bluuebunny/crossref_metadata_2025 huggingface dataset:
New Human Immunodeficiency Virus Diagnoses Among Men Who Have Sex With Men Attending Sexually Transmitted Disease Clinics, STD Surveillance Network, January 2010 to June 2013
Authors: Llata Eloisa , Braxton Jim , Asbel Lenore , Kerani Roxanne P. , Murphy Ryan , Pugsley River , Pathela Preeti , Schumacher Christina , Tabidze Irina , Weinstock Hillard S.
Published: February 2018

Objective

To estimate new human immunodeficiency virus (HIV) diagnosis rates among HIV negative men who have sex with men (MSM) who are repeatedly tested for HIV in sexually transmitted disease (STD) clinics and assess the impact of demographic and disease-specific characteristics that are associated with higher HIV diagnosis rates.

Study Design

Retrospective analysis using 2010 to 2013 data from the STD Surveillance Network (SSuN), a sentinel surveillance system comprised of health departments in 12 cities conducting sentinel surveillance in 40 STD clinics. We analyzed data from all MSM repeatedly (≥2 times) tested for HIV, with an initial negative HIV test required for staggered cohort entry. Follow-up time was accrued from the date of the first negative HIV test to the most recent negative test or the first positive HIV test. The STD diagnoses during the follow-up period were reviewed. We estimated HIV diagnoses rates (number of HIV diagnoses/total number of person-years [PY] at risk) by demographic and clinical characteristics with 95% confidence intervals (CI) using an inverse variance weighted random effects model, adjusting for heterogeneity between SSuN jurisdictions.

Results

Overall, 640 HIV diagnoses occurred among 14,824 individuals and 20,951.6 PY of observation, for an adjusted incidence of HIV diagnosis of 3.0 per 100 PY (95% CI, 2.6–3.4). Rates varied across race/ethnicity groups with the highest rate among Blacks (4.7/100 PY; 95% CI, 4.1–5.3) followed by Hispanics, whites, and persons of other races/ethnicities. Men who have sex with men having a diagnosis of primary or secondary (P&S) syphilis on or after the first negative HIV test had a higher new HIV diagnosis rate (7.2/100 PY; 95% CI, 5.8–9.0) compared with MSM who did not have a P&S syphilis diagnosis (2.8/100 PY; 95% CI, 2.6–3.1). Men who have sex with men who tested positive for rectal gonorrhea (6.3/100 PY; 95% CI, 5.7–6.9) or rectal chlamydia (5.6/100 PY; 95% CI, 4.6–6.6) had higher rates of new HIV diagnosis when compared to those with negative test results.

Conclusions

Men who have sex with men attending SSuN STD clinics have high rates of new HIV diagnoses, particularly those with a previous diagnosis of P&S syphilis, rectal chlamydia, and/or gonorrhea. Sexually transmitted disease clinics continue to be important clinical setting for diagnosing HIV among MSM populations.
Preliminary Use of the Physical and Neurological Examination of Subtle Signs for Detecting Subtle Motor Signs in Adolescents With Sport-Related Concussion
Authors: Stephens Jaclyn A. , Denckla Martha B. , McCambridge Teri , Slomine Beth S. , Mahone E. Mark , Suskauer Stacy J.
Published: February 2018

Sensitive examination tools are needed to optimize evaluation after sports-related concussion. The Physical and Neurological Examination of Subtle Signs was preliminarily examined for sensitivity to motor changes in a pilot cohort of adolescents aged 13–17 yrs with sports-related concussion. A total of 15 adolescents (5 female adolescents) with sports-related concussion were evaluated up to three times: within 2 wks of injury, approximately 1 mo later (mean, 35 days between visits), and for those not recovered at the second visit, again after clinical recovery (mean, 70 days between the first and last visits for all participants). Comparison data were acquired from 20 age- and sex-matched healthy control athletes with no history of concussion who were evaluated twice (mean, 32 days apart). Main effects of group, time, and interaction effects were evaluated with an analysis of covariance, which controlled for socioeconomic status, times tested, and days between testing sessions. Adolescents with concussion had poorer Physical and Neurological Examination of Subtle Signs performance than controls did at all time points. Performance improved between visits within the concussion group, with no change within the control group. These findings suggest that the Physical and Neurological Examination of Subtle Signs merits additional study in larger cohorts and in combination with other markers of injury to facilitate an enhanced understanding of sports-related concussion and recovery.
Femoral Artery Bypass Graft Pseudoaneurysm Rupture in a Transfemoral Amputee
Authors: Dallas Jonathan , Block John J. , Bastas Gerasimos
Published: February 2018

The case of a patient with an actively bleeding pseudoaneurysm associated with remnants of a polytetrafluoroethylene femoral bypass graft in his transfemoral residual limb is described. Initial graft placement was due to peripheral arterial disease. During subsequent transfemoral amputation, remnants of the nonpatent graft were retained in the residuum. After 4 yrs of lower limb prosthesis use, a proximal anastomosis pseudoaneurysm developed (with avulsion of graft remnants). The patient presented to clinic with a 5-day history of increased left groin fullness and largely nonradiating pain (rated 10/10). He was diagnosed with a pseudoaneurysm (1.9 cm) originating from the left common femoral artery and an associated hematoma (8 cm) on computed tomography; this required emergent reoperation. This case highlights the importance surrounding the decision to leave or explant neovascularization materials, which may carry significant risk for infection or physical disruption complications in residual limbs.
Improved Detection of Foreign Bodies on Radiographs Using X-ray Dark-Field and Phase-Contrast Imaging
Authors: Hellbach Katharina , Beller Ebba , Schindler Andreas , Schoeppe Franziska , Hesse Nina , Baumann Alena , Schinner Regina , Auweter Sigrid , Hauke Christian , Radicke Marcus , Meinel Felix G.
Published: February 2018

Purpose

The aim of this study was to investigate whether the detection of foreign bodies can be improved using dark-field and phase-contrast radiography compared with conventional (transmission) radiographs.

Materials and Methods

Experiments were performed using ex vivo pig paws, which were prepared with differently sized foreign bodies of metal, wood, and glass (n = 10 each). Paws without foreign bodies served as controls (n = 30). All images were acquired using an experimental grating-based large object radiography system. Five blinded readers (second- to fourth-year radiology residents) were asked to assess the presence or absence of any foreign body. Sensitivity and specificity for the detection of metal, wood, glass, and any foreign body were calculated and compared using McNemar test and generalized linear mixed models.

Results

Sensitivity for the detection of metal foreign bodies was 100% for all readers and image combinations. The sensitivity for the detection of wooden foreign bodies increased from 2% for transmission images to 78% when dark-field images were added (P < 0.0001). For glass foreign bodies, sensitivity increased from 84% for transmission images to 96% when adding phase-contrast images (P = 0.041). Sensitivity for the detection of any foreign body was 91% when transmission, dark-field, and phase-contrast images were viewed simultaneously, compared with 62% for transmission images alone (P < 0.0001). Specificity was 99% to 100% across all readers and radiography modalities.

Conclusions

Adding dark-field images substantially improves the detection of wooden foreign bodies compared with the analysis of conventional (transmission) radiographs alone. Detection of glass foreign bodies was moderately improved when adding phase-contrast images.
Early Response Assessed by Contrast-Enhanced Ultrasound in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy
Authors: Dong Ting
Published: February 2018

The study was aimed to investigate the role of contrast-enhanced ultrasound (CEUS) in evaluating the response of patients with breast cancer after receiving neoadjuvant chemotherapy (NAC). A systematic search was conducted in PubMed, Spring, Wanfang, and CNKI databases from 1923 to December 2016. Based on fixed effect model or randomized effects model, standardized mean difference (SMD) with its 95% confidence interval (95% CI) was calculated in accordance with heterogeneity analysis. Cochran Q and I2 tests were used to measure heterogeneity. Sensitivity analysis was performed to evaluate the strength of the meta-analysis. In total, 8 studies were enrolled in the meta-analysis. Tumor size of breast cancer was obviously decreased when evaluated by CEUS (SMD, 0.96; 95% CI, 0.76–1.15) after NAC. After aggregating the data by the fixed effect model, the CEUS time-intensity curve showed a great reduction in the area under the curve of patients receiving NAC (SMD, 0.38; 95% CI, 0.08–0.69). Based on CEUS, tumor size and area under the CEUS time-intensity curve were both reduced. We suggest that the CEUS is a promising tool for evaluating the response of breast cancer after NAC.
Myofibroblastoma of the Breast
Authors: Yilmaz Ravza , Akkavak Gulcin , Ozgur Eren , Onder Semen , Ozkurt Enver , Dursun Memduh
Published: February 2018

Myofibroblastoma (MFB) of the breast is an uncommon benign stromal tumor. Herein, we present histopathologically proven MFB that hyperechoic well-defined breast mass in the ultrasonography and circumscribed high-density mass in mammography. Additionally, internal septations and hyperintense appearance on magnetic resonance imaging are very valuable findings in the differential diagnosis of MFB.
Parasite-mediated microhabitat segregation between congeneric hosts
Authors: Friesen Olwyn C. , Poulin Robert , Lagrue Clément
Published: February 2018

Parasite-mediated competition can shape community structure and host distribution. If two species compete for resources, parasites may indirectly change the outcome of competition. We tested the role of a trematode parasite in mediating microhabitat use by congeneric isopods
Austridotea annectens
and
Austridotea lacustris
. Although both isopods share resources, they rarely co-occur in the same discrete microhabitats. We set up mesocosms with and without competition and/or parasites to examine the role of parasites in host distribution and habitat segregation.
Austridotea annectens
showed a clear preference for one microhabitat type regardless of competition or parasitic infection. By contrast,
A. lacustris
showed little habitat selection in the absence of competition, but favoured sandy habitats in the presence of uninfected
A. annectens
and rocky habitats when competing with infected
A. annectens
. Our results suggest that parasites in one species affect the distribution of another species, and mediate competition between these species. We demonstrated the impacts of a parasite on the microhabitat use of its host's competitor. This also represents an example of a super-extended phenotype, where a parasite affects the phenotype of a non-host.
Social cues trigger differential immune investment strategies in a non-social insect,
Tenebrio molitor
Authors: Gallagher Joe D. , Siva-Jothy Michael T. , Evison Sophie E. F.
Published: February 2018

Social immunization (SI) is a horizontal transfer of immunity that protects naive hosts against infection following exposure to infected nestmates. While mainly documented in eusocial insects, non-social species also share similar ecological features which favour the development of group-level immunity. Here, we investigate SI in
Tenebrio molitor
by pairing naive females with a pathogen-challenged conspecific for 72 h before measuring a series of immune and fitness traits. We found no evidence for SI, as beetles who cohabited with a live pathogen-challenged conspecific were not better protected against bacterial challenge. However, exposure to a heat-killed-bacteria-challenged conspecific appeared to increase pathogen tolerance, which manifested in differential fitness investment. Our results together suggest that
T. molitor
do respond to immune-related cues in the social environment, despite not showing a classic immunization response as predicted.
A multiscale active structural model of the arterial wall accounting for smooth muscle dynamics
Authors: Coccarelli Alberto , Edwards David Hughes , Aggarwal Ankush , Nithiarasu Perumal , Parthimos Dimitris
Published: February 2018

Arterial wall dynamics arise from the synergy of passive mechano-elastic properties of the vascular tissue and the active contractile behaviour of smooth muscle cells (SMCs) that form the media layer of vessels. We have developed a computational framework that incorporates both these components to account for vascular responses to mechanical and pharmacological stimuli. To validate the proposed framework and demonstrate its potential for testing hypotheses on the pathogenesis of vascular disease, we have employed a number of pharmacological probes that modulate the arterial wall contractile machinery by selectively inhibiting a range of intracellular signalling pathways. Experimental probes used on ring segments from the rabbit central ear artery are: phenylephrine, a selective
α
1-adrenergic receptor agonist that induces vasoconstriction; cyclopiazonic acid (CPA), a specific inhibitor of sarcoplasmic/endoplasmic reticulum Ca
2+
-ATPase; and ryanodine, a diterpenoid that modulates Ca
2+
release from the sarcoplasmic reticulum. These interventions were able to delineate the role of membrane versus intracellular signalling, previously identified as main factors in smooth muscle contraction and the generation of vessel tone. Each SMC was modelled by a system of nonlinear differential equations that account for intracellular ionic signalling, and in particular Ca
2+
dynamics. Cytosolic Ca
2+
concentrations formed the catalytic input to a cross-bridge kinetics model. Contractile output from these cellular components forms the input to the finite-element model of the arterial rings under isometric conditions that reproduces the experimental conditions. The model does not account for the role of the endothelium, as the nitric oxide production was suppressed by the action of L-NAME, and also due to the absence of shear stress on the arterial ring, as the experimental set-up did not involve flow. Simulations generated by the integrated model closely matched experimental observations qualitatively, as well as quantitatively within a range of physiological parametric values. The model also illustrated how increased intercellular coupling led to smooth muscle coordination and the genesis of vascular tone.
Tracking random walks
Authors: Gallotti Riccardo , Louf Rémi , Luck Jean-Marc , Barthelemy Marc
Published: February 2018

In empirical studies, trajectories of animals or individuals are sampled in space and time. Yet, it is unclear how sampling procedures bias the recorded data. Here, we consider the important case of movements that consist of alternating rests and moves of random durations and study how the estimate of their statistical properties is affected by the way we measure them. We first discuss the ideal case of a constant sampling interval and short-tailed distributions of rest and move durations, and provide an exact analytical calculation of the fraction of correctly sampled trajectories. Further insights are obtained with simulations using more realistic long-tailed rest duration distributions showing that this fraction is dramatically reduced for real cases. We test our results for real human mobility with high-resolution GPS trajectories, where a constant sampling interval allows one to recover at best 18% of the movements, while over-evaluating the average trip length by a factor of 2. Using a sampling interval extracted from real communication data, we recover only 11% of the moves, a value that cannot be increased above 16% even with ideal algorithms. These figures call for a more cautious use of data in quantitative studies of individuals' movements.
Shark skin-inspired designs that improve aerodynamic performance
Authors: Domel August G. , Saadat Mehdi , Weaver James C. , Haj-Hariri Hossein , Bertoldi Katia , Lauder George V.
Published: February 2018

There have been significant efforts recently aimed at improving the aerodynamic performance of aerofoils through the modification of their surfaces. Inspired by the drag-reducing properties of the tooth-like denticles that cover the skin of sharks, we describe here experimental and simulation-based investigations into the aerodynamic effects of novel denticle-inspired designs placed along the suction side of an aerofoil. Through parametric modelling to query a wide range of different designs, we discovered a set of denticle-inspired surface structures that achieve simultaneous drag reduction and lift generation on an aerofoil, resulting in lift-to-drag ratio improvements comparable to the best-reported for traditional low-profile vortex generators and even outperforming these existing designs at low angles of attack with improvements of up to 323%. Such behaviour is enabled by two concurrent mechanisms: (i) a separation bubble in the denticle's wake altering the flow pressure distribution of the aerofoil to enhance suction and (ii) streamwise vortices that replenish momentum loss in the boundary layer due to skin friction. Our findings not only open new avenues for improved aerodynamic design, but also provide new perspective on the role of the complex and potentially multifunctional morphology of shark denticles for increased swimming efficiency.
Hidden Markov models for monitoring circadian rhythmicity in telemetric activity data
Authors: Huang Qi , Cohen Dwayne , Komarzynski Sandra , Li Xiao-Mei , Innominato Pasquale , Lévi Francis , Finkenstädt Bärbel
Published: February 2018

Wearable computing devices allow collection of densely sampled real-time information on movement enabling researchers and medical experts to obtain objective and non-obtrusive records of actual activity of a subject in the real world over many days. Our interest here is motivated by the use of activity data for evaluating and monitoring the circadian rhythmicity of subjects for research in chronobiology and chronotherapeutic healthcare. In order to translate the information from such high-volume data arising we propose the use of a Markov modelling approach which (i) naturally captures the notable square wave form observed in activity data along with heterogeneous ultradian variances over the circadian cycle of human activity, (ii) thresholds activity into different states in a probabilistic way while respecting time dependence and (iii) gives rise to circadian rhythm parameter estimates, based on probabilities of transitions between rest and activity, that are interpretable and of interest to circadian research.
Realizing ‘integral control’ in living cells: how to overcome leaky integration due to dilution?
Authors: Qian Yili , Del Vecchio Domitilla
Published: February 2018

A major problem in the design of synthetic genetic circuits is robustness to perturbations and uncertainty. Because of this, there have been significant efforts in recent years in finding approaches to implement integral control in genetic circuits. Integral controllers have the unique ability to make the output of a process adapt perfectly to disturbances. However, implementing an integral controller is challenging in living cells. This is because a key aspect of any integral controller is a ‘memory’ element that stores the accumulation (integral) of the error between the output and its desired set-point. The ability to realize such a memory element in living cells is fundamentally challenged by the fact that all biomolecules dilute as cells grow, resulting in a ‘leaky’ memory that gradually fades away. As a consequence, the adaptation property is lost. Here, we propose a general principle for designing integral controllers such that the performance is practically unaffected by dilution. In particular, we mathematically prove that if the reactions implementing the integral controller are all much faster than dilution, then the adaptation error due to integration leakiness becomes negligible. We exemplify this design principle with two synthetic genetic circuits aimed at reaching adaptation of gene expression to fluctuations in cellular resources. Our results provide concrete guidance on the biomolecular processes that are most appropriate for implementing integral controllers in living cells.
Overcoming clofazimine intrinsic toxicity: statistical modelling and characterization of solid lipid nanoparticles
Authors: Chaves Luíse L. , Lima Sofia , Vieira Alexandre C. C. , Ferreira Domingos , Sarmento Bruno , Reis Salette
Published: February 2018

The aim of this work was to develop solid lipid nanoparticles (SLNs) loaded with clofazimine (CLZ) (SLNs-CLZ) to overcome its intrinsic toxicity and low water solubility, for oral drug delivery. A Box–Behnken design was constructed to unravel the relations between the independent variables in the selected responses. The optimized SLNs-CLZ exhibited the following properties: particle size
ca
230 nm, zeta potential of −34.28 mV, association efficiency of 72% and drug loading of 2.4%, which are suitable for oral delivery. Further characterization included Fourier transformed infrared spectroscopy that confirmed the presence of the drug and the absence of chemical interactions. By differential scanning calorimetry was verified the amorphous state of CLZ. The storage stability studies ensured the stability of the systems over a period of 12 weeks at 4°C.
In vitro
cytotoxicity studies evidenced no effect of both drug-loaded and unloaded SLNs on MKN-28 gastric cells and on intestinal cells, namely Caco-2 and HT29-MTX cells up to 25 µg ml
−1
in CLZ. Free CLZ solutions exhibited IC
50
values of 16 and 20 µg ml
−1
for Caco-2 and HT29-MTX cells, respectively. It can be concluded that the optimized system, designed considering important variables for the formulation of poorly soluble drugs, represents a promising platform for oral CLZ delivery.
Rapid juvenile hormone downregulation in subordinate wasp queens facilitates stable cooperation
Authors: Tibbetts Elizabeth A. , Fearon Michelle L. , Wong Ellery , Huang Zachary Y. , Tinghitella Robin M.
Published: February 2018

In many cooperatively breeding animals, subordinate group members have lower reproductive capacity than dominant group members. Theory suggests subordinates may downregulate their reproductive capacity because dominants punish subordinates who maintain high fertility. However, there is little direct experimental evidence that dominants cause physiological suppression in subordinates. Here, we experimentally test how social interactions influence subordinate reproductive hormones inPolistes dominulapaper wasps.Polistes dominulaqueens commonly found nests in cooperative groups where the dominant queen is more fertile than the subordinate queen. In this study, we randomly assigned wasps to cooperative groups, assessed dominance behaviour during group formation, then measured levels of juvenile hormone (JH), a hormone that mediatesPolistesfertility. Within three hours, lowest ranking subordinates had less JH than dominants or solitary controls, indicating that group formation caused rapid JH reduction in low-ranking subordinates. In a second experiment, we measured the behavioural consequences of experimentally increasing subordinate JH. Subordinates with high JH-titres received significantly more aggression than control subordinates or subordinates from groups where the dominant's JH was increased. These results suggest that dominants aggressively punished subordinates who attempted to maintain high fertility. Low-ranked subordinates may rapidly downregulate reproductive capacity to reduce costly social interactions with dominants. Rapid modulation of subordinate reproductive physiology may be an important adaptation to facilitate the formation of stable, cooperative groups.
Profound genetic divergence and asymmetric parental genome contributions as hallmarks of hybrid speciation in polyploid toads
Authors: Betto-Colliard Caroline , Hofmann Sylvia , Sermier Roberto , Perrin Nicolas , Stöck Matthias
Published: February 2018

The evolutionary causes and consequences of allopolyploidization, an exceptional pathway to instant hybrid speciation, are poorly investigated in animals. In particular, when and why hybrid polyploids versus diploids are produced, and constraints on sources of paternal and maternal ancestors, remain underexplored. Using the Palearctic green toad radiation (including bisexually reproducing species of three ploidy levels) as model, we generate a range-wide multi-locus phylogeny of 15 taxa and present four new insights: (i) at least five (up to seven) distinct allotriploid and allotetraploid taxa have evolved in the Pleistocene; (ii) all maternal and paternal ancestors of hybrid polyploids stem from two deeply diverged nuclear clades (6 Mya, 3.1–9.6 Mya), with distinctly greater divergence than the parental species of diploid hybrids found at secondary contact zones; (iii) allotriploid taxa possess two conspecific genomes and a deeply diverged allospecific one, suggesting that genomic imbalance and divergence are causal for their partly clonal reproductive mode; (iv) maternal versus paternal genome contributions exhibit asymmetry, with the maternal nuclear (and mitochondrial) genome of polyploids always coming from the same clade, and the paternal genome from the other. We compare our findings with similar patterns in diploid/polyploid vertebrates, and suggest deep ancestral divergence as a precondition for successful allopolyploidization.
Deep-sea starfish from the Arctic have well-developed eyes in the dark
Authors: Birk Marie Helene , Blicher Martin E. , Garm Anders
Published: February 2018

Asteroids, starfish, are important members of the macro-benthos in almost all marine environments including the deep sea. Starfish are in general assumed to be largely olfactory guided, but recent studies have shown that two tropical shallow water species rely on vision alone to find their habitat at short distances. Their compound eyes are found at the tip of each arm and they vary little between examined species. Still, nothing is known about vision in the species found in the aphotic zone of the deep sea or whether they even have eyes. Here, 13 species of starfish from Greenland waters, covering a depth range from shallow waters to the deep sea below 1000 m, were examined for the presence of eyes and optical and morphological examinations were used to estimate the quality of vision. Further, species found in the aphotic zone below 320 m were checked for bioluminescence. All species, except the infaunalCtenodiscus crispatus, had eyes, and two were found to be bioluminescent. Interestingly, one of the species found in the aphotic zone,Novodinia americana, had close to the highest spatial resolution known for starfish eyes along with being bioluminescent. Accordingly, we hypothesize that this species communicates visually using bioluminescent flashes putatively for reproductive purposes. Other species have greatly enhanced sensitivity with few large ommatidia but at the sacrifice of spatial resolution. The discovery of eyes in deep-sea starfish with a huge variation in optical quality and sensitivity indicates that their visual ecology also differs greatly.
Seed ingestion and germination in rattlesnakes: overlooked agents of rescue and secondary dispersal
Authors: Reiserer Randall S. , Schuett Gordon W. , Greene Harry W.
Published: February 2018

Seed dispersal is a key evolutionary process and a central theme in the population ecology of terrestrial plants. The primary producers of most land-based ecosystems are propagated by and maintained through various mechanisms of seed dispersal that involve both abiotic and biotic modes of transportation. By far the most common biotic seed transport mechanism is zoochory, whereby seeds, or fruits containing them, are dispersed through the activities of animals. Rodents are one group of mammals that commonly prey on seeds (granivores) and play a critical, often destructive, role in primary dispersal and the dynamics of plant communities. In North America, geomyid, heteromyid and some sciurid rodents have specialized cheek pouches for transporting seeds from plant source to larder, where they are often eliminated from the pool of plant propagules by consumption. These seed-laden rodents are commonly consumed by snakes as they forage, but unlike raptors, coyotes, bobcats, and other endothermic predators which eat rodents and are known or implicated to be secondary seed dispersers, the role of snakes in seed dispersal remains unexplored. Here, using museum-preserved specimens, we show that in nature three desert-dwelling rattlesnake species consumed heteromyids with seeds in their cheek pouches. By examining the entire gut we discovered, furthermore, that secondarily ingested seeds can germinate in rattlesnake colons. In terms of secondary dispersal, rattlesnakes are best described as diplochorous. Because seed rescue and secondary dispersal in snakes has yet to be investigated, and because numerous other snake species consume granivorous and frugivorous birds and mammals, our observations offer direction for further empirical studies of this unusual but potentially important channel for seed dispersal.
Probing the rate-determining region of the potential energy surface for a prototypical ion–molecule reaction
Authors: Xie Changjian , Liu Xinguo , Sweeny Brendan C. , Miller Thomas M. , Ard Shaun G. , Shuman Nicholas S. , Viggiano Albert A. , Guo Hua
Published: February 2018

We report a joint experimental–theoretical study of the F
–
 + HCl → HF + Cl
−
reaction kinetics. The experimental measurement of the rate coefficient at several temperatures was made using the selected ion flow tube method. Theoretical rate coefficients are calculated using the quasi-classical trajectory method on a newly developed global potential energy surface, obtained by fitting a large number of high-level
ab initio
points with augmentation of long-range electrostatic terms. In addition to good agreement between experiment and theory, analyses suggest that the ion–molecule reaction rate is significantly affected by shorter-range interactions, in addition to the traditionally recognized ion–dipole and ion–induced dipole terms. Furthermore, the statistical nature of the reaction is assessed by comparing the measured and calculated HF product vibrational state distributions to that predicted by the phase space theory.

This article is part of the theme issue ‘Modern theoretical chemistry’.
Statistical mechanics of binary mixture adsorption in metal–organic frameworks in the osmotic ensemble
Authors: Dunne Lawrence J. , Manos George
Published: February 2018

Although crucial for designing separation processes little is known experimentally about multi-component adsorption isotherms in comparison with pure single components. Very few binary mixture adsorption isotherms are to be found in the literature and information about isotherms over a wide range of gas-phase composition and mechanical pressures and temperature is lacking. Here, we present a quasi-one-dimensional statistical mechanical model of binary mixture adsorption in metal–organic frameworks (MOFs) treated exactly by a transfer matrix method in the osmotic ensemble. The experimental parameter space may be very complex and investigations into multi-component mixture adsorption may be guided by theoretical insights. The approach successfully models breathing structural transitions induced by adsorption giving a good account of the shape of adsorption isotherms of CO
2
and CH
4
adsorption in MIL-53(Al). Binary mixture isotherms and co-adsorption-phase diagrams are also calculated and found to give a good description of the experimental trends in these properties and because of the wide model parameter range which reproduces this behaviour suggests that this is generic to MOFs. Finally, a study is made of the influence of mechanical pressure on the shape of CO
2
and CH
4
adsorption isotherms in MIL-53(Al). Quite modest mechanical pressures can induce significant changes to isotherm shapes in MOFs with implications for binary mixture separation processes.

This article is part of the theme issue ‘Modern theoretical chemistry’.
Interactions of C
+
(
2

P
J

) with rare gas atoms: incipient chemical interactions, potentials and transport coefficients
Authors: Tuttle William D. , Thorington Rebecca L. , Viehland Larry A. , Breckenridge W. H. , Wright Timothy G. 
Published: February 2018

Accurate interatomic potentials were calculated for the interaction of a singly charged carbon cation, C
+
, with a single rare gas atom, RG (RG = Ne–Xe). The RCCSD(T) method and basis sets of quadruple-ζ and quintuple-ζ quality were employed; each interaction energy was counterpoise corrected and extrapolated to the basis set limit. The lowest C
+
(
2
P
) electronic term of the carbon cation was considered, and the interatomic potentials calculated for the diatomic terms that arise from these:
2
Π and
2
Σ
+
. Additionally, the interatomic potentials for the respective spin-orbit levels were calculated, and the effect on the spectroscopic parameters was examined. In doing this, anomalously large spin-orbit splittings for RG = Ar–Xe were found, and this was investigated using multi-reference configuration interaction calculations. The latter indicated a small amount of RG → C
+
electron transfer and this was used to rationalize the observations. This is taken as evidence of an incipient chemical interaction, which was also examined via contour plots, Birge–Sponer plots and various population analyses across the C
+
-RG series (RG = He–Xe), with the latter showing unexpected results. Trends in several spectroscopic parameters were examined as a function of the increasing atomic number of the RG atom. Finally, each set of RCCSD(T) potentials was employed, including spin-orbit coupling to calculate the transport coefficients for C
+
in RG, and the results were compared with the limited available data.

This article is part of the theme issue ‘Modern theoretical chemistry’.
Phosphorothioate-modified DNA oligonucleotides inactivate CRISPR-Cpf1 mediated genome editing
Authors: Li Bin , Zeng Chunxi , Li Wenqing , Zhang Xinfu , Luo Xiao , Zhao Weiyu , Zhang Chengxiang , Dong Yizhou
Published: February 2018

CRISPR-Cpf1, a microbial adaptive immune system discovered from Prevotella and Francisella 1, employs a single-stranded CRISPR RNA (crRNA) to induce double stranded DNA breaks1. To modulate genome editing activity of Cpf1 in human cells, we designed a series of crRNA variants including DNA-crRNA and RNA-crRNA duplexes, and identified that phosphorothioate (PS)-modified DNA-crRNA duplex completely blocked the function of Cpf1 mediated gene editing. More importantly, without prehybridization, this PS-modified DNA was able to regulate Cpf1 activity in a time-and dose-dependent manner. Mechanistic studies indicate that PS-modified DNA oligonucleotides hinder the binding between Cpf1-crRNA complex and target DNA substrate. Consequently, phosphorothioate-modified DNA oligonucleotides provide a tunable platform to inactivate Cpf1 mediated genome editing.
2,4-Diaminothieno[3,2-d]pyrimidines, a new class of anthelmintic with activity against adult and egg stages of whipworm
Authors: Partridge Frederick A. , Forman Ruth , Willis Nicky J. , Bataille Carole J.R. , Murphy Emma A. , Brown Anwen E. , Heyer-Chauhan Narinder , Marinič Bruno , Sowood Daniel J.C. , Wynne Graham M. , Else Kathryn J. , Russell Angela J. , Sattelle David B.
Published: February 2018

The human whipworm Trichuris trichiura is a parasite that infects around 500 million people globally, with consequences including damage to physical growth and educational performance. Current drugs such as mebendazole have a notable lack of efficacy against whipworm, compared to other soil-transmitted helminths. Mass drug administration programs are therefore unlikely to achieve eradication and new treatments for trichuriasis are desperately needed. All current drug control strategies focus on post-infection eradication, targeting the parasite in vivo. Here we propose developing novel anthelmintics which target the egg stage of the parasite in the soil as an adjunct environmental strategy. As evidence in support of such an approach we describe the actions of a new class of anthelmintic compounds, the 2,4-diaminothieno[3,2-d]pyrimidines (DATPs). This compound class has found broad utility in medicinal chemistry, but has not previously been described as having anthelmintic activity. Importantly, these compounds show efficacy against not only the adult parasite, but also both the embryonated and unembryonated egg stages and thereby may enable a break in the parasite lifecycle.

Author Summary

The human whipworm, Trichuris trichiura, infects around 500 million people globally, impacting on their physical growth and educational performance. There are currently huge mass drug administration (MDA) programs aiming to control whipworm, along with the other major soil transmitted helminths, Ascaris and hookworm. However single doses of albendazole and mebendazole, which are used in MDA, have particularly poor effectiveness against whipworm, with cure rates less than 40%. This means that MDA may not be able to control and eliminate whipworm infection, and risks the spread of resistance to albendazole and mebendazole in the parasite population.

We are attempting to develop new treatments for parasitic worm infection, particularly focused on whipworm. We report the identification of a class of compounds, diaminothienopyrimidines (DATPs), which have not previously been described as anthelmintics. These compounds are effective against adult stages of whipworm, and also block the development of the model nematode C. elegans.

Our DATP compounds reduce the ability of treated eggs to successfully establish infection in a mouse model of human whipworm. These results support a potential environmental spray to control whipworm by targeting the infectious egg stage in environmental hotspots.
Proteomics as a metrological tool to evaluate genome annotation accuracy following de novo genome assembly: a case study using the Atlantic bottlenose dolphin (Tursiops truncatus)
Authors: Neely Benjamin A. , Ellisor Debra L. , Davis W. Clay
Published: February 2018

Background

The last decade has witnessed dramatic improvements in whole-genome sequencing capabilities coupled to drastically decreased costs, leading to an inundation of high-quality de novo genomes. For this reason, continued development of genome quality metrics is imperative. The current study utilized the recently updated Atlantic bottlenose dolphin (Tursiops truncatus) genome and annotation to evaluate a proteomics-based metric of genome accuracy.

Results

Proteomic analysis of six tissues provided experimental confirmation of 10 402 proteins from 4 711 protein groups, almost 1/3 of the possible predicted proteins in the genome. There was an increased median molecular weight and number of identified peptides per protein using the current T. truncatus annotation versus the previous annotation. Identification of larger proteins with more identified peptides implied reduced database fragmentation and improved gene annotation accuracy. A metric is proposed, NP10, that attempts to capture this quality improvement. When using the new T. truncatus genome there was a 21 % improvement in NP10. This metric was further demonstrated by using a publicly available proteomic data set to compare human genome annotations from 2004, 2013 and 2016, which had a 33 % improvement in NP10.

Conclusions

These results demonstrate that new whole-genome sequencing techniques can rapidly generate high quality de novo genome assemblies and emphasizes the speed of advancing bioanalytical measurements in a non-model organism. Moreover, proteomics may be a useful metrological tool to benchmark genome accuracy, though there is a need for reference proteomic datasets to facilitate this utility in new de novo and existing genomes.
Mitigating the lack of knowledge about long noncoding RNA: extracting biological functions
Authors: Adam Yagoub A. I. , Ruiz Evandro Eduardo Seron , Macedo Alessandra Alaniz
Published: February 2018

Long non-coding RNAs (lncRNAs) play crucial roles in diverse biological processes. For example, they help to regulate gene expression and to shape the 3D organization of the cellular nucleus. However, their functions in these processes are not well known. Most of the ongoing research efforts regarding lncRNAs have focused on predicting their properties and their functions. Here, we aimed to extract the biological functions of lncRNAs referred in the biomedical literature. To this end, we performed gene enrichment tests for 417 verified gene names extracted from the scientific literature. We also succeeded in extracting biologically significant functions from 2455 single sentences of 2513 scientific abstracts retrieved from the PubMed digital library. These sentences had to be filtered to eliminate those that did not mention a biological function. They were also split into 2-3-grams and the meaningful function annotations based on Gene Ontology terms were extracted. The results provided by the gene enrichment test and the knowledge gained by automatic extraction of information from the scientific literature showed that lncRNAs play a critical role in all biological and cellular processes. Although simple natural language processing techniques fulfilled our purposes of extracting concepts concerning the biological functions of lncRNAs, in the future, we aim to use more sophisticated methods, such as grammatical rules, to extract more functions and to generate a full database for the biological functions related to lncRNAs.
Integrating healthcare and research genetic data empowers the discovery of 49 novel developmental disorders
Authors: Kaplanis Joanna , Samocha Kaitlin E. , Wiel Laurens , Zhang Zhancheng , Arvai Kevin J. , Eberhardt Ruth Y. , Gallone Giuseppe , Lelieveld Stefan H. , Martin Hilary C. , McRae Jeremy F. , Short Patrick J. , Torene Rebecca I. , Boer Elke de , Danecek Petr , Gardner Eugene J. , Huang Ni , Lord Jenny , Martincorena Iñigo , Pfundt Rolph , Reijnders Margot R. F. , Yeung Alison , Yntema Helger G. , Study DDD , Vissers Lisenka E. L. M. , Juusola Jane , Wright Caroline F. , Brunner Han G. , Firth Helen V. , FitzPatrick David R. , Barrett Jeffrey C. , Hurles Matthew E. , Gilissen Christian , Retterer Kyle
Published: February 2018

De novomutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 299 significantly DD-associated genes, including 49 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 500 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.
MirGeneDB 2.0: The metazoan microRNA complement
Authors: Fromm Bastian , Domanska Diana , Høye Eirik , Ovchinnikov Vladimir , Kang Wenjing , Aparicio-Puerta Ernesto , Johansen Morten , Flatmark Kjersti , Mathelier Anthony , Hovig Eivind , Hackenberg Michael , Friedländer Marc R. , Peterson Kevin J.
Published: February 2018

Small non-coding RNAs have gained substantial attention due to their roles in animal development and human disorders. Among them, microRNAs are unique because individual gene sequences are conserved across the animal kingdom. In addition, unique and mechanistically well understood features can clearly distinguishbona fidemiRNAs from the myriad other small RNAs generated by cells. However, making this separation is not a common practice and, thus, not surprisingly, the heterogeneous quality of available miRNA complements has become a major concern in microRNA research. We addressed this by extensively expanding our curated microRNA gene database MirGeneDB to 45 organisms that represent the full taxonomic breadth of Metazoa. By consistently annotating and naming more than 10,900 microRNA genes in these organisms, we show that previous microRNA annotations contained not only many false positives, but surprisingly lacked more than 2,100bona fidemicroRNAs. Indeed, curated microRNA complements of closely related organisms are very similar and can be used to reconstruct Metazoan evolution. MirGeneDB represents a robust platform for microRNA-based research, providing deeper and more significant insights into the biology and evolution of miRNAs but also biomedical and biomarker research. MirGeneDB is publicly and freely available athttp://mirgenedb.org/.
Causal interactions from proteomic profiles: molecular data meets pathway knowledge
Authors: Babur Özgün , Luna Augustin , Korkut Anil , Durupinar Funda , Siper Metin Can , Dogrusoz Ugur , Aslan Joseph E. , Sander Chris , Demir Emek
Published: February 2018

Measurement of changes in protein levels and in post-translational modifications, such as phosphorylation, can be highly informative about the phenotypic consequences of genetic differences or about the dynamics of cellular processes. Typically, such proteomic profiles are interpreted intuitively or by simple correlation analysis. Here, we present a computational method to generate causal explanations for proteomic profiles using prior mechanistic knowledge in the literature, as recorded in cellular pathway maps. To demonstrate its potential, we use this method to analyze the cascading events after EGF stimulation of a cell line, to discover new pathways in platelet activation, to identify influential regulators of oncoproteins in breast cancer, to describe signaling characteristics in predefined subtypes of ovarian and breast cancers, and to highlight which pathway relations are most frequently activated across 32 cancer types. Causal pathway analysis, that combines molecular profiles with prior biological knowledge captured in computational form, may become a powerful discovery tool as the amount and quality of cellular profiling rapidly expands. The method is freely available at http://causalpath.org.