bluuebunny/crossref_metadata_2025 huggingface dataset:
The Association Between Empirical Antibiotic Treatment and Mortality in Severe Infections Caused by Carbapenem-resistant Gram-negative Bacteria: A Prospective Study
Authors: Zak-Doron Yael , Dishon Benattar Yael , Pfeffer Iris , Daikos George L , Skiada Anna , Antoniadou Anastasia , Durante-Mangoni Emanuele , Andini Roberto , Cavezza Giusi , Leibovici Leonard , Yahav Dafna , Eliakim-Raz Noa , Carmeli Yehuda , Nutman Amir , Paul Mical ,   AIDA Study Group, Levi Inbar , Paul Mical , Benattar Yael Dishon , Dickstein Yaakov , Bitterman Roni , Zayyad Hiba , Koppel Fidi , Zak-Doron Yael , Altunin Sergey , Andria Nizar , Neuberger Ami , Stern Anat , Petersiel Neta , Raines Marina , Karban Amir , Leibovici Leonard , Yahav Dafna , Eliakim-Raz Noa , Zusman Oren , Elbaz Michal , Atamna Heyam , Daitch Vered , Babich Tanya , Carmeli Yehuda , Nutman Amir , Adler Amos , Levi Inbar , Daikos George L , Skiada Anna , Pavleas Ioannis , Antoniadou Anastasia , Kotsaki Antigoni , Durante-Mangoni Emanuele , Andini Roberto , Iossa Domenico , Bernardo Mariano , Cavezza Giusi , Bertolino Lorenzo , GiuffrÃ¨ Giuseppe , Giurazza Roberto , Cuccurullo Susanna , Galdo Maria , Murino Patrizia , Cristinziano Adriano , Corcione Antonio , Zampino Rosa , Pafundi Pia Clara , Mouton Johan , Friberg Lena , Kristoffersso Anders
Published: April 2018

Background

Empirical colistin should be avoided. We aimed to evaluate the association between covering empirical antibiotics (EAT) and mortality for infections caused by carbapenem-resistant gram-negative bacteria (CRGNB).

Methods

This was a secondary analysis of a randomized controlled trial, including adults with bloodstream infections, pneumonia, or urosepsis caused by CRGNB. All patients received EAT followed by covering targeted therapy. The exposure variable was covering EAT in the first 48 hours. The outcome was 28-day mortality. We adjusted the analyses by multivariable regression analysis and propensity score matching.

Results

The study included 406 inpatients with severe CRGNB infections, mostly Acinetobacter baumannii (312/406 [77%]). Covering EAT was given to 209 (51.5%) patients, mostly colistin (n = 200). Patients receiving noncovering EAT were older, more frequently unconscious and dependent, carrying catheters, and mechanically ventilated with pneumonia. Mortality was 84 of 197 (42.6%) with noncovering vs 96 of 209 (45.9%) with covering EAT (P = .504). Covering EAT was not associated with survival in the adjusted analysis; rather, there was a weak association with mortality (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.02–1.84). Results were similar for colistin monotherapy and colistin-carbapenem combination EAT. In the propensity score–matched cohort (n = 338) covering antibiotics were not significantly associated with mortality (OR, 1.42; 95% CI, .91–2.22). Similar results were obtained in an analysis of 14-day mortality.

Conclusions

Empirical use of colistin before pathogen identification, with or without a carbapenem, was not associated with survival following severe infections caused by CRGNBs, mainly A. baumannii.
Andrew Chi-Chih Yao: the future of quantum computing
Authors: Poo Mu-ming , Wang Ling
Published: April 2018

Quantum computing and quantum computers have attracted much attention from both the academic community and industry in recent years. By exploiting the quantum properties of materials, scientists are aiming to overcome Moore's law of miniaturization and develop novel quantum computers. The concept of quantum computing was first introduced by the distinguished physicist Richard Feynman in 1981. As one of the early pioneers in this field, Turing Award laureate Andrew Chi-Chih Yao made a seminal contribution in developing the theoretical basis for quantum computation in 1993. Since 2011, he has served as the founding director of Tsinghua University's Center for Quantum Information (CQI), which aims to become a world-class research center for quantum computing. In a recent interview with NSR, Yao recounted the history of quantum computing and expressed his view on the future of this field. He suggests that quantum computers could excel in many tasks such as the design of new materials and drugs as well as in the simulation of chemical reactions, but they may not supersede traditional computers in tasks for which traditional computers are already proven to be highly efficient.
Antimicrobial Agent Shortages: The New Norm for Infectious Diseases Physicians
Authors: Gundlapalli Adi V , Beekmann Susan E , Graham Donald R , Polgreen Philip M ,   Members of the Emerging Infections Network
Published: April 2018

Background

In 2012, the US Food and Drug Administration (FDA) required drug manufacturers to give advance notice of impending drug shortages. A survey of infectious diseases (ID) physicians was undertaken to determine the impact of this requirement and to follow-up on prior perceptions of ID physicians on shortages of antimicrobial agents.

Methods

We used a web-based survey of ID physician members of the Emerging Infections Network in 2016.

Results

Of the 701 of 1597 members (44%) who responded, 70% reported the need to modify their antimicrobial choice because of a shortage in the prior 2 years. A majority (73%) reported the shortages affected patient care or outcomes by the use of broader-spectrum (75%), more costly (58%), less effective second-line (45%), or more toxic agents (37%). The most commonly reported antimicrobials in short supply were piperacillin-tazobactam, ampicillin-sulbactam, meropenem, cefotaxime, and cefepime. Respondents learned of shortages from hospital notification, from a colleague, contact from pharmacy after ordering the agent in short supply, or FDA or other website. The antimicrobial stewardship programs (ASPs) of a majority (83%) of respondents’ institutions had developed approaches to deal with shortages. Although 71% indicated that communications were sufficient, most (87%) did not perceive any improvement in communications about shortages since the 2012 FDA requirement.

Conclusions

The persistence of antimicrobial agent shortages reported by ID physicians is disturbing as is the resulting need to use broader-spectrum or more toxic agents. The prominent role of ASPs in helping to deal with shortages, effective communication channels, and the lack of perceived improvement in FDA’s communication strategy merit further consideration.
Potential Impact of Populations Drift on Botrytis Occurrence and Resistance to Multi- and Single-Site Fungicides in Florida Southern Highbush Blueberry Fields
Authors: Amiri A. , Zuniga A. I. , Peres N. A.
Published: April 2018

Incidence of blossom blight and Botrytis fruit rot (BFR), caused by Botrytis cinerea, on two southern highbush blueberry cultivars was evaluated in several blueberry fields grown in the vicinity (BB-Str(+)) or not (BB-Str(−)) of strawberry fields in central Florida. Blossom blight and BFR incidence were higher in BB-Str(+) fields in 2014 and significantly higher in 2015 compared to BB-Str(−) fields. In total, 613 B. cinerea isolates (i.e., 181 and 432 isolates from BB-Str(−) and BB-Str(+) fields, respectively) were collected. The isolates were evaluated for sensitivity to eight single-site and one multisite fungicides using a spore germination and a germ tube elongation assay. Overall, 5, 15, 24, 28, 54, and 93% of isolates collected from BB-Str(−) were resistant to penthiopyrad, cyprodinil, boscalid, fenhexamid, pyraclostrobin, and thiophanate-methyl, respectively. Respective resistance frequencies in BB-Str(+) isolates were 10, 30, 65, 66, 89, and 99%. Resistance frequencies for all fungicides were always higher in BB-Str(+) fields compared to BB-Str(−) fields. Isolates exhibiting resistance to six or five fungicides simultaneously were predominant (50 to 70%) in blueberry fields regardless if they were grown in the vicinity of strawberry fields or not. Among 308 and 305 B. cinerea isolates tested in 2014 and 2015, 41.8 and 47.1%, respectively, showed reduced sensitivity to the multisite fungicide captan. The lower label rate of captan applied preventively did not control isolates with reduced sensitivity on detached blueberry fruit. These findings suggest a potential population flow between strawberry and blueberry fields that may impact blossom blight and gray mold development in blueberry fields. The relatively lower fungicide input applied to blueberry fields compared with strawberry fields seems to be sufficient to select for resistance and multiple-resistant phenotypes in B. cinerea populations in blueberry.
Relationship Between Institutional Investment in High-Value Care (HVC) Performance Improvement and Internal Medicine Residents’ Perceptions of HVC Training
Authors: Ryskina Kira L. , Smith Cynthia D. , Arora Vineet M. , Zaas Aimee K. , Halvorsen Andrew J. , Weissman Arlene , Wahi-Gururaj Sandhya
Published: April 2018

Purpose

To measure the association between institutional investment in high-value care (HVC) performance improvement and resident HVC experiences.

Method

The authors analyzed data from two 2014 surveys assessing institutions’ investments in HVC performance improvement as reported by program directors (PDs) and residents’ perceptions of the frequency of HVC teaching, participation in HVC-focused quality improvement (QI), and views on HVC topics. The authors measured the association between institutional investment and resident-reported experiences using logistic regression, controlling for program and resident characteristics.

Results

The sample included 214 programs and 9,854 residents (59.3% of 361 programs, 55.2% of 17,851 residents surveyed). Most PDs (158/209; 75.6%) reported some support. Residents were more likely to report HVC discussions with faculty at least a few times weekly if they trained in programs that offered HVC-focused faculty development (odds ratio [OR] = 1.19; 95% confidence interval [CI] 1.04–1.37; P = .01), that supported such faculty development (OR = 1.21; 95% CI 1.04–1.41; P = .02), or that provided physician cost-of-care performance data (OR = 1.19; 95% CI 1.03–1.39; P = .02). Residents were more likely to report participation in HVC QI if they trained in programs with a formal HVC curriculum (OR = 1.83; 95% CI 1.48–2.27; P < .001) or with HVC-focused faculty development (OR = 1.46; 95% CI 1.15–1.85; P = .002).

Conclusions

Institutional investment in HVC-related faculty development and physician feedback on costs of care may increase the frequency of HVC teaching and resident participation in HVC-related QI.
Why Pull the Arrow When You Cannot See the Target? Framing Professionalism Goals in Medical Education
Authors: Doukas David J. , Volpe Rebecca L.
Published: April 2018

Professionalism is essential for a successful physician–patient relationship and widely acknowledged as an intrinsic and important component of medical education for learners at all levels, from medical school to residency to continuing medical education. The problem is defining the educational end points for learners and then determining how to assess these outcomes. This Invited Commentary focuses on what medical educators can and should do to refine the vision of professionalism in medical education. The authors propose a multistep process in which learners, educators, and the public are engaged in articulating clearly and definitively the end points of professionalism education.
Using Different Expectation Mechanisms to Optimize Treatment of Patients With Medical Conditions: A Systematic Review
Authors: Kube Tobias , Glombiewski Julia Anna , Rief Winfried
Published: April 2018

Objective

Patients' expectations have been shown to predict the course and treatment success of a variety of medical conditions. Therefore, expectation-focused psychological interventions (EFPIs) have been developed to use these expectation effects clinically. Importantly, EFPI differ with regard to the particular expectation mechanism being addressed, i.e., expectation optimization or expectation violation. The aims of this systematic review were to give an overview of the application of these expectation interventions and to evaluate their effectiveness.

Methods

Several databases were searched to identify clinical trials or experimental studies that conducted EFPI among participants with various medical conditions. Risk of bias was evaluated using the Cochrane Risk of Bias tool.

Results

Eleven studies (N = 944) investigating different medical conditions (coronary heart disease, cancer, chronic pain) were included. Qualitative synthesis revealed positive effects of EFPI on clinical outcome variables in all studies. Expectation optimization approaches yielded particularly promising results. Because of the large heterogeneity of outcome measures, quantitative synthesis was not possible.

Conclusion

This review highlights the potential of EFPI for optimizing treatment of patients with medical conditions. However, it seems that different expectation mechanisms might have different application possibilities. Therefore, we provide suggestions for further developing EFPI to tailor treatment and develop personalized psychological interventions. We argue that for this purpose, it is important to consider both disease-specific aspects and patients' personality traits. In addition, we discuss future challenges such as implementing EFPI into routine medical care.
Utilization and Cost Analysis of Lung Transplantation and Survival After 10 Years of Adapting the Lung Allocation Score
Authors: Keller Cesar A. , Gonwa Thomas A. , White Launia J. , Rucci March E. , Visscher Sue L. , Kennedy Cassie C. , Daly Richard C. , Naessens James M.
Published: April 2018

Background.

Lungs are allocated in the United States using the lung allocation score (LAS). We investigated the effect of LAS trends on lung transplant-related costs, healthcare utilization, and mortality.

Methods.

Utilization data from Mayo Clinic (Florida and Minnesota) from 2005 to 2015 were obtained from the electronic health records (N = 465). Costs were categorized as 1-year posttransplant or transplant episode and standardized using 2015 Medicare reimbursement and cost-to-charge ratios. Regression analysis was used to assess the relationship of LAS to length of stay (LOS), mortality, and cost of transplant.

Results.

The mean LAS at transplant increased from 45.7 to 58.3 during the study period, whereas the 1-year survival improved from 88.1% to 92.5% (P < 0.0001). The proportion of patients transplanted with LAS of 60 or greater increased from 16.9% to 33.3%. Posttransplant, overall, and intensive care unit LOS increased with increasing LAS. Patients with higher LAS had substantially higher transplant episode costs. An increase of LAS at transplant by 10 points increased inflation-adjusted costs by 12.0% (95% confidence interval, 9.3%–14.5%).

Conclusions.

The mean LAS at transplant has significantly increased over time associated with increases in LOS, resource utilization and cost. Lung allocation score has not jeopardized overall survival, but a high LAS (>60) at transplant is associated with increased mortality.
Deprogramming Baconianism: The meaning of
desiderata
in the eighteenth century
Authors: Keller Vera
Published: April 2018

The historiographical construct of the ‘Baconian programme’ rose to prominence in the mid-twentieth century. It has since shaped views of Bacon and his followers, particularly concerning Bacon's utilitarianism. It has also set expectations concerning how defined and prescriptive Bacon's vision of the future ought to be for later Baconians. Yet, neither Bacon nor those who claimed to follow him thought of his work in programmatic ways. The early modern view of Bacon's futuristic writing allowed his followers great agency in re-sketching it to fit changing times. This essay first follows the rise of a ‘Baconian programme’ in historiography. It then returns to the past to outline some of the rich vocabulary for future-oriented writing deployed by the first generation of Bacon's self-proclaimed followers. Finally, testing how Bacon's plans appeared over a longer durée, it skips forward to Peter Shaw (1694–1763) and Joseph Priestley (1733–1804). Shaw employed one of Bacon's futuristic terms (
desiderata
), dropped another (
optativa
) and developed the significance of a new category (hint). Shaw's case illustrates the creativity that even Bacon's most ardent followers expected to be within their rights. Baconianism invited future redrafting and haphazard invention, rather than adherence to a predictive programme.
Pathways for maintenance of telomeres and common fragile sites during DNA replication stress
Authors: Özer Özgün , Hickson Ian D.
Published: April 2018

Oncogene activation during tumour development leads to changes in the DNA replication programme that enhance DNA replication stress. Certain regions of the human genome, such as common fragile sites and telomeres, are particularly sensitive to DNA replication stress due to their inherently ‘difficult-to-replicate’ nature. Indeed, it appears that these regions sometimes fail to complete DNA replication within the period of interphase when cells are exposed to DNA replication stress. Under these conditions, cells use a salvage pathway, termed ‘mitotic DNA repair synthesis (MiDAS)’, to complete DNA synthesis in the early stages of mitosis. If MiDAS fails, the ensuing mitotic errors threaten genome integrity and cell viability. Recent studies have provided an insight into how MiDAS helps cells to counteract DNA replication stress. However, our understanding of the molecular mechanisms and regulation of MiDAS remain poorly defined. Here, we provide an overview of how DNA replication stress triggers MiDAS, with an emphasis on how common fragile sites and telomeres are maintained. Furthermore, we discuss how a better understanding of MiDAS might reveal novel strategies to target cancer cells that maintain viability in the face of chronic oncogene-induced DNA replication stress.
Critical review: involvement of endoplasmic reticulum stress in the aetiology of Alzheimer's disease
Authors: Hashimoto Shoko , Saido Takaomi C.
Published: April 2018

The endoplasmic reticulum (ER) stress response is regarded as an important process in the aetiology of Alzheimer's disease (AD). The accumulation of pathogenic misfolded proteins and the disruption of intracellular calcium (Ca2+) signalling are considered to be fundamental mechanisms that underlie the induction of ER stress, leading to neuronal cell death. Indeed, a number of studies have proposed molecular mechanisms linking ER stress to AD pathogenesis based on results fromin vitrosystems and AD mouse models. However, stress responsivity was largely different between each mouse model, even though all of these models display AD-related pathologies. While several reports have shown elevated ER stress responses in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (Tg) AD mouse models, we and other groups, in contrast, observed no such ER stress response in APP-single-Tg orApp-knockin mice. Therefore, it is debatable whether the ER stress observed in APP and PS1 double-Tg mice is due to AD pathology. From these findings, the roles of ER stress in AD pathogenesis needs to be carefully addressed in future studies. In this review, we summarize research detailing the relationship between ER stress and AD, and analyse the results in detail.
Contrasting ecological roles of non-native ungulates in a novel ecosystem
Authors: Gawel Ann Marie , Rogers Haldre S. , Miller Ross H. , Kerr Alexander M.
Published: April 2018

Conservation has long focused on preserving or restoring pristine ecosystems. However, understanding and managing novel ecosystems has grown in importance as they outnumber pristine ecosystems worldwide. While non-native species may be neutral or detrimental in pristine ecosystems, it is possible that even notorious invaders could play beneficial or mixed roles in novel ecosystems. We examined the effects of two long-established non-native species—Philippine deer (
Rusa marianna
) and feral pigs (
Sus scrofa
)—in Guam, Micronesia, where native vertebrate frugivores are functionally absent leaving forests devoid of seed dispersers. We compared the roles of deer and pigs on seedling survival, seed dispersal and plant community structure in limestone karst forests. Deer, even at low abundances, had pronounced negative impacts on forest communities by decreasing seedling and vine abundance. By contrast, pigs showed no such relationship. Also, many viable seeds were found in pig scats, whereas few were found in deer scats, suggesting that pigs, but not deer, provide an ecosystem function—seed dispersal—that has been lost from Guam. Our study presents a discrepancy between the roles of two non-native species that are traditionally managed as a single entity, suggesting that ecological function, rather than identity as a non-native, may be more important to consider in managing novel systems.
Structure and phylogeography of two tropical predators, spinner (Stenella longirostris) and pantropical spotted (S. attenuata) dolphins, from SNP data
Authors: Leslie Matthew S. , Morin Phillip A.
Published: April 2018

Little is known about global patterns of genetic connectivity in pelagic dolphins, including how circumtropical pelagic dolphins spread globally following the rapid and recent radiation of the subfamily delphininae. In this study, we tested phylogeographic hypotheses for two circumtropical species, the spinner dolphin (Stenella longirostris) and the pantropical spotted dolphin (Stenella attenuata), using more than 3000 nuclear DNA single nucleotide polymorphisms (SNPs) in each species. Analyses for population structure indicated significant genetic differentiation between almost all subspecies and populations in both species. Bayesian phylogeographic analyses of spinner dolphins showed deep divergence between Indo-Pacific, Atlantic and eastern tropical Pacific Ocean (ETP) lineages. Despite high morphological variation, our results show very close relationships between endemic ETP spinner subspecies in relation to global diversity. The dwarf spinner dolphin is a monophyletic subspecies nested within a major clade of pantropical spinner dolphins from the Indian and western Pacific Ocean populations. Population-level division among the dwarf spinner dolphins was detected—with the northern Australia population being very different from that in Indonesia. In contrast to spinner dolphins, the major boundary for spotted dolphins is between offshore and coastal habitats in the ETP, supporting the current subspecies-level taxonomy. Comparing these species underscores the different scale at which population structure can arise, even in species that are similar in habitat (i.e. pelagic) and distribution.
Dietary specialization is linked to reduced species durations in North American fossil canids
Authors: Balisi Mairin , Casey Corinna , Van Valkenburgh Blaire
Published: April 2018

How traits influence species persistence is a fundamental question in ecology, evolution and palaeontology. We test the relationship between dietary traits and both species duration and locality coverage over 40 million years in North American canids, a clade with considerable ecomorphological disparity and a dense fossil record. Because ecomorphological generalization—broad resource use—may enable species to withstand disturbance, we predicted that canids of average size and mesocarnivory would exhibit longer durations and wider distributions than specialized larger or smaller species. Second, because locality coverage might reflect dispersal ability and/or survivability in a range of habitats, we predicted that high coverage would correspond with longer durations. We find a nonlinear relationship between species duration and degree of carnivory: species at either end of the carnivory spectrum tend to have shorter durations than mesocarnivores. Locality coverage shows no relationship with size, diet or duration. To test whether generalization (medium size, mesocarnivory) corresponds to an adaptive optimum, we fit trait evolution models to previously generated canid phylogenies. Our analyses identify no single optimum in size or diet. Instead, the primary model of size evolution is a classic Cope's Rule increase over time, while dietary evolution does not conform to a single model.
Behavioural responses of spinner dolphins to human interactions
Authors: Fumagalli Maddalena , Cesario Amina , Costa Marina , Harraway John , Notarbartolo di Sciara Giuseppe , Slooten Elisabeth
Published: April 2018

There is increasing evidence that whale and dolphin watching activities have detrimental effects on targeted cetacean populations. In Egypt, spinner dolphins regularly occur in the resting areas of Samadai, Satayah and Qubbat'Isa reefs. In-water human interactions with dolphins are regulated with a time-area closure system at Samadai, unregulated at Satayah and non-existent at Qubbat'Isa. This provided an ideal experimental setting to advance our understanding of the effects of tourism on a species highly sensitive to disturbances. Our study confirmed that the intensity and duration of interactions, and therefore, dolphin exposure to tourism, differed among the study sites. Compared with the Qubbat'Isa control site, behavioural reactions to boats and swimmers at the two tourism sites suggested that dolphin rest was disrupted, especially around the middle of the day and especially at Satayah, where dolphin tourism is unregulated. Our results indicate also that the dolphin protection measures at Samadai reduce the level of disturbance. We recommend that similar measures be implemented at other dolphin tourism locations, and that no new operations be initiated until the long-term impacts on dolphin populations are better understood. Our experience emphasizes the need to adopt precautionary approaches in research and management of whale and dolphin watching.
New Guinea bone daggers were engineered to preserve social prestige
Authors: Dominy Nathaniel J. , Mills Samuel T. , Yakacki Christopher M. , Roscoe Paul B. , Carpenter R. Dana
Published: April 2018

Bone daggers were once widespread in New Guinea. Their purpose was both symbolic and utilitarian; they functioned as objects of artistic expression with the primary function of stabbing and killing people at close quarters. Most daggers were shaped from the tibiotarsus of cassowaries, but daggers shaped from the femora of respected men carried greater social prestige. The greater cross-sectional curvature of human bone daggers indicates superior strength, but the material properties of cassowary bone are unknown. It is, therefore, uncertain whether the macrostructure of human bone daggers exists to compensate for inferior material properties of human femora or to preserve the symbolic value of a prestigious object. To explore this question, we used computed tomography to examine the structural mechanics of 11 bone daggers, 10 of which are museum-accessioned objects of art. We found that human and cassowary bones have similar material properties and that the geometry of human bone daggers results in higher moments of inertia and a greater resistance to bending. Data from finite-element models corroborated the superior mechanical performance of human bone daggers, revealing greater resistance to larger loads with fewer failed elements. Taken together, our findings suggest that human bone daggers were engineered to preserve symbolic capital, an outcome that agrees well with the predictions of signalling theory.
Entrainment in the master equation
Authors: Margaliot Michael , Grüne Lars , Kriecherbauer Thomas
Published: April 2018

The master equation plays an important role in many scientific fields including physics, chemistry, systems biology, physical finance and sociodynamics. We consider the master equation with periodic transition rates. This may represent an external periodic excitation like the 24 h solar day in biological systems or periodic traffic lights in a model of vehicular traffic. Using tools from systems and control theory, we prove that under mild technical conditions every solution of the master equation converges to a periodic solution with the same period as the rates. In other words, the master equation entrains (or phase locks) to periodic excitations. We describe two applications of our theoretical results to important models from statistical mechanics and epidemiology.
Effects of the inclusion of a mixed
Psychrotrophic
bacteria strain for sewage treatment in constructed wetland in winter seasons
Authors: Tang Meizhen , Li Zhengtao , Yang Yuewei , Chen Junfeng , Jiang Jie
Published: April 2018

Constructed wetlands (CWs) have been used globally in wastewater treatment for years. CWs represent an efficient ecological system which is both energy-saving and low in investment for construction and operational cost. In addition, CWs also have the advantage of being easy to operate and maintain. However, the operation of CWs at northern latitudes (both mid and high) is sometimes quite demanding, due to the inhibitory effect of low temperatures that often occur in winter. To evaluate the wastewater treatment performance of a culture of mixed
Psychrotrophic
bacteria strains in an integrated vertical-flow CW, the removal rates of ammonia nitrogen (NH
3
–N), chemical oxygen demand (COD), nitrite nitrogen

(

NO
2
−

−

N
)

, nitrate nitrogen

(

NO
3
−

−

N
)

and total phosphorus (TP) were quantified at different bacterial dosages to determine the best bacterial dosage and establish kinetic degradation models of the mixed strains. The bacterial culture was made up of
Psychrobacter
TM-1,
Sphingobacterium
TM-2 and
Pseudomonas
TM-3, mixed together at a volume/volume ratio of 1 : 1 : 1 (at bacterial suspension concentrations of 4.4 × 10
9
 ml
−1
). Results showed that the organic pollutants (nitrogen and phosphorus) in the sewage could be efficiently removed by the culture of mixed
Psychrotrophic
bacteria. The optimal dosage of this mixed bacteria strain was 2.5%, and the treatment efficiency of COD, NH
3
–N,

NO
2
−

−

N

,

NO
3
−

−

N

, total nitrogen and TP were stable at 91.8%, 91.1%, 88.0%, 93.8%, 94.8% and 95.2%, respectively, which were 1.5, 2.0, 2.1, 1.5, 2.2 and 1.3 times those of the control group. In addition, a pseudo-first-order degradation model was a good fit for the degradation pattern observed for each of these pollutants.
Longitudinal tracking of Plasmodium falciparum clones in complex infections by amplicon deep sequencing
Authors: Lerch Anita , Koepfli Cristian , Hofmann Natalie E. , Kattenberg Johanna H. , Rosanas-Urgell Anna , Betuela Inoni , Mueller Ivo , Felger Ingrid
Published: April 2018

Background

Longitudinal tracking of individual Plasmodium falciparum strains in multi-clonal infections is essential for investigating infection dynamics of malaria. The traditional genotyping techniques did not permit tracking changes in individual clone density during persistent natural infections. Amplicon deep sequencing (Amp-Seq) offers a tool to address this knowledge gap.

Methods

The sensitivity of Amp-Seq for relative quantification of clones was investigated using three molecular markers, ama1-D2, ama1-D3, and cpmp. Amp-Seq and length-polymorphism based genotyping were compared for their performance in following minority clones in longitudinal samples from Papua New Guinea.

Results

Amp-Seq markers were superior to length-polymorphic marker msp2 in detecting minority clones (sensitivity Amp-Seq: 95%, msp2: 85%). Multiplicity of infection (MOI) by Amp-Seq was 2.32 versus 1.73 for msp2. The higher sensitivity had no effect on estimates of force of infection because missed minority clones were detected in preceding or succeeding bleeds. Individual clone densities were tracked longitudinally by Amp-Seq despite MOI>1, thus providing an additional parameter for investigating malaria infection dynamics.

Conclusion

Amp-Seq based genotyping of longitudinal samples improves detection of minority clones and estimates of MOI. Amp-Seq permits tracking of clone density over time to study clone competition or the dynamics of specific, i.e. resistance-associated genotypes.
Short loop motif profiling of protein interaction networks in acute myeloid leukaemia
Authors: Chung Sun Sook , Laddach Anna , Thomas N. Shaun B. , Fraternali Franca
Published: April 2018

Recent advances in biotechnologies for genomics and proteomics have expanded our understanding of biological components which play crucial roles in complex mechanisms related to cancer. However, it is still challenging to extract from the available knowledge reliable targets to use in a translational setting. The reasons for this are manifold, but essentially distilling real biological signal from heterogeneous “big data” collections is the major hurdle. Here, we aim to establish an in-silico pipeline to explore mutations and their effects on protein-protein interactions, with a focus on acute myeloid leukaemia (AML), one of the most common blood cancers with the highest mortality rate. Our method, based on cyclic interactions of a small number of proteins topologically linked in the network (short loop network motifs), highlights specific protein-protein interactions (PPIs) and their functions in AML when compared with other leukaemias. We also developed a new property named ‘short loop commonality’ to measure indirect PPIs occurringviacommon short loop interactions. This new method detects “modules” of PPI networks (PPINs) enriched with common biological functions which have proteins that contain mutation hotspots. We further perform 3D structural modelling to extract atomistic details, which shows that such hotspots map to PPI interfaces as well as active sites. Thus, our study proposes a framework for the macroscopic and microscopic investigation of PPINs, their relation to cancers, and highlights important functional modules in the network to be exploited in targeted drug screening.
Host sexual dimorphism affects the outcome of within-host pathogen competition
Authors: Gipson Stephen A.Y. , Jimenez Luis , Hall Matthew D.
Published: April 2018

Natural infections often consist multiple pathogens of the same or different species. In multiple infections, pathogens compete for access to host resources and fitness is determined by how well a pathogen can reproduce compared to its competitors. Given the propensity for males and females to exhibit variation in pathogen-induced reduction in lifespan or fecundity, we explore how host sex may modulate the competitive ability of pathogens, potentially favouring the transmission of different pathogen genotypes. Using the Daphnia magna - Pasteuria ramosa model system, we exposed male and female hosts to either a single genotype infection or coinfections consisting of two pathogen genotypes of varying levels of virulence, measured as pathogen-induced reduction in host lifespan. We found that co-infections within females generally favoured the transmission of the more virulent pathogen genotype. Conversely, co-infections within male hosts resulted in equal transmission of competing genotypes, or favoured the transmission of the less virulent pathogen genotype in treatments where it established prior to the more virulent competitor. These results suggest that sex is a form of host heterogeneity which may influence the evolution of virulence within co-infection contexts and that one sex may be a reservoir for pathogen genetic diversity in nature.
Distinct prefrontal top-down circuits differentially modulate sensorimotor behavior
Authors: Huda Rafiq , Sipe Grayson O. , Breton-Provencher Vincent , Cruz K. Guadalupe , Pho Gerald N. , Adam Elie , Gunter Liadan M. , Sullins Austin , Wickersham Ian R. , Sur Mriganka
Published: April 2018

Sensorimotor behaviors require processing of behaviorally relevant sensory cues and the ability to select appropriate responses from a vast behavioral repertoire. Top-down modulation by the prefrontal cortex (PFC) is thought to be key for both processes but the precise role of specific circuits remains unclear. We examined the sensorimotor function of anatomically distinct outputs from a subdivision of the mouse PFC, the anterior cingulate cortex (ACC). Using a visually guided two-choice behavioral paradigm with multiple cue-response mappings, we dissociated the sensory and motor response components of sensorimotor control. Projection-specific two-photon calcium imaging and optogenetic manipulations show that ACC outputs to the superior colliculus, a key midbrain structure for response selection, principally coordinate specific motor responses. Importantly, ACC outputs exert top-down control by reducing the innate response bias of the superior colliculus. In contrast, ACC outputs to the visual cortex facilitate sensory processing of visual cues. Our results ascribe motor and sensory roles to ACC projections to the superior colliculus and the visual cortex and demonstrate for the first time a circuit motif for PFC function wherein anatomically non-overlapping output pathways coordinate complementary but distinct aspects of visual sensorimotor behavior.
Leucocyte integrins but not caspases or NLR inflammasome are associated with lipopolysaccharide recognition and response in barramundi (Lates calcarifer)
Authors: Zoccola Emmanuelle C. , Kellie Stuart , Barnes Andrew C.
Published: April 2018

The inflammatory response of fish to LPS is subdued, attributed to absence of TLR4, a key pro-inflammatory receptor for LPS in mammals. Nevertheless, LPS is processed in fish in a T-independent manner and is a protective antigen in fish vaccines, yet pathways for processing LPS in fish remain to be elucidated. Here, we report that caspases and NOD-like receptor inflammasomes typically responsible for LPS recognition and processing in mammals lack critical domains or are absent in barramundi (Lates calcarifer). However, leucocyte integrins MAC-1 and LFA-1 induce pro-inflammatory cytokine expression poststimulation with LPS. Moreover, MAC-1 and LFA-1 were detected on the surface of neutrophil- and lymphocyte-like cells respectively in the barramundi spleen by immunocytochemistry, and leucocytes displaying MAC-1 or LFA-1 bound to Factor X and ESM-1 respectively. Our results implicate MAC-1 and LFA-1 in immune processing of LPS in barramundi and potentially in antigen processing in fish.
Characterization of genomic DNA of lactic acid bacteria for activation of plasmacytoid dendritic cells
Authors: Horie Akira , Tomita Yasuyuki , Oshio Konomi , Fujiwara Daisuke , Fujii Toshio
Published: April 2018

Lactococcus lactisstrain Plasma (LC-Plasma) possesses strong activity of stimulating plasmacytoid dendritic cells (pDCs) via the TLR9-Myd88 pathway. To reveal the effective genome structure for pDCs stimulatory activity, we performed anin vitroscreening, using randomly selected DNA fragments from the LC-Plasma genome. The results showed that CpG motifs are necessary factor for active DNA fragment, but the copy number of CpG motifs did not show strong correlation to the pDCs stimulatory activity of DNA fragment. We also found that the G+C contents of DNA fragments have significant negative effects on pDCs stimulatory activity. We also performed bioinformatics analysis of genome of lactic acid bacteria (LAB) and investigated the relation between CpG copy number in the genome and pDCs stimulatory activity. We found that strains of lactic acid bacteria (LAB) with high copy number of CpG motifs in the low-G+C region of the genome had higher probability of having high pDCs stimulatory activity. Three species,L.lactissubsp.lactis, Leuconostoc mesenteroides, andPediococcus pentosaceuswere the typical examples of high pDCs stimulatory activity LAB.

Importance

This study provides a new perspective on the structure of DNA fragments that are able to activate pDCs via the TLR9-Myd88 pathway. The information from this study should be useful for designing new DNA fragments, including phosphodiesterbond-DNA oligomers containing CpG motifs and DNA-containing vaccines. This work also presented anin silicoscreening method for identifying bacterial species that are able to activate pDCs. Therefore, this study should be useful for providing data for the development of vaccine adjuvants and therapeutics for infectious and allergic diseases.
Machine learning based prediction of functional capabilities in metagenomically assembled microbial genomes
Authors: Farrell Fred , Soyer Orkun S. , Quince Christopher
Published: April 2018

The increasing popularity of genome resolved meta genomics - the binning of genomes of potentially uncultured organisms direct from the environmental DNA - has resulted in a deluge of draft genomes. There is a pressing need to develop methods to interpret this data. Here, we used machine learning to predict functional and metabolic traits of microbes from their genomes. We collated an extensive database of 84 phenotypic traits associated with 9407 prokaryotic genomes and trained different machine learning models on this data. We found that a lasso logistic regression based on the frequency of gene orthologs had the best combination of functional prediction performance and interpretability. This model was able to classify 65 phenotypic traits with greater than 90
Asymmetrical template-DNA strand segregation can explain density-associated mutation-rate plasticity
Authors: Aanen Duur K. , Debets Alfons J.M.
Published: April 2018

The mutation rate is a fundamental factor in evolutionary genetics. Recently, mutation rates were found to be strongly reduced at high density in a wide range of unicellular organisms, prokaryotic and eukaryotic. Independently, cell division was found to become more asymmetrical at increasing density in diverse organisms; in yeast, some ‘mother’ cells continue dividing, while their ‘offspring’ cells do not divide further. Here, we investigate how this increased asymmetry in cell division at high density can be reconciled with reduced mutation-rate estimates. We calculated the expected number of mutant cells due to replication errors under various modes of segregation of template-DNA strands and copy-DNA strands, both under exponential and under linear growth. We show that the observed reduction in the mutation rate at high density can be explained if mother cells preferentially retain the template-DNA strands, since new mutations are then confined to non-dividing daughter cells thus reducing the spread of mutant cells. Any other inheritance mode results in anincreasein the number of mutant cells at higher density. The proposed hypothesis that patterns of DNA-strand segregation are density dependent fundamentally challenges our current understanding of mutation-rate estimates and extends the distinction between germline and soma to unicellular organisms.
Filamin-A susceptibility to calpain-mediated cleavage as a marker of dynamic conformational changes in intact platelets
Authors: Buitrago Lorena , Coller Barry S.
Published: April 2018

Filamin-A (FlnA), an actin-binding protein that organizes the actin cytoskeleton and mechanically links transmembrane glycoproteins to the cytoskeleton, associates with platelet receptors integrin αIIbβ3, glycoprotein-Ib (GPIb), and integrin α2β1. Fibrinogen, von Willebrand Factor (vWF) and collagen, binding to these receptors mechanically connect the extracellular matrix to the cytoskeleton. Here we identified that under standardized conditions, platelet activation and ligand binding to αIIbβ3, GPIb, or α2β1, generates reproducible patterns of FlnA cleavage after platelet lysis. We exploited this novel assay to study the impact of ligand binding and receptor activation on the platelet cytoskeleton. We identified that: i) the FlnA modification that renders it cleavable by calpain after platelet lysis, requires both ligand binding and either internal force (e.g; clot retraction) or external forces (e.g; stirring and aggregating), ii) FlnA modification depends on actin polymerization downstream of integrin αIIbβ3 and integrin α2β1, but not downstream of GPIb signaling, iii) FlnA modification is reversible in time when platelets are activated with convulxin (Cvx), collagen, von Willebrand factor (vWF) or thrombin receptor activating peptide (T6), and this reversibility correlates with platelet dissagregation, iv) in contrast to the reversible nature of platelet aggregation and FlnA modification by activation with Cvx, collagen, ristocetin or T6, when platelets are activated by thrombin the platelet do not disaggregate and FlnA remains cleavable. Our data demonstrate that αIIbβ3, α2β1 and GPIb can each exert tension on the cytoskeleton by virtue of binding ligand under conditions of shear. We further identified a unique role for αIIbβ3-fibrin interactions in creating sustained cytoskeletal tension, with implications for thrombus stability and clot retraction.
Colonic Epithelial miR-31 Associates with the Development of Crohn’s Phenotypes
Authors: Keith Benjamin P. , Barrow Jasmine B. , Toyonaga Takahiko , Kazgan Nevzat , O’Connor Michelle Hoffner , Shah Neil D. , Schaner Matthew S. , Wolber Elisabeth A. , Trad Omar K. , Gipson Greg R. , Pitman Wendy A. , Kanke Matthew , Saxena Shruti J. , Chaumont Nicole , Sadiq Timothy S. , Koruda Mark J. , Cotney Paul A. , Allbritton Nancy , Trembath Dimitri G. , Sylvester Francisco , Furey Terrence S. , Sethupathy Praveen , Sheikh Shehzad Z.
Published: April 2018

Crohn’s disease (CD) is highly heterogeneous, due in large part to variability in cellular processes that underlie the natural history of CD, thereby confounding effective therapy. There is a critical need to advance understanding of the cellular mechanisms that drive CD heterogeneity. In this study, small RNA-sequencing and microRNA profiling in the colon revealed two distinct molecular subtypes, each with different clinical associations, in both adult and treatment-naïve pediatric CD patients. Notably, we found that microRNA-31 (miR-31) expression by itself can stratify patients into these two subtypes. Through detailed analysis of several colonic mucosa cell types from adult patients, we found that differential levels of miR-31 are particularly pronounced in epithelial cells. We generated patient crypt-derived epithelial colonoids and showed that miR-31 expression differences preserved in this ex-vivo system. In adult patients, low colonic miR-31 expression levels at the time of surgery are associated with post-operative recurrence of ileal disease. In pediatric patients, lower miR-31 expression at the time of diagnosis is associated with the future development of fibrostenotic ileal CD requiring surgery. These findings represent an important step forward in designing more effective clinical trials and developing personalized therapies for CD.
Patterning of a telencephalon-like region in the adult brain of amphioxus
Authors: Benito-Gutiérrez Èlia , Stemmer Manuel , Rohr Silvia D , Schuhmacher Laura N , Tang Jocelyn , Marconi Aleksandra , Jékely Gáspár , Arendt Detlev
Published: April 2018

The evolutionary origin of the vertebrate telencephalon remains unsolved. A major challenge has been the identification of homologous brain parts in invertebrate chordates. Here we report evidence for a telencephalic region in the brain of amphioxus, the most basally branching invertebrate chordate. This region is characterised, like its vertebrate counterpart, by the combined expression of the telencephalic markers FoxG1, Emx and Lhx2/9. It is located at the anterior neural border and dorsal-ventrally patterned, as in vertebrates, by the antagonistic expression of Pax4/6 and Nkx2.1, and a ventral Hh signal. This part of the brain develops only after metamorphosis via sustained proliferation of neuronal progenitors at the ventricular zone. This is concomitant with a massive expansion of late differentiating neuronal types as revealed by neuropeptide and neurotransmitter profiling. Overall, our results suggest that the adult amphioxus brain shows remarkable similarities to the vertebrate embryonic brain, thus providing a key missing link in understanding the invertebrate-to-vertebrate transition in chordate brain evolution.