bluuebunny/crossref_metadata_2025 huggingface dataset:
Resuscitative endovascular balloon occlusion of the inferior vena cava is made hemodynamically possible by concomitant endovascular balloon occlusion of the aorta—A porcine study
Authors: Wikström Maria B. , Krantz Johannes , Hörer Tal M. , Nilsson Kristofer F.
Published: August 2019

BACKGROUND

Resuscitative endovascular balloon occlusion of the vena cava inferior (REBOVC) may provide a minimal invasive alternative for hepatic vascular and inferior vena cava isolation in severe retrohepatic bleeding. However, circulatory stability may be compromised by the obstruction of venous return. The aim was to explore which combinations of arterial and venous endovascular balloon occlusions, and the Pringle maneuver, are hemodynamically possible in a normovolemic pig model. The hypothesis was that lower-body venous blood pooling from REBOVC can be avoided by prior resuscitative endovascular aortic balloon occlusion (REBOA).

METHODS

Nine anesthetized, ventilated, instrumented, and normovolemic pigs were used to explore the hemodynamic effects of 11 combinations of REBOA and REBOVC, with or without the Pringle maneuver, in randomized order. The occlusions were performed for 5 minutes but interrupted if systolic blood pressure dropped below 40 mm Hg. Hemodynamic variables were measured.

RESULTS

Proximal REBOVC, isolated or in combination with other methods of occlusion, caused severely decreased systemic blood pressure and cardiac output, and had to be terminated before 5 minutes. The decreases in systemic blood pressure and cardiac output were avoided by REBOA at the same or a more proximal level. The Pringle maneuver had similar hemodynamic effects to proximal REBOVC.

CONCLUSION

A combination of REBOA and REBOVC provides hemodynamic stability, in contrast to REBOVC alone or with the Pringle maneuver, and may be a possible adjunct in severe retrohepatic venous bleedings.
Frailty as a Predictor of Mortality in Patients With Interstitial Lung Disease Referred for Lung Transplantation
Authors: Montgomery Elyn , Macdonald Peter S. , Newton Phillip J. , Chang Sungwon , Jha Sunita R. , Hannu Malin K. , Thomson Claire , Havryk Adrian , Malouf Monique
Published: August 2019

Background.

Frailty is a clinically recognized syndrome of decreased physiological reserve and a key contributor to suboptimal clinical outcomes in various lung disease groups. Interstitial lung disease (ILD) is fast approaching chronic obstructive pulmonary disease as the number one indication for lung transplantation worldwide. Our aim was to assess whether frailty is a predictor of mortality in patients with ILD referred for lung transplantation in an Australian cohort.

Methods.

Consecutive patients with ILD referred or on the waiting list for lung transplantation from May 2013 to December 2017 underwent frailty assessment using the modified Fried’s frailty phenotype. Frailty was defined as a positive response to ≥3 of the following 5 components: weak grip strength, slowed walking speed, poor appetite, physical inactivity, and exhaustion.

Results.

One hundred patients (82 male:18 female; age, 59 ± 7 y; range, 30–70) underwent frailty assessment. Twenty-four of 100 (24%) were assessed as frail. Frailty was associated with anemia, hypoalbuminemia, low creatinine, and the use of supplemental oxygen (all P < 0.05). Frailty was independent of age, gender, measures of pulmonary dysfunction (Pao
2, forced vital capacity percentage predicted, total lung capacity, total lung capacity percentage predicted, Dlco, or Dlco percentage predicted), cognitive impairment, or depression. Frailty and Dlco % predicted were independent predictors of increased all-cause mortality: 1-year actuarial survival was 86 ± 4% in the nonfrail group compared with 58 ± 10% for the frail group (P = 0.002).

Conclusions.

Frailty is common among patients referred for lung transplant with a diagnosis of ILD and is associated with a marked increase in mortality.
Bone Metabolism Impairment in Heart Transplant: Results From a Prospective Cohort Study
Authors: Seguro Luis F.B.C. , Pereira Rosa M.R. , Seguro Luciana P.C. , Caparbo Valeria F. , Avila Monica S. , Mangini Sandrigo , Campos Iascara W. , Gaiotto Fabio A. , Marcondes-Braga Fabiana G. , Bacal Fernando
Published: August 2019

Background.

Data on the prevention of fractures after heart transplant (HTx) are controversial in the literature. Understanding the effects of HTx on bone may guide appropriate treatments in this high-risk population.

Methods.

Seventy adult HTx patients were followed for 12 months. Clinical and laboratory parameters, bone mineral density, microarchitecture, and vertebral fractures were assessed at baseline (after intensive care unit discharge) and at 6 and 12 months. Patients received recommendations regarding calcium intake and vitamin D supplementation after HTx.

Results.

At baseline, 27% of patients had osteoporosis, associated with the length of hospitalization before HTx (P = 0.001). Bone mineral density decreased in the first 6 months, with partial recovery later. Bone microarchitecture deteriorated, mainly in the trabecular bone in the first 6 months and cortical bone in the subsequent 6 months. At baseline, 92.9% of patients had vitamin D levels <30 ng/mL and 20.0% <10 ng/mL. Patients also had calcium at the lower limit of normal, high alkaline phosphatase, and high bone resorption biomarker. These abnormalities were suggestive of impaired bone mineralization and normalized at 6 months with correction of vitamin D deficiency. The majority of vertebral fractures were identified at baseline (23% of patients). After multivariate analyses, only a lower fat mass persisted as a risk factor for vertebral fractures (odds ratio, 1.23; 95% confidence interval, 1.04-1.47; P = 0.012).

Conclusions.

High frequencies of densitometric osteoporosis, vitamin D deficiency, bone markers abnormalities, and vertebral fractures were observed shortly after HTx. Calcium and vitamin D supplementation should be the first step in correcting bone mineralization impairment before specific osteoporosis treatment.
Patient Survival After Kidney Transplantation: Important Role of Graft-sustaining Factors as Determined by Predictive Modeling Using Random Survival Forest Analysis
Authors: Scheffner Irina , Gietzelt Matthias , Abeling Tanja , Marschollek Michael , Gwinner Wilfried
Published: August 2019

Background.

Identification of the relevant factors for death can improve patient’s individual risk assessment and decision making. A well-documented patient cohort (n = 892) in a renal transplant program with protocol biopsies was used to establish multivariable models for risk assessment at 3 and 12 months posttransplantation by random survival forest analysis.

Methods.

Patients transplanted between 2000 and 2007 were observed for up to 11 years. Loss to follow-up was negligible (n = 15). A total of 2251 protocol biopsies and 1214 biopsies for cause were performed. All rejections and clinical borderline rejections in protocol biopsies were treated.

Results.

Ten-year patient survival was 78%, with inferior survival of patients with graft loss. Using all pre- and posttransplant variables until 3 and 12 months (n = 65), the obtained models showed good performance to predict death (concordance index: 0.77–0.78). Validation with a separate cohort of patients (n = 349) showed a concordance index of 0.76 and good discrimination of risks by the models, despite substantial differences in clinical variables. Random survival forest analysis produced robust models over a wide range of parameter settings. Besides well-established risk factors like age, cardiovascular disease, type 2 diabetes, and graft function, posttransplant urinary tract infection and rejection treatment were important factors. Urinary tract infection and rejection treatment were not specifically associated with death due to infection or malignancy but correlated strongly with inferior graft function and graft loss.

Conclusions.

The established models indicate the important areas that need special attention in the care of renal transplant patients, particularly modifiable factors like graft rejection and urinary tract infection.
What's New in the Treatment of Migraine?
Authors: Digre Kathleen B.
Published: August 2019

Background:

Migraine is very common. In addition to affecting visual quality of life, migraine can be seen in the neuro-ophthalmology office with regularity. Treatment is critical to assist in the reduction of disability and symptoms. Knowing the evidence-based new treatments is important for every neuro-ophthalmologist.

Methods:

Using PubMed, and using the term migraine as it related to the terms treatment, evidence-based, calcitonin gene-related peptide (CGRP) inhibitor or antibody, electrical stimulation, vagal nerve stimulation, a literature review was performed.

Results:

Aside from standard well-described and evidence-based therapies for the acute treatment and prevention of migraine, many new therapies have received FDA approval. In this review, we summarize the contribution of new classes of migraine-specific therapies: CGRP antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) for prevention and inhibitors referred to as gepants (ubrogepant and rimegepant) for acute treatment. We also cover newer medications about to be approved, such as lasmitiditan. Devices, including the hand-held vagal nerve stimulator, supraorbital stimulation, transmagnetic stimulation, and remote electrical stimulation, are now approved by the FDA for treatment of migraine.

Conclusion:

Many new and exciting therapies exist for the treatment of migraine. Keeping up with this rapidly evolving field is important in reducing disability from the common disease of migraine.
A Novel Approach to Treating Moderate to Severe Incontinence-Associated Dermatitis and Intertriginous Dermatitis
Authors: Tammel Karyl , Benike Deborah , Sievers Beth
Published: August 2019

BACKGROUND:

Patients with moderate to severe incontinence-associated dermatitis (IAD) and intertriginous dermatitis (ITD) often experience pain that negatively affects activities of daily living. While traditional treatments, such as skin protectants including ointment or cream-based products, cyanoacrylate-based monomers, and wicking agents, help some patients, those with moderate to severe cases require more aggressive treatments to accelerate healing.

CASE SERIES:

This article describes a series of 4 hospitalized patients who presented with moderate to severe IAD and/or ITD with and without fungal infections. These patients were treated with therapies that went beyond routine skin care regimens, which included treatment with a combination of 0.25% acetic acid, a topical steroid agent, or a topical antifungal when necessary. The patients included a 74-year-old woman admitted with hypovolemic shock, an 82-year-old obese woman with pulmonary hypertension and heart failure, an 80-year-old woman with medically complicated obesity, and a 54-year-old morbidly obese woman admitted with sepsis.

CONCLUSION:

The outcome achieved using this novel approach was successful in treating moderate to severe IAD and ITD in these cases.
MIXTURE: an improved algorithm for immune tumor microenvironment estimation based on gene expression data
Authors: Fernández Elmer A. , Mahmoud Yamil D. , Veigas Florencia , Rocha Darío , Balzarini Mónica , Lujan Hugo D. , Rabinovich Gabriel A. , Girotti M. Romina
Published: August 2019

RNA sequencing has proved to be an efficient high-throughput technique to robustly characterize the presence and quantity of RNA in tumor biopsies at a given time. Importantly, it can be used to computationally estimate the composition of the tumor immune infiltrate and to infer the immunological phenotypes of those cells. Given the significant impact of anti-cancer immunotherapies and the role of the associated immune tumor microenvironment (ITME) on its prognosis and therapy response, the estimation of the immune cell-type content in the tumor is crucial for designing effective strategies to understand and treat cancer. Current digital estimation of the ITME cell mixture content can be performed using different analytical tools. However, current methods tend to over-estimate the number of cell-types present in the sample, thus under-estimating true proportions, biasing the results. We developed MIXTURE, a noise-constrained recursive feature selection for support vector regression that overcomes such limitations. MIXTURE deconvolutes cell-type proportions of bulk tumor samples for both RNA microarray or RNA-Seq platforms from a leukocyte validated gene signature. We evaluated MIXTURE over simulated and benchmark data sets. It overcomes competitive methods in terms of accuracy on the true number of present cell-types and proportions estimates with increased robustness to estimation bias. It also shows superior robustness to collinearity problems. Finally, we investigated the human immune microenvironment of breast cancer, head and neck squamous cell carcinoma, and melanoma biopsies before and after anti-PD-1 immunotherapy treatment revealing associations to response to therapy which have not seen by previous methods.
Indirect actuation reduces flight power requirements inManduca sextavia elastic energy exchange
Authors: Gau Jeff , Gravish Nick , Sponberg Simon
Published: August 2019

In the vast majority of flying insects, wing movements are generated indirectly via the deformations of the exoskeleton. Indirect measurements of inertial and aerodynamic power requirements suggest that elastic energy exchange in spring-like structures may reduce the high power requirements of flight by recovering energy from one wingstroke to the next. We directly measured deformation mechanics and elastic energy storage in a hawkmothManduca sextathorax by recording the force required to deform the thorax over a frequency range encompassing typical wingbeat frequencies. We found that a structural damping model, not a viscoelastic model, accurately describes the thorax’s linear spring-like properties and frequency independent dissipation. The energy recovered from thorax deformations is sufficient to minimize flight power requirements. By removing the passive musculature, we find that the exoskeleton determines thorax mechanics. To assess the factors that determine the exoskeleton’s spring-like properties, we isolated functional thorax regions, disrupted strain in an otherwise intact thorax, and compared results to a homogeneous hemisphere. We found that mechanical coupling between spatially separated thorax regions improves energy exchange performance. Furthermore, local mechanical properties depend on global strain patterns. Finally, the addition of scutum deformations via indirect actuation provides additional energy recovery without added dissipation.
Membrane-bounded nucleoid discovered in a cultivated bacterium of the candidate phylum ‘Atribacteria’
Authors: Katayama Taiki , Nobu Masaru K. , Kusada Hiroyuki , Meng Xian-Ying , Yoshioka Hideyoshi , Kamagata Yoichi , Tamaki Hideyuki
Published: August 2019

A key feature that differentiates prokaryotes from eukaryotes is the absence of an intracellular membrane surrounding the chromosomal DNA. Here, we report isolation of an anaerobic bacterium that possesses an additional intracytoplasmic membrane surrounding a nucleoid, affiliates with the yet-to-be-cultivated ubiquitous phylum ‘Ca. Atribacteria’, and possesses unique genomic features likely associated with organization of complex cellular structure. Exploration of the uncharted microorganism overturned the prevailing dogma of prokaryotic cell structure.
Long-term associative memory in rats: effects of familiarization period in object-place-context recognition test
Authors: Shimoda Shota , Ozawa Takaaki , Ichitani Yukio , Yamada Kazuo
Published: August 2019

Spontaneous recognition tests, which utilize rodents’ innate tendency to explore novelty, can evaluate not only simple non-associative recognition memory but also more complex associative memory in animals. In the present study, we investigated whether the length of the object familiarization period (sample phase) improved subsequent novelty discrimination in the spontaneous object, place, and object-place-context (OPC) recognition tests in rats. In the OPC test, rats showed a significant novelty preference only when the familiarization period was 30 min but not when it was 5 min or 15 min. However, the rats exhibited a successful discrimination between the stayed and replaced objects under 15 min and 30 min familiarization period conditions in the place recognition test and between the novel and familiar objects under all conditions of 5, 15 and 30 min in the object recognition test. Our results suggest that the extension of the familiarization period improves performance in the spontaneous recognition paradigms, and a longer familiarization period is necessary for long-term associative recognition memory than for non-associative memory.
Genetic variation in herbivore resistance within a strawberry crop wild relative (Fragaria vesca L.)
Authors: Weber Daniela , Egan Paul A. , Muola Anne , Stenberg Johan A.
Published: August 2019

To decrease the dependency on chemical pesticides, the resistance of cultivated strawberry to pests needs to be increased. While genetic resources within domesticated varieties are limited, wild genotypes are predicted to show high heritable variation in useful resistance traits. We collected 86 wild accessions of Fragaria vesca L. from central Sweden and screened this germplasm for antibiosis (pest survival and performance) and antixenosis (pest preference) traits active against the strawberry leaf beetle (Galerucella tenella L.). First, extensive common garden experiments were used to study antibiosis traits in the sampled plant genotypes. Heritable genetic variation among plant genotypes was found for several antibiosis traits. Second, controlled cafeteria experiments were used to test for plant genetic variation in antixenosis traits. The leaf beetles avoided egg laying on plant genotypes possessing high antibiosis. This indicates a high degree of concordance between antibiosis and antixenosis, and that the beetles’ egg-laying behaviour optimizes the fitness of their offspring. The existence of high genetic variation in key resistance traits suggests that wild woodland strawberry contains untapped resources that are sought to reduce pesticide-dependence in cultivated strawberry. Given that only a very small portion of the species’ distribution area was sampled, even higher variation may be expected at the continental scale. As a whole, the genetic resources identified in this study serve to strengthen the position of woodland strawberry as a key crop wild relative.
Screening yeast display libraries against magnetized yeast cell targets enables efficient isolation of membrane protein binders.
Authors: Bacon Kaitlyn , Burroughs Matthew , Blain Abigail , Menegatti Stefano , Rao Balaji M
Published: August 2019

When isolating binders from yeast displayed combinatorial libraries, a soluble, recombinantly expressed form of the target protein is typically utilized. As an alternative, we describe the use of target proteins displayed as surface fusions on magnetized yeast cells. In our strategy, the target protein is co-expressed on the yeast surface with an iron oxide binding protein; incubation of these yeast cells with iron oxide nanoparticles results in their magnetization. Subsequently, binder cells that interact with the magnetized target cells can be isolated using a magnet. Using a known binder-target pair with modest binding affinity (KD ~ 400 nM), we showed that a binder present at low frequency (1 in 105) could be enriched >100-fold, in a single round of screening, suggesting feasibility of screening combinatorial libraries. Subsequently, we screened yeast display libraries of Sso7d and nanobody variants against yeast displayed targets to isolate binders specific to the cytosolic domain of the mitochondrial membrane protein TOM22 (KD ~ 271-2009 nM) and the extracellular domain of the c-Kit receptor (KD ~ 131 to KD >2000 nM). Additional studies showed that the TOM22 binders identified using this approach could be used for the enrichment of mitochondria from cell lysates, thereby confirming binding to the native mitochondrial protein. The ease of expressing a membrane protein or a domain thereof as a yeast cell surface fusion - in contrast to recombinant soluble expression - makes the use of yeast-displayed targets particularly attractive. Therefore, we expect the use of magnetized yeast cell targets will enable efficient isolation of binders to membrane proteins.
Deletion of calcineurin from GFAP-expressing astrocytes impairs excitability of cerebellar and hippocampal neurons through astroglial Na+/K+ATPase
Authors: Tapella Laura , Soda Teresa , Mapelli Lisa , Bortolotto Valeria , Bondi Heather , Ruffinatti Federico A , Dematteis Giulia , Stevano Alessio , Dionisi Marianna , Ummarino Simone , Ruscio Annalisa Di , Distasi Carla , Grilli Mariagrazia , Genazzani Armando A , D’Angelo Egidio , Moccia Francesco , Lim Dmitry
Published: August 2019

Astrocytes perform important housekeeping functions in the nervous system including maintenance of adequate neuronal excitability, although the regulatory mechanisms are currently poorly understood. The astrocytic Ca2+/calmodulin-activated phosphatase calcineurin (CaN) is implicated in the development of reactive gliosis and neuroinflammation, but its roles, including the control of neuronal excitability, in healthy brain is unknown. We have generated a mouse line with conditional knockout (KO) of CaN B1 (CaNB1) in glial fibrillary acidic protein (GFAP)-expressing astrocytes (astroglialcalcineurinknock-out, ACN-KO). Here we report that postnatal and astrocyte-specific ablation of CaNB1 did not alter normal growth and development as well as adult neurogenesis. Yet, we found that specific deletion of astrocytic CaN selectively impairs intrinsic neuronal excitability in hippocampal CA1 pyramidal neurons and cerebellar granule cells (CGCs). This impairment was associated with a decrease in after-hyperpolarization in CGC, while passive properties were unchanged, suggesting impairment of K+homeostasis. Indeed, blockade of Na+/K+-ATPase (NKA) with ouabain phenocopied the electrophysiological alterations observed in ACN-KO CGCs. In addition, NKA activity was significantly lower in cerebellar and hippocampal lysates and in pure astrocytic cultures from ACN-KO mice. While no changes were found in protein levels, NKA activity was inhibited by the specific CaN inhibitor FK506 in both cerebellar lysates and primary astroglia from control mice, suggesting that CaN directly modulates NKA activity and in this manner controls neuronal excitability. In summary, our data provide formal evidence for the notion that astroglia is fundamental for controlling basic neuronal functions and place CaN center-stage as an astrocytic Ca2+-sensitive switch.
A cross-species neural integration of gravity for motor optimisation
Authors: Gaveau Jeremie , Grospretre Sidney , Angelaki Dora , Papaxanthis Charalambos
Published: August 2019

Recent kinematic results, combined with model simulations, have provided support for the hypothesis that the human brain uses an internal model of gravity to shape motor patterns that minimise muscle effort. Because many different muscular activation patterns can give rise to the same trajectory, here we analyse muscular activation patterns during single-degree-of-freedom arm movements in various directions, which allow to specifically investigating gravity-related movement properties. Using a well-known decomposition method of tonic and phasic electromyographic activities, we demonstrate that phasic EMGs present systematic negative phases. This negativity demonstrates that gravity effects are harvested to save muscle effort and reveals that the brain implements an optimal motor plan using gravity to accelerate downward and decelerate upward movements. Furthermore, for the first time, we compare experimental findings in humans to monkeys, thereby generalising the Effort-optimization strategy across species.
Estrogen mediates acute elastic fibre homeostasis in skin
Authors: Saville Charis R , Holmes David F , Swift Joe , Derby Brian , Emmerson Elaine , Hardman Matthew J , Sherratt Michael J
Published: August 2019

Remodelling of the dermal extracellular matrix makes a major contribution to skin fragility in the elderly. The peri-menopausal period in females is also associated with an age-like phenotype which can be reversed by hormone replacement therapy. This suggests a direct link between circulating hormone levels and tissue ageing. Despite work investigating the role of estrogen as a regulator of collagen fibril abundance and structure, the influence of estrogen on the elastic fibre system remains poorly defined. Here we used an ovariectomised (Ovx) mouse surgical menopause model to show that just 7 weeks of acute hormone deficiency significantly decreased skin tensile strength and elasticity. Systemic replacement of 17β-estradiol to physiological levels protected against these changes to the skin mechanical properties. Moreover, acute hormone deficiency differentially influenced dermal structural networks, significantly decreasing dermal elastic fibre abundance without discernible effect on collagen fibril organisation or abundance. We suggest that this specific elastic fibre proteolysis may be driven by extracellular protease activity, or be a consequence of significant adipocyte hypertrophy. 17β-estradiol supplementation in Ovx micein vivoprotected the elastic fibre system. Treatment of human dermal fibroblasts with 17β-estradiolin vitroinduced the selective upregulation of tropoelastin, fibrillin-1 and associated elastic fibre-associated proteins (including EMILINs and fibulins). In summary, these data show that the elastic fibre system is significantly perturbed by estrogen deprivation. Thus, pharmacological intervention may slow the acute effects of menopause and potentially the chronic effects of ageing in skin.
Feedback control of a two-component signaling system by an Fe-S-binding receiver domain
Authors: Stein Benjamin J. , Fiebig Aretha , Crosson Sean
Published: August 2019

Two-component signaling systems (TCSs) function to detect environmental cues and transduce this information into a change in transcription. In its simplest form, TCS-dependent regulation of transcription entails phosphoryl-transfer from a sensory histidine kinase to its cognate DNA-binding receiver protein. However, in certain cases, auxiliary proteins may modulate TCSs in response to secondary environmental cues.Caulobacter crescentusFixT is one such auxiliary regulator. FixT is composed of a single receiver domain and functions as a feedback inhibitor of the FixL-FixJ (FixLJ) TCS, which regulates the transcription of genes involved in adaptation to microaerobiosis. We sought to define the impact offixTonCaulobactercell physiology and to understand the molecular mechanism by which FixT represses FixLJ signaling.fixTdeletion results in excess production of porphyrins and premature entry into stationary phase, demonstrating the importance of feedback inhibition of the FixLJ signaling system. Although FixT is a receiver domain, it does not affect dephosphorylation of the oxygen-sensor kinase FixL or phosphoryltransfer from FixL to its cognate receiver FixJ. Rather, FixT represses FixLJ signaling by inhibiting the FixL autophosphorylation reaction. We have further identified a 4-cysteine motif inCaulobacterFixT that binds an Fe-S cluster and protects the protein from degradation by the Lon protease. Our data support a model in which oxidation of this Fe-S cluster promotes degradation of FixTin vivo. This proteolytic mechanism facilitates clearance the of the FixT feedback inhibitor from the cell under normoxia and resets the FixLJ system for a future microaerobic signaling event.

Importance

Two-component signal transduction systems (TCSs) are broadly conserved in the bacterial kingdom and generally contain two molecular components: a sensor histidine kinase and a receiver protein. Sensor histidine kinases alter their phosphorylation state in direct response to a physical or chemical cue, whereas receiver proteins “receive” the phosphoryl group from the kinase to regulate a change in cell physiology. We have discovered that a single-domain receiver protein, FixT, binds an Fe-S cluster and controlsCaulobacterheme homeostasis though its function as a negative feedback regulator of the oxygen-sensor kinase, FixL. We provide evidence that the Fe-S cluster protects FixT from Lon-dependent proteolysis in the cell and endows FixT with the ability to function as a second, autonomous oxygen/redox sensor in the FixL-FixJ signaling pathway. This study introduces a novel mechanism of regulated TCS feedback control by an Fe-S-binding receiver domain.
Six-state amino acid recoding is not an effective strategy to offset the effects of compositional heterogeneity and saturation in phylogenetic analyses
Authors: Hernandez Alexandra M. , Ryan Joseph F.
Published: August 2019

Six-state amino acid recoding strategies are commonly applied to combat the effects of compositional heterogeneity and substitution saturation in phylogenetic analyses. While these methods have been endorsed from a theoretical perspective, their performance has never been extensively tested. Here, we test the effectiveness of 6-state recoding approaches by comparing the performance of analyses on recoded and non-recoded datasets that have been simulated under gradients of compositional heterogeneity or saturation. In all of our simulation analyses, non-recoding approaches greatly outperformed 6-state recoding approaches. Our results suggest that 6-state recoding strategies are not effective in the face of high saturation. Further, while recoding strategies do buffer the effects of compositional heterogeneity, the loss of information that accompanies 6-state recoding outweighs its benefits, even in the most compositionally heterogeneous datasets. In addition, we evaluate recoding schemes with 9, 12, 15, and 18 states and show that these all outperform 6-state recoding. Our results have important implications for the more than 70 published papers that have incorporated 6-state recoding, many of which have significant bearing on relationships across the tree of life.
Vasoactive intestinal peptide confers anticipatory mucosal immunity by regulating ILC3 activity
Authors: Seillet Cyril , Luong Kylie , Tellier Julie , Jacquelot Nicolas , Shen Rui Dong , Hickey Peter , Wimmer Verena C. , Whitehead Lachlan , Rogers Kelly , Smyth Gordon K. , Garnham Alexandra L. , Ritchie Matthew , Belz Gabrielle T.
Published: August 2019

ILC3-mediated IL-22 cytokine production is critical for the maintenance of immune homeostasis in the gastrointestinal tract. Here, we show that group 3 ILC (ILC3) constitutive function is not constant across the day but instead oscilliates between active and resting phases. Coordinate responsiveness of ILC3 in the intestine depended on food-induced expression of the neuronal hormone vasoactive intestinal peptide (VIP). Intestinal ILC3 expressed high levels of the G protein-coupled receptor, VIPR2, and activation via enteric neuronal VIP markedly enhanced IL-22 production and conferred gut protection. Conversely, deficiency of VIPR2 signalling led to impaired production of IL-22 by ILC3 and increased susceptibility to inflammatory gut disease. As such, intrinsic cellular rhythms synergise with the cyclic patterns of food intake to drive IL-22 thereby syncronizing intestinal epithelial protection via the ILC3 VIP-VIPR2 pathway.
Revisiting the Natural History of Pulmonary Tuberculosis: a Bayesian Estimation of Natural Recovery and Mortality rates
Authors: Ragonnet Romain , Flegg Jennifer A. , Brilleman Samuel L. , Tiemersma Edine , Melsew Yayehirad A. , McBryde Emma S. , Trauer James M.
Published: August 2019

Background

Tuberculosis (TB) natural history remains poorly characterised and new investigations are impossible as it would be unethical to follow up TB patients without treating them. Estimates of TB burden and mortality rely heavily on TB self-recovery and mortality rates, as around 40% of individuals with TB are never detected, making their prognosis entirely dependent on the disease natural history.

Methods

We considered the reports identified in a previous systematic review of studies from the prechemotherapy era, and extracted detailed data on mortality over time. We used a continuous-time Markov model in a Bayesian framework to estimate the rates of TB-induced mortality and self-cure. A hierarchical model was employed to allow estimates to vary by cohort. Inference was performed separately for smear-positive TB (SP-TB) and smear-negative TB (SN-TB).

Results

We included 41 cohorts of SP-TB patients and 19 cohorts of pulmonary SN-TB patients in the analysis. No data were available on extrapulmonary TB. The posterior median estimates of the TB-specific mortality rates were 0.390 year−1 (0.329-0.452, 95% credible interval) and 0.025 year−1 (0.016-0.036) for SP-TB and SN-TB patients, respectively. The estimates for self-recovery rates were 0.233 year−1 (0.179-0.293) and 0.147 year−1 (0.087-0.248) for SP-TB and SN-TB patients, respectively. These rates correspond to average durations of untreated TB of 1.57 years (1.37-1.81) and 5.35 years (3.42-8.23) for SP-TB and SN-TB, respectively, when assuming a natural mortality rate of 0.014 year−1 (i.e. a 70-year life expectancy).

Conclusions

TB-specific mortality rates are around 15 times higher for SP-TB than for SN-TB patients. This difference was underestimated dramatically in previous TB modelling studies that parameterised models based on the ratio of 3.3 between the 10-year case fatality of SP-TB and SN-TB. Our findings raise important concerns about the accuracy of past and current estimates of TB mortality and predicted impact of control interventions on TB mortality.
Microbial community and geochemical analyses of trans-trench sediments for understanding the roles of hadal environments
Authors: Hiraoka Satoshi , Hirai Miho , Matsui Yohei , Makabe Akiko , Minegishi Hiroaki , Tsuda Miwako , Juliarni  , Rastelli Eugenio , Danovaro Roberto , Corinaldesi Cinzia , Kitahashi Tomo , Tasumi Eiji , Nishizawa Manabu , Takai Ken , Nomaki Hidetaka , Nunoura Takuro
Published: August 2019

Hadal trench bottom (>6,000 m below sea level) sediments harbor higher microbial cell abundance compared to adjacent abyssal plain sediments. This is supported by the accumulation of sedimentary organic matter (OM), facilitated by trench topography. However, the distribution of benthic microbes in different trench systems has not been explored yet. Here, we carried out small subunit ribosomal RNA gene tag sequencing for 92 sediment subsamples of seven abyssal and seven hadal sediment cores collected from three trench regions in the northwest Pacific Ocean: the Japan, Izu-Ogasawara, and Mariana Trenches. Tag-sequencing analyses showed specific distribution patterns of several phyla associated with oxygen and nitrate. The community structure was distinct between abyssal and hadal sediments, following geographic locations and factors represented by sediment depth. Co-occurrence network revealed six potential prokaryotic consortiums that covaried across regions. Our results further support that the endogenous OM cycle is driven by hadal currents and/or rapid burial shapes microbial community structures at trench bottom sites, in addition to vertical deposition from the surface ocean. Our trans-trench analysis highlights intra- and inter-trench distributions of microbial assemblages and geochemistry in surface seafloor sediments, providing novel insights into ultra-deep-sea microbial ecology, one of the last frontiers on our planet.
Decreasing human body temperature in the United States since the Industrial Revolution
Authors: Protsiv Myroslava , Ley Catherine , Lankester Joanna , Hastie Trevor , Parsonnet Julie
Published: August 2019

In the US, the normal, oral temperature of adults is, on average, lower than the canonical 37°C established in the 19th century. We postulated that body temperature has decreased over time. Using measurements from three cohorts--the Union Army Veterans of the Civil War (N=23,710; measurement years 1860-1940), the National Health and Nutrition Examination Survey I (N=15,301; 1971-1975), and the Stanford Translational Research Integrated Database Environment (N=150,280; 2007-2017)--we determined that mean body temperature in men and women, after adjusting for age, height, weight and, in some models date and time of day, has decreased monotonically by 0.03°C per birth decade. A similar decline within the Union Army cohort as between cohorts, makes measurement error an unlikely explanation. This substantive and continuing shift in body temperature—a marker for metabolic rate—provides a framework for understanding changes in body habitus and human longevity over the last 200 years.
Rationale for targeting BCL6 inMLL-rearranged acute lymphoblastic leukemia
Authors: Hurtz Christian , Chan Lai N. , Geng Huimin , Ballabio Erica , Xiao Gang , Deb Gauri , Khoury Haytham , Chen Chun-Wei , Armstrong Scott A. , Chen Jianjun , Ernst Patricia , Melnick Ari , Milne Thomas , Müschen Markus
Published: August 2019

Chromosomal rearrangements of themixed lineage leukemia(MLL) gene occur in ∼10% of B-cell acute lymphoblastic leukemia (B-ALL) and define a group of patients with dismal outcomes. Immunohistochemical staining of bone marrow biopsies from most of these patients revealed aberrant expression of BCL6, a transcription factor that promotes oncogenic B-cell transformation and drug resistance in B-ALL. Our genetic and ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to theBCL6promoter and up-regulated BCL6 expression. While oncogenic MLL fusions strongly induced aberrant BCL6 expression in B-ALL cells, germlineMLLwas required to up-regulate Bcl6 in response to physiological stimuli during normal B-cell development. Inducible expression of Bcl6 increasedMLLmRNA levels, which was reversed by genetic deletion and pharmacological inhibition of Bcl6, suggesting a positive feedback loop between MLL and BCL6. Highlighting the central role of BCL6 inMLL-rearranged B-ALL, conditional deletion and pharmacological inhibition of BCL6 compromised leukemogenesis in transplant recipient mice and restored sensitivity to vincristine chemotherapy inMLL-rearranged B-ALL patient samples. Oncogenic MLL fusions strongly induced transcriptional activation of the proapoptotic BH3-only molecule BIM, while BCL6 was required to curb MLL-induced expression of BIM. Notably, peptide (RI-BPI) and small molecule (FX1) BCL6 inhibitors derepressed BIM and synergized with the BH3-mimetic ABT-199 in eradicatingMLL-rearranged B-ALL cells. These findings uncover MLL-dependent transcriptional activation of BCL6 as a previously unrecognized requirement of malignant transformation by oncogenic MLL fusions and identified BCL6 as a novel target for the treatment of MLL-rearranged B-ALL.
Economic inequality: problems and perspectives for interdisciplinary accounting research
Authors: Tweedie Dale , Hazelton James
Published: August 2019

Purpose

The purpose of this paper is to encourage and advance interdisciplinary accounting research on economic inequality.

Design/methodology/approach

The authors review prior research into economic inequality, including two new papers in this issue, to identify topics where economic inequality and accounting research intersect. The authors then draw on prior accounting research to identify frameworks accounting scholars already use apposite to analysing these topics.

Findings

Economic inequality cuts across major accounting topics, including measurement, reporting and tax. Inequality also bears on an influential agenda in interdisciplinary accounting research to hold corporations and states accountable for their impacts. Four prior research frameworks accounting scholars might apply to this agenda are: critical Marxian or post-Marxian; accounting ethics; advocacy; and disclosure studies.

Social implications

A growing body of social scientific research, as well as influential global institutions, social movements and political debates, raise concerns over inequitable global distributions of wealth and income. The authors explore ways accounting scholars can help redress these inequities.

Originality/value

While economic inequality affects billions of people, accounting scholarship is yet to give these inequities the attention their scale and social impact merits. The authors suggest ways accounting researchers can make substantive contributions to addressing this issue.
Who gets all the PIE? Regulation of the statutory audit for private UK companies
Authors: Clacher Iain , Duboisée de Ricquebourg Alan , May Amy
Published: August 2019

Purpose

While recently introduced EU regulation on the statutory audit of public interest entities (PIEs) aims to improve audit competition and quality, its success and impact depends on the definition of a PIE applied across the various EU Member States. In the UK, even though little is known about their auditing choices, these changes will not apply to most private companies despite their importance to the wider economy. The purpose of this paper is to provide an in-depth analysis of the private company audit market and examine the lobbying behaviour of the accounting profession around the definition of a PIE in the UK.

Design/methodology/approach

Using a large panel of independent private company audits in the UK and a textual analysis of submitted comment letters to a government consultation on the new regulation, this paper presents a comprehensive analysis of the audit market for private companies by measuring supplier concentration using four different measures of market share, and of the lobbying behaviour of the accounting profession.

Findings

There are two main findings. First, the private company audit market is characterised by low auditor switching rates along with a tight oligopoly of the largest independent private company audits maintained by the Big Four audit firms. Second, the lobbying behaviour of accounting and audit firms sought, and succeeded, to limit the scope of the definition of a PIE in the UK, consistent with the theoretical predictions of monopoly capitalism and the theory of professions.

Originality/value

The paper shows that the definition and scope of a PIE needs revisiting both within the UK and across all EU Member States, with a view to including more of these economically important private companies and highlights the policy challenge of increasing competition and choice in a concentrated audit market.
Modelling the penetration of magnetic flux in thin superconducting films with shell transformations
Authors: Burger Loïc , Geuzaine Christophe , Henrotte Francois , Vanderheyden Benoît
Published: August 2019

Purpose

Finite element (FE) models are considered for the penetration of magnetic flux in type-II superconductor films. A shell transformation allows boundary conditions to be applied at infinity with no truncation approximation. This paper aims to determine the accuracy and efficiency of shell transformation techniques in such non-linear eddy current problems.

Design/methodology/approach

A three-dimensional H – ϕ formulation is considered, where the reaction field is calculated in the presence of a uniform applied field. The shell transformation is used in the far-field region, and the uniform applied field is introduced through surface terms, so as to avoid infinite energy terms. The resulting field distributions are compared against known solutions for different geometries (thin disks and thin strips in the critical state, square thin films). The influence of the shape, size and mesh quality of the far-field regions are discussed.

Findings

The formulation is shown to provide accurate results for a number of film geometries and shell transformation shapes. The size of the far-field region has to be chosen in such a way to properly capture the asymptotic decay of the fields, and a practical procedure to determine this size is provided.

Originality/value

The importance of the size of the far-field region in a shell transformation and its proximity to the conducting domains are both highlighted. This paper also provides a numerical way to apply a constant magnetic field in a given region, while the source, on which only the far-field behaviour of the applied field depends, is excluded from the model.
Comparison of different vector Preisach models for the simulation of ferromagnetic materials
Authors: Nierla Michael , Loeffler Michael , Kaltenbacher Manfred , Rupitsch Stefan Johann
Published: August 2019

Purpose

The numerical computation of magnetization processes in moving and rotating assemblies requires the usage of vector hysteresis models. A commonly used model is the so-called Mayergoyz vector Preisach model, which applies the scalar Preisach model into multiple angles of the halfspace. The usage of several scalar models, which are optionally weighted differently, enables the description of isotropic as well as anisotropic materials. The flexibility is achieved, however, at the cost of multiple scalar model evaluations. For solely isotropic materials, two vector Preisach models, based on an extra rotational operator, might offer a lightweight alternative in terms of evaluation cost. The study aims at comparing the three mentioned models with respect to computational efficiency and practical applicability.

Design/methodology/approach

The three mentioned vector Preisach models are compared with respect to their computational costs and their representation of magnetic polarization curves measured by a vector vibrating sample magnetometer.

Findings

The results prove the applicability of all three models to practical scenarios and show the higher efficiency of the vector models based on rotational operators in terms of computational time.

Originality/value

Although the two vector Preisach models, based on an extra rotational operator, have been proposed in 2012 and 2015, their practical application and inversion has not been tested yet. This paper not only shows the usability of these particular vector Preisach models but also proves the efficiency of a special stageless evaluation approach that was proposed in a former contribution.