Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Sticta torii sp. nov., a remarkable lichen of high conservation priority from northwestern North America

peer reviewedSticta torii Simon & Goward sp. nov. is an isidiate lichen on Alnus, Malus and Picea branches in hypermaritime regions of northwestern North America. It is a rare species, currently known from only a few localities along a narrow longitudinal range in Southeast Alaska, British Columbia and Oregon. It differs from S. fuliginosa and S. sylvatica in its smaller, more irregular lobes and generally well-developed fringe of marginal isidia, and from S. beauvoisii in its smaller size, less elongate lobes and distinctly arbuscular to penicillate marginal isidia. Also diagnostic are the cyphellae, the basal portions of which bear cells with numerous papillae – a feature shared with a small group of closely allied neotropical species including the recently described S. arbuscula and S. arbusculotomentosa. These latter species, however, bear tomentum over the upper surface, unlike S. torii, which is glabrous

LecideaceaeMcCuneEtAl2017-ITS

DNA sequence data, ITS, alignment

LecideaceaeMcCuneEtAl2017-nuLSU

DNA sequence data, nuLSU, alignmen

Data from: New taxa and a case of ephemeral spore production in Lecideaceae from western North America

Cyclohymenia epilithica is a newly described genus and species from Oregon and Washington, U.S.A. It occurs on noncalcareous rock in the oceanic forests west of the crest of the Cascade Range. Unlike most other North American species in the Lecideaceae, it is restricted to shady habitats in cool, wet, temperate climates. It is distinguished from other members of the family by its thick, pale gray green, epilithic thallus; immersed apothecia that superficially appear like perithecia or pycnidia; and ascocarps that usually contain a central sterile column surrounded by a ring-shaped hymenium. The structure and position of the ascocarp appear to be unique among Lecideaceae and related families. The species is also unusual in producing short-lived asci; most collections have barren apothecia. Lecidea atrobrunnea subsp. deplanaica is raised to the species level. The taxon deserves specific rank, not just from its distinctive chemistry, but also from morphology, distribution, and ecology that differ from L. atrobrunnea s.str. The newly described Lecidea uniformis from Oregon and Washington, mainly west of the Cascade crest, is similar in many ways to L. fuscoatra, but the areoles are uniformly brown and do not have a differentiated gray, blackish, or whitish edge. DNA sequence data support the taxa Cyclohymenia epilithica and L. uniformis

Biodiversity and ecology of lichens of Kenai Fjords National Park, Alaska.

We inventoried lichens in Kenai Fjords National Park in Alaska, USA We assembled the known information on occurrence and ecology of lichens in this park by combining field, herbarium, and literature studies. Our results provide baseline data on lichen occurrence that may be used in resource condition assessments, vulnerability assessments, long-term ecological monitoring, and resource management. We report a total of 616 taxa of lichenized fungi from the Park, plus an additional five subspecies and three varieties, all of which are new additions to the National Park Service database for this park unit. An additional five species of nonlichenized lichenicolous fungi are reported here. Eight non-lichenized fungi that are traditionally treated with lichens are also included, most of these associated with bark of particular host species. Four taxa new to North America are reported here (Arctomia delicatula var. acutior, Aspicilia dudinensis, Myriospora myochroa, and Ochrolechia bahusiensis), along with 44 species new to Alaska. Numerous species have been confirmed using ITS barcoding sequences. Also several records assigned to the genus level are reported, many of those are likely new species