bluuebunny/crossref_metadata_2025 huggingface dataset:
Continuous Casting of High Carbon Steel: How Does Hard Cooling Influence Solidification, Micro - and Macro Segregation?
Authors: Nicholas Grundy A. , Münch Steve , Feldhaus Stephan , Bratberg Johan
Published: May 2019

One technology that is often employed in continuous casting of high-carbon steel billets to minimize centre - (or macro) segregation is hard secondary cooling. Investigations unanimously show, that hard cooling significantly reduces macro-segregation, but a mechanism for the reduced segregation is rarely given. In this paper the solidification of high carbon tire cord grade C80D cast as a 150x150 mm billet is calculated using the proprietary SMS Group solidification simulation package CHILL using steel properties calculated with the Thermo-Calc Software package and TCFE steels database. The obtained cooling rates in the billet for hard and soft secondary cooling are used to run solidification simulations considering solute redistribution using the diffusion module DICTRA. It is shown that for cooling rates achieved in continuous casting the steel solidifies far away from equilibrium. The solidification profile and solidus temperature lie in between the Scheil solidification model and the para-equilibrium Scheil model with carbon defined as a fast diffusing element. The calculated cooling rates and temperature gradients are used to simulate the solidification microstructure 20 mm from the billet surface using the phase field approach and the MICRESS® software package linked to Thermo-Calc through the TQ interface. This model clearly shows, that the most probable mechanism by which hard cooling reduces segregation is trapping of solutes between the intricately branched dendrite microstructure that results from the steep temperature gradients achieved when applying hard secondary cooling.
Three-dimensional study of nodule clustering and heterogeneous strain localization for tailored material properties in ductile iron
Authors: Olofsson Jakob , Salomonsson Kent , Dahle Arne K. , Mathiesen Ragnvald H.
Published: May 2019

Tailored heterogeneous distributions of microstructural features enable extraordinary material performance in biological and physiological structures such as trees, the aortic arch, human teeth and dinosaur skulls. In ductile iron, a heterogeneous distribution in size and morphology of graphite nodules and variations of the fractions of ferrite and pearlite are created during solidification, and varies as a function of parameters such as local cooling rate, segregation and flow. In the current work, the size distribution as well as the orientation and relation between graphite nodules is obtained by a three-dimensional reconstruction of a ductile iron microstructure from X-ray tomography. The effect of the nodule morphology and clustering on the localization of plastic strains is studied numerically using finite element analysis of the reconstructed microstructure. Real castings have a variation in geometry, solidification conditions and are subjected to variations in loads. A framework for optimized geometry and solidification conditions in order to design and deliver castings with tailored local material performance is proposed.
The Knight Move Conjecture is false
Authors: Manolescu Ciprian , Marengon Marco
Published: May 2019

The Knight Move Conjecture claims that the Khovanov homology of any knot decomposes as direct sums of some “knight move” pairs and a single “pawn move” pair. This is true for instance whenever the Lee spectral sequence from Khovanov homology to

Q

2

\mathbb {Q}^2

converges on the second page, as it does for all alternating knots and knots with unknotting number at most

2
2

. We present a counterexample to the Knight Move Conjecture. For this knot, the Lee spectral sequence admits a non-trivial differential of bidegree

(
1
,
8
)

(1,8)

.
A nonlocal transport equation describing roots of polynomials under differentiation
Authors: Steinerberger Stefan
Published: May 2019

Let

p
n

p_n

be a polynomial of degree

n
n

having all its roots on the real line distributed according to a smooth function

u
(
0
,
x
)

u(0,x)

. One could wonder how the distribution of roots behaves under iterated differentation of the function, i.e., how the density of roots of

p
n

(
k
)

p_n^{(k)}

evolves. We derive a nonlinear transport equation with nonlocal flux
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="u Subscript t Baseline plus StartFraction 1 Over pi EndFraction left-parenthesis arc tangent left-parenthesis StartFraction upper H u Over u EndFraction right-parenthesis right-parenthesis Subscript x Baseline equals 0 on s u p p left-brace u greater-than 0 right-brace comma">

u
t

+

1
π

(
arctan
⁡

(

H
u

u

)

)

x

=
0

on
 
supp
⁡

{
u
>
0
}

,

\begin{equation*} u_t + \frac {1}{\pi }\left ( \arctan { \left ( \frac {Hu}{ u}\right )} \right )_x = 0 \qquad \text {on} ~\operatorname {supp} \left \{u>0\right \}, \end{equation*}

where

H
H

is the Hilbert transform. This equation has three very different compactly supported solutions: (1) the arcsine distribution

u
(
t
,
x
)
=
(
1
−

x
2

)

−
1

/

2

χ

(
−
1
,
1
)

u(t,x) = (1-x^2)^{-1/2} \chi _{(-1,1)}

, (2) the family of semicircle distributions

u
(
t
,
x
)
=

2
π

(
T
−
t
)
−

x
2

,

\begin{equation*} u(t,x) = \frac {2}{\pi } \sqrt {(T-t) - x^2}, \end{equation*}

and (3) a family of solutions contained in the Marchenko–Pastur law.
Dominance phenomena: mutation, scattering and cluster algebras
Authors: Reading Nathan
Published: May 2019

An exchange matrix

B
B

dominates an exchange matrix

B
′

B’

if the signs of corresponding entries weakly agree, with the entry of

B
B

always having weakly greater absolute value. When

B
B

dominates

B
′

B’

, interesting things happen in many cases (but not always): the identity map between the associated mutation-linear structures is often mutation-linear; the mutation fan for

B
B

often refines the mutation fan for

B
′

B’

; the scattering (diagram) fan for

B
B

often refines the scattering fan for

B
′

B’

; and there is often an injective homomorphism from the principal-coefficients cluster algebra for

B
′

B’

to the principal-coefficients cluster algebra for

B
B

, preserving

g

\mathbf {g}

-vectors and sending the set of cluster variables for

B
′

B’

(or an analogous larger set) into the set of cluster variables for

B
B

(or an analogous larger set). The scope of the description “often” is not the same in all four contexts and is not settled in any of them. In this paper, we prove theorems that provide examples of these dominance phenomena.
Polarization and sprouting of endothelial cells by angiopoietin-1 require PAK2 and paxillin-dependent Cdc42 activation
Authors: Boscher Cécile , Gaonac’h-Lovejoy Vanda , Delisle Chantal , Gratton Jean-Philippe
Published: May 2019

Binding of angiopoietin-1 (Ang-1) to its receptor Tie2 on endothelial cells (ECs) promotes vessel barrier integrity and angiogenesis. Here, we identify PAK2 and paxillin as critical targets of Ang-1 responsible for EC migration, polarization, and sprouting. We found that Ang-1 increases PAK2-dependent paxillin phosphorylation and remodeling of focal adhesions and that PAK2 and paxillin are required for EC polarization, migration, and angiogenic sprouting in response to Ang-1. Our findings show that Ang-1 triggers Cdc42 activation at the leading edges of migrating ECs, which is dependent on PAK2 and paxillin expression. We also established that the polarity protein Par3 interacts with Cdc42 in response to Ang-1 in a PAK2- and paxillin-dependent manner. Par3 is recruited at the leading edges of migrating cells and in focal adhesion, where it forms a signaling complex with PAK2 and paxillin in response to Ang-1. These results show that Ang-1 triggers EC polarization and angiogenic sprouting through PAK2-dependent paxillin activation and remodeling of focal adhesions, which are necessary for local activation of Cdc42 and the associated polarity complex. We have shown that PAK2 controls a signaling pathway important for angiogenic sprouting that links focal adhesions to polarity signaling in ECs.
The Effects of Preventive Home Visits on Older People’s Use of Health Care and Social Services and Related Costs
Authors: Liimatta Heini A , Lampela Pekka , Kautiainen Hannu , Laitinen-Parkkonen Pirjo , Pitkala Kaisu H
Published: May 2019

Background

We use data from a randomized controlled trial on preventive home visits exploring effectiveness on health-related quality of life. In this article, we examine the intervention’s cost-effectiveness and effects on quality-adjusted life years in older home-dwelling adults.

Methods

There were 422 independently home-dwelling participants in the randomized, controlled trial, all aged more than 75 years, with equal numbers in the control and intervention groups. The intervention took place in a municipality in Finland and consisted of multiprofessional preventive home visits. We gathered the data on health care and social services use from central registers and medical records during 1 year before the intervention and 2 years after the intervention. We analyzed the total health care and social services use and costs per person-years and the difference in change in health-related quality of life as measured using the 15D measure. We calculated quality-adjusted life years and incremental cost-effectiveness ratios.

Results

There was no significant difference in baseline use of services or in the total use and costs of health care and social services during the 2-year follow-up between the two groups. In the intervention group, health-related quality of life declined significantly more slowly compared with the control group (–0.015), but there was no significant difference in quality-adjusted life years gained between the groups. The cost-effectiveness plane showed 60% of incremental cost-effectiveness ratios lying in the dominant quadrant, representing additional effects with lower costs.

Conclusions

This multiprofessional preventive home visit intervention appears to have positive effects on health-related quality of life without accruing additional costs.

The clinical trial registration number

ACTRN12616001411437.
Horizontal Reputation and Strategic Audience Management
Authors: Bouvard Matthieu , Lévy Raphaël
Published: May 2019

We study how a decision maker uses his reputation to simultaneously influence the actions of multiple receivers with heterogenous biases. The reputational payoff is single-peaked around a bliss reputation at which the incentives of the average receiver are perfectly aligned. We establish the existence of two equilibria characterized by repositioning toward this bliss reputation that only differ through a multiplier capturing the efficiency of reputational incentives. Repositioning is moderate in the more efficient equilibrium, but the less efficient equilibrium features overreactions, and welfare may then be lower than in the no-reputation case. We highlight how strategic audience management (e.g., centralization, delegation to third parties with dissenting objectives) alleviates inefficient reputational incentives, and how multiple organizational or institutional structures may arise in equilibrium as a result.
Maize with fewer nodal roots allocates mass to more lateral and deep roots that improve nitrogen uptake and shoot growth
Authors: Guo Haichao , York Larry M
Published: May 2019

Reallocating root biomass from nodal roots to lateral and early-emerging axial roots allows maize to capture more nitrogen under limiting conditions, including by increasing foraging at depth.
3D Exoscope System in Neurosurgery—Comparison of a Standard Operating Microscope With a New 3D Exoscope in the Cadaver Lab
Authors: Herlan Stephan , Marquardt Jakob S , Hirt Bernhard , Tatagiba Marcos , Ebner Florian H
Published: May 2019

BACKGROUND

For decades, the operating microscope has been the “gold standard” visualization device in neurosurgery. The development of endoscopy revolutionized different surgical disciplines, whereas in neurosurgery, the endoscope is commonly used as an additional device more than as single visualization tool. Invention of a 3D exoscope system opens new possibilities in visualization and ergonomics in neurosurgery.

OBJECTIVE

To assess the prototype of a 3D exoscope (3D exoscope, year of manufacture 2015, FA Aesculap, Tüttlingen, Germany) as neurosurgical visualization device in comparison to a standard operating microscope.

METHODS

A pterional approach was performed in 3 ETOH-fixed specimens (6 sides). A standard operating microscope was compared to a 3D exoscope prototype. Dimensions like visual field, magnification, illumination, ergonomics, depth effect, and 3D impression were compared.

RESULTS

In all approaches, the structures of interest could be clearly visualized with both devices. Magnification showed similar results. The exoscope had more magnification potential, whereas the visual quality got worse in higher magnification levels. The illumination showed better results in the microscope. Surgeons felt more comfortable with the 3D exoscope, concerning ergonomic considerations. Depth effect and 3D impression showed similar results. None of the surgeons felt uncomfortable using the exoscope.

CONCLUSION

The operating microscope is the gold standard visualization tool in neurosurgery because of its illumination, stereoscopy, and magnification. Nevertheless, it causes ergonomic problems. The prototype of a 3D exoscope showed comparable features in visual field, stereoscopic impression, and magnification, with a clear benefit concerning the ergonomic possibilities.
Endoscopic Interhemispheric Disconnection for Intractable Multifocal Epilepsy: Surgical Technique and Functional Neuroanatomy
Authors: Sufianov Albert A , Cossu Giulia , Iakimov Iurii A , Sufianov Rinat A , Markin Egor S , Stefanov Stefan Z , Zemmoura Ilyess , Messerer Mahmoud , Daniel Roy T
Published: May 2019

BACKGROUND

Callosotomy represents a palliative procedure for intractable multifocal epilepsy. The extent of callosotomy and the benefits of adding anterior and posterior commissurotomy are debated.

OBJECTIVE

To describe a new technique of a purely endoscopic procedure to disconnect the corpus callosum, the anterior, posterior, and habenular commissures through the use of a single burr hole via a transfrontal transventricular route.

METHODS

Our surgical series was retrospectively reviewed in terms of seizure control (Engel's class) and complication rate. Five cadaveric specimens were used to demonstrate the surgical anatomy of commissural fibers and third ventricle.

RESULTS

The procedure may be divided into 3 steps: (1) endoscopic transventricular transforaminal anterior commissure disconnection; (2) disconnection of posterior and habenular commissures; and (3) total callosotomy. Fifty-seven patients were included in the analysis. A favorable outcome in terms of epilepsy control (Engel class 1 to 3) was found in 71.4% of patients undergoing callosotomy coupled with anterior, posterior, and habenular commissure disconnection against 53% of patients with isolated callosotomy (P = .26). Patients with drop attacks had better epilepsy outcome independently from the surgical procedure used.

CONCLUSION

The full endoscopic callosotomy coupled with disconnection of anterior, posterior and habenular commissures is a safe alternative to treat multifocal refractory epilepsy. A gain in seizure outcome might be present in this cohort of patients treated with total interhemispheric disconnection when compared with isolated callosotomy. Larger studies are required to confirm these findings.
Sensitivity of Bipolaris oryzae Isolates Pathogenic on Cultivated Wild Rice to the Quinone Outside Inhibitor Azoxystrobin
Authors: Castell-Miller Claudia V. , Samac Deborah A.
Published: May 2019

The occurrence of fungal brown spot, caused by Bipolaris oryzae, has increased in cultivated wild rice (Zizania palustris) paddies in spite of the use of azoxystrobin-based fungicides. The active ingredient blocks electron transfer at the quinone outside inhibitor (QoI) site in the mitochondrial cytochrome b within the bc1 complex, thus obstructing respiration. The in vitro averaged EC50 of baseline isolates collected in 2007 before widespread fungicide use was estimated to be 0.394 µg/ml with PROBIT and 0.427 µg/ml with linear regression analyses. Isolates collected during 2008, 2015, and 2016 had a range of sensitivity as measured by relative spore germination (RG) at a discriminatory dose of 0.4 µg/ml azoxystrobin. Isolates with a higher (≥80%) and lower RG (≤40%) had the wild type nucleotides at amino acid positions F129, G137, and G143 of cytochrome b, sites known to be associated with QoI fungicide resistance. Two Group I introns were found in the QoI target area. The splicing site for the second intron was found immediately after the codon for G143. A mutation for fungicide resistance at this location would hinder splicing and severely reduce fitness. B. oryzae expresses an alternative oxidase in vitro, which allows the fungus to survive inhibition of respiration by azoxystrobin. This research indicates that B. oryzae has not developed resistance to QoI fungicides, although monitoring for changes in sensitivity should be continued. Judicious use of QoI fungicides within an integrated disease management system will promote an effective and environmentally sound control of the pathogen in wild rice paddies.
Black Lung Disease Resurges in Appalachian Coal Miners
Authors: Potera Carol
Published: May 2019

Earlier detection and treatment are needed.
New Warning for Fluoroquinolone Antibiotics
Authors: Aschenbrenner Diane S.
Published: May 2019

The Food and Drug Administration has added a warning to the labeling of all fluoroquinolone antibiotics stating that these drugs can increase the risk of rupture or dissection of aortic aneurysms.

NPs should avoid prescribing fluoroquinolones to patients at risk for aortic aneurysms unless no other therapy is available.
EBP 2.0: From Strategy to Implementation
Authors: Tucker Sharon J. , Gallagher-Ford Lynn
Published: May 2019

This is the first article in a new series about evidence-based practice (EBP) that builds on AJN’s award-winning previous series—Evidence-Based Practice, Step by Step—published between 2009 and 2011 (to access the series, go to http://links.lww.com/AJN/A133). This follow-up series will feature case studies illustrating the various strategies that can be used to implement EBP changes—one of the most challenging steps in the EBP process.
RADseq analyses reveal concordant Indian Ocean biogeographic and phylogeographic boundaries in the reef fishDascyllus trimaculatus
Authors: Salas E. M. , Bernardi G. , Berumen M. L. , Gaither M. R. , Rocha L. A.
Published: May 2019

Population genetic analysis is an important tool for estimating the degree of evolutionary connectivity in marine organisms. Here, we investigate the population structure of the three-spot damselfishDascyllus trimaculatusin the Red Sea, Arabian Sea and Western Indian Ocean, using 1174 single nucleotide polymorphisms (SNPs). Neutral loci revealed a signature of weak genetic differentiation between the Northwestern (Red Sea and Arabian Sea) and Western Indian Ocean biogeographic provinces. Loci potentially under selection (outlier loci) revealed a similar pattern but with a much stronger signal of genetic structure between regions. The Oman population appears to be genetically distinct from all other populations included in the analysis. While we could not clearly identify the mechanisms driving these patterns (isolation, adaptation or both), the datasets indicate that population-level divergences are largely concordant with biogeographic boundaries based on species composition. Our data can be used along with genetic connectivity of other species to identify the common genetic breaks that need to be considered for the conservation of biodiversity and evolutionary processes in the poorly studied Western Indian Ocean region.
Establishment of the falling film evaporation model and correlation of the overall heat transfer coefficient
Authors: Fang Jing , Li Kaixuan , Diao Mengyu
Published: May 2019

In order to study the heat transfer of the falling film evaporator with phase change on both sides, in this paper we built the mathematical model and the physical model where the liquid film inside the tube is laminar and turbulent. The film thickness of the condensate at different axial positions, total condensate volume and velocity distribution, and temperature distribution of condensate outside the tube can be obtained by calculating the proposed model. Meanwhile, the liquid film thickness, velocity distribution and temperature distribution inside the tube were obtained by numerical simulation by considering the influence of the liquid film with different compositions on the heat transfer during fluid flow. With ethanol–water as the system, the overall heat transfer coefficient and heat transfer quantity of the falling film evaporator were obtained by the calculation of the model. The accuracy of the proposed model was confirmed by experiments. The model and the calculation of heat transfer proposed in this paper have enormous significance for the basic data and theoretical guidance of the heat transfer performance prediction and operational optimization of the evaporator.
Direct and converse nonlinear magnetoelectric coupling in multiferroic composites with ferromagnetic and ferroelectric phases
Authors: Zhang Juanjuan , Fang Chao , Weng George J.
Published: May 2019

In this paper, we develop a theoretical principle to calculate the direct and converse magnetoelectric (ME) coupling response of ferromagnetic/ferroelectric composites with 2–2 connectivity. We first present an experimentally based constitutive equation for Terfenol-D, and then build the mechanism of domain switch for the ferroelectric phase. In the latter, the change of Gibbs free energy, thermodynamic driving force and kinetic equations for domain growth are also established. These two sets of constitutive equations are shown to capture the experimental data of Terfenol-D and PZT, respectively, well. For the direct effect under an applied magnetic field, the induced electric field and the overall ME coupling coefficient are determined. For the converse effect under an applied electric field, the induced magnetization and the excited magnetic field are obtained. Both the induced electric filed under direct effect and the excited magnetic field under converse effect are shown to display the hysteretic characteristics, and also in good agreement with experiments. We conclude that the developed theory can both qualitatively and quantitatively reflect the essential features of nonlinear direct and converse ME coupling of the multiferroic composites.
Sexual selection drives the evolution of male wing interference patterns
Authors: Hawkes M. F. , Duffy E. , Joag R. , Skeats A. , Radwan J. , Wedell N. , Sharma M. D. , Hosken D. J. , Troscianko J.
Published: May 2019

The seemingly transparent wings of many insects have recently been found to display unexpected structural coloration. These structural colours (wing interference patterns: WIPs) may be involved in species recognition and mate choice, yet little is known about the evolutionary processes that shape them. Furthermore, to date investigations of WIPs have not fully considered how they are actually perceived by the viewers' colour vision. Here, we use multispectral digital imaging and a model ofDrosophilavision to compare WIPs of male and femaleDrosophila simulansfrom replicate populations forced to evolve with or without sexual selection for 68 generations. We show that WIPs modelled inDrosophilavision evolve in response to sexual selection and provide evidence that WIPs correlate with male sexual attractiveness. These findings add a new element to the otherwise well-describedDrosophilacourtship display and confirm that wing colours evolve through sexual selection.
Extensive eccentric contractions in intact cardiac trabeculae: revealing compelling differences in contractile behaviour compared to skeletal muscles
Authors: Tomalka André , Röhrle Oliver , Han June-Chiew , Pham Toan , Taberner Andrew J. , Siebert Tobias
Published: May 2019

Force enhancement (FE) is a phenomenon that is present in skeletal muscle. It is characterized by progressive forces upon active stretching—distinguished by a linear rise in force—and enhanced isometric force following stretching (residual FE (RFE)). In skeletal muscle, non-cross-bridge (XB) structures may account for this behaviour. So far, it is unknown whether differences between non-XB structures within the heart and skeletal muscle result in deviating contractile behaviour during and after eccentric contractions. Thus, we investigated the force response of intact cardiac trabeculae during and after isokinetic eccentric muscle contractions (10% of maximum shortening velocity) with extensive magnitudes of stretch (25% of optimum muscle length). The different contributions of XB and non-XB structures to the total muscle force were revealed by using an actomyosin inhibitor. For cardiac trabeculae, we found that the force–length dynamics during long stretch were similar to the total isometric force–length relation. This indicates that no (R)FE is present in cardiac muscle while stretching the muscle from 0.75 to 1.0 optimum muscle length. This finding is in contrast with the results obtained for skeletal muscle, in which (R)FE is present. Our data support the hypothesis that titin stiffness does not increase with activation in cardiac muscle.
Inferring collective behaviour from a fossilized fish shoal
Authors: Mizumoto Nobuaki , Miyata Shinya , Pratt Stephen C.
Published: May 2019

Collective motion by animal groups can emerge from simple rules that govern each individual's interactions with its neighbours. Studies of extant species have shown how such rules yield coordinated group behaviour, but little is known of their evolutionary origins or whether extinct group-living organisms used similar rules. Here, we report evidence consistent with coordinated collective motion in a fossilized group of the extinct fish
Erismatopterus levatus
, and we infer possible behavioural rules that underlie it. We found traces of two rules for social interaction similar to those used by extant fishes: repulsion from close individuals and attraction towards neighbours at a distance. Moreover, the fossilized fish showed group-level structures in the form of oblong shape and high polarization, both of which we successfully reproduced in simulations incorporating the inferred behavioural rules. Although it remains unclear how the fish shoal's structure was preserved in the fossil, these findings suggest that fishes have been forming shoals by combining sets of simple behavioural rules since at least the Eocene. Our study highlights the possibility of exploring the social communication of extinct animals, which has been thought to leave no fossil record.
Hormonal regulation of Semaphorin 7a in ER+ breast cancer drives therapeutic resistance
Authors: Crump Lyndsey S , Wyatt Garhett , Rutherford Taylor R , Richer Jennifer K , Porter Weston W , Lyons Traci R
Published: May 2019

Approximately 70% of all breast cancers are estrogen receptor positive (ER+BC) and endocrine therapy has improved survival for patients with ER+BC. Yet, up to half of these tumors recur within 20 years. Recurrent ER+BCs develop resistance to endocrine therapy; thus, novel targets are needed to treat recurrent ER+BC. We found that semaphorin 7A (SEMA7A) confers significantly decreased patient survival rates in ER+BC. We show that SEMA7A is hormonally regulated in ER+BC, but its expression does not uniformly decrease with anti-estrogen treatments. Additionally, overexpression of SEMA7A in ER+ cell lines drives increased in vitro growth in the presence of estrogen-deprivation, tamoxifen, and fulvestrant. In in vivo studies, we found that SEMA7A confers primary tumor resistance to fulvestrant and, importantly, induced lung metastases. Finally, we identify pro-survival signaling as a therapeutic vulnerability of ER+SEMA7A+ tumors and propose that targeting with inhibitors of survival signaling such as venetoclax may have efficacy for treating SEMA7A+ tumors.

SIGNIFICANCE

We report that SEMA7A predicts for, and likely contributes to, poor response to standard-of-care therapies and suggest that patients with SEMA7A+ER+ tumors may benefit from alternative therapeutic strategies.
Exploring Conformational Transitions and Free Energy Profiles of Proton Coupled Oligopeptide Transporters
Authors: Batista Mariana R. B. , Watts Anthony , Costa-Filho Antonio J.
Published: May 2019

Proteins involved in peptide uptake and transport belong to the proton-coupled oligopeptide transporter (POT) family. Crystal structures of POT family members reveal a common fold consisting of two domains of six transmembrane α helices that come together to form a “V” shaped transporter with a central substrate binding site. Proton coupled oligopeptide transporters operate through an alternate access mechanism, where the membrane transporter undergoes global conformational changes, alternating between inward-facing (IF), outward-facing (OF) and occluded (OC) states. Conformational transitions are promoted by proton and ligand binding, however, due to the absence of crystallographic models of the outward-open state, the role of H+ and ligands are still not fully understood. To provide a comprehensive picture of the POT conformational equilibrium, conventional and enhanced sampling molecular dynamics simulations of PepTst in the presence or absence of ligand and protonation were performed. Free energy profiles of the conformational variability of PepTst were obtained from microseconds of adaptive biasing force (ABF) simulations. Our results reveal that both, proton and ligand, significantly change the conformational free energy landscape. In the absence of ligand and protonation, only transitions involving IF and OC states are allowed. After protonation of the residue Glu300, the wider free energy well for Glu300 protonated PepTst indicates a greater conformational variability relative to the apo system, and OF conformations becames accessible. For the Glu300 Holo-PepTst, the presence of a second free energy minimum suggests that OF conformations are not only accessible, but also, stable. The differences in the free energy profiles demonstrate that transitions toward outward facing conformation occur only after protonation and, probably, this should be the first step in the mechanism of peptide transport. Our extensive ABF simulations provide a fully atomic description of all states of the transport process, offering a model for the alternating access mechanism and how protonation and ligand control the conformational changes.

Graphical TOC Entry
Mlh1 haploinsufficiency induces microsatellite instability specifically in intestine
Authors: Shrestha Kul S. , Aska Elli-Mari , Tuominen Minna M. , Kauppi Liisa
Published: May 2019

Tumors of Lynch syndrome (LS) patients display high levels of microsatellite instability (MSI), which results from complete loss of DNA mismatch repair (MMR), in line with Knudson’s two-hit hypothesis. Why some organs, in particular those of the gastrointestinal (GI) tract, are especially prone to tumorigenesis in LS remains unknown. We hypothesized that MMR is haploinsufficient in certain tissues, compromising microsatellite stability in a tissue-specific manner before tumorigenesis. Using mouse genetics, we tested how levels of MLH1, a central MMR protein, affect microsatellite stability in vivo and whether elevated MSI is detectable prior to loss of MMR function and to neoplastic growth. We assayed MSI by sensitive single-molecule PCR in normal jejunum and spleen of 4- and 12-month old Mlh1+/+, Mlh1+/− and Mlh1−/− mice, accompanied by measurements of Mlh1 mRNA and MLH1 protein expression levels.

While spleen MLH1 levels of Mlh1+/− mice were, as expected, approximately 50% compared to wildtype mice, MLH1 levels in jejunum varied substantially between individual Mlh1+/− mice and decreased with age. Apparently, Mlh1+/− mice with soma-wide Mlh1 promoter methylation were the most venerable to MLH1 expression level decrease in jejunum. MLH1 levels (prior to complete loss of the protein) inversely correlated with MSI severity in Mlh1+/− jejunum, while in spleens of the same mice, MLH1 levels and microsatellites remained stable. Thus, Mlh1 haploinsufficiency affects specifically the intestine where MMR levels are particularly labile, inducing MSI in normal cells long before neoplasia. A similar mechanism likely also operates in the human GI epithelium, and could explain the wide range in age of onset of LS-associated tumorigenesis.
Tyr1 phosphorylation promotes the phosphorylation of Ser2 on the C-terminal domain of RNA polymerase II by P-TEFb
Authors: Mayfield Joshua E. , Irani Seema , Escobar Edwin E. , Zhang Zhao , Burkholder Nathanial T. , Robinson Michelle R. , Mehaffey M. Rachel , Sipe Sarah N. , Yang Wanjie , Prescott Nicholas A. , Kathuria Karan R. , Liu Zhijie , Brodbelt Jennifer S. , Zhang Yan
Published: May 2019

The Positive Transcription Elongation Factor b (P-TEFb) phosphorylates Ser2 residues of RNA polymerase II’s C-terminal domain (CTD) and is essential for the transition from transcription initiation to elongationin vivo. Surprisingly, P-TEFb exhibits Ser5 phosphorylation activityin vitro. The mechanism garnering Ser2 specificity to P-TEFb remains elusive and hinders understanding of the transition from transcription initiation to elongation. Throughin vitroreconstruction of CTD phosphorylation, mass spectrometry analysis, and chromatin immunoprecipitation sequencing (ChIP-seq) analysis we uncover a mechanism by which Tyr1 phosphorylation directs the kinase activity of P-TEFb and alters its specificity from Ser5 to Ser2. The loss of Tyr1 phosphorylation causes a reduction of phosphorylated Ser2 and accumulation of RNA polymerase II in the promoter region as detected by ChIP-seq. We demonstrate the ability of Tyr1 phosphorylation to generate a heterogeneous CTD modification landscape that expands the CTD’s coding potential. These findings provide direct experimental evidence for a combinatorial CTD phosphorylation code wherein previously installed modifications direct the identity and abundance of subsequent coding events by influencing the behavior of downstream enzymes.
Sensory Stimulation-Induced Astrocytic Calcium Signaling in Electrically Silent Ischemic Penumbra
Authors: Murmu Reena P. , Fordsmann Jonas C. , Cai Changsi , Brazhe Alexey , Thomsen Kirsten J. , Lauritzen Martin
Published: May 2019

Middle cerebral artery occlusion (MCAO) induces ischemia characterized by a densely ischemic focus, and a less densely ischemic penumbral zone in which neurons and astrocytes display age-dependent dynamic variations in spontaneous Ca2+ activities. However, it is unknown whether penumbral nerve cells respond to sensory stimulation early after stroke onset, which is critical for understanding stimulation-induced stroke therapy. In this study, we investigated the ischemic penumbra’s capacity to respond to somatosensory input. We examined adult (3- to 4-month-old) and old (18- to 24-month-old) male mice at 2–4 hours after MCAO, using two-photon microscopy to record somatosensory stimulation-induced neuronal and astrocytic Ca2+ signals in the ischemic penumbra. In both adult and old mice, MCAO abolished spontaneous and stimulation-induced electrical activity in the penumbra, and strongly reduced stimulation-induced Ca2+ responses in neuronal somas (35–82%) and neuropil (92–100%) in the penumbra. In comparison, after stroke, stimulation-induced astrocytic Ca2+ responses in the penumbra were only moderately reduced (by 54–62%) in adult mice, and were even better preserved (reduced by 31–38%) in old mice.

Our results suggest that somatosensory stimulation evokes astrocytic Ca2+ activity in the ischemic penumbra. We hypothesize that the relatively preserved excitability of astrocytes, most prominent in aged mice, may modulate protection from ischemic infarcts during early somatosensory activation of an ischemic cortical area. Future neuroprotective efforts in stroke may target spontaneous or stimulation-induced activity of astrocytes in the ischemic penumbra.
ChIPSummitDB: A ChIP-seq-based database of human transcription factor binding sites and the topological arrangements of the proteins bound to them
Authors: Czipa Erik , Schiller Mátyás , Nagy Tibor , Kontra Levente , Steiner László , Koller Júlia , Pálné-Szén Orsolya , Barta Endre
Published: May 2019

ChIP-Seq reveals genomic regions where proteins, e.g. transcription factors (TFs) interact with DNA. A substantial fraction of these regions, however, do not contain the cognate binding site for the TF of interest. This phenomenon might be explained by protein-protein interactions and co-precipitation of interacting gene regulatory elements. We uniformly processed 3,727 human ChIP-Seq data sets and determined the cistrome of 292 TFs, as well as the distances between the TF binding motif centers and the ChIP-Seq peak summits.

ChIPSummitDB enables the analysis of ChIP-Seq data using multiple approaches. The 292 cistromes and corresponding ChIP-Seq peak sets can be browsed in GenomeView. Overlapping SNPs can be inspected in dbSNPView. Most importantly, the MotifView and PairShiftView pages show the average distance between motif centers and overlapping ChIP-Seq peak summits and distance distributions thereof, respectively.

In addition to providing a comprehensive human TF binding site collection, the ChIPSummitDB database and web interface allows for the examination of the topological arrangement of TF complexes genome-wide. ChIPSummitDB is freely accessible at http://summit.med.unideb.hu/summitdb/. The database will be regularly updated and extended with the newly available human and mouse ChIP-Seq data sets.
Origins, admixture dynamics and homogenization of the African gene pool in the Americas
Authors: Gouveia Mateus H. , Borda Victor , Leal Thiago P. , Moreira Rennan G. , Bergen Andrew W. , Aquino Marla M. , Araujo Gilderlanio S. , Araujo Nathalia M. , Kehdy Fernanda S.G. , Liboredo Raquel , Machado Moara , Magalhaes Wagner C.S. , Michelin Lucas A. , Rodrigues Maíra R. , Rodrigues-Soares Fernanda , Sant Anna Hanaisa P. , Santolalla Meddly L. , Scliar Marília O. , Soares-Souza Giordano , Zamudio Roxana , Zolini Camila , Dean Michael , Gilman Robert H. , Guio Heinner , Rocha Jorge , Pereira Alexandre C. , Barreto Mauricio L. , Horta Bernardo L. , Lima-Costa Maria F. , Mbulaiteye Sam M. , Chanock Stephen J. , Tishkoff Sarah A. , Yeager Meredith , Tarazona-Santos Eduardo
Published: May 2019

The Transatlantic Slave Trade transported more than 9 million Africans to the Americas between the early 16th and the mid-19th centuries. We performed genome-wide analysis of 6,267 individuals from 22 populations and observed an enrichment in West-African ancestry in northern latitudes of the Americas, whereas South/East African ancestry is more prevalent in southern South-America. This pattern results from distinct geographic and geopolitical factors leading to population differentiation. However, we observed a decrease of 68% in the African gene pool between-population diversity within the Americas when compared to the regions of origin from Africa, underscoring the importance of historical factors favoring admixture between individuals with different African origins in the New World. This is consistent with the excess of West-Central Africa ancestry (the most prevalent in the Americas) in the US and Southeast-Brazil, respect to historical-demography expectations. Also, in most of the Americas, admixture intensification occurred between 1,750 and 1,850, which correlates strongly with the peak of arrivals from Africa. This study contributes with a population genetics perspective to the ongoing social, cultural and political debate regarding ancestry, race, and admixture in the Americas.

Significance Statement

Differently from most genetic studies, that have estimated the overall African ancestry in the Americas, we perform a finer geographic analysis and infer how different African groups contributed to North-, South-American and Caribbean populations, in the context of geographic and geopolitical factors. We also perform a formal comparison of information from demographic history records of the Transatlantic Slave Trade with inferences based on genomic diversity of current populations. Our approach reveals the distinct regional African ancestry roots of different populations from North-, South-America and the Caribe and other important aspects of the historical process of mestizaje and its dynamics in the American continent.
Selection of sequence motifs and generative Hopfield-Potts models for protein families
Authors: Shimagaki Kai , Weigt Martin
Published: May 2019

Statistical models for families of evolutionary related proteins have recently gained interest: in particular pairwise Potts models, as those inferred by the Direct-Coupling Analysis, have been able to extract information about the three-dimensional structure of folded proteins, and about the effect of amino-acid substitutions in proteins. These models are typically requested to reproduce the one- and two-point statistics of the amino-acid usage in a protein family, i.e. to capture the so-called residue conservation and covariation statistics of proteins of common evolutionary origin. Pairwise Potts models are the maximum-entropy models achieving this. While being successful, these models depend on huge numbers of ad hoc introduced parameters, which have to be estimated from finite amount of data and whose biophysical interpretation remains unclear. Here we propose an approach to parameter reduction, which is based on selecting collective sequence motifs. It naturally leads to the formulation of statistical sequence models in terms of Hopfield-Potts models. These models can be accurately inferred using a mapping to restricted Boltzmann machines and persistent contrastive divergence. We show that, when applied to protein data, even 20-40 patterns are sufficient to obtain statistically close-to-generative models. The Hopfield patterns form interpretable sequence motifs and may be used to clusterize amino-acid sequences into functional sub-families. However, the distributed collective nature of these motifs intrinsically limits the ability of Hopfield-Potts models in predicting contact maps, showing the necessity of developing models going beyond the Hopfield-Potts models discussed here.
Spatial organization of cells and variable expression of autophagy, apoptosis, and neurodevelopmental genes might underlie selective brain region vulnerability in Attention-Deficit/Hyperactivity Disorder
Authors: Hess Jonathan L. , Radonjić Nevena V. , Patak Jameson , Glatt Stephen J. , Faraone Stephen V.
Published: May 2019

Genetically influenced changes in brain organization occur over the course of development. Large-scale brain imaging studies by the ENIGMA Consortium identified structural changes associated with attention-deficit/hyperactivity disorder (ADHD). It is not clear why some brain regions are impaired and others spared by the etiological risks for ADHD. We hypothesized that spatial variation in brain cell organization and/or pathway expression levels contribute to selective brain region vulnerability (SBRV) in ADHD. In this study, we used the largest available collection of imaging results from the ADHD ENIGMA Consortium along with high-resolution postmortem brain microarray data from Allen Brain Atlas from 22 sub-cortical and cortical brain regions to investigate our selective brain region vulnerability (SBRV) hypothesis. We performed deconvolution of the bulk transcriptomic data to determine abundances of neuronal and non-neuronal cells in the brain. We then assessed the relationships between gene set expression levels, cell abundance, and standardized effect sizes representing regional changes in brain sizes in cases of ADHD. Our analysis yielded significant correlations between apoptosis, autophagy, and neurodevelopment genes with reductions in regional brain sizes in ADHD, along with associations to regional abundances of dopaminergic neurons, astrocytes, oligodendrocytes, and neural progenitor cells. This works provides novel mechanistic insights into SBRV in ADHD.
Evolution of Larval Segment Position across 12DrosophilaSpecies
Authors: Kalay Gizem , Atallah Joel , Sierra Noemie C. , Tang Austin M. , Crofton Amanda E. , Murugesan Mohan K. , Wykoff-Clary Sherri , Lott Susan E.
Published: May 2019

Many developmental traits that are critical to the survival of the organism are also robust. These robust traits are resistant to phenotypic change in the face of variation. This presents a challenge to evolution. In this paper, we asked whether and how a well-established robust trait,Drosophilasegment patterning, changed over the evolutionary history of the genus. We compared segment position scaled to body length at the first-instar larval stage among 12Drosophilaspecies. We found that relative segment position has changed many times across the phylogeny. Changes were frequent, but primarily small in magnitude. Phylogenetic analysis demonstrated that rates of change in segment position are variable along theDrosophilaphylogenetic tree, and that these changes can occur in short evolutionary timescales. Correlation between position shifts of segments decreased as the distance between two segments increased, suggesting local control of segment position. The posterior-most abdominal segment showed the highest magnitude of change on average, had the highest rate of evolution between species, and appeared to be evolving more independently as compared to the rest of the segments. This segment was exceptionally elongated in the cactophilic species in our dataset, raising questions as to whether this change may be adaptive.
A common molecular basis to the convergent evolution of the selfing syndrome in Capsella
Authors: Woźniak Natalia Joanna , Kappel Christian , Marona Cindy , Altschmied Lothar , Neuffer Barbara , Sicard Adrien
Published: May 2019

Whether, and to what extent, phenotypic evolution follows predictable genetic paths, remains an important question in evolutionary biology. Convergent evolution of similar characters provides a unique opportunity to address this question. The transition to selfing and the associated changes in flower morphology are among the most prominent examples of repeated evolution in plants. Yet, to date no studies have directly compared the extent of similarities between convergent adaptations to selfing. In this study, we take advantage of the independent transitions to self-fertilization in the genus Capsella to test the existence of genetic and developmental constraints imposed on flower evolution in the context of the selfing syndrome. While C. rubella and C. orientalis have emerged independently, both have evolved almost identical flower characters. Not only the evolutionary outcome is identical but, in both cases, the same developmental strategies underlie the convergent reduction of flower size. This has been associated with convergent evolution of gene-expression changes. The transcriptomic changes common to both selfing lineages are enriched in genes with low-network connectivity and with organ-specific expression patterns. Comparative genetic mapping also indicates that, at least in the case of petal size evolution, these similarities are largely caused by mutations at the same loci. Together, these results suggest that the limited availability of low-pleiotropy paths predetermine closely related species to similar evolutionary outcomes.