Automating crystallographic structure solution and refinement of protein-ligand complexes.

High-throughput drug-discovery and mechanistic studies often require the determination of multiple related crystal structures that only differ in the bound ligands, point mutations in the protein sequence and minor conformational changes. If performed manually, solution and refinement requires extensive repetition of the same tasks for each structure. To accelerate this process and minimize manual effort, a pipeline encompassing all stages of ligand building and refinement, starting from integrated and scaled diffraction intensities, has been implemented in Phenix. The resulting system is able to successfully solve and refine large collections of structures in parallel without extensive user intervention prior to the final stages of model completion and validation

Exile Vol. XLIII No. 2

41st Year Title Page i Epigraphy by Ezra Pound ii Table of Contents iii / Contributors\u27 Notes 70-71 Editorial Board 72-73 ART Untitled by Kari Hernquist \u2799 4 Talking Out my Window by Heather Trabert \u2797 13 Renamed I by Ben Blake \u2797 18 photo paint by alex e. blazer \u2797 23 Butterfly by Mary Donnelley \u2797 32 unabridged by alex e. blazer \u2797 37 Holding Me In by Heather Trabert \u2797 43 Untitled by Kari Hernquist \u2797 55 Untitled by Camille Gammon-Hittelman \u2799 61 Stars by Mary Donnelley \u2797 69 POETRY Victrola by erin c. malone \u2799 1 All by Kellam Ayres \u2797 2-3 curtailed sun in the net by alex e. blazer \u2797 5 the weaker sex by Bekah Taylor \u2700 6 A poem concerning a silent manifesto by Colin Bossen \u2798 14 Father by Alison Stine \u2700 15 Vacant by Sean Boyle \u2700 16 Ecstasy by Amy spears \u2798 17 Seven Haikus by Jen Suster \u2797 21 Pages from a Diary by Trish Klei \u2797 22 Watching an Ageless Woman and an Ancient Trade by Heather Trabert \u2797 24-25 Still Waters by Jay Brandeis \u2799 26 just shy of freedom by Sean Boyle \u2700 36 [Touch the mothers you never knew] by Heather Trabert \u2797 38 Fishing for Meaning by Bekah Taylor \u2700 39 the novel by Sara Brown \u2799 40-41 annihilation by erin c. malone \u2799 42 Upon Enlistment by Trish Klei \u2797 44 the expatriate by erin c. malone \u2799 47 Rockettes by Trish Klei \u2797 48-49 Abstraction by Colin Bossen \u2798 54 always kinesis by alex e. blazer \u2797 56-57 Lily by Alison Stine \u2700 58-59 Falling In by Bekah Taylor \u2700 60 this bird has flown by paul durica \u2700 62-63 exfoliating some sun by alex e. blazer \u2797 64 Liberation: May 8, 1945 by Jen suster \u2797 65 PROSE Journal: 12 December 1996 through 15 January 1997 by Lynn Tramonte \u2798 7-12 Ash by paul durica \u2700 19-20 Birdhouse by Tyler Smith \u2797 27-35 Party in December by paul durica \u2700 45-46 Smoke Circles by Alison Stine \u2700 50-53 Seal by Lynn Tramonte \u2798 66-68 All submissions are reviewed on an anonymous basis, and all editorial decisions are shared equally among the members of the Editorial Board. -72 Cover art Toy Child by Ben Blake \u2797 -7

A genome-wide scan for common alleles affecting risk for autism

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm&lt; 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest

Reticulated Platelets as Predictor of Myocardial Injury and 30 Day Mortality After Non-cardiac Surgery

Objective: A pre-operative marker for identification of patients at risk of peri-operative adverse events and 30 day mortality might be the percentage of young, reticulated platelets (pRP). This study aimed to determine the predictive value of pre-operative pRP on post-operative myocardial injury (PMI) and 30 day mortality, in patients aged ≥ 60 years undergoing moderate to high risk non-cardiac surgery. Methods: The incidence of PMI (troponin I > 0.06 μg/L) and 30 day mortality was compared for patients with normal and high pRP (≥2.82%) obtained from The Utrecht Patient Orientated Database. The predictive pRP value was assessed using logistic regression. A prediction model for PMI or 30 day mortality with known risk factors was compared with a model including increased pRP using the area under the receiving operator characteristics curve (AUROC). Results: In total, 26.5% (607/2289) patients showed pre-operative increased pRP. Increased pRP was associated with more PMI and 30 day mortality compared with normal pRP (36.1% vs. 28.3%, p < .001 and 8.6% vs. 3.6%, p < .001). The median pRP was higher in patients suffering PMI and 30 day mortality compared with not (2.21 [IQR: 1.57–3.11] vs. 2.07 [IQR: 1.52–1.78], p = .002, and 2.63 [IQR: 1.76–4.15] vs. 2.09 [IQR: 1.52–3.98], p < .001). pRP was independently related to PMI (OR: 1.28 [95% CI: 1.04–1.59], p = .02) and 30 day mortality (OR: 2.35 [95% CI: 1.56–3.55], p < .001). Adding increased pRP to the predictive model of PMI or 30 day mortality did not increase the AUROC 0.71 vs. 0.72, and 0.80 vs. 0.81. Conclusion: In patients undergoing major non-cardiac surgery, increased pre-operative pRP is related to 30 day mortality and PMI

XUV excitation followed by ultrafast non-adiabatic relaxation in PAH molecules as a femto-astrochemistry experiment

15Highly excited molecular species are at play in the chemistry of interstellar media and are involved in the creation of radiation damage in a biological tissue. Recently developed ultrashort extreme ultraviolet light sources offer the high excitation energies and ultrafast time-resolution required for probing the dynamics of highly excited molecular states on femtosecond (fs) (1 fs=10−15s) and even attosecond (as) (1 as=10−18 s) timescales. Here we show that polycyclic aromatic hydrocarbons (PAHs) undergo ultrafast relaxation on a few tens of femtoseconds timescales, involving an interplay between the electronic and vibrational degrees of freedom. Our work reveals a general property of excited radical PAHs that can help to elucidate the assignment of diffuse interstellar absorption bands in astrochemistry, and provides a benchmark for the manner in which coupled electronic and nuclear dynamics determines reaction pathways in large molecules following extreme ultraviolet excitation.openopenMarciniak, A.*; Despré, V.; Barillot, T.; Rouzée, A.; Galbraith, M.C.E.; Klei, J.; Yang, C.-H.; Smeenk, C.T.L.; Loriot, V.; Reddy, S. Nagaprasad; Tielens, A.G.G.M.; Mahapatra, S.; Kuleff, A.I.; Vrakking, M.J.J.; Lépine, F.Marciniak, A.; Despré, V.; Barillot, T.; Rouzée, A.; Galbraith, M. C. E.; Klei, J.; Yang, C. -H.; Smeenk, C. T. L.; Loriot, V.; Reddy, S. Nagaprasad; Tielens, A. G. G. M.; Mahapatra, S.; Kuleff, A. I.; Vrakking, M. J. J.; Lépine, F

Efficacy of different treatment regimes against setariosis (Setaria tundra, Nematoda: Filarioidea) and associated peritonitis in reindeer

<p>Abstract</p> <p>Background</p> <p>When a severe peritonitis outbreak in semi-domesticated reindeer was noticed in 2003 in Finland, the concerned industry urged immediate preventive actions in order to avoid detrimental effects of <it>S. tundra </it>and further economical losses. A research programme was swiftly initiated to study <it>S. tundra </it>and its impact on the health and wellbeing of reindeer.</p> <p>Methods</p> <p>The ultimate aim of this study was to test the efficacy of different treatment regimes against <it>S. tundra </it>and associated peritonitis in reindeer. The timing of the trials was planned to be compatible with the annual rhythm of the reindeer management; (1) the treatment of calves in midsummer, during routine calf ear marking, with ivermectin injection prophylaxis and deltamethrin pour-on solution as a repellent against insect vectors, (2) the treatment of infected calves in early autumn with ivermectin injection, and (3) ivermectin treatment of breeding reindeer in winter. The results were assessed using the post mortem inspection data and <it>S. tundra </it>detection. Finally, to evaluate on the population level the influence of the annual (late autumn-winter) ivermectin treatment of breeding reindeer on the transmission dynamics of <it>S. tundra</it>, a questionnaire survey was conducted.</p> <p>Results</p> <p>In autumn, ivermectin treatment was efficient against peritonitis and in midsummer had a slight negative impact on the degree of peritonitis and positive on the fat layer, but deltamethrin had none. Ivermectin was efficient against adult <it>S. tundra </it>and its smf. All the reindeer herding cooperatives answered the questionnaire and it appeared that antiparasitic treatment of reindeer population was intense during the study period, when 64–90% of the animals were treated. In the southern part of the Finnish reindeer husbandry area, oral administration of ivermectin was commonly used.</p> <p>Conclusion</p> <p>Autumn, and to a lesser degree summer, treatment of reindeer calves with injectable ivermectin resulted in decreased severity of peritonitis and perihepatitis in reindeer calves due to setariosis. In the case of necessity for animal welfare reasons, treatment during early autumn round ups should be considered. On the population level, massive and routinely applied antiparasitic treatments can improve the health of breeding reindeer and decrease the mortality and the number of carriers but during the outbreak could not prevent its movement and expansion to the North.</p