Discovery of 2,3′-diindolylmethanes as a novel class of PCSK9 modulators

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low density lipoprotein receptor (LDLR). Anti-PCSK9 agents have been approved for the treatment of hypercholesterolemia. We recently discovered a series of small-molecule PCSK9 modulators that contains a relatively small pharmacophore of 2,3′-diindolylmethane with molecular weights around only 250. These molecules can significantly lower the amount of PCSK9 protein in a cell-based phenotypic assay. Our SAR studies yielded compound 16 with a IC₅₀-value of 200 nM. No obvious cytotoxicity was observed at concentrations below 50 µM.     

Infections and human tissue transplants: review of FDA MedWatch reports 2001–2004

Background More than 1.5 million tissue allografts are transplanted annually in the U.S. As part of the federal effort to improve tissue safety, FDA’s May 2005 Current Good Tissue Practices (CGTP) Rule requires tissue establishments to report to FDA serious infectious adverse events following allograft transplantation. To provide baseline data, we summarize reports of such infections received by FDA prior to the CGTP Rule. Methods We reviewed reports received by FDA’s MedWatch adverse event reporting system during 2001–2004. Our case definition was a reported infection in a human tissue transplant recipient within 1 year of transplantation. We examined demographics, tissue type, clinical outcomes and interventions, infectious organism(s), time from transplant to infection and reporter characteristics. Results We identified 83 reports of infections following allograft transplantations. Median patient age was 40 years (range: 1 month–87 years). The allografts included heart valves (42%), tendons (33%), bones (8%), blood vessels (6%), ocular tissues (5%), and skin (4%). Commonly reported outcomes and interventions were hospitalization (72%), antibiotic therapy (46%) and graft removal (42%). Nine of 11 patients who expired had received heart valves. In 65 reports that identified suspected organisms, bacteria were most common (42), followed by fungi (25) and prions (1). The median time from transplant to infection was 5.5 weeks (range: 3 days–52 weeks). Tissue manufacturers submitted 26% of reports. Among the remaining 74%, the reporters were quality assurance staff, infection control or risk management personnel (45%); physicians (15%); consumers (15%); nurses (13%); and surgical staff (12%). Conclusion This is the first review of reports to FDA for infections following allograft tissue transplantations. Infections led to serious outcomes and involved many tissue types. Although we were unable to confirm that reported infections were caused by the suspected tissue product, required reporting by tissue establishments and improvements in adverse event investigation will help to improve tissue safety surveillance.     

New synonyms of two Arabian ants of the genus Monomorium Mayr, 1855 (Hymenoptera,Formicidae)

Synonymy of two Arabian Monomorium Mayr, 1855 species is proposed: Monomorium exiguum Forel, 1894 = Monomorium desertorum Collingwood & Agosti, 1996, syn. n.; Monomorium subopacum Smith, 1858 = Monomorium mintiribe Collingwood & Agosti, 1996, syn. n. A lectotype for Monomorium venustum Smith, 1858 is designated. Information on nesting habits of Monomorium exiguum and Monomorium venustum in the Kingdom of Saudi Arabia are provided for the first time. Recently collected records for Monomorium exiguum, Monomorium subopacum, and Monomorium venustum from the Kingdom of Saudi Arabia and United Arab Emirates are listed.     

Interplay between minor and major groove-binding transcription factors Sox2 and Oct1 in translocation on DNA studied by paramagnetic and diamagnetic NMR

The pathways whereby Sox2 scans DNA to locate its specific binding site are investigated by NMR in specific and nonspecific Sox2·DNA complexes and in a specific ternary complex with Oct1 on the Hoxb1 regulatory element. Direct transfer of Sox2 between nonspecific sites on different DNA molecules occurs without dissociation into free solution at a rate of ～10(6) M(-1) s(-1), whereas one-dimensional sliding proceeds with a diffusion constant of ≥0.1 μm(2)·s(-1). Translocation of Sox2 from one specific DNA site to another occurs via jumping, involving complete dissociation into free solution (k(d) ～5-6 s(-1)) followed by reassociation (k(a) ～5 × 10(8) M(-1) s(-1)). In the presence of Oct1 bound to an adjacent specific site, k(d) is reduced by more than 10-fold. Paramagnetic relaxation measurements, however, demonstrate that sparsely populated (<1%), transient states involving nonspecifically bound Sox2 in rapid exchange with specifically bound Sox2 are sampled in both binary Sox2·DNA- and ternary Oct1·Sox2·Hoxb1-DNA-specific complexes. Moreover, Sox2 modulates the mechanism of translocation of Oct1. Both Sox2 and the Oct1 POU(HD) domain are transiently released from the specific ternary complex by sliding to an adjacent nonspecific site, followed by direct transfer to another DNA molecule, whereas the Oct1 POU(S) domain is fixed to its specific site through direct interactions with Sox2. Intermolecular translocation of POU(HD) results in the formation of a bridged intermediate spanning two DNA molecules, enhancing the probability of complete intermolecular translocation of Oct1. By way of contrast, in the specific Oct1·DNA binary complex, POU(S) undergoes direct intermolecular translocation, whereas POU(HD) scans the DNA by sliding.     

滇南、滇东南黑冠长臂猿分布与数量

滇南、滇东南曾是黑冠长臂猿广泛分布的地区之一。为掌握该地区近年黑冠长臂猿分布及种群数量现状,从2003年7月~2004年12月,采用访问调查及利用鸣声定位法进行了实地调查。调查结果显示,在近40000km2的范围内,东黑冠长臂猿(Nomascussp.cf.nasutus)在云南境内可能已消失;西黑冠长臂猿(N.concolor)亦仅发现4~7个种群,且孤立分布于3个地区(金平芭蕉河2群6只,金平西隆山1-2群,绿春黄连山1~3群,总计不超过25只),而在江城牛倮河自然保护区、马关古林箐自然保护区、麻栗坡老君山自然保护区及屏边大围山自然保护区可能已绝迹。滇南、滇东南黑冠长臂猿分布区缩小及种群数量剧减,主要与栖息地丧失及过度捕猎有关。     

Caught in the Psychiatric Net: Meanings and Experiences of ADHD,Pediatric Bipolar Disorder and Mental Health Treatment Among a Diverse Group of Families in the United States

Based on a 13-month ethnographic meaning-centered study of the lived experience of behavioral and emotional disorders among children and families living in the United States, this article highlights the range of orientations to mental health problems and treatment among families from diverse backgrounds. Detailed case portraits of three families are presented to illustrate the various meanings that psychiatric diagnoses and mental health treatments take on within families, with medicalized perspectives holding less salience among African-American families relative to Euro-Americans in the study. The diverse orientations to problems among families in the study suggest that, despite the dominance of biochemical and neurological explanations for behavioral and emotional distress in contemporary U.S. culture, and especially U.S. psychiatry, nonpathological interpretations have not been wholly eclipsed by broad trends toward biologization and medicalization. Families’ experiences are positioned to reveal the allure, as well as the limitations, of biopsychiatric approaches to behavioral and emotional problems.

Disjunct distributions in Gerris species (Insecta: Hemiptera: Gerridae): an analysis based on spatial and taxonomic patterns of genetic diversity

Aim  To perform a comparative analysis of distribution and genetic diversity in three closely related water strider species ( Gerris ) in order to shed light on a putative disjunct distribution in Gerris gillettei .
Location  Canada and the western United States.
Methods  Entomological collections from Canada and the United States were surveyed for records of Gerris pingreensis , G. gillettei and Gerris incognitus in order to establish the distribution range of each species. Using samples from present populations, mitochondrial and nuclear DNA sequence variation were used to construct minimum-spanning networks. Distribution patterns and genetic diversity were then compared among species.
Results  Our results showed that G. incognitus is a genetically distinct species with an unsuspected disjunct distribution. Gerris pingreensis and G. gillettei were found to share genetic polymorphism and they displayed spatial differences only in terms of haplotype distribution, suggesting that they form a single species.
Main conclusions  Distributional and molecular information uncover unusual distribution patterns and underline taxonomic uncertainty in a group of three closely related Gerris species. Vicariance and failure to recolonize following the last glaciation could explain the G. incognitus disjunction. Morphological and DNA-based species identifications suggest different post-glacial recolonization processes for G.   pingreensis and G. gillettei . The putative discontinuous range of G. gillettei may be explained as disjunct phenotypes of a single species.     

Effect of eland density and foraging on Combretum apiculatum physiognomy in a semi-arid savannah

We studied the impacts of eland density on the physiognomy of Combretum apiculatum . We divided the study area into two zones: high eland density zone (≤8 km from watering point) and low eland density zone (≥8 km from watering point). Eland density was determined in each zone using walking transects. Combretum apiculatum height and diameter and levels of eland damage were measured in each zone. Eland density was 1.92 and 0.86 km⁻² for high and low-density zones respectively. We recorded 239 C. apiculatum trees, 138 in low-density zone and 101 in high-density zone. Mean C. apiculatum height was 2.88 ± 0.67 m and 5.05 ± 1.04 m for high and low eland density zones respectively. High eland density prevented the recruitment of C. apiculatum from the 2.6–5.5 m height class to the >5.6 m height class. Although extensive tree damage occurred at <2.5 m height stratum, C. apiculatum showed resilience as recruitment into the 2.6–5.5 m height class continued. We concluded that high eland density prevents recruitment of C. apiculatum to higher height classes while at the same time causing extensive tree damage at lower height strata.     

Restoration of genetic connectivity among Northern Rockies wolf populations

Probably no conservation genetics issue is currently more controversial than the question of whether grey wolves (Canis lupus) in the Northern Rockies have recovered to genetically effective levels. Following the dispersal‐based recolonization of Northwestern Montana from Canada, and reintroductions to Yellowstone and Central Idaho, wolves have vastly exceeded population recovery goals of 300 wolves distributed in at least 10 breeding pairs in each of Wyoming, Idaho and Montana. With >1700 wolves currently, efforts to delist wolves from endangered status have become mired in legal battles over the distinct population segment (DPS) clause of the Endangered Species Act (ESA), and whether subpopulations within the DPS were genetically isolated. An earlier study by vonHoldt et al. (2008) suggested Yellowstone National Park wolves were indeed isolated and was used against delisting in 2008. Since then, wolves were temporarily delisted, and a first controversial hunting season occurred in fall of 2009. Yet, concerns over the genetic recovery of wolves in the Northern Rockies remain, and upcoming District court rulings in the summer of 2010 will probably include consideration of gene flow between subpopulations. In this issue of Molecular Ecology, vonHoldt et al. (2010) conduct the largest analysis of gene flow and population structure of the Northern Rockies wolves to date. Using an impressive sampling design and novel analytic methods, vonHoldt et al. (2010) show substantial levels of gene flow between three identified subpopulations of wolves within the Northern Rockies, clarifying previous analyses and convincingly showing genetic recovery.     

Fat frogs,mobile genes: unexpected phylogeographic patterns for the ornate chorus frog (Pseudacris ornata)

The southeastern coastal plain of the United States is a region marked by extraordinary phylogeographic congruence that is frequently attributed to the changing sea levels that occurred during the glacial‐interglacial cycles of the Pleistocene epoch. A phylogeographic break corresponding to the Apalachicola River has been suggested for many species studied to date that are endemic to this region. Here, we used this pattern of phylogeographic congruence to develop and test explicit hypotheses about the genetic structure in the ornate chorus frog (Pseudacris ornata). Using 1299 bp of mtDNA sequence and seven nuclear microsatellite markers in 13 natural populations of P. ornata, we found three clades corresponding to geographically distinct regions; one spans the Apalachicola River (Southern Clade), one encompasses Georgia and South Carolina (Central Clade) and a third comprises more northerly individuals (Northern Clade). However, it does not appear that typical phylogeographic barriers demarcate these clades. Instead, isolation by distance across the range of the entire species explained the pattern of genetic variation that we observed. We propose that P. ornata was historically widespread in the southeastern United States, and that a balance between genetic drift and migration was the root of the genetic divergence among populations. Additionally, we investigated fine‐scale patterns of genetic structure and found the spatial scale at which there was significant genetic structure varied among the regions studied. Furthermore, we discuss our results in light of other phylogeographic studies of southeastern coastal plain organisms and in relation to amphibian conservation and management.