bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine learning to predict the long-term risk of myocardial infarction and cardiac death based on clinical risk, coronary calcium, and epicardial adipose tissue: a prospective study
Authors: Commandeur Frederic , Slomka Piotr J , Goeller Markus , Chen Xi , Cadet Sebastien , Razipour Aryabod , McElhinney Priscilla , Gransar Heidi , Cantu Stephanie , Miller Robert J H , Rozanski Alan , Achenbach Stephan , Tamarappoo Balaji K , Berman Daniel S , Dey Damini
Published: November 2019

Aims

Our aim was to evaluate the performance of machine learning (ML), integrating clinical parameters with coronary artery calcium (CAC), and automated epicardial adipose tissue (EAT) quantification, for the prediction of long-term risk of myocardial infarction (MI) and cardiac death in asymptomatic subjects.

Methods and results

Our study included 1912 asymptomatic subjects [1117 (58.4%) male, age: 55.8 ± 9.1 years] from the prospective EISNER trial with long-term follow-up after CAC scoring. EAT volume and density were quantified using a fully automated deep learning method. ML extreme gradient boosting was trained using clinical co-variates, plasma lipid panel measurements, risk factors, CAC, aortic calcium, and automated EAT measures, and validated using repeated 10-fold cross validation. During mean follow-up of 14.5 ± 2 years, 76 events of MI and/or cardiac death occurred. ML obtained a significantly higher AUC than atherosclerotic cardiovascular disease (ASCVD) risk and CAC score for predicting events (ML: 0.82; ASCVD: 0.77; CAC: 0.77, P < 0.05 for all). Subjects with a higher ML score (by Youden’s index) had high hazard of suffering events (HR: 10.38, P < 0.001); the relationships persisted in multivariable analysis including ASCVD-risk and CAC measures (HR: 2.94, P = 0.005). Age, ASCVD-risk, and CAC were prognostically important for both genders. Systolic blood pressure was more important than cholesterol in women, and the opposite in men.

Conclusions

In this prospective study, machine learning used to integrate clinical and quantitative imaging-based variables significantly improves prediction of MI and cardiac death compared with standard clinical risk assessment. Following further validation, such a personalized paradigm could potentially be used to improve cardiovascular risk assessment.
Efficacy of JAK inhibitors in Crohn’s Disease
Authors: Rogler Gerhard
Published: November 2019

Inhibition of Janus kinases [JAKs] in Crohn’s disease [CD] patients has shown conflicting results in clinical trials. Tofacitinib, a pan-JAK inhibitor, showed efficacy in ulcerative colitis [UC] and has been approved for the treatment of patients with moderate to severe UC. In contrast, studies in CD patients were disappointing and the primary end point of clinical remission could not be met in the respective phase II induction and maintenance trials. Subsequently, the clinical development of tofacitinib was discontinued in CD. In contrast, efficacy of filgotinib, a selective JAK1 inhibitor, in CD patients was demonstrated in the randomized, double-blinded, placebo-controlled phase II FITZROY study. Upadacitinib also showed promising results in a phase II trial in moderate to severe CD. Subsequently, phase III programmes in CD have been initiated for both substances, which are still ongoing. Several newer molecules of this class of orally administrated immunosuppressants are being tested in clinical programmes. The concern of side effects of systemic JAK inhibition is addressed by either exclusively intestinal action or higher selectivity [Tyk2 inhibitors]. In general, JAK inhibitors constitute a new promising class of drugs for the treatment of CD.
Biosensors design in yeast and applications in metabolic engineering
Authors: Qiu Chenxi , Zhai Haotian , Hou Jin
Published: November 2019

Engineering microbial cell factories is a potential approach of sustainable production of chemicals, fuels and pharmaceuticals. However, testing the production of molecules in high throughput is still a time-consuming and laborious process since product synthesis usually does not confer a clear phenotype. Therefore, it is necessary to develop new techniques for fast high-producer screening. Genetically encoded biosensors are considered to be promising devices for high-throughput analysis owing to their ability to sense metabolites and couple detection to an actuator, thereby facilitating the rapid detection of small molecules at single-cell level. Here, we review recent advances in the design and engineering of biosensors in Saccharomyces cerevisiae, and their applications in metabolic engineering. Three types of biosensor are introduced in this review: transcription factor based, RNA-based and enzyme-coupled biosensors. The studies to improve the features of biosensors are also described. Moreover, we summarized their metabolic engineering applications in dynamic regulation and high producer selection. Current challenges in biosensor design and future perspectives on sensor applications are also discussed.
The Telegraphic Revolution: Speed, Space and Time in the Nineteenth Century*
Authors: Johnston Jean-Michel
Published: November 2019

This article investigates the impact of the ‘communications revolution’ upon experiences of time and space during the nineteenth century. Focusing upon the first three decades of telegraphic communication, it unpacks the assumptions underlying linear narratives of ‘acceleration’ and ‘time-space compression’ to understand the roots of Germany’s fraught relationship to modernity. In doing so, it highlights the importance of the changes which took place between the 1848 revolutions and the early years of the Kaiserreich and which laid the foundations for the peculiarities of the Wilhelmine Era. During this period, it argues, the perceived impact of telegraphic communication, the ‘expansion’ or ‘contraction’ of space and time, varied from one person and place to another, reflecting the technology’s progressive and uneven expansion across Germany. Access to new networks of communication was dependent upon, and in turn influenced, the changing status of individuals, towns and the countryside experiencing the forces of industrialization, market capitalism and globalization. Speed, space and time, as a result, became a measure of the divisions emerging in modern Germany.
Candidate Biomarkers of Suicide Crisis Syndrome: What to Test Next? A Concept Paper
Authors: Calati Raffaella , Nemeroff Charles B , Lopez-Castroman Jorge , Cohen Lisa J , Galynker Igor
Published: November 2019

Background

There has been increasing interest in both suicide-specific diagnoses within the psychiatric nomenclature and related biomarkers. Because the Suicide Crisis Syndrome—an emotional crescendo of several interrelated symptoms—seems to be promising for the identification of individuals at risk of suicide, the aim of the present paper is to review the putative biological underpinnings of the Suicide Crisis Syndrome symptoms (entrapment, affective disturbance, loss of cognitive control, hyperarousal, social withdrawal).

Methods

A PubMed literature search was performed to identify studies reporting a link between each of the 5 Suicide Crisis Syndrome symptoms and biomarkers previously reported to be associated with suicidal outcomes.

Results

Disturbances in the hypothalamic-pituitary-adrenal axis, with dysregulated corticotropin-releasing hormone and cortisol levels, may be linked to a sense of entrapment. Affective disturbance is likely mediated by alterations in dopaminergic circuits involved in reward and antireward systems as well as endogenous opioids. Loss of cognitive control is linked to altered neurocognitive function in the areas of executive function, attention, and decision-making. Hyperarousal is linked to autonomic dysregulation, which may be characterized by a reduction in both heart rate variability and electrodermal activity. Social withdrawal has been associated with oxytocin availability. There is also evidence that inflammatory processes may contribute to individual Suicide Crisis Syndrome symptoms.

Conclusion

The Suicide Crisis Syndrome is a complex syndrome that is likely the consequence of distinct changes in interconnected neural, neuroendocrine, and autonomic systems. Available clinical and research data allow for development of empirically testable hypotheses and experimental paradigms to scrutinize the biological substrates of the Suicide Crisis Syndrome.
Interleukin-34 expression in ovarian cancer: a possible correlation with disease progression
Authors: Endo Hiraku , Hama Naoki , Baghdadi Muhammad , Ishikawa Kozo , Otsuka Ryo , Wada Haruka , Asano Hiroshi , Endo Daisuke , Konno Yosuke , Kato Tatsuya , Watari Hidemichi , Tozawa Akiko , Suzuki Nao , Yokose Tomoyuki , Takano Atsushi , Kato Hisamori , Miyagi Yohei , Daigo Yataro , Seino Ken-ichiro
Published: November 2019

Ovarian cancer is the second-most lethal gynecological malignancy and the seventh-commonest cause of cancer-related death in women around the world. Most of the ovarian cancer patients are diagnosed at advanced stages and suffer from recurrence after primary cytoreductive surgery and standard first-line chemotherapy. Thus, the successful management of ovarian cancer patients requires the identification of factors that contribute to progression and relapse. Interleukin-34 (IL-34) is a novel cytokine that acts as a tissue-specific ligand of colony-stimulating factor-1 receptor (CSF-1R). In cancer, IL-34 exerts pro-tumorigenic functions that promote tumor growth, metastasis, angiogenesis, immune suppression and therapeutic resistance. In this study, we evaluate the impact of IL-34 on progression and survival of ovarian cancer patients. First, IL-34 was found to be expressed in several human ovarian cancer cell lines and cancer tissues from patients. The expression of IL-34 was enhanced by cytotoxic chemotherapy in ovarian cancer cell lines and cancer tissues from chemotherapy-treated ovarian cancer patients. Importantly, high IL-34 expression correlated with worse progression-free survival (PFS) and overall survival in different cohorts. The assessment of PFS based on a combination between IL34 expression and other related genes such as CSF1R and CD163 helped further to reach more statistical significance compared with IL34 alone. Furthermore, in the murine ovarian cancer cell HM-1 in vivo model, it was suggested that IL-34-derived tumor cells was correlated with tumor progression and survival by modulating the immune environment. Collectively, these findings indicate a possible correlation between IL-34 expression and disease progression in ovarian cancer patients and the mouse model.
Influence of Host Plant Species and Fertilization Regime on Larval Performance and Feeding Preference of the Redbacked Cutworm and the Pale Western Cutworm (Lepidoptera: Noctuidae)
Authors: Batallas Ronald E , Evenden Maya L
Published: November 2019

The redbacked cutworm, Euxoa ochrogaster (Guenée), and the pale western cutworm, Agrotis orthogonia (Morrison), are generalist pests that cause sporadic economic damage to several annual crops in the Canadian Prairies. Early larval instars feed on foliage, whereas mature larvae eat into the stem and sever crop seedlings. Here, we evaluate the influence of annual crop species and host fertilization on the larval performance and feeding preference of both cutworm species. Performance is the ability of an insect to reach its maximum growth potential. The first set of experiments evaluated larval development and preference on canola (Brassica napus L. [Capparales: Brassicaeae]), field peas (Pisum sativa L. [Fabales: Fabaceae]), and spring wheat (Triticum aestivum L. [Cyperales: Poaceae]). The redbacked cutworm had higher performance on canola and peas, while the pale western cutworm had higher performance on wheat. In multiple-choice feeding experiments, the redbacked cutworm consumed more canola, whereas the pale western cutworm consumed more spring wheat. The third set of experiments evaluated larval development on fertilized and unfertilized seedlings of canola and spring wheat seedlings. When fed unfertilized seedlings, the redbacked cutworm had better performance on canola than spring wheat, whereas pale western cutworm had better performance on spring wheat than canola. Fertilizer application enhanced the performance of both cutworms regardless of the crop species. Despite their generalist feeding behavior, both cutworm species have a larval feeding preference for the host plant on which they achieve high performance. Canola-cereal cropping is a common crop rotation schedule in the region; however, this tactic will not negatively impact cutworm performance.
Molecular Features and Expression Patterns of Vitellogenin Receptor in Calliptamus italicus (Orthoptera: Acrididae)
Authors: Xiang Min , Sang Di , Dong Bin , Hu Hongxia , Ji Rong , Wang Han
Published: November 2019

Vitellogenin receptor (VgR) mediates the intake of vitellin via oocytes, thus exerting an important role in vitellogenesis. In this study, reverse transcription-polymerase chain reaction (RT-PCR) and rapid-amplification of cDNA ends techniques were adopted to clone the CiVgR gene, namely the VgR gene of Calliptamus italicus, i.e., Orthopteran. The full length of CiVgR was 5,589 bp, and the open reading frame was estimated to be 5,265 bp, which encoded 1,754 amino acids (aa). Sequence alignment analysis showed that CiVgR belonged to the superfamily of low-density lipoprotein receptor genes, which contained several conserved domains, including ligand-binding domains, epidermal growth factor precursor homology domains, transmembrane domains, and cytoplasmic domains. However, no O-linked sugar domain was identified. Phylogenetic analysis showed that CiVgR had the closest genetic relationship to Blattarias. RT-PCR showed that CiVgR was only specifically expressed in the ovarian tissue of females. quantitative real time polymerase chain reaction showed that the transcription of CiVgR already appeared in the fourth-instar nymph of C. italicus, which gradually increased after adult emergence, peaked at the previtellogenesis stage, and then started to decrease. The expression pattern of CiVgR was closely associated with vitellogenesis. The findings of this study further our understanding of the molecular mechanisms involved in the reproduction of C. italicus, and provide new ideas to control this insect.
Comparative Mitogenomic Analysis of the Eurydema Genus in the Context of Representative Pentatomidae (Hemiptera: Heteroptera) Taxa
Authors: Zhao Wanqing , Zhao Qing , Li Min , Wei Jiufeng , Zhang Xianhong , Zhang Hufang
Published: November 2019

The family Pentatomidae, the largest within the superfamily Pentatomoidae, comprises about 5,000 species; many of which are economically important pests. Although the phylogeny of Pentatomidae species has been studied using various molecular markers, their phylogenetic relationships remain controversial. Recently, mitochondrial genomes (mitogenomes) have been extensively employed to examine the phylogenetics and evolution of different insects, and in this study, we sequenced complete/near-complete mitochondrial genomes from five shield bug species of Eurydema to gain a better understanding of phylogenetic relationships in the Pentatomidae. The five mitogenomes ranged in length from 15,500 to 16,752 bp and comprised 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and a control region. We compared mitogenomic characteristics of the Pentatomidae and constructed phylogenetic trees using Bayesian inference and maximum likelihood methods. Our results showed that gene arrangements, base composition, start/stop codons, gene overlaps, and RNA structures were conserved within the Pentatomidae and that congeneric species shared more characteristics. Saturation and heterogeneity analyses revealed that our PCGs and PCGRNA datasets were valid for phylogenetic analysis. Phylogenetic analyses showed consistent topologies based on BI and ML methods. These analyses strongly supported that Eurydema species belong to the tribe Strachiini, and formed a sister group with Pentatomini. The relationships among Eurydema species were shown to be consistent with their morphological features. (Strachiini + Pentatomini) was found to be a stable sibling of the clade comprising Cappaeini, Graphosomini, and Carpocorini. Furthermore, our results indicated that Graphosoma rubrolineatum (Heteroptera: Pentatomidae) belongs to the Pentatominae and not the Podopinae.
Understanding Immunity in Children Vaccinated With Live Attenuated Influenza Vaccine
Authors: Shannon Ian , White Chantelle L , Nayak Jennifer L
Published: November 2019

Live attenuated influenza vaccine (LAIV), or FluMist, was approved for use in the United States in 2003. This vaccine, administered intranasally, offers the advantage of stimulating immunity at the site of infection in the upper respiratory tract and, by mimicking natural infection, has the potential to elicit a multifaceted immune response. However, the development of immunity following LAIV administration requires viral replication, causing vaccine effectiveness to be impacted by both the replicative fitness of the attenuated viruses being administered and the degree of the host’s preexisting immunity. In this review, we discuss the current state of knowledge regarding the mechanisms of protection elicited by LAIV in children, contrast this with immune protection that develops upon vaccination with inactivated influenza vaccines, and briefly discuss both the potential advantages as well as challenges offered by this vaccination platform.
Exploring Scale Direction Effects and Response Behavior across PC and Smartphone Surveys
Authors: Krebs Dagmar , Höhne Jan Karem
Published: November 2019

The effects of scale direction on response behavior are well known in the survey literature, where a variety of theoretical approaches are discussed, and mixed empirical findings are reported. In addition, different types of survey completion devices seem to vary in their susceptibility to scale direction effects. In this study, we therefore investigate the effect of scale direction and device type on response behavior in PC and smartphone surveys. To do so, we conducted a web survey experiment in a German non-probability access panel (N = 3,401) using a two-step split-ballot design with four groups that are defined by device type (PC and smartphone) and scale direction (decremental and incremental). The results reveal that both PCs and smartphones are robust against scale direction effects. The results also show that response behavior differs substantially between PCs and smartphones, indicating that the device type (PC or smartphone) matters. In particular, the findings show that the comparability of data obtained through multi-device surveys is limited.
Chasing candidate Supergiant Fast X-ray Transients in the 1000 orbits INTEGRAL/IBIS catalogue
Authors: Sguera V , Sidoli L , Bird A J , Paizis A , Bazzano A
Published: November 2019

We report results from an investigation at hard X-rays (above 18 keV) and soft X-rays (below 10 keV) of a sample of X-ray transients located on the Galactic plane and detected with the bursticity method, as reported in the latest 1000 orbits INTEGRAL/IBIS catalogue. Our main aim has been to individuate those with X-rays characteristics strongly resembling Supergiant Fast X-ray Transients (SFXTs). As a result, we found four unidentified fast X-ray transients which now can be considered good SFXT candidates. In particular, three transients (IGR J16374–5043, IGR J17375–3022, and IGR J12341–6143) were very poorly studied in the literature before the current work, and our findings largely improved the knowledge of their X-ray characteristics. The other transient (XTE J1829–098) was previously studied in detail only below 10 keV, conversely the current work provides the first detailed study in outburst above 18 keV. In addition we used archival infrared observations of the transients to pinpoint, among the field objects, their best candidate counterpart. We found that their photometric properties are compatible with an early-type spectral classification, further supporting our proposed nature of SFXTs. Infrared spectroscopy is advised to confirm or disprove our interpretation. The reported findings allowed a significant increase of the sample of candidate SFXTs known to date, effectively doubling their number.
Comorbidities in ANCA-associated vasculitis
Authors: Kronbichler Andreas , Leierer Johannes , Gauckler Philipp , Shin Jae Il
Published: November 2019

The prognosis of patients with ANCA-associated vasculitis has improved over the past decades, but overall survival rates are still unsatisfactory. Recent research has focused on complications of immunosuppressive measures and comorbidities of ANCA-associated vasculitis. This review focuses on thromboembolic and cardiovascular events. A considerably increased risk of thromboembolic events has been reported, which is associated with active disease and impaired coagulation factors. There is mounting evidence that a hypercoagulable state is present even in patients in remission, and studies investigating the impact of tailored anticoagulation are needed to reduce the burden of thromboembolism. Cardiovascular mortality is one of the leading causes of death and accelerated atherosclerosis is frequently observed in patients with ANCA-associated vasculitis. A high frequency of patients develops hypertension, diabetes mellitus and hypercholesterolaemia, either as a consequence of immunosuppression or associated with the underlying disease. The current control of modifiable cardiovascular risk factors is insufficient and thorough reviews should be performed periodically. Treatment of these risk factors should be adopted according to current recommendations related to individual cardiovascular risk prediction.
Lysobacter enzymogenes Employs Diverse Genes for Inhibiting Hypha Growth and Spore Germination of Soybean Fungal Pathogens
Authors: Yu Menghao , Zhang Guiying , Jiang Jiasong , Du Liangcheng , Zhao Youfu
Published: November 2019

Lysobacter enzymogenes strain C3 (LeC3) is a potential biocontrol agent for plant diseases caused by fungi and oomycetes. Understanding the interaction between LeC3 and soybean pathogens at the molecular level could help improve its biocontrol efficacy. In this study, we obtained mutants with decreased abilities in inhibiting hypha growth of the white mold pathogen Sclerotinia sclerotiorum. Insertion sites for 50 mutants, which no longer inhibited S. sclerotiorum hypha growth in dual cultural assay, were determined and seven mutants were selected for further characterization. These seven mutants also completely lost their abilities in suppressing spore germination of Fusarium virguliforme, the causal agent of soybean sudden death syndrome. Furthermore, mutation of the seven genes, which encode diguanylate cyclase, transcriptional regulators from the TetR family, hemolysin III family channel protein, type IV secretion system VirB10 protein, phenol hydroxylase, and phosphoadenosine phosphosulfate reductase, respectively, led to reduced production or secretion of four extracellular enzymes and heat-stable antifungal factor (HSAF). These results suggest that these seven genes play important roles in L. enzymogenes in suppressing hypha growth and spore germination of fungal pathogens, probably by influencing production or secretion of extracellular enzymes and HSAF.
Mathematical modelling identifies the role of adaptive immunity as a key controller of respiratory syncytial virus in cotton rats
Authors: Wethington Darren , Harder Olivia , Uppulury Karthik , Stewart William C. L. , Chen Phylip , King Tiffany , Reynolds Susan D. , Perelson Alan S. , Peeples Mark E. , Niewiesk Stefan , Das Jayajit
Published: November 2019

Respiratory syncytial virus (RSV) is a common virus that can have varying effects ranging from mild cold-like symptoms to mortality depending on the age and immune status of the individual. We combined mathematical modelling using ordinary differential equations (ODEs) with measurement of RSV infection kinetics in primary well-differentiated human bronchial epithelial culturesin vitroand in immunocompetent and immunosuppressed cotton rats to glean mechanistic details that underlie RSV infection kinetics in the lung. Quantitative analysis of viral titre kinetics in our mathematical model showed that the elimination of infected cells by the adaptive immune response generates unique RSV titre kinetic features including a faster timescale of viral titre clearance than viral production, and a monotonic decrease in the peak RSV titre with decreasing inoculum dose. Parameter estimation in the ODE model using a nonlinear mixed effects approach revealed a very low rate (average single-cell lifetime > 10 days) of cell lysis by RSV before the adaptive immune response is initiated. Our model predicted negligible changes in the RSV titre kinetics at early times post-infection (less than 5 dpi) but a slower decay in RSV titre in immunosuppressed cotton rats compared to that in non-suppressed cotton rats at later times (greater than 5 dpi)in silico.These predictions were in excellent agreement with the experimental results. Our combined approach quantified the importance of the adaptive immune response in suppressing RSV infection in cotton rats, which could be useful in testing RSV vaccine candidates.
The life and work of Robert J. Adcock. Part I: the figure of the Earth
Authors: Müller Wolfgang H. , Howarth Richard J.
Published: November 2019

The American mathematician Robert Jackson Adcock (1826–1895) is an obscure figure, hitherto associated with the history of regression analysis and least-squares, whose identity and life are described in Part II of this work. In 1872, he self-published a pamphlet, ‘Gravitation to the sphere and the two ellipsoids of revolution: ratio of the axes of a rotating fluid mass’, which seems to have been largely ignored at the time. It effectively became lost thereafter, until a copy was recently discovered in the Library of the Royal Society. In it, he determined the degree of flattening assumed by a rotating homogeneous
ellipsoidal
fluid Earth with a uniform density, subject to gravitational attraction and in hydrostatic equilibrium—a problem previously considered, but not solved, by Newton, Laplace, Gauss and Dirichlet. Adcock successfully obtained an explicit solution for the potential of a homogeneous ellipsoid and correctly calculated the flattening of such a model. Until now, this result was believed to have first been obtained by a German engineer, Otto Heymann, in 1935. Adcock's pamphlet is transcribed here with a commentary on its contents. It is hoped that recognition of his remarkable achievement will enhance his reputation as a mathematician.
The life and work of Robert J. Adcock. Part II: biography and establishment of authorship
Authors: Howarth Richard J. , Müller Wolfgang H.
Published: November 2019

Between 1870 and 1896, the American mathematician Robert Jackson Adcock (1826–1895) contributed a number of short articles to early mathematical journals such as
The Analyst
. His biography is given here for the first time. An obscure figure hitherto associated with the history of regression analysis and least-squares, he has, on occasion, been confused with a nephew of the same name. Before the American Civil War, Adcock was first a pupil and then taught at the Western Military Institute, which became the Kentucky Military Institute, near Frankfort, Kentucky. Afterwards, despite occasionally being hospitalized during periods of mental illness, he became a wealthy farmer who could afford mathematical recreation as a hobby. His self-published pamphlet ‘Gravitation to the sphere and the two ellipsoids of revolution’ (1872), recently discovered in the Library of the Royal Society, is discussed in Part I. Here we establish his authorship of all mathematical works by ‘R. J. Adcock’.
Virtual stick balancing: sensorimotor uncertainties related to angular displacement and velocity
Authors: Kovacs Balazs A. , Milton John , Insperger Tamas
Published: November 2019

Sensory uncertainties and imperfections in motor control play important roles in neural control and Bayesian approaches to neural encoding. However, it is difficult to estimate these uncertainties experimentally. Here, we show that magnitude of the uncertainties during the generation of motor control force can be measured for a virtual stick balancing task by varying the feedback delay,
τ
. It is shown that the shortest stick length that human subjects are able to balance is proportional to
τ
 2
. The proportionality constant can be related to a combined effect of the sensory uncertainties and the error in the realization of the control force, based on a delayed proportional-derivative (PD) feedback model of the balancing task. The neural reaction delay of the human subjects was measured by standard reaction time tests and by visual blank-out tests. Experimental observations provide an estimate for the upper boundary of the average sensorimotor uncertainty associated either with angular position or with angular velocity. Comparison of balancing trials with 27 human subjects to the delayed PD model suggests that the average uncertainty in the control force associated purely with the angular position is at most 14% while that associated purely with the angular velocity is at most 40%. In the general case when both uncertainties are present, the calculations suggest that the allowed uncertainty in angular velocity will always be greater than that in angular position.
Are we truly special and unique? A replication of Goldenberg
et al.
(2001)
Authors: Rodríguez-Ferreiro Javier , Barberia Itxaso , González-Guerra Jordi , Vadillo Miguel A.
Published: November 2019

According to the mortality salience hypothesis of terror management theory, reminders of our future death increase the necessity to validate our cultural worldview and to enhance our self-esteem. In Experiment 2 of the study ‘I am not an animal: Mortality salience, disgust, and the denial of human creatureliness’, Goldenberg
et al.
(Goldenberg
et al.
2001
J. Exp. Psychol. Gen.
130
, 427–435. (
doi:10.1037/0096-3445.130.3.427
)) observed that participants primed with questions about their death provided more positive evaluations to an essay describing humans as distinct from animals than control participants presented with questions regarding another aversive situation. In a replication of this experiment conducted with 128 volunteers, we did not observe evidence for a mortality salience effect.
Can a rapid-access vascular limb salvage service improve one-year amputation outcomes for patients with chronic limb-threatening ischaemia?
Authors: Nickinson A.T.O. , Dimitrova J. , Houghton J.S.M. , Rate L. , Dubkova S. , Lines H. , Gray L.J. , Nduwayo S. , Payne T. , Sayers R.D. , Davies R.S.M.
Published: November 2019

Background

Vascular limb salvage services can potentially improve outcomes for patients with chronic limb-threatening ischaemia (CLTI), although their description within the literature is limited. This study aims to evaluate the 12-month outcomes for an outpatient-based vascular limb salvage (VaLS) clinic and investigate times-to-treatment.

Methods

An analysis of a prospectively maintained database, involving all patients diagnosed with CLTI within the VaLS clinic from February 2018-February 2019, was undertaken. Data were compared to two comparator cohorts, identified from coding data; 1) patients managed prior to the clinic, between May 2017-February 2018 (Pre-Clinic’ [PC]), and 2) patients managed outside of clinic, between February 2018-February 2019 (‘Alternative Pathways’ [AP]). Freedom from major amputation at 12 months was the primary outcome. Kaplan-Meier plots and adjusted Cox’s proportional hazard models (aHR) were utilised to compare outcomes.

Results

Five-hundred and sixty-six patients (VaLS=158, AP=173, PC=235) were included (median age=74 years). Patients managed within the VaLS cohort were significantly more likely to be free from major amputation (90.5%) compared to both the AP (82.1%, aHR 0.52, 95% CI 0.28-0.98, p=.041) and the PC (80.0%; aHR 0.50, 95% CI 0.28-0.91, p=.022) cohorts at 12 months, after adjustment for age, disease severity and presence of diabetes.

Conclusions

A limb salvage clinic may help improve the rate of major amputation and provides a reproducible model which delivers timely vascular assessment in an ambulatory setting. Further evaluation is required to assess longer-term outcomes.
Putative conjugative plasmids with tcdB and cdtAB genes in clinical Clostridium difficile strains from MLST clades C-I, 2 and 4
Authors: Ramírez-Vargas Gabriel , Rodríguez César
Published: November 2019

The major toxins of Clostridium difficile (TcdA, TcdB, CDT) are encoded chromosomally in nearly all known strains. Following up on a previous report, we found five new examples of a family of putative conjugative plasmids with tcdB and cdtAB in clinical C. difficile isolates from MLST Clades C-I, 2, and 4.
Big data reveals deep associations in physical examination indicators and can help predict overall underlying health status
Authors: Wang Haixin , Shuai Ping , Deng Yanhui , Yang Jiyun , Zhang Shanshan , Yin Yi , Wang Lin , Li Dongyu , Yong Tao , Liu Yuping , Huang Lulin
Published: November 2019

Because of lacking of the systematic investigation of correlations between the physical examination indicators (PEIs), currently most of them are independently used for disease warning. This results in very limited diagnostic values of general physical examination. Here, we first systematically analyzed the correlations between 221 PEIs in healthy and in 34 unhealthy states in 803,614 peoples in China. We revealed rich relevant between PEIs in healthy physical status (7,662 significant correlations, 31.5% of all). However, in disease conditions, the PEI correlations changed. We further focused on the difference of these PEIs between healthy and 35 unhealthy physical status, 1,239 significant PEI difference were discovered suggesting as candidate disease markers. Finally, we established machine learning algorithms to predict the health status by using 15%-16% PEIs by feature extraction, which reached 66%-99% precision predictions depending on the physical state. This new encyclopedia of PEI correlation provides rich information to chronic disease diagnosis. Our developed machine learning algorithms will have fundamental impact in practice of general physical examination.
Kinesin-2 from C. reinhardtii is an atypically fast and auto-inhibited motor that is activated by heterotrimerization for intraflagellar transport
Authors: Sonar Punam , Youyen Wiphu , Cleetus Augustine , Wisanpitayakorn Pattipong , Mousavi Iman S. , Stepp Willi L. , Hancock William O. , Tüzel Erkan , Ökten Zeynep
Published: November 2019

The construction and function of virtually all cilia require the universally conserved process of Intraflagellar Transport (IFT) [1, 2]. During the atypically fast IFT in the green alga C. reinhardtii, up to ten kinesin-2 motors ‘line up’ in a tight assembly on the trains [3], provoking the question of how these motors coordinate their action to ensure smooth and fast transport along the flagellum without standing in each other’s way. Here, we show that the heterodimeric FLA8/10 kinesin-2 alone is responsible for the atypically fast IFT in C. reinhardtii. Notably, in single-molecule studies, FLA8/10 moved at speeds matching those of in vivo IFT [4], but additionally displayed a slow velocity distribution, indicative of auto-inhibition. Addition of the KAP subunit to generate the heterotrimeric FLA8/10/KAP relieved this inhibition, thus providing a mechanistic rationale for heterotrimerization with the KAP subunit in fully activating FLA8/10 for IFT in vivo. Finally, we link fast FLA8/10 and slow KLP11/20 kinesin-2 from C. reinhardtii and C. elegans through a DNA tether to understand the molecular underpinnings of motor coordination during IFT in vivo. For motor pairs from both species, the co-transport velocities very nearly matched the single-molecule velocities, and the complexes both spent roughly 80% of the time with only one of the two motors attached to the microtubule. Thus, irrespective of phylogeny and kinetic properties, kinesin-2 motors prefer to work alone without sacrificing efficiency. Our findings thus offer a simple mechanism for how efficient IFT is achieved across diverse organisms despite being carried out by motors with different properties.
Using deep mutational scanning to benchmark variant effect predictors and identify disease mutations
Authors: Livesey Benjamin J. , Marsh Joseph A.
Published: November 2019

To deal with the huge number of novel protein-coding variants identified by genome and exome sequencing studies, many computational variant effect predictors (VEPs) have been developed. Such predictors are often trained and evaluated using different variant datasets, making a direct comparison between VEPs difficult. In this study, we use 31 previously published deep mutational scanning (DMS) experiments, which provide quantitative, independent phenotypic measurements for large numbers of single amino acid substitutions, in order to benchmark and compare 46 different VEPs. We also evaluate the ability of DMS measurements and VEPs to discriminate between pathogenic and benign missense variants. We find that DMS experiments tend to be superior to the top-ranking predictors, demonstrating the tremendous potential of DMS for identifying novel human disease mutations. Among the VEPs, DeepSequence clearly stood out, showing both the strongest correlations with DMS data and having the best ability to predict pathogenic mutations, which is especially remarkable given that it is an unsupervised method. We further recommend SNAP2, DEOGEN2, SNPs&GO and REVEL based upon their performance in these analyses.
Combining SIMS and mechanistic modelling to reveal nutrient kinetics in an algal-bacterial mutualism
Authors: Laeverenz Schlogelhofer Hannah , Peaudecerf François J. , Bunbury Freddy , Whitehouse Martin J. , Foster Rachel A. , Smith Alison G. , Croze Ottavio A.
Published: November 2019

Microbial communities are of considerable significance for biogeochemical processes, for the health of both animals and plants, and for biotechnological purposes. A key feature of the interactions between microbes is the exchange of nutrients between cells. Isotope labelling followed by analysis with secondary ion mass spectrometry (SIMS) can identify nutrient fluxes and heterogeneity of substrate utilisation on a single cell level. Here we present a novel approach that combines SIMS with a mechanistic model to reveal otherwise inaccessible nutrient kinetics. The method is applied to study the onset of a synthetic mutualistic partnership between a vitamin B12-dependent mutant of the alga Chlamydomonas reinhardtii and the B12-producing, heterotrophic bacterium Mesorhizobium loti, which is supported by algal photosynthesis. Results show that an initial pool of fixed carbon delays the onset of mutualistic cross-feeding, and the model allows quantification of this delay. Our method is widely applicable to other microbial systems, and will contribute to furthering a mechanistic understanding of microbial interactions.
Plant Bioindicators of Pollution in Sadat City, Western Nile Delta, Egypt
Authors: Azzazy M. F.
Published: November 2019

This study investigated using plants growing in industrial and residential areas as bioindicators and biomarkers of industrial pollution by analyzing flavonoids and metals in Bougainvillea glabra leaves by HPLC-MS, neutron activation analysis, and atomic absorption spectrophotometry. There were significantly higher levels of flavonoids and phenolic compounds in plants growing in industrial areas compared to those growing in residential zones (P<0.05). Metal accumulation in leaves was also significantly higher in the industrial zone than the residential zone: iron, lead, zinc, nickel, and manganese were present at significantly higher levels in plants growing near steel factories compared to those growing in the residential zone (P<0.05). Air, water, and soil samples associated with the studied plants in both areas were analyzed for metals. In general, heavy metal concentrations in the industrial zone were significantly higher than those in the residential zone, but the concentrations of the heavy metals in air, water, and soil were under legal environmental limits.
Comparative and population genomics approaches reveal the basis of adaptation to deserts in a small rodent
Authors: Tigano Anna , Colella Jocelyn P. , MacManes Matthew D.
Published: November 2019

Organisms that live in deserts offer the opportunity to investigate how species adapt to environmental conditions that are lethal to most plants and animals. In the hot deserts of North America, high temperatures and lack of water are conspicuous challenges for organisms living there. The cactus mouse (Peromyscus eremicus) displays several adaptations to these conditions, including low metabolic rate, heat tolerance, and the ability to maintain homeostasis under extreme dehydration. To investigate the genomic basis of desert adaptation in cactus mice, we built a chromosome-level genome assembly and resequenced 26 additional cactus mouse genomes from two locations in southern California (USA). Using these data, we integrated comparative, population, and functional genomic approaches. We identified 16 gene families exhibiting significant contractions or expansions in the cactus mouse compared to 17 other Myodontine rodent genomes, and found 232 sites across the genome associated with selective sweeps. Functional annotations of candidate gene families and selective sweeps revealed a pervasive signature of selection at genes involved in the synthesis and degradation of proteins, consistent with the evolution of cellular mechanisms to cope with protein denaturation caused by thermal and hyperosmotic stress. Other strong candidate genes included receptors for bitter taste, suggesting a dietary shift towards chemically defended desert plants and insects, and a growth factor involved in lipid metabolism, potentially involved in prevention of dehydration. Understanding how species adapted to the recent emergence of deserts in North America will provide an important foundation for predicting future evolutionary responses to increasing temperatures, droughts and desertification in the cactus mouse and other species.
Combining electrophysiology with MRI enhances learning of surrogate-biomarkers
Authors: Engemann Denis Alexander , Kozynets Oleh , Sabbagh David , Lemaitre Guillaume , Varoquaux Gaël , Liem Franziskus , Gramfort Alexandre
Published: November 2019

Electrophysiological methods, i.e., M/EEG provide unique views into brain health. Yet, when building predictive models from brain data, it is often unclear how electrophysiology should be combined with other neuroimaging methods. Information can be redundant, useful common representations of multimodal data may not be obvious and multimodal data collection can be medically contraindicated, which reduces applicability. Here, we propose a multimodal model to robustly combine MEG, MRI and fMRI for prediction. We focus on age prediction as surrogate biomarker in 674 subjects from the Cam-CAN. Strikingly, MEG, fMRI and MRI showed additive effects supporting distinct brain-behavior associations. Moreover, the contribution of MEG was best explained by source-topography of power spectra between 8 and 30 Hz. Finally, we demonstrate that the model maintains benefits of stacking when data is missing. The proposed framework hence enables multimodal learning for a wide range of biomarkers from diverse types of brain signals.
Chemical signals act as the main reproductive barrier between sister and mimeticHeliconiusbutterflies
Authors: González-Rojas M.F. , Darragh K. , Robles J , Linares M. , Schulz S , McMillan W.O , Jiggins C.D , Pardo-Diaz C , Salazar C
Published: November 2019

Colour pattern has been long recognised as the trait that drives mate recognition betweenHeliconiusspecies that are phylogenetically close. However, when this cue is compromised such as in cases of mimetic, sympatric and closely related species, alternative mating signals must evolve to ensure reproductive isolation and species integrity. The closely related speciesHeliconius melpomene malletiandH. timareta florencia, occur in the same geographic region and despite being co-mimics they display strong reproductive isolation. In order to test which cues differ between species, and therefore potentially contribute to reproductive isolation, we quantified differences in wing phenotype and male chemical profile. As expected, wing colour pattern was indistinguishable between the two species while the chemical profile of their male sex pheromones showed marked differences. We then conducted behavioural experiments to study the importance of these signals in mate recognition by females. In agreement with our previous results, we found that pheromones and not wing colour pattern drive the preference of females by conspecific males. In addition, experiments with hybrid males and females suggested an important genetic component for both pheromone production and preference. Altogether, these results suggest that pheromones are the major reproductive barrier opposing gene flow between these two sister and co-mimic species.
Cultural variation in voting patterns reflects the landscape of US genetic diversity: A test of the cultural niche hypothesis
Authors: Hodgson Jason A.
Published: November 2019

Humans are unique in the animal world in the extent to which we have the potential to affect our own biological evolution through culturally mediated behavioural variation. However, there is scant clear evidence of the phenomenon. Here, I estimate genetic diversity for every county in the US by merging demographic data from the 2010 US Census with genomic reference populations and show that genetic diversity is predicted by cultural variation as reflected by the 2016 Presidential Election. Remarkably, the 2016 Election alone explains 18% of US county-level variation in genetic diversity, with diversity decreasing as Trump support increases. When state level variation is included in the model, 71% of variation is explained. Within states, genetic segregation increases with cultural segregation. I then tested whether the observed genetic patterns might be explained by culture acting on race and ethnicity and found that genetic diversity tends to increase with racial and ethnic diversity, and that the 2016 Election is an even better predictor of the US landscape of ethnic diversity. Finally, I measured patterns of ethnic assortative mating nationwide from the Census data, and found that ethnic assortment is primarily explained by the proportion of minorities in each county, and that the most diverse counties are the most assortative. Overall, regional variation in cultural tolerance appears to be structuring biological diversity on a massive scale. Also, assortative mating is maintaining ethnic and genetic diversity within the most diverse and tolerant areas. Culture is a primary driver of biological evolution across the US.