bluuebunny/crossref_metadata_2025 huggingface dataset:
Harmonic terahertz gyrotron with a double confocal quasi-optical cavity
Authors: Fu Wenjie , Guan Xiaotong , Yan Yang
Published: April 2019

To reduce mode competition in a high-harmonic terahertz gyrotron, the gyrotron with a quasi-optical confocal cavity is proposed. Theoretical and experimental investigations demonstrate that the confocal cavity has good-mode selection and is suitable for high-harmonic operation. However, due to the transverse nonuniformity of the radio frequency field, the beam–wave interaction efficiency is low in the confocal cavity. To mitigate this drawback, the double confocal cavity is investigated in this study. Through three-dimensional particle-in-cell simulation on a designed 330-GHz gyrotron with a double confocal cavity, the physical mechanism of beam–wave interactions in a double confocal cavity is analyzed and presented.
Unsupervised machine learning in atomistic simulations, between predictions and understanding
Authors: Ceriotti Michele
Published: April 2019

Automated analyses of the outcome of a simulation have been an important part of atomistic modeling since the early days, addressing the need of linking the behavior of individual atoms and the collective properties that are usually the final quantity of interest. Methods such as clustering and dimensionality reduction have been used to provide a simplified, coarse-grained representation of the structure and dynamics of complex systems from proteins to nanoparticles. In recent years, the rise of machine learning has led to an even more widespread use of these algorithms in atomistic modeling and to consider different classification and inference techniques as part of a coherent toolbox of data-driven approaches. This perspective briefly reviews some of the unsupervised machine-learning methods—that are geared toward classification and coarse-graining of molecular simulations—seen in relation to the fundamental mathematical concepts that underlie all machine-learning techniques. It discusses the importance of using concise yet complete representations of atomic structures as the starting point of the analyses and highlights the risk of introducing preconceived biases when using machine learning to rationalize and understand structure-property relations. Supervised machine-learning techniques that explicitly attempt to predict the properties of a material given its structure are less susceptible to such biases. Current developments in the field suggest that using these two classes of approaches side-by-side and in a fully integrated mode, while keeping in mind the relations between the data analysis framework and the fundamental physical principles, will be key to realizing the full potential of machine learning to help understand the behavior of complex molecules and materials.
A finite element approach to forward modeling of nuclear magnetic resonance measurements in coupled pore systems
Authors: Mitchell Jonathan , Souza Andre , Fordham Edmund , Boyd Austin
Published: April 2019

Porous media characterized by a hierarchy of length scales are ubiquitous in industry and nature, and include carbonate rocks, cements, heterogeneous catalysts, and biological cells. Nuclear magnetic resonance (NMR) is a popular tool for studying liquid-saturated porous materials, where the spin relaxation rate is generally considered proportional to pore size. However, in porous granular media, the relaxation rate is modified by diffusion between the intraparticle and interparticle pores. The observed relaxation rates do not reflect the pore size under such conditions. Deconvolving the various contributions of surface relaxation, geometry, and diffusion is nontrivial, and forward models are a powerful technique for elucidating the underlying pore structure. Various forward models have been proposed previously, including analytic solutions and random walk simulations. Here, a finite element method is adopted to simulate the diffusion of nuclear magnetization in a coupled pore geometry. We validate our model against existing solutions and use the simulations to determine the surface relaxivity of powdered silica by matching experimental results. The finite element approach is more versatile than other modeling methods, allowing direct visualization of the diffusing magnetization and being trivially extensible to multidimensional NMR exchange experiments.
Unfolding of a diblock chain and its anomalous diffusion induced by active particles
Authors: Xia Yi-qi , Shen Zhuang-lin , Tian Wen-de , Chen Kang
Published: April 2019

We study the structural and dynamical behavior of an A-B diblock chain in the bath of active Brownian particles (ABPs) by Brownian dynamics simulations in two dimensions. We are interested in the situation that the effective interaction between the A segments is attractive, while that between the B segments is repulsive. Therefore, in thermal (nonactive) equilibrium, the A block “folds” into a compact globule, while the B block is in the expanded coil state. Interestingly, we find that the A block could “unfold” sequentially like unknitting a sweater, driven by the surrounding ABPs when the propelling strength on them is beyond a certain value. This threshold value decreases and then levels off as the length of the B block increases. We also find a simple power-law relation between the unfolding time of the A block and the self-propelling strength and an exponential relation between the unfolding time and the length of the B block. Finally, we probe the translational and rotational diffusion of the chain and find that both of them show “super-diffusivity” in a large time window, especially when the self-propelling strength is small and the A block is in the folded state. Such super-diffusivity is due to the strong asymmetric distribution of ABPs around the chain. Our work provides new insights into the behavior of a polymer chain in the environment of active objects.
How Ca2+ influx is attenuated in the heart during a “fight or flight” response
Authors: Bazmi Maedeh , Escobar Ariel L.
Published: April 2019

Bazmi and Escobar highlight a recent investigation of the mechanisms that regulate Ca2+ influx during sympathetic stimulation.
Spinors on Singular Spaces and the Topology of Causal Fermion Systems
Authors: Finster Felix , Kamran Niky
Published: April 2019

Causal fermion systems and Riemannian fermion systems are proposed as a framework for describing non-smooth geometries. In particular, this framework provides a setting for spinors on singular spaces. The underlying topological structures are introduced and analyzed. The connection to the spin condition in differential topology is worked out. The constructions are illustrated by many simple examples like the Euclidean plane, the two-dimensional Minkowski space, a conical singularity, a lattice system as well as the curvature singularity of the Schwarzschild space-time. As further examples, it is shown how complex and Kähler structures can be encoded in Riemannian fermion systems.
Becker’s conjecture on Mahler functions
Authors: Bell Jason , Chyzak Frédéric , Coons Michael , Dumas Philippe
Published: April 2019

In 1994, Becker conjectured that if

F
(
z
)

F(z)

is a

k
k

-regular power series, then there exists a

k
k

-regular rational function

R
(
z
)

R(z)

such that

F
(
z
)

/

R
(
z
)

F(z)/R(z)

satisfies a Mahler-type functional equation with polynomial coefficients where the initial coefficient satisfies

a
0

(
z
)
=
1

a_0(z)=1

. In this paper, we prove Becker’s conjecture in the best-possible form; we show that the rational function

R
(
z
)

R(z)

can be taken to be a polynomial

z
γ

Q
(
z
)

z^\gamma Q(z)

for some explicit nonnegative integer

γ
\gamma

and such that

1

/

Q
(
z
)

1/Q(z)

is

k
k

-regular.
Effects of the Dipeptidyl Peptidase 4 Inhibitor Alogliptin on Blood Pressure in Hypertensive Patients with Type 2 Diabetes Mellitus
Authors: Kishimoto Shinji , Kinoshita Yoshihiko , Matsumoto Takeshi , Maruhashi Tatsuya , Kajikawa Masato , Matsui Shogo , Hashimoto Haruki , Takaeko Yuji , Kihara Yasuki , Chayama Kazuaki , Goto Chikara , Mohamad Yusoff Farina , Nakashima Ayumu , Noma Kensuke , Higashi Yukihito
Published: April 2019

BACKGROUND

The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors on blood pressure in patients with diabetes mellitus (DM) are controversial. There is no information on the effect of DPP-4 inhibitors on blood pressure and arterial stiffness in hypertensive patients with DM. We evaluated the effects of alogliptin on blood pressure and arterial stiffness in hypertensive patients with type 2 diabetes mellitus (T2DM).

METHODS

Blood pressure and brachial-ankle pulse wave velocity (baPWV) were measured before and after 3, 6, and 12 months of treatment with alogliptin in 22 hypertensive patients with T2DM.

RESULTS

After 3, 6, and 12 months, alogliptin treatment decreased hemoglobin A1c from 7.0 ± 0.97% to 6.4 ± 0.61%, 6.3 ± 0.58%, and 6.3 ± 0.75% (P < 0.01, respectively), glucose from 8.6 ± 4.39 mmol/l to 7.05 ± 2.16, 7.05 ± 2.28, and 6.44 ± 1.50 mmol/l (P < 0.01, respectively), systolic blood pressure from 137 ± 18 mm Hg to 127 ± 13, 125 ± 15, and 120 ± 17 mm Hg (P < 0.01, respectively), diastolic blood pressure from 79 ± 13 mm Hg to 74 ± 8, 74 ± 10, and 70 ± 8 mm Hg (P < 0.01, respectively) and baPWV from 1,947 ± 349 cm/second to 1,774 ± 259, 1,856 ± 361, and 1,756 ± 286 cm/second (P < 0.01, respectively). A baseline baPWV value of 1,643 cm/second was the optimal cut-off value for patients who had reduced blood pressure after treatment with alogliptin (sensitivity of 83.3% and specificity of 75.0%).

CONCLUSIONS

Alogliptin was associated with improvements not only in glucose metabolism but also in blood pressure and arterial stiffness in hypertensive patients with T2DM. The cut-off value of baPWV may enable identification of responders of decrease in blood pressure by alogliptin in hypertensive patients with T2DM.

CLINICAL TRIALS REGISTRATION

Registration Number for Clinical Trial: UMIN000007722.
iCircDA-MF: identification of circRNA-disease associations based on matrix factorization
Authors: Wei Hang , Liu Bin
Published: April 2019

Circular RNAs (circRNAs) are a group of novel discovered non-coding RNAs with closed-loop structure, which play critical roles in various biological processes. Identifying associations between circRNAs and diseases is critical for exploring the complex disease mechanism and facilitating disease-targeted therapy. Although several computational predictors have been proposed, their performance is still limited. In this study, a novel computational method called iCircDA-MF is proposed. Because the circRNA-disease associations with experimental validation are very limited, the potential circRNA-disease associations are calculated based on the circRNA similarity and disease similarity extracted from the disease semantic information and the known associations of circRNA-gene, gene-disease and circRNA-disease. The circRNA-disease interaction profiles are then updated by the neighbour interaction profiles so as to correct the false negative associations. Finally, the matrix factorization is performed on the updated circRNA-disease interaction profiles to predict the circRNA-disease associations. The experimental results on a widely used benchmark dataset showed that iCircDA-MF outperforms other state-of-the-art predictors and can identify new circRNA-disease associations effectively.
Stability Indicating TLC Method for Quantification of Brexpiprazole in Bulk and Its Pharmaceutical Dosage Form and Determination of Content Uniformity
Authors: Thakkar Anjali M , Chhalotiya Usmangani K , Parekh Nikunj , Desai Jaineel V , Shah Dimal A
Published: April 2019

A sensitive, selective and precise high performance thin layer chromatographic method has been developed and validated for the quantification of Brexpiprazole in bulk drug and in pharmaceutical dosage form. The method employed HPTLC aluminum plates (pre-coated with silica gel 60 F254) as stationary phase while n-butanol was used as mobile phase. The Rf value of Brexpiprazole was observed to be 0.38. The densitometric analysis was carried out in absorbance mode at 215 nm. The linear regression analysis data for the calibration plots showed a good linear relationship for Brexpiprazole over a concentration range of 200–1,600 ng band−1. The limit of detection and limit of quantification for Brexpiprazole was found to be 66 and 200 ng band−1. To find out the possible degradation pathway, forced degradation studies were performed. The stock solutions of Brexpiprazole (1,000 μg mL−1) were subjected to acid and alkali hydrolysis, chemical oxidation, dry heat degradation and photo degradation. The drug was found to be susceptible to acid and alkali hydrolysis, chemical oxidation, photo degradation and dry heat. The degraded product peaks were well resolved from the pure drug peak with significant difference in their Rf values. Stressed samples were analyzed using developed HPTLC method. The proposed method was validated with respect to linearity, accuracy, precision and robustness. The method was successfully applied to the estimation of Brexpiprazole in marketed formulation and determination of content uniformity of tablet formulation. Statistical analysis showed that the method is repeatable, selective, and precise.
Male and female guppies differ in problem-solving abilities
Authors: Lucon-Xiccato Tyrone , Gatto Elia , Bisazza Angelo
Published: April 2019

In a number of species, males and females have different ecological roles and therefore might be required to solve different problems. Studies on humans have suggested that the 2 sexes often show different efficiencies in problem-solving tasks; similarly, evidence of sex differences has been found in 2 other mammalian species. Here, we assessed whether a teleost fish species, the guppy, Poecilia reticulata, displays sex differences in the ability to solve problems. In Experiment 1, guppies had to learn to dislodge a disc that occluded a feeder from which they had been previously accustomed to feed. In Experiment 2, guppies had to solve a version of the detour task that required them to learn to enter a transparent cylinder from the open sides to reach a food reward previously freely available. We found evidence of sex differences in both problem-solving tasks. In Experiment 1, females clearly outperformed males, and in Experiment 2, guppies showed a reversed but smaller sex difference. This study indicates that sex differences may play an important role in fish’s problem-solving similar to what has previously been observed in some mammalian species.
The role of RcsA in the adaptation and survival of Escherichia coli K92
Authors: Navasa Nicolás , Ferrero Miguel Ángel , Rodríguez-Aparicio Leandro B , Monteagudo-Mera Andrea , Gutiérrez Sergio , Martínez-Blanco Honorina
Published: April 2019

The Rcs phosphorelay is a two-component signal transduction system that senses stressful environmental signals such as desiccation or low temperatures, which serve as natural inducers in bacteria. RcsA is an important coregulator in this system involved in some functions regulated by the Rcs system, including biofilm formation and capsule synthesis. In this sense, we previously showed that RcsA is necessary for colanic acid synthesis in Escherichia coli K92. Here, using an E. coli K92ΔrcsA mutant lacking rcsA gene we further characterize the implications of RcsA on E. coli K92 survival under osmotic and oxidative stressful conditions, and bacterial attachment and biofilm formation on both biotic and abiotic surfaces. Our results show that RcsA protects E. coli K92 against osmotic and, especially, oxidative stress at low temperatures. In addition, RcsA did not interfere in biofilm formation in any surface tested, including polystyrene, stainless steel, silicone, Teflon, aluminum and glass. By contrast, deletion of rcsA increased bacterial attachment to the caco-2 cells monolayer used as biotic surface.
Inconvenient Truths About Human Longevity
Authors: Olshansky S Jay , Carnes Bruce A
Published: April 2019

The rise in human longevity is one of humanity’s crowning achievements. Although advances in public health beginning in the 19th century initiated the rise in life expectancy, recent gains have been achieved by reducing death rates at middle and older ages. A debate about the future course of life expectancy has been ongoing for the last quarter century. Some suggest that historical trends in longevity will continue and radical life extension is either visible on the near horizon or it has already arrived; whereas others suggest there are biologically based limits to duration of life, and those limits are being approached now. In “inconvenient truths about human longevity” we lay out the line of reasoning and evidence for why there are limits to human longevity; why predictions of radical life extension are unlikely to be forthcoming; why health extension should supplant life extension as the primary goal of medicine and public health; and why promoting advances in aging biology may allow humanity to break through biological barriers that influence both life span and health span, allowing for a welcome extension of the period of healthy life, a compression of morbidity, but only a marginal further increase in life expectancy.
A Systematic Review and Meta-analysis of Environmental, Lifestyle, and Health Factors Associated With DNA Methylation Age
Authors: Ryan Joanne , Wrigglesworth Jo , Loong Jun , Fransquet Peter D , Woods Robyn L
Published: April 2019

DNA methylation (DNAm) algorithms of biological age provide a robust estimate of an individual’s chronological age and can predict their risk of age-related disease and mortality. This study reviewed the evidence that environmental, lifestyle and health factors are associated with the Horvath and Hannum epigenetic clocks. A systematic search identified 61 studies. Chronological age was correlated with DNAm age in blood (median .83, range .13–.99). In a meta-analysis body mass index (BMI) was associated with increased DNAm age (Hannum β: 0.07, 95% CI 0.04 to 0.10; Horvath β: 0.06, 95% CI 0.02 to 0.10), but there was no association with smoking (Hannum β: 0.12, 95% CI −0.50 to 0.73; Horvath β:0.18, 95% CI −0.10 to 0.46). DNAm age was positively associated with frailty (three studies, n = 3,093), and education was negatively associated with the Hannum estimate of DNAm age specifically (four studies, n = 13,955). For most other exposures, findings were too inconsistent to draw conclusions. In conclusion, BMI was positively associated with biological aging measured using DNAm, with some evidence that frailty also increased aging. More research is needed to provide conclusive evidence regarding other exposures. This field of research has the potential to provide further insights into how to promote slower biological aging and ultimately prolong healthy life.
Nursing Staff Time and Care Quality in Long-Term Care Facilities: A Systematic Review
Authors: Armijo-Olivo Susan , Craig Rodger , Corabian Paula , Guo Bing , Souri Sepideh , Tjosvold Lisa
Published: April 2019

Background and Objectives

In long-term care (LTC) facilities, nursing staff are important contributors to resident care and well-being. Despite this, the relationships between nursing staff coverage, care hours, and quality of resident care in LTC facilities are not well understood and have implications for policy-makers. This systematic review summarizes current evidence on the relationship between nursing staff coverage, care hours, and quality of resident care in LTC facilities.

Research Design and Methods

A structured literature search was conducted using four bibliographic databases and gray literature sources. Abstracts were screened by two independent reviewers using Covidence software. Data from the included studies were summarized using a pretested extraction form. The studies were critically appraised, and their results were synthesized narratively.

Results

The systematic searched yielded 15,842 citations, of which 54 studies (all observational) were included for synthesis. Most studies (n = 53, 98%) investigated the effect of nursing staff time on resident care. Eleven studies addressed minimum care hours and quality of care. One study examined the association between different nursing staff coverage models and resident outcomes. Overall, the quality of the included studies was poor.

Discussion and Implications

Because the evidence was inconsistent and of low quality, there is uncertainty about the direction and magnitude of the association between nursing staff time and type of coverage on quality of care. More rigorously designed studies are needed to test the effects of different cutoffs of care hours and different nursing coverage models on the quality of resident care in LTC facilities.
Impact of Changing Treatment Strategies on Outcomes in Pediatric Ulcerative Colitis
Authors: Bolia Rishi , Rajanayagam Jeremy , Hardikar Winita , Alex George
Published: April 2019

Background

In recent years, treatment strategies for ulcerative colitis have evolved with an early step-up approach, the availability of biologicals, and therapeutic drug monitoring.

We carried out this study to evaluate the effect of these changes on disease outcomes.

Methods

In this retrospective review, 2 time periods were defined: Group 1 (2005–2010) and Group 2 (2011–2016). Baseline demographic, endoscopic parameters, and medication use were compared. Overall colectomy rate, number of disease flares per year, and number of hospital admissions per year were compared between the 2 groups.

Results

Group 1 had 71 children, and in children in Group 2. The use of 5-ASA increased in Group 2 (Group 2, 99.2% vs. Group 1, 84.5%, P = 0.0007). In addition, infliximab and thiopurines were introduced earlier in the disease course.

The 2-year cumulative probability of colectomy decreased from 14% to 3% (P = 0.02) between the 2 periods. No change in median number of flares per year [Group 1, 0.41 (IQR 0.6) vs. Group 2, 0.62 (IQR 0.91), P = 0.28] or median number of hospital admissions per year [Group 1, 0.30 (IQR 0.77) vs. Group 2, 0.21 (IQR 0.75), P = 0.52] was seen.

Thereafter, we proceeded to identify the changes in treatment strategies that were responsible for the reduction in colectomy and we found that the use of infliximab OR 3.7 (95% CI 1.1–11.7), P = 0.02, was independently associated with it.

Conclusions

A reduction in 2-year colectomy rates has been observed in patients with pediatric ulcerative colitis since biologics have become available for its treatment. The numbers of disease-flares rates and hospital admissions remain unchanged.
Antiemetic prophylaxis with temozolomide: an audit from a tertiary care center
Authors: Patil Vijay M , Chandrasekharan Arun , Vallathol Dilip Harindran , Malhotra Mridul , Abhinav Ram , Agarwal Priti , Rajpurohit Anu , Tonse Raees , Bhattacharjee Atanu , Jalali Rakesh
Published: April 2019

Background

In our previous experience, a significant proportion of patients who received 5-HT3 antagonist monotherapy with adjuvant temozolomide (150-200 mg/m2) had chemotherapy-induced nausea and vomiting (CINV). This is an audit comparing the multiple antiemetic therapies in the prevention of temozolomide-associated CINV.

Methods

This was a retrospective audit. Adult glioma patients treated with temozolomide at a dose of 150-200 mg/m2 between October 2017 and June 2018 were selected for this analysis. Three antiemetic prophylaxis were used in this time period: ondansetron (October 2017 to November 2017), ondansetron + domperidone (December 2017 to February 2018), and ondansetron + olanzapine (March 2018 to June 2018). The rates of nausea and vomiting were compared among the 3 cohorts using the chi-squared test with Bonferroni correction. A P value of less than .016 was considered significant.

Results

A total of 360 patients were selected for this analysis. There were 91 patients in the ondansetron prophylaxis group (25.3%), 113 (31.4%) in the ondansetron plus domperidone group, and 156 (43.3%) in the ondansetron plus olanzapine group. The overall incidence of nausea and vomiting was 25.0% (n = 90) and 7.2% (n = 26). Overall the rates of nausea (P = .052) and vomiting (P = .481) were similar in all 3 cohorts. However, the rates of grade 2 and above nausea (P = .012) and vomiting (P = .015) were significantly lower in the olanzapine group.

Conclusion

The combination of ondansetron with olanzapine leads to a statistically significant decrease in the rate of moderate-to-severe emesis and nausea and needs to be explored in a prospective study.
Comparative cardiovascular risk of allopurinol versus febuxostat in patients with gout: a nation-wide cohort study
Authors: Kang Eun Ha , Choi Hyon K , Shin Anna , Lee Yun Jong , Lee Eun Bong , Song Yeong Wook , Kim Seoyoung C
Published: April 2019

Objective

To compare cardiovascular (CV) risk among gout patients initiating allopurinol vs febuxostat.

Methods

Using 2002–2015 Korean National Health Insurance Service data for the entire Korean population, we conducted a cohort study on gout patients initiating allopurinol or febuxostat. The primary outcome was a composite CV end point of myocardial infarction, stroke/transient ischaemic attack, or coronary revascularization. Secondary outcomes were individual components of the primary outcome, and all-cause mortality. We used propensity score-matching with a 4:1 ratio for allopurinol and febuxostat initiators to control for confounding. Competing risk analyses were done for non-fatal outcomes accounting for deaths.

Results

We included 39 640 allopurinol initiators propensity score-matched on 9910 febuxostat initiators. The mean age was 59.1 years and 78.4% were male. The incidence rate per 100 person-years for the primary outcome was 1.89 for allopurinol and 1.84 for febuxostat initiators. The corresponding hazard ratio comparing allopurinol vs febuxostat initiators was 1.09 (95% CI: 0.90, 1.32). No significant difference was found for the secondary outcomes, including all-cause mortality (hazard ratio 0.96; 95% CI: 0.79, 1.16). Subgroup analyses limited to those at high CV risk and to equipotent-dose initiators (i.e. allopurinol ⩾300 mg/day vs febuxostat ⩾40 mg/day) showed similar results.

Conclusion

Overall, this large Korean population-based study suggests no difference in the risk of non-fatal CV events and all-cause mortality between allopurinol and febuxostat initiators. These findings are consistent with the recent US Medicare population study, although the current study population consisted of younger Asians.
Effects of supplementing organic microminerals and methionine with or without limiting growth during the rearing phase of replacement gilts on lameness, growth, and body composition1
Authors: Fabà Lluís , Gasa Josep , Tokach Mike D , Varella Evelia , Solà-Oriol David
Published: April 2019

Previous research suggested that lameness in growing pigs could be reduced using feeding strategies, such as limiting growth rate and supplementing trace minerals (TM) and (or) methionine (Met). The present study evaluates effects of 1) TM and Met and 2) limiting total lysine (Lys) during the rearing phase (90 d) of gilts (as a means to limit growth rate) on lameness, performance, and sow claw health and productivity (to first parity). Gilts (n = 240; 58.0 ± 11.1 kg body weight [BW]) were blocked, distributed into pens of 10 gilts, and pens were allocated to a 2 × 2 factorial arrangement. Factors were: 1) control or TM plus Met, which provided additional 10, 20, and 50 mg/kg of chelated copper, manganese, and zinc, respectively (0.1%, Aplomotec Plus, Tecnología & Vitaminas, S.L.; Alforja, Spain), and a 1.01 Met:Lys ratio and 2) standard Lys was formulated to meet growth requirements or low Lys to 19% below growth requirements. Feeding was provided through two phases, first between 119 and 163 d of age (phase I) and the second between 163 and 209 d of age (phase II). Diets had 2.43 and 2.31 Mcal net energy/kg for phases I and II, respectively, and were offered ad libitum. Low Lys did not affect feed intake but rather reduced average daily gain (ADG) by 6.35% and the final BW by 3.80% compared with standard Lys (P < 0.001). Low Lys reduced ADG (P < 0.001) and gain:feed (P = 0.012) during phase I but not during phase II. Lameness prevalence was 7.92% during rearing and increased with time (P < 0.001). Final BW (151 kg) and ADG (989 g) were similar (P > 0.05) whether gilts displayed lameness or not. Lameness was low in severity and not affected by dietary factors. However, TM- plus Met-fed gilts were 19.2 kg heavier (P = 0.016) than were control at lameness detection. On the sow farm, there was no evidence for differences in lameness or claw lesions among previous dietary treatments. In conclusion, lameness prevalence during the rearing phase was similar, independent of TM plus Met supplement, low Lys, or the interaction. Insufficient reduction of ADG and low severity in lameness may have limited the potential of dietary treatments. Moreover, a greater deficiency of Lys would be needed to achieve the degree of growth reduction previously reported to lessen lameness through feed restriction.
Metabolism and Lung Toxicity of Inhaled Naphthalene: Effects of Postnatal Age and Sex
Authors: Carratt Sarah A , Kovalchuk Nataliia , Ding Xinxin , Van Winkle Laura S
Published: April 2019

Human exposure to naphthalene (NA), an acute lung toxicant and possible human carcinogen, is primarily through inhalation. Acute lung toxicity and carcinogenesis are thought to be related because the target sites for both are similar. To understand susceptibility of the developing lung to cytotoxicity of inhaled NA, we exposed neonatal (7 days), juvenile (3 weeks), and adult mice to 5 or 10 ppm NA vapor for 4 h. We measured vacuolated airway epithelium morphometrically, quantified NA and NA-glutathione levels in plasma and lung, and quantified gene expression in microdissected airways. NA inhalation caused airway epithelial cytotoxicity at all ages, in both sexes. Contrary to a previous study that showed the greatest airway epithelial cytotoxicity in neonatal mice following intraperitoneal NA injection, we observed the most extensive airway epithelial toxicity in older, juvenile, animals exposed to NA by inhalation. Juvenile female animals were the most susceptible. Furthermore, NA inhalation in juvenile animals resulted in damage to conducting airway Club cells that was greater in proximal versus distal airways. We also found NA tissue burden and metabolism differed by age. Gene expression pathway analysis was consistent with the premise that female juvenile mice are more predisposed to damage; DNA damage and cancer pathways were upregulated. Our data demonstrate special susceptibility of young, juvenile mice to NA inhalation-induced cytotoxicity, highlight the importance of route of exposure and airway location in toxicity of chemicals in the developing lung, and provide metabolic and molecular insights for further identification of mechanisms underlying age and sex differences in NA toxicity.
A quantitative
in silico
platform for simulating cytotoxic and nanoparticle drug delivery to solid tumours
Authors: Wijeratne Peter A. , Vavourakis Vasileios
Published: April 2019

The role of tumour–host mechano-biology and the mechanisms involved in the delivery of anti-cancer drugs have been extensively studied using
in vitro
and
in vivo
models. A complementary approach is offered by
in silico
models, which can also potentially identify the main factors affecting the transport of tumour-targeting molecules. Here, we present a generalized three-dimensional
in silico
modelling framework of dynamic solid tumour growth, angiogenesis and drug delivery. Crucially, the model allows for drug properties—such as size and binding affinity—to be explicitly defined, hence facilitating investigation into the interaction between the changing tumour–host microenvironment and cytotoxic and nanoparticle drugs. We use the model to qualitatively recapitulate experimental evidence of delivery efficacy of cytotoxic and nanoparticle drugs on matrix density (and hence porosity). Furthermore, we predict a highly heterogeneous distribution of nanoparticles after delivery; that nanoparticles require a high porosity extracellular matrix to cause tumour regression; and that post-injection transvascular fluid velocity depends on matrix porosity, and implicitly on the size of the drug used to treat the tumour. These results highlight the utility of predictive
in silico
modelling in better understanding the factors governing efficient cytotoxic and nanoparticle drug delivery.
SWINGER: a clustering algorithm for concurrent coupling of atomistic and supramolecular liquids
Authors: Zavadlav Julija , Marrink Siewert J. , Praprotnik Matej
Published: April 2019

In this contribution, we review recent developments and applications of a dynamic clustering algorithm SWINGER tailored for the multiscale molecular simulations of biomolecular systems. The algorithm on-the-fly redistributes solvent molecules among supramolecular clusters. In particular, we focus on its applications in combination with the adaptive resolution scheme, which concurrently couples atomistic and coarse-grained molecular representations. We showcase the versatility of our multiscale approach on a few applications to biomolecular systems coupling atomistic and supramolecular water models such as the well-established MARTINI and dissipative particle dynamics models and provide an outlook for future work.
Leveraging Endogenous ADAR for Programmable Editing on RNA
Authors: Qu Liang , Yi Zongyi , Zhu Shiyou , Wang Chunhui , Cao Zhongzheng , Zhou Zhuo , Yuan Pengfei , Yu Ying , Tian Feng , Liu Zhiheng , Bao Ying , Zhao Yanxia , Wei Wensheng
Published: April 2019

Nucleic acid editing carries enormous potential for biological research and the development of therapeutics. Current tools for DNA or RNA editing rely on introducing exogenous proteins into living organisms, which is subject to potential risks or technical barriers due to possible aberrant effector activity, delivery limits and immunogenicity. Here, we report a programmable approach that employs a short RNA to leverage endogenous ADAR (Adenosine Deaminase Acting on RNA) proteins for targeted RNA editing. We engineered an RNA that is partially complementary to the target transcript to recruit native ADAR1 or ADAR2 to change adenosine to inosine at a specific site. We designated this new method as LEAPER (Leveraging Endogenous ADAR for Programmable Editing on RNA) and the ADAR-recruiting RNA as arRNA. arRNA, either expressed from plasmid or viral vector, or synthesized as an oligonucleotide, could achieve desirable editing. LEAPER has a manageable off-target rate on the targeted transcripts and rare global off-targets. We demonstrated that LEAPER could restore p53 function by repairing a specific cancer-relevant point mutation. Moreover, LEAPER could apply to a broad spectrum of cell types including multiple human primary cells, and it restored the α-L-iduronidase catalytic activity in Hurler syndrome patient-derived primary fibroblasts without evoking innate immune responses. As a single molecule system akin to RNAi, LEAPER enables precise and efficient RNA editing, offering the transformative potential for basic research and therapeutics.
Testing the predictability of morphological evolution in contrasting thermal environments
Authors: Pilakouta Natalie , Humble Joseph L. , Hill Iain D.C. , Arthur Jessica , Costa Ana P.B. , Smith Bethany A. , Kristjánsson Bjarni K. , Skúlason Skúli , Killen Shaun S. , Lindström Jan , Metcalfe Neil B. , Parsons Kevin J.
Published: April 2019

In light of climate change, the ability to predict evolutionary responses to temperature changes is of central importance for conservation efforts. Prior work has focused on exposing model organisms to different temperatures for just one or a few generations under laboratory conditions. Using a ‘natural experiment’, we show that studying parallel evolution in wild populations from contrasting thermal environments presents a more powerful approach for understanding and predicting responses to climate change. More specifically, we used a unique study system in Iceland, where freshwater populations of threespine sticklebacks (Gasterosteus aculeatus) are found in waters warmed by geothermal activity, adjacent to populations in ambient-temperature water. We used three sympatric and three allopatric warm-cold population pairs to test for repeated patterns of morphological divergence in relation to thermal habitat. We found that thermal habitat explained over 50% of body shape variation: fish from warm habitats had a deeper mid-body, a shorter jaw, and smaller eyes. Our common garden experiment showed that most of these morphological differences between thermal habitats were heritable. Lastly, absence of gene flow seems to facilitate parallel divergence across thermal habitats: all three allopatric population pairs were on a common evolutionary trajectory, whereas sympatric pairs followed different trajectories. Our findings therefore suggest that morphological responses to rising temperatures can be predictable when there is limited gene flow. On the other hand, migration of individuals between different thermal habitats or microhabitats can exaggerate nonparallel evolution and reduce our ability to predict evolutionary responses.
Alzheimer’s patient brain myeloid cells exhibit enhanced aging and unique transcriptional activation
Authors: Srinivasan Karpagam , Friedman Brad A. , Etxeberria Ainhoa , Huntley Melanie A. , van der Brug Marcel P. , Foreman Oded , Paw Jonathan S. , Modrusan Zora , Beach Thomas G. , Serrano Geidy E. , Hansen David V.
Published: April 2019

Gene expression changes in brain microglia from mouse models of Alzheimer’s disease (AD) are highly characterized and reflect specific myeloid cell activation states that could modulate AD risk or progression. While some groups have produced valuable expression profiles for human brain cells1–4, the cellular clarity with which we now view transcriptional responses in mouse AD models has not yet been realized for human AD tissues due to limited availability of fresh tissue samples and technological hurdles of recovering transcriptomic data with cell-type resolution from frozen samples. We developed a novel method for isolating multiple cell types from frozen post-mortem specimens of superior frontal gyrus for RNA-Seq and identified 66 genes differentially expressed between AD and control subjects in the myeloid cell compartment. Myeloid cells sorted from fusiform gyrus of the same subjects showed similar changes, and whole tissue RNA analyses further corroborated our findings. The changes we observed did not resemble the “damage-associated microglia” (DAM) profile described in mouse AD models5, or other known activation states from other disease models. Instead, roughly half of the changes were consistent with an “enhanced human aging” phenotype, whereas the other half, including the AD risk gene APOE, were altered in AD myeloid cells but not differentially expressed with age. We refer to this novel profile in human Alzheimer’s microglia/myeloid cells as the HAM signature. These results, which can be browsed at research-pub.gene.com/BrainMyeloidLandscape/reviewVersion, highlight considerable differences between myeloid activation in mouse models and human disease, and provide a genome-wide picture of brain myeloid activation in human AD.
Sex and Racial Differences in Cardiovascular Disease Risk in Patients with Atrial Fibrillation
Authors: O’Neal Wesley T. , Alam Aniqa B. , Sandesara Pratik B. , Claxton J’Neka S. , MacLehose Richard F. , Chen Lin Y. , Bengtson Lindsay G. S. , Chamberlain Alanna M. , Norby Faye L. , Lutsey Pamela L. , Alonso Alvaro
Published: April 2019

Background

Outcomes among atrial fibrillation (AF) patients may differ according to race/ethnicity and sex due to differences in biology, the prevalence of cardiovascular risk factors, and the use and effectiveness of AF treatments. We aimed to characterize patterns of cardiovascular risk across subgroups of AF patients by sex and race/ethnicity, since doing so may provide opportunities to identify interventions. We also evaluated whether these patterns changed over time.

Methods

We utilized administrative claims data from the Optum Clinformatics® Datamart database from 2009 to 2015. Patients with AF with ≥6 months of enrollment prior to the first non-valvular AF diagnosis were included in the analysis. Final analysis utilized Cox proportional hazard models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for cardiovascular outcomes stratified by sex and race/ethnicity. An additional analysis stratified outcomes by calendar year of AF diagnosis to evaluate changes in outcomes over time.

Results

In a cohort of 380,636 AF patients, women had a higher risk of ischemic stroke [HR (95% CI):1.25 (1.19, 1.31)] and lower risk of heart failure and myocardial infarction [HR (95% CI): 0.91 (0.88, 0.94) and 0.81 (0.77, 0.86), respectively)] compared to men. Black patients had elevated risk across all endpoints compared to whites, while Hispanics and Asian Americans showed no significant differences in any outcome compared to white patients. These sex and race/ethnic differences did not change over time.

Conclusions

We found sex and race/ethnic disparities in risk of cardiovascular outcomes among AF patients, without evidence of improvement over time.
Single-cell analysis of a mutant library generated using CRISPR-guided deaminase
Authors: Jun Soyeong , Lim Hyeonseob , Chun Honggu , Lee Ji Hyun , Bang Duhee
Published: April 2019

CRISPR-based screening methods using single-cell RNA sequencing (scRNA-seq) technology enable comprehensive profiling of gene perturbations from knock-out mutations. However, evaluating substitution mutations using scRNA-seq is currently limited. We combined CRISPR RNA-guided deaminase and scRNA-seq technology to develop a platform for introducing mutations in multiple genes and assessing the mutation-associated signatures. Using this platform, we generated a library consisting of 420 sgRNAs, performed sgRNA tracking analysis, and assessed the effect size of the response to vemurafenib in the melanoma cell line, which has been well-studied via knockout-based drop-out screens. However, a substitution mutation library screen has not been applied and transcriptional information for mechanisms of action was not assessed. Our platform permits discrimination of several candidate mutations that function differently from other mutations by integrating sgRNA candidates and gene expression readout. We anticipate that our platform will enable high-throughput analyses of the mechanisms related to a variety of biological events.
Surveillance based dynamic empirical therapy in a health care facility: an artificial intelligence approach
Authors: Houy Nicolas , Flaig Julien
Published: April 2019

We present a solution method to the problem of choosing empirical treatments that minimize the cumulative infected patient-days in the long run in a health care facility. We rely on the stochastic version of a compartmental model to describe the spread of an infecting organism in the health care facility, and the emergence and spread of resistance to two drugs. We assume that the parameters of the model are known. Empirical treatments are chosen at the beginning of each period based on the count of patients with each health status. The same treatment is then administered to all patients, including uninfected patients, during the period and cannot be adjusted until the next period. Our solution method is a variant of the Monte-Carlo tree search algorithm. In our simulations, it allows to reduce the average cumulative infected patient-days over two years by 47.0% compared to the best standard therapy. We explain how our algorithm can be used either to perform online optimization, or to produce data for quantitative analysis.
Bioinformatics Pipeline using JUDI: Just Do It
Authors: Pal Soumitra , Przytycka Teresa M.
Published: April 2019

Large-scale data analysis in Bioinformatics requires executing several software in a pipelined fashion. Generally each stage in a pipeline takes considerable computing resources and several workflow management systems (WMS), e.g., Snakemake and Nextflow, have been developed to ensure in case of multiple invocation of the pipeline, only the bare minimum stages that are affected by the changes across invocations get executed. However, when the pipeline needs to be executed with different settings of parameters, e.g., thresholds, underlying algorithms, etc. these WMS require significant scripting to ensure an optimal execution of the pipeline. We developed JUDI on top of a Python based WMS, DoIt, for a systematic handling of pipeline parameter settings based on the principles of DBMS that simplifies plug-and-play scripting. The effectiveness of JUDI is demonstrated in a pipeline for analyzing large scale HT-SELEX data for transcription factor and DNA binding where JUDI reduces scripting by a factor of five.

Availability

https://github.com/ncbi/JUDI
SequelTools: A Suite of Tools for Working with PacBio Sequel Raw Sequence Data
Authors: Hufnagel David E. , Hufford Matthew B. , Seetharam Arun S.
Published: April 2019

Background

PacBio sequencing is an incredibly valuable third-generation DNA sequencing method due to very long read lengths, ability to detect methylated bases, and its real-time sequencing methodology. Yet, hitherto no tool was available for analyzing the quality of, subsampling, and filtering PacBio data.

Results

Here we present SequelTools, a command-line program containing three tools: Quality Control, Read Subsampling, and Read Filtering. The Quality Control tool quickly processes PacBio Sequel raw sequence data from multiple SMRTcells producing multiple statistics and publication-quality plots describing the quality of the data including N50, read length and count statistics, PSR, and ZOR. The Read Subsampling tool allows the user to subsample reads by one or more of the following criteria: longest subreads per CLR or random CLR selection. The Read Filtering tool provides options for normalizing data by filtering out certain low-quality scraps reads and/or by minimum CLR length. SequelTools is implemented in bash, R, and Python using only standard libraries and packages and is platform independent.

Conclusions

SequelTools is a program that provides the only free, fast, and easy-to-use quality control tool, and the only program providing this kind of read sumbsampling and read filtering for PacBio Sequel raw sequence data, and is available at https://github.com/ISUgenomics/SequelTools