bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Upper Aging Blepharoplasty on Upper and Lower Eyelid Position
Authors: Park Jinhwan , Choi Boyoon , Baek Sehyun
Published: February 2018

Purpose:

Change in eyelid position after upper blepharoplasty is an important factor that can affect postoperative patient satisfaction. However, no one has investigated eyelid changes during follow-up for upper eyelid surgery. Thus, the purpose of this study was to investigate position changes in the upper and lower eyelids during the follow-up period after upper blepharoplasty in Korean.

Methods:

The authors retrospectively reviewed the clinical records of patients who underwent upper blepharoplasty for uncomplicated upper eyelid dermatochalasis. Digital photographs were taken preoperatively, immediately after surgery, and at 1 week postoperative, 1 month postoperative, and 3 months postoperative. Our main-effect variables were marginal reflex distance (MRD) 1 and 2 and palpebral fissure height (PFH), which were measured from digital photographs using ImageJ software.

Results:

We enrolled 180 eyes from 90 patients (M: 35 and F: 55) with a mean age of 63.8 ± 10.3 years. The eyelid measurements (MRD1, MRD2, PFH) taken preoperatively, immediately after surgery, and 1 week, 1 month, and 3 months postoperative were, respectively: MRD1 (mm): 2.56 ± 1.08, 1.91 ± 0.86, 2.21 ± 1.02, 2.66 ± 1.01, 2.75 ± 0.99; MRD2 (mm): 4.91 ± 0.93, 4.62 ± 0.87, 4.68 ± 0.90, 4.87 ± 0.86, 4.91 ± 0.83; and PFH (mm): 7.48 ± 1.64, 6.53 ± 1.46, 6.89 ± 1.53, 7.52 ± 1.51, 7.65 ± 1.49. All postoperative measurements for MRD1 and PFH were significantly different from the preoperative measurement, except for measurements taken 1 month postoperative. MRD2 measurements differed significantly from the preoperative measurements immediately after surgery and 1 week postoperative. Among age, preoperative PFH, and amount of skin-muscle resection, only preoperative PFH significantly affected PFH changes immediately after surgery and at 3 months postoperative (OR 0.636, 95% CI 0.478–0.847, OR 0.506, 95% CI 0.386–0.663).

Conclusion:

All eyelid measurements (MRD1, MRD2, and PFH) decreased 1 week postoperatively from values immediately after surgery, but MRD1 and PFH increased slightly 3 months postoperative. We note that postoperative changes in PFH may be large in patients with large PFH before blepharoplasty. It should also be noted that reverse ptosis of the lower eyelid occurs immediately after upper eyelid surgery.
Disparities in Rates of Surgical Intervention Among Racial and Ethnic Minorities in Medicare Accountable Care Organizations
Authors: Schoenfeld Andrew J. , Sturgeon Daniel J. , Dimick Justin B. , Bono Christopher M. , Blucher Justin A. , Barton Lauren B. , Weissman Joel S. , Haider Adil H.
Published: February 2018

Objective:

To assess the effect of Accountable Care Organizations (ACOs) on the use of surgical services among racial and ethnic minorities.

Background:

Health reform efforts were expected to reduce healthcare disparities. The impact of ACOs on existing disparities in access to surgical care remains unknown.

Methods:

We used national Medicare data (2009–2014) to compare rates of surgery among white, African American, Hispanic, and Asian Medicare beneficiaries for coronary artery bypass grafting, colectomy, total hip arthroplasty, hip fracture repair, and lumbar spine surgery. We performed a pre-post difference in differences analysis between African American, Hispanic, and Asian patients receiving surgical care in ACO and non-ACO organizations before and after the implementation of ACOs. The time period 2009 to 2011 was considered the pre-ACO period, and 2012 to 2014 the post-ACO period.

Results:

Rates of surgical intervention in the ACO cohort were significantly lower (P < 0.001) as compared to non-ACOs for whites, African Americans, Hispanics, and Asians in both the pre- and post-ACO periods. There was no significant difference in the adjusted change in the rate of surgical interventions among minority patients as compared to whites in ACOs and non-ACOs between 2009 to 2011 and 2012 to 2014. The odds of receiving surgical intervention were lowest for minority patients in ACOs during the post-ACO period (P < 0.001).

Conclusions:

We found persistent differences in the use of surgery among racial and ethnic minorities between the time periods 2009 to 2011 and 2012 to 2014. These disparities were not impacted by the formation of ACOs. Programs that specifically incentivize ACOs to improve surgical access for minorities may be necessary.
Successful escape of bombardier beetles from predator digestive systems
Authors: Sugiura Shinji , Sato Takuya
Published: February 2018

Some prey animals can escape from the digestive systems of predators after being swallowed. To clarify the ecological factors that determine the success of such an escape, we investigated how the bombardier beetle
Pheropsophus jessoensis
escapes from two toad species,
Bufo japonicus
and
B
.
torrenticola
, under laboratory conditions.
Pheropsophus jessoensis
ejects a hot chemical spray from the tip of the abdomen when it is attacked. Although all toads swallowed the bombardier beetles, 43% of the toads vomited the beetles 12–107 min after swallowing them. All the vomited beetles were still alive and active. Our experiment showed that
P
.
jessoensis
ejected hot chemicals inside the toads, thereby forcing the toads to vomit. Large beetles escaped more frequently than small beetles, and small toads vomited the beetles more frequently than large toads. Our results demonstrate the importance of the prey–predator size relationship in the successful escape of prey from inside a predator.
Fabrication and electromagnetic performance of talc/NiTiO
3
composite
Authors: Qin Wen-Li , Xia Tian , Ye Ying , Zhang Ping-Ping
Published: February 2018

In this study, the electromagnetic (EM) performance of talc/NiTiO
3
composite was evaluated. The morphology of talc displayed a lamella structure; there were many nanoparticles of NiTiO
3
coated on the talc lamella
.
Thermal destruction occurred, which increased the surface area from 2.51 m
2
 g
−1
to 79.09 m
2
 g
−1
at the calcined stage at 650°C. The presence of NiTiO
3
increased dielectric loss and magnetic loss of talc. The calculation of EM wave absorption of talc/NiTiO
3
obtained a maximum reflection loss of −11.94 dB at the thickness of 6.85 mm; the optimum thickness for microwave absorption is 6.3–7.3 mm. This study revealed a new approach for fabricating an EM absorber and broadening applications of both talc and NiTiO
3
in EM absorption.
External immunity in ant societies: sociality and colony size do not predict investment in antimicrobials
Authors: Penick Clint A. , Halawani Omar , Pearson Bria , Mathews Stephanie , López-Uribe Margarita M. , Dunn Robert R. , Smith Adrian A.
Published: February 2018

Social insects live in dense groups with a high probability of disease transmission and have therefore faced strong pressures to develop defences against pathogens. For this reason, social insects have been hypothesized to invest in antimicrobial secretions as a mechanism of external immunity to prevent the spread of disease. However, empirical studies linking the evolution of sociality with increased investment in antimicrobials have been relatively few. Here we quantify the strength of antimicrobial secretions among 20 ant species that cover a broad spectrum of ant diversity and colony sizes. We extracted external compounds from ant workers to test whether they inhibited the growth of the bacterium
Staphylococcus epidermidis
. Because all ant species are highly social, we predicted that all species would exhibit some antimicrobial activity and that species that form the largest colonies would exhibit the strongest antimicrobial response. Our comparative approach revealed that strong surface antimicrobials are common to particular ant clades, but 40% of species exhibited no antimicrobial activity at all. We also found no correlation between antimicrobial activity and colony size. Rather than relying on antimicrobial secretions as external immunity to control pathogen spread, many ant species have probably developed alternative strategies to defend against disease pressure.
Discovery of benzothiazolylquinoline conjugates as novel human A
3
receptor antagonists: biological evaluations and molecular docking studies
Authors: Sarkar Bidisha , Maiti Santanu , Jadhav Gajanan Raosaheb , Paira Priyankar
Published: February 2018

Adenosine is known as an endogenous purine nucleoside and it modulates a wide variety of physiological responses by interacting with adenosine receptors. Among the four adenosine receptor subtypes, the A
3
receptor is of major interest in this study as it is overexpressed in some cancer cell lines. Herein, we have highlighted the strategy of designing the
h
A
3
receptor targeted novel benzothiazolylquinoline scaffolds. The radioligand binding data of the reported compounds are rationalized with the molecular docking results. Compound
6a
showed best potency and selectivity at
h
A
3
among other adenosine receptors.
Evaluating the personality structure of semi-captive Asian elephants living in their natural habitat
Authors: Seltmann Martin W. , Helle Samuli , Adams Mark J. , Mar Khyne U , Lahdenperä Mirkka
Published: February 2018

Data on personality for long-lived, highly social wild mammals with high cognitive abilities are rare. We investigated the personality structure of Asian elephants (Elephas maximus) by using a large sample of semi-captive timber elephants in Myanmar. Data were collected during 2014–2017 using questionnaires, for which elephant riders (mahouts) rated 28 behavioural adjectives of elephants. Repeated questionnaires were obtained for each elephant from several raters whenever possible, resulting in 690 ratings of 150 female and 107 male elephants. We started by performing a confirmatory factor analysis to compare the fit of our data to a previously published captive elephant personality structure. Owing to a poor fit of this model to our data, we proceeded by performing explanatory factor analysis to determine the personality structure in our study population. This model suggested that personality in these elephants was manifested as three factors that we labelled as Attentiveness, Sociability and Aggressiveness. This structure did not differ between the sexes. These results provide the basis for future research on the link between personality and reproductive success in this endangered species and more generally, help to resolve the selective pressures on personalities in long-lived, highly social species.
Equal-area criterion in power systems revisited
Authors: Sun Yong , Ma Jinpeng , Kurths Jürgen , Zhan Meng
Published: February 2018

The classic equal-area criterion (EAC) is of key importance in power system analysis, and provides a powerful, pictorial and quantitative means of analysing transient stability (i.e. the system's ability to maintain stable operation when subjected to a large disturbance). Based on the traditional EAC, it is common sense in engineering that there is a critical cleaning time (CCT); namely, a power system is stable (unstable) if a fault is cleared before (after) this CCT. We regard this form of CCT as bipartite. In this paper, we revisit the EAC theory and, surprisingly, find different kinds of transient stability behaviour. Based on these analyses, we discover that the bipartite CCT is only one type among four major types, and, actually, the forms of CCT can be diversified. In particular, under some circumstances, a system may have no CCT or show a periodic CCT. Our theoretical analysis is verified by numerical simulations in a single-machine-infinite-bus system and also in multi-machine systems. Thus, our study provides a panoramic framework for diverse transient stability behaviour in power systems and also may have a significant impact on applications of multi-stability in various other systems, such as neuroscience, climatology or photonics.
How the formation of amyloid plaques and neurofibrillary tangles may be related: a mathematical modelling study
Authors: Kuznetsov I. A. , Kuznetsov A. V.
Published: February 2018

We develop a mathematical model that enables us to investigate possible mechanisms by which two primary markers of Alzheimer's disease (AD), extracellular amyloid plaques and intracellular tangles, may be related. Our model investigates the possibility that the decay of anterograde axonal transport of amyloid precursor protein (APP), caused by toxic tau aggregates, leads to decreased APP transport towards the synapse and APP accumulation in the soma. The developed model thus couples three processes: (i) slow axonal transport of tau, (ii) tau misfolding and agglomeration, which we simulated by using the Finke–Watzky model and (iii) fast axonal transport of APP. Because the timescale for tau agglomeration is much larger than that for tau transport, we suggest using the quasi-steady-state approximation for formulating and solving the governing equations for these three processes. Our results suggest that misfolded tau most likely accumulates in the beginning of the axon. The analysis of APP transport suggests that APP will also likely accumulate in the beginning of the axon, causing an increased APP concentration in this region, which could be interpreted as a ‘traffic jam’. The APP flux towards the synapse is significantly reduced by tau misfolding, but not due to the APP traffic jam, which can be viewed as a symptom, but rather due to the reduced affinity of kinesin-1 motors to APP-transporting vesicles.
The ductile/brittle transition provides the critical test for materials failure theory
Authors: Christensen Richard M.
Published: February 2018

It is reasoned that any materials failure theory that claims generality must give full account of ductile versus brittle failure behaviour. Any such proposed theory especially must admit the capability to generate the ductile/brittle transition. A derivation of the failure surface orientations from a particular isotropic materials failure theory reveals that uniaxial tension has its ductile/brittle transition at
T
/
C
 = 1/2, where
T
and
C
are the uniaxial strengths. Between this information and the corresponding ductile/brittle transition in uniaxial compression it becomes possible to derive the functional form for the fully three-dimensional ductile/brittle transition. These same general steps of verification must be fulfilled for any other candidate general failure theory.
Evidence for parent-of-origin effects and interparental conflict in seeds of an ancient flowering plant lineage
Authors: Povilus Rebecca A. , Diggle Pamela K. , Friedman William E.
Published: February 2018

Theoretical and empirical studies have long connected the evolutionary innovation of endosperm, a genetically biparental product of a double fertilization process unique to flowering plants (angiosperms), to conflicting parental interests over offspring provisioning. Yet, none of these studies examined interparental conflict in representatives of any of the most ancient angiosperm lineages. We performed reciprocal interploidy crosses in the water lilyNymphaea thermarum, a member of one of the most ancient angiosperm lineages, Nymphaeales. We find that an excess of paternal genomes is associated with an increase in endosperm growth. By contrast, maternal ploidy negatively influences development or growth of all seed components, regardless of paternal genome dosage. Most relevant to the conflict over distribution of maternal resources, however, is that growth of the perisperm (seed storage tissue derived from the maternal sporophyte, found in all Nymphaeales) is unaffected by paternal genome dosage—ensuring maternal control of maternal resources. We conclude that the evolutionary transfer of embryo-nourishing function from a genetically biparental endosperm to a genetically maternal perisperm can be viewed as an effective maternal strategy to recapture control of resource distribution among progeny, and thus that interparental conflict has influenced the evolution of seed development in this ancient angiosperm lineage.
Genomics of end-Pleistocene population replacement in a small mammal
Authors: Kotlík Petr , Marková Silvia , Konczal Mateusz , Babik Wiesław , Searle Jeremy B.
Published: February 2018

Current species distributions at high latitudes are the product of expansion from glacial refugia into previously uninhabitable areas at the end of the last glaciation. The traditional view of postglacial colonization is that southern populations expanded their ranges into unoccupied northern territories. Recent findings on mitochondrial DNA (mtDNA) of British small mammals have challenged this simple colonization scenario by demonstrating a more complex genetic turnover in Britain during the Pleistocene–Holocene transition where one mtDNA clade of each species was replaced by another mtDNA clade of the same species. Here, we provide evidence from one of those small mammals, the bank vole (Clethrionomys glareolus), that the replacement was genome-wide. Using more than 10 000 autosomal SNPs we found that similar to mtDNA, bank vole genomes in Britain form two (north and south) clusters which admix. Therefore, the genome of the original postglacial colonists (the northern cluster) was probably replaced by another wave of migration from a different continental European population (the southern cluster), and we gained support for this by modelling with approximate Bayesian computation. This finding emphasizes the importance of analysis of genome-wide diversity within species under changing climate in creating opportunities for sophisticated testing of population history scenarios.
Repeatable group differences in the collective behaviour of stickleback shoals across ecological contexts
Authors: Jolles Jolle W. , Laskowski Kate L. , Boogert Neeltje J. , Manica Andrea
Published: February 2018

Establishing how collective behaviour emerges is central to our understanding of animal societies. Previous research has highlighted how universal interaction rules shape collective behaviour, and that individual differences can drive group functioning. Groups themselves may also differ considerably in their collective behaviour, but little is known about the consistency of such group variation, especially across different ecological contexts that may alter individuals' behavioural responses. Here, we test if randomly composed groups of sticklebacks differ consistently from one another in both their structure and movement dynamics across an open environment, an environment with food, and an environment with food and shelter. Based on high-resolution tracking data of the free-swimming shoals, we found large context-associated changes in the average behaviour of the groups. But despite these changes and limited social familiarity among group members, substantial and predictable behavioural differences between the groups persisted both within and across the different contexts (group-level repeatability): some groups moved consistently faster, more cohesively, showed stronger alignment and/or clearer leadership than other groups. These results suggest that among-group heterogeneity could be a widespread feature in animal societies. Future work that considers group-level variation in collective behaviour may help understand the selective pressures that shape how animal collectives form and function.
How oxygen gave rise to eukaryotic sex
Authors: Hörandl Elvira , Speijer Dave
Published: February 2018

How did full meiotic eukaryotic sex evolve and what was the
immediate
advantage allowing it to develop? We propose that the crucial determinant can be found in internal reactive oxygen species (ROS) formation at the start of eukaryotic evolution approximately 2 × 10
9
years ago. The large amount of ROS coming from a bacterial endosymbiont gave rise to DNA damage and vast increases in host genome mutation rates. Eukaryogenesis and chromosome evolution represent adaptations to oxidative stress. The host, an archaeon, most probably already had repair mechanisms based on DNA pairing and recombination, and possibly some kind of primitive cell fusion mechanism. The detrimental effects of internal ROS formation on host genome integrity set the stage allowing evolution of meiotic sex from these humble beginnings. Basic meiotic mechanisms thus probably evolved in response to endogenous ROS production by the ‘pre-mitochondrion’. This alternative to mitosis is crucial under novel, ROS-producing stress situations, like extensive motility or phagotrophy in heterotrophs and endosymbiontic photosynthesis in autotrophs. In multicellular eukaryotes with a germline–soma differentiation, meiotic sex with diploid–haploid cycles improved efficient purging of deleterious mutations. Constant pressure of endogenous ROS explains the ubiquitous maintenance of meiotic sex in practically all eukaryotic kingdoms. Here, we discuss the relevant observations underpinning this model.
Dynamic simulations of many-body electrostatic self-assembly
Authors: Lindgren Eric B. , Stamm Benjamin , Maday Yvon , Besley Elena , Stace A. J.
Published: February 2018

Two experimental studies relating to electrostatic self-assembly have been the subject of dynamic computer simulations, where the consequences of changing the charge and the dielectric constant of the materials concerned have been explored. One series of calculations relates to experiments on the assembly of polymer particles that have been subjected to tribocharging and the simulations successfully reproduce many of the observed patterns of behaviour. A second study explores events observed following collisions between single particles and small clusters composed of charged particles derived from a metal oxide composite. As before, observations recorded during the course of the experiments are reproduced by the calculations. One study in particular reveals how particle polarizability can influence the assembly process.

This article is part of the theme issue ‘Modern theoretical chemistry’.
C

n

(
n
=2−4): current status
Authors: Varandas A. J. C. , Rocha C. M. R.
Published: February 2018

The major aspects of the C
2
, C
3
and C
4
elemental carbon clusters are surveyed. For C
2
, a brief analysis of its current status is presented. Regarding C
3
, the most recent results obtained in our group are reviewed with emphasis on modelling its potential energy surface which is particularly complicated due to the presence of multiple conical intersections. As for C
4
, the most stable isomeric forms of both triplet and singlet spin states and their possible interconversion pathways are examined afresh by means of accurate
ab initio
calculations. The main strategies for modelling the ground triplet C
4
potential are also discussed. Starting from a truncated cluster expansion and a previously reported DMBE form for C
3
, an approximate four-body term is calibrated from the
ab initio
energies. The final six-dimensional global DMBE form so obtained reproduces all known topographical aspects while providing an accurate description of the C
4
linear–rhombic isomerization pathway. It is therefore commended for both spectroscopic and reaction dynamics studies.

This article is part of the theme issue ‘Modern theoretical chemistry’.
Application of one-dimensional semiclassical transition state theory to the CH
3
OH + H ⇌ CH
2
OH/CH
3
O + H
2
reactions
Authors: Shan Xiao , Clary David C.
Published: February 2018

The rate constants of the two branches of H-abstractions from CH
3
OH by the H-atom and the corresponding reactions in the reverse direction are calculated using the one-dimensional semiclassical transition state theory (1D SCTST). In this method, only the reaction mode vibration of the transition state (TS) is treated anharmonically, while the remaining internal degrees of freedom are treated as they would have been in a standard TS theory calculation. A total of eight
ab initio
single-point energy calculations are performed in addition to the computational cost of a standard TS theory calculation. This allows a second-order Richardson extrapolation method to be employed to improve the numerical estimation of the third- and fourth-order derivatives, which in turn are used in the calculation of the anharmonic constant. Hindered-rotor (HR) vibrations are identified in the equilibrium states of CH
3
OH
and CH
2
OH, and the TSs of the reactions. The partition function of the HRs are calculated using both a simple harmonic oscillator model and a more sophisticated one-dimensional torsional eigenvalue summation (1D TES) method. The 1D TES method can be easily adapted in 1D SCTST computation. The resulting 1D SCTST with 1D TES rate constants show good agreement to previous theoretical and experimental works. The effects of the HR on rate constants for different reactions are also investigated.

This article is part of the theme issue ‘Modern theoretical chemistry’.
High-accuracy water potential energy surface for the calculation of infrared spectra
Authors: Mizus Irina I. , Kyuberis Aleksandra A. , Zobov Nikolai F. , Makhnev Vladimir Yu. , Polyansky Oleg L. , Tennyson Jonathan
Published: February 2018

Transition intensities for small molecules such as water and CO
2
can now be computed with such high accuracy that they are being used to systematically replace measurements in standard databases. These calculations use high-accuracy
ab initio
dipole moment surfaces and wave functions from spectroscopically determined potential energy surfaces (PESs). Here, an extra high-accuracy PES of the water molecule (H
2
16
O) is produced starting from an
ab initio
PES which is then refined to empirical rovibrational energy levels. Variational nuclear motion calculations using this PES reproduce the fitted energy levels with a standard deviation of 0.011 cm
−1
, approximately three times their stated uncertainty. The use of wave functions computed with this refined PES is found to improve the predicted transition intensities for selected (problematic) transitions. A new room temperature line list for H
2
16
O is presented. It is suggested that the associated set of line intensities is the most accurate available to date for this species.

This article is part of the theme issue ‘Modern theoretical chemistry’.
Kinetics and dynamics of near-resonant vibrational energy transfer in gas ensembles of atmospheric interest
Authors: McCaffery Anthony J.
Published: February 2018

This study of near-resonant, vibration–vibration (V–V) gas-phase energy transfer in diatomic molecules uses the theoretical/computational method, of Marsh & McCaffery (Marsh & McCaffery 2002J. Chem. Phys.117, 503 (doi:10.1063/1.1489998)) The method uses the angular momentum (AM) theoretical formalism to compute quantum-state populations within the component molecules of large, non-equilibrium, gas mixtures as the component species proceed to equilibration. Computed quantum-state populations are displayed in a number of formats that reveal the detailed mechanism of the near-resonant V–V process. Further, the evolution of quantum-state populations, for each species present, may be followed as the number of collision cycles increases, displaying the kinetics of evolution for each quantum state of the ensemble's molecules. These features are illustrated for ensembles containing vibrationally excited N2in H2, O2and N2initially in their ground states.

This article is part of the theme issue ‘Modern theoretical chemistry’.
Hartree–Fock implementation using a Laguerre-based wave function for the ground state and correlation energies of two-electron atoms
Authors: King Andrew W. , Baskerville Adam L. , Cox Hazel
Published: February 2018

An implementation of the Hartree–Fock (HF) method using a Laguerre-based wave function is described and used to accurately study the ground state of two-electron atoms in the fixed nucleus approximation, and by comparison with fully correlated (FC) energies, used to determine accurate electron correlation energies. A variational parameter
A
is included in the wave function and is shown to rapidly increase the convergence of the energy. The one-electron integrals are solved by series solution and an analytical form is found for the two-electron integrals. This methodology is used to produce accurate wave functions, energies and expectation values for the helium isoelectronic sequence, including at low nuclear charge just prior to electron detachment. Additionally, the critical nuclear charge for binding two electrons within the HF approach is calculated and determined to be
Z
HF
C
=1.031 177 528.

This article is part of the theme issue ‘Modern theoretical chemistry’.
Isomers and energy landscapes of micro-hydrated sulfite and chlorate clusters
Authors: Hey John C. , Doyle Emily J. , Chen Yuting , Johnston Roy L.
Published: February 2018

We present putative global minima for the micro-hydrated sulfite SO
3
2−
(H
2
O)

N

and chlorate ClO
3
−
(H
2
O)

N

systems in the range 3≤
N
≤15 found using basin-hopping global structure optimization with an empirical potential. We present a structural analysis of the hydration of a large number of minimized structures for hydrated sulfite and chlorate clusters in the range 3≤
N
≤50. We show that sulfite is a significantly stronger net acceptor of hydrogen bonding within water clusters than chlorate, completely suppressing the appearance of hydroxyl groups pointing out from the cluster surface (dangling OH bonds), in low-energy clusters. We also present a qualitative analysis of a highly explored energy landscape in the region of the global minimum of the eight water hydrated sulfite and chlorate systems.

This article is part of the theme issue ‘Modern theoretical chemistry’.
Modulation of slow and fast oscillations by direct current stimulation in the cerebral cortex in vitro
Authors: D’Andola Mattia , Weinert Julia F. , Mattia Maurizio , Sanchez-Vives Maria V.
Published: February 2018

Non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), play a growing role in the treatment of neurological disorders. However, the mechanisms by which electric fields modulate cortical network activity are only partially understood. To explore the spatiotemporal modulation of cortical activity by electric fields (DC fields), we exposed neocortical slices to constant fields of varying intensity and direction and we measured their effect on the low (<1 Hz) and high frequencies (beta 15-30 Hz and gamma 30-90 Hz) of spontaneously generated cortical oscillations. Slow oscillations consist of Up (active) and Down (silent) states. We found that DC fields ranging from -6 to +6 V/m induced an exponential increase in the frequency of slow oscillations through the regulation of the excitability and duration of Down states, while hardly affecting Up states duration. A computational model based on the mean-field theory of attractor dynamics provided a mechanistic and quantitative description of the network dynamics underlying such precise modulation of slow oscillatory frequency. The modulation of high frequencies by DC fields was less consistent, the high frequency power varying with the intensity of the fields only in a fraction of slices. Interestingly, negative DC fields of increasing intensities progressively and effectively reversed the increase in high frequency power induced by kainate application. Our findings have implications for the understanding of cortical oscillations and the mechanisms by which they are modulated by DC fields and may contribute to the future development of tools with an accurate spatiotemporal control of cortical activity.

Significance statement

Acting on the brain through electrical stimulation in order to correct dysfunctions or to induce functional recovery is a relatively common technique nowadays used in the clinical realm. In spite of the existence of previous studies on the effect of electric fields on neuronal and network physiology, questions regarding the mechanisms underlying exogenous electrical modulation of cortical dynamics still remain open. We demonstrate that continuous electric fields between -6 and +6 V/m induce a precise modulation of slow and fast cortical rhythms. Based on both experimental evidence and theoretical analysis, we describe some of the mechanistic underpinnings at play and provide useful information for the development of tools with better spatiotemporal control of cortical activity.
A nonlinear updating algorithm captures suboptimal inference in the presence of signal-dependent noise
Authors: Egger Seth W. , Jazayeri Mehrdad
Published: February 2018

Bayesian models of behavior have advanced the idea that humans combine prior beliefs and sensory observations to minimize uncertainty. How the brain implements Bayes-optimal inference, however, remains poorly understood. Simple behavioral tasks suggest that the brain can flexibly represent and manipulate probability distributions. An alternative view is that brain relies on simple algorithms that can implement Bayes-optimal behavior only when the computational demands are low. To distinguish between these alternatives, we devised a task in which Bayes-optimal performance could not be matched by simple algorithms. We asked subjects to estimate and reproduce a time interval by combining prior information with one or two sequential measurements. In the domain of time, measurement noise increases with duration. This property makes the integration of multiple measurements beyond the reach of simple algorithms. We found that subjects were able to update their estimates using the second measurement but their performance was suboptimal, suggesting that they were unable to update full probability distributions. Instead, subjects’ behavior was consistent with an algorithm that predicts upcoming sensory signals, and applies a nonlinear function to errors in prediction to update estimates. These results indicate that inference strategies humans deploy may deviate from Bayes-optimal integration when the computational demands are high.
Single-cell analysis of progenitor cell dynamics and lineage specification of the human fetal kidney
Authors: Menon Rajasree , Otto Edgar A. , Kokoruda Austin , Zhou Jian , Zhang Zidong , Yoon Euisik , Chen Yu-Chih , Troyanscaya Olga , Spence Jason R. , Kretzler Matthias , Cebrián Cristina
Published: February 2018

The mammalian kidney develops through repetitive and reciprocal interactions between the ureteric bud and the metanephric mesenchyme to give rise to the entire collecting system and the nephrons, respectively. Most of our knowledge of the developmental regulators driving this process has been gained from the study of gene expression and functional genetics in mice and other animal models. In order to shed light on human kidney development, we have used singlecell transcriptomics to characterize gene expression in different cell population, and to study individual cell dynamics and lineage trajectories during development. Single cell transcriptome analyses of 3,865 cells identified 17 clusters of specific cell types as defined by their gene expression profile, including markers of ureteric bud tip- and metanephric mesenchyme-specific progenitors, as well as their intermediate and differentiated lineages including the mature collecting ducts, the renal vesicle and comma- and s-shaped bodies, immature and mature podocytes, proximal tubules, loops of Henle and distal tubules. Other lineages identified include mesangium and cortical and medullary interstitium, endothelial and immune cells as well as hematopoietic cells. Novel markers for these cell types were revealed in the analysis as well as components of key signaling pathways driving renal development in animal models. Altogether, we provide a comprehensive and dynamic gene expression array of the human developing kidney at the single-cell level.
Modeling Polypharmacy Side Effects with Graph Convolutional Networks
Authors: Zitnik Marinka , Agrawal Monica , Leskovec Jure
Published: February 2018

Motivation: The use of drug combinations, termed polypharmacy, is common to treat patients with complex diseases or co-existing conditions. However, a major consequence of polypharmacy is a much higher risk of adverse side effects for the patient. Polypharmacy side effects emerge because of drug-drug interactions, in which activity of one drug may change, favorably or unfavorably, if taken with another drug. The knowledge of drug interactions is often limited because these complex relationships are rare, and are usually not observed in relatively small clinical testing. Discovering polypharmacy side effects thus remains an important challenge with significant implications for patient mortality and morbidity.

Results: Here, we present Decagon, an approach for modeling polypharmacy side effects. The approach constructs a multimodal graph of protein-protein interactions, drug-protein target interactions, and the polypharmacy side effects, which are represented as drug-drug interactions, where each side effect is an edge of a different type. Decagon is developed specifically to handle such multimodal graphs with a large number of edge types. Our approach develops a new graph convolutional neural network for multirelational link prediction in multimodal networks. Unlike approaches limited to predicting simple drug-drug interaction values, Decagon can predict the exact side effect, if any, through which a given drug combination manifests clinically. Decagon accurately predicts polypharmacy side effects, outperforming baselines by up to 69%. We find that it automatically learns representations of side effects indicative of co-occurrence of polypharmacy in patients. Furthermore, Decagon models particularly well polypharmacy side effects that have a strong molecular basis, while on predominantly non-molecular side effects, it achieves good performance because of effective sharing of model parameters across edge types. Decagon opens up opportunities to use large pharmacogenomic and patient population data to flag and prioritize polypharmacy side effects for follow-up analysis via formal pharmacological studies.

Availability: Source code and preprocessed datasets are at: http://snap.stanford.edu/decagon.

Contact:jure@cs.stanford.edu
Gallic Acid Disrupts Aβ1-42 Aggregation and Rescues Cognitive Decline of APP/PS1 Transgenic Mouse
Authors: Yu Mei , Chen Xuwei , Liu Jihong , Ma Quan , Chen Hao , Zhou Lin , Yang Sen , Zheng Lifeng , Ning Chengqing , Xu Jing , Gao Tianming , Hou Sheng Tao
Published: February 2018

Alzheimer’s disease (AD) treatment represents one of the largest unmet medical needs. Developing drugs capable of preventing Aβ aggregation is an excellent approach to prevent and treat AD. Here, we show that gallic acid (GA), a naturally occurring polyphenolic small molecule rich in grape seeds and fruits, has the capacity to alleviate cognitive decline of APP/PS1 transgenic mouse through reduction of Aβ1-42 aggregation and neurotoxicity. Oral administration of GA not only improved the spatial reference memory and spatial working memory of early stage AD mice (4-month-old), but also significantly reduced the more severe deficits in spatial learning, reference memory, short-term recognition and spatial working memory of the late stage AD mice (9-month-old). The hippocampal long-term-potentiation (LTP) was also significantly elevated in the GA-treated late stage APP/PS1 AD mice. Atomic force microscopy (AFM), dynamic light scattering (DLS) and thioflavin T (ThT) fluorescence densitometry analyses showed that GA can reduce Aβ1-42 aggregation from forming toxic oligomers and fibrils. Indeed, pre-incubating GA with oligomeric Aβ1-42 reduced Aβ 1-42-mediated intracellular calcium influx and neurotoxicity. Molecular docking studies identified that the 3,4,5-hydroxyle groups of GA were essential in noncovalently stabilizing GA binding to the Lys28-Ala42 salt bridge and the -COOH group is critical for disrupting the salt bridge of Aβ1-42. The predicated covalent interaction through Schiff-base formation between the carbonyl group of the oxidized product and ε-amino group of Lys16 is also critical for the disruption of Aβ1-42 S-shaped triple-β-motif and toxicity. Together, these studies demonstrated that GA can prevent and protect the AD brain through disrupting Aβ1-42 aggregation.
Super-multiplexed fluorescence microscopy via photostability contrast
Authors: Orth Antony , Ghosh Richik N. , Wilson Emma , Doughney Timothy , Brown Hannah , Reineck Philipp , Thompson Jeremy , Gibson Brant C.
Published: February 2018

Many areas of biological research rely heavily on fluorescence microscopy to observe and quantify the inner workings of the cell. Traditionally, multiple types of cellular structures or biomolecules are visualized simultaneously with spectrally distinct fluorescent labels. A high degree of multiplexing is desirable as it affords the experiment greater information content, speeding up research timelines. Multiplexing can be increased by imaging a larger number of spectral channels, however, the wide emission spectra of most fluorophores limits multiplexing to four or five labels in standard fluorescence microscopes. Further multiplexing requires another dimension of contrast. Here, we show that photostability differences can be used to distinguish between fluorescent labels. By combining photobleaching characteristics with a novel unmixing algorithm, we resolve up to three fluorescent labels in a single spectral channel and unmix fluorescent labels with nearly identical emission spectra. We apply our technique to organic dyes, autofluorescent biomolecules and fluorescent proteins, and show that the latter are particularly well suited to our method as their bleaching is often reversible. Our approach has the potential to triple the multiplexing capabilities of any digital widefield or confocal fluorescence microscope with no additional hardware, making it readily accessible to a wide range of researchers.
Two parallel pathways implement robust propionate catabolism and detoxification in mycobacteria
Authors: Tummler Katja , Zimmermann Michael , Schubert Olga T. , Aebersold Ruedi , Kühn Clemens , Sauer Uwe , Klipp Edda
Published: February 2018

Tuberculosis remains a major global health threat with over 1.5 million deaths each year. Mycobacterium tuberculosis’ success story is related to a flexible metabolism, allowing growth despite restrictive conditions within the human host.

Host lipids stores are a major carbon source in vivo. Their catabolism yields propionyl-CoA, which is processed by two parallel pathways, the methylmalonyl CoA pathway and the methylcitrate pathway. Both pathways are considered potential drug targets. The methylcitrate pathway is upregulated in the pathological context. However, intermediates of this pathway can be cytotoxic and Mtb’s preference for its usage remains unclear.

We combine thermodynamic kinetic modeling, quantitative proteomics and time-resolved metabolomics to characterize the interplay between the two pathways and to show their functionalities in an efficient and fast propionate catabolism.

We find that the methylcitrate pathway acts as a transcriptionally regulated, high capacity catabolic pathway due to its favorable thermodynamics and metabolic control distribution. In contrast, the methylmalonyl pathway is constitutively fulfilling biosynthetic tasks and can quickly detoxify propionate pulses, but is thermodynamically restricted to lower capacity.
Zebrafish sp7 mutants show tooth cycling independent of attachment, eruption and poor differentiation of teeth
Authors: Kague E , Witten P.E , Soenens M , Campos CL , Lubiana T , Fisher S , Hammond C , Robson Brown K , Passos-Bueno MR , Huysseune A
Published: February 2018

The capacity to fully replace teeth continuously makes zebrafish an attractive model to explore regeneration and tooth development. The requirement of attachment bone for the appearance of replacement teeth has been hypothesized but not yet investigated. The transcription factor sp7 (osterix) is known in mammals to play an important role during odontoblast differentiation and root formation. Here we study tooth replacement in the absence of attachment bone using sp7 zebrafish mutants. We analysed the pattern of tooth replacement at different stages of development and demonstrated that in zebrafish lacking sp7, attachment bone is never present, independent of the stage of tooth development or fish age, yet replacement is not interrupted. Without bone of attachment we observed abnormal orientation of teeth, and abnormal connection of pulp cavities of predecessor and replacement teeth. Mutants lacking sp7 show arrested dentinogenesis, with non-polarization of odontoblasts and only a thin layer of dentin deposited. Osteoclast activity was observed in sp7 mutants; due to the lack of bone of attachment, remodelling was diminished but nevertheless present along the pharyngeal bone. We conclude that tooth replacement is ongoing in the sp7 mutant despite poor differentiation and defective attachment. Without bone of attachment tooth orientation and pulp organization are compromised.
Human mediated dispersal of cats in the Neolithic Central Europe
Authors: Baca Mateusz , Popović Danijela , Panagiotopoulou Hanna , Marciszak Adrian , Krajcarz Magdalena , Krajcarz Maciej T. , Makowiecki Daniel , Węgleński Piotr , Nadachowski Adam
Published: February 2018

Archaeological and genetic evidence suggest that all domestic cats derive from the Near Eastern wildcat (Felis silvestris lybica) and were domesticated twice, first in the Near East around 10 000 years ago and for the second time in Ancient Egypt ca. 3 500 years ago. The spread of the domesticated form in Europe occurred much later, primarily mediated by Greek and Phoenician traders and afterwards by Romans who introduced cats to Western and Central Europe around 2 000 years ago. We investigated mtDNA of HoloceneFelisremains and provide evidence of an unexpectedly early presence of cats bearing the Near Eastern wildcat mtDNA haplotypes in Central Europe, being ahead of Roman Period by over 2 000 years. The appearance of the Near Eastern wildcats in Central Europe coincide with the peak of Neolithic settlement density, moreover most of those cats belonged to the same mtDNA lineages as those domesticated in the Near East. Thus, although we cannot fully exclude that the Near Eastern wildcats appeared in Central Europe as a result of introgression with European wildcat, our findings strongly support the hypothesis that the Near Eastern wildcats spread across Europe together with the first farmers, perhaps as commensal animals. We also found that cats dated to the Neolithic period belonged to different mtDNA lineages than those brought to Central Europe in Roman times, this supports the hypothesis that the gene pool of contemporary European domestic cats might have been established from two different source populations that contributed in different periods.
Rapid multi-locus sequence typing direct from uncorrected long reads using Krocus
Authors: Page Andrew J. , Keane Jacqueline A.
Published: February 2018

Genome sequencing is rapidly being adopted in reference labs and hospitals for bacterial outbreak investigation and diagnostics where time is critical. Seven gene multi-locus sequence typing is a standard tool for broadly classifying samples into sequence types, allowing, in many cases, to rule a sample in or out of an outbreak, or allowing for general characteristics about a bacterial strain to be inferred. Long read sequencing technologies, such as from PacBio or Oxford Nanopore, can produce read data within minutes of an experiment starting, unlike short read sequencing technologies which require many hours/days. However, the error rates of raw uncorrected long read data are very high. We present Krocus which can predict a sequence type directly from uncorrected long reads, and which was designed to consume read data as it is produced, providing results in minutes. It is the only tool which can do this from uncorrected long reads. We tested Krocus on over 600 samples sequenced with using long read sequencing technologies from PacBio and Oxford Nanopore. It provides sequence types on average within 90 seconds, with a sensitivity of 94% and specificity of 97%, directly from uncorrected raw sequence reads. The software is written in Python and is available under the open source license GNU GPL version 3.