bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of hesperidin consumption on cardiovascular risk biomarkers: a systematic review of animal studies and human randomized clinical trials
Authors: Pla-Pagà L , Companys J , Calderón-Pérez L , Llauradó E , Solà R , Valls R M , Pedret A
Published: May 2019

Context

The cardioprotective effects of the flavonoid hesperidin, which is present in citrus products, are controversial and unclear. This systematic review was conducted in accordance with the PRISMA 2015 guidelines.

Objective

To evaluate the current evidence from animal and human clinical studies and thus determine whether the consumption of hesperidin exerts beneficial effects on cardiovascular risk factors.

Data sources

PICOS (Population, Intervention, Comparison, Outcome, and Study Design) criteria defined the research question. Searches of the PubMed and Cochrane Plus databases were conducted and studies that met the inclusion criteria and were published in English in the last 15 years were included.

Data extraction

The first author, year of publication, study design, characteristics of animals and humans, intervention groups, dose of hesperidin, route of administration, duration of the intervention, cardiovascular risk biomarkers assessed, and results observed were extracted from the included articles.

Results

A total of 12 animal studies and 11 randomized clinical trials met the inclusion criteria. In the animal studies, the glucose, total and LDL cholesterol, and triglyceride levels decreased with chronic flavonoid consumption. In the human studies, endothelial function improved with flavonoid consumption, whereas no conclusive results were observed for the other biomarkers.

Conclusions

Animal studies have revealed that hesperidin and hesperetin consumption reduces glucose levels and various lipid profile parameters. However, a definitive conclusion cannot be drawn from the existing human clinical trials. Further research is needed to confirm whether the findings observed in animal models can also be observed in humans.

Systematic Review Registration

Prospero registration number CRD42018088942.
Differential Recovery in Early- and Late-Onset Delayed Facial Palsy Following Vestibular Schwannoma Resection
Authors: Chang Stephano , Makarenko Serge , Despot Ivan , Dong Charles , Westerberg Brian D , Akagami Ryojo
Published: May 2019

BACKGROUND

Delayed facial palsy (DFP) after resection of vestibular schwannomas (VS) is worsening of facial nerve function after an initially normal postoperative result.

OBJECTIVE

To characterize different types of DFP, compare recovery rates, and review of series of outcomes in patients following resection of VS.

METHODS

Between 2001 and 2017, 434 patients (51% female) with VS underwent resection. We categorized the patients who developed facial palsy into groups based on timing of onset after surgery, immediate facial palsy (IFP), early-onset DFP (within 48 h), and late-onset DFP (after 48 h). Introduction of facial nerve motor-evoked potentials (fMEP) in 2002 and a change of practice utilizing perioperative minocycline in 2005 allowed for historical analysis of these interventions.

RESULTS

Mean age of study cohort was 49.1 yr (range 13-81 yr), with 19.8% developing facial palsy. The late-onset DFP group demonstrated a significantly faster recovery than the early-onset DFP group (2.8 ± 0.5 vs 47 ± 8 wk,P < .0001), had prolonged latency to palsy onset after initiating perioperative minocycline (7.3 vs 12.5 d,P = .001), and had a nonsignificant trend towards faster recovery from facial palsy with use of minocycline (2.6 vs 3.4 wk,P = .11).

CONCLUSION

Given the timings, it is likely axonal degeneration is responsible for early-onset DFP, while demyelination and remyelination lead to faster facial nerve recovery in late-onset DFP. Reported anti-apoptotic properties of minocycline could account for the further delay in onset of DFP, and possibly reduce the rate and duration of DFP in the surgical cohort.
Tofacitinib modulates the VZV-specific CD4+ T cell immune response in vitro in lymphocytes of patients with rheumatoid arthritis
Authors: Almanzar Giovanni , Kienle Felix , Schmalzing Marc , Maas Anna , Tony Hans-Peter , Prelog Martina
Published: May 2019

Objective

RA is a chronic inflammatory disease characterized by lymphocyte infiltration and release of inflammatory cytokines. Previous studies have shown that treatment with Janus kinase inhibitors, such as tofacitinib, increased the incidence rate of herpes zoster compared with conventional DMARDs. Therefore, this study aimed to investigate the effect of tofacitinib on the varicella-zoster-virus (VZV)-specific T cell immune response.

Methods

The effect of tofacitinib on the VZV-specific T cell immune response was determined by evaluating the IFNγ production, the proliferative capacity, the VZV-induced differentiation into effector and memory T cells, the expression of activation marker CD69 and helper T cell type 1 (Th1)-characteristic chemokine receptors, such as CXCR3 and CCR5, as well as cytotoxic activity (perforin and granzyme B expression) of CD4+ T cells of patients with RA compared with healthy donors upon stimulation with VZV antigen in vitro.

Results

Tofacitinib significantly reduced the IFNγ production, proliferation, activation, and CXCR3 expression of VZV-specific CD4+ T cells in a dose-dependent manner in short- and long-term lymphocyte culture. No effect on the distribution of naive, effectors or memory, or on the expression of perforin or granzyme B by VZV-specific CD4+ T cells was observed.

Conclusion

This study showed that tofacitinib significantly modulated the Th1 response to VZV. The poor VZV-specific cellular immune response in patients with RA may be considered in recommendations regarding appropriate vaccination strategies for enhancing the VZV-specific Th1 response.
Effects of increasing dietary zinc on growth performance and carcass characteristics of pigs raised under commercial conditions1,2
Authors: Cemin Henrique S , Woodworth Jason C , Tokach Mike D , Dritz Steve S , DeRouchey Joel M , Goodband Robert D , Usry James L
Published: May 2019

A total of 2,430 pigs (PIC 337 × 1050; Hendersonville, TN; initially 30.1 kg) were used in a 113-d growth trial to determine the effects of increasing dietary Zn on growth performance and carcass characteristics of finishing pigs raised under commercial conditions. Pens of pigs were assigned to be fed one of five dietary treatments in a randomized complete block design. Treatments consisted of 50, 87.5, 125, 162.5, or 200 mg/kg added Zn from Zn hydroxychloride (IntelliBond Z, Micronutrients, Indianapolis, IN). Two identical barns were used for a total of 18 pens per treatment with 27 pigs per pen. Experimental diets were fed in five phases and contained a vitamin-trace mineral premix without added Zn. Pens of pigs were weighed approximately every 2 wk to calculate average daily gain (ADG), average daily feed intake (ADFI), and gain-to-feed ratio (G:F). At the end of the experimental period, pigs were tattooed with a pen identification number and transported to a packing plant to measure hot carcass weight (HCW), backfat, loin depth, and calculated lean percentage. Data were analyzed block nested within barn as a random effect and pen as the experimental unit. From days 0 to 42, pigs fed diets with increasing added Zn had lower (linear, P = 0.043) ADFI and a tendency (P = 0.092) for lower ADG. From days 42 to 113, increasing added Zn resulted in a quadratic response (P = 0.042) for ADFI and a tendency (linear, P = 0.056) for improved G:F. Overall (days 0 to 113), there were tendencies for quadratic responses for ADFI (P = 0.073) and G:F (P = 0.059), with the greatest G:F observed when 125 mg/kg of Zn was fed. Increasing added Zn resulted in a linear increase (P < 0.001) in daily Zn intake. There were no differences (P > 0.10) in overall ADG, final body weight, HCW, backfat, loin depth, lean percentage, mortality, and removal rate. In conclusion, there were no improvements in ADG when feeding beyond 50 mg/kg added Zn; however, providing 125 mg/kg added Zn resulted in the greatest G:F.
Effects of zinc source and level on growth performance and carcass characteristics of finishing pigs1,2
Authors: Cemin Henrique S , Carpenter Corey B , Woodworth Jason C , Tokach Mike D , Dritz Steve S , DeRouchey Joel M , Goodband Robert D , Usry James L
Published: May 2019

An experiment was conducted to determine the effects of added Zn source and level on growth performance and carcass characteristics of finishing pigs. A total of 1,980 pigs divided into 2 groups [group 1: 1,008 pigs, TR4 × (Fast Large White × PIC L02) and group 2: 972 pigs, PIC 337 × 1,050], initially 33.3 kg, were used in a 103- or 114-d growth trial in groups 1 and 2, respectively. Treatments were arranged in a 2 × 3 factorial with 2 sources of added Zn, Zn hydroxychloride (ZnHyd; IntelliBond Z, Micronutrients, Indianapolis, IN) or Zn sulfate (ZnSO4), and 3 levels of added Zn (50, 100, or 150 mg/kg). Diets contained a vitamin-trace mineral premix without added Zn and provided 76 and 162 mg/kg Fe and Cu, respectively. All diets contained 750 FTU/kg phytase. There was a total of 14 replicates per treatment. Pens of pigs were weighed approximately every 2 wk to determine average daily gain (ADG), average daily feed intake, and gain-to-feed ratio. At the end of the experiment, pigs were transported to a packing plant to determine hot carcass weight (HCW), backfat depth, loin depth, and lean percentage. Overall, there was no evidence (P > 0.10) for interactive effects of added Zn source and level for growth performance and carcass characteristics. Pigs fed diets with increasing added Zn had a tendency (P = 0.093) for a quadratic response in ADG, with the greatest ADG observed at 100 mg/kg added Zn. There was a linear improvement (P = 0.010) in carcass yield and a quadratic response (P = 0.045) in HCW, with pigs fed 100 mg/kg added Zn having the highest HCW. Pigs fed diets with ZnHyd had improved (P = 0.017) carcass yield and a tendency (P = 0.058) for greater HCW compared with pigs fed ZnSO4. In summary, under the commercial conditions of the study and with diets containing 750 FTU/kg phytase, there were relatively small improvements in ADG of growing-finishing pigs fed added Zn beyond 50 mg/kg. Providing higher levels of added Zn improved carcass characteristics. Zinc source did not influence growth performance, but ZnHyd improved carcass characteristics compared with ZnSO4.
Predicting Human Infection Risk: Do Rodent Host Resistance Models Add Value?
Authors: Wu Kai Connie , Zhong Yu , Maher Jonathan
Published: May 2019

Use of genetically engineered rodents is often considered a valuable exercise to assess potential safety concerns associated with the inhibition of a target pathway. When there are potential immunomodulatory risks associated with the target, these genetically modified animals are often challenged with various pathogens in an acute setting to determine the risk to humans. However, the applicability of the results from infection models is seldom assessed when significant retrospective human data become available. Thus, the purpose of the current review is to compare the outcomes of infectious pathogen challenge in mice with genetic deficiencies in TNF-α, IL17, IL23, or Janus kinase pathways with infectious outcomes caused by inhibitors of these pathways in humans. In general, mouse infection challenge models had modest utility for hazard identification and were generally only able to predict overall trends in infection risk. These models did not demonstrate significant value in evaluating specific types of pathogens that are either prevalent (ie rhinoviruses) or of significant concern (ie herpes zoster). Similarly, outcomes in mouse models tended to overestimate the severity of infection risk in human patients. Thus, there is an emerging need for more human-relevant models that have better predictive value. Large meta-analyses of multiple clinical trials or post-marketing evaluations remains the gold-standard for characterizing the true infection risk to patients.
Cultivar Resistance to Common Scab Disease of Potato Is Dependent on the Pathogen Species
Authors: Clarke Christopher R. , Kramer Charles G. , Kotha Raghavendhar R. , Wanner Leslie A. , Luthria Devanand L. , Kramer Matthew
Published: May 2019

Common scab of potato is a superficial tuber disease caused by Streptomyces species that produce the phytotoxin thaxtomin. Because common scab development is highly dependent on the effects of this single toxin, the current operating paradigm in common scab pathology is that a potato cultivar resistant to one strain of the common scab pathogen is resistant to all strains. However, cultivar resistance to common scab disease identified in one breeding program is often not durable when tested in other potato breeding programs across the United States. We infected 55 potato cultivar populations with three distinct species of the common scab pathogen and identified cultivars that were resistant or susceptible to all three species and cultivars that had widely varying resistance dependent on the pathogen species. Overall lower virulence was associated with the strain that produces the least thaxtomin. This result showcases several cultivars of potato that are expected to be resistant to the majority of common scab populations but also highlights that many potato cultivars are resistant to only specific species of the pathogen. These results demonstrate that extension specialists and growers must consider their local population of the common scab pathogen when selecting which cultivars to plant for common scab resistance.
The impact of pelvic lateral rotation on hindlimb kinematics and stride length in the red-legged running frog,Kassina maculata
Authors: Collings Amber J. , Porro Laura B. , Hill Cameron , Richards Christopher T.
Published: May 2019

Some frog species, such asKassina maculata(red-legged running frog), use an asynchronous walking/running gait as their primary locomotor mode. Prior comparative anatomy work has suggested that lateral rotation of the pelvis improves walking performance by increasing hindlimb stride length; however, this hypothesis has never been tested. Using non-invasive methods, experimental high-speed video data collected from eight animals were used to create two three-dimensional kinematic models. These models, each fixed to alternative local anatomical reference frames, were used to investigate the hypothesis that lateral rotation of the mobile ilio-sacral joint in the anuran pelvis plays a propulsive role in walking locomotion by increasing hindlimb stride length. All frogs used a walking gait (duty factor greater than 0.5) despite travelling over a range of speeds (0.04–0.23 m s−1). The hindlimb joint motions throughout a single stride were temporally synchronized with lateral rotation of the pelvis. The pelvis itself, on average, underwent an angular excursion of 12.71° (±4.39°) with respect to the body midline during lateral rotation. However, comparison between our two kinematic models demonstrated that lateral rotation of the pelvis only increases the cranio-caudal excursion of the hindlimb modestly. Thus, we propose that pelvic lateral rotation is not a stride length augmenting mechanism inK. maculata.
Direct measurement of swimming and diving kinematics of giant Atlantic bluefin tuna (Thunnus thynnus)
Authors: Gleiss Adrian C. , Schallert Robert J. , Dale Jonathan J. , Wilson Steve G. , Block Barbara A.
Published: May 2019

Tunas possess a range of physiological and mechanical adaptations geared towards high-performance swimming that are of considerable interest to physiologists, ecologists and engineers. Advances in biologging have provided significant improvements in understanding tuna migrations and vertical movement patterns, yet our understanding of the locomotion and swimming mechanics of these fish under natural conditions is limited. We equipped Atlantic bluefin tuna (Thunnus thynnus) with motion-sensitive tags and video cameras to quantify the gaits and kinematics used by wild fish. Our data reveal significant variety in the locomotory kinematics of Atlantic bluefin tuna, ranging from continuous locomotion to two types of intermittent locomotion. The tuna sustained swimming speeds in excess of 1.5 m s−1(0.6 body lengths s−1), while beating their tail at a frequency of approximately 1 Hz. While diving, some descents were entirely composed of passive glides, with slower descent rates featuring more gliding, while ascents were primarily composed of active swimming. The observed swimming behaviour of Atlantic bluefin tuna is consistent with theoretical models predicting such intermittent locomotion to result in mechanical and physiological advantages. Our results confirm that Atlantic bluefin tuna possess behavioural specializations to increase their locomotory performance, which together with their unique physiology improve their capacity to use pelagic and mesopelagic habitats.
Investigation on the compositions of unsymmetrical dimethylhydrazine treatment with different oxidants using solid-phase micro-extraction-gas chromatography–mass spectrometer
Authors: Huang Dan , Liu Xiangxuan , Wang Xuanjun , Huang Zhiyong , Xie Zheng , Wang Huanchun
Published: May 2019

The majority of unsymmetrical dimethylhydrazine (UDMH) treatments produce lots of toxic by-products, among which
N
-Nitrosodimethylamine (NDMA) is a strong carcinogen. The compositions of the by-products are important for evaluating the treatment efficiency and understanding the UDMH degradation mechanism to achieve UDMH mineralization. The intermediate and end products of UDMH treatment with different oxidants were investigated by using a simple and fast method, solid-phase micro-extraction (SPME) in combination with gas chromatography–mass spectrometry (GC-MS). The effects of several parameters (coating fibre, salt addition, pH, sampling time and desorption time) were studied to optimize analyte recovery. The best response can be attained by the 65 µm PDMS/DVB fibre at pH 7 during 10 min after desorption of 1 min in the GC inlet. The intermediate and final oxidative products of UDMH wastewater treatment with different oxidants (O
3
, Mn
2+
/O
3
, Fe
2+
/H
2
O
2
) were investigated. The results showed that the UDMH treatment with O
3
could lead to high yields of NDMA. Metal catalytic ozonation could largely minimize the formation of NDMA. No NDMA was observed in the final decontaminated samples after treatment with Fe
2+
/H
2
O
2
. The NDMA formation and degradation mechanism were discussed based on the intermediates. This study is expected to provide useful information for controlling NDMA formation during UDMH wastewater treatment.
Pathobiological features favouring the intercontinental dissemination of highly pathogenic avian influenza virus
Authors: Li Xueying , Xu Bing , Shaman Jeffrey
Published: May 2019

Avian influenza viruses (AIVs) are a continued threat to global health and economy. Unlike other highly pathogenic AIVs, novel H5N8 disseminated very quickly from Korea to other areas in Asia, Europe and even North America following its first outbreak in 2014. However, the pathobiological features of the virus that favoured its global translocation remain unknown. In this study, we used a compartmental model to examine the avian epidemiological characteristics that would support the geographical spread of influenza by bird migration, and to provide recommendations for AIV surveillance in wild bird populations. We simulated virus transmission and translocation in a migratory bird population while varying four system properties: (i) contact transmission rate; (ii) infection recovery rate; (iii) mortality rate induced by infection; and (iv) migratory recovery rate. Using these simulations, we then calculated extinction and translocation probabilities for influenza during spring migration as a function of the altered properties. We find that lower infection recovery rates increase the likelihood of AIV translocation in migratory bird populations. In addition, lower mortality rates or migration recovery rates also favour translocation. Our results identify pathobiological features supporting AIV intercontinental dissemination risk and suggest that characteristic differences exist among H5N8 and other AIV subtypes that have not translocated as rapidly (e.g. H5N6 and H5N1).
Theoretical framework for higher-order quantum theory
Authors: Bisio Alessandro , Perinotti Paolo
Published: May 2019

Higher-order quantum theory is an extension of quantum theory where one introduces transformations whose input and output are transformations, thus generalizing the notion of channels and quantum operations. The generalization then goes recursively, with the construction of a full hierarchy of maps of increasingly higher order. The analysis of special cases already showed that higher-order quantum functions exhibit features that cannot be tracked down to the usual circuits, such as indefinite causal structures, providing provable advantages over circuital maps. The present treatment provides a general framework where this kind of analysis can be carried out in full generality. The hierarchy of higher-order quantum maps is introduced axiomatically with a formulation based on the language of types of transformations. Complete positivity of higher-order maps is derived from the general admissibility conditions instead of being postulated as in previous approaches. The recursive characterization of convex sets of maps of a given type is used to prove equivalence relations between different types. The axioms of the framework do not refer to the specific mathematical structure of quantum theory, and can therefore be exported in the context of any operational probabilistic theory.
Making big data small
Authors: Fan Wenfei
Published: May 2019

Big data analytics is often prohibitively costly and is typically conducted by parallel processing with a cluster of machines. Is big data analytics beyond the reach of small companies that can only afford limited resources? This paper tackles this question by presenting Boundedly EvAlable SQL (
BEAS
), a system for querying big relations with constrained resources. The idea is to make big data small. To answer a query posed on a dataset, it often suffices to access a small fraction of the data no matter how big the dataset is. In the light of this,
BEAS
answers queries on big data by identifying and fetching a small set of the data needed. Under available resources, it computes exact answers whenever possible and otherwise approximate answers with accuracy guarantees. Underlying
BEAS
are principled approaches of bounded evaluation and data-driven approximation, the focus of this paper.
Phylogenomics of Aplacophora (Mollusca, Aculifera) and a solenogaster without a foot
Authors: Kocot Kevin M. , Todt Christiane , Mikkelsen Nina T. , Halanych Kenneth M.
Published: May 2019

Recent molecular phylogenetic investigations strongly supported the placement of the shell-less, worm-shaped aplacophoran molluscs (Solenogastres and Caudofoveata) and chitons (Polyplacophora) in a clade called Aculifera, which is the sister taxon of all other molluscs. Thus, understanding the evolutionary history of aculiferan molluscs is important for understanding early molluscan evolution. In particular, fundamental questions about evolutionary relationships within Aplacophora have long been unanswered. Here, we supplemented the paucity of available data with transcriptomes from 25 aculiferans and conducted phylogenomic analyses on datasets with up to 525 genes and 75 914 amino acid positions. Our results indicate that aplacophoran taxonomy requires revision as several traditionally recognized groups are non-monophyletic. Most notably, Cavibelonia, the solenogaster taxon defined by hollow sclerites, is polyphyletic, suggesting parallel evolution of hollow sclerites in multiple lineages. Moreover, we describeApodomenia enigmaticasp. nov.,a bizarre new species that appears to be a morphological intermediate between Solenogastres and Caudofoveata. This animal is not a missing link, however; molecular and morphological studies show that it is a derived solenogaster that lacks a foot, mantle cavity and radula. Taken together, these results shed light on the evolutionary history of Aplacophora and reveal a surprising degree of morphological plasticity within the group.
Cognitive ability and fertility among Swedish men born 1951–1967: evidence from military conscription registers
Authors: Kolk Martin , Barclay Kieron
Published: May 2019

We examine the relationship between cognitive ability and childbearing patterns in contemporary Sweden using administrative register data. The topic has a long history in the social sciences and has been the topic of a large number of studies, many reporting a negative gradient between intelligence and fertility. We link fertility histories to military conscription tests with intelligence scores for all Swedish men born 1951–1967. We find a positive relationship between intelligence scores and fertility, and this pattern is consistent across the cohorts we study. The relationship is most pronounced for the transition to a first child, and men with the lowest categories of IQ scores have the fewest children. Using fixed effects models, we additionally control for all factors that are shared by siblings, and after such adjustments, we find a stronger positive relationship between IQ and fertility. Furthermore, we find a positive gradient within groups at different levels of education. Compositional differences of this kind are therefore not responsible for the positive gradient we observe—instead, the relationship is even stronger after controlling for both educational careers and parental background factors. In our models where we compare brothers to one another, we find that, relative to men with IQ 100, the group with the lowest category of cognitive ability have 0.56 fewer children, and men with the highest category have 0.09 more children.
Ignoring stratigraphic age uncertainty leads to erroneous estimates of species divergence times under the fossilized birth–death process
Authors: Barido-Sottani Joëlle , Aguirre-Fernández Gabriel , Hopkins Melanie J. , Stadler Tanja , Warnock Rachel
Published: May 2019

Fossil information is essential for estimating species divergence times, and can be integrated into Bayesian phylogenetic inference using the fossilized birth–death (FBD) process. An important aspect of palaeontological data is the uncertainty surrounding specimen ages, which can be handled in different ways during inference. The most common approach is to fix fossil ages to a point estimate within the known age interval. Alternatively, age uncertainty can be incorporated by using priors, and fossil ages are then directly sampled as part of the inference. This study presents a comparison of alternative approaches for handling fossil age uncertainty in analysis using the FBD process. Based on simulations, we find that fixing fossil ages to the midpoint or a random point drawn from within the stratigraphic age range leads to biases in divergence time estimates, while sampling fossil ages leads to estimates that are similar to inferences that employ the correct ages of fossils. Second, we show a comparison using an empirical dataset of extant and fossil cetaceans, which confirms that different methods of handling fossil age uncertainty lead to large differences in estimated node ages. Stratigraphic age uncertainty should thus not be ignored in divergence time estimation and instead should be incorporated explicitly.
Single molecule dynamics of Dishevelled at the plasma membrane and Wnt pathway activation
Authors: Ma Wenzhe , Chen Maorong , Kang Hong , Steinhart Zachary , Angers Stephane , He Xi , Kirschner Marc W.
Published: May 2019

Dvl (Dishevelled) is one of several essential non-enzymatic components of the Wnt signaling pathway. In most current models, Dvl forms complexes with Wnt ligand receptors, Fzd and LRP5/6 at the plasma membrane, which then recruits other components of the destruction complex leading to inactivation of β-catenin degradation. Although this model is widespread, direct evidence for this process is lacking. In this study, we tagged mEGFP to C-terminus of dishevlled2 gene using CRISPR/Cas9 induced homologous recombination and observed its dynamics directly at the single molecule level with Total Internal Reflection Fluorescence (TIRF) microscopy. We focused on two questions: 1) What is the native size and the dynamic features of membrane-associated Dvl complexes during Wnt pathway activation? 2) What controls the behavior of these complexes? We found that membrane bound Dvl2 is predominantly monomer in the absent of Wnt (mean size 1.10). Wnt3a stimulation leads to an increase in the total concentration of membrane-bound Dvl2 from 0.08/μm2 to 0.34/μm2. Wnt3a also leads to increased oligomerization which raises the weighted averaged mean size of Dvl2 complexes to 1.4; with 65% of Dvl still as monomers. The driving force for Dvl2 oligomerization is the increased concentration of Dvl2 at the membrane caused by increased affinity of Dvl2 for Fzd, the Dvl2 and Fzd binding is independent of LRP5/6. The oligomerized Dvl2 complexes have greatly increased dwell time, 2~3 minutes compared to less than 1 second for monomeric Dvl2. These properties make Dvl a unique scaffold dynamically changing its state of assembly and stability at the membrane in response to Wnt ligands.

Significance Statement

Canonical Wnt signaling is one of the most widely distributed pathways in metazoan development. Despite intense genetic and biochemical study for over 35 years, the major features of signaling across the plasma membrane are still poorly understood. Dishevelled serves as an essential bridge between the membrane receptors and downstream signaling components. Attempts to reconstruct the pathway and analyze its biochemical features in vitro have been hampered by Dishevelled’s tendency to aggregate in vitro and to form large aggregates of dubious significance in vivo. To obtain a molecular understanding of the role of Dvl in Wnt signaling, while circumventing these aggregation problems we have expressed a fluorescent tagged Dishevelled in cells at their physiological concentration and quantified the size distribution of Dishevelled before and after Wnt treatment. We found that limited oligomerization in response to the Wnt ligand is very dynamic and provides a key step of signal transduction.
A Network of Phosphatidylinositol 4,5-bisphosphate Binding Sites Regulate Gating of the Ca2+-activated Cl− Channel ANO1 (TMEM16A)
Authors: Yu Kuai , Jiang Tao , Cui YuanYuan , Tajkhorshid Emad , Hartzell H. Criss
Published: May 2019

ANO1 (TMEM16A) is a Ca2+-activated Cl− channel that regulates diverse cellular functions including fluid secretion, neuronal excitability, and smooth muscle contraction. ANO1 is activated by elevation of cytosolic Ca2+ and modulated by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). Here we describe a closely concerted experimental and computational study, including electrophysiology, mutagenesis, functional assays, and extended sampling of lipid-protein interactions with molecular dynamics (MD) to characterize PI(4,5)P2 binding modes and sites on ANO1. ANO1 currents in excised inside-out patches activated by 270 nM Ca2+ at +100 mV are increased by exogenous PI(4,5)P2 with an EC50 = 1.24 µM. The effect of PI(4,5)P2 is dependent on membrane voltage and Ca2+ and is explained by a stabilization of the ANO1 Ca2+-bound open state. Unbiased atomistic MD simulations with 1.4 mol% PI(4,5)P2 in a phosphatidylcholine bilayer identified 8 binding sites with significant probability of binding PI(4,5)P2. Three of these sites captured 85% of all ANO1 - PI(4,5)P2 interactions. Mutagenesis of basic amino acids near the membrane-cytosol interface found three regions of ANO1 critical for PI(4,5)P2 regulation that correspond to the same three sites identified by MD. PI(4,5)P2 is stabilized by hydrogen bonding between amino acid sidechains and phosphate/hydroxyl groups on PI(4,5)P2. Binding of PI(4,5)P2 alters the position of the cytoplasmic extension of TM6, which plays a crucial role in ANO1 channel gating, and increases the accessibility of the inner vestibule to Cl−ions. We propose a model consisting of a network of three PI(4,5)P2 binding sites at the cytoplasmic face of the membrane allosterically regulating ANO1 channel gating.

Significance statement

Membrane proteins dwell in a sea of phospholipids that not only structurally stabilize the proteins by providing a hydrophobic environment for their transmembrane segments, but also dynamically regulate protein function. While many cation channels are known to be regulated by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), relatively little is known about anion channel regulation by phosphoinositides. Using a combination of patch clamp electrophysiology and atomistic molecular dynamics simulations, we have identified several PI(4,5)P2 binding sites in ANO1 (TMEM16A), a Cl− channel that performs myriad physiological functions from epithelial fluid secretion to regulation of electrical excitability. These binding sites form a band at the cytosolic interface of the membrane that we propose constitute a network to dynamically regulate this highly allosteric protein.
Temporal perturbation of Erk dynamics reveals network architecture of FGF2-MAPK signaling
Authors: Blum Yannick , Mikelson Jan , Dobrzyński Maciej , Ryu Hyunryul , Jacques Marc-Antoine , Jeon Noo Li , Khammash Mustafa , Pertz Olivier
Published: May 2019

Stimulation of PC-12 cells with epidermal (EGF) versus nerve (NGF) growth factors (GFs) biases the distribution between transient and sustained single-cell ERK activity states, and between proliferation and differentiation fates within a cell population. We report that fibroblast GF (FGF2) evokes a distinct behavior that consists of a gradually changing population distribution of transient/sustained ERK signaling states in response to increasing inputs in a dose response. Temporally-controlled GF perturbations of MAPK signaling dynamics applied using microfluidics reveals that this wider mix of ERK states emerges through the combination of an intracellular feedback, and competition of FGF2 binding to FGF receptors (FGFR) and heparan-sulfate proteoglycans (HSPGs) co-receptors. We show that the latter experimental modality is instructive for model selection using a Bayesian parameter inference. Our results provide novel insights into how different receptor tyrosine kinase (RTK) systems differentially wire the MAPK network to fine tune fate decisions at the cell population-level.

Microfluidics, Erk Signaling Dynamics, Mechanistic Modelling, Parameter Estimation, Cell Fate Determination
Differential local stability governs the metamorphic fold-switch of bacterial virulence factor RfaH
Authors: Galaz-Davison P. , Molina J.A. , Silletti S. , Komives E.A. , Knauer S.H. , Artsimovitch I. , Ramírez-Sarmiento C.A.
Published: May 2019

A regulatory factor RfaH, present in many Gram-negative bacterial pathogens, is required for transcription and translation of long operons encoding virulence determinants. Escherichia coli RfaH action is controlled by a unique large-scale structural rearrangement triggered by recruitment to transcription elongation complexes through a specific DNA sequence within these operons. Upon recruitment, the C-terminal domain of this two-domain protein refolds from an α-hairpin, which is bound to the RNA polymerase binding site within the N-terminal domain of RfaH, into an unbound β-barrel that interacts with the ribosome to enable translation. Although structures of the autoinhibited (α-hairpin) and active (β-barrel) states and plausible refolding pathways have been reported, how this reversible switch is encoded within RfaH sequence and structure is poorly understood. Here, we combined hydrogen-deuterium exchange measurements by mass spectrometry and nuclear magnetic resonance with molecular dynamics to evaluate the differential local stability between both RfaH folds. Deuteron incorporation reveals that the tip of the C-terminal hairpin (residues 125-145) is stably folded in the autoinhibited state (∼20% deuteron incorporation), while the rest of this domain is highly flexible (>40% deuteron incorporation) and its flexibility only decreases in the β-folded state. Computationally-predicted ΔGs agree with these results by displaying similar anisotropic stability within the tip of the α-hairpin and on neighboring N-terminal domain residues. Remarkably, the β-folded state shows comparable stability to non-metamorphic homologs. Our findings provide information critical for understanding the metamorphic behavior of RfaH and other chameleon proteins, and for devising targeted strategies to combat bacterial diseases.

Significance

Infections caused by Gram-negative bacteria are a worldwide health threat due to rapid acquisition of antibiotic resistance. RfaH, a protein essential for virulence in several Gram-negative pathogens, undergoes a large-scale structural rearrangement in which one RfaH domain completely refolds. Refolding transforms RfaH from an inactive state that restricts RfaH recruitment to a few target genes into an active state that binds to, and couples, transcription and translation machineries to elicit dramatic activation of gene expression. However, the molecular basis of this unique conformational change is poorly understood. Here, we combine molecular dynamics and structural biology to unveil the hotspots that differentially stabilize both states of RfaH. Our findings provide novel insights that will guide design of inhibitors blocking RfaH action.
Androgen-regulated transcription ofESRP2drives alternative splicing patterns in prostate cancer
Authors: Munkley Jennifer , Ling Li , Krishnan S R Gokul , Hysenaj Gerald , Scott Emma , Oo Htoo Zarni , Maia Teresa M. , Cheung Kat , Ehrmann Ingrid , Livermore Karen E. , Zielinska Hanna , Thompson Oliver , Knight Bridget , McCullagh Paul , McGrath John , Crundwell Malcolm , Harries Lorna W. , Daugaard Mads , Cockell Simon , Barbosa-Morais Nuno L. , Oltean Sebastian , Elliott David J
Published: May 2019

Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulatorESRP2. BothESRP2and its close paralogESRP1are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including a key splicing switch in the metastatic regulatorFLNBwhich is associated with disease relapse.ESRP2expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this,FLNBsplicing was reciprocally switched by the AR antagonist bicalutamide (Casodex®). Our data reveal a new mechanism of splicing control in prostate cancer with important implications for metastatic disease progression.

Key points

Transcriptional regulation of ESRP2 by the androgen receptor controls splice isoform patterns in prostate cancer cells.

Splicing switches regulated by the androgen-ESRP2 axis include a splice isoform in theFLNBgene that is a known metastatic driver.

Both ESRP1 and ESRP2 are highly expressed in prostate cancer tissue.

Ectopic expression of ESRP1 and 2 inhibits prostate cancer cell growth.

By repressing ESRP2 expression androgen deprivation therapy (ADT) may dampen epithelial splicing programmes to inadvertently prime disease progression towards metastasis.
Immunosuppressive regimens based on Cyclophospamide or Calcineurin inhibitors: Comparison of their effect in the long term outcome of Primary Membranous Nephropathy
Authors: Stangou Maria , Marinaki Smaragdi , Papachristou Evangelos , Kolovou Chrysanthi , Sambani Erasmia , Zerbala Synodi , Papadea Panagiota , Balafa Olga , Rapsomanikis Karolos-Pavlos , Andrikos Aimilios , Manolakaki Panagiota , Papadopoulou Dorothea , Mitsopoulos Efstathios , Andronikidi Paraskevi-Eyh , Choulitoudi Vasiliki , Moustakas George , Galitsiou Dimitra , Dafnis Eugene , Stylianou Constantinos , Stefanidis Ioannis , Golfinopoulos Spyridon , Panagoutsos Stylianos , Tsilivigkou Maria , Papadogianakis Apostolos , Tzanakis Ioannis , Sioulis Athanasios , Vlachakos Dimitrios , Grapsa Eirini , Spaia Sophia , Kaperonis Nikolaos , Paliouras Christos , Dioudis Christos , Papoulidou Fani , Apostolou Theofanis , Iatrou Christos , Boletis Ioannis , Goumenos Dimitrios , Papagianni Aikaperini
Published: May 2019

Management of the Primary Membranous Nephropathy (PMN) usually involves administration of immunosuppressives. Cyclophosphamide (Cyclo) and Calcineurin Inhibitors (CNIs) are both widely used but only limited data exist to compare their efficacy in long term follow-up.

Aim

of the present study was to estimate and compare long term effects of Cyclo and CNIs in patients with PMN.

Patients-Methods

Clinical data, histologic findings and long term outcome were retrospectively studied. The response to treatment and rate of relapse was compared between patients treated with CNIs or Cyclo based immunosuppressive regimens.

Results

Twenty three centers participated in the study, with 752 PMN patients (Mean age 53.4(14-87)yrs, M/F 467/285), followed for 10.1±5.7 years. All patients were initially treated with Renin Angiotensin Aldosterone System inhibitors (RAASi) for at least 6 months. Based on their response and tolerance to initial treatment, patients were divided into 3 groups, group I with spontaneous remission, who had no further treatment, group II, continued on RAASi only, and group III on RAASi+immunosuppression. Immunosuppressive regimes were mainly based on CNIs or Cyclo. Frequent relapses and failure to treatment were more common between patients who had started on CNIs (n=381) compared to those initially treated with Cyclo (n=110), relapse rate: 25.2% vs. 6.4%, p<0.0001, and no response rate: 22.5% vs. 13.6%, p=0.04, respectively.

Conclusions

Long term follow up showed that administration of Cyclo in PMN is followed by better preservation of renal function, increased response rate and less frequent relapses, compared to CNIs.
Optimizing the fitting initial condition for the parallel intrinsic diffusivity in NODDI: An extensive empirical evaluation
Authors: Guerrero Jose M. , Adluru Nagesh , Bendlin Barbara B. , Goldsmith H. Hill , Schaefer Stacey M. , Davidson Richard J. , Kecskemeti Steven R. , Zhang Hui , Alexander Andrew L.
Published: May 2019

Purpose

NODDI is widely used in parameterizing microstructural brain properties. The model includes three signal compartments: intracellular, extracellular, and free water. The neurite compartment intrinsic parallel diffusivity (d‖) is set to 1.7 µm2⋅ms−1, though the effects of this assumption have not been extensively explored. This work seeks to optimize d‖ by minimizing the model residuals.

Methods

The model residuals were evaluated in function of d‖ over the range from 0.5 to 3.0 µm2⋅ms−1. This was done with respect to tissue type (i.e., white matter versus gray matter), sex, age (infancy to late adulthood), and diffusion-weighting protocol (maximum b-value). Variation in the estimated parameters with respect to d‖ was also explored.

Results

Results show the optimum d‖ is significantly lower for gray matter relative to 1.7 µm2⋅ms−1 and to white matter. Infants showed significantly decreased optimum d‖ in gray and white matter. Minor optimum d‖ differences were observed versus diffusion protocol. No significant sex effects were observed. Additionally, changes in d‖ resulted in significant changes to the estimated NODDI parameters.

Conclusion

Future implementations of NODDI would benefit from d‖ optimization, particularly when investigating young populations and/or gray matter.
How do brassinosteroids activate their receptors?
Authors: Moffett Alexander S. , Shukla Diwakar
Published: May 2019

Brassinosteroids (BRs) are an important class of plant growth hormones which signal through BRI1 and BAK1, leucine-rich repeat receptor-like kinases (LRR-RLKs). When bound to the BRI1 island domain, BRs act as a “molecular glue”, mediating interactions between BRI1 and BAK1 extracellular domains. However, it is unclear how much other factors contribute to BR-induced BRI1-BAK1 association, including stabilization of the BRI1 island domain and large conformational changes in BRI1. We use several molecular dynamics simulation-based methods to explore the contributions of each mechanism to BR-dependent Arabidopsis thaliana BRI1-BAK1 association. We find that specific BR interactions make major contributions to BRI1-BAK1 association free energy. BR binding stabilizes the BRI1 island domain, while BRI1 undergoes a large conformational change to form a secondary interface with BAK1. These results suggest that each mechanism plays a part in BR signal transduction while raising questions about the functional role of conformational dynamics in other LRR-RLKs.
The neural basis of tadpole transport in poison frogs
Authors: Fischer Eva K. , Roland Alexandre B. , Moskowitz Nora A. , Tapia Elicio E. , Summers Kyle , Coloma Luis A. , O’Connell Lauren A.
Published: May 2019

Parental care has evolved repeatedly and independently across animals. While the ecological and evolutionary significance of parental behaviour is well recognized, underlying mechanisms remain poorly understood. We took advantage of behavioural diversity across closely related species of South American poison frogs (Family Dendrobatidae) to identify neural correlates of parental behaviour shared across sexes and species. We characterized differences in neural induction, gene expression in active neurons, and activity of specific neuronal types in three species with distinct parental care patterns: male uniparental, female uniparental, and biparental. We identified the medial pallium and preoptic area as core brain regions associated with parental care, independent of sex and species. Identification of neurons active during parental care confirms a role for neuropeptides associated with care in other vertebrates as well as identifying novel candidates. Our work is the first to explore neural and molecular mechanisms of parental care in amphibians and highlights the potential for mechanistic studies in closely related but behaviourally variable species to build a more complete understanding of how shared principles and species-specific diversity govern parental care and other social behaviour.