bluuebunny/crossref_metadata_2025 huggingface dataset:
Online multiple object tracking using confidence score‐based appearance model learning and hierarchical data association
Authors: Liu Mingjie , Jin Cheng‐Bin , Yang Bin , Cui Xuenan , Kim Hakil
Published: October 2018

The goal of multiple object tracking (MOT) is to estimate the locations of objects and maintain their identities consistently to yield their individual trajectories. MOT has been developed enormously, but it is still a challenging work due to similar appearances of different objects and occlusion by other objects or background in a complex scene. In this study, the authors propose confidence score‐based appearance model learning and hierarchical data association for MOT. First, the confidence score is used to divide associated tracklet‐detection in the first stage data association into confident and unconfident results, and in the second stage, data association is applied to unconfident tracklet‐detection to improve the performance. Furthermore, it can be employed to enhance the robustness of the appearance model and due to the fast confidence score calculation, it can balance the accuracy and processing time. The experimental results with challenging public datasets show distinct performance improvement over other state‐of‐the‐art methods and demonstrate the effect of the authors’ method for online MOT.
Development of a global batch clustering with gradient descent and initial parameters in colour image classification
Authors: Li Peilin , Lee Sang‐Heon , Park Jae‐Sam
Published: October 2018

This study addresses two issues from batch clustering using K‐means algorithm in colour image classification application. One of the major issues is the drifting phenomenon in the batch clustering due to the stochastic nature of the clustering procedure. Also in literature, the initial parameter is important to direct the clustering algorithm converge to the proper local solution. In this study, a new algorithm is proposed to address these two issues in application. Recently, a research found that the principal component analysis (PCA) result directly indicates the membership of the clusters in K‐means algorithm. Hence using this, the first part of the proposed algorithm shows the possibility to estimate the initial parameters accurately for K‐means with a hierarchical manner of PCA solution. In addition, a gradient descent approach is used for the global batch clustering to reduce the drifting and hence speed up convergence in the refining stage. All necessary proofs and justifications are also provided. The evaluation study has shown that the proposed algorithm performs better than the original K‐means clustering algorithms with various initial parameter estimation processes.
Isolated Buck‐Boost converters with AC‐TLR and dual‐transformer structure for wide output voltage range applications
Authors: Wu Hongfei , Sun Kai , Liu Tingting , Xing Yan
Published: October 2018

A novel isolated buck–boost (IBB) converter with a dual‐transformer (DT) and an active‐controlled three‐level rectifier (AC‐TLR) is proposed in this study. A new family of IBB converters is derived with different implementations of the AC‐TLR. The two transformers in the converter supply power to the output alternatively through the phase‐shift control of the active switch in the AC‐TLR. A voltage‐doubler configuration is built and three voltage levels are generated with the DT and AC‐TLR structure. Therefore, the diodes and switches in the rectifier sustain only half of the high‐output voltage and turns ratios of the transformers are reduced. In addition, the zero‐voltage‐switching operation of all the active switches on both the primary and secondary sides is achieved and the reverse‐recovery problem of all the diodes is alleviated in the wide operation range. Furthermore, the output voltage of the converter is regulated in a wide range due to the buck and boost voltage conversion characteristics of the converter. The operational principles, modulation and characteristics of the converter are presented. Finally, a 400 V input and 350–750 V output prototype is built and tested to verify the effectiveness of the proposed converters.
Microgrid operation improvement by adaptive virtual impedance
Authors: Eskandari Mohsen , Li Li
Published: October 2018

Microgrids (MGs) are regarded as the best solution for optimal integration of the renewable energy sources into power systems. However, novel control strategies should be developed because of the distinct inherent feature of MG components in comparison to conventional power systems. Although the droop‐based control method is adopted in the MG to share power among distributed generation units, its dependency to grid parameters makes its implementation not as convenient as that in conventional power systems. Virtual impedance has been proposed as the complementary part of droop control in MGs. In this study, adaptive virtual impedance is designed considering its effects on the system performance in the MG including: (i) decoupling active and reactive power control by making the grid X/R ratio high, (ii) maximum transferable power through the feeder, (iii) stability concern and (iv) precise reactive power sharing in different operating modes as well as smooth transition from connected mode to islanded mode (IM). To this end, a novel method is proposed to determine the reactive power reference of distributed generation (DG) units according to their contribution in reactive power sharing in IM. In addition, simulation in MATLAB/Simulink environment is conducted to assess the performance of the control system.
SS 433: Two robust determinations fix the mass ratio
Authors: Bowler M. G.
Published: October 2018

Context. The unique Galactic microquasar SS 433 is an X-ray binary with a 13.08 day orbital period. Over some forty years, estimates of the mass of the compact object have spanned the range 1–30 solar masses; from neutron star to massive stellar black hole.

Aims. To fix the mass ratio q and hence the mass of the super-Eddington accretor.

Methods. We present a new and robust estimate of q derived from data on the circumbinary disk and compare it with a recent determination from the observed constancy of the binary period.

Results. These two robust analyses agree to a remarkable extent. They reinforce each other; q is ∼0.7 and the mass of the compact object 15 ± 2 M⊙.

Conclusions. The mass is such as to identify the compact object as a massive stellar black hole.
Metabolic pathways associated with right ventricular adaptation to pulmonary hypertension: 3D analysis of cardiac magnetic resonance imaging
Authors: Attard Mark I , Dawes Timothy J W , de Marvao Antonio , Biffi Carlo , Shi Wenzhe , Wharton John , Rhodes Christopher J , Ghataorhe Pavandeep , Gibbs J Simon R , Howard Luke S G E , Rueckert Daniel , Wilkins Martin R , O’Regan Declan P
Published: October 2018

Aims

We sought to identify metabolic pathways associated with right ventricular (RV) adaptation to pulmonary hypertension (PH). We evaluated candidate metabolites, previously associated with survival in pulmonary arterial hypertension, and used automated image segmentation and parametric mapping to model their relationship to adverse patterns of remodelling and wall stress.

Methods and results

In 312 PH subjects (47.1% female, mean age 60.8 ± 15.9 years), of which 182 (50.5% female, mean age 58.6 ± 16.8 years) had metabolomics, we modelled the relationship between the RV phenotype, haemodynamic state, and metabolite levels. Atlas-based segmentation and co-registration of cardiac magnetic resonance imaging was used to create a quantitative 3D model of RV geometry and function—including maps of regional wall stress. Increasing mean pulmonary artery pressure was associated with hypertrophy of the basal free wall (β = 0.29) and reduced relative wall thickness (β = −0.38), indicative of eccentric remodelling. Wall stress was an independent predictor of all-cause mortality (hazard ratio = 1.27, P = 0.04). Six metabolites were significantly associated with elevated wall stress (β = 0.28–0.34) including increased levels of tRNA-specific modified nucleosides and fatty acid acylcarnitines, and decreased levels (β = −0.40) of sulfated androgen.

Conclusion

Using computational image phenotyping, we identify metabolic profiles, reporting on energy metabolism and cellular stress-response, which are associated with adaptive RV mechanisms to PH.
The myth of voluntary uptake of proven fishing gear: investigations into the challenges inspiring change in fisheries
Authors: Eayrs Stephen , Pol Michael
Published: October 2018

We describe an investigation into the challenges faced by fishing gear technologists inspiring the voluntary uptake of proven fishing gear by fishers, defined as fishing gear that has satisfied research objectives following field trials between fishers and fishing gear technologists. We applied a multifaceted approach to understand how the uptake rate of this fishing gear can be achieved based on the results of a 3-year ICES-FAO Working Group on Fishing Technology and Fish Behaviour (WGFTFB) topic group on change management in fisheries. This was supported by an online survey and interview of WGFTFB members, comprising mainly of fishing gear technologists and researchers from Europe and North America, and a review of projects in the US Northwest Atlantic to evaluate the performance of fishing gear in close collaboration with fishers. We found that widespread voluntary uptake of proven fishing gear by fishers is rare, and usually takes place over many years if at all. The uptake of this gear was more likely occur in the face of perceived financial benefit or impending regulation, although financial benefit was not always sufficient inducement for fishers change their gear. The effectiveness of outreach programmes to inspire the uptake of this gear was also found to be questionable, and the efficacy of incentives was limited and inconsistent, even if the informational deficit of fishers was low. Few WGFTFB members were found to use change management models such as that by Kotter, and they relied mainly on informal, ad hoc approaches to inspire the uptake of proven fishing gear. Based on our findings we posit a need to (i) examine our assumptions about the behaviour of fishers, (ii) augment communication of the results of fishing gear research, (iii) focus on emotions to overcome motivational deficits, and (iv) consider how the application of change management models can improve the ability of fishing gear technologists to inspire the uptake of proven fishing gear by fishers.
Recent trends in US mortality in early and middle adulthood: racial/ethnic disparities in inter-cohort patterns
Authors: Zang Emma , Zheng Hui , Yang Yang Claire , Land Kenneth C
Published: October 2018

Background

A striking increase in the all-cause mortality of US middle-aged non-Hispanic Whites in the past two decades has been documented by previous studies. The inter-cohort patterns in US mortality, as well as their racial/ethnic disparities, are still unclear.

Methods

Using official mortality data, we study US annual mortality rates for ages 25–54 from 1990 to 2016 by gender and race/ethnicity. We conduct an age-period-cohort analysis to disentangle the period and cohort forces driving the absolute changes in mortality across cohorts. Nine leading causes of death are also explored to explain the inter-cohort mortality patterns and their racial/ethnic disparities.

Results

We find cohort-specific elevated mortality trends for gender- and race/ethnicity-specific populations. For non-Hispanic Blacks and Hispanics, Baby Boomers have increased mortality trends compared with other cohorts. For non-Hispanic White females, it is late-Gen Xers and early-Gen Yers for whom the mortality trends are higher than other cohorts. For non-Hispanic White males, the elevated mortality pattern is found for Baby Boomers, late-Gen Xers, and early-Gen Yers. The mortality pattern among Baby Boomers is at least partially driven by mortality related to drug poisoning, suicide, external causes, chronic obstructive pulmonary disease and HIV/AIDS for all race and gender groups affected. The elevated mortality patterns among late-Gen Xers and early-Gen Yers are at least partially driven by mortality related to drug poisonings and alcohol-related diseases for non-Hispanic Whites. Differential patterns of drug poisoning-related mortality play an important role in the racial/ethnic disparities in these mortality patterns.

Conclusions

We find substantial racial/ethnic disparities in inter-cohort mortality patterns. Our findings also point to the unique challenges faced by younger generations.
Animal Models for Influenza A Virus Infection Incorporating the Involvement of Innate Host Defenses: Enhanced Translational Value of the Porcine Model
Authors: Starbæk Sofie M R , Brogaard Louise , Dawson Harry D , Smith Allen D , Heegaard Peter M H , Larsen Lars E , Jungersen Gregers , Skovgaard Kerstin
Published: October 2018

Influenza is a viral respiratory disease having a major impact on public health. Influenza A virus (IAV) usually causes mild transitory disease in humans. However, in specific groups of individuals such as severely obese, the elderly, and individuals with underlying inflammatory conditions, IAV can cause severe illness or death. In this review, relevant small and large animal models for human IAV infection, including the pig, ferret, and mouse, are discussed. The focus is on the pig as a large animal model for human IAV infection as well as on the associated innate immune response. Pigs are natural hosts for the same IAV subtypes as humans, they develop clinical disease mirroring human symptoms, they have similar lung anatomy, and their respiratory physiology and immune responses to IAV infection are remarkably similar to what is observed in humans. The pig model shows high face and target validity for human IAV infection, making it suitable for modeling many aspects of influenza, including increased risk of severe disease and impaired vaccine response due to underlying pathologies such as low-grade inflammation. Comparative analysis of proteins involved in viral pattern recognition, interferon responses, and regulation of interferon-stimulated genes reveals a significantly higher degree of similarity between pig, ferret, and human compared with mice. It is concluded that the pig is a promising animal model displaying substantial human translational value with the ability to provide essential insights into IAV infection, pathogenesis, and immunity.
Factors Associated With U.S. Army Physician Service After Obligation Completion
Authors: Wiesen Andrew R , Marcum Rodd E , Soltis Michele A , Peterson Kris A
Published: October 2018

Introduction

Approximately, 320 physicians enter active duty in the U.S. Army each year, replacing a similar number separating from service. Despite the significant costs involved in educating and training physicians, factors associated with continued active service after completing obligations have not been well studied.

Materials and Methods

A retrospective cohort study was conducted of all U.S. Army physicians who graduated medical school in 1987 or later and entered active physician service on or before December 31, 2015. A Cox proportional hazards model was used to evaluate the likelihood of continued service after initial obligations to the Army were satisfied. A logistic regression model examined the likelihood of reaching retirement eligibility for the subgroup entering service before October 1998.

Results

Of the 10,490 physicians who met inclusion criteria, 8,009 physicians completed their service obligation by the end of the study. There were 4,524 physicians who entered service before October 1998 and were eligible for the retirement analysis. Several factors were found to be independently associated with a higher likelihood of continued post-obligation service and reaching retirement eligibility. These factors were: years of active service accumulated when obligations were complete; preventive medicine and infectious disease specialization; and male gender.

Conclusions

The physicians most likely to continue serving after completion of their obligation and ultimately retire are those who had the most years of service accumulated when they could leave the Army. Graduates from the Uniformed Services University of the Health Sciences (USU) incur an obligation of 7 years vs. 4 years for most other programs. USU also attracts a higher proportion of applicants with prior military service and pre-medical school service obligations. The lack of significant difference in service after obligation completion or achievement of retirement eligibility between USU and non-USU graduates was explained by the greater total service of USU graduates when their obligations were complete. Changing the obligation and incentives, such as salary, for other accessioning programs to mirror the USU model would likely minimize service differences between USU and non-USU graduates.
Modified Battlefield Acupuncture Does Not Reduce Pain or Improve Quality of Life in Patients with Lower Extremity Surgery
Authors: Crawford Paul , Moss David A , Crawford Amanda J , Sharon Danny J
Published: October 2018

Introduction

This study seeks to determine if modified Battlefield Acupuncture is more effective at relieving acute extremity pain, reducing medication use, and improving quality of life than placebo acupuncture or standard care after lower extremity surgery.

Methods

We conducted a multi-site 3-arm randomized, double-blind controlled trial of standard care alone versus standard care + placebo auricular acupuncture with semi-permanent needles versus standard care + modified battlefield acupuncture with semi-permanent needles for lower extremity surgery at two Air Force hospitals. Subjects reported pain level immediately after acupuncture, 24, 48, 168, and 720 hours later to a blinded research associate. Additionally, subjects completed a PIQ-6 30 days post-operatively, and opioid use was tracked for 30 days post-operatively.

Results

Two hundred thiry-three subjects >18 years old (92 females and 141 males) with a mean age of 44.5 years were randomized with 81 randomized to modified BFA, 74 randomized to placebo acupuncture, and 78 randomized to standard care. Overall pain levels were unchanged at each time point between groups. Outcomes showed unchanged pain, opioid and quality of life between groups.

Conclusion

The use of modified battlefield acupuncture protocol does not change pain opioid use or quality of life in those with lower extremity surgery.
Speed tuning to real-world-and retinal motion in cortical motion regions
Authors: Hacialihafiz Didem Korkmaz , Bartels Andreas
Published: October 2018

Motion signals can arise for two reasons in the retina: due to self-motion or due to real motion in the environment. Prior studies on speed tuning always measured joint responses to real and retinal motion, and for some of the more recently identified human motion processing regions, speed tuning has not been examined in at all. We localized motion regions V3A, V6, V5/MT, MST and cingulate sulcus visual area (CSv) in 20 human participants, and then measured their responses to motion velocities from 1-24 degrees per second. Importantly, we used a pursuit paradigm that allowed us to quantify responses to objective and retinal motion separately. In order to provide optimal stimulation, we used stimuli with natural image statistics derived from Fourier scrambles of natural images. The results show that all regions increased responses with higher speeds for both, retinal and objective motion. V3A stood out in that it was the only region whose slope of the speed-response function for objective motion was higher than that for retinal motion. V6, V5/MT, MST and CSv did not differ in objective and retinal speed slopes, even though V5/MT and MST tended to respond more to objective motion at all speeds. These results reveal highly similar speed tuning functions for early and high-level motion regions, and support the view that human V3A encodes primarily objective rather than retinal motion signals.
Electrospray sample injection for single-particle imaging with X-ray lasers
Authors: Bielecki Johan , Hantke Max F. , Daurer Benedikt J. , Reddy Hemanth K. N. , Hasse Dirk , Larsson Daniel S. D. , Gunn Laura H. , Svenda Martin , Munke Anna , Sellberg Jonas A. , Flueckiger Leonie , Pietrini Alberto , Nettelblad Carl , Lundholm Ida , Carlsson Gunilla , Okamoto Kenta , Timneanu Nicusor , Westphal Daniel , Kulyk Olena , Higashiura Akifumi , van der Schot Gijs , Loh Duane , Wysong Taylor E. , Bostedt Christoph , Gorkhover Tais , Iwan Bianca , Seibert M. Marvin , Osipov Timur , Walter Peter , Hart Philip , Bucher Maximilian , Ulmer Anatoli , Ray Dipanwita , Carini Gabriella , Ferguson Ken R. , Andersson Inger , Andreasson Jakob , Hajdu Janos , Maia Filipe R. N. C.
Published: October 2018

The possibility of imaging single proteins constitutes an exciting challenge for X-ray lasers. Despite encouraging results on large particles, imaging small particles has proven to be difficult for two reasons: not quite high enough pulse intensity from currently available X-ray lasers and, as we demonstrate here, contamination of the aerosolised molecules by non-volatile contaminants in the solution. The amount of contamination on the sample depends on the initial droplet-size during aerosolisation. Here we show that with our electrospray injector we can decrease the size of aerosol droplets and demonstrate virtually contaminant-free sample delivery of organelles, small virions, and proteins. The results presented here, together with the increased performance of next generation X-ray lasers, constitute an important stepping stone towards the ultimate goal of protein structure determination from imaging at room temperature and high temporal resolution.
Rational construction of compact de novo-designed biliverdin-binding proteins
Authors: Sheehan Molly M. , Magaraci Michael S. , Kuznetsov Ivan A. , Mancini Joshua A. , Kodali Goutham , Moser Christopher C. , Leslie Dutton P. , Chow Brian Y.
Published: October 2018

We report the rational construction of ade novo-designed biliverdin-binding protein by first principles of protein design, informed by energy minimization modeling in Rosetta. The self-assembling tetrahelical bundles bind biliverdin IXa (BV) cofactor auto-catalyticallyin vitro, similar to photosensory proteins that bind BV (and related bilins, or linear tetrapyrroles) despite lacking sequence and structural homology to the natural counterparts. Upon identifying a suitable site for cofactor ligation to the protein scaffold, stepwise placement of residues stabilized BV within the hydrophobic core. Rosetta modeling was used in the absence of a high-resolution structure to define the structure-function of the binding pocket. Holoprotein formation indeed stabilized BV, resulting in increased far-red BV fluorescence. By removing segments extraneous to cofactor stabilization or bundle stability, the initial 15-kilodaltonde novo-designed fluorescence-activating protein (“dFP”) was truncated without altering its optical properties, down to a miniature 10-kilodalton “mini,” in which the protein scaffold extends only a half-heptad repeat beyond the hypothetical position of the bilin D-ring. This work demonstrates how highly compact holoprotein fluorochromes can be rationally constructed usingde novoprotein design technology and natural cofactors.
Protein-protein binding pathways and calculations of rate constants using fully continuous explicit solvent simulations
Authors: Saglam Ali S. , Chong Lillian T.
Published: October 2018

A grand challenge in the field of biophysics has been the complete characterization of protein-protein binding processes at atomic resolution. This characterization requires the direct simulation of binding pathways starting from the initial unbound state and proceeding through states that are too transient to be captured by experiment. Here we applied the weighted ensemble path sampling strategy to enable atomistic simulation of protein-protein binding pathways. Our simulation generated 203 fully continuous binding pathways for the bacterial proteins, barnase and barstar, yielding a computed kon that is within error of experiment. Results reveal that the formation of the “encounter complex” intermediate is rate limiting with ~11% of all diffusional collisions being productive. Consistent with experiment, our simulations identify R59 as the most kinetically important barnase residue for the binding process. Furthermore, protein desolvation occurs late in the binding process during the rearrangement of the encounter complex to the native complex. Notably, the positions of interfacial crystallographic water molecules that bridge hydrogen bonds between barnase and barstar are occupied upon formation of the native complex in our simulations. Our simulations were completed within a month using 1600 CPU cores at a time, demonstrating that it is now practical to carry out atomistic simulations of protein-protein binding processes, particularly using the latest GPU-accelerated computing.
CTCF looping is established during gastrulation in medaka embryos
Authors: Nakamura Ryohei , Motai Yuichi , Kumagai Masahiko , Nishiyama Haruyo , Durand Neva C. , Kondo Kaori , Kondo Takashi , Tsukahara Tatsuya , Shimada Atsuko , Lieberman Aiden Erez , Morishita Shinichi , Takeda Hiroyuki
Published: October 2018

Genome architecture plays a critical role in gene regulation, but how the structures seen in mature cells emerge during embryonic development remains poorly understood. Here, we study early development in medaka (the Japanese killifish, Oryzias latipes) at 12 time points before, during, and after gastrulation which is the most dramatic event in early embryogenesis, and characterize transcription, protein binding, and genome architecture. We find that gastrulation is most associated with drastic changes in genome architecture, including the formation of the first loops between sites bound by the insulator protein CTCF and great increase in the size of contact domains. However, the position of CTCF is fixed throughout medaka embryogenesis. Interestingly, genome-wide transcription precedes the emergence of mature domains and CTCF-CTCF loops.
Evolutionary exploitation of PD-L1 expression in hormone receptor positive breast cancer
Authors: West Jeffrey , Park Derek , Harmon Cathal , Williamson Drew , Ashcroft Peter , Maestrini Davide , Ardaseva Alexandra , Bravo Rafael , Sahoo Prativa , Khong Hung , Luddy Kimberly , Robertson-Tessi Mark
Published: October 2018

Based on clinical data from hormone positive breast cancer patients, we determined that there is a potential tradeoff between reducing tumor burden and altering metastatic potential when administering combination therapy of aromatase inhibitors and immune checkpoint inhibitors. While hormone-deprivation therapies serve to reduce tumor size in the neoadjuvant setting pre-surgery, they may induce tumors to change expression patterns towards a metastatic phenotype. We used mathematical modeling to explore how the timing of the therapies affects tumor burden and metastatic potential with an eye toward developing a dynamic prognostic score and reducing both tumor size and risk of metastasis.
Atlas of Subcellular RNA Localization Revealed by APEX-seq
Authors: Fazal Furqan M. , Han Shuo , Kaewsapsak Pornchai , Parker Kevin R. , Xu Jin , Boettiger Alistair N. , Chang Howard Y. , Ting Alice Y.
Published: October 2018

We introduce APEX-seq, a method for RNA sequencing based on spatial proximity to the peroxidase enzyme APEX2. APEX-seq in nine distinct subcellular locales produced a nanometer-resolution spatial map of the human transcriptome, revealing extensive and exquisite patterns of localization for diverse RNA classes and transcript isoforms. We uncover a radial organization of the nuclear transcriptome, which is gated at the inner surface of the nuclear pore for cytoplasmic export of processed transcripts. We identify two distinct pathways of messenger RNA localization to mitochondria, each associated with specific sets of transcripts for building complementary macromolecular machines within the organelle. APEX-seq should be widely applicable to many systems, enabling comprehensive investigations of the spatial transcriptome.
Causally investigating cortical dynamics and signal processing by targeting natural system attractors with precisely timed stimulation
Authors: Lisitsyn Dmitriy , Ernst Udo A.
Published: October 2018

1

Electrical stimulation is a promising tool for interacting with neuronal dynamics to identify neural mechanisms that underlie cognitive function. Since effects of a single short stimulation pulse typically vary greatly and depend on the current network state, many experimental paradigms have rather resorted to continuous or periodic stimulation in order to establish and maintain a desired effect. However, such an approach explicitly leads to forced and ‘unnatural’ brain activity. Further, continuous stimulation can make it hard to parse the recorded activity and separate neural signal from stimulation artifacts. In this study we propose an alternate strategy: by monitoring a system in realtime, we use the existing preferred states or attractors of the network and to apply short and precise pulses in order to switch between its preferred states. When pushed into one of its attractors, one can use the natural tendency of the system to remain in such a state to prolong the effect of a stimulation pulse, opening a larger window of opportunity to observe the consequences on cognitive processing. To elaborate on this idea, we consider flexible information routing in the visual cortex as a prototypical example. When processing a stimulus, neural populations in the visual cortex have been found to engage in synchronized gamma activity. In this context, selective signal routing is achieved by changing the relative phase between oscillatory activity in sending and receiving populations (communication through coherence, CTC). In order to explore how perturbations interact with CTC, we investigate a biophysically realistic network exhibiting similar synchronization and signal routing phenomena. We develop a closed-loop stimulation paradigm based on the phase-response characteristics of the network and demonstrate its ability to establish desired synchronization states. By measuring information content throughout the model, we evaluate the effect of signal contamination caused by the stimulation in relation to the magnitude of the injected pulses and intrinsic noise in the system. Finally, we demonstrate that, up to a critical noise level, precisely timed perturbations can be used to artificially induce the effect of attention by selectively routing visual signals to higher cortical areas.
Rapid Tilt-Series Acquisition for Electron Cryotomography
Authors: Chreifi Georges , Chen Songye , Metskas Lauren Ann , Kaplan Mohammed , Jensen Grant J.
Published: October 2018

Using a new Titan Krios stage equipped with a single-axis holder, we developed two methods to accelerate the collection of tilt-series. We demonstrate a continuous-tilting method that can record a tilt-series in seconds (about 100x faster than current methods), but with loss of details finer than ∼4 nm. We also demonstrate a fast-incremental method that can record a tilt-series about 10x faster than current methods and with similar resolution. We characterize the utility of both methods in real biological electron cryotomography workflows. We identify opportunities for further improvements in hardware and software and speculate on the impact such advances could have on structural biology.
Unc 51–like autophagy-activating kinase (ULK1) mediates clearance of free α-globin in β-thalassemia
Authors: Lechauve Christophe , Keith Julia , Khandros Eugene , Fowler Stephanie , Mayberry Kalin , Freiwan Abdullah , Thom Christopher S. , Delbini Paola , Romero Emilio Boada , Zhang Jingjing , Motta Irene , Tillman Heather , Cappellini M. Domenica , Kundu Mondira , Weiss Mitchell J.
Published: October 2018

Erythroid maturation is coordinated to maximize the production of hemoglobin A heterotetramers (α2β2) and minimize the accumulation of potentially toxic free α- or β-globin subunits. In β-thalassemia, mutations in the β-globin gene cause a build-up of free α-globin, which forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality-control systems mitigate β-thalassemia pathophysiology by degrading toxic free α-globin. We show that loss of the Unc 51–like autophagy-activating kinase geneUlk1in β-thalassemic mice reduces autophagic clearance of α-globin in red cell precursors and exacerbates disease phenotypes, whereas inactivation of the canonical autophagy geneAtg5has minimal effects. Systemic treatment with rapamycin to inhibit the ULK1 inhibitor mTORC1 reduces α-globin precipitates and lessens pathologies in β-thalassemic mice, but not in those lackingUlk1. Similarly, rapamycin reduces free α-globin accumulation in erythroblasts derived from β-thalassemic patient CD34+hematopoietic progenitors. Our findings identify a new, drug-regulatable pathway for ameliorating β-thalassemia.

One Sentence Summary

Rapamycin alleviates β-thalassemia by stimulating ULK1-dependent autophagy of toxic free α-globin.
Human Handedness: Genetics, Microtubules, Neuropsychiatric Diseases and Brain Language Areas
Authors: Wiberg A. , Douaud G. , Ng M. , Al Omran Y. , Alfaro-Almagro F. , Marchini J. , Bennett D.L. , Smith S. , Furniss D.
Published: October 2018

Background

The skew in distribution of handedness is a uniquely human trait, and has fascinated researchers for centuries. The heritability of handedness is estimated at 25%, but defining genetic variants contributing to this trait has so far proved elusive.

Methods

We performed GWAS of self-reported handedness in UK Biobank, a prospective cohort study of ∼500,000 individuals. Furthermore, we investigated correlations between our associated SNPs and brain imaging-derived phenotypes (IDPs) from >9,000 individuals in UK Biobank, as well as between self-reported handedness and IDPs.

Results

Our association study of 38,322 left-handers vs 356,567 right-handers (excluding ambidextrous participants) revealed three genome-wide significant loci (rs199512, 17q21.31, p=4.1x10−9; rs45608532, 22q11.22, p=1.4x10−8; rs13017199, 2q34, p=3.3x10−8). In the imaging study, we found strong associations between rs199512 and diffusion MRI measures mainly in white matter tracts connecting language-related brain regions (p<2.0x10−6). Direct investigation between handedness and IDPs revealed numerous associations with functional connectivity between the same language-related areas of the brain. A second GWAS of non-right handers (n=44,631) vs right-handers (n=356,567) revealed an additional locus: rs3094128, 6p21.33, p=2.9x10−8. Three of the four associated loci (2q34, 17q21.31, 6p21.33) contain genes that encode microtubule-related proteins that are highly expressed in the brain: MAP2, MAPT and TUBB. These genes are strongly implicated in the pathogenesis of diseases that are known to affect an excess of left-handed people, including schizophrenia.

Conclusions

This is the first GWAS to identify genome-wide significant loci for human handedness in the general population, and the genes at these loci have biological plausibility in contributing to neurodevelopmental lateralization of brain organisation, which appears to predispose both to left-handedness and to certain neurodegenerative and psychiatric diseases.
Connect-seq to superimpose molecular on anatomical neural circuit maps
Authors: Hanchate Naresh K. , Lee Eun Jeong , Ellis Andria , Kondoh Kunio , Kuang Donghui , Basom Ryan , Trapnell Cole , Buck Linda B.
Published: October 2018

The mouse brain contains ~100 million neurons interconnected in a vast array of neural circuits. The identities and functions of individual neuronal components of most circuits are undefined. Here we describe a method, termed ‘Connect-seq’, which combines retrograde viral tracing and single cell transcriptomics to uncover the molecular identities of upstream neurons in a specific circuit and the signaling molecules they use to communicate. Connect-seq can generate a molecular map that can be superimposed on a neuroanatomical map to permit molecular and genetic interrogation of how the neuronal components of a circuit control its function. Application of this method to hypothalamic neurons controlling physiological responses to fear and stress reveal subsets of upstream neurons that express diverse constellations of signaling molecules and can be distinguished by their anatomical locations.
Doctoring knowledge or acknowledging doctors?
Authors: Carter Jennifer , Smith Erin F. , Gelves‐Gomez Francisco
Published: October 2018

Doctoral forms of study are now diverse, although debate exists about whether ontological differences separate the research‐based Doctor of Philosophy (PhD) from alternative doctoral forms that contribute to professional practice. The purpose and processes of doctoral study and prevailing market logics that suit the knowledge economy affect the doctoral experience. Solutions entail relationality between the ideas that members of society hold about the ontology and purpose of the PhD and alternative doctoral forms, individual existential desires, and the materialities of the contemporary workplace. The PhD discursively contributes to both academic and professional becoming, with deep disciplinary mastery of threshold concepts. Disciplinary learning groups offer a critical and sometimes transforming experience. In addition to preparing the next generation of academics, the traditional PhD offers high‐level generic skills that are rare outside academia. In geography, especially, these skills are increasingly valued in society, not least when combined with diverse content that is highly relevant to contemporary global challenges. Institutions might help staff and candidates resist neoliberal tendencies for timely completions and offer a more appropriate learning experience, alongside ethical and transparent promotion of the purpose and practices of the doctoral experience. In time, such changes might signal a transformation influencing how all actors from society, the institution of higher education, supervisory staff, and doctoral candidates imagine doctoral and post‐doctoral work—“acknowledging” doctoral expertise and its societal value from both within and outside the academy.
HbA1c predicts long‐term postoperative mortality in patients with unknown glycemic status at admission for vascular surgery: An exploratory study
Authors: Hjellestad Iren D. , Søfteland Eirik , Husebye Eystein S. , Jonung Torbjørn
Published: October 2018

Background

Peripheral arterial disease (PAD) and diabetes mellitus (DM) represent major public health challenges and are tightly associated. To facilitate early diagnosis, HbA1c has been implemented as the preferred diagnostic tool for the diagnosis of type 2 DM. In this study, we compared and evaluated HbA1c, fasting plasma glucose (FPG), and 2‐hour post‐load glucose values to determine which test best predicted mortality in patients with PAD.

Methods

In all, 273 PAD patients with unknown glycemic status admitted to Haukeland University Hospital for elective surgery between October 2006 and September 2007 were included in the study. All 273 patients underwent a standard oral glucose tolerance test (OGTT) in addition to determination of HbA1c; patients were then grouped into those with DM, intermediate hyperglycemia, and normoglycemia according to World Health Organization and International Expert Committee criteria.

Results

All‐cause mortality was 40% over a 9‐year follow‐up period. After adjusting for age, sex, and relevant medication, HbA1c was a predictor for mortality (hazard ratio [HR] 1.54; 95% confidence interval [CI] 1.03‐2.32]; P = 0.04). The association did not achieve statistical significance in a fully adjusted Cox regression model, although the effect estimation of HbA1c on all‐cause mortality remained largely unchanged (HR 1.39; 95% CI 0.92‐2.09; P = 0.13). The OGTT was not a predictor of long‐term mortality.

Conclusions

The results indicate that HbA1c is a useful marker in the preoperative screening of patients of unknown glycemic status at the time of admission for vascular surgery, and may identify people at high risk of long‐term mortality following surgical treatment for PAD.
Electroencephalographic (EEG) density spectral array monitoring in children during sevoflurane anaesthesia: a prospective observational study
Authors: de Heer I. J. , Bouman S. J. M. , Weber F.
Published: October 2018

Electroencephalographic density spectral array monitoring has been developed to facilitate the interpretation of unprocessed electroencephalogram signals. The primary aim of this prospective observational study, performed in a tertiary children's hospital, was to identify the clinical applicability and validity of density spectral array monitoring in infants and children during sevoflurane anaesthesia. We included 104 children, aged < 6 years, undergoing elective surgery during sevoflurane anaesthesia. We investigated the correlation between non‐steady state end‐tidal sevoflurane and the expression of the four electroencephalogram frequency bands β, α, θ and δ, representing density spectral array. Patients were divided into three age groups (< 6 months, 6–12 months, > 12 months). There was a significant correlation between end‐tidal sevoflurane and density spectral array in the age groups 6–12 months (p < 0.05) and 1–6 years (p < 0.0001). In infants < 6 months of age, the relative percentages of density spectral array did not correlate with end‐tidal sevoflurane. The main finding was that different end‐tidal concentrations of sevoflurane produce age‐dependent changes in the density spectral array power spectrum. In infants younger than 6 months‐old, α and β coherence are absent, whereas θ and δ oscillations have already emerged. In cases where anaesthesia was too deep, this presented as burst suppression on the electroencephalogram, θ disappeared, leaving the electroencephalographic activity in the δ range. Future research should address this issue, aiming to clarify whether the emergence of θ oscillations in infants helps to prevent sevoflurane overdosing.
A Hybrid Phase I-II/III Clinical Trial Design Allowing Dose Re-Optimization in Phase III
Authors: Chapple Andrew G. , Thall Peter F.
Published: October 2018

Conventionally, evaluation of a new drug, A, is done in three phases. Phase I is based on toxicity to determine a “maximum tolerable dose” (MTD) of A, phase II is conducted to decide whether A at the MTD is promising in terms of response probability, and if so a large randomized phase III trial is conducted to compare A to a control treatment, usually based on survival time or progression free survival time. It is widely recognized that this paradigm has many flaws. A recent approach combines the first two phases by conducting a phase I-II trial, which chooses an optimal dose based on both efficacy and toxicity, and evaluation of A at the selected optimal phase I-II dose then is done in a phase III trial. This paper proposes a new design paradigm, motivated by the possibility that the optimal phase I-II dose may not maximize mean survival time with A. We propose a hybridized design, which we call phase I-II/III, that combines phase I-II and phase III by allowing the chosen optimal phase I-II dose of A to be re-optimized based on survival time data from phase I-II patients and the first portion of phase III. The phase I-II/III design uses adaptive randomization in phase I-II, and relies on a mixture model for the survival time distribution as a function of efficacy, toxicity, and dose. A simulation study is presented to evaluate the phase I-II/III design and compare it to the usual approach that does not re-optimize the dose of A in phase III.
Omega‐3 fatty acids regulate plasticity in distinct hippocampal glutamatergic synapses
Authors: Aryal Sanjay , Hussain Suleman , Drevon Christian A. , Nagelhus Erlend , Hvalby Øyvind , Jensen Vidar , Walaas Sven Ivar , Davanger Svend
Published: October 2018

Dietary omega‐3 fatty acids accumulate and are actively retained in central nervous system membranes, mainly in synapses, dendrites and photoreceptors. Despite this selective enrichment, their impact on synaptic function and plasticity has not been fully determined at the molecular level. In this study, we explored the impact of omega‐3 fatty acid deficiency on synaptic function in the hippocampus. Dietary omega‐3 fatty acid deficiency for 5 months after weaning led to a 65% reduction in the concentration of docosahexaenoic acid in whole brain synaptosomal phospholipids with no impact on global dopaminergic or serotonergic turnover. We observed reduced concentrations of glutamate receptor subunits, including GluA1, GluA2 and NR2B, and synaptic vesicle proteins synaptophysin and synaptotagmin 1 in hippocampal synaptosomes of omega‐3 fatty acid‐deficient mice as compared to the omega‐3 fatty acid rich group. In contrast, an increased concentration of neuronal inositol 1,4,5‐trisphosphate‐receptor (IP3‐R) was observed in the deficient group. Furthermore, omega‐3 fatty acid deficiency reduced the long‐term potentiation (LTP) in stratum oriens of the hippocampal CA1 area, but not in stratum radiatum. Thus, omega‐3 fatty acids seem to have specific effects in distinct subsets of glutamatergic synapses, suggesting specific molecular interactions in addition to altering plasma membrane properties on a more global scale.
Spatial structure facilitates the accumulation and persistence of antibiotic‐resistant mutants in biofilms
Authors: France Michael T. , Cornea Ana , Kehlet‐Delgado Hanna , Forney Larry J.
Published: October 2018

The emergence and spread of antibiotic resistance in bacterial pathogens are a global crisis. Because many bacterial infections are caused by pathogens that reside in biofilms, we sought to investigate how biofilms influence the evolution of antibiotic resistance. We hypothesize that the inherent spatial structure of biofilms facilitates the accumulation and persistence of spontaneously evolved antibiotic‐resistant mutants. To test this, we tracked the frequency of mutants resistant to kanamycin and rifampicin in biofilm populations of Escherichia coli before, during, and after an antibiotic treatment regimen. Our results show that biofilms accumulate resistant mutants even in the absence of antibiotics. This resistance was found to be heritable and thus unlike the phenotypic plasticity of so‐called “persister cells” that have been shown to occur in biofilms. Upon exposure to an antibiotic, resistant mutants swept to high frequency. Following the conclusion of treatment, these resistant mutants remained at unexpectedly high frequencies in the biofilms for over 45 days. In contrast, when samples from kanamycin‐treated biofilms were used to found well‐mixed liquid cultures and propagated by serial transfer, the frequency of resistant cells dramatically decreased as they were outcompeted by sensitive clones. These observations suggest that the emergence of antibiotic resistance through spontaneous mutations in spatially structured biofilms may significantly contribute to the emergence and persistence of mutants that are resistant to antibiotics used to treat bacterial infections.