bluuebunny/crossref_metadata_2025 huggingface dataset:
Real‐life Anti‐tumor Necrosis Factor Experience in More Than 500 Patients
Authors: Merrick Victoria M. , Mortier Kajal , Williams Linda J. , Muhammed Rafeeq , Auth Marcus K.H. , Elawad Mamoun , Fell John M.E. , Beattie R. Mark , Loganathan Sabarinathan , Torrente Franco , Morris Mary‐Anne , Charlton Charles , Croft Nick M. , Rodrigues Astor , Furman Mark , Vadamalayan Babu , Jenkins Huw , Zamvar Veena , Mitton Sally G. , Chong Sonny , Cosgrove Mike , Akobeng Anthony , Wilson David C. , Russell Richard K.
Published: July 2017

Objective:

The aim of this study was to measure the effectiveness, safety, and use of anti‐tumor necrosis Factor (TNF) therapy in pediatric inflammatory bowel disease in the United Kingdom (UK).

Methods:

Prospective UK audit of patients newly starting anti‐TNF therapy. Disease severity was assessed using Physician Global Assessment +/or the Paediatric Crohn Disease Activity Index.

Results:

A total of 37 centers participated (23/25 specialist pediatric inflammatory bowel disease sites). A total of 524 patients were included: 429 with Crohn disease (CD), 76 with ulcerative colitis (UC), and 19 with IBD unclassified (IBDU). Eighty‐seven percent (488/562) of anti‐TNF was infliximab; commonest indication was active luminal CD 77% (330/429) or chronic refractory UC/IBDU 56% (53/95); 79% (445/562) had concomitant co‐immunosuppression. In CD (267/429 male), median time from diagnosis to treatment was 1.42 years (interquartile range 0.63–2.97). Disease (at initiation) was moderate or severe in 91% (156/171) by Physician Global Assessment compared to 41% (88/217) by Paediatric Crohn Disease Activity Index (Kappa (κ) 0.28 = only “fair agreement”; P < 0.001.

Where documented, 77% (53/69) of patients with CD responded to induction; and 65% (46/71) entered remission. A total of 2287 infusions and 301.96 years of patient’ follow‐up (n = 385) are represented; adverse events affected 3% (49/1587) infliximab and 2% (2/98) adalimumab infusions (no deaths or malignancies). Peri‐anal abscess drainage was less common after anti‐TNF initiation (CD), that is 26% (27/102) before, 7% (3/42) after (P = 0.01); however, pre and post anti‐TNF data collection was not over equal time periods.

Conclusions:

Anti‐TNFs are effective treatments, usually given with thiopurine co‐immunosuppression. This study highlights deficiencies in formal documentation of effect and disparity between disease severity scoring tools, which need to be addressed to improve ongoing patient care.
Intervention for Feeding Difficulties in Children With a Complex Medical History
Authors: Marshall Jeanne , Hill Rebecca J. , Wallace Meagan , Dodrill Pamela
Published: July 2017

Objective:

This study aimed to compare outcomes of different multidisciplinary feeding therapy approaches in children with feeding difficulties.

Methods:

Children aged 2 to 6 years with feeding difficulties and a medically complex history (MC) were recruited. Children with feeding difficulties and a nonmedically complex history (NMC) were included as a comparison group. Participants attended a clinical assessment, and eligible participants were randomized to receive targeted feeding intervention incorporating either operant conditioning or systematic desensitization. Parents could elect to receive intervention in an intensive (10 sessions in a week) or weekly (10 sessions during 10 weeks) format. Both groups received immersive parent training. A review was completed 3 months post‐intervention.

Results:

In total, 98 participants were eligible to participate (MC, n = 43; NMC, n = 55). Data from 20 children from the MC group (47%) and 41 children from the NMC group (75%) were included in the final analysis. Clinically significant improvements were observed following both arms of therapy, consistent with previous research. Parents of children in the MC arm were significantly more likely to elect for intensive intervention than weekly (MC = 12/20, 60%; 12/41, 29%; P = 0.02).

Conclusions:

Both therapy protocols were considered clinically effective. The difference in attrition rates between the etiological groups suggests primary differences in how service delivery should be managed. Progress for the medically complex child may be slower while medical issues are stabilized, or while the focus for parents shifts to other developmental areas. In planning services for a medically complex group, therefore, it is essential that consideration be given to medical and family needs.
Fat Grafting in Hollow Upper Eyelids and Volumetric Upper Blepharoplasty
Authors: Ramil Mariano E.
Published: July 2017

Background:

Periorbital volume loss creates a shadow frame, and traditional excisional blepharoplasties may aggravate the situation. Divergence in filling treatments establishes a demand for simple and reproducible techniques to achieve consistent results. Here, the author’s hollow upper eyelid evaluation and treatment approach are presented.

Methods:

A retrospective photographic analysis was conducted of 32 women who underwent fat grafting for hollow upper eyelids between 2012 and 2016. Preoperative and postoperative evaluations of upper eyelid ratios at the medial and lateral corneal limbus, together with lateral contour modifications, were used to determine the efficacy of the technique to restore youthful proportions and contours.

Results:

Preoperative analysis showed 20 eyelids with an inner shadow, or A-pattern; and 44 eyelids with the complete extension of the hollow, or C-pattern. Three patients presented mild blepharoptosis, and eight patients had undergone a previous upper blepharoplasty. Mean grafting volume was 0.4 cc in the deep plane and 2.8 cc in the superficial plane. Fat grafting exclusively was performed in six patients, improving all ratios and correcting the A-pattern deformity. Volumetric upper blepharoplasty combining fat grafting in two levels and orbicularis oculi muscle imbrication was performed in 26 patients, correcting every inverted ratio (p < 0.001). On the lateral view, all cases with a concave pattern changed to a convex one, regardless of the approach used.

Conclusion:

Synergy between fat grafting and orbicularis imbrication proved adequate to restore the lateral convex contour and return youthful proportions to the hollow upper eyelids.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Importance of Early Detection and Cardiovascular Surgical Intervention in Marfan Syndrome
Authors: DelloStritto Rita , Branham Steve , Chemmachel Christina , Patel Jayna , Skolkin Dayna , Gilani Salima , Uleanya Klever
Published: July 2017

Marfan syndrome is an autosomal dominant connective tissue disorder that affects multiple systems, including the skeletal, ligamentous, oculofacial, pulmonary, abdominal, neurological, and cardiovascular systems. Cardiovascular complications, which involve the aorta and aortic valve, contribute most significantly to patient morbidity and mortality. A literature review was conducted on pathophysiology of the disease and recommendations for early diagnosis and treatment. Diagnosis largely relies on clinical features and a thorough history. Echocardiogram is used for monitoring aortic abnormalities and disease progression. Aortic valve-sparing surgery is indicated in any valvular abnormality and in patients with a murmur. Aortic root replacement is indicated prophylactically in women who want to give birth with diameters greater than 40 mm, anyone with a diameter greater than 50 mm, and progressive dilatation of greater than 5 mm per year. Medical management involves antihypertensive therapy. It is imperative for all health care providers to understand the clinical features, progression, and management of Marfan syndrome to appropriately care for their patients. Ensuring regular follow-up and adherence to medical and surgical prophylaxis is essential to patient well-being.
Prevalence of Pulmonary Embolism in Patients Presenting to the Emergency Department for Syncope
Authors: Davis Philip , Evans Dian Dowling
Published: July 2017

The Research to Practice column is intended to improve the research critique skills of the advanced practice registered nurse and the emergency nurse (RN) and to assist with the translation of research into practice. For each column, a topic and a research study are selected. The research article is then reviewed and critiqued, and the findings are discussed in relation to a patient scenario. In this column, we examine the findings of P. Prandoni et al. (2016) from their article, titled “Prevalence of Pulmonary Embolism Among Patients Hospitalized for Syncope.”
Update on Sepsis Treatment in the Emergency Department
Authors: Weant Kyle A. , Bailey Abby M.
Published: July 2017

Sepsis continues to be a devastating, costly, and challenging syndrome to manage in emergency departments (ED) across the nation, and its impact seems to be only increasing. Recently, consensus recommendations have made some profound changes in the way we approach, classify, and treat sepsis. The ED serves as an important initial screening and intervention point for sepsis, and ED care can have a profound impact on overall morbidity and mortality. The provision of early fluid resuscitation, antimicrobial therapy, and vasopressor therapy, if appropriate, is essential in early care. The intent of this review was to compare and contrast changes associated with the management of sepsis in the ED, with particular focus on guideline recommendations for pharmacotherapeutic management.
Development of a targeted sequencing approach to identify prognostic, predictive and diagnostic markers in paediatric solid tumours
Authors: Izquierdo Elisa , Yuan Lina , George Sally , Hubank Michael , Jones Chris , Proszek Paula , Shipley Janet , Gatz Susanne A , Stinson Caedyn , Moore Andrew S. , Clifford Steven C. , Hicks Debbie , Lindsey Janet , Hill Rebecca , Jacques Thomas S. , Chalker Jane , Thway Khin , O’Connor Simon , Marshall Lynley , Moreno Lucas , Pearson Andrew , Chesler Louis , Walker Brian A. , De Castro David Gonzalez
Published: July 2017

The implementation of personalised medicine in childhood cancers has been limited by a lack of clinically validated multi-target sequencing approaches specific for paediatric solid tumours. In order to support innovative clinical trials in high-risk patients with unmet need, we have developed a clinically relevant targeted sequencing panel spanning 311 kb and comprising 78 genes involved in childhood cancers. A total of 132 samples were used for the validation of the panel, including Horizon Discovery cell blends (n=4), cell lines (n=15), formalin-fixed paraffin embedded (FFPE, n=83) and fresh frozen tissue (FF, n=30) patient samples. Cell blends containing known single nucleotide variants (SNVs, n=528) and small insertion-deletions (indels n=108) were used to define panel sensitivities of ≥98% for SNVs and ≥83% for indels [95% CI] and panel specificity of ≥98% [95% CI] for SNVs. FFPE samples performed comparably to FF samples (n=15 paired). Of 95 well-characterised genetic abnormalities in 33 clinical specimens and 13 cell lines (including SNVs, indels, amplifications, rearrangements and chromosome losses), 94 (98.9%) were detected by our approach. We have validated a robust and practical methodology to guide clinical management of children with solid tumours based on their molecular profiles. Our work demonstrates the value of targeted gene sequencing in the development of precision medicine strategies in paediatric oncology.
Is coding a relevant metaphor for the brain?
Authors: Brette Romain
Published: July 2017

Short abstract

I argue that the popular neural coding metaphor is often misleading. First, the “neural code” often spans both the experimental apparatus and the brain. Second, a neural code is information only by reference to something with a known meaning, which is not the kind of information relevant for a perceptual system. Third, the causal structure of neural codes (linear, atemporal) is incongruent with the causal structure of the brain (circular, dynamic). I conclude that a causal description of the brain cannot be based on neural codes, because spikes are more like actions than hieroglyphs.

Long abstract

“Neural coding” is a popular metaphor in neuroscience, where objective properties of the world are communicated to the brain in the form of spikes. Here I argue that this metaphor is often inappropriate and misleading. First, when neurons are said to encode experimental parameters, the neural code depends on experimental details that are not carried by the coding variable. Thus, the representational power of neural codes is much more limited than generally implied. Second, neural codes carry information only by reference to things with known meaning. In contrast, perceptual systems must build information from relations between sensory signals and actions, forming a structured internal model. Neural codes are inadequate for this purpose because they are unstructured. Third, coding variables are observables tied to the temporality of experiments, while spikes are timed actions that mediate coupling in a distributed dynamical system. The coding metaphor tries to fit the dynamic, circular and distributed causal structure of the brain into a linear chain of transformations between observables, but the two causal structures are incongruent. I conclude that the neural coding metaphor cannot provide a basis for theories of brain function, because it is incompatible with both the causal structure of the brain and the informational requirements of cognition.
Conjunction of Factors Triggering Waves of Seasonal Influenza
Authors: Chattopadhyay Ishanu , Kıcıman Emre , Elliott Joshua W. , Shaman Jeffrey L. , Rzhetsky Andrey
Published: July 2017

Understanding the subtle confluence of factors triggering pan-continental, seasonal epidemics of influenza-like illness is an extremely important problem, with the potential to save tens of thousands of lives and billions of dollars every year in the US alone. Beginning with several large, longitudinal datasets on putative factors and clinical data on the disease and health status of over 150 million human subjects observed over a decade, we investigated the source and the mechanistic triggers of epidemics. Our analysis included insurance claims for a significant cross-section of the US population in the past decade, human movement patterns inferred from billions of tweets, whole-US weekly weather data covering the same time span as the medical records, data on vaccination coverage over the same period, and sequence variations of key viral proteins. We also explicitly accounted for the spatio-temporal auto-correlations of infectious waves, and a host of socioeconomic and demographic factors. We carried out multiple orthogonal statistical analyses on these diverse, large geo-temporal datasets to bolster and corroborate our findings. We conclude that the initiation of a pan-continental influenza wave emerges from the simultaneous realization of a complex set of conditions, the strongest predictor groups are as follows, ranked by importance: (1) the host population’s socio- and ethno-demographic properties; (2) weather variables pertaining to relevant area specific humidity, temperature, and solar radiation; (3) the virus’ antigenic drift over time; (4) the host population’s land-based travel habits, and; (5) the spatio-temporal dynamics’ immediate history, as reflected in the influenza wave autocorrelation. The models we infer are demonstrably predictive (area under the Receiver Operating Characteristic curve ≈ 80%) when tested with out-of-sample data, opening the door to the potential formulation of new population-level intervention and mitigation policies.
DiGeST: Distributed Computing for Scalable Gene and Variant Ranking with Hadoop/Spark
Authors: Borgne Yann-Aël Le , Helaers Raphaël , Lenaerts Tom , Abramowicz Marc , Smits Guillaume , Bontempi Gianluca
Published: July 2017

Background

The advent of next-generation sequencing technologies has opened new avenues for clinical genomics research. In particular, as sequencing costs continue to decrease, an ever-growing number of clinical genomics institutes now rely on DNA sequencing studies at varying scales - genome, exome, mendeliome - for uncovering disease-associated variants or genes, in both rare and non-rare diseases.

A common methodology for identifying such variants or genes is to rely on genetic association studies (GAS), that test whether allele or genotype frequencies differ between two groups of individuals, usually diseased subjects and healthy controls. Current bioinformatics tools for performing GAS are designed to run on standalone machines, and do not scale well with the increasing size of study designs and the search for multi-locus genetic associations. More efficient distributed and scalable data analysis solutions are needed to address this challenge.

Results

We developed a Big Data solution stack for distributing computations in genetic association studies, that address both single and multi-locus associations. The proposed stack, called DiGeST (Distributed Gene/variant Scoring Tool) is divided in two main components: a Hadoop/Spark high-performance computing back-end for efficient data storage and distributed computing, and a Web front-end providing users with a rich set of options to filter, compare and explore exome data from different sample populations. Using exome data from the 1000 Genomes Project, we show that our distributed implementation smoothly scales with computing resources. We make the resulting software stack Open-Source, and provide virtualisation scripts to run the complete environment both on standalone machine or Hadoop-based cluster.

Conclusions

Hadoop/Spark provides a powerful and well-suited distributed computing framework for genetic association studies. Our work illustrates the flexibility, ease of use and scalability of the framework, and more generally advocates for its wider adoption in bioinformatics pipelines.
A new full-length virus genome sequencing method reveals that antiviral RNAi changes geminivirus populations in field-grown cassava
Authors: Mehta Devang , Hirsch-Hoffmann Matthias , Were Mariam , Patrignani Andrea , Were Hassan , Gruissem Wilhelm , Vanderschuren Hervé
Published: July 2017

Deep-sequencing of virus isolates using short-read sequencing technologies is problematic since viruses are often present in complexes sharing a high-degree of sequence identity. The full-length genomes of such highly-similar viruses cannot be assembled accurately from short sequencing reads. We present a new method, CIDER-Seq (Circular DNA Enrichment Sequencing) which successfully generates accurate full-length virus genomes from individual sequencing reads with no sequence assembly required. CIDER-Seq operates by combining a PCR-free, circular DNA enrichment protocol with Single Molecule Real Time sequencing and a new sequence deconcatenation algorithm. We apply our technique to produce more than 1,200 full-length, highly accurate geminivirus genomes from RNAi-transgenic and control plants in a field trial in Kenya. Using CIDER-Seq we can demonstrate for the first time that the expression of antiviral doublestranded RNA (dsRNA) in transgenic plants causes a consistent shift in virus populations towards species sharing low homology to the transgene derived dsRNA. Our results show that CIDER-seq is a powerful, cost-effective tool for accurately sequencing circular DNA viruses, with future applications in deep-sequencing other forms of circular DNA such as transposons and plasmids.
Using epidemiological principles to explain fungicide resistance management strategies: why do mixtures outperform alternations?
Authors: Elderfield James A.D. , Lopez-Ruiz Francisco J. , van den Bosch Frank , Cunniffe Nik J.
Published: July 2017

Whether fungicide resistance management is optimised by spraying chemicals with different modes of action as a mixture (i.e. simultaneously) or in alternation (i.e. sequentially) has been studied by experimenters and modellers for decades, largely inconclusively.

We use previously-parameterised and validated mathematical models of wheat septoria leaf blotch and grapevine powdery mildew to test which strategy provides better resistance management, using the total yield before fungicide-resistance causes disease control to become economically-ineffective (“lifetime yield”) to measure effectiveness.

Lifetime yield is optimised by spraying as much low-risk fungicide as is permitted, combined with slightly more high-risk fungicide than needed for acceptable initial disease control, applying these fungicides as a mixture. This is invariant to model parameterisation and structure, as well as the pathosystem in question. However if comparison focuses on other metrics, for example lifetime yield at full label dose, either mixtures or alternation can be optimal.

Our work shows how epidemiological principles can explain the evolution of fungicide resistance, and highlights a theoretical framework to address the question of whether mixtures or alternation provide better resistance management. Our work also demonstrates that precisely how spray strategies are compared must be given extremely careful consideration.
Catecholaminergic Manipulation Alters Dynamic Network Topology Across Behavioral States
Authors: Shine James M. , van den Brink Ruud L. , Hernaus Dennis , Nieuwenhuis Sander , Poldrack Russell A.
Published: July 2017

The human brain is able to flexibly adapt its information processing capacity to meet a variety of cognitive challenges. Recent evidence suggests that this flexibility is reflected in the dynamic reorganization of the functional connectome. The ascending catecholaminergic arousal systems of the brain are a plausible candidate mechanism for driving alterations in network architecture, enabling efficient deployment of cognitive resources when the environment demands them. We tested this hypothesis by analyzing both task-free and task-based fMRI data following the administration of atomoxetine, a noradrenaline reuptake inhibitor, compared to placebo, in two separate human fMRI studies. Our results demonstrate that the manipulation of central catecholamine levels leads to a reorganization of the functional connectome in a manner that is sensitive to ongoing cognitive demands.
Functional corticostriatal connection topographies predict goal directed behaviour in humans
Authors: Marquand Andre F. , Haak Koen V. , Beckmann Christian F.
Published: July 2017

Anatomical tracing studies in non-human primates have suggested that corticostriatal connectivity is topographically organized: nearby locations in striatum are connected with nearby locations in cortex. The topographic organization of corticostriatal connectivity is thought to underpin many goal-directed behaviours, but these topographies have not been completely characterised in humans and their relationship to uniquely human behaviours remains to be fully determined. Instead, the dominant approach employs parcellations that cannot model the continuous nature of the topography, nor accommodate overlapping cortical projections in the striatum. Here, we employ a different approach to studying human corticostriatal circuitry: we estimate smoothly-varying and spatially overlapping ‘connection topographies’ from resting state fMRI. These correspond exceptionally well with and extend the topographies predicted from primate tracing studies. We show that striatal topography is preserved in regions not previously known to have topographic connections with the striatum and that many goal-directed behaviours can be mapped precisely onto individual variations in the spatial layout of striatal connectivity.
VPS18 recruits VPS41 to the human HOPS complex via a RING-RING interaction
Authors: Hunter Morag R. , Scourfield Edward J. , Emmott Edward , Graham Stephen C.
Published: July 2017

Eukaryotic cells use conserved multisubunit membrane tethering complexes, including CORVET and HOPS, to control the fusion of endomembranes. These complexes have been extensively studied in yeast, but to date there have been far fewer studies of metazoan CORVET and HOPS. Both of these complexes comprise six subunits: a common four-subunit core and two unique subunits. Once assembled, these complexes function to recognise specific endosomal membrane markers and facilitate SNARE-mediated membrane fusion. CORVET promotes the homotypic fusion of early endosomes, while HOPS promotes the fusion of lysosomes to late endosomes and autophagosomes. Many of the subunits of both CORVET and HOPS contain putative C-terminal zinc-finger domains. Here, the contribution of these domains to the assembly of the human CORVET and HOPS complexes has been examined. Using biochemical techniques, we demonstrate that the zinc-containing RING domains of human VPS18 and VPS41 interact directly to form a stable heterodimer. In cells, these RING domains are able to integrate into endogenous HOPS, showing that the VPS18 RING domain is required to recruit VPS41 to the core complex subunits. Importantly, this mechanism is not conserved throughout eukaryotes, as yeast Vps41 does not contain a C-terminal zinc-finger motif. The subunit analogous to VPS41 in human CORVET is VPS8, in which the RING domain has an additional C-terminal segment that is predicted to be disordered. Both the RING and disordered C-terminal domains are required for integration of VPS8 into endogenous CORVET complexes, suggesting that HOPS and CORVET recruit VPS41 and VPS8 via distinct molecular interactions.
Atomic pair distribution function at the Brazilian Synchrotron Light Laboratory: application to the Pb1–xLaxZr0.40Ti0.60O3ferroelectric system
Authors: Saleta M. E. , Eleotério M. , Mesquita A. , Mastelaro V. R. , Granado E.
Published: July 2017

This work reports the setting up of the X-ray diffraction and spectroscopy beamline at the Brazilian Synchrotron Light Laboratory for performing total scattering experiments to be analyzed by atomic pair distribution function (PDF) studies. The results of a PDF refinement for Al2O3standard are presented and compared with data acquired at a beamline of the Advanced Photon Source, where it is common to perform this type of experiment. A preliminary characterization of the Pb1–xLaxZr0.40Ti0.60O3ferroelectric system, withx= 0.11, 0.12 and 0.15, is also shown.
Crystal structure and luminescent properties of novel coordination polymers constructed with bifurandicarboxylic acid
Authors: Huang Xianyu , Chen Daoliang , He Mingrui , Li Jianfeng , Huang Jiawei , Li Baolin
Published: July 2017

Four novel coordination polymers (CPs) assembled with [2,2′-bifuran]-5,5′-dicarboxylic acid (H2L) and metal ions ZnII, CdIIor CoIIhave been successfully synthesized. Their molecular structures have been determined to be Zn(L)(H2O)2(1), [Zn(L)(DMF)]2(2), [Cd(L)(EtOH)(DMF)2]2(3) and Co(L)(H2O)4·(H2O)2(4) by crystallographic analysis. It is found that (2) exhibits a two-dimensional infinite framework, whereas the others exhibit a one-dimensional framework. Both (2) and (3) exhibit ligand-based emission which is blue-shifted compared with the emission from the H2Lligand. Time-resolved spectroscopic measurement reveals that the complexes exhibit a similar lifetime with that of the ligand, which confirms that the emission of the complexes originates from the ligand.
Multi-temperature study of potassium uridine-5′-monophosphate: electron density distribution and anharmonic motion modelling
Authors: Jarzembska Katarzyna N. , Ślepokura Katarzyna , Kamiński Radosław , Gutmann Matthias J. , Dominiak Paulina M. , Woźniak Krzysztof
Published: July 2017

Uridine, a nucleoside formed of a uracil fragment attached to a ribose ringviaa β-N1-glycosidic bond, is one of the four basic components of ribonucleic acid. Here a new anhydrous structure and experimental charge density distribution analysis of a uridine-5′-monophosphate potassium salt, K(UMPH), is reported. The studied case constitutes the very first structure of a 5′-nucleotide potassium salt according to the Cambridge Structural Database. The excellent crystal quality allowed the collection of charge density data at various temperatures,i.e.10, 100, 200 and 300 K on one single crystal. Crystal structure and charge density data were analysed thoroughly in the context of related literature-reported examples. Detailed analysis of the charge density distribution revealed elevated anharmonic motion of part of the uracil ring moiety relatively weakly interacting with the neighbouring species. The effect was manifested by alternate positive and negative residual density patterns observed for these atoms, which `disappear' at low temperature. It also occurred that the potassium cation, quite uniformly coordinated by seven O atoms from all molecular fragments of the UMPH−anion, including the O atom from the ribofuranose ring, can be treated as spherical in the charge density model which was supported by theoretical calculations. Apart from the predominant electrostatic interactions, four relatively strong hydrogen bond types further support the stability of the crystal structure. This results in a compact and quite uniform structure (in all directions) of the studied crystal, as opposed to similar cases with layered architecture reported in the literature.
Accurate charge densities from powder X-ray diffraction – a new version of the Aarhus vacuum imaging-plate diffractometer
Authors: Tolborg Kasper , Jørgensen Mads R. V. , Christensen Sebastian , Kasai Hidetaka , Becker Jacob , Walter Peter , Dippel Ann-Christin , Als-Nielsen Jens , Iversen Bo B.
Published: July 2017

In recent years powder X-ray diffraction has proven to be a valuable alternative to single-crystal X-ray diffraction for determining electron-density distributions in high-symmetry inorganic materials, including subtle deformation in the core electron density. This was made possible by performing diffraction measurements in vacuum using high-energy X-rays at a synchrotron-radiation facility. Here we present a new version of our custom-built in-vacuum powder diffractometer with the sample-to-detector distance increased by a factor of four. In practice this is found to give a reduction in instrumental peak broadening by approximately a factor of three and a large improvement in signal-to-background ratio compared to the previous instrument. Structure factors of silicon at room temperature are extracted using a combined multipole–Rietveld procedure and compared withab initiocalculations and the results from the previous diffractometer. Despite some remaining issues regarding peak asymmetry, the new diffractometer yields structure factors of comparable accuracy to the previous diffractometer at low angles and improved accuracy at high angles. The high quality of the structure factors is further assessed by modelling of core electron deformation with results in good agreement with previous investigations.
Experimental charge-density studies: data reduction and model quality: the more the better?
Authors: Herbst-Irmer Regine , Stalke Dietmar
Published: July 2017

In this review, recent developments concerning data and model quality in experimental charge-density investigations from a personal view-point are described. Data quality is not only achieved by the high resolution, highI/σ(I) values, low mergingRvalues and high multiplicity. The quality of the innermost reflections especially is crucial for mapping the density distribution of the outermost valence electrons and can be monitored by (I/σ)asymptotic. New detector technologies seem to be promising improvements. Empirical corrections to correct for low-energy contamination of mirror-focused X-ray data and for resolution- and temperature-dependent errors caused by factors such as thermal diffuse scattering are described. Shashlik-like residual density patterns can indicate the need for an anharmonic description of the thermal motion of individual atoms. The physical reliability of the derived model must be thoroughly analysed. The derived probability density functions for the mean-squared atomic vibrational displacements especially should have only small negative values. The treatment of H atoms has been improved by methods to estimate anisotropic thermal motion. For very high resolution data, the polarization of the core density cannot be neglected. Several tools to detect systematic errors are described. A validation tool is presented that easily detects when the refinement of additional parameters yields a real improvement in the model or simply overfits the given data. In all investigated structures, it is proved that the multipole parameters of atoms with a comparable chemical environment should be constrained to be identical. The use of restraints could be a promising alternative.
Insights on spin delocalization and spin polarization mechanisms in crystals of azido copper(II) dinuclear complexes through the electron spin density Source Function
Authors: Gatti Carlo , Macetti Giovanni , Lo Presti Leonardo
Published: July 2017

The Source Function (SF) tool was applied to the analysis of thetheoreticalspin density in azido CuIIdinuclear complexes, where the azido group, acting as a coupler between the CuIIcations, is linked to the metal centres either in an end-on or in an end–end fashion. Results for only the former structural arrangement are reported in the present paper. The SF highlights to which extent the magnetic centres contribute to determine the local spin delocalization and polarization at any point in the dimetallic complex and whether an atom or group of atoms of the ligands act in favour or against a given local spin delocalization/polarization. Ball-and-stick atomic SF percentage representations allow for a visualization of the magnetic pathways and of the specific role played by each atom along these paths, at given reference points. Decomposition of SF contributions in terms of a magnetic and of a relaxation component provides further insight. Reconstruction of partial spin densities by means of the Source Function has for the first time been introduced. At variance with the standard SF percentage representations, such reconstructions offer a simultaneous view of the sources originating from specific subsets of contributing atoms, in a selected molecular plane or in the whole space, and are therefore particularly informative. The SF tool is also used to evaluate the accuracy of the analysed spin densities. It is found that those obtained at the unrestricted B3LYP DFT level, relative to those computed at the CASSCF(6,6) level, greatly overestimate spin delocalization to the ligands, but comparatively underestimate magnetic connection (spin transmission) among atoms, along the magnetic pathways. As a consequence of its excessive spin delocalization, the UB3LYP method also overestimates spin polarization mechanisms between the paramagnetic centres and the ligands. Spin delocalization measures derived from the refinement of Polarized Neutron Diffraction data seem in general superior to those obtained through the DFT UB3LYP approach and closer to the far more accurate CASSCF results. It is also shown that a visual agreement on the spin-resolved electron densities ραand ρβderived from different approaches does not warrant a corresponding agreement between their associated spin densities.
A theoretical-electron-density databank using a model of real and virtual spherical atoms
Authors: Nassour Ayoub , Domagala Slawomir , Guillot Benoit , Leduc Theo , Lecomte Claude , Jelsch Christian
Published: July 2017

A database describing the electron density of common chemical groups using combinations of real and virtual spherical atoms is proposed, as an alternative to the multipolar atom modelling of the molecular charge density. Theoretical structure factors were computed from periodic density functional theory calculations on 38 crystal structures of small molecules and the charge density was subsequently refined using a density model based on real spherical atoms and additional dummy charges on the covalent bonds and on electron lone-pair sites. The electron-density parameters of real and dummy atoms present in a similar chemical environment were averaged on all the molecules studied to build a database of transferable spherical atoms. Compared with the now-popular databases of transferable multipolar parameters, the spherical charge modelling needs fewer parameters to describe the molecular electron density and can be more easily incorporated in molecular modelling software for the computation of electrostatic properties. The construction method of the database is described. In order to analyse to what extent this modelling method can be used to derive meaningful molecular properties, it has been applied to the urea molecule and to biotin/streptavidin, a protein/ligand complex.
Exploring charge density analysis in crystals at high pressure: data collection, data analysis and advanced modelling
Authors: Casati Nicola , Genoni Alessandro , Meyer Benjamin , Krawczuk Anna , Macchi Piero
Published: July 2017

The possibility to determine electron-density distribution in crystals has been an enormous breakthrough, stimulated by a favourable combination of equipment for X-ray and neutron diffraction at low temperature, by the development of simplified, though accurate, electron-density models refined from the experimental data and by the progress in charge density analysis often in combination with theoretical work. Many years after the first successful charge density determination and analysis, scientists face new challenges, for example: (i) determination of the finer details of the electron-density distribution in the atomic cores, (ii) simultaneous refinement of electron charge and spin density or (iii) measuring crystals under perturbation. In this context, the possibility of obtaining experimental charge density at high pressure has recently been demonstrated [Casatiet al.(2016).Nat. Commun.7, 10901]. This paper reports on the necessities and pitfalls of this new challenge, focusing on the speciessyn-1,6:8,13-biscarbonyl[14]annulene. The experimental requirements, the expected data quality and data corrections are discussed in detail, including warnings about possible shortcomings. At the same time, new modelling techniques are proposed, which could enable specific information to be extracted, from the limited and less accurate observations, like the degree of localization of double bonds, which is fundamental to the scientific case under examination.
In-house time-resolved photocrystallography on the millisecond timescale using a gated X-ray hybrid pixel area detector
Authors: Casaretto Nicolas , Schaniel Dominik , Alle Paul , Wenger Emmanuel , Parois Pascal , Fournier Bertrand , Bendeif El-Eulmi , Palin Cyril , Pillet Sébastien
Published: July 2017

With the remarkable progress of accelerator-based X-ray sources in terms of intensity and brightness, the investigation of structural dynamics from time-resolved X-ray diffraction methods is becoming widespread in chemistry, biochemistry and materials science applications. Diffraction patterns can now be measured down to the femtosecond time-scale using X-ray free electron lasers or table-top laser plasma X-ray sources. On the other hand, the recent developments in photon counting X-ray area detectors offer new opportunities for time-resolved crystallography. Taking advantage of the fast read-out, the internal stacking of recorded images, and the gating possibilities (electronic shutter) of the XPAD hybrid pixel detector, we implemented a laboratory X-ray diffractometer for time-resolved single-crystal X-ray diffraction after pulsed laser excitation, combined with transient optical absorption measurement. The experimental method and instrumental setup are described in detail, and validated using the photoinduced nitrosyl linkage isomerism of sodium nitroprusside, Na2[Fe(CN)5NO]·2H2O, as proof of principle. Light-induced Bragg intensity relative variations ΔI(hkl)/I(hkl) of the order of 1%, due to the photoswitching of the NO ligand, could be detected with a 6 ms acquisition window. The capabilities of such a laboratory time-resolved experiment are critically evaluated.
In crystalloactivity tests with latent apple tyrosinase and two mutants reveal the importance of the mutated sites for polyphenol oxidase activity
Authors: Kampatsikas Ioannis , Bijelic Aleksandar , Pretzler Matthias , Rompel Annette
Published: July 2017

Tyrosinases are type 3 copper enzymes that belong to the polyphenol oxidase (PPO) family and are able to catalyze both theortho-hydroxylation of monophenols and their subsequent oxidation too-quinones, which are precursors for the biosynthesis of colouring substances such as melanin. The first plant pro-tyrosinase fromMalus domestica(MdPPO1) was recombinantly expressed in its latent form (56.4 kDa) and mutated at four positions around the catalytic pocket which are believed to influence the activity of the enzyme. Mutating the amino acids, which are known as activity controllers, yielded the mutantsMdPPO1-Ala239Thr andMdPPO1-Leu243Arg, whereas mutation of the so-called water-keeper and gatekeeper residues resulted in the mutantsMdPPO1-Glu234Ala andMdPPO1-Phe259Ala, respectively. The wild-type enzyme and two of the mutants,MdPPO1-Ala239Thr andMdPPO1-Phe259Ala, were successfully crystallized, leading to single crystals that diffracted to 1.35, 1.55 and 1.70 Å resolution, respectively. All crystals belonged to space groupP212121, exhibiting similar unit-cell parameters:a= 50.70,b= 80.15,c = 115.96 Å for the wild type,a= 50.58,b= 79.90,c= 115.76 Å forMdPPO1-Ala239Thr anda = 50.53,b= 79.76,c= 116.07 Å forMdPPO1-Phe259Ala.In crystalloactivity tests with the crystals of the wild type and the two mutants were performed by adding the monophenolic substrate tyramine and the diphenolic substrate dopamine to crystal-containing drops. The effects of the mutation on the activity of the enzyme were observed by colour changes of the crystals owing to the conversion of the substrates to dark chromophore products.
A new solvate of epalerstat, a drug for diabetic neuropathy
Authors: Putra Okky Dwichandra , Umeda Daiki , Fukuzawa Kaori , Gunji Mihoko , Yonemochi Etsuo
Published: July 2017

Epalerstat {systematic name: (5Z)-5-[(2E)-2-methyl-3-phenylprop-2-en-1-ylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidine-3-acetic acid} crystallized as an acetone monosolvate, C15H13NO3S2·C3H6O. In the epalerstat molecule, the methylpropylenediene moiety is inclined to the phenyl ring and the five-membered rhodamine ring by 21.4 (4) and 4.7 (4)°, respectively. In addition, the acetic acid moiety is found to be almost normal to the rhodamine ring, making a dihedral angle of 85.1 (2)°. In the crystal, a pair of O—H...O hydrogen bonds between the carboxylic acid groups of epalerstat molecules form inversion dimers with an R
2
2(8) loop. The dimers are linked by pairs of C—H...O hydrogen bonds, enclosing R
2
2(20) loops, forming chains propagating along the [101] direction. In addition, the acetone molecules are linked to the chain by a C—H...O hydrogen bond. Epalerstat acetone monosolvate was found to be isotypic with epalerstat tertrahydrofuran solvate [Umeda et al. (2017). Acta Cryst. E73, 941–944].
Activity inhibition and crystal polymorphism induced by active-site metal swapping
Authors: Yekwa Elsie , Khourieh Joelle , Canard Bruno , Papageorgiou Nicolas , Ferron François
Published: July 2017

TheArenaviridaefamily is one of the two RNA viral families that encode a 3′–5′ exonuclease in their genome. An exonuclease domain is found in theArenaviridaenucleoprotein and targets dsRNA specifically. This domain is directly involved in suppression of innate immunity in the host cell. Like most phosphate-processing enzymes, it requires a divalent metal ion such as Mg2+(or Mn2+) as a cofactor to catalyse nucleotide-cleavage and nucleotide-transfer reactions. On the other hand, calcium (Ca2+) inhibits this enzymatic activity, in spite of the fact that Mg2+and Ca2+present comparable binding affinities and biological availabilities. Here, the molecular and structural effects of the replacement of magnesium by calcium and its inhibition mechanism for phosphodiester cleavage, an essential reaction in the viral process of innate immunity suppression, are studied. Biochemical data and high-resolution structures of theMopeia virusexonuclease domain complexed with each ion are reported for the first time. The consequences of the ion swap for the stability of the protein, the catalytic site and the functional role of a specific metal ion in enabling the catalytic cleavage of a dsRNA substrate are outlined.
Toscana virusnucleoprotein oligomer organization observed in solution
Authors: Baklouti Amal , Goulet Adeline , Lichière Julie , Canard Bruno , Charrel Rémi N. , Ferron François , Coutard Bruno , Papageorgiou Nicolas
Published: July 2017

Toscana virus(TOSV) is an arthropod-borne virus belonging to thePhlebovirusgenus within theBunyaviridaefamily. As in other bunyaviruses, the genome of TOSV is made up of three RNA segments. They are encapsidated by the nucleoprotein (N), which also plays an essential role in virus replication. To date, crystallographic structures of phlebovirus N have systematically revealed closed-ring organizations which do not fully match the filamentous organization of the ribonucleoprotein (RNP) complex observed by electron microscopy. In order to further bridge the gap between crystallographic data on N and observations of the RNP by electron microscopy, the structural organization of recombinant TOSV N was investigated by an integrative approach combining X-ray diffraction crystallography, transmission electron microscopy, small-angle X-ray scattering, size-exclusion chromatography and multi-angle laser light scattering. It was found that in solution TOSV N forms open oligomers consistent with the encapsidation mechanism of phlebovirus RNA.
An overview of comparative modelling and resources dedicated to large-scale modelling of genome sequences
Authors: Lam Su Datt , Das Sayoni , Sillitoe Ian , Orengo Christine
Published: July 2017

Computational modelling of proteins has been a major catalyst in structural biology. Bioinformatics groups have exploited the repositories of known structures to predict high-quality structural models with high efficiency at low cost. This article provides an overview of comparative modelling, reviews recent developments and describes resources dedicated to large-scale comparative modelling of genome sequences. The value of subclustering protein domain superfamilies to guide the template-selection process is investigated. Some recent cases in which structural modelling has aided experimental work to determine very large macromolecular complexes are also cited.
[μ-1,4-Bis(diphenylphosphanyl)butane-κ2
P:P′]bis{(4-benzyl-2-neopentyl-1,2,4-triazol-3-ylidene)[(1,2,5,6-η)-cycloocta-1,5-diene]iridium(I)} bis(tetrafluoroborate) dichloromethane disolvate
Authors: Idrees Karam B. , Astashkin Andrei V. , Rajaseelan Edward
Published: July 2017

The title compound, [Ir2(C14H19N3)2(C8H12)2(C28H28P2)](BF4)2·2CH2Cl2, has triclinic (P-1) symmetry and the dication lies about an inversion center located at the mid-point of the butane chain of the phosphine ligand. The IrI ion has a distorted square-planar coordination geometry. The N-heterocyclic carbene ligand has an extended S-shaped conformation. The diphosphine ligand acts as a bridge between the two metal centers. This is the first structural report of a complex where the square-planar iridium centers are bridged by a phosphine ligand, and it is of interest with respect to catalysis in transfer hydrogenation reactions. Parts of the triazole and cyclooctadiene ligands and the tetrafluoroborate anion are disordered over two sets of sites.
5-Nitro-1-(prop-2-en-1-yl)-1H-indazole
Authors: Boulhaoua Mohammed , Essaghouani Abdelhanine , Lahmidi Sanae , Benchidmi Mohammed , Essassi El Mokhtar , Mague Joel T.
Published: July 2017

In the crystal, the title molecule, C10H9N3O2, packs in layers approximately parallel to (100), which are formed by the association of zigzag chains constructed by weak C—H...O interactions. The allyl group is disordered over two positions, with a ratio of their occupancies close to 70:30.