bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence, explanation, and telling histories of violence: A response to Dragojević, Braun, and Fedorowycz
Authors: Bergholz Max
Published: July 2018

In myriad forms, violence remains a crucial and, arguably, an increasingly dominant form of political practice by a host of actors in the contemporary world. It is thus not surprising that during the past two decades research on various aspects of violence has increased significantly. Historians have long been the central chroniclers of the violent past, but others, especially social scientists, have recently moved into the spotlight with a host of compelling analyses about the origins, dynamics, and effects of violence, including those of riots, pogroms, civil war, and genocide, among others. Today, the story of violent human behavior is one that many scholars seek to tell and explain, and in a host of different ways — from research methodology and scale, to narrative style. Yet regardless of who seeks to tell histories of violence, the question of what drives people to inflict immense pain and large-scale death on others continues to remain a perplexing question in today's world, and thus is one that remains in urgent need of attention from researchers.
Starvation induces rapid degradation of selective autophagy receptors by endosomal microautophagy
Authors: Mejlvang Jakob , Olsvik Hallvard , Svenning Steingrim , Bruun Jack-Ansgar , Abudu Yakubu Princely , Larsen Kenneth Bowitz , Brech Andreas , Hansen Tom E. , Brenne Hanne , Hansen Terkel , Stenmark Harald , Johansen Terje
Published: July 2018

It is not clear to what extent starvation-induced autophagy affects the proteome on a global scale and whether it is selective. In this study, we report based on quantitative proteomics that cells during the first 4 h of acute starvation elicit lysosomal degradation of up to 2–3% of the proteome. The most significant changes are caused by an immediate autophagic response elicited by shortage of amino acids but executed independently of mechanistic target of rapamycin and macroautophagy. Intriguingly, the autophagy receptors p62/SQSTM1, NBR1, TAX1BP1, NDP52, and NCOA4 are among the most efficiently degraded substrates. Already 1 h after induction of starvation, they are rapidly degraded by a process that selectively delivers autophagy receptors to vesicles inside late endosomes/multivesicular bodies depending on the endosomal sorting complex required for transport III (ESCRT-III). Our data support a model in which amino acid deprivation elicits endocytosis of specific membrane receptors, induction of macroautophagy, and rapid degradation of autophagy receptors by endosomal microautophagy.
Germline-activating mutations in PIK3CD compromise B cell development and function
Authors: Avery Danielle T. , Kane Alisa , Nguyen Tina , Lau Anthony , Nguyen Akira , Lenthall Helen , Payne Kathryn , Shi Wei , Brigden Henry , French Elise , Bier Julia , Hermes Jana R. , Zahra David , Sewell William A. , Butt Danyal , Elliott Michael , Boztug Kaan , Meyts Isabelle , Choo Sharon , Hsu Peter , Wong Melanie , Berglund Lucinda J. , Gray Paul , O’Sullivan Michael , Cole Theresa , Holland Steven M. , Ma Cindy S. , Burkhart Christoph , Corcoran Lynn M. , Phan Tri Giang , Brink Robert , Uzel Gulbu , Deenick Elissa K. , Tangye Stuart G.
Published: July 2018

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd. In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.
Sex Drugs and Corporate Ventriloquism: How to Evaluate Science Policies Intended to Manage Industry-Funded Bias
Authors: Holman Bennett , Geislar Sally
Published: July 2018

“Female sexual dysfunction” is the type of contested disease that has sparked concern about the role of the pharmaceutical industry in medical science. Many policies have been proposed to manage industry influence without carefully evaluating whether the proposed policies would be successful. We consider a proposal for incorporating citizen stakeholders into scientific research and show, via a detailed case study of the pharmaceutical regulation of flibanserin (misleadingly marketed as the “female Viagra”), that such programs can be co-opted. In closing, we use Holman’s asymmetric arms race framework as a tool for evaluating policies in industry-funded science.
Wishful Thinking and Values in Science
Authors: Steel Daniel
Published: July 2018

This article examines the concept of wishful thinking in philosophical literature on science and values. It suggests that this term tends to be used in an overly broad manner that fails to distinguish between separate types of bias, mechanisms that generate biases, and general theories that might explain those mechanisms. I explain how confirmation bias is distinct from wishful thinking and why it is more useful for examining the relationship between cognitive bias and beliefs about the existence of injustices.
What and How Do Cancer Systems Biologists Explain?
Authors: Plutynski Anya , Bertolaso Marta
Published: July 2018

In this article, we argue, first, that there are very different research projects that fall under the heading of “systems biology of cancer.” While they share some general features, they differ in their aims and theoretical commitments. Second, we argue that some explanations in systems biology of cancer are concerned with properties of signaling networks (such as robustness or fragility) and how they may play an important causal role in patterns of vulnerability to cancer. Further, some systems biological explanations are compelling illustrations of how “top-down” and “bottom-up” approaches to the same phenomena may be integrated.
Blood pressure, heart rate, and mortality in chronic obstructive pulmonary disease: the SUMMIT trial
Authors: Byrd James Brian , Newby David E , Anderson Julie A , Calverley Peter M A , Celli Bartolome R , Cowans Nicholas J , Crim Courtney , Martinez Fernando J , Vestbo Jørgen , Yates Julie , Brook Robert D ,   the SUMMIT Investigators
Published: July 2018

Aims

To characterize the relationship between blood pressure (BP) or heart rate and mortality and morbidity in chronic obstructive pulmonary disease (COPD).

Methods and results

We performedpost hoc analysis of baseline BP or heart rate and all-cause mortality and cardiovascular events in the SUMMIT trial. SUMMIT was a randomized double-blind outcome trial of 16 485 participants (65 ± 8 years, 75% male, and 47% active smokers) enrolled at 1368 sites in 43 countries. Participants with moderate COPD with or at risk for cardiovascular disease (CVD) were randomized to placebo, long-acting beta agonist, inhaled corticosteroid, or their combination. All-cause mortality increased in relation to high systolic [≥140 mmHg; hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12–1.45] or diastolic (≥90 mmHg; HR 1.35, 95% CI 1.14–1.59) BP and low systolic (<120 mmHg; HR 1.36, 95% CI 1.13–1.63) or diastolic (<80 mmHg; HR 1.15, 95% CI 1.00–1.32) BP. Higher heart rates (≥80 per minute; HR 1.39, 95% CI 1.21–1.60) and pulse pressures (≥80 mmHg; HR 1.39, 95% CI 1.07–1.80) were more linearly related to increases in all-cause mortality. The risks of cardiovascular events followed similar patterns to all-cause mortality. Similar findings were observed in subgroups of patients without established CVD.

Conclusion

A ‘U-shaped’ relationship between BP and all-cause mortality and cardiovascular events exists in patients with COPD and heightened cardiovascular risk. A linear relationship exists between heart rate and all-cause mortality and cardiovascular events in this population. These findings extend the prognostic importance of BP to this growing group of patients and raise concerns that both high and low BP may pose health risks.
Weak-lensing mass calibration of the Sunyaev–Zel’dovich effect using APEX-SZ galaxy clusters
Authors: Nagarajan A , Pacaud F , Sommer M , Klein M , Basu K , Bertoldi F , Lee A T , Ade P A R , Bender A N , Ferrusca D , Halverson N W , Horellou C , Johnson B R , Kennedy J , Kneissl R , Menten K M , Reichardt C L , Tucker C , Westbrook B
Published: July 2018

The use of galaxy clusters as precision cosmological probes relies on an accurate determination of their masses. However, inferring the relationship between cluster mass and observables from direct observations is difficult and prone to sample selection biases. In this work, we use weak lensing as the best possible proxy for cluster mass to calibrate the Sunyaev–Zel’dovich (SZ) effect measurements from the APEX-SZ experiment. For a well-defined (ROSAT) X-ray complete cluster sample, we calibrate the integrated Comptonization parameter, YSZ, to the weak-lensing derived total cluster mass, M500. We employ a novel Bayesian approach to account for the selection effects by jointly fitting both the SZ Comptonization, YSZ–M500, and the X-ray luminosity, Lx–M500, scaling relations. We also account for a possible correlation between the intrinsic (lognormal) scatter of Lx and YSZ at fixed mass. We find the corresponding correlation coefficient to be $r= 0.47_{-0.35}^{+0.24}$, and at the current precision level our constraints on the scaling relations are consistent with previous works. For our APEX-SZ sample, we find that ignoring the covariance between the SZ and X-ray observables biases the normalization of the YSZ–M500 scaling high by 1–2σ and the slope low by ∼1σ, even when the SZ effect plays no role in the sample selection. We conclude that for higher precision data and larger cluster samples, as anticipated from on-going and near-future cluster cosmology experiments, similar biases (due to intrinsic covariances of cluster observables) in the scaling relations will dominate the cosmological error budget if not accounted for correctly.
Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Evaluation and Treatment of Patients With Thoracolumbar Spine Trauma: Novel Surgical Strategies
Authors: Chi John H , Eichholz Kurt M , Anderson Paul A , Arnold Paul M , Dailey Andrew T , Dhall Sanjay S , Harrop James S , Hoh Daniel J , Qureshi Sheeraz , Rabb Craig H , Raksin P B , Kaiser Michael G , O’Toole John E
Published: July 2018

BACKGROUND

Treatment of thoracolumbar burst fractures has traditionally involved spinal instrumentation with fusion performed with standard open surgical techniques. Novel surgical strategies, including instrumentation without fusion and percutaneous instrumentation alone, have been considered less invasive and more efficient treatments.

OBJECTIVE

To review the current literature and determine the role of fusion in instrumented fixation, as well as the role of percutaneous instrumentation, in the treatment of patients with thoracolumbar burst fractures.

METHODS

The task force members identified search terms/parameters and a medical librarian implemented the literature search, consistent with the literature search protocol (see Appendix I), using the National Library of Medicine PubMed database and the Cochrane Library for the period from January 1, 1946 to March 31, 2015.

RESULTS

A total of 906 articles were identified and 38 were selected for full-text review. Of these articles, 12 articles met criteria for inclusion in this systematic review.

CONCLUSION

There is grade A evidence for the omission of fusion in instrumented fixation for thoracolumbar burst fractures. There is grade B evidence that percutaneous instrumentation is as effective as open instrumentation for thoracolumbar burst fractures.

RECOMMENDATIONS

QUESTION

Does the addition of arthrodesis to instrumented fixation improve outcomes in patients with thoracic and lumbar burst fractures?

RECOMMENDATION

It is recommended that in the surgical treatment of patients with thoracolumbar burst fractures, surgeons should understand that the addition of arthrodesis to instrumented stabilization has not been shown to impact clinical or radiological outcomes, and adds to increased blood loss and operative time.

Strength of Recommendation: Grade A

QUESTION

How does the use of minimally invasive techniques (including percutaneous instrumentation) affect outcomes in patients undergoing surgery for thoracic and lumbar fractures compared to conventional open techniques?

RECOMMENDATION

Stabilization using both open and percutaneous pedicle screws may be considered in the treatment of thoracolumbar burst fractures as the evidence suggests equivalent clinical outcomes.

Strength of Recommendation: Grade B

The full version of the guideline can be reviewed at: https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_12.
Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Evaluation and Treatment of Patients With Thoracolumbar Spine Trauma: Neurological Assessment
Authors: Harrop James S , Chi John H , Anderson Paul A , Arnold Paul M , Dailey Andrew T , Dhall Sanjay S , Eichholz Kurt M , Hoh Daniel J , Qureshi Sheeraz , Rabb Craig H , Raksin P B , Kaiser Michael G , O’Toole John E
Published: July 2018

QUESTION 1

Which neurological assessment tools have demonstrated internal reliability and validity in the management of patients with thoracic and lumbar fractures (ie, do these instruments provide consistent information between different care providers)?

RECOMMENDATION 1

Numerous neurologic assessment scales (Functional Independence Measure, Sunnybrook Cord Injury Scale and Frankel Scale for Spinal Cord Injury) have demonstrated internal reliability and validity in the management of patients with thoracic and lumbar fractures. Unfortunately, other contemporaneous measurement scales (ie, American Spinal Cord Injury Association Impairment Scale) have not been specifically studied in patients with thoracic and lumbar fractures.

Strength of Recommendation: Grade C

QUESTION 2

Are there any clinical findings (eg, presenting neurological grade/function) in patients with thoracic and lumbar fractures that can assist in predicting clinical outcomes?

RECOMMENDATION 2

Entry American Spinal Injury Association Impairment Scale grade, sacral sensation, ankle spasticity, urethral and rectal sphincter function, and AbH motor function can be used to predict neurological function and outcome in patients with thoracic and lumbar fractures (Table I https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_4_table1).

Strength of Recommendation: Grade B

The full version of the guideline can be reviewed at: https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_4.
Structural variation during dog domestication: insights from gray wolf and dhole genomes
Authors: Wang Guo-Dong , Shao Xiu-Juan , Bai Bing , Wang Junlong , Wang Xiaobo , Cao Xue , Liu Yan-Hu , Wang Xuan , Yin Ting-Ting , Zhang Shao-Jie , Lu Yan , Wang Zechong , Wang Lu , Zhao Wenming , Zhang Bing , Ruan Jue , Zhang Ya-Ping
Published: July 2018

Several processes like phenotypic evolution, disease susceptibility and environmental adaptations, which fashion the domestication of animals, are largely attributable to structural variations (SVs) in the genome. Here, we present high-quality draft genomes of the gray wolf (Canis lupus) and dhole (Cuon alpinus) with scaffold N50 of 6.04 Mb and 3.96 Mb, respectively. Sequence alignment comprising genomes of three canid species reveals SVs specific to the dog, particularly 16 315 insertions, 2565 deletions, 443 repeats, 16 inversions and 15 translocations. Functional annotation of the dog SVs associated with genes indicates their enrichments in energy metabolisms, neurological processes and immune systems. Interestingly, we identify and verify at population level an insertion fully covering a copy of the AKR1B1 (Aldo-Keto Reductase Family 1 Member B) transcript. Transcriptome analysis reveals a high level of expression of the new AKR1B1 copy in the small intestine and liver, implying an increase in de novo fatty acid synthesis and antioxidant ability in dog compared to gray wolf, likely in response to dietary shifts during the agricultural revolution. For the first time, we report a comprehensive analysis of the evolutionary dynamics of SVs during the domestication step of dogs. Our findings demonstrate that retroposition can birth new genes to facilitate domestication, and affirm the importance of large-scale genomic variants in domestication studies.
High Maternal Circulating Cotinine During Pregnancy is Associated With Persistently Shorter Stature From Birth to Five Years in an Asian Cohort
Authors: Ng Sharon , Aris Izzuddin M , Tint Mya Thway , Gluckman Peter D , Godfrey Keith M , Shek Lynette Pei-Chi , Yap Fabian , Tan Kok Hian , Lek Ngee , Teoh Oon Hoe , Chan Yiong Huak , Chong Mary Foong-Fong , Lee Yung Seng , Chong Yap-Seng , Kramer Michael S , Chan Shiao-Yng
Published: July 2018

Background

Self-reported maternal active smoking has been associated with reduced offspring birth length and shorter stature in early and late childhood.

Objective

To use circulating cotinine as an objective biomarker to investigate the association between smoking and environmental tobacco smoke (ETS) exposure in pregnancy and longitudinal measures of offspring length/height from birth to 60 months.

Methods

In 969 maternal-offspring dyads from the GUSTO cohort, maternal plasma cotinine at 26–28 weeks’ gestation was measured by LC/MS/MS and categorized into four groups: Group 1: cotinine <0.17 ng/mL (the assay’s detection limit) and no ETS exposure; Group 2: cotinine <0.17 ng/mL but self-reported ETS; Group 3: cotinine 0.17–13.99 ng/mL (ETS or light smoking); Group 4: cotinine ≥14 ng/mL (active smoking).

Results

Adjusting for infant sex, gestational age at birth, ethnicity, maternal age, education, parity, BMI, and height, Group 4 offspring were shorter at birth [z-score β = −0.42 SD units (SDs) (95% CI = −0.77 to −0.06)] than Group 1 offspring. Group 4 offspring continued to be shorter at older ages, with similar effect sizes at 3 months [−0.57 SDs (−0.95 to −0.20)], 36 months [−0.53 SDs (−0.92 to −0.15)], 48 months [−0.43 SDs (−0.81 to −0.04)], and 60 months [−0.57 SDs (−0.96 to −0.17)]. Associations were particularly marked in boys. No significant differences in stature were observed in Groups 2 or 3 compared with Group 1.

Conclusions

This Asian longitudinal study associated high prenatal cotinine with persistently shorter stature in offspring from birth and into early childhood, whilst low prenatal cotinine levels and ETS exposure showed no such association.

Implications

Little is known about the long-term effects of prenatal tobacco exposure on offspring stature in Asia where passive smoking is common. This study has used an objective biomarker to reveal that the association of prenatal tobacco exposure with offspring length/height mainly occurs at a high maternal cotinine level of greater than 14 ng/mL in pregnancy, consistent with active smoking, but no significant associations were found with lower cotinine levels, consistent with passive smoking. Encouraging women to quit smoking prior to or during pregnancy may avert the long-term negative impact on their child’s height despite appreciable prenatal ETS exposure.
The nature and scope of patient-sharing network research: a novel, important area for network science
Authors: Robbins Rebecca , Seixas Azizi , Schoenthaler Antoinette
Published: July 2018

A robust literature exists that draws on social network approaches to understand connections among individuals, and healthcare and behavior-related implications. This article offers commentary on the scoping review conducted by Dugoff et al. that examines “patient-sharing” networks, their characteristics, and various methodological approaches. The scoping review conducted by Dugoff et al. examines the characteristics and methods employed in patient-sharing network studies. It identified the most common measures used in patient-sharing network research, as well as theories used in patient-sharing network studies. Dugoff et al. also identified many studies that examined healthcare utilization considerations for patient sharing. Understanding the connections between providers and the flow of patients between providers could lend insight into barriers and enablers to efficient healthcare systems.
Evaluation of the genomic diversity of viruses infecting bacteria, archaea and eukaryotes using a common bioinformatic platform: steps towards a unified taxonomy
Authors: Aiewsakun Pakorn , Adriaenssens Evelien M. , Lavigne Rob , Kropinski Andrew M. , Simmonds Peter
Published: July 2018

Genome Relationship Applied to Virus Taxonomy (GRAViTy) is a genetics-based tool that computes sequence relatedness between viruses. Composite generalized Jaccard (CGJ) distances combine measures of homology between encoded viral genes and similarities in genome organizational features (gene orders and orientations). This scoring framework effectively recapitulates the current, largely morphology and phenotypic-based, family-level classification of eukaryotic viruses. Eukaryotic virus families typically formed monophyletic groups with consistent CGJ distance cut-off dividing between and within family divergence ranges. In the current study, a parallel analysis of prokaryotic virus families revealed quite different sequence relationships, particularly those of tailed phage families (Siphoviridae, Myoviridae and Podoviridae), where members of the same family were generally far more divergent and often not detectably homologous to each other. Analysis of the 20 currently classified prokaryotic virus families indeed split them into 70 separate clusters of tailed phages genetically equivalent to family-level assignments of eukaryotic viruses. It further divided several bacterial (Sphaerolipoviridae, Tectiviridae) and archaeal (Lipothrixviridae) families. We also found that the subfamily-level groupings of tailed phages were generally more consistent with the family assignments of eukaryotic viruses, and this supports ongoing reclassifications, including Spounavirinae and Vi1virus taxa as new virus families. The current study applied a common benchmark with which to compare taxonomies of eukaryotic and prokaryotic viruses. The findings support the planned shift away from traditional morphology-based classifications of prokaryotic viruses towards a genome-based taxonomy. They demonstrate the feasibility of a unified taxonomy of viruses into which the vast body of metagenomic viral sequences may be consistently assigned.
Distinct Cortical-Thalamic-Striatal Circuits Through the Parafascicular Nucleus
Authors: Mandelbaum Gil , Taranda Julian , Haynes Trevor M. , Hochbaum Daniel R. , Huang Kee Wui , Hyun Minsuk , Venkataraju Kannan Umadevi , Straub Christoph , Wang Wengang , Robertson Keiramarie , Osten Pavel , Sabatini Bernardo L.
Published: July 2018

The thalamic parafascicular nucleus (PF), an excitatory input to the basal ganglia, is targeted with deep-brain-stimulation to alleviate a range of neuropsychiatric symptoms. Furthermore, PF lesions disrupt the execution of correct motor actions in uncertain environments. Nevertheless, the circuitry of the PF and its contribution to action selection are poorly understood. We find that, in mice, PF forms the densest subcortical projection to the striatum. This projection arises from transcriptionally- and physiologically-distinct classes of PF neurons that are also reciprocally connected with functionally-distinct cortical regions, differentially innervate striatum neurons, and are not synaptically connected in PF. Thus, mouse PF contains heterogeneous neurons that are organized into parallel and independent associative, limbic, and motor circuits. Furthermore, these subcircuits share motifs of cortical-PF-cortical and cortical-PF-striatum organization that allow each PF subregion, via its precise connectivity with cortex, to coordinate diverse inputs to striatum.
Short term depression shapes information transmission in a constitutively active GABAergic synapse
Authors: Lavian Hagar , Korngreen Alon
Published: July 2018

Short-term depression is a low pass filter of synaptic information that reduces and flattens synaptic information transfer at high presynaptic firing frequencies. This view questions the relevance of spontaneous high firing rates in some networks. In the indirect pathway of the basal ganglia, spontaneously active neurons in the globus pallidus (GP) form depressing inhibitory synapses in the basal ganglia output nuclei. Using numerical modeling and whole-cell recordings from single entopeduncular nucleus (EP) neurons in rat brain slices we investigated the contribution of the different firing rates of GP neurons to information transmission in the indirect pathway. Wholecell recordings showed significant variability in steady-state depression which decreased as stimulation frequency increased. Modeling predicted that this variability would translate into different postsynaptic noise levels during constitutive presynaptic activity. Our simulations further predicted that individual GP-EP synapses mediate gain control. However, when we consider integration of multiple inputs, the large range of GP firing rates would enable different modes of information transmission in which the magnitude and temporal features of postsynaptic modulation would change as a function of present and past firing rates of GP neurons. Finally, we predict that changes in dopamine levels can shift the action of GP neurons from rate coding to gain modulation. Our results thus demonstrate how short-term synaptic depression shapes information transmission in the basal ganglia in particular and via GABAergic synapses in general.

Significant statement

Synapses displaying short-term depression are low-pass filters of synaptic input. Consequently, when presynaptic firing is high, little information passes to the postsynaptic neuron. However, many neurons fire at relatively high frequencies all the time. Are their synapses constantly silenced by depression? We tested this apparent contradiction in the indirect pathway of the basal ganglia, where neurons from the globus pallidus (GP) form constitutively active depressing synapses on basal ganglia output. We hypothesized that the different rates of ongoing activity underlie different modes of action for GP neurons. We show that the synaptic and structural properties of the indirect pathway map GP baseline frequencies to different postsynaptic signals, thus demonstrating how short-term synaptic depression shapes information transmission in the basal ganglia.
Chronic infections can shape epidemic exposure: Pathogen co-occurrence networks in the Serengeti lions
Authors: Fountain-Jones Nicholas M. , Packer Craig , Jacquot Maude , Blanchet F. Guillaume , Terio Karen , Craft Meggan E.
Published: July 2018

Pathogens are embedded in a complex network of microparasites that can collectively or individually alter disease dynamics and outcomes. Chronic pathogens, for example, can either facilitate or compete with subsequent pathogens thereby exacerbating morbidity and mortality. Pathogen interactions are ubiquitous in nature, but poorly understood, particularly in wild populations. We report here on ten years of serological and molecular data in African lions, leveraging comprehensive demographic and behavioral data to utilize pathogen networks to test if chronic infections shape infection by acute pathogens. We combine network and community ecology approaches to assess broad network structure and characterize associations between pathogens across spatial and temporal scales. We found significant non-random structure in the lion-pathogen co-occurrence network and identified potential facilitative and competitive interactions between acute and chronic pathogens. Our results provide a novel insight for untangling the complex associations underlying pathogen co-occurrence networks.
Neuronal overexpression ofDYRK1A/minibrainalters motor decline, neurodegeneration and synaptic plasticity inDrosophila
Authors: Lowe Simon A , Usowicz Maria M , Hodge James JL
Published: July 2018

Down syndrome (DS) is characterised by abnormal cognitive and motor development, and later in life by progressive Alzheimer’s disease (AD)-like dementia, neuropathology, declining motor function and shorter life expectancy. It is caused by trisomy of chromosome 21 (Hsa21), but how individual Hsa21 genes contribute to various aspects of the disorder is incompletely understood. Previous work has demonstrated a role for triplication of the Hsa21 geneDYRK1Ain cognitive and motor deficits, as well as in altered neurogenesis and neurofibrillary degeneration in the DS brain, but its contribution to other DS phenotypes is unclear. Here we demonstrate that overexpression ofminibrain(mnb), theDrosophilaortholog ofDYRK1A, in theDrosophilanervous system accelerated age-dependent decline in motor performance and shortened lifespan. Overexpression ofmnbin the eye was neurotoxic and overexpression in ellipsoid body neurons in the brain caused age-dependent neurodegeneration. At the larval neuromuscular junction, an established model for mammalian central glutamatergic synapses, neuronalmnboverexpression enhanced spontaneous vesicular transmitter release. It also slowed recovery from short-term depression of evoked transmitter release induced by high-frequency nerve stimulation and increased the number of boutons in one of the two glutamatergic motor neurons innervating the muscle. These results provide further insight into the roles ofDYRK1Atriplication in abnormal aging and synaptic dysfunction in DS.

Author summary

Down syndrome (DS) is caused by three copies of chromosome 21 instead of the usual two. It is characterised by cognitive and motor deficits, which worsen with age resulting in Alzheimer’s disease (AD). Which genes on chromosome 21 cause these phenotypes is incompletely understood. Here we demonstrate that neuronal overexpression ofminibrain, theDrosophilaortholog of the chromosome 21 geneDYRK1A, causes age-dependent degeneration of brain neurons, accelerates age-dependent decline in motor performance and shortens lifespan. It also modifies presynaptic structure, enhances spontaneous transmitter release and slows recovery from short-term depression of synaptic transmission at a model glutamatergic synapse. These findings give insight into the role ofDYRK1Aoverexpression in aberrant aging and altered information processing in DS and AD.
A post-translational modification of the sheath modulatesFrancisellatype VI secretion system assembly and function
Authors: Ziveri Jason , Chhuon Cerina , Jamet Anne , Prigent Guénolé , Rytter Héloïse , Tros Fabiola , Barel Monique , Coureuil Mathieu , Lays Claire , Henry Thomas , Keep Nicholas H , Guerrera Ida Chiara , Charbit Alain
Published: July 2018

Francisella tularensisis a facultative intracellular pathogen that causes the zoonotic disease tularemia in human and animal hosts. This bacterium possesses a non-canonical type VI secretion systems (T6SS) required for phagosomal escape and access to its replicative niche in the cytosol of infected macrophages. KCl stimulation has been previously used to trigger assembly and secretion of the Francisella T6SS in culture. We found that the amounts of essentially all the TSS6 proteins remained unchanged upon KCl stimulation. We therefore hypothesized that a post-translational modification might be involved in T6SS assembly. A whole cell phosphoproteomic analysis allowed us to identify a unique phosphorylation site on IglB, the TssC homologue and key component of the T6SS sheath. Importantly, the phosphorylated form of IglB was not present in the contracted sheath and 3D modeling indicated that the charge repulsion provoked by addition of a phosphogroup on tyrosine 139 was likely to weaken the stability of the sheath structure. Substitutions of the phosphorylatable residue of IglB (tyrosine 139) with alanine or with phosphomimetics prevented T6SS formation and totally impaired phagosomal escape. In contrast, the substitution with the non-phosphorylatable aromatic analog phenylalanine impaired but did not prevent phagosomal escape and cytosolic bacterial multiplication in J774-1 macrophages. Altogether these data suggest that phosphorylation of the sheath participates to T6SS disassembly. Post-translational modifications of the sheath may represent a previously unrecognized mechanism to finely modulate the dynamics of T6SS assembly-disassembly.

Data are available via ProteomeXchange with identifier PXD012507.

Synopsis

Francisellapossesses a non-canonical T6SS that is essential for efficient phagosomal escape and access to the cytosol of infected macrophages. KCl stimulation has been previously used to trigger assembly and secretion of the Francisella T6SS in culture. We found that KCl stimulation did not result in an increased production of TSS6 proteins. We therefore hypothesized that a post-translational modification might be involved in T6SS assembly. Using a global and site-specific phosphoproteomic analysis ofFrancisellawe identified a unique phosphorylation site on IglB, the TssC homologue and a key component of the T6SS contractile sheath. We show that this site plays a critical role in T6SS biogenesis and propose that phosphorylation may represent a new mechanism affecting the dynamics of sheath formation.
Pathogen diversity drives the evolution of promiscuous peptide binding of human MHC-II alleles
Authors: Manczinger Máté , Boross Gábor , Kemény Lajos , Müller Viktor , Lenz Tobias L. , Papp Balázs , Pál Csaba
Published: July 2018

Major histocompatibility complex (MHC) molecules mediate the adaptive immune response against pathogens. Certain MHC alleles are generalists: they present an exceptionally large variety of antigenic peptides. However, the functional implications of such elevated epitope binding promiscuity in the MHC molecules are largely unknown. According to what we term the pathogen-driven promiscuity hypothesis, exposure to a broad range of pathogens favors the evolution of highly promiscuous MHC variants. Consistent with this hypothesis, we found that in pathogen-rich geographical regions, humans are more likely to carry promiscuous MHC class II DRB1 alleles, and the switch between high and low promiscuity levels has occurred repeatedly and in a rapid manner during human evolution. We also show that selection for promiscuous peptide binding shapes MHC genetic diversity. In sum, our study offers a conceptually novel mechanism to explain the global distribution of allelic variants of a key human immune gene by demonstrating that pathogen pressure maintains promiscuous MHC class II alleles. More generally, our work highlights the hitherto neglected role of epitope binding promiscuity in immune defense, with implications for medical genetics and epidemiology.
HiPLA: High-throughput imaging Proximity Ligation Assay
Authors: Serebryannyy Leonid A. , Misteli Tom
Published: July 2018

Protein-protein interactions are essential for cellular structure and function. To delineate how the intricate assembly of protein interactions contribute to cellular processes in health and disease, new methodologies that are both highly sensitive and can be applied at large scale are needed. Here, we develop HiPLA (high-throughput imaging proximity ligation assay), a method that employs the antibody-based proximity ligation assay in a high-throughput imaging screening format to systematically probe protein interactomes. Using HiPLA, we probe the interaction of 60 proteins and associated PTMs with the nuclear lamina in a model of the premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS). We identify a subset of proteins that differentially interact with the nuclear lamina in HGPS. In combination with quantitative indirect immunofluorescence, we find that the majority of differential interactions were accompanied by corresponding changes in expression of the interacting protein. Taken together, HiPLA offers a novel approach to probe cellular protein-protein interaction at a large scale and reveals mechanistic insights into the assembly of protein complexes.
Root stem cell niche organizer specification by molecular convergence of PLETHORA and SCARECROW transcription factor modules
Authors: Shimotohno Akie , Heidstra Renze , Blilou Ikram , Scheres Ben
Published: July 2018

Continuous formation of somatic tissues in plants requires functional stem cell niches where undifferentiated cells are maintained. In Arabidopsis thaliana, PLETHORA (PLT) and SCARECROW (SCR) genes are outputs of apical–basal and radial patterning systems, and both are required for root stem cell specification and maintenance. The WUSCHEL-RELATED HOMEOBOX 5 (WOX5) gene is specifically expressed in and required for functions of a small group of root stem cell organizer cells, also called the quiescent center (QC). PLT and SCR are required for QC function, and their expression overlaps in the QC; however, how they specify the organizer has remained unknown. We show that PLT and SCR genetically and physically interact with plant-specific teosinte-branched cycloidea PCNA (TCP) transcription factors to specify the stem cell niche during embryogenesis and maintain organizer cells post-embryonically. PLT–TCP–SCR complexes converge on PLT-binding sites in the WOX5 promoter to induce expression.
Crystal structures of 2-aminopyridine citric acid salts: C5H7N2
+·C6H7O7
− and 3C5H7N2
+·C6H5O7
3−
Authors: Prakash Shet M. , Naveen S. , Lokanath N. K. , Suchetan P. A. , Warad Ismail
Published: July 2018

2-Aminopyridine and citric acid mixed in 1:1 and 3:1 ratios in ethanol yielded crystals of two 2-aminopyridinium citrate salts, viz. C5H7N2
+·C6H7O7
− (I) (systematic name: 2-aminopyridin-1-ium 3-carboxy-2-carboxymethyl-2-hydroxypropanoate), and 3C5H7N2
+·C6H5O7
3− (II) [systematic name: tris(2-aminopyridin-1-ium) 2-hydroxypropane-1,2,3-tricarboxylate]. The supramolecular synthons present are analysed and their effect upon the crystal packing is presented in the context of crystal engineering. Salt I is formed by the protonation of the pyridine N atom and deprotonation of the central carboxylic group of citric acid, while in II all three carboxylic groups of the acid are deprotonated and the charges are compensated for by three 2-aminopyridinium cations. In both structures, a complex supramolecular three-dimensional architecture is formed. In I, the supramolecular aggregation results from Namino—H...Oacid, Oacid...H—Oacid, Oalcohol—H...Oacid, Namino—H...Oalcohol, Npy—H...Oalcohol and Car—H...Oacid interactions. The molecular conformation of the citrate ion (CA3−) in II is stabilized by an intramolecular Oalcohol—H...Oacid hydrogen bond that encloses an S(6) ring motif. The complex three-dimensional structure of II features Namino—H...Oacid, Npy—H...Oacid and several Car—H...Oacid hydrogen bonds. In the crystal of I, the common charge-assisted 2-aminopyridinium–carboxylate heterosynthon exhibited in many 2-aminopyridinium carboxylates is not observed, instead chains of N—H...O hydrogen bonds and hetero O—H...O dimers are formed. In the crystal of II, the 2-aminopyridinium–carboxylate heterosynthon is sustained, while hetero O—H...O dimers are not observed. The crystal structures of both salts display a variety of hydrogen bonds as almost all of the hydrogen-bond donors and acceptors present are involved in hydrogen bonding.
IMAGINE: neutrons reveal enzyme chemistry
Authors: Schröder Gabriela C. , O'Dell William B. , Myles Dean A. A. , Kovalevsky Andrey , Meilleur Flora
Published: July 2018

Neutron diffraction is exquisitely sensitive to the positions of H atoms in protein crystal structures. IMAGINE is a high-intensity, quasi-Laue neutron crystallography beamline developed at the High Flux Isotope Reactor (HFIR) at Oak Ridge National Laboratory. This state-of-the-art facility for neutron diffraction has enabled detailed structural analysis of macromolecules. IMAGINE is especially suited to resolve individual H atoms in protein structures, enabling neutron protein structures to be determined at or near atomic resolutions from crystals with volumes of less than 1 mm3 and unit-cell edges of less than 150 Å. Beamline features include elliptical focusing mirrors that deliver neutrons into a 2.0 × 3.2 mm focal spot at the sample position, and variable short- and long-wavelength cutoff optics that provide automated exchange between multiple wavelength configurations. This review gives an overview of the IMAGINE beamline at the HFIR, presents examples of the scientific questions being addressed at this beamline, and highlights important findings in enzyme chemistry that have been made using the neutron diffraction capabilities offered by IMAGINE.
Biological small-angle neutron scattering: recent results and development
Authors: Mahieu Emilie , Gabel Frank
Published: July 2018

Small-angle neutron scattering (SANS) has increasingly been used by the structural biology community in recent years to obtain low-resolution information on solubilized biomacromolecular complexes in solution. In combination with deuterium labelling and solvent-contrast variation (H2O/D2O exchange), SANS provides unique information on individual components in large heterogeneous complexes that is perfectly complementary to the structural restraints provided by crystallography, nuclear magnetic resonance and electron microscopy. Typical systems studied include multi-protein or protein–DNA/RNA complexes and solubilized membrane proteins. The internal features of these systems are less accessible to the more broadly used small-angle X-ray scattering (SAXS) technique owing to a limited range of intra-complex and solvent electron-density variation. Here, the progress and developments of biological applications of SANS in the past decade are reviewed. The review covers scientific results from selected biological systems, including protein–protein complexes, protein–RNA/DNA complexes and membrane proteins. Moreover, an overview of recent developments in instruments, sample environment, deuterium labelling and software is presented. Finally, the perspectives for biological SANS in the context of integrated structural biology approaches are discussed.
5,5-Diphenyl-2-thioxoimidazolidin-4-one dimethyl sulfoxide monosolvate
Authors: Aziz Hamid , Saeed Aamer , Simpson Jim
Published: July 2018

In the title solvate, C15H12N2OS·C2H6OS, the thioxoimidazolidin-4-one molecule and solvent molecule are linked by an N—H...O hydrogen bond. The planar imidazolidine ring (r.m.s. deviation = 0.022 Å) is inclined to the phenyl substituents in the 5-position by 69.57 (7) and 72.62 (6)°. In the crystal, N—H...O, C—H...O and C—H...S hydrogen bonds, together with C—H...π interactions, generate [100] chains, which stack along the a-axis direction.
Effect of laser power on amorphous forming capability and corrosion performance of laser thermal sprayed Al-Ni-Fe-Gd coatings
Authors: Baoxu Yan , Dejun Kong
Published: July 2018

Purpose

The amorphous Al-Ni-Fe-Gd coatings were fabricated to improve anti-corrosion performance of offshore platforms.

Design/methodology/approach

The amorphous Al-Ni-Fe-Gd coatings were first fabricated on S355 steel using the laser thermal spraying.

Findings

The amorphous forming capability and corrosion resistance increases with the laser powers increasing.

Research Limitations/implications

The amorphous Al-Ni-Fe-Gd coatings were applied on S355 steel of offshore platforms to increase its long-term heavy and anti-corrosion protection.

Originality/value

The amorphous Al-Ni-Fe-Gd coatings were first fabricated using a laser thermal spraying, improving its anti-corrosion.
Project scheduling with time, cost and risk trade-off using adaptive multiple objective differential evolution
Authors: Tran Duc Hoc , Long Luong Duc
Published: July 2018

Purpose

As often in project scheduling, when the project duration is shortened to reduce total cost, the total float is lost resulting in more critical or nearly critical activities. This, in turn, results in reducing the probability of completing the project on time and increases the risk of schedule delays. The objective of project management is to complete the scope of work on time, within budget in a safe fashion of risk to maximize overall project success. The purpose of this paper is to present an effective algorithm, named as adaptive multiple objective differential evolution (DE) for project scheduling with time, cost and risk trade-off (AMODE-TCR).

Design/methodology/approach

In this paper, a multi-objective optimization model for project scheduling is developed using DE algorithm. The AMODE modifies a population-based search procedure by using adaptive mutation strategy to prevent the optimization process from becoming a purely random or a purely greedy search. An elite archiving scheme is adopted to store elite solutions and by aptly using members of the archive to direct further search.

Findings

A numerical construction project case study demonstrates the ability of AMODE in generating non-dominated solutions to assist project managers to select an appropriate plan to optimize TCR problem, which is an operation that is typically difficult and time-consuming. Comparisons between the AMODE and currently widely used multiple objective algorithms verify the efficiency and effectiveness of the developed algorithm. The proposed model is expected to help project managers and decision makers in successfully completing the project on time and reduced risk by utilizing the available information and resources.

Originality/value

The paper presented a novel model that has three main contributions: First, this paper presents an effective and efficient adaptive multiple objective algorithms named as AMODE for producing optimized schedules considering time, cost and risk simultaneously. Second, the study introduces the effect of total float loss and resource control in order to enhance the schedule flexibility and reduce the risk of project delays. Third, the proposed model is capable of operating automatically without any human intervention.