bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of the use of neuromuscular blocking agents on acute respiratory distress syndrome outcomes: A systematic review
Authors: Paramore Samantha
Published: June 2018

Background and purpose:

Acute respiratory distress syndrome (ARDS) is a high-mortality disease with limited treatment options. Optimization of gas exchange while limiting damage to the lungs is key. The use of neuromuscular blocking agents may limit hypoxemia while preventing ventilator-induced lung injury.

Methods:

A literature search was conducted using Ovid Medline and the exploded MeSH terms ARDS, acute respiratory distress syndrome, neuromuscular blockade, neuromuscular blocking agents, and paralytics. With limitations applied, three original randomized controlled trials investigating the use of neuromuscular blocking agents (NMBAs) in severe ARDS were identified and reviewed.

Conclusions:

Two of the three trials demonstrated improved primary outcomes with the use of NMBA. The third trial was underpowered (due to unanticipated low mortality in the control group) and did not show a statistically significant improvement in the primary outcome. As all the original research was conducted by the same group, further investigation is necessary to assess generalizability and confirm results. Currently, additional research is underway, focusing on early enrollment and narrow inclusion criteria.

Implications for practice:

Secondary analysis from two separate groups concluded the improved outcomes, with no evidence of increased risk of critical illness polyneuropathy or myopathy, suggest that the use of NMBAs in severe ARDS is appropriate.
Food and Drug Administration upscheduling of hydrocodone and the effects on nurse practitioner pain management practices
Authors: Mack Rachel
Published: June 2018

Background and purpose:

In 2013, the Advisory Committee of the Food and Drug Administration determined hydrocodone combination medications (HCMs) needed tighter regulation due to high abuse potential; they recommended upscheduling HCMs from Schedule III to II. The purpose of this study was to examine the effect of upscheduling of HCMs on pain management practices of advanced practiced registered nurses (APRNs) in Oklahoma.

Methods:

In this qualitative study, 25 participants described their primary care experiences after the upscheduling. A thematic analysis was used to understand the effects on APRN pain management practices.

Conclusions:

The upscheduling of HCMs has greatly affected the pain management practices of APRNs in a state where Schedule II narcotic prescribing is forbidden. Findings will assist APRNs with improving patient access to care, implementing practice regulations, and exploring options for alternative pain therapies in primary care.

Implications for practice:

Upscheduling of HCMs has had a severe impact on APRNs, affecting their prescribing practices and leading to increased referrals. They noted limited treatment options, increased health care costs, and decreased access to care. The APRNs understand the problem of prescription opioid abuse, diversion, and misuse. A consensus model could standardize the regulatory process for APRNs, increase interstate mobility for practice, and increase access to APRN care nationwide.
Towards more specific treatment for diabetic dyslipidemia
Authors: Rodriguez Valentina , Newman Jonathan D. , Schwartzbard Arthur Z.
Published: June 2018

Purpose of review

Treatment of diabetic dyslipidemia is necessary because of its impact on cardiovascular disease, which is the leading cause of death in patients with diabetes. In the past, standard treatment of diabetic dyslipidemia focused only on correcting lipids. Although this remains the mainstay of treatment, because new antihyperglycemic treatments reduce cardiovascular events with minimal effect on dyslipidemia, a new approach is both timely and relevant.

Recent findings

LDL-lowering remains the focus of treatment for diabetic dyslipidemia, especially in patients with both diabetes and cardiovascular disease (CVD). Higher intensity statin therapy or lower LDL cholesterol goals are recommended in these patients. Combination therapy, especially with ezetimibe, fibrates, bile acid sequestrants, PCSK9 inhibitors and omega 3 fatty acids should be considered along with selected new agents to reduce glycemia.

As diabetic dyslipidemia plays a key role in CVD, aggressive treatment is indicated. New research targets include apo-CIII and lipoprotein(a) [Lp(a)]. In addition, new antihyperglycemic therapy is changing diabetes care and altering treatment guidelines. The most recent American Diabetes Association Standards of Care has expanded its recommendations for people with CVD and diabetes, suggesting that medications validated to improve cardiac health should be strongly considered.
Metformin, lipids and atherosclerosis prevention
Authors: Jenkins Alicia J. , Welsh Paul , Petrie John R.
Published: June 2018

Purpose of review

We provide an overview of recent publications that extend clinically relevant knowledge relating to metformin's effects on lipids and atherosclerotic vascular disease and/or provide insights into the drug's mechanisms of action on the heart and vasculature.

Recent findings

We focus on original research in humans or in human tissues. Several recently completed randomized clinical trials have reported effects of metformin on surrogate measures of atherosclerotic vascular disease, including carotid–intima media thickness, vascular reactivity and calcification in people with Type 1 (T1D) and Type 2 (T2D) diabetes as well as nondiabetic dysglycaemia. In addition, observational studies have provided novel insights into the mechanisms of metformin's effects on carotid plaque, monocytes/macrophages, vascular smooth muscle and endothelial cells, including via 5’-adenosine monophosphate-activated protein kinase (AMPK) activation.

Recent trials based on surrogate outcome measures have provided further data suggesting protective effects of metformin against vascular disease in youth and adults with Type 1 diabetes, as well as in adults with prediabetes and Type 2 diabetes. In parallel, human tissue and cell studies have provided new insights into pleiotropic effects of metformin and suggest novel drug targets. As metformin is an inexpensive agent with an established safety profile, larger scale clinical trials based on hard clinical outcomes [cardiovascular disease (CVD) events] are now indicated.
Defining kidney allograft benefit from successful pancreas transplant: separating fact from fiction
Authors: Wiseman Alexander C. , Stites Erik , Kennealey Peter
Published: June 2018

Purpose of review

To define the natural history of kidney allograft loss related to recurrent diabetes following transplant, and to understand the potential benefit of pancreas transplantation upon kidney allograft survival.

Recent findings

A postulated benefit of simultaneous pancreas kidney transplant is that, unlike kidney transplant alone, euglycemia from the added pancreas allograft may confer a nephroprotective benefit and prevent recurrent diabetic nephropathy in the renal allograft. Recent large database analyses and long-term histological assessments have been published that assist in quantifying the problem of recurrent diabetic nephropathy and answering the question of the potential benefits of euglycemia. Further data may be extrapolated from larger single-center series that follow the prognosis of early posttransplant diabetes mellitus as another barometer of risk from diabetic nephropathy and graft loss.

Recurrent diabetic nephropathy following kidney transplant is a relatively rare, late occurrence and its clinical significance is significantly diminished by the competing risks of death and chronic alloimmune injury. Although there are hints of a protective effect upon kidney graft survival with pancreas transplant, these improvements are small and may take decades to appreciate. Clinical decision-making regarding pancreas transplant solely based upon nephroprotective effects of the kidney allograft should be avoided.
A Workshop for Addressing the Impact of the Imposter Syndrome on Clinical Nurse Specialists
Authors: Haney Tina Sweeney , Birkholz Lorri , Rutledge Carolyn
Published: June 2018

Purpose:

The imposter syndrome creates feelings of self-doubt in individuals, which can result in emotional paralysis preventing them from achieving their fullest potential. Clinical nurse specialists are not immune to this phenomenon. The purpose of this article is to describe an educational program designed to assist healthcare professionals, including clinical nurse specialist students, in identifying, understanding, and addressing imposter syndrome.

Description of Program:

Interprofessional students from 8 professions came together for a 2-week interprofessional education experience that included a 1-day workshop. After experiential team building and small group encounters with complicated standardized patients, students were introduced to the imposter syndrome. Students completed the Clance Impostor Phenomenon Scale and engaged in rich dialogue about the phenomenon, its effects, and personal strategies to overcome its impact.

Outcome:

When surveyed using the Clance Impostor Phenomenon Scale, clinical nurse specialist students consistently had high imposter tendencies. As a result of the program, students expressed feelings of liberation and empowerment.

Conclusion:

Clinical nurse specialist students can be impacted by the imposter syndrome, which has a potential to decrease their confidence, thus limiting their ability to practice at their highest potential. Programs that empower the clinical nurse specialists to recognize and address this phenomenon may increase their ability to optimize their role in healthcare.
Use of Roof-Shaped Costochondral Cartilage for Correction of Saddle Nose Deformity
Authors: Irmak Fatih , Yazar Sevgi K. , Sirvan Selami S. , Yazar Memet , Karsidag Semra
Published: June 2018

Background:

Cartilage grafts are routinely used in secondary and posttraumatic rhinoplasty. However, in most cases, there are weak areas in the nasal bones and upper lateral cartilages. The purpose of this study was to seek a solution for the keystone area and dorsum of the nose in revision and posttraumatic rhinoplasty cases, and reconstruction of saddle nose deformity including upper lateral cartilage with a roof-shaped graft.

Methods:

A retrospective review of reconstructive rhinoplasties performed for saddle nose deformities was conducted. A part of the costochondral graft was carved and thinned (roof graft) for reconstruction of the keystone area and upper lateral cartilages, and another portion was used for making a neoseptal (reconstructed septum) graft and strut graft. The roof graft was capped onto the neoseptal graft with sutures, and this cartilage framework was adapted with fitting the cranial edge of the neoseptal cartilage between the nasal bones. Finally, the strut graft was fixed to the cartilage framework.

Results:

A significant improvement in nasal shape and overall appearance was achieved in all cases, and 71.42 percent of patients recovered from nasal obstruction. No gross absorption, graft exposure, or recurrence of deformities was observed.

Conclusions:

Surgical correction of a saddle-shaped nose should be an acceptable and uncomplicated technique, and the cosmetic result should be totally acceptable. There are many management options for a saddle-shaped nose. Use of roof grafts (shrunk gull-wing grafts) with neoseptal and strut grafts enables simulation of the internal nasal valve and results in a natural nasal position.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Human Acellular Dermis as Spacer for Small-Joint Arthroplasty: Analysis of Revascularization in a Rabbit Trapeziectomy Model
Authors: Banks Kian , Squitieri Lee , Bramos Athanasios , Johnson Maxwell B. , Gardner Daniel J. , Pourmoussa Austin J. , Jung Eunson , Lee Gene K. , Perrault David P. , Fedenko Alexander , Kim Gene H. , Han Bo , Hong Young-Kwon , Kulber David A. , Wong Alex K.
Published: June 2018

Background:

Carpometacarpal joint osteoarthritis affects 8 to 12 percent of the general population. Surgical management provides symptomatic relief for 78 percent of patients who fail conservative therapy, but little consensus exists regarding which surgical procedure provides superior patient outcomes. Recent human trials substituted exogenous acellular dermal matrices in the bone space, but there are no quantitative histologic data on the outcome of acellular dermal matrices in this environment. The authors aimed to quantify the revascularization and recellularization of acellular dermal matrices in the joint space using a rabbit model.

Methods:

Bilateral lunate carpal bones were surgically removed in New Zealand rabbits. Acellular dermal matrix and autologous tissue were implanted in place of the lunate of the right and left wrists, respectively. Acellular dermal matrix was also implanted subcutaneously as a nonjoint control. Histologic and immunofluorescence analysis was performed after collection at 0, 6, and 12 weeks.

Results:

Quantitative analysis of anti–α-smooth muscle actin and CD31 immunofluorescence revealed a sequential and comparable increase of vascular lumens in joint space and subcutaneous acellular dermal matrices. In contrast, autologous tissue implanted in the joint space did not have a similar increase in α-smooth muscle actin–positive or CD31-positive lumens. Semiquantitative analysis revealed increased cellularity in both autologous and acellular dermal matrix wrist implants at each time point, whereas average cellularity of subcutaneous acellular dermal matrix peaked at 6 weeks and regressed by 12 weeks. Trichrome and Sirius red staining revealed abundant collagen at all time points.

Conclusion:

The trapeziectomy joint space supports both cellular and vascular ingrowth into human acellular dermal matrix.
Candida auris
Authors: Saris Katja , Meis Jacques F. , Voss Andreas
Published: June 2018

Purpose of review

To give an update on the recent emergence of Candida auris.

Recent findings

C. auris is a pathogen, that evades present therapeutic options, that is highly virulent, causes disease in all types of patients, and spreads easily in the environment and among patients, thereby posing an imminent threat to our patients. The fact that C. auris, in addition, is more resilient to environmental disinfection and frequently misclassified during microbiological diagnostics only heightens its potential as a ‘perfect villain.’

Healthcare institutions, especially hospitals, need to ensure that their diagnostic and infection control policies to handle C. auris are in place.
Intraoperative Neural Monitoring in Endoscopic Thyroidectomy Via Bilateral Areola Approach
Authors: Zhang Daqi , Fu Qingfeng , Dionigi Gianlorenzo , Wang Tie , Xin Jingwei , Zhang Jiao , Xue Gaofeng , Li Hongbo , Sun Hui
Published: June 2018

Objective:

The aim of this report was dual: (a) to describe the step by step standardized intraoperative neural monitoring (IONM) procedure for recurrent laryngeal nerve (RLN) and external branch of the superior laryngeal nerve focusing on percutaneous IONM method, and (b) evaluation and outcomes of intermittent IONM in 237 endoscopic thyroidectomy via bilateral areolar approach cases.

Materials and Methods:

A 10-mm curved incision is made along the margin of the right areola at the 2 to 4 o’clock position for the 30-degree endoscope. Bilaterally 5-mm incisions are required on the edges of the areola at the 11 to 12 o’clock positions as accessory operating ports. Ball-tip, monopolar, single-use, standard stimulating probe with a 10-cm handle and 9-cm shaft is adopted percutaneously for IONM. As reference, on the dominant thyroid lesion side, a 0.5-cm circle is drawn with the center at the intersection of a line 2-cm lateral to the anterior median line and a line 2-cm above the line connecting the bilateral clavicular heads. After ensuring with ultrasonography that no vessels are within the puncture passage, the skin is pierced with an 18-G syringe needle. After withdrawing the needle, the probe is carefully inserted through the tract. IONM is performed according to standards of equipment set up, anesthesia, tube positioning verification tests, and electromyography determinations.

Results:

A total of 277 nerves at risk were favorably monitored with percutaneous probe stimulation. RLN, vagus nerve, and external branch of the superior laryngeal nerve were successfully determined. There were no instances of IONM malfunction, equipment displacement, or interference with the other endoscopic instruments. IONM probe insertion incision determined no scarring or morbidity in the neck. The incidence of RLN monolateral temporary palsy was 6%.

Conclusions:

Standardized monitoring in endoscopic thyroidectomy via bilateral areolar approach is feasible. IONM was implemented by means of percutaneous stimulating probe.
Calcium activation of cortical neurons by continuous electrical stimulation: Frequency-dependence, temporal fidelity and activation density
Authors: Michelson Nicholas J. , Eles James R. , Vazquez Alberto L. , Ludwig Kip A , Kozai Takashi DY
Published: June 2018

Electrical stimulation of the brain has become a mainstay of fundamental neuroscience research and an increasingly prevalent clinical therapy. Despite decades of use in basic neuroscience research and the growing prevalence of neuromodulation therapies, gaps in knowledge regarding activation or inactivation of neural elements over time have limited its ability to adequately interpret evoked downstream responses or fine-tune stimulation parameters to focus on desired responses. In this work, in vivo two-photon microscopy was used to image neuronal calcium activity in layer 2/3 neurons of somatosensory cortex (S1) in male C57BL/6J-Tg(Thy1-GCaMP6s)GP4.3Dkim/J mice during 30 s of continuous electrical stimulation at varying frequencies. We show frequency-dependent differences in spatial and temporal somatic responses during continuous stimulation. Our results elucidate conflicting results from prior studies reporting either dense spherical activation of somas biased towards those near the electrode, or sparse activation of somas at a distance via axons near the electrode. These findings indicate that the neural element specific temporal response local to the stimulating electrode changes as a function of applied charge density and frequency. These temporal responses need to be considered to properly interpret downstream circuit responses or determining mechanisms of action in basic science experiments or clinical therapeutic applications.

Significance Statement

Microstimulation of small populations of neurons has the potential to ameliorate symptoms associated with several neurological disorders. However, the specific mechanisms by which microstimulation elicits therapeutic responses are unclear. This work examines the effects of continuous microstimulation on the local population of neurons surrounding the implanted electrode. Stimulation was found to elicit spatiotemporal neuronal responses in a frequency dependent manner. These findings suggest that stimulation frequency may be an important consideration for applications in research or therapy. Further research aimed at understanding these neuronal activation properties may provide insight into the mechanistic mode of action of continuous microstimulation.
Molecular basis for the evolution of species-specific hemoglobin capture by pathogenicStaphylococcus
Authors: Choby Jacob E. , Buechi Hanna B. , Farrand Allison J. , Skaar Eric P. , Barber Matthew F.
Published: June 2018

Metals are a limiting resource for pathogenic bacteria and must be scavenged from host proteins. Hemoglobin provides the most abundant source of iron in the human body and is required by several pathogens to cause invasive disease. However, the consequences of hemoglobin evolution for bacterial nutrient acquisition remain unclear. Here we show that the α- and β-globin genes exhibit strikingly parallel signatures of adaptive evolution across simian primates. Rapidly evolving sites in hemoglobin correspond to binding interfaces of IsdB, a bacterial hemoglobin receptor encoded by pathogenicStaphylococcus aureus. Using an evolution-guided experimental approach, we demonstrate that divergence between primates and staphylococcal isolates governs hemoglobin recognition and bacterial growth. Reintroducing putative adaptive mutations in α- or β-globin proteins is sufficient to impairS. aureusbinding, providing a mechanism for the evolution of disease resistance. These findings suggest that bacterial hemoprotein capture has driven repeated evolutionary conflicts with hemoglobin during primate descent.
Captivity and exposure to the emerging fungal pathogen Batrachochytrium salamandrivorans are linked to perturbation and dysbiosis of the amphibian skin microbiome
Authors: Bates Kieran A , Shelton Jennifer MG , Mercier Victoria L , Hopkins Kevin P , Harrison Xavier A , Petrovan Silviu O , Fisher Matthew C
Published: June 2018

The emerging fungal pathogen, Batrachochytrium salamandrivorans (Bsal) is responsible for the catastrophic decline of European salamanders and poses a threat to amphibians globally. The amphibian skin microbiome is strongly associated with disease outcome for several host-pathogen systems, yet its role in Bsal infection remains unresolved. In addition, many in-vivo Bsal studies to date have relied on specimens that have been kept in captivity for long periods without considering the influence of environment on the microbiome and how this may impact the host response to pathogen exposure. We characterised the impact of captivity and exposure to Bsal on the skin bacterial and fungal communities of two co-occurring European newt species, the smooth newt (Lissotriton vulgaris) and the great-crested newt (Triturus cristatus). Bsal infection and subsequent mortality in both newt species was associated with perturbation of the skin microbiome and possible dysbiosis. In addition, reduced microbial diversity and changes in microbiome structure accompanied the transition of newts from the wild to captivity, suggesting a possible decline in microbe-associated protection and increased risk of infection by opportunistic pathogens. Our findings advance current understanding of the role of host-associated microbiota in Bsal infection and highlight important considerations for ex-situ amphibian conservation programmes.
Staphylococcus aureusCas9 is a multiple-turnover enzyme
Authors: Yourik Paul , Fuchs Ryan T. , Mabuchi Megumu , Curcuru Jennifer L. , Brett Robb G.
Published: June 2018

Cas9 nuclease is the key effector of type II CRISPR adaptive immune systems found in bacteria. The nuclease can be programmed by a single guide RNA (sgRNA) to cleave DNA in a sequence-specific manner. This property has led to its widespread adoption as a genome editing tool in research laboratories and holds great promise for biotechnological and therapeutic applications. The general mechanistic features of catalysis by Cas9 homologs are comparable; however, a high degree of diversity exists among the protein sequences, which may result in subtle mechanistic differences.S. aureus(SauCas9) and especiallyS. pyogenes(SpyCas9) are among the best-characterized Cas9 proteins and share about 17% sequence identity. A notable feature of SpyCas9 is an extremely slow rate of reaction turnover, which is thought to limit the amount of substrate DNA cleavage. Usingin vitrobiochemistry and enzyme kinetics we directly compare SpyCas9 and SauCas9 activities. Here, we report that in contrast to SpyCas9, SauCas9 is a multiple-turnover enzyme, which to our knowledge is the first report of such activity in a Cas9 homolog. We also show that DNA cleaved with SauCas9 does not undergo any detectable single-stranded degradation after the initial double-stranded break observed previously with SpyCas9, thus providing new insights and considerations for future design of CRISPR/Cas9-based applications.
Understanding the Liver Under Heat Stress With Statistical Learning: A Multiomics Computational Approach
Authors: Hubbard Allen , Zhang Xiaoke , Jastrebski Sara , Singh Abhi , Schmidt Carl
Published: June 2018

We present results from a pipeline developed to integrate multi-omics data in order to explore the heat stress response in the liver of the modern broiler chicken. Heat stress is a significant cause of productivity loss in the poultry industry, both in terms of increased livestock morbidity and its negative influence on average feed efficiency. This study focuses on the liver because it is an important regulator of metabolism, controlling many of the physiological processes impacted by prolonged heat stress. Using statistical learning methods, we identify genes and metabolites that may regulate the heat stress response in the liver and adaptations required to acclimate to prolonged heat stress. Our findings provide more detailed context for genomic studies and generates hypotheses about dietary interventions that can mitigate the negative influence of heat stress on the poultry industry.

Abbreviation Term

RNA-seq

Ribonucleic Acid Sequencing

GWA

Genome Wide Association

SNP

Single Nucleotide Polymorphism

PCA

Principal Component Analysis

GTEX

Genotype Tissue Expression

K1

rate constant for forward reaction

K2

rate constant for reverse reaction

F6P

fructose-6-phosphate

G3P

glycerol-3-phosphate

S100Z

S100 Calcium Binding Protein Z

FBP2

Fructose-Bisphosphatase-2

NADKD1

NAD Kinase, mitochondrial

NAD

Nicotinamide Adenine Dinucleotide

NADP

Nicotinamide Adenine Dinucleotide Phoshpate

NADPH

Nicotinamide Adenine Dinucleotide Phosphate, Reduced
Open source modules for tracking animal behavior and closed-loop stimulation based on Open Ephys and Bonsai
Authors: Buccino Alessio Paolo , Lepperød Mikkel Elle , Dragly Svenn-Arne , Häfliger Philipp , Fyhn Marianne , Hafting Torkel
Published: June 2018

Objective

A major goal in systems neuroscience is to determine the causal relationship between neural activity and behavior. To this end, methods that combine monitoring neural activity, behavioral tracking, and targeted manipulation of neurons in closed-loop are powerful tools. However, commercial systems that allow these types of experiments are usually expensive and rely on non-standardized data formats and proprietary software which may hinder user-modifications for specific needs. In order to promote reproducibility and data-sharing in science, transparent software and standardized data formats are an advantage. Here, we present an open source, low-cost, adaptable, and easy to set-up system for combined behavioral tracking, electrophysiology and closed-loop stimulation.

Approach

Based on the Open Ephys system (www.open-ephys.org) we developed multiple modules to include real-time tracking and behavior-based closed-loop stimulation. We describe the equipment and provide a step-by-step guide to set up the system. Combining the open source software Bonsai (bonsai-rx.org) for analyzing camera images in real time with the newly developed modules in Open Ephys, we acquire position information, visualize tracking, and perform tracking-based closed-loop stimulation experiments. To analyze the acquired data we provide an open source file reading package in Python.

Main results

The system robustly visualizes real-time tracking and reliably recovers tracking information recorded from a range of sampling frequencies (30-1000Hz). We combined electrophysiology with the newly-developed tracking modules in Open Ephys to record place cell and grid cell activity in the hippocampus and in the medial entorhinal cortex, respectively. Moreover, we present a case in which we used the system for closed-loop optogenetic stimulation of entorhinal grid cells.

Significance

Expanding the Open Ephys system to include animal tracking and behavior-based closed-loop stimulation extends the availability of high-quality, low-cost experimental setup within standardized data formats serving the neuroscience community.
Phase-type distributions in population genetics
Authors: Hobolth Asger , Siri-Jégousse Arno , Bladt Mogens
Published: June 2018

Probability modelling for DNA sequence evolution is well established and provides a rich framework for understanding genetic variation between samples of individuals from one or more populations. We show that both classical and more recent models for coalescence (with or without recombination) can be described in terms of the so-called phase-type theory, where complicated and tedious calculations are circumvented by the use of matrices. The application of phase-type theory consists of describing the stochastic model as a Markov model by appropriately setting up a state space and calculating the corresponding intensity and reward matrices. Formulae of interest are then expressed in terms of these aforementioned matrices. We illustrate this by a few examples calculating the mean, variance and even higher order moments of the site frequency spectrum in the multiple merger coalescent models, and by analysing the mean and variance for the number of segregating sites for multiple samples in the two-locus ancestral recombination graph. We believe that phase-type theory has great potential as a tool for analysing probability models in population genetics. The compact matrix notation is useful for clarification of current models, in particular their formal manipulation (calculation), but also for further development or extensions.
Quantitative Late Quaternary climate reconstruction from plant macrofossil proxy in Western North America
Authors: Harbert Robert S. , Nixon Kevin C.
Published: June 2018

The Late Quaternary packrat (Neotomaspp.) midden plant macrofossil record in western North America is an exceptional record of biotic change that provides strong evidence of past climate. In this study we generate quantitative estimates of climate from plant community composition of more than 600 individual paleomiddens over the past 50,000 years. This is the first large-scale application of CRACLE, a quantitative climate inference method that uses plant community composition as a climatic proxy under and individualistic concept of plant community assembly. The results are spatiotemporally specific estimates of temperature, precipitation, available moisture, and seasonal patterns that are consistent with well understood global climate patterns, but provide previously unavailable detail and precision of the regional paleoclimate in western North America. Rapid warming is estimated at the Pleistocene-Holocene transition, at a conservative estimate of ca. 1°C per millennium. Previously projected future temperature increases suggest a rate of increase of more than 2°C over the next century, an astonishing 10X the rate experienced at any point during the past 50,000 years in Western North America. These analyses form a baseline demonstration of how the growing paleoecological record of packrat midden plant macrofossils is able to provide quantitative estimates of paleoclimate that aid in understanding the complexities of, and biotic responses to the regional climate system.
The effect of susceptible and resistant potato cultivars on bacterial communities in the tuberosphere of potato in soil suppressive or conducive to common scab disease
Authors: Kopecky Jan , Samkova Zuzana , Sarikhani Ensyeh , Kyselková Martina , Omelka Marek , Kristufek Vaclav , Divis Jiri , Grundmann Geneviève G. , Moenne-Loccoz Yvan , Sagova-Mareckova Marketa
Published: June 2018

Connections between the structure of bacterial communities in suppressive soils and potato resistance to common scab (CS) are not well understood. In this study, one resistant and one susceptible cultivar were grown in a conducive and suppressive field to assess cultivar resistance × soil suppressiveness interactions. The resistant cultivar had a higher Mg content in periderm compare to susceptible cultivar, while suppressive soil had lower pH (5.3 vs 5.9), N, C, P, Ca contents but higher Fe and S compared with the conducive soil. Bacteria and actinobacteria numbers were higher in the conducive soil. Copy numbers oftxtBgene (coding for a pathogenicity determinant) were similar in both soils but were higher in the conducive soil (for periderm samples) and in the susceptible cultivar (for conducive soil samples). Taxonomic microarray analysis and Illumina sequencing of 16S rRNA genes amplicon showed that bacterial community differed between resistant vs susceptible cultivar and to a lesser extend between suppressive vs conducive soil. Bacteria participating in soil suppression belonged toPseudomonadaceae, Bradyrhizobiaceae, AcetobacteraceaeandPaenibacillaceae, while resistant cultivars selected a bacterial community resembling that of the suppressive soil, which was enriched inNitrospiraeandAcidobacteria. Thus, the analysis of soil suppressiveness×cultivar resistance interactions enabled to gain new insight to CS control in the field.

IMPORTANCE

It was demonstrated that potato cultivars susceptible and resistant to common scab select differing bacterial community and above that this trait is further modified in suppressive and conducive soil. Common scab severity was diminished by either resistant cultivar or suppressive soil but without additive effect between them. Out of the two factors, potato cultivar had a more significant influence on tuberosphere bacterial community composition than soil. Results highlighted the usefulness of both cultivar resistance and soil suppressiveness traits in understanding and managing disease control of crops.
Chance and pleiotropy dominate genetic diversity in complex bacterial environments
Authors: Noda-Garcia Lianet , Davidi Dan , Korenblum Elisa , Elazar Assaf , Putintseva Ekaterina , Aharoni Asaph , Tawfik Dan S.
Published: June 2018

How does environmental complexity affect the evolution of single genes? Here, we measured the effects of a set of mutants ofBacillus subtilisglutamate dehydrogenase across 19 different environments - from homogenous single cell populations in liquid media to heterogeneous biofilms, plant roots and soil communities. The effects of individual gene mutations on organismal fitness were highly reproducible in liquid cultures. Strikingly, however, 84% of the tested alleles showed opposing fitness effects under different growth conditions (environmental pleiotropy). In biofilms and soil samples, different alleles dominated in parallel replica experiments. Accordingly, we found that in these heterogeneous cell communities the fate of mutations was dictated by a combination of selection and drift. The latter relates to programmed prophage excisions that occurred along biofilm development. Overall, per individual condition, by the combined action of selection, pleiotropy and chance, a wide range of glutamate dehydrogenase mutations persisted and sometimes fixated. However, across longer periods and multiple environments, nearly all this diversity would be lost - indeed, considering all environments and conditions we have tested, wild-type is the fittest allele.
Different SUMO Paralogs Determine the Fate of WT and Mutant CFTRs: Biogenesis vs. Degradation
Authors: Gong Xiaoyan , Liao Yong , Ahner Annette , Larsen Mads Breum , Wang Xiaohui , Bertrand Carol A. , Frizzell Raymond A.
Published: June 2018

A pathway for CFTR degradation is initiated by Hsp27 which cooperates with Ubc9 and binds to the common F508del mutant to modify it with SUMO-2/3. These SUMO paralogs form poly-chains, which are recognized by the ubiquitin ligase, RNF4, for proteosomal degradation. Here, protein array analysis identified the SUMO E3, PIAS4, which increased WT and F508del CFTR biogenesis in CFBE airway cells. PIAS4 increased immature CFTR three-fold and doubled expression of mature CFTR, detected by biochemical and functional assays. In cycloheximide chase assays, PIAS4 slowed immature F508del degradation 3-fold and stabilized mature WT CFTR at the PM. PIAS4 knockdown reduced WT and F508del CFTR expression by 40-50%, suggesting a physiological role in CFTR biogenesis. PIAS4 modified F508del CFTR with SUMO-1in vivoand reduced its conjugation to SUMO-2/3. These SUMO paralog specific effects of PIAS4 were reproducedin vitrousing purified F508del NBD1 and SUMOylation reaction components. PIAS4 reduced endogenous ubiquitin conjugation to F508del CFTR by ~50%, and blocked the impact of RNF4 on mutant CFTR disposal. These findings indicate that different SUMO paralogs determine the fates of WT and mutant CFTRs, and they suggest that a paralog switch during biogenesis can direct these proteins to different outcomes: biogenesis vs. degradation.
The genomic landscape of recombination rate variation inChlamydomonas reinhardtiireveals a pronounced effect of linked selection
Authors: Hasan Ahmed R. , Ness Rob W.
Published: June 2018

Recombination confers a major evolutionary advantage by breaking up linkage disequilibrium (LD) between harmful and beneficial mutations and facilitating selection. Here, we use genome-wide patterns of LD to infer fine-scale recombination rate variation in the genome of the model green algaChlamydomonas reinhardtiiand estimate rates of LD decay across the entire genome. We observe recombination rate variation of up to two orders of magnitude, finding evidence of recombination hotspots playing a role in the genome. Recombination rate is highest just upstream of genic regions, suggesting the preferential targeting of recombination breakpoints in promoter regions. Furthermore, we observe a positive correlation between GC content and recombination rate, suggesting a role for GC-biased gene conversion or selection on base composition within the GC-rich genome ofC. reinhardtii. We also find a positive relationship between nucleotide diversity and recombination, consistent with widespread influence of linked selection in the genome. Finally, we use estimates of the effective rate of recombination to calculate the rate of sex that occurs in natural populations of this important model microbe, estimating a sexual cycle roughly every 770 generations. We argue that the relatively infrequent rate of sex and large effective population size creates an population genetic environment that increases the influence of linked selection on the genome.
Network Inference from Perturbation Time Course Data
Authors: Sarmah Deepraj , Smith Gregory R , Bouhaddou Mehdi , Stern Alan D. , Erskine James , Birtwistle Marc R
Published: June 2018

Networks underlie much of biology from subcellular to ecological scales. Yet, understanding what experimental data are needed and how to use them for unambiguously identifying the structure of even small networks remains a broad challenge. Here, we integrate a dynamic least squares framework into established modular response analysis (DL-MRA), that specifies sufficient experimental perturbation time course data to robustly infer arbitrary two and three node networks. DL-MRA considers important network properties that current methods often struggle to capture: (i) edge sign and directionality; (ii) cycles with feedback or feedforward loops including self-regulation; (iii) dynamic network behavior; (iv) edges external to the network; and (v) robust performance with experimental noise. We evaluate the performance of and the extent to which the approach applies to cell state transition networks, intracellular signaling networks, and gene regulatory networks. Although signaling networks are often an application of network reconstruction methods, the results suggest that only under quite restricted conditions can they be robustly inferred. For gene regulatory networks, the results suggest that incomplete knockdown is often more informative than full knockout perturbation, which may change experimental strategies for gene regulatory network reconstruction. Overall, the results give a rational basis to experimental data requirements for network reconstruction and can be applied to any such problem where perturbation time course experiments are possible.
DivIVA concentrates mycobacterial cell envelope assembly for initiation and stabilization of polar growth
Authors: Melzer Emily S. , Sein Caralyn E. , Chambers James J. , Sloan Siegrist M.
Published: June 2018

In many model organisms, diffuse patterning of cell wall peptidoglycan synthesis by the actin homolog MreB enables the bacteria to maintain their characteristic rod shape. InCaulobacter crescentusandEscherichia coli, MreB is also required to sculpt this morphologyde novo. Mycobacteria are rod-shaped but expand their cell wall from discrete polar or sub-polar zones. In this genus, the tropomyosin-like protein DivIVA is required for the maintenance of cell morphology. DivIVA has also been proposed to direct peptidoglycan synthesis to the tips of the mycobacterial cell. The precise nature of this regulation is unclear, as is its role in creating rod shape from scratch. We find that DivIVA localizes nascent cell wall and covalently associated mycomembrane but is dispensable for the assembly process itself.Mycobacterium smegmatisrendered spherical by peptidoglycan digestion or by DivIVA depletion are able to regain rod shape at the population level in the presence of DivIVA. At the single cell level, there is a close spatiotemporal correlation between DivIVA foci, rod extrusion and concentrated cell wall synthesis. Thus, although the precise mechanistic details differ from other organisms,M. smegmatisalso establish and propagate rod shape by cytoskeleton-controlled patterning of peptidoglycan. Our data further support the emerging notion that morphology is a hardwired trait of bacterial cells.
Single olfactory receptors set odor detection thresholds
Authors: Dewan Adam , Cichy Annika , Zhang Jingji , Miguel Kayla , Feinstein Paul , Rinberg Dmitry , Bozza Thomas
Published: June 2018

In many species, survival depends on olfaction, yet the mechanisms that underlie olfactory sensitivity are not well understood. Here, we examine how a conserved subset of olfactory receptors, the trace amine-associated receptors (TAARs) determine odor detection thresholds of mice to amines. We find that deleting all TAARs, or even single TAARs, results in significant odor detection deficits. This finding is not limited to TAARs, as the deletion of a canonical odorant receptor reduced behavioral sensitivity to its preferred ligand. Remarkably, behavioral threshold is set solely by the most sensitive receptor, with no contribution from other highly sensitive receptors. In addition, increasing the number of sensory neurons (and glomeruli) expressing a threshold-determining TAAR does not improve detection, indicating that sensitivity is not limited by the typical complement of sensory neurons. Our findings demonstrate that olfactory thresholds are set by the single highest affinity receptor, and suggest that TAARs are evolutionarily conserved because they determine the sensitivity to a class of biologically relevant chemicals.
Predicting clone genotypes from tumor bulk sequencing of multiple samples
Authors: Miura Sayaka , Gomez Karen , Murillo Oscar , Huuki Louise A , Vu Tracy , Buturla Tiffany , Kumar Sudhir
Published: June 2018

Motivation

Analyses of data generated from bulk sequencing of tumors have revealed extensive genomic heterogeneity within patients. Many computational methods have been developed to enable the inference of genotypes of tumor cell populations (clones) from bulk sequencing data. However, the relative and absolute accuracy of available computational methods in estimating clone counts and clone genotypes is not yet known.

Results

We have assessed the performance of nine methods, including eight previously-published and one new method (CloneFinder), by analyzing computer simulated datasets. CloneFinder, LICHeE, CITUP, and cloneHD inferred clone genotypes with low error (<5% per clone) for a majority of datasets in which the tumor samples contained evolutionarily-related clones. Computational methods did not perform well for datasets in which tumor samples contained mixtures of clones from different clonal lineages. Generally, the number of clones was underestimated by cloneHD and overestimated by Phy-loWGS, and BayClone2, Canopy, and Clomial required prior information regarding the number of clones. AncesTree and Canopy did not produce results for a large number of datasets.

Conclusions

Deconvolution of clone genotypes from single nucleotide variant (SNV) frequency differences among tumor samples remains challenging, so there is a need to develop more accurate computational methods and robust software for clone genotype inference.

Availability and Implementation

CloneFinder is implemented in Python and is available fromhttps://github.com/gstecher/CloneFinderAPI.

Contact

s.kumar@temple.edu

Supplementary information

Supplementary data are available atBioinformaticsonline
Thermodynamic constraints on the regulation of metabolic fluxes
Authors: Dai Ziwei , Locasale Jason W.
Published: June 2018

Nutrition and metabolism are fundamental to cellular function in physiological and pathological contexts. Metabolic activity (i.e. rates, flow, or most commonly referred to as flux) is constrained by thermodynamics and regulated by the activity of enzymes. The general principles that relate biological and physical variables to metabolic control are incompletely understood. Using metabolic control analysis in several representative topological structures of metabolic pathways as models, we derive exact results and conduct computer simulations that define relationships between thermodynamics, enzyme activity, and flux control. We confirm that metabolic pathways that are very far from equilibrium are controlled by the activity of upstream enzymes. However, in general, metabolic pathways have a more adaptable pattern of regulation, controlled minimally by thermodynamics and not necessarily by the specific enzyme that generates the given reaction. These findings show how the control of metabolic pathways, which are rarely very far from equilibrium, is largely set by the overall flux through a pathway rather than by the enzyme which generates the flux or by thermodynamics.
How many, and when? Optimising targeted gene flow for a step change in the environment
Authors: Kelly E. , Phillips BL.
Published: June 2018

Targeted gene flow is an emerging conservation strategy that involves translocating individuals with particular traits to places where they are of benefit, thereby increasing a population’s evolutionary resilience. While the idea can work in theory, questions remain as to how best to implement it. Here, we vary timing of introduction and size of the introduced cohort to maximise our objective – survival of the recipient population’s genome. We demonstrate our approach using the northern quoll, an Australian marsupial predator threatened by the toxic cane toad. We highlight a general trade-off between maintaining a local genome and reducing population extinction risk, but show that key management levers can optimise this so that 100% of the population’s genome is preserved. In our case, any action was better than not acting at all (even with strong outbreeding depression), but the size of the benefit was sensitive to timing and size of the introduction.