazine 12 gave the corresponding seco derivative 14. seco-Porphyrazine 14 mediates the generation of singlet oxygen with a quantum yield of 0.74.