bluuebunny/crossref_metadata_2025 huggingface dataset:
Mesoscopic coarse-grained representations of fluids rigorously derived from atomistic models
Authors: Han Yining , Dama James F. , Voth Gregory A.
Published: July 2018

Mesoscopic models are widely used to study complex organization and transport phenomena in chemical and biological systems. Defining a rigorous procedure by which a mesoscopic coarse-grained (CG) representation for a fluid can be constructed from an atomistic fine-grained (FG) model is a long-standing question in the field. The connection of these CG models with the FG level of description, which might be built by CG mappings from the FG model, is often unclear. The present paper introduces a new CG mapping scheme that uses dynamically self-consistent smooth centroidal Voronoi tessellation to address this challenging problem. The new mapping scheme is applied to the coarse-graining of supercritical Lennard-Jones fluid systems at different CG resolutions under both quiescent conditions and non-equilibrium shear flow. The method generates continuous, stable, and ergodic CG trajectories and quantitatively captures the slow collective motions of the underlying FG fluids. A parameterization of the CG models from the mapped CG trajectory is then developed based on the Mori-Zwanzig formalism. The Generalized Langevin Equation describes the dynamics of CG variables, and the parameterized result is shown to reproduce the structural and dynamical correlations of the CG system. The new dynamical mapping scheme and the parameterization protocol open up an avenue for direct bottom-up construction of mesoscopic models of fluids in a Lagrangian description.
Compressibility and fractal dimension analysis in the bituminous coal specimens
Authors: Zhang Bo , Zhu Jie , He Fa , Jiang Yaodong
Published: July 2018

Coal is the typical multi-pore media. Numerous experiments have been done to investigate the pore structure of coal. Mercury intrusion porosimetry is still a popular way to analyze the pore characteristics. Compressibility effect on the mercury intrusion porosimetry data cannot be ignored. So N2 adsorption (NA) and mercury intrusion porosimetry (MIP) were applied to analyze the pore structure of coal. In this paper, the mercury intrusion process was divided into three stages including interpore filling, large intrapore filling, and small intrapore filling. The fractal analysis is an important mathematical method, which is widely used to evaluate heterogeneity in the size-dependent distribution of porosity. The fractal characteristics of pore structures in four coal samples with the same rank were also investigated. Three pore fractal dimensions corresponding to the three stages of mercury intrusion, D1C, D2C, and D3C were calculated with the Brooks–Corey capillary pressure model. Df calculated with Farin model is used to estimate an overall fractal dimension. The correlation between the pore fractal dimension and the pore size distribution (PSD) characteristics was further discussed.
CMOS compatible low-power volatile atomic switch for steep-slope FET devices
Authors: Lim Seokjae , Yoo Jongmyung , Song Jeonghwan , Woo Jiyong , Park Jaehyuk , Hwang Hyunsang
Published: July 2018

In this paper, we demonstrate a volatile atomic switch that can be utilized for obtaining steep subthreshold swing (SS) (<5 mV/dec) characteristics in FETs. We propose a CMOS-compatible atomic switch (W/Cu2S/W) that demonstrates volatility and immunity to the voltage–time dilemma. Furthermore, we enhance the device characteristics by examining the composition control, scaling of device size, and film thickness. Then, the atomic switch is integrated with a conventional transistor that has a large SS (>60 mV/dec). The result shows an improvement in the SS, which results from the transition of the atomic switch between the ON and OFF states, which is caused by the formation and rupture of a conductive filament. As a result, excellent switching characteristics are obtained for the FETs, such as low IOFF (∼10−5 μA/μm), high ION/IOFF ratio (∼105), low VDD (∼0.25 V), and steep SS (<5 mV/dec).
Reverse-martensitic hcp-to-fcc transformation in technetium under shock compression
Authors: Kim Eunja , Weck Philippe F. , Mattsson Thomas R.
Published: July 2018

The equation of state and principal shock Hugoniot of the elemental technetium to 285 GPa were predicted from ab initio molecular dynamics simulations using Erpenbeck's approach based on the Rankine-Hugoniot jump conditions. The phase space was sampled by carrying out NVT simulations for isotherms between 300 and 4500 K and densities ranging from ρ ≃ 11.4 to 16.7 g/cm3. A temperature-driven hcp → fcc reverse-martensitic phase transformation is predicted to occur at T ≃ 2800 K in Tc bulk subjected to shock loading. The results from dynamic compression were compared to recent diamond-anvil-cell hydrostatic compression data and cold-curve predictions using the density functional theory. The melting curve of Tc is predicted from Lindemann's criterion.
The calculations of thermophysical properties of low-temperature carbon plasma
Authors: Apfelbaum E. M.
Published: July 2018

The thermophysical properties (pressure, internal energy, conductivity, thermal conductivity, and thermal power) and the chemical composition have been calculated for carbon plasma at temperatures of 10–100 kK and densities less than 1 g/cm3. The used calculation model has been developed on the basis of the chemical approach and relaxation time approximation. The approximations used in the present model are valid under considered conditions. The plasma composition obtained in the present model is in good agreement with the available data of other researches.
Additive polarizabilities of halides in ionic liquids and organic solvents
Authors: Heid Esther , Heindl Moritz , Dienstl Patricia , Schröder Christian
Published: July 2018

The design of room-temperature ionic liquids featuring high refractive indices is desirable for a number of applications. Introducing strongly polarizable (poly)halides as anions is a promising route to increase the polarizability of an ionic liquid and thus the refractive index. Based on the experimental refractive indices and mass densities of imidazolium ionic liquids, additive atomic polarizabilities and volumes for chlorine, bromine, and iodine are determined. In addition, atomic polarizabilities and volumes for halide atoms in organic solvents are calculated and compared to ionic liquids. We find that especially iodine behaves differently in anions than in neutral or cationic species. A quantum-mechanical calculation of molecular and atomic polarizabilities complements and enhances the designed regression analysis. The gained insights into halide polarizability and volume are deployed to predict the refractive index of arbitrary ionic liquids.
Scandium-organic frameworks: progress and prospects
Authors: Barsukova Marina O. , Sapchenko Sergey A. , Dybtsev Danil N. , Fedin Vladimir P.
Published: July 2018

Metal-organic frameworks (MOFs) represent a class of crystalline coordination compounds with periodic structures composed of metal cations or clusters connected by organic linkers. In recent years, increasing interest has been attracted to the synthesis and study of MOFs based on oxophilic cations of early transition metals, first of all, ZrIV, HfIV, TiIV and ScIII, and also main group AlIII cations. The carboxylate complexes of these metals possess high stability, which ensures the chemical robustness of the corresponding coordination polymers. The MOFs based on scandium (III) and oxygen-containing ligands are promising for the design of porous materials possessing high specific surface areas, high hydrolytic and thermal stabilities of the coordination framework and diverse functional properties. This review addresses the chemistry of metal-organic frameworks based on scandium (III). Published data on the synthesis and crystal structure characterization of scandium-containing coordination polymers available before 2018 are discussed. The properties of these compounds are considered.

The bibliography includes 101 references
Impacts of windbreak shelter on crop and livestock production
Authors: Baker T. P. , Moroni M. T. , Mendham D. S. , Smith R. , Hunt M. A.
Published: July 2018

Agroforestry (the integration of trees into agricultural landscapes) has been promoted, in Australia and elsewhere, as a way to increase farm productivity by providing a wide range of benefits. Despite this, adoption of agroforestry in Australian agricultural systems remains low. To implement agroforestry, farmers must be convinced the benefits of including trees outweigh the costs. This review evaluates the available quantitative data on shelter benefits with emphasis on Australian conditions, identifies key research gaps and determines if there is sufficient knowledge to make accurate predictions about impacts on farm productivity.
Availability of quantitative data on windbreak shelter benefits was examined in five key areas; water use and evaporation, crop/pasture production, livestock mortality, livestock productivity and the capacity to model impacts of windbreaks on crop/livestock systems. Good quantitative data exists for many areas, particularly for changes in environmental conditions following tree establishment, however there were many gaps in key areas. Importantly, the ability to predict crop growth under spatially and temporally variable environmental conditions and the impact of windbreaks on livestock productivity is not yet able to be meaningfully quantified. Thus modelling the profitability of windbreaks is difficult and existing models require additional quantitative data to validate and improve them.
Role of carbon allocation efficiency in the temperature dependence of autotroph growth rates
Authors: García-Carreras Bernardo , Sal Sofía , Padfield Daniel , Kontopoulos Dimitrios-Georgios , Bestion Elvire , Schaum C.-Elisa , Yvon-Durocher Gabriel , Pawar Samrāt
Published: July 2018

Significance

To predict how plant growth rate will respond to temperature requires understanding how temperature drives the underlying metabolic rates. Although past studies have considered the temperature dependences of photosynthesis and respiration rates underlying growth, they have largely overlooked the temperature dependence of carbon allocation efficiency. By combining a mathematical model that links exponential growth rate of a population of photosynthetic cells to photosynthesis, respiration, and carbon allocation; to an experiment on a freshwater alga; and to a database covering a wide range of taxa, we show that allocation efficiency is crucial for predicting how growth rates will respond to temperature change across aquatic and terrestrial autotrophs, at both short and long (evolutionary) timescales.
Identifying a large number of high-yield genes in rice by pedigree analysis, whole-genome sequencing, and CRISPR-Cas9 gene knockout
Authors: Huang Ju , Li Jing , Zhou Jun , Wang Long , Yang Sihai , Hurst Laurence D. , Li Wen-Hsiung , Tian Dacheng
Published: July 2018

Significance

Finding the genes that control a complex trait is difficult because each gene may have only minor phenotypic effects. Quantitative trait loci mapping and genome-wide association study techniques have been developed for this purpose but are laborious and time-consuming. Here we developed a method combining pedigree analysis, whole-genome sequencing, and CRISPR-Cas9 technology. By sequencing the parents and descendants of IR8, the Green Revolution “miracle rice,” we identified many genes that had been retained in the pedigree by selection for high yield. Knockout and knockdown studies showed that a large proportion of the identified genes are essential or have phenotypic effects related to production. Our approach provides a powerful means for identifying genes involved in a complex trait.
Elesclomol restores mitochondrial function in genetic models of copper deficiency
Authors: Soma Shivatheja , Latimer Andrew J. , Chun Haarin , Vicary Alison C. , Timbalia Shrishiv A. , Boulet Aren , Rahn Jennifer J. , Chan Sherine S. L. , Leary Scot C. , Kim Byung-Eun , Gitlin Jonathan D. , Gohil Vishal M.
Published: July 2018

Significance

Inherited pathogenic mutations in genes required for copper delivery to cytochrome
c
oxidase (CcO) perturb mitochondrial energy metabolism and result in fatal mitochondrial disease. A prior attempt to treat human patients with these mutations by direct copper supplementation was not successful, possibly because of inefficient copper delivery to the mitochondria. We performed a targeted search to identify compounds that can efficiently transport copper across biological membranes and identified elesclomol (ES), an investigational anticancer drug, as the most efficient copper delivery agent. ES rescues CcO function in yeast, zebrafish, and mammalian models of copper deficiency by increasing cellular and mitochondrial copper content. Thus, our study offers a possibility of repurposing this anticancer drug for the treatment of disorders of copper metabolism.
Computational discovery of chemically patterned surfaces that effect unique hydration water dynamics
Authors: Monroe Jacob I. , Shell M. Scott
Published: July 2018

Significance

By combining molecular dynamics simulation with genetic algorithm optimization, we show how nanoscale surface chemical patterning provides a broad strategy to engineer materials with designed hydration water dynamics. Moreover, we find a striking, general relationship between interfacial water’s dynamics and thermodynamic properties that spans many different surface types, suggesting the potential for a unified understanding of the interplay between water structure and mobility as well as a thermodynamic basis for practical surface engineering to control dynamics. These findings may translate to powerful materials design principles for the development of industrially relevant separations and catalytic processes, where precise control of water dynamics at interfaces strongly influences performance.
LPS inactivation by a host lipase allows lung epithelial cell sensitization for allergic asthma
Authors: Qian Guojun , Jiang Wei , Zou Benkun , Feng Jintao , Cheng Xiaofang , Gu Jie , Chu Tianqing , Niu Chen , He Rui , Chu Yiwei , Lu Mingfang
Published: July 2018

Allergic asthma is a chronic inflammatory disease primarily mediated by Th2 immune mechanisms. Numerous studies have suggested that early life exposure to lipopolysaccharide (LPS) is negatively associated with allergic asthma. One proposed mechanism invokes desensitization of lung epithelial cells by LPS. We report here that acyloxyacyl hydrolase (AOAH), a host lipase that degrades and inactivates LPS, renders mice more susceptible to house dust mite (HDM)–induced allergic asthma. Lung epithelial cells from Aoah−/− mice are refractory to HDM stimulation, decreasing dendritic cell activation and Th2 responses. Antibiotic treatment that diminished commensal LPS-producing bacteria normalized Aoah−/− responses to HDM, while giving LPS intrarectally ameliorated asthma. Aoah−/− mouse feces, plasma, and lungs contained more bioactive LPS than did those of Aoah+/+ mice. By inactivating commensal LPS, AOAH thus prevents desensitization of lung epithelial cells. An enzyme that prevents severe lung inflammation/injury in Gram-negative bacterial pneumonia has the seemingly paradoxical effect of predisposing to a Th2-mediated airway disease.
How Organizational Hierarchy Affects Information Production
Authors: Skrastins Janis , Vig Vikrant
Published: July 2018

We exploit a variation in organizational hierarchy induced by a reorganization plan implemented in roughly 2,000 bank branches in India. We do so to investigate how organizational hierarchy affects the allocation of credit. We find that increased hierarchization of a branch induces credit rationing, reduces loan performance, and generates standardization in loan contracts. Additionally, we find that hierarchical structures perform better in environments characterized by a high degree of corruption, highlighting the benefits of hierarchies in restraining rent-seeking activities. Overall, our results are consistent with the view that valuable information may be lost in hierarchical structures.

Received May 4, 2018; editorial decision April 30, 2018 by Editor Itay Goldstein. Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Run-to-Run Sequencing Variation Can Introduce Taxon-Specific Bias in the Evaluation of Fungal Microbiomes
Authors: Song Zewei , Schlatter Dan , Gohl Daryl M. , Kinkel Linda L.
Published: July 2018

The routine use of high-throughput sequencing to profile microbial communities necessitates improved protocols for detecting and adjusting for variation among sequencing runs for marker gene analysis. Although mock communities are widely used as a control among runs, the composition and diversity of mock communities, in most cases, are orders of magnitude lower than the actual samples. We demonstrated that replicated biological samples (“technical replicates”) are superior to a mock community in detecting variation and potential bias among sequencing runs. We present a case in which technical replicates of three soil samples were sequenced in three MiSeq runs containing samples from multiple experiments. The technical replicate samples revealed a potentially biased, outlier sequencing run, from which several Ascomycota taxa were substantially underestimated. Similar bias was seen in the other samples sequenced but was not detected using the mock community. Our study demonstrates that using technical replicates along with traditional mock communities provide additional quality control information and aid in detecting outlier sequencing runs.
Inherited gynaecological cancers
Authors: George Angela
Published: July 2018

Purpose of review

There is an increasing interest in the role of routine testing for germline mutations in the management and outcome of gynaecological cancers as the therapeutic options for these patients develop, and knowledge about specific gene risks increase. This review focuses on recent literature assessing these areas of interest.

Recent findings

Systemic treatment options continue to increase, with two recent studies (SOLO2 and ARIEL-3) of the use of PARP inhibitors in the maintenance setting; and approval of pembrolizomab for mismatch repair deficient/microsatellite unstable tumours. Several studies have addressed the resultant increased demand for testing for Lynch syndrome and BRCA1/2 mutations in endometrial and ovarian cancers, respectively. Finally, several studies have assessed gene and age-specific risks for ovarian cancer, and the role of specific site mutations within BRCA2 in determining duration of PARP response, and clinical outcome.

The use of genomic information to guide treatment choices, and inform outcome is an exciting and rapidly expanding field. These recent studies provide additional support to suggest that testing for inherited mutations should be a routine part of care for these gynaecological patients care.
Framework for Critical Care in Obstetrics
Authors: Baird Suzanne McMurtry , Martin Stephanie
Published: July 2018

In 2015, The American College of Obstetricians and Gynecologists and the Society for Maternal Fetal Medicine issued a joint care consensus document intended to develop standards for designations of levels of maternal care that are complimentary to, but distinct from, neonatal levels of care. Level III and Level IV centers must be prepared to provide obstetric intensive care services. Developing a critical care obstetric program is a resource-intensive process that requires a carefully planned strategic effort essential for successful program implementation and sustainability. In this article, a framework utilizing key components of program development is discussed including environment, scope, model, education and training, maternal transport, and unique aspects of care for women who become critically ill during pregnancy or the postpartum period.
Foreign body ingestion in pediatric patients
Authors: Gurevich Yoseph , Sahn Benjamin , Weinstein Toba
Published: July 2018

Purpose of review

The purpose of this article is to review clinical manifestations and management of common pediatric foreign body ingestions, with a particular focus on some of the current trends.

Recent findings

Foreign body ingestion (FBI) is a problem that is frequently encountered by pediatric providers. As new toys and products enter the marketplace, there may also be new dangers from those objects not initially recognized. Some of the recent trends and findings in pediatric FBI include an increase in adolescent injury from ingestion of laundry detergent pods because of a popular game where participants are encouraged to bite or swallow the pods, and injuries associated with ingesting parts of a popular toy known as a ‘Fidget Spinner’.

Adverse events resulting from FBI range the entire gamut from nonexistent or minor symptoms to moderate injury and rarely may be fatal. Factors such as age, type of object ingested, anatomic location of the foreign body, and timing from ingestion to receipt of medical attention all determine the risk posed to the child and guide management decisions. Because of the constant development of products, and the potential for the emergence of new and dangerous trends among children, continued surveillance by the medical community is important in monitoring and managing injuries associated with FBI.
CNO Rounding Using an Electronic Tracking Tool
Authors: Schoster Meade Stephanie , Gormley Denise K.
Published: July 2018

Nurse executives must develop creative solutions to improve staff perceptions of the work environment and decrease turnover, as well as stay connected with their staff. This article summarizes an innovative closed feedback loop using an electronic record incorporated into chief nursing officer rounding and the impact on NDNQI survey results.
Rural Level III centers in an inclusive trauma system reduce the need for interfacility transfer
Authors: Galanis Daniel J. , Steinemann Susan , Rosen Linda , Bronstein Alvin C. , Biffl Walter L.
Published: July 2018

BACKGROUND

Development of Level III trauma centers in a regionalized system facilitates early stabilization and prompt transfer to a higher level center. The resources to care for patients at Level III centers could also reduce the burden of interfacility transfers. We hypothesized that the development and designation of Level III centers in an inclusive trauma system resulted in lower rates of transfer, with no increase in morbidity or mortality among the non-transferred patients.

METHODS

State trauma registry data from January 2009 through September 2015 were examined from five rural hospitals that transfer patients to our highest (Level II) trauma center and resource hospital. These five rural hospitals began receiving state support in 2010 to develop their trauma programs and were subsequently verified and designated Level III centers (three in 2011, two in 2013). Multivariate logistic regression was used to examine the adjusted odds of patient transfers and adverse outcomes, while controlling for age, gender, penetrating mechanism, presence of a traumatic brain injury, arrival by ambulance, and category of Injury Severity Score. The study period was divided into “Before” Level III center designation (2009–2010) and “After” (2011–2015).

RESULTS

7,481 patient records were reviewed. There was a decrease in the proportion of patients who were transferred After (1,281/5,737) compared to Before (516/1,744) periods (22% vs. 30%, respectively). After controlling for the various covariates, the odds of patient transfer were reduced by 32% (p < 0.0001) during the After period. Among non-transferred patients, there were no significant increases in adjusted odds of mortality, or hospitalizations of seven days or more, Before versus After.

CONCLUSIONS

Development of rural Level III trauma centers in a regionalized system can significantly reduce the need for transfer to a remote, higher level trauma center. This may benefit the patient, family, and trauma system, with no adverse effect upon patient outcome.

LEVEL OF EVIDENCE

Epidemiological, level III.
In ovo
microbial communities: a potential mechanism for the initial acquisition of gut microbiota among oviparous birds and lizards
Authors: Trevelline Brian K. , MacLeod Kirsty J. , Knutie Sarah A. , Langkilde Tracy , Kohl Kevin D.
Published: July 2018

Vertebrate gut microbiota mediate critical physiological processes known to affect host fitness, but the mechanisms that expose wildlife to pioneer members of this important microbial community are not well understood. For example, oviparous vertebrates are thought to acquire gut microbiota through post-natal exposure to the external environment, but recent evidence from placental mammals suggests that the vertebrate reproductive tract harbours microbiota that may inoculate offspring
in utero
. These findings suggest that oviparous vertebrates may be capable of acquiring pioneer microbiota
in ovo
, but this phenomenon remains unexplored. To fill this knowledge gap, we used culture-independent inventories to determine if the eggs of wild birds and lizards harboured
in ovo
microbial communities. Our approach revealed distinct
in ovo
bacterial communities, but fungal communities were indistinguishable from controls. Further, lizard eggs from the same clutch had bacterial community structures that were more similar to each other than to unrelated individuals. These results suggest that oviparous vertebrates may acquire maternal microbiota
in ovo
, possibly through the inoculation of egg yolk prior to shelling. Therefore, this study may provide a first glimpse of a phenomenon with substantial implications for our understanding of the ecological and evolutionary factors shaping gut microbial communities.
Conformational dynamics and enzyme evolution
Authors: Petrović Dušan , Risso Valeria A. , Kamerlin Shina Caroline Lynn , Sanchez-Ruiz Jose M.
Published: July 2018

Enzymes are dynamic entities, and their dynamic properties are clearly linked to their biological function. It follows that dynamics ought to play an essential role in enzyme evolution. Indeed, a link between conformational diversity and the emergence of new enzyme functionalities has been recognized for many years. However, it is only recently that state-of-the-art computational and experimental approaches are revealing the crucial molecular details of this link. Specifically, evolutionary trajectories leading to functional optimization for a given host environment or to the emergence of a new function typically involve enriching catalytically competent conformations and/or the freezing out of non-competent conformations of an enzyme. In some cases, these evolutionary changes are achieved through distant mutations that shift the protein ensemble towards productive conformations. Multifunctional intermediates in evolutionary trajectories are probably multi-conformational, i.e. able to switch between different overall conformations, each competent for a given function. Conformational diversity can assist the emergence of a completely new active site through a single mutation by facilitating transition-state binding. We propose that this mechanism may have played a role in the emergence of enzymes at the primordial, progenote stage, where it was plausibly promoted by high environmental temperatures and the possibility of additional phenotypic mutations.
Neural correlates of effort-based valuation with prospective choices
Authors: Aridan Nadav , Malecek Nicholas J. , Poldrack Russell A. , Schonberg Tom
Published: July 2018

How is effort integrated in value-based decision-making? Animal models and human neuroimaging studies, primarily linked the anterior cingulate cortex (ACC) and ventral striatum (VS) to the integration of effort in valuation. Other studies demonstrated the role of these regions in invigoration to effort demands, thus it is hard to separate the neural activity linked to anticipation and subjective valuation from actual performance. Here, we studied the neural basis of effort valuation separated from performance. We scanned forty participants with fMRI and they were asked to accept or reject monetary gambles that could be resolved with future performance of a familiar grip force effort challenge or a fixed risk prospect. Participants’ willingness to accept prospective gambles reflected discounting of values by physical effort and risk. Choice-locked neural activation in contralateral primary sensory cortex and ventromedial prefrontal cortex (vmPFC) tracked the magnitude of prospective effort the participants faced, independent of choice time and monetary stakes. Estimates of subjective value discounted by effort were found to be tracked by the activation of a network of regions common to valuation under risk and delay, including vmPFC, VS and sensorimotor cortex. Together, our findings show separate neural mechanisms underlying prospective effort and actual effort performance.
Promiscuous targeting of cellular proteins by Vpr drives massive proteomic remodelling in HIV-1 infection
Authors: Greenwood Edward JD , Williamson James C , Sienkiewicz Agata , Naamati Adi , Matheson Nicholas J , Lehner Paul J
Published: July 2018

HIV-1 encodes four ‘accessory proteins’ (Vif, Vpr, Vpu and Nef), dispensable for viral replication in vitro, but essential for viral pathogenesis in vivo. Well characterised cellular targets have been associated with Vif, Vpu and Nef, which counteract host restriction and promote viral replication. Conversely, whilst several substrates of Vpr have been described, their biological significance remains unclear. Here, we use complementary, unbiased mass spectrometry-based approaches to demonstrate that Vpr is both necessary and sufficient for DCAF1/DDB1/CUL4 E3 ubiquitin ligase-mediated degradation of at least 38 cellular proteins, causing systems-level changes to the cellular proteome. We therefore propose that promiscuous targeting of multiple host factors underpins complex Vpr-dependent cellular phenotypes, and validate this in the case of G2/M cell cycle arrest. Our model explains how Vpr modulates so many cell biological processes, and why the functional consequences of previously described Vpr targets, identified and studied in isolation, have proved elusive.
A neural basis of probabilistic computation in visual cortex
Authors: Walker Edgar Y. , James Cotton R. , Ma Wei Ji , Tolias Andreas S.
Published: July 2018

Bayesian models of behavior suggest that organisms represent uncertainty associated with sensory variables. However, the neural code of uncertainty remains elusive. A central hypothesis is that uncertainty is encoded in the population activity of cortical neurons in the form of likelihood functions. We studied the neural code of uncertainty by simultaneously recording population activity from the primate visual cortex during a visual categorization task in which trial-to-trial uncertainty about stimulus orientation was relevant for the decision. We decoded the likelihood function from the trial-to-trial population activity and found that it predicted decisions better than a point estimate of orientation. This remained true when we conditioned on the true orientation, suggesting that internal fluctuations in neural activity drive behaviorally meaningful variations in the likelihood function. Our results establish the role of population-encoded likelihood functions in mediating behavior, and provide a neural underpinning for Bayesian models of perception.
Drug susceptibility testing and mortality in patients treated for tuberculosis in high-burden countries
Authors: Zürcher Kathrin , Ballif Marie , Fenner Lukas , Borrell Sonia , Keller Peter M. , Gnokoro Joachim , Marcy Olivier , Yotebieng Marcel , Diero Lameck , Carter E. Jane , Rockwood Neesha , Wilkinson Robert J. , Cox Helen , Ezati Nicholas , Abimiku Alash’le G. , Collantes Jimena , Avihingsanon Anchalee , Kawkitinarong Kamon , Reinhard Miriam , Hömke Rico , Huebner Robin , Gagneux Sebastien , Böttger Erik C. , Egger Matthias ,   on behalf of the International Epidemiology Databases to Evaluate AIDS (IeDEA)
Published: July 2018

Background

Drug resistance and HIV co-infection are challenges for the global control of tuberculosis.

Methods

We collected Mycobacterium tuberculosis isolates from adult patients in Côte d’Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand, stratified by HIV status and tuberculosis drug resistance. Molecular or phenotypic drug susceptibility testing (DST) was done locally and at the Swiss tuberculosis reference laboratory. We examined mortality during treatment according to DST results and treatment adequacy in logistic regression models adjusting for sex, age, sputum microscopy and HIV status.

Findings

634 tuberculosis patients were included; median age was 33.2 years, 239 (37.7%) were female, 272 (42.9%) HIV-positive and 69 (10.9%) patients died. Based on the reference laboratory DST, 394 (62.2%) strains were pan-susceptible, 45 (7.1%) mono-resistant, 163 (25.7%) multidrug-resistant (MDR-TB), and 30 (4.7%) had pre-extensive or extensive drug resistance (pre-XDR/XDR-TB). Results of reference and local laboratories were discordant in 121 (19.1%) cases, corresponding to a sensitivity of 84.3% and a specificity of 90.8%. In patients with drug-resistant tuberculosis, discordant results were associated with increased mortality (risk ratio 1.81; 95% CI 1.07-3.07). In logistic regression, compared to adequately treated patients with pan-susceptible strains, the adjusted odds ratio for death was 4.23 (95% CI 2.16-8.29) for adequately treated patients with drug-resistant strains and 21.54 (95% CI 3.36-138.1) for inadequately treated patients with drug-resistant strains. HIV status was not associated with mortality.

Interpretation

Using a reference laboratory standard, inaccurate DST leading to inappropriate treatment of drug-resistant tuberculosis, but not HIV infection, contributed to mortality.
High-throughput retrieval of physical DNA for NGS-identifiable clones in phage display library
Authors: Noh Jinsung , Kim Okju , Jung Yushin , Han Haejun , Kim Jung-Eun , Kim Soohyun , Lee Sanghyub , Park Jaeseong , Jung Rae Hyuck , Kim Sang il , Park Jaejun , Han Jerome , Lee Hyunho , Kyun Yoo Duck , Lee Amos C. , Kwon Euijin , Ryu Taehoon , Chung Junho , Kwon Sunghoon
Published: July 2018

In antibody discovery, in-depth analysis of an antibody library and high-throughput retrieval of clones in the library are crucial to identifying and exploiting rare clones with different properties. However, existing methods have several technical limitations such as low process throughput from laborious cloning process and waste of the phenotypic screening capacity from unnecessary repetitive tests on the dominant clones. To overcome the limitations, we developed a new high-throughput platform for the identification and retrieval of clones in the library, TrueRepertoire™. TrueRepertoire™ provides highly accurate sequences of the clones with linkage information between heavy and light chains of the antibody fragment. Additionally, the physical DNA of clones can be retrieved in high throughput based on the sequence information. We validated the high accuracy of the sequences and demonstrated that there is no platform-specific bias. Moreover, the applicability of TrueRepertoire™ was demonstrated by a phage-displayed single-chain variable fragment (scFv) library targeting human hepatocyte growth factor (hHGF) protein.
Modeling Cellular Resource Allocation Reveals Low Phenotypic Plasticity of C4 Plants and Infers Environments of C4 Photosynthesis Evolution
Authors: Sundermann Esther M. , Lercher Martin J. , Heckmann David
Published: July 2018

-

The regulation of resource allocation in biological systems observed today is the cumulative result of natural selection in ancestral and recent environments. To what extent are observed resource allocation patterns in different photosynthetic types optimally adapted to current conditions, and to what extend do they reflect ancestral environments? Here, we explore these questions for C3, C4, and C3-C4 intermediate plants of the model genus Flaveria.

-

We developed a detailed mathematical model of carbon fixation, which accounts for various environmental parameters and for energy and nitrogen partitioning across photosynthetic components. This allows us to assess environment-dependent plant physiology and performance as a function of resource allocation patterns.

-

To achieve maximal CO2 fixation rates under growth conditions differing from those experienced during their evolution, C4 species need to re-allocate significantly more nitrogen between photosynthetic components than their C3 relatives. As this is linked to a limited phenotypic plasticity, observed resource distributions in C4 plants still reflect optimality in ancestral environments, allowing their quantitative inference.

-

Our work allows us to quantify environmental effects on resource allocation and performance of photosynthetic organisms. This understanding paves the way for interpreting present photosynthetic physiology in the light of evolutionary history.
Epigenome-based prediction of gene expression across species
Authors: Ebert Peter , Lengauer Thomas , Bock Christoph
Published: July 2018

Background

Cross-species studies of epigenetic regulation have great potential, yet most epige-nome mapping has focused on human, mouse, and a small number of other model organisms. Here we explore whether existing reference epigenome collections can be leveraged for analyzing other species, by extrapolation and predictive transfer of epigenome information from established model organisms to less well annotated non-model organisms.

Results

We developed a methodology for cross-species mapping of epigenome data, which we used for predicting tissue-specific gene expression across twelve mammalian and one avian species. Specifically, we trained gradient boosting classifiers to predict gene expression status from reference epigenome data in human and mouse, and we applied these classifiers to epigenome profiles that were computationally transferred between species. The resulting predictions indeed identified tissue-specific differences in gene expression in the target species, thus providing initial validation of the concept of cross-species epigenome extrapolation.

Conclusions

Our study establishes a workflow for cross-species epigenome mapping and epigenome-based prediction of gene expression, highlighting the future potential of using epigenome maps from reference species to annotate a potentially large number of target species.
Panoramic stitching of heterogeneous single-cell transcriptomic data
Authors: Hie Brian , Bryson Bryan , Berger Bonnie
Published: July 2018

Researchers are generating single-cell RNA sequencing (scRNA-seq) profiles of diverse biological systems1–4 and every cell type in the human body.5 Leveraging this data to gain unprecedented insight into biology and disease will require assembling heterogeneous cell populations across multiple experiments, laboratories, and technologies. Although methods for scRNA-seq data integration exist6,7, they often naively merge data sets together even when the data sets have no cell types in common, leading to results that do not correspond to real biological patterns. Here we present Scanorama, inspired by algorithms for panorama stitching, that overcomes the limitations of existing methods to enable accurate, heterogeneous scRNA-seq data set integration. Our strategy identifies and merges the shared cell types among all pairs of data sets and is orders of magnitude faster than existing techniques. We use Scanorama to combine 105,476 cells from 26 diverse scRNA-seq experiments across 9 different technologies into a single comprehensive reference, demonstrating how Scanorama can be used to obtain a more complete picture of cellular function across a wide range of scRNA-seq experiments.
Programmatic Detection of Diploid-Triploid Mixoploidy via Whole Genome Sequencing
Authors: Holt James M , Birch Camille L , Brown Donna M , Cogan Joy D , Hamid Rizwan , Dorrani Naghmeh , Herzog Matthew R , Lee Hane , Martinez Julian ,   Undiagnosed Diseases Network, Dipple Katrina , Vilain Eric , Phillips John A , Worthey Elizabeth A
Published: July 2018

Purpose

Mixoploidy is a type of mosaicism where an organism is a mixture of cells with different numbers of chromosomes. There are a broad range of phenotypes associated with mixoploidy that vary greatly depending on the fraction of cells that are non-diploid, their chromosome number, their distribution, and presumably the specific variation present in the patient. Clinical detection of mixoploidy is important for diagnosis.

Methods

We developed a method to detect mixoploidy from clinical whole genome sequencing (WGS) data through the identification of excess of variant calls centered on unusual B-allele frequencies. Our method isolates the signal from these variants using trio calls and then solves a basic linear equation to estimate levels of diploid-triploid mixoploidy within the sample.

Results

We show that our method reflects the results from a cytogenetic test. We provide examples detailing how our method has been used to identify diploid-triploid mixoploid individuals from within the NIH Undiagnosed Diseases Network. We present confirmatory findings obtained by clinical cytogenetic testing and show that our method can be used to identify the diploid-triploid ratio in these cases.

Conclusion

WGS data from patients with rare diseases can be used to identify mixoploid individuals. Individuals with certain characteristics as discussed should be tested for mixoploidy as part of standard clinical pipeline procedures. Scripts that perform this calculation are publicly available athttps://github.com/HudsonAlpha/mixoviz.
Plasmodium falciparum Niemann-Pick Type C1-Related Protein is a Druggable Target Required for Parasite Membrane Homeostasis
Authors: Istvan Eva S. , Das Sudipta , Bhatnagar Suyash , Beck Josh R. , Owen Edward , Llinás Manuel , Ganesan Suresh M. , Niles Jacquin C. , Winzeler Elizabeth A. , Vaidya Akhil B. , Goldberg Daniel E.
Published: July 2018

Plasmodium parasites possess a protein with homology to Niemann-Pick Type C1 proteins (Plasmodium falciparum Niemann-Pick Type C1-Related protein, PfNCR1). We isolated parasites with resistance-conferring mutations in PfNCR1 during selections with three diverse small-molecule antimalarial compounds and show that the mutations are causative for compound resistance. PfNCR1 protein knockdown results in severely attenuated growth and confers hypersensitivity to the compounds. Compound treatment or protein knockdown leads to increased sensitivity of the parasite plasma membrane (PPM) to the amphipathic glycoside saponin and engenders digestive vacuoles (DVs) that are small and malformed. Immuno-electron microscopy and split-GFP experiments localize PfNCR1 to the PPM. Our experiments show that PfNCR1 activity is critically important for the composition of the PPM and is required for DV biogenesis, suggesting PfNCR1 as a novel antimalarial drug target.
Sulforaphane Alters the Acidification of the Vacuole to Trigger Cell Death
Authors: Wilcox Alexander , Murphy Michael , Tucker Douglass , Laprade David , Roussel Breton , Hallisey Victoria , Chin Christopher , Brass Abraham , Austriaco Nicanor
Published: July 2018

Sulforaphane (SFN) is a compound [1-isothiocyanato-4-(methylsulfinyl)- butane] found in broccoli and other cruciferous vegetables that is currently of interest because of its potential as a chemopreventive and a chemotherapeutic drug. Recent studies in a diverse range of cellular and animal models have shown that SFN is involved in multiple intracellular signaling pathways that regulate cell death, cell cycle progression, and cell invasion. In order to better understand the mechanisms of action behind SFN-induced cell death, we undertook an unbiased genome wide screen with the yeast knockout (YKO) library to identify SFN sensitive (SFNS) mutants. Our mutants were enriched with knockouts in genes linked to vacuolar function suggesting a link between this organelle and SFN’s mechanism of action in yeast. Our subsequent work revealed that SFN increases the vacuolar pH of yeast cells and that varying the vacuolar pH can alter the sensitivity of yeast cells to the drug. In fact, several mutations that lower the vacuolar pH in yeast actually made the cells resistant to SFN (SFNR). Finally, we show that human lung cancer cells with more acidic compartments are also SFNR suggesting that SFN’s mechanism of action identified in yeast may carry over to higher eukaryotic cells.
Metabolic deregulation in prostate cancer
Authors: Srihari Sriganesh , Tattam Paula , Simpson Rebecca , Smith Elliot
Published: July 2018

Introduction

The prostate exhibits a unique metabolism that changes during initial neoplasia to aggressive prostate cancer (PCa) and metastasis. The study of PCa metabolism thus represents a new avenue for diagnostics, particularly early diagnosis of aggressive PCa cases.

Results

Here, using transcriptomics data from The Cancer Genome Atlas (498 PCa patients), we identified six metabolic subgroups (C1-C6) of PCa that showed distinct disease-free survival outcomes (p<0.0001). In particular, we identified at least two PCa subgroups (C5 and C3) that exhibited significant poor prognosis (~70% and 30-40% relapse by the first 72 months; hazards ratios 9.4 and 4.4, respectively, relative to the best prognosis cluster C4 that showed <20% relapse even by 120 months). The subgroups were reproducible in an independent dataset from Taylors et al. 2010 (215 patients; p=0.00088). The subgroups displayed distinct metabolic profiles vis-à-vis normal tissues; measured as ‘deregulation’ of metabolic pathways (using Pathifier, Drier & Domany, 2013). In particular, the poor-prognosis subgroups C5 and C3 showed considerable deregulation for pathways involved in synthesis and catabolism of complex forms of lipids and carbohydrates, amino acids, and TCA cycle, and these were exhibited in parallel or in the face of glycolysis, a common form of energy production in cancer cells. Furthermore, the subgroups were significantly over-enriched for different sets of genetic alterations [particularly, deletions/mutations in BRCA1 and TP53 (C5), RB1 and STK11(C3); and AR amplifications (C1); p≤8.6E-04], suggesting that distinct alterations may be underpinning the subgroups and ‘pushing’ the subgroups towards their unique metabolic profiles. Finally, applying the classifier to blood expression profiles from 42 active surveillance (AS) and 65 advanced castrate resistant PCa (ACRPC) patients determined based on prostate-specific antigen (PSA) levels (Olmos et al., 2012) assigned 70.77% ACPRC, and interestingly reassigned 59.52% AS patients to at least one of the poor prognosis subgroups (C5, C3) with 35.71% to the poor and metabolically deregulated subgroup C3.

Conclusion

The identification of PCa subgroups displaying distinct clinical outcomes solely from metabolic expression profiles of PCa tumours reiterates the significant link between deregulated metabolism and PCa outcomes (Eidelman et al., 2017). On the other hand, the time to biochemical relapse (rise in PSA levels) was not indicative of the early relapse seen for the metabolically deregulated subgroups C3 and C5 (these show considerably late BCR compared to C4). Our study thus highlights specific processes (elevated lipid and carbohydrate metabolism pathways) that could be better indicators than PSA for early diagnosis of aggressive PCa.