bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term Outcome of Endoscopic and Percutaneous Transhepatic Approaches for Biliary Complications in Liver Transplant Recipients
Authors: Rönning Jesper , Berglund Erik , Arnelo Urban , Ericzon Bo-Göran , Nowak Greg
Published: March 2019

Background

Biliary complications occur in 6% to 34% of liver transplant recipients, for which endoscopic retrograde cholangiopancreatography has become widely accepted as the first-line therapy. We evaluated long-term outcome of biliary complications in patients liver transplanted between 2004 and 2014 at Karolinska University Hospital, Stockholm.

Methods

Data were retrospectively collected, radiological images were analyzed for type of biliary complication, and graft and patient survivals were calculated.

Results

In 110 (18.5%) of 596 transplantations, there were a total of 153 cases of biliary complications: 68 (44.4%) anastomotic strictures, 43 (28.1%) nonanastomotic strictures, 24 (15.7%) bile leaks, 11 (7.2%) cases of stone- and/or sludge-related problems, and 7 (4.6%) cases of mixed biliary complications. Treatment success rates for each complication were 90%, 73%, 100%, 82% and 80%, respectively. When the endoscopic approach was unsatisfactory or failed, percutaneous transhepatic cholangiography or a combination of treatments was often successful (in 18 of 24 cases). No procedure-related mortality was observed. Procedure-related complications were reported in 7.7% of endoscopic retrograde cholangiopancreatography and 3.8% of percutaneous transhepatic cholangiography procedures. Patient survival rates, 1, 3, 5, and 10 years posttransplant in patients with biliary complications were 92.7%, 80%, 74.7%, and 54.1%, respectively, compared with 92%, 86.6%, 83.7%, and 72.8% in patients free from biliary complications (P < 0.01). Similarly, long-term graft survival was lower in the group experiencing biliary complications (P < 0.0001).

Conclusions

Endoscopic and percutaneous approaches for treating biliary complications are safe and efficient and should be considered complementing techniques. Despite a high treatment success rate of biliary complications, their occurrence still has a significant negative impact on patient and graft long-term survivals.
Strengthening Global Efforts to Combat Organ Trafficking and Transplant Tourism: Implications of the 2018 Edition of the Declaration of Istanbul
Authors: Martin Dominique E. , Van Assche Kristof , Domínguez-Gil Beatriz , López-Fraga Marta , García Gallont Rudolf , Muller Elmi , Capron Alexander M.
Published: March 2019

The 2018 Edition of the Declaration of Istanbul on Organ Trafficking and Transplant Tourism (DoI) provides an updated set of principles and definitions to guide policymakers and health professionals working in organ donation and transplantation. A draft of the new edition was circulated to the public and transplant professionals through an online consultation process, which also sought feedback on a draft explanatory article that explained the principles and discussed some of their practical implications. Both drafts were revised in response to feedback from participants in the consultation. We present here the discussion article, which is intended to assist stakeholders in applying the principles of the DoI by providing more detailed information about the meaning and potential implications of implementing the DoI in various contexts.
Significant Hyperfibrinolysis in a Patient With Intracardiac Thrombosis: To Give Antifibrinolytics or Not?
Authors: Simon Eric R. , Darling Christopher D. , Hammel Laura L.
Published: March 2019

The hemostatic system is a delicate balance between the coagulation, anticoagulation, and fibrinolytic systems and is responsible for preventing both hemorrhage and thrombosis. End stage liver disease is characterized by a rebalanced hemostatic system that is fragile and easily tipped towards either hemorrhage or thrombosis. During an orthotopic liver transplantation, patients are exposed to a wide variety of factors that can shift them from a hypercoagulable state to a hypocoagulable state almost instantaneously. The treatment for these two disease states contradict each other, and therefore patients in this condition can be extremely difficult to manage. Here, we present a patient who underwent an orthotopic liver transplantation and suffered an intracardiac thrombosis shortly after reperfusion of the donor graft, that resolved with supportive care, who then went on to develop severe persistent hyperfibrinolysis and massive hemorrhage that was successfully treated with an antifibrinolytic agent.
Retinal Findings in Two Patients With Tumefactive Multiple Sclerosis
Authors: Neuhouser Adam , Sanders Riley , Burks John R. , Chacko Joseph
Published: March 2019

Tumefactive multiple sclerosis (TMS) often presents a diagnostic challenge because it can mimic neoplastic, infectious, or ischemic disease. We describe 2 patients with TMS with retinal findings of venous sheathing and bone spicule pigmentation. Mechanisms for such findings are discussed.
Mash Screen: High-throughput sequence containment estimation for genome discovery
Authors: Ondov Brian D , Starrett Gabriel J , Sappington Anna , Kostic Aleksandra , Koren Sergey , Buck Christopher B , Phillippy Adam M
Published: March 2019

The MinHash algorithm has proven effective for rapidly estimating the resemblance of two genomes or metagenomes. However, this method cannot reliably estimate the containment of a genome within a metagenome. Here we describe an online algorithm capable of measuring the containment of genomes and proteomes within either assembled or unassembled sequencing read sets. We describe several use cases, including contamination screening and retrospective analysis of metagenomes for novel genome discovery. Using this tool, we provide containment estimates for every NCBI RefSeq genome within every SRA metagenome, and demonstrate the identification of a novel polyomavirus species from a public metagenome.
Genetic inhibition ofPCSK9, atherogenic lipoprotein concentrations, and calcific aortic valve stenosis
Authors: Perrot Nicolas , Moschetta Donato , Boekholdt S. Matthijs , Valerio Vincenza , Martinsson Andreas , Capoulade Romain , Mass Elvira , Clavel Marie-Annick , Wareham Nicholas J. , Dina Christian , Chen Hao Yu , Engert James C. , Thanassoulis George , Mathieu Patrick , Bossé Yohan , Pibarot Philippe , Smith J. Gustav , Camera Marina , Thériault Sébastien , Poggio Paolo , Arsenault Benoit J.
Published: March 2019

Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition reduces plasma concentrations of low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB) and lipoprotein(a) [Lp(a)]. Atherogenic lipoprotein levels have been linked with calcific aortic valve stenosis (CAVS). Our objectives were to determine the association between variants inPCSK9and lipoprotein-lipid levels, coronary artery disease (CAD) and CAVS, and to evaluate if PCSK9 could be implicated in aortic valve interstitial cells (VICs) calcification.

Methods

We built a genetic risk score weight for LDL-C levels (wGRS) using 10 independentPCSK9single nucleotide polymorphisms and determined its association with lipoprotein-lipid levels in 9692 participants of the EPIC-Norfolk study. We investigated the association between the wGRS and CAD and CAVS in the UK Biobank, as well as the association between thePCSK9R46L variant and CAVS in a meta-analysis of published prospective, population-based studies (Copenhagen studies, 1463 cases/101,620 controls) and unpublished studies (UK Biobank, 1350 cases/349,043 controls, Malmö Diet and Cancer study, 682 cases/5963 controls and EPIC-Norfolk study, 508 cases/20,421 controls). We evaluated PCSK9 expression and localization in explanted aortic valves by capillary Western blot and immunohistochemistry in patients with and without CAVS. Von Kossa staining was used to visualize aortic leaflet calcium deposits. PCSK9 expression under oxidative stress conditions in VICs was assessed.

Results

The wGRS was significantly associated with lower LDL-C and apoB (p<0.001), but not with Lp(a). In the UK Biobank, the association ofPCSK9variants with CAD were positively correlated with their effects on apoB levels. CAVS was less prevalent in carriers of thePCSK9R46L variant [odds ratio=0.71 (95% confidence interval, 0.57-0.88), p<0.001]. PCSK9 expression was elevated in the aortic valves of patients with aortic sclerosis and CAVS compared to controls. In calcified leaflets, PCSK9 co-localized with calcium deposits. PCSK9 expression was induced by oxidative stress in VICs.

Conclusion

Genetic inhibition ofPCSK9is associated with lifelong reductions in the levels of non-Lp(a) apoB-containing lipoproteins as well as lower odds of CAD and CAVS. PCSK9 is abundant in fibrotic and calcified aortic leaflets. Oxidative stress increases PCSK9 expression in VICs. These results provide a rationale for performing randomized clinical trials of PCSK9 inhibition in CAVS.
Translation enhancement by a Dictyostelium gene sequence in Escherichia coli
Authors: Kondo Tomo , Yumura Shigehiko
Published: March 2019

Methods for heterologous protein production in Escherichia coli have revolutionized biotechnology and the bioindustry. It is ultimately important to increase the amount of protein product from bacteria. To this end, a variety of tools, such as effective promoters, have been developed. Here, we present a versatile molecular tool based on a phenomenon termed “translation enhancement by a Dictyostelium gene sequence” (“TED”) in E. coli. We found that protein expression was increased when a gene sequence of Dictyostelium discoideum was placed upstream of the Shine-Dalgarno sequence located between the promoter and the initiation codon of a target gene. The most effective sequence among the genes examined was mlcR, which encodes the myosin regulatory light chain, a subunit of myosin II. Serial deletion analysis revealed that at least 10 bases of the 3’ end of the mlcR gene enhanced the production of green fluorescent protein in cells. We applied this tool to a T7 expression system and found that the expression level of the proteins tested was increased when compared with the conventional method. Thus, current protein production systems can be improved by combination with TED.
Antibiotic resistome and microbial community structure during anaerobic co-digestion of food waste, paper and cardboard
Authors: Kanger Kärt , Guilford Nigel G.H. , Lee HyunWoo , Nesbø Camilla L. , Truu Jaak , Edwards Elizabeth A.
Published: March 2019

Antimicrobial resistance is a globally recognized public health risk. High incidence of antibiotic resistant bacteria and antibiotic resistance genes (ARGs) in solid organic waste necessitates the development of effective treatment strategies. The objective of this study was to assess ARG diversity and abundance as well as the relationship between resistome and microbial community structure during anaerobic co-digestion (AD) of food waste, paper and cardboard. A lab-scale solid-state AD system consisting of six sequentially fed leach beds (each with a solids retention time of 42 days) and an upflow anaerobic sludge blanket (UASB) reactor was operated under mesophilic conditions continuously for 88 weeks to successfully treat municipal organic waste and produce biogas. A total of ten samples from digester feed and digestion products were collected for microbial community analysis including SSU rRNA gene sequencing, total community metagenome sequencing and quantitative PCR. Taxonomic analyses revealed that AD changed the taxonomic profile of the microbial community: digester feed was dominated by bacterial and eukaryotic taxa while anaerobic digestate possessed a large proportion of archaea mainly belonging to the methanogenic genusMethanosaeta. ARGs were identified in all samples with significantly higher richness and relative abundance per 16S rRNA gene in digester feed compared to digestion products. Multidrug resistance was the most abundant ARG type. AD was not able to completely remove ARGs as shown by ARGs detected in digestion products. Using metagenomic assembly and binning we detected potential bacterial hosts of ARGs in digester feed, that includedErwinia, Bifidobacteriaceae, Lactococcus lactisandLactobacillus.

IMPORTANCE

Solid organic waste is a significant source of antibiotic resistance genes (ARGs) (1) and effective treatment strategies are urgently required to limit the spread of antimicrobial resistance. Here we studied the antibiotic resistome and microbial community structure within an anaerobic digester treating a mixture of food waste, paper and cardboard. We observed a significant shift in microbial community composition and a reduction in ARG diversity and abundance after 6 weeks of digestion. We identified the host organisms of some of the ARGs including potentially pathogenic as well as non-pathogenic bacteria, and we detected mobile genetic elements required for horizontal gene transfer. Our results indicate that the process of sequential solid-state anaerobic digestion of food waste, paper and cardboard tested herein provides a significant reduction in the relative abundance of ARGs per 16S rRNA gene.
A single dose of dietary nitrate increases maximal muscle speed and power in healthy older men and women
Authors: Coggan Andrew R. , Hoffman Richard L. , Gray Derrick A. , Moorthi Ranjani N. , Thomas Deepak P. , Leibowitz Joshua L. , Thies Dakkota , Peterson Linda R.
Published: March 2019

Background

Aging results in reductions in maximal muscular strength, speed, and power, which often lead to functional limitations highly predictive of disability, institutionalization, and mortality in the elderly. This may be partially due to reduced nitric oxide (NO) bioavailability. We therefore hypothesized that dietary nitrate (NO3−), a source of NO via the NO3− → nitrite (NO2−) → NO enterosalivary pathway, could increase muscle contractile function in older subjects.

Methods

Twelve healthy older (age 71±1 y) subjects were studied using a randomized, doubleblind, placebo-controlled, crossover design. After fasting overnight, subjects were tested 2 h after ingesting beetroot juice containing or devoid of 13.4±0.5 mmol NO3−. Plasma NO3− and NO2− and breath NO were measured periodically, and muscle function was determined using isokinetic dynamometry.

Results

NO3− ingestion increased (P<0.001) plasma NO3−, plasma NO2−, and breath NO by 1050%, 140%, and 110%, respectively. Maximal velocity of knee extension increased (P<0.01) by 1.1±0.3 rad/s, or by 10.9±3.5%. Maximal knee extensor power increased (P<0.05) by 0.14±0.06 W/kg, or by 4.4±2.3%.

Conclusions

Acute dietary NO3− intake improves muscle contractility in older individuals. These findings have important implications for this population, in whom diminished muscle function can lead to functional limitations, dependence, and even premature death.
Scans of the MYC mRNA reveal multiple stable secondary structures—including a 3′ UTR motif, conserved across vertebrates, that can affect gene expression
Authors: O’Leary Collin A. , Andrews Ryan J. , Tompkins Van S. , Chen Jonathan L. , Childs-Disney Jessica L. , Disney Matthew D. , Moss Walter N.
Published: March 2019

The MYC gene encodes a human transcription factor and proto-oncogene that is dysregulated in over half of all known cancers. To better understand potential post-transcriptional regulatory features affecting MYC expression, we analyzed secondary structure in the MYC mRNA using a program that is optimized for finding small locally-folded motifs with a high propensity for function. This was accomplished by calculating folding metrics across the MYC sequence using a sliding analysis window and generating unique consensus base pairing models weighted by their lower-than-random predicted folding energy. A series of 30 motifs were identified, primarily in the 5’ and 3’ untranslated regions, which show evidence of structural conservation and compensating mutations across vertebrate MYC homologs. This analysis was able to recapitulate known elements found within an internal ribosomal entry site, as well as discover a novel element in the 3’ UTR that is unusually stable and conserved. This novel motif was shown to affect MYC expression: likely via modulation of miRNA target accessibility. In addition to providing basic insights into mechanisms that regulate MYC expression, this study provides numerous, potentially druggable RNA targets for the MYC gene, which is considered “undruggable” at the protein level.
The DNA-binding protein HTa fromThermoplasma acidophilumis an archaeal histone analog
Authors: Hocher Antoine , Rojec Maria , Swadling Jacob B. , Esin Alexander , Warnecke Tobias
Published: March 2019

Histones are a principal constituent of chromatin in eukaryotes and fundamental to our understanding of eukaryotic gene regulation. In archaea, histones are phylogenetically widespread, often highly abundant, but not universal: several archaeal lineages have lost histone genes from their coding repertoire. What prompted or facilitated these losses and how archaea without histones organize their chromatin remains largely unknown. Here, we use micrococcal nuclease digestion followed by high-throughput sequencing (MNase-Seq) to elucidate primary chromatin architecture in an archaeon without histones, the acido-thermophilic archaeonThermoplasma acidophilum. We confirm and extend prior results showing thatT. acidophilumharbours a HU family protein, HTa, that is highly expressed and protects a sizeable fraction of the genome from MNase digestion. Charting HTa-based chromatin architecture across the growth cycle and comparing it to that of three histone-encoding archaea (Methanothermus fervidus, Thermococcus kodakarensisandHaloferax volcanii), we then present evidence that HTa is an archaeal histone analog. HTa-protected fragments are GC-rich, display histone-like mono- and dinucleotide patterns around a conspicuous dyad, exhibit relatively invariant positioning throughout the growth cycle, and show archaeal histone-like oligomerization dynamics. Our results suggest that HTa, a DNA-binding protein of bacterial origin, has converged onto an architectural role filled by histones in other archaea.
A nematode-specific gene underlies bleomycin-response variation inCaenorhabditis elegans
Authors: Brady Shannon C. , Zdraljevic Stefan , Bisaga Karol W. , Tanny Robyn E. , Cook Daniel E. , Lee Daehan , Wang Ye , Andersen Erik C.
Published: March 2019

Bleomycin is a powerful chemotherapeutic drug used to treat a variety of cancers. However, individual patients vary in their responses to bleomycin. The identification of genetic differences that underlie this response variation could improve treatment outcomes by tailoring bleomycin dosages to each patient. We used the model organismCaenorhabditis elegansto identify genetic determinants of bleomycin-response differences by performing linkage mapping on recombinants derived from a cross between the laboratory strain (N2) and a wild strain (CB4856). This approach identified a small genomic region on chromosome V that underlies bleomycin-response variation. Using near-isogenic lines and strains with CRISPR-Cas9 mediated deletions and allele replacements, we discovered that a novel nematode-specific gene (scb-1) is required for bleomycin resistance. Although the mechanism by which this gene causes variation in bleomycin responses is unknown, we suggest that a rare variant present in the CB4856 strain might cause differences in the potential stress-response function ofscb-1between the N2 and CB4856 strains, thereby leading to differences in bleomycin resistance.
Sphingomyelin is critical in organizing phosphoinositide dynamics during phagocytic uptake of Mycobacterium tuberculosis
Authors: Niekamp Patrick , Guzman Gaelen , Leier Hans , Rashidfarrokhi Ali , Richina Veronica , Holthius Joost , Tafesse Fikadu G.
Published: March 2019

Tuberculosis, the pathological result of infection by Mycobacterium tuberculosis (M.tb), represents a massive and persistent global health burden with vast overrepresentation in regions with poor access to healthcare. This pathogen survives intracellularly within lung macrophages, and has been shown to extensively reprogram the host lipid compartment to the effect of enhanced survival and immune evasion. Sphingolipids are a class of lipid with extensive functions in a wide variety of cellular contexts, including apoptosis, autophagy, stress response, and inflammation. There remains a significant knowledge gap surrounding the lipid-mediated interactions between M.tb and its host. Our investigation aims to explore the mechanisms through which M.tb harnesses host-derived sphingolipids to gain entry to the host and to survive intracellularly. To this end, we use chemical and genetic perturbations of the sphingolipid de novo synthesis pathway and fluorescence microscopy to show that sphingolipids are required for efficient phagocytosis of M.tb. We furthermore show that the dynamics of phosphoinositides at the phagosomal synapse are perturbed upon blockade of sphingolipid synthesis. Finally, we demonstrate that perturbing the homeostasis of a specific sphingolipid (sphingomyelin) through both enrichment and depletion at the cell surface reduces M.tb uptake. This work represents a first step in building comprehensive knowledge of the mechanisms of host-pathogen interactions in M.tb, and demonstrates a cohort of methodologies that may be applied to a variety of pathogenic contexts.
New transcriptional circuit evolved by coding sequence changes in a master regulator followed by cis-regulatory changes in its target genes
Authors: Britton Candace S. , Sorrells Trevor R. , Johnson Alexander D.
Published: March 2019

While changes in both the coding-sequence of transcriptional regulators and in the cis-regulatory sequences recognized by them have been implicated in the evolution of transcriptional circuits, little is known of how they evolve in concert. We describe an evolutionary pathway in fungi where a new transcriptional circuit (a-specific gene repression by Matα2) evolved by coding changes in an ancient master regulator, followed millions of years later by cis-regulatory sequence changes in the genes of its future regulon. We discerned this order of events by analyzing a group of species in which the coding changes in the regulator are present, but the cis-regulatory changes in the target genes are not. In this group we show that the coding changes became necessary for the regulator’s deeply conserved function and were therefore preserved. We propose that the changes first arose without altering the overall function of the regulator (although changing the details of its mechanism) and were later co-opted to “jump start” the formation of the new circuit.
Consequences of recombination for the evolution of the mating type locus inChlamydomonas reinhardtii
Authors: Hasan Ahmed R. , Duggal Jaspreet K. , Ness Rob W.
Published: March 2019

Rationale

Recombination suppression in sex chromosomes and mating type loci can lead to degeneration due to reduced selection efficacy and Muller’s ratchet effects. However, genetic exchange in the form of non-crossover gene conversions may still take place within crossover-suppressed regions. Recent work has found evidence that gene conversion may explain the low levels of allelic differentiation in the dimorphic mating type locus (MT) of the isogamous algaChlamydomonas reinhardtii. However, no one has tested whether gene conversion is sufficient to avoid the degeneration of functional sequence withinMT.

Methods

Here, we calculate levels of linkage disequilibrium (LD) acrossMTas a proxy for recombination rate and investigate its relationship to patterns of population genetic variation and the efficacy of selection in the region.

Results

We find that levels of LD predict selection efficacy acrossMT, and that purifying selection is stronger in shared genes thanMT-limited genes to the point of being equivalent to that of autosomal genes.

Conclusions

We argue that isogamous systems without secondary sexual characteristics exhibit reduced selective pressure to differentiate sex chromosomes, and that recombination via gene conversion plays an important role in both reducing differentiation and preventing degeneration of crossover suppressed mating type loci.
Short-term depression and long-term plasticity together tune sensitive range of synaptic plasticity
Authors: Deperrois Nicolas , Graupner Michael
Published: March 2019

Synaptic efficacy is subjected to activity-dependent changes on short- and long time scales. While short-term changes decay over minutes, long-term modifications last from hours up to a lifetime and are thought to constitute the basis of learning and memory. Both plasticity mechanisms have been studied extensively but how their interaction shapes synaptic dynamics is little known. To investigate how both short- and long-term plasticity together control the induction of synaptic depression and potentiation, we used numerical simulations and mathematical analysis of a calcium-based model, where pre- and postsynaptic activity induces calcium transients driving synaptic long-term plasticity. We found that the model implementing known synaptic short-term dynamics in the calcium transients can be successfully fitted to long-term plasticity data obtained in visual- and somatosensory cortex. Interestingly, the impact of spike-timing and firing rate changes on plasticity occurs in the prevalent firing rate range, which is different in both cortical areas considered here. Our findings suggest that short- and long-term plasticity are together tuned to adapt plasticity to area-specific activity statistics such as firing rates.

Author summary

Synaptic long-term plasticity, the long-lasting change in efficacy of connections between neurons, is believed to underlie learning and memory. Synapses furthermore change their efficacy reversibly in an activity-dependent manner on the subsecond time scale, referred to as short-term plasticity. It is not known how both synaptic plasticity mechanisms – long- and short-term – interact during activity epochs. To address this question, we used a biologically-inspired plasticity model in which calcium drives changes in synaptic efficacy. We applied the model to plasticity data from visual- and somatosensory cortex and found that synaptic changes occur in very different firing rate ranges, which correspond to the prevalent firing rates in both structures. Our results suggest that short- and long-term plasticity act in a well concerted fashion.
Molecular Phenotyping of Oxidative Stress in Diabetes Mellitus with Point-of-care NMR system
Authors: Peng Weng Kung , Chen Lan , Boehm Bernhard O , Han Jongyoon , Loh Tze Ping
Published: March 2019

Diabetes mellitus is one of the fastest growing health burdens globally. Oxidative stress which has been implicated to the pathogenesis of diabetes complication (e.g., cardiovascular event) were, however, poorly understood. We report a novel approach to rapidly manipulate the redox chemistry (in a single drop) of blood using point-of-care NMR system. We exploit the fact that oxidative stress changes the subtle molecular motion of water-proton in the blood, and thus inducing a measurable shift in magnetic resonance relaxation properties. This technique is label-free and the whole assays finish in a few minutes. Various redox states of the hemoglobin were mapped out using our newly proposed two-dimensional map, known as T1-T2magnetic state diagram. We demonstrated the clinical utilities of this technique to rapidly sub-stratify diabetes subjects based on their oxidative status (in conjunction to the traditional glycemic level), to improve the patient risk stratification and thus the overall outcome of clinical diabetes care and management. (155 words)

Key Points for Summaries

A novel approach to rapidly manipulate the redox chemistry (in a single drop) of blood using point-of-care NMR system.

Assessment of the oxidative status, in conjunction to their glycemic level allows sub-stratification of diabetes subjects which was demonstrated clinically.

Visual Abstract
The size of the immune repertoire of bacteria
Authors: Bradde Serena , Nourmohammad Armita , Goyal Sidhartha , Balasubramanian Vijay
Published: March 2019

Some bacteria and archaea possess an immune system, based on the CRISPR-Cas mechanism, that confers adaptive immunity against phage. In such species, individual bacteria maintain a “cassette” of viral DNA elements called spacers as a memory of past infections. The typical cassette contains a few dozen spacers. Given that bacteria can have very large genomes, and since having more spacers should confer a better memory, it is puzzling that so little genetic space would be devoted by bacteria to their adaptive immune system. Here, we identify a fundamental trade-off between the size of the bacterial immune repertoire and effectiveness of response to a given threat, and show how this tradeoff imposes a limit on the optimal size of the CRISPR cassette.
Robust Determination of Protein Allosteric Signaling Pathways
Authors: Botello-Smith Wesley M. , Luo Yun
Published: March 2019

To understand how protein function changes upon an allosteric perturbation, such as ligand binding and mutation, significant progress in characterizing allosteric network from molecular dynamics (MD) simulations has been made. However, determining which amino acid(s) play an essential role in the propagation of signals may prove challenging, even when the location of the source and sink is known for a protein or protein complex. This challenge is mainly due to the large fluctuations in protein dynamics that cause instability of the network topology within a single trajectory or between multiple replicas. To solve this problem, we introduce the current-flow betweenness scheme, originated from electrical network theory, to protein dynamical network analysis. To demonstrate the benefit of this new method, we chose a prototypic allosteric enzyme (IGPS or HisH-HisF dimer) as our benchmark system. Using multiple replicas of simulations and multiple network topology comparison metrics (edge ranking, path length, and node frequency), we show that the current-flow betweenness provides a significant improvement in the convergence of the allosteric networks. The improved stability of the network topology allows us to generate a delta-network between the apo and holo forms of the protein. We illustrated that the delta-network is a more rigorous way to capture the subtle changes in the networks that would otherwise be neglected by comparing node usage frequencies alone. We have also investigated the use of a linear smoothing function to improve the stability of the contact map. The methodology presented here is general and may be applied to other topology and weighting schemes. We thus conclude that, for determining protein signaling pathways between the pair(s) of source and sink, multiple MD simulation replicas are necessary and the current-flow betweenness scheme introduced here provides a more robust approach than the geodesic scheme based on correlation edge weighting.

For Table of Contents Only
Advancing Computational Biology and Bioinformatics Research Through Open Innovation Competitions
Authors: Blasco Andrea , Endres Michael G. , Sergeev Rinat A. , Jonchhe Anup , Macaluso Max , Narayan Rajiv , Natoli Ted , Paik Jin H. , Briney Bryan , Wu Chunlei , Su Andrew I. , Subramanian Aravind , Lakhani Karim R.
Published: March 2019

Open data science and algorithm development competitions offer a unique avenue for rapid discovery of better computational strategies. We highlight three examples in computational biology and bioinformatics research where the use of competitions has yielded significant performance gains over established algorithms. These include algorithms for antibody clustering, imputing gene expression data, and querying the Connectivity Map (CMap). Performance gains are evaluated quantitatively using realistic, albeit sanitized, data sets. The solutions produced through these competitions are then examined with respect to their utility and the prospects for implementation in the field. We present the decision process and competition design considerations that lead to these successful outcomes as a model for researchers who want to use competitions and non-domain crowds as collaborators to further their research.
A Mathematical Model for the Immune-Mediated Theory of Metastasis
Authors: Rhodes Adam , Hillen Thomas
Published: March 2019

Accumulating experimental and clinical evidence suggest that the immune response to cancer is not exclusively anti-tumor. Indeed, the pro-tumor roles of the immune system — as suppliers of growth and pro-angiogenic factors or defenses against cytotoxic immune attacks, for example — have been long appreciated, but relatively few theoretical works have considered their effects. Inspired by the recently proposed “immune-mediated” theory of metastasis, we develop a mathematical model for tumor-immune interactions at two anatomically distant sites, which includes both anti-and pro-tumor immune effects, and the experimentally observed tumor-induced phenotypic plasticity of immune cells (tumor “education” of the immune cells). Upon confrontation of our model to experimental data, we use it to evaluate the implications of the immune-mediated theory of metastasis. We find that tumor education of immune cells may explain the relatively poor performance of immunotherapies, and that many metastatic phenomena, including metastatic blow-up, dormancy, and metastasis to sites of injury, can be explained by the immune-mediated theory of metastasis. Our results suggest that further work is warranted to fully elucidate the protumor effects of the immune system in metastatic cancer.
Low-dose antibiotics can collapse gut bacterial populations via a gelation transition
Authors: Schlomann Brandon H. , Wiles Travis J. , Wall Elena S. , Guillemin Karen , Parthasarathy Raghuveer
Published: March 2019

Antibiotics can profoundly alter the intestinal microbiome even at the sublethal concentrations often encountered through environmental contamination. The mechanisms by which low-dose antibiotics induce large yet highly variable changes in gut communities have remained elusive. We therefore investigated the impact of antibiotics on intestinal bacteria using larval zebrafish, whose experimental tractability enables high-resolution in vivo examination of response dynamics. Live imaging revealed that sublethal doses of the common antibiotic ciprofloxacin lead to severe drops in bacterial abundance, coincident with changes in spatial organization that increase susceptibility to intestinal expulsion. Strikingly, our data can be mapped onto a physical model of living gels that links bacterial aggregation and expulsion to nonequilibrium abundance dynamics, providing a framework for predicting the impact of antibiotics on the intestinal microbiome.
Trophy hunting mediates sex‐specific associations between early‐life environmental conditions and adult mortality in bighorn sheep
Authors: Douhard Mathieu , Festa‐Bianchet Marco , Landes Julie , Pelletier Fanie
Published: March 2019

Environmental conditions during early development, from conception to sexual maturity, can have lasting consequences on fitness components. Although adult life span often accounts for much of the variation in fitness in long‐lived animals, we know little about how early environment affects adult life span in the wild, and even less about whether these effects differ between the sexes.

Using data collected over 45 years from wild bighorn sheep (Ovis canadensis), we investigated the effects of early environment on adult mortality in both sexes, distinguishing between natural and anthropogenic sources of mortality.

We used the average body mass of yearlings (at about 15 months of age) as a yearly index of environmental quality. We first examined sex differences in natural mortality responses to early environment by censoring harvested males in the year they were shot. We then investigated sex differences in the effects of early environment on overall mortality (natural and hunting mortality combined). Finally, we used path analysis to separate the direct influence of early environment from indirect influences, mediated by age at first reproduction, adult mass and horn length.

As early environmental conditions improved, natural adult mortality decreased in both sexes, although for males the effect was not statistically supported. Sex differences in the effects of early environment on adult mortality were detected only when natural and hunting mortality were pooled. Males that experienced favourable early environment had longer horns as adults and died earlier because of trophy hunting, which does not mimic natural mortality. Females that experienced favourable early environment started to reproduce earlier and early primiparity was associated with reduced mortality, suggesting a silver‐spoon effect.

Our results show that early conditions affect males and females differently because of trophy hunting. These findings highlight the importance of considering natural and anthropogenic environmental factors across different life stages to understand sex differences in mortality.
Determinants of elephant foraging behaviour in a coupled human‐natural system: Is brown the new green?
Authors: Branco Paola S. , Merkle Jerod A. , Pringle Robert M. , Pansu Johan , Potter Arjun B. , Reynolds Alana , Stalmans Marc , Long Ryan A.
Published: March 2019

Crop raiding by wildlife poses major threats to both wildlife conservation and human well‐being in agroecosystems worldwide. These threats are particularly acute in many parts of Africa, where crop raiders include globally threatened megafauna such as elephants, and where smallholder agriculture is a primary source of human livelihood. One framework for understanding herbivore feeding behaviour, the forage‐maturation hypothesis, predicts that herbivores should align their movements with intermediate forage biomass (i.e., peak green‐up); this phenomenon is known as “surfing the green wave.” Crop‐raiding elephants, however, often consume not just foliage, but also fruits and tubers (e.g., maize and potatoes), which generally mature after seasonal peaks in photosynthetic activity. Thus, although elephants have been reported to surf the green wave in natural habitats, they may utilize a different strategy in cultivated landscapes by selecting crops that are “browning down.”

We sought to understand the factors that underpin movement of elephants into agricultural landscapes.

In Mozambique's Gorongosa National Park, we used movement data from GPS‐collared elephants, together with precipitation records, remotely sensed estimates of landscape greenness (NDVI), DNA‐based diet analysis, measurements of plant nutritional quality and survey‐based metrics of crop availability to understand spatiotemporal variation in elephant crop‐raiding behaviour.

Elephants tracked peak NDVI while foraging inside the Park. During the dry season, however, when NDVI within the Park declined and availability of mature crops was high, crop raiding increased dramatically, and elephants consistently selected crop plants that were browning down while foraging in cultivated landscapes. Crops contained significantly higher digestible energy than wild food plants, but comparable (and sometimes lower) levels of digestible protein, suggesting that this foraging strategy maximized energy rather than protein intake.

Our study is the first to combine GPS tracking data with high‐resolution diet analysis and community‐based reporting of crop availability to reveal fine‐scale plasticity in foraging behaviour of elephants at the human–wildlife interface. Our results extend the forage‐maturation hypothesis by showing that elephants surf waves of plant brown‐down in cultivated landscapes. These findings can aid efforts to reduce human–elephant conflict by enabling wildlife managers to prioritize mitigation actions in time and space with limited resources.
Modelling multi‐species and multi‐mode contact networks: Implications for persistence of bovine tuberculosis at the wildlife–livestock interface
Authors: Wilber Mark Q. , Pepin Kim M. , Campa Henry , Hygnstrom Scott E. , Lavelle Michael J. , Xifara Tatiana , VerCauteren Kurt C. , Webb Colleen T.
Published: March 2019

Individual‐ and species‐level heterogeneity in contact rates can alter the ability of a pathogen to invade a host community. Many pathogens have multiple modes of transmission—by direct or indirect contact. It is important to identify the role of heterogeneity in different types of transmission when managing the risk of disease spillover at the interface among different host species.

We developed a network‐based analysis to explore how individual‐ and species‐level heterogeneity shape multi‐mode contact networks. We applied this network‐based approach to contact data from proximity loggers collected in a multi‐species host community that contributes to the spillover of the disease bovine tuberculosis (bTB) to cattle populations in Michigan, USA. We used this approach to (a) quantify how individual‐ and species‐level heterogeneity influence direct and indirect contacts in this system, (b) explore how management interventions to control spillovers, such as the installation of deer fences, can alter observed contact networks and c) predict the role that wildlife species have in maintaining bTB in the community.

We found that individual‐ and species‐level heterogeneity disproportionately influenced indirect and direct contact networks, with individual‐level heterogeneity having a greater effect on indirect contact networks and species‐level heterogeneity having a greater effect on direct contact networks. We also found that the installation of deer fences significantly reduced deer‐specific indirect contacts. We used the results from our network analysis to show that white‐tailed deer (Odocoileus virginianus) could act as the sole reservoir host for bTB in this community with important implications for understanding past bTB dynamics and managing the persistence of bTB in the future.

Synthesis and applications. Analyses of epidemiological networks rarely account for multiple modes of contact, which can lead to an incomplete understanding of how individual‐ and species‐level heterogeneity affect disease transmission. The multi‐mode, multi‐species network analysis we develop in this study illustrates that individual‐ and species‐level heterogeneity can play significantly different roles depending on the type of contact network considered. This has important implications when managing disease at the wildlife–livestock interface, where strategies may need to be multi‐pronged to account for the variable role of heterogeneity on different modes of contact.
Relationships between plant traits, soil properties and carbon fluxes differ between monocultures and mixed communities in temperate grassland
Authors: De Long Jonathan R. , Jackson Benjamin G. , Wilkinson Anna , Pritchard William J. , Oakley Simon , Mason Kelly E. , Stephan Jörg G. , Ostle Nicholas J. , Johnson David , Baggs Elizabeth M. , Bardgett Richard D.
Published: March 2019

The use of plant traits to predict ecosystem functions has been gaining growing attention. Above‐ground plant traits, such as leaf nitrogen (N) content and specific leaf area (SLA), have been shown to strongly relate to ecosystem productivity, respiration and nutrient cycling. Furthermore, increasing plant functional trait diversity has been suggested as a possible mechanism to increase ecosystem carbon (C) storage. However, it is uncertain whether below‐ground plant traits can be predicted by above‐ground traits, and if both above‐ and below‐ground traits can be used to predict soil properties and ecosystem‐level functions.

Here, we used two adjacent field experiments in temperate grassland to investigate if above‐ and below‐ground plant traits are related, and whether relationships between plant traits, soil properties and ecosystem C fluxes (i.e. ecosystem respiration and net ecosystem exchange) measured in potted monocultures could be detected in mixed field communities.

We found that certain shoot traits (e.g. shoot N and C, and leaf dry matter content) were related to root traits (e.g. root N, root C:N and root dry matter content) in monocultures, but such relationships were either weak or not detected in mixed communities. Some relationships between plant traits (i.e. shoot N, root N and/or shoot C:N) and soil properties (i.e. inorganic N availability and microbial community structure) were similar in monocultures and mixed communities, but they were more strongly linked to shoot traits in monocultures and root traits in mixed communities. Structural equation modelling showed that above‐ and below‐ground traits and soil properties improved predictions of ecosystem C fluxes in monocultures, but not in mixed communities on the basis of community‐weighted mean traits.

Synthesis. Our results from a single grassland habitat detected relationships in monocultures between above‐ and below‐ground plant traits, and between plant traits, soil properties and ecosystem C fluxes. However, these relationships were generally weaker or different in mixed communities. Our results demonstrate that while plant traits can be used to predict certain soil properties and ecosystem functions in monocultures, they are less effective for predicting how changes in plant species composition influence ecosystem functions in mixed communities.
The relationship of woody plant size and leaf nutrient content to large‐scale productivity for forests across the Americas
Authors: Šímová Irena , Sandel Brody , Enquist Brian J. , Michaletz Sean T. , Kattge Jens , Violle Cyrille , McGill Brian J. , Blonder Benjamin , Engemann Kristine , Peet Robert K. , Wiser Susan K. , Morueta‐Holme Naia , Boyle Brad , Kraft Nathan J. B. , Svenning Jens‐Christian
Published: March 2019

Ecosystem processes are driven by both environmental variables and the attributes of component species. The extent to which these effects are independent and/or dependent upon each other has remained unclear. We assess the extent to which climate affects net primary productivity (NPP) both directly and indirectly via its effect on plant size and leaf functional traits.

Using species occurrences and functional trait databases for North and South America, we describe the upper limit of woody plant height within 200 × 200 km grid‐cells. In addition to maximum tree height, we quantify grid‐cell means of three leaf traits (specific leaf area, and leaf nitrogen and phosphorus concentration) also hypothesized to influence productivity. Using structural equation modelling, we test the direct and indirect effects of environment and plant traits on remotely sensed MODIS‐derived estimates of NPP, using plant size (satellite‐measured canopy height and potential maximum tree height), leaf traits, growing season length, soil nutrients, climate and disturbances as explanatory variables.

Our results show that climate affects NPP directly as well as indirectly via plant size in both tropical and temperate forests. In tropical forests NPP further increases with leaf phosphorus concentration, whereas in temperate forests it increases with leaf nitrogen concentration. In boreal forests, NPP most strongly increases with increasing temperature and neither plant size nor leaf traits have a significant influence.

Synthesis. Our results suggest that at large spatial scales plant size and leaf nutrient traits can improve predictions of forest productivity over those based on climate alone. However, at higher latitudes their role is overridden by stressful climate. Our results provide independent empirical evidence for where and how global vegetation models predicting carbon fluxes could benefit from including effects of plant size and leaf stoichiometry.