bluuebunny/crossref_metadata_2025 huggingface dataset:
Stone Tools: Their Relevance for Historians and the Study of Historical Processes
Authors: Pargeter Justin
Published: January 2019

From at least 3.4 million years ago to historic periods, humans and their ancestors used stone as the raw material for tool production. Archeologists find stone tools on all the planet’s habitable landmasses, even in its cold and ecologically sparse Arctic regions. Their ubiquity and durability inform archeologists about important dimensions of human behavioral variability. Stone tools’ durability also gives them the ability to contribute to the study of long-term historical processes and the deeper regularities and continuities underlying processes of change. Over the last two millennia as ceramics, livestock, European goods, and eventually Europeans themselves arrived in southern Africa, stone tools remained. As social, environmental, economic, and organizational upheavals buffeted African hunter-gatherers, they used stone tools to persist in often marginal landscapes. Indigenous Africans’ persistence in the environment of their evolutionary origins is due in large part to these “small things forgotten.” Stone tools and their broader contexts of use provide one important piece of information to address some of archaeology and history’s “big issues,” such as resilience in small-scale societies, questions of human mobility and migrations, and the interactions of humans with their environments. Yet, stone tools differ in important ways from the technologies historians are likely to be familiar with, such as ceramics and metallurgy, in being reductive. While ceramics are made by adding and manipulating clay-like substances, stone tools are made by removing material through the actions of grinding, pecking, or fracture. Metals sit somewhere in between ceramics and stone: they can be made through the reduction of ores, but they can also be made through additive processes when one includes recycling of old metals. Stone-tool technologies can also be more easily and independently reinvented than these other technologies. These distinctions, along with the details of stone tool production and use, hold significance for historians wishing to investigate the role of technology in social organization, economy, consumption, contact, and cultural change.
Juxta-annular right atrial anchoring of prosthetic mitral valves in endocarditis with anterior annulus destruction†
Authors: El Beyrouti Hazem , Kornberger Angela , Beiras-Fernandez Andres , Vahl Christian-Friedrich
Published: January 2019

Destruction of the mitral annulus is associated with poor outcomes. We present the treatment of endocarditis using a technique that enables secure anchoring of prosthetic valves where the anterior part of the mitral annulus is severely disrupted. It was used in 5 patients. Follow-up at 10 ± 4 months showed the valves intact without recurrence of endocarditis. Mortality was limited to 1 patient who died of non-cardiac causes. We conclude that partial right atrial anchoring is a useful bail-out and enables favourable outcomes in patients with extensive loss of the (peri)annular tissue due to endocarditis.
Family Law 2019
Authors: Sendall Jane
Published: January 2019

Family Law takes a highly practical, student-centred approach to the essential law and procedure at the heart of family law. Providing a comprehensive guide to the subject, it focuses on relationship breakdown, money and property, children, and domestic abuse. A concise writing style and short chapters ensure focused learning, while chapter summaries and self-test questions help students to consolidate their knowledge and identify areas for further study. Throughout the book case studies and examples are used, demonstrating how family law applies in practice and helping to prepare students for their future careers. The book also features diagrams and flowcharts throughout, helping to improve understanding of complex processes or areas of difficulty. Topics that are covered include: family law practice and the first interview; public funding; alternative dispute resolution in family law; judicial separation and nullity; divorce; defences to divorce; jurisdiction; procedure for a matrimonial order; the Civil Partnership Act 2004; dissolution of a civil partnership; financial orders following divorce or dissolution; financial orders; pre-marital agreements; procedure for financial orders; variation, collection, and enforcement of financial orders; protecting assets and the family home in financial order proceedings; separation and maintenance agreements; child support; pensions in financial proceedings; and taxation in family law.
2. Funding
Authors: Sendall Jane
Published: January 2019

This chapter discusses the changes made to public funding in family cases; the availability of public funding for family law proceedings; the levels of funding available to the client; the tests to determine whether a client is eligible for public funding; and the recovery of public funding through the statutory charge.
5. Separation and Nullity
Authors: Sendall Jane
Published: January 2019

This chapter discusses the remedy of separation as an alternative to divorce proceedings. It also examines nullity as a remedy, including void and voidable marriages and civil partnerships, as well as a remedy for escaping forced marriages.
6. Divorce
Authors: Sendall Jane
Published: January 2019

This chapter discusses the grounds for divorce under the Matrimonial Causes Act 1973. These include adultery, unreasonable behaviour, desertion, two years’ separation plus consent, and five years’ separation. The chapter explores each of the five possible facts that prove the ground for divorce and explains the relevance of continued cohabitation between the parties.
10. Civil Partnership Act 2004
Authors: Sendall Jane
Published: January 2019

This chapter discusses the scope of the Civil Partnership Act 2004 (CPA 2004) and the formation of civil partnerships. It also explains the differences between civil partnership and marriage. The CPA 2004 enables same-sex couples to form legally recognized civil partnerships. Once a partnership has been formed, civil partners assume many legal rights and responsibilities for each other, third parties, and the State.
19. Pensions in Financial Proceedings
Authors: Sendall Jane
Published: January 2019

This chapter covers pensions and pension orders available to the court. It discusses pension as a financial instrument and how a pension is valued. The chapter explains how pensions are dealt with following divorce or dissolution, including pension offsetting, pension attachment, and pension sharing.
Regularity Bootstrapping for 4th-order Nonlinear Elliptic Equations
Authors: Bhattacharya Arunima , Warren Micah
Published: January 2019

We consider nonlinear 4th-order elliptic equations of double divergence type. We show that for a certain class of equations where the nonlinearity is in the Hessian, solutions that are $C^{2,\alpha }$ enjoy interior estimates on all derivatives.
Morbidity and mortality outcomes in neonates who were transferred from home and hospitals to the only neonatal intensive care unit in Guinea: a descriptive report using routinely collected health data
Authors: Cherif Mahamoud Sama , Dahal Prabin , Mansoor Rashid , Camara Facely , Bah Abdourahamane , Kone Alpha , Cherif Fatoumata , Kasse Dienaba , Diakite Mandiou , Diallo Mamadou Pathe
Published: January 2019

Background

The Sustainable Development Goal (SDG) for neonatal mortality has identified its reduction as one of the main targets to be achieved by 2030. We provide a descriptive report on neonatal outcomes from the only neonatal intensive care unit (NICU) in Guinea.

Methods

Data collection took place between November 2004 and May 2005 at the NICU of the Institute of Child Health in the capital, Conakry. A descriptive summary of the neonatal, maternal and intrapartum characteristics is reported.

Results

A total of 294 neonates were admitted to the NICU incubators during the study period, transferred either from hospitals (48%) or directly from their homes (52%). The most common reasons for admission were foetal distress (37.1%) and maternal–foetal infections (35.4%). Among 270 neonates with known outcome, the overall mortality among the admitted children remained high at 20.7% (56/270),with a large proportion of the deaths (71.4%, 40/56) occurring within 7 d of their admission. The mortality rate was 23.7% (31/131) among the neonates who were admitted to our NICU after home birth and 17.9% (25/139) among those who were transferred from hospitals (OR: 1.41, 95% CI: 0.75–2.67).

Conclusion

Almost one in every five neonates who were admitted to the NICU incubator died during the study period. More hospitals equipped with NICU facilities are urgently required if Guinea is to achieve the SDG target for neonatal mortality.
Ontogeny of Polycotylid Long Bone Microanatomy and Histology
Authors: O’Keefe F R , Sander P M , Wintrich T , Werning S
Published: January 2019

Plesiosauria is an extinct clade of diapsid marine reptiles that evolved in the Late Triassic and radiated globally for the remainder of the Mesozoic. The recent description of a pregnant specimen of Polycotylus latipinnis demonstrates that some plesiosaurs were viviparous. To establish a baseline of histological data on plesiosaur ontogeny, we sampled the mother and fetus of the gravid plesiosaur specimen. To widen the base of data concerning ontogeny and life history of plesiosaurs, we gathered additional morphologic and histologic data from a securely identified growth series of polycotylids from the Pierre Shale of South Dakota. Paleohistological thin sections were prepared from the three humeri. Both adults show a dense, heavily remodeled cortex consisting entirely of longitudinally oriented secondary osteons, except for a thin rind of superficial primary bone. The mother exhibits an external fundamental system, indicating it was fully mature; the other adult does not. In both adults the cortex grades into a spongy medulla, comprising large vascular canals and erosion rooms surrounded by secondary lamellar trabecular bone, and lacking a marrow cavity. The fetal humerus possesses a medullary region similar to that of the Dolichorhynchops bonneri adult, although its lamellar bone is primary and deposited around calcified cartilage. The medulla is demarcated from the cortex by a prominent Kastschenko’s line. The cortex of the fetus is a relatively thin layer of periosteal woven bone, longitudinally to radially vascularized, and interfingered with columns of osteoblasts surrounded by rapidly-deposited extracellular matrix. The neonate humerus resembles the fetus, with its trabeculae identical in both size and histology, although it lacks calcified cartilage. The cortex is also similar but much thicker, consisting entirely of rapidly deposited, radially vascularized, woven to fibrolamellar bone. The cortex carries a line near its surface. This feature is not a line of arrested growth, but a sudden change in vascular angle and increase in bone density. We argue this feature is a birth line indicating a change in growth regime, possibly in response to increased hydrodynamic forces after birth. The birth line indicates that the neonate was about 40% of maternal length when born. Our histological data demonstrate that polycotylids had very high fetal growth rates, and that birth size was large. Comparison with the geologically oldest plesiosaur confirms that rapid growth evolved in the Triassic, although histological details differ, and the degree to which the polycotylid ontogenetic pattern is generalizable to other plesiosaurs is currently unknown. Further histological research utilizing full growth series is needed, particularly for Jurassic taxa.
Clinical value of (1,3)-β-D-glucan, mannan, antimannan IgG and IgM antibodies in diagnosis of invasive candidiasis
Authors: Li Fengtian , Yu Xiaotian , Ye Liyan , Zhou Guang , Wang Leili , Luo Yanping
Published: January 2019

Diagnosis of invasive candidiasis (IC) is still challenging due to absence of specific clinical signs and symptoms. In this study we investigate the clinical value of (1,3)-β-D-glucan (BDG), mannan (MN), antimannan immunoglobulin G (AM-IgG), and antimannan immunoglobulin M (AM-IgM) assay in diagnosis of IC. During 2016 to 2018 serum samples from 71 patients with IC and 185 patients without IC were collected. Serum samples from 41 patients with bacteremia were also enrolled as additional control. Significant differences in mean serum biomarkers levels between IC and control group were observed. At low cutoff threshold the sensitivity and specificity of BDG (70 pg/ml), MN (50 pg/ml), AM-IgG (80 AU/ml), and AM-IgM (80 AU/ml) assay were 64.8% and 90.8%, 64.8 and 89.2%,74.6% and 87.0%, 57.7% and 60.0%, respectively. Combined use of BDG/MN, BDG/AM-IgG and MN/AM-IgG improved the sensitivity and specificity to 85.9% and 81.1%, 85.9% and 80.0%, 81.7% and 81.6%, respectively. The combination of BDG/MN, BDG/AM-IgG, or MN/AM-IgG may provide an encouraging approach for diagnosis of IC.
Dust bombardment can explain the extremely elongated shape of 1I/’Oumuamua and the lack of interstellar objects
Authors: Vavilov Dmitrii E , Medvedev Yurii D
Published: January 2019

Asteroid 1I/’Oumuamua is the first observed interstellar object. Its light-curve amplitude indicates that the object is highly elongated with an axial ratio of at least 5:1. The absence of such elongated asteroids in the Solar system and the apparent lack of observed interstellar objects are intriguing problems. Here we show that ’Oumuamua may have originated as a slightly elongated asteroid about 500 × 300 m in size. Surface erosion, caused by interstellar dust bombardment, subsequently increased the axial ratio. Simply travelling through the interstellar medium for 0.03 to 2 Gyr would have sufficed to give 1I its present shape. Passing through a 10 pc dust cloud with a grain density of 10−23 g cm−3 at 50 km s−1 would have had a similar effect on ’Oumuamua’s form. Smaller objects of around 100 m in diameter can travel the Galactic disc for merely 30 Myr before they are disrupted. This could explain the small number of interstellar objects observed to date.
PATIENT DOSE SURVEY BASED ON SIZE-SPECIFIC DOSE ESTIMATE AND ACCEPTABLE QUALITY DOSE IN CHEST AND ABDOMEN/PELVIS CT EXAMINATIONS
Authors: Mehdipour Ali , Parsi Masoumeh , Khorram Faezeh-Sadat
Published: January 2019

The practical aspects of two recently developed patient dose optimization methods in computed tomography (CT) examinations, size-specific dose estimate (SSDE) and acceptable quality dose (AQD), were verified for the chest and abdomen/pelvis examinations. A dose survey was performed in a CT institute by considering patients lateral diameter, weight and body mass index (BMI). The AQD tables for weight and BMI groups and SSDE threshold curves were obtained. The mean of volume CT dose index and dose length product for standard-size patients were compared with the national diagnostic reference levels (NDRLs) of Iran. The results show that patient doses are below the NDRLs. It is more reliable to report the AQDs based on SSDE and for BMI groups which can well take into account patient size in the dose optimization process. The SSDE threshold curves can be determined with more precision by including dose data of all possible sizes in the curves.
Gene Duplication and Mutation in the Emergence of a Novel Aggressive Allele of the AVR-Pik Effector in the Rice Blast Fungus
Authors: Longya Apinya , Chaipanya Chaivarakun , Franceschetti Marina , Maidment Josephine H. R. , Banfield Mark J. , Jantasuriyarat Chatchawan
Published: January 2019

Higher yield potential and greater yield stability are common targets for crop breeding programs, including those in rice. Despite these efforts, biotic and abiotic stresses continue to impact rice production. Rice blast disease, caused by Magnaporthe oryzae, is the most devastating disease affecting rice worldwide. In the field, resistant varieties are unstable and can become susceptible to disease within a few years of release due to the adaptive potential of the blast fungus, specifically in the effector (avirulence [AVR]) gene pool. Here, we analyzed genetic variation of the effector gene AVR-Pik in 58 rice blast isolates from Thailand and examined the interaction between AVR-Pik and the cognate rice resistance gene Pik. Our results reveal that Thai rice blast isolates are very diverse. We observe four AVR-Pik variants in the population, including three previously identified variants, AVR-PikA, AVR-PikD, and AVR-PikE, and one novel variant, which we named AVR-PikF. Interestingly, 28 of the isolates contained two copies of AVR-Pik, always in the combination of AVR-PikD and AVR-PikF. Blast isolates expressing only AVR-PikF show high virulence to rice cultivars encoding allelic Pik resistance genes, and the AVR-PikF protein does not interact with the integrated heavy metal–associated domain of the Pik resistance protein in vitro, suggesting a mechanism for immune evasion.
Factors Influencing Clinical and Setting Pathways After Discharge From an Acute Palliative/Supportive Care Unit
Authors: Mercadante Sebastiano , Adile Claudio , Ferrera Patrizia , Casuccio Alessandra
Published: January 2019

Aim:

The aim of this study was to assess the factors which influence the care pathway after discharge from an acute palliative supportive care unit (APSCU).

Methods:

Patients’ demographics, indications for admission, kind of admission, the presence of a caregiver, awareness of prognosis, data on anticancer treatments in the last 30 days, ongoing treatment (on/off or uncertain), the previous care setting, analgesic consumption, and duration of admission were recorded. The Edmonton Symptom Assessment Scale (ESAS) at admission and at time of discharge (or the day before death), CAGE (cut down, annoy, guilt, eye-opener), and the Memorial Delirium Assessment Scale (MDAS), were used. At time of discharge, the subsequent referral to other care settings (death, home, home care, hospice, oncology), and the pathway of oncologic treatment were reconsidered (on/off, uncertain).

Results:

A total of 314 consecutive cancer patients admitted to the APSCU were surveyed. Factors independently associated with on-therapy were the lack of a caregiver, home discharge, and short hospital admission, in comparison with off-treatment, and less admission for other symptoms, shorter hospital admission, discharge at home, and better well-being, when compared with “uncertain.” Similarly, many factors were associated with discharge setting, but the only factor independently associated with discharge home was being “on-therapy.”

Conclusions:

The finding of this study is consistent with an appropriate selection of patients after being discharged by an APSCU, that works as a bridge between active treatments and supportive/palliative care, according the concept of early and simultaneous care.
Simultaneous parameter estimation and variable selection via the logit-normal continuous analogue of the spike-and-slab prior
Authors: Thomson W. , Jabbari S. , Taylor A. E. , Arlt W. , Smith D. J.
Published: January 2019

We introduce a Bayesian prior distribution, the logit-normal continuous analogue of the spike-and-slab, which enables flexible parameter estimation and variable/model selection in a variety of settings. We demonstrate its use and efficacy in three case studies—a simulation study and two studies on real biological data from the fields of metabolomics and genomics. The prior allows the use of classical statistical models, which are easily interpretable and well known to applied scientists, but performs comparably to common machine learning methods in terms of generalizability to previously unseen data.
Wing morphing allows gulls to modulate static pitch stability during gliding
Authors: Harvey C. , Baliga V. B. , Lavoie P. , Altshuler D. L.
Published: January 2019

A gliding bird's ability to stabilize its flight path is as critical as its ability to produce sufficient lift. In flight, birds often morph the shape of their wings, but the consequences of avian wing morphing on flight stability are not well understood. Here, we investigate how morphing the gull elbow joint in gliding flight affects their static pitch stability. First, we combined observations of freely gliding gulls and measurements from gull wing cadavers to identify the wing configurations used during gliding flight. These measurements revealed that, as wind speed and gusts increased, gulls flexed their elbows to adopt wing shapes characterized by increased spanwise camber. To determine the static pitch stability characteristics of these wing shapes, we prepared gull wings over the anatomical elbow range and measured the developed pitching moments in a wind tunnel. Wings prepared with extended elbow angles had low spanwise camber and high passive stability, meaning that mild perturbations could be negated without active control. Wings with flexed elbow angles had increased spanwise camber and reduced static pitch stability. Collectively, these results demonstrate that gliding gulls can transition across a broad range of static pitch stability characteristics using the motion of a single joint angle.
Linearized reconstruction for diffuse optical spectroscopic imaging
Authors: Ammari Habib , Jin Bangti , Zhang Wenlong
Published: January 2019

In this paper, we present a novel reconstruction method for diffuse optical spectroscopic imaging with a commonly used tissue model of optical absorption and scattering. It is based on linearization and group sparsity, which allows the diffusion coefficient and absorption coefficient to be recovered simultaneously, provided that their spectral profiles are incoherent and a sufficient number of wavelengths are judiciously taken for the measurements. We also discuss the reconstruction for an imperfectly known boundary and show that, with multi-wavelength data, the method can reduce the influence of modelling errors and still recover the absorption coefficient. Extensive numerical experiments are presented to support our analysis.
Corpus Colossal: A Bibliometric Analysis of Neuroscience Abstracts and Impact Factor
Authors: Kenkel William M.
Published: January 2019

A field’s priorities are thought to be reflected by the contents of its high-impact journals. Researchers in turn may choose to pursue research objectives based on what is believed to be most highly valued by their peers. By compiling a corpus of abstracts from within the field neuroscience, I was able to analyze which terms had differential frequencies between 12 high-impact and 13 medium-impact journals. Approximately 50,000 neuroscience abstracts were analyzed over the years 2014-2018. Several broad trends emerged from the analysis of which terms were biased towards high-impact journals. Generally speaking, high-impact journals tended to feature: genetic or psychiatric studies, use of the latest and most sophisticated methods, examinations of the orbitofrontal cortex or amygdala, and/or use of human or non-mammalian subjects. Medium-impact journals tended to feature motor or cardiovascular studies, use of older methods, examinations of caudal brain regions, and/or rats as subjects.
Disentangling sRNA-Seq data to study RNA communication between species
Authors: Bermúdez-Barrientos JR , Ramírez-Sánchez O , Chow FWN , Buck AH , Abreu-Goodger C
Published: January 2019

Many organisms exchange small RNAs during their interactions, and these RNAs can target or bolster defense strategies in host-pathogen systems. Current sRNA-Seq technology can determine the small RNAs present in any symbiotic system, but there are very few bioinformatic tools available to interpret the results. We show that one of the biggest challenges comes from sequences that map equally well to the genomes of both interacting organisms. This arises due to the small size of the sRNA compared to large genomes, and because many of the produced sRNAs come from genomic regions that encode highly conserved miRNAs, rRNAs or tRNAs. Here we present strategies to disentangle sRNA-Seq data from samples of communicating organisms, developed using diverse plant and animal species that are known to exchange RNA with their parasites. We show that sequence assembly, both de novo and genome-guided, can be used for sRNA-Seq data, greatly reducing the ambiguity of mapping reads. Even confidently mapped sequences can be misleading, so we further demonstrate the use of differential expression strategies to determine the true parasitic sRNAs within host cells. Finally, we validate our methods on new experiments designed to probe the nature of the extracellular vesicle sRNAs from the parasitic nematode H. bakeri that get into mouse epithelial cells.
Simultaneous proteomics and three PTMomics characterization of pro-inflammatory cytokines stimulated INS-1E cells using TiO2enrichment strategy
Authors: Huang Honggang , Drici Lylia , Lassen Pernille S. , Palmisano Giuseppe , Larsen Martin R.
Published: January 2019

Diverse protein post-translational modifications (PTMs) in proteins form complex combinatorial patterns to regulate the protein function and biological processes in a fine-tuning manner. Reversible phosphorylation, cysteines (Cys) modification, and N-linked glycosylation are essentially involved in cellular signaling pathways of pro-inflammatory cytokines, which can induce beta cell death and diabetes. Here we developed a novel mass spectrometry–based proteomic strategy (termed TiCPG) for the simultaneous comprehensive characterization of the proteome and three post-translational modifications (PTMomes) by applying TiO2enrichment of peptides with reversibly modified Cysteine (rmCys), Phosphorylation, and sialylated N-linked (SAN-) Glycosylation from low amount of sample material with largely minimized sample loss. We applied this TiCPG strategy to quantitatively study the change of the three PTMs in β-cell-like INS-1E cells subject to pro-inflammatory cytokines stimulation. It enabled efficient enrichment and quantitative analysis of 8346 rmCys sites, 10321 phosphosites and 1906 SAN-glycosylation sites from 5853 proteins. Significant regulation was found on 100 proteins at the total protein level, while much higher degree of regulation was identified on 3025 peptides with PTMs from 1490 proteins. The three PTMs were co-regulated in proteins, but demonstrated differential spatial and temporal patterns related to protein cellular localization and function in the time course of cytokines stimulation, and they were extensively involved in essential signaling pathways related to pro-inflammatory cytokine mediated β-cell apoptosis, such as the inducible NO synthase (NOS2) signaling pathway, Overall, the TiCPG strategy is proved as a straight forward and powerful tool for multiple PTMomics studies.
Computational Analysis of Insulin-Glucagon Signalling Network: Implications of Bistability in Metabolic Homeostasis and Disease states
Authors: Somvanshi Pramod R , Tomar Manu , Kareenhalli Venkatesh
Published: January 2019

Insulin and glucagon control plasma macronutrient homeostasis through their signalling network composed of multiple feedback and crosstalk mechanisms. To understand how these interactions contribute to metabolic homeostasis and disease states, we analysed the steady state response of metabolic regulation (catabolic or anabolic) with respect to structural and input perturbations in the integrated signalling network, for varying levels of plasma glucose. Structural perturbations revealed: the positive feedback of AKT on IRS is responsible for the bistability in anabolic zone (glucose >5.5 mmol); the positive feedback of calcium on cAMP is responsible for ensuring ultrasensitive response in catabolic zone (glucose <4.5 mmol); the crosstalk between AKT and PDE3 is responsible for efficient catabolic response under low glucose condition; the crosstalk between DAG and PKC regulates the span of anabolic bistable region with respect to plasma glucose levels. The macronutrient perturbations revealed: varying plasma amino acids and fatty acids from normal to high levels gradually shifted the bistable response towards higher glucose range eventually making the response catabolic or unresponsive to increasing glucose levels. The analysis reveals that certain macronutrient composition may be more conducive to homeostasis than others. The network perturbations that may contribute to disease states such as diabetes, obesity and cancer are discussed.
Automated methods for 3D Segmentation of Focused Ion Beam-Scanning Electron Microscopic Images
Authors: Caffrey Brian , Maltsev Alexander V. , Gonzalez-Freire Marta , Hartnell Lisa M. , Ferrucci Luigi , Subramaniam Sriram
Published: January 2019

Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) is an imaging approach that enables analysis of the 3D architecture of cells and tissues at resolutions that are 1-2 orders of magnitude higher than that possible with light microscopy. The slow speeds of data collection and analysis are two critical problems that limit more extensive use of FIB-SEM technology. Here, we present a robust method that enables rapid, large-scale acquisition of data from tissue specimens, combined with an approach for automated data segmentation using machine learning, which dramatically increases the speed of image analysis. We demonstrate the feasibility of these methods through the 3D analysis of human muscle tissue by showing that our process results in an improvement in speed of up to three orders of magnitude as compared to manual approaches for data segmentation. All programs and scripts we use are open source and are immediately available for use by others.

Impact Statement

The high-throughput, easy-to-use and versatile segmentation pipeline described in our manuscript will enable rapid, large-scale statistical analysis of sub-cellular structures in tissues.
Image-based metric of invasiveness predicts response to adjuvant temozolomide for primary glioblastoma
Authors: Massey Susan Christine , White Haylye , Whitmire Paula , Doyle Tatum , Johnston Sandra K. , Singleton Kyle W. , Jackson Pamela R. , Hawkins-Daarud Andrea , Bendok Bernard R. , Porter Alyx B. , Vora Sujay , Sarkaria Jann N. , Mrugala Maciej M. , Swanson Kristin R.
Published: January 2019

Temozolomide (TMZ) has been the standard-of-care chemotherapy for glioblastoma (GBM) patients for more than a decade. Despite this long time in use, significant questions remain regarding how best to optimize TMZ therapy for individual patients. Understanding the relationship between TMZ response and factors such as number of adjuvant TMZ cycles, patient age, patient sex, and image-based tumor features, might help predict which GBM patients would benefit most from TMZ, particularly for those whose tumors are not MGMT methylated. Using a cohort of 90 newly-diagnosed GBM patients treated according to the Stupp protocol, we examined the relationships between several patient and tumor characteristics and volumetric and survival outcomes during adjuvant chemotherapy. Volumetric changes in MR imaging abnormalities during adjuvant therapy were used to assess TMZ response. T1Gd volumetric response is associated with younger patient age, increased number of TMZ cycles, longer time to nadir volume, and decreased tumor invasiveness. Moreover, increased adjuvant TMZ cycles corresponded with improved volumetric response only among more nodular tumors, and this volumetric response was associated with improved survival outcomes. Finally, in a subcohort of patients with known MGMT methylation status, MGMT methylated tumors were more diffusely invasive than unmethylated tumors, suggesting that the improved response in nodular tumors is not driven by a preponderance of MGMT methylated tumors. Our finding that less diffusely invasive tumors are associated with greater volumetric response to TMZ suggests that patients with these tumors may benefit from additional cycles of adjuvant TMZ, even for those without MGMT methylation.
Highly Heritable and Functionally Relevant Breed Differences in Dog Behavior
Authors: MacLeant Evan L , Snyder-Mackler Noah , vonHoldt Bridgett M. , Serpell James A.
Published: January 2019

Variation across dog breeds presents a unique opportunity for investigating the evolution and biological basis of complex behavioral traits. We integrated behavioral data from more than 17,000 dogs from 101 breeds with breed-averaged genotypic data (N = 5,697 dogs) from over 100,000 loci in the dog genome. Across 14 traits, we found that breed differences in behavior are highly heritable, and that clustering of breeds based on behavior accurately recapitulates genetic relationships. We identify 131 single nucleotide polymorphisms associated with breed differences in behavior, which are found in genes that are highly expressed in the brain and enriched for neurobiological functions and developmental processes. Our results provide insight into the heritability and genetic architecture of complex behavioral traits, and suggest that dogs provide a powerful model for these questions.
Regeneration in the absence of a blastema requires cell division but is not tied to wound healing in the ctenophoreMnemiopsis leidyi
Authors: Ramon-Mateu Julia , Ellison Tori , Angelini Thomas E. , Martindale Mark Q.
Published: January 2019

Background

The ability to regenerate is a widely distributed but highly variable trait among metazoans. A variety of modes of regeneration has been described for different organisms, however, many questions regarding the origin and evolution of these strategies remain unanswered. Most species of ctenophore (or “comb jellies”), a clade of marine animals that branch off at the base of the animal tree of life, possess an outstanding capacity to regenerate. However, the cellular and molecular mechanisms underlying this ability are unknown. We have used the ctenophoreMnemiopsis leidyias a system to study wound healing and adult regeneration and provide some first-time insights of the cellular mechanisms involved in the regeneration of one of the most ancient extant group of multicellular animals.

Results

We show that cell proliferation is activated at the wound site and is indispensable for whole-body regeneration. Wound healing occurs normally in the absence of cell proliferation forming a scar-less wound epithelium. No blastema-like structure is generated at the cut site, rather undifferentiated cells assume the correct location of missing structures and differentiate in place. Pulse-chase experiments and surgical intervention show that cells originating in the main regions of cell proliferation (the tentacle bulbs) do not seem to contribute to the formation of new structures after surgical challenge, suggesting a local source of cells during regeneration. While exposure to cell-proliferation blocking treatment inhibits regeneration, the ability to regenerate is recovered when the treatment ends (days after the original cut), suggesting that ctenophore regenerative capabilities are constantly ready to be triggered and they are somehow separable of the wound healing process.

Conclusions

Ctenophore regeneration takes place through a process of cell proliferation-dependent non blastemal-like regeneration and is temporally separable of the wound healing process. The remarkable ability to replace missing tissue, the many favorable experimental features (e.g. optical clarity, high fecundity, rapid regenerative performance, stereotyped cell lineage, sequenced genome), and the early branching phylogenetic position in the animal tree, all point to the emergence of ctenophores as a new model system to study the evolution of animal regeneration.
Nano-enhanced optical gene delivery to retinal degenerated mice
Authors: Batabyal Subrata , Gajjeraman Sivakumar , Bhattacharya Sulagna , Wright Weldon , Mohanty Samarendra
Published: January 2019

The efficient and targeted delivery of genes and other impermeable therapeutic molecules into retinal cells is of immense importance for therapy of various visual disorders. Traditional methods for gene delivery require viral transfection, or chemical methods that suffer from one or many drawbacks such as invasiveness, low efficiency, lack of spatially targeted delivery, and can generally have deleterious effects such as unexpected inflammatory responses and immunological reactions. Here, we introduce a continuous wave near-infrared laser-based Nano-enhanced Optical Delivery (NOD) method for spatially controlled delivery of opsin-encoding genes into retinain-vivo. In this method, the optical field enhancement by gold nanorods is utilized to transiently permeabilize cell membrane enabling delivery of exogenous impermeable molecules to nanorod-binding cells in laser-irradiated regions. The successful delivery and expression of opsin in targeted retina after in-vivo NOD in the mice models of retinal degeneration opens new vista for re-photosensitizing retina with geographic atrophies as in dry age-related macular degeneration (AMD).
Meta-analysis of targeted metabolomics data from heterogeneous biological samples provides insights into metabolite dynamics
Authors: Lee Ho-Joon , Kremer Daniel M. , Sajjakulnukit Peter , Zhang Li , Lyssiotis Costas A.
Published: January 2019

Introduction

Mass spectrometry-based metabolomics coupled to liquid chromatography, or LC-MS metabolomics, has become the most popular tool for global metabolite abundance profiling to study metabolism. However, the physicochemical complexity of metabolites poses a major challenge for reliable measurements of metabolite abundance. One way to address the issue is to use multiple chromatographic methods to capture a greater range of molecular diversity. We previously developed a tandem mass spectrometry-based label-free targeted metabolomics analysis framework coupled to two distinct chromatographic methods, reversed-phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC), with dynamic multiple reaction monitoring (dMRM) for simultaneous detection of over 200 metabolites to study core metabolic pathways.

Objectives

We aim to analyze a large-scale heterogeneous data compendium generated from our LC-MS/MS platform with both RPLC and HILIC methods to systematically assess measurement quality in biological replicate groups and to gain insights into metabolite dynamics across different biological conditions.

Methods

Our metabolomics framework was applied in a wide range of experimental systems including cancer cell lines, tumors, extracellular media, primary cells, immune cells, organoids, organs (e.g. pancreata), tissues, and sera from human and mice. We also developed computational and statistical analysis pipelines, which include hierarchical clustering, replicate-group CV analysis, correlation analysis, and case-control paired analysis.

Results

We generated a compendium of 42 heterogeneous deidentified datasets with 635 samples using both RPLC and HILIC methods. There exist signature metabolites that correspond to heterogeneous phenotypes, involved in several metabolic pathways. The RPLC method shows overall better reproducibility than the HILIC method for most metabolites including polar amino acids. Correlation analysis reveals high confidence metabolites irrespective of experimental systems such as methionine, phenylalanine, and taurine. We also identify homocystine, reduced glutathione, and phosphoenolpyruvic acid as highly dynamic metabolites across all case-control paired samples.

Conclusions

Our study is expected to serve as a resource and a reference point for a systematic analysis of label-free LC-MS/MS targeted metabolomics data in both RPLC and HILIC methods with dMRM.
Detecting Circular RNA from High-throughput Sequence Data with de Bruijn Graph
Authors: Li Xin , Wu Yufeng
Published: January 2019

Circular RNA is a type of non-coding RNA, which has a circular structure. Many circular RNAs are stable and contain exons, but are not translated into proteins. Circular RNA has important functions in gene regulation and plays an important role in some human diseases. Several biological methods, such as RNase R treatment, have been developed to identify circular RNA. Multiple bioinformatics tools have also been developed for circular RNA detection with high-throughput sequence data. In this paper, we present circDBG, a new method for circular RNA detection with de Bruijn graph. We conduct various experiments to evaluate the performance of CircDBG based on both simulated and real data. Our results show that CircDBG finds more reliable cir-cRNAs with low bias, has more efficiency in running time, and performs better in balancing accuracy and sensitivity than existing methods. As a byproduct, we also introduce a new method to classify circular RNAs based on reads alignment. Finally, we report a potential chimeric circular RNA that is found by CircDBG based on real sequence data. CircDBG can be downloaded from https://github.com/lxwgcool/CircDBG.
Molecular Landscape of Anti-Drug Antibodies Reveals the Mechanism of the Immune Response Following Treatment with TNFα Antagonists
Authors: Vaisman-Mentesh Anna , Rosenstein Shai , Yavzori Miri , Dror Yael , Fudim Ella , Ungar Bella , Kopylov Uri , Picard Orit , Kigel Aya , Ben-Horin Shomron , Benhar Itai , Wine Yariv
Published: January 2019

Drugs formulated from monoclonal antibodies (mAbs) are clinically effective in various diseases. Repeated administration of mAbs, however, elicits an immune response in the form of anti-drug-antibodies (ADA), thereby reducing the drug’s efficacy. Notwithstanding their importance, the molecular landscape of ADA and the mechanisms involved in their formation are not fully understood. Using a newly developed quantitative bio-immunoassay, we found that ADA concentrations specific to TNFα antagonists can exceed extreme concentrations of 1 mg/ml with a wide range of neutralization capacity. Our data further suggest a preferential use of the λ light chain in a subset of neutralizing ADA. Moreover, we show that administration of TNFα antagonists result in a vaccine-like response whereby ADA formation is governed by the extrafollicular T cell-independent immune response. Our bio-immunoassay coupled with insights on the nature of the immune response can be leveraged to improve mAb immunogenicity assessment and facilitate improvement in therapeutic intervention strategies.
Birth-and-death evolution of the fatty acyl-CoA reductase (FAR) gene family and diversification of cuticular hydrocarbon synthesis in Drosophila
Authors: Finet Cédric , Slavik Kailey , Pu Jian , Carroll Sean B. , Chung Henry
Published: January 2019

The birth-and-death evolutionary model proposes that some members of a multigene family are phylogenetically stable and persist as a single copy over time whereas other members are phylogenetically unstable and undergo frequent duplication and loss. Functional studies suggest that stable genes are likely to encode essential functions, while rapidly evolving genes reflect phenotypic differences in traits that diverge rapidly among species. One such class of rapidly diverging traits are insect cuticular hydrocarbons (CHCs), which play dual roles in chemical communications as short-range recognition pheromones as well as protecting the insect from desiccation. Insect CHCs diverge rapidly between related species leading to ecological adaptation and/or reproductive isolation. Because the CHC and essential fatty acid biosynthetic pathways share common genes, we hypothesized that genes involved in the synthesis of CHCs would be evolutionary unstable, while those involved in fatty acid-associated essential functions would be evolutionary stable. To test this hypothesis, we investigated the evolutionary history of the fatty acyl-CoA reductases (FARs) gene family that encodes enzymes in CHC synthesis. We compiled a unique dataset of 200 FAR proteins across 12 Drosophila species. We uncovered a broad diversity in FAR content which is generated by gene duplications, subsequent gene losses, and alternative splicing. We also show that FARs expressed in oenocytes and presumably involved in CHC synthesis are more unstable than FARs from other tissues. We suggest that a comparative approach investigating the birth-and-death evolution of gene families can identify candidate genes involved in rapidly diverging traits between species.
Proximate causes and consequences of intergenerational influences of salient sensory experience
Authors: Aoued Hadj S , Sannigrahi Soma , Hunter Sarah C , Doshi Nandini , Chan Anthony , Walum Hasse , Dias Brian G
Published: January 2019

Salient sensory environments experienced by a parental generation can exert intergenerational influences on offspring, including offspring not conceived at the time of the parental experience. While these data provide an exciting new perspective on biological inheritance, questions remain about causes and consequences of intergenerational influences of salient sensory experience. We have previously shown that exposing male mice to a salient olfactory experience like olfactory fear conditioning results in offspring demonstrating a sensitivity to the odor used to condition the paternal generation and possessing an enhanced neuroanatomical representation for that odor. In this study, we first injected RNA extracted from sperm of male mice that underwent olfactory fear conditioning into naïve single cell zygotes and found that both male and female adults that develop from these embryos have increased sensitivity and enhanced neuroanatomical representation for the odor (Odor A) with which the paternal male had been conditioned. Next, we found that female, but not male offspring sired by males conditioned with Odor A show enhanced freezing when presented with Odor A after being exposed to a sub-threshold olfactory fear conditioning protocol that consisted of only a single Odor A + shock pairing. Our data provide evidence that RNA found in the paternal germline after exposure to salient sensory experiences can contribute to intergenerational influences of such experiences, and that such intergenerational influences confer an element of adaptation to the filial generation. In so doing, our work suggests that some causes (sperm RNA) and consequences (behavioral flexibility) of intergenerational influences of parental experiences are conserved across experiences as diverse as stressors, dietary manipulations, and sensory experiences.
Plasticity in evolutionary games
Authors: Dridi Slimane
Published: January 2019

The ability to respond appropriately to environmental cues is fundamental to the success of all forms of life, but previous theoretical studies of the evolution of plasticity make so diverse assumptions that the conditions under which plasticity can emerge in evolving populations are unclear when fitness is frequency-dependent. We study the effect of adding plastic types to symmetric evolutionary games. Since frequency-dependence induces an evolutionary change in the environment of players, one might expect that plastic individuals who can adapt their phenotypes to the environment could have a fitness advantage over simpler purely genetically determined phenotypes. In our model, plastic individuals can detect the type of their opponent before an interaction and condition their action on it. Even though it might appear as an outstanding advantage, such an ability cannot guarantee global stability in all games for even the smallest positive plasticity costs. We identify classes of games where plasticity can or cannot be globally or locally stable. In games where the standard replicator dynamics converge to a pure state, costly plasticity cannot invade an equilibrium population. Costly plasticity can however be locally stable, but the way to achieve this is not to play the best-response to any possible encountered type. Rather, part of the stability success of plastic types is based on establishing Pareto-efficiency as residents; in certain social dilemma games such as the Prisoner’s Dilemma and the Snowdrift game, this implies that plastic types need to cooperate with a strictly positive probability in order to ensure their stability against invasion by pure types. Zero-sum games always allow for the global stability of plastic types. This study offers a more principled way of thinking about the evolutionary emergence of plasticity in social scenarios, and helps demonstrate that such an emergence is strongly dependent on the type of game individuals are faced with.