bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding intercalation compounds for sodium-ion batteries and beyond
Authors: Kaufman Jonas L. , Vinckevičiūtė Julija , Krishna Kolli Sanjeev , Gabriel Goiri Jon , Van der Ven Anton
Published: July 2019

Intercalation compounds are popular candidate electrode materials for sodium-ion batteries and other ‘beyond lithium-ion’ technologies including potassium- and magnesium-ion batteries. We summarize first-principles efforts to elucidate the behaviour of such compounds in the layered and spinel structures. Trends based on the size and valence of the intercalant and the ionicity of the host are sufficient to explain phase stability and ordering phenomena, which in turn determine the equilibrium voltage profile. For the layered structures, we provide an overarching view of intercalant orderings in prismatic coordination based on antiphase boundaries, which has important consequences for diffusion. We examine details of stacking sequence transitions between different layered structures by calculating stacking fault energies and discussing the nature of dislocations. A better understanding of these transitions will likely aid the development of batteries with improved cyclability.

This article is part of a discussion meeting issue ‘Energy materials for a low carbon future’.
Enhancing the thermoelectric properties of Sr

1−
x

Pr

2
x
/3

□

x

/3
TiO

3±
δ

through control of crystal structure and microstructure
Authors: Ekren Dursun , Azough Feridoon , Freer Robert
Published: July 2019

A-site deficient perovskites are among the most important
n
-type thermoelectric oxides. Ceramics of Sr

1−
x

Pr

2
x
/3

□

x

/3
TiO
3
(
x
 = 0.1–1.0) were prepared by solid-state reaction at 1700–1723 K using highly reducing atmospheres. Samples with the highest Sr content had a cubic crystal structure

(
P
m

3
¯

m
)

; incorporating Pr with A-site vacancies led to a reduction in symmetry to tetragonal (
I4/mcm
) and then orthorhombic (
Cmmm
) crystal structures. HRTEM showed Pr
2/3
TiO
3
had a layered structure with alternating fully and partially occupied A-sites and a short-range order along the (100) direction. Electrical conductivity was highest in samples of high symmetry (
x
 ≤ 0.40), where the microstructures featured core-shell and domain structures. This enabled a very high power factor of approximately 1.75 × 10
−3
 W m
−1
 K
−2
at 425 K. By contrast, at high Pr content, structural distortion led to reduced electron transport; enhanced phonon scattering (from mass contrast, local strain and cation–vacancy ordering) led to reduced, glass-like, thermal conductivity. Carbon burial sintering increased the oxygen deficiency leading to increased carrier concentration, a maximum power factor of approximately 1.80 × 10
−3
 W m
−1
 K
−2
at 350 K and thermoelectric figure of merit of 0.26 at 865 K. The paper demonstrates the importance of controlling both crystal structure and microstructure to enhance thermoelectric performance.

This article is part of a discussion meeting issue ‘Energy materials for a low carbon future’.
Intermittent Lactobacilli-containing Vaginal Probiotic or Metronidazole Use to Prevent Bacterial Vaginosis Recurrence: Safety and Preliminary Efficacy by Microscopy and Sequencing
Authors: van de Wijgert Janneke H.H.M. , Verwijs Marijn C. , Agaba Stephen K. , Bronowski Christina , Mwambarangwe Lambert , Uwineza Mireille , Lievens Elke , Nivoliez Adrien , Ravel Jacques , Darby Alistair C.
Published: July 2019

Bacterial vaginosis (BV) is associated with HIV acquisition and adverse pregnancy outcomes. Recurrence after metronidazole treatment is high. HIV-negative, non-pregnant Rwandan BV patients were randomized to four groups (n=17/group) after seven-day oral metronidazole treatment: behavioral counseling only (control), or counseling plus intermittent use of oral metronidazole, Ecologic Femi+ vaginal capsule (containing multiple Lactobacillus and one Bifidobacterium species), or Gynophilus LP vaginal tablet (L. rhamnosus 35) for two months. Vaginal microbiota assessments at all visits included Gram stain Nugent scoring and 16S rRNA gene qPCR and HiSeq sequencing. All interventions were safe. BV (Nugent 7-10) incidence was 10.18 per person-year at risk in the control group, and lower in the metronidazole (1.41/person-year; p=0.004), Ecologic Femi+ (3.58/person-year; p=0.043), and Gynophilus LP groups (5.36/person-year; p=0.220). In mixed effects models adjusted for hormonal contraception/pregnancy, sexual risk-taking, and age, metronidazole and Ecologic Femi+ users, each compared to controls, had higher Lactobacillus and lower BV-anaerobes concentrations and/or relative abundances, and were less likely to have a dysbiotic vaginal microbiota type by sequencing. Inter-individual variability was high and effects disappeared soon after intervention cessation. Lactobacilli-based vaginal probiotics warrant further evaluation because, in contrast to antibiotics, they are not expected to negatively affect microbiota or cause antimicrobial resistance.
Using collaboration networks to identify authorship bias in meta-analyses
Authors: Moulin Thiago C. , Amaral Olavo B.
Published: July 2019

Meta-analytic methods are powerful resources to summarize the existing evidence concerning a given research question, and are widely used in many academic fields. However, meta-analyses can be vulnerable to various sources of bias, which should be considered to avoid inaccuracies. Many of these sources can be related to study authorship, as both methodological choices and researcher bias may lead to deviations in results between different research groups. In this work, we describe a method to objectively attribute study authorship within a given meta-analysis to different research groups by using graph cluster analysis of collaboration networks. We then provide empirical examples of how the research group of origin can impact effect size in distinct types of meta-analyses, demonstrating how non-independence between within-group results can bias effect size estimates if uncorrected. Finally, we show that multilevel random-effects models using research group as a level of analysis can be a simple tool for correcting biases related to study authorship.
Cluster analysis successfully identifies clinically meaningful knee valgus moment patterns: Frequency of early peaks reflects sex-specific ACL injury incidence
Authors: Sigurðsson Haraldur B. , Briem Kristín
Published: July 2019

Background

Biomechanical studies of ACL injury risk factors report heterogenous results, analyze only a fraction of the data, and do not analyze data in accordance with the injury mechanism. Extracting a peak value of relevance to ACL injuries is challenging due to differences in the relative timing of the peak value.

Aims/Hypotheses

The aim was to cluster analyze the knee valgus moment time series curve shape in the early stance phase. We hypothesized that 1a) There would be few discrete curve shapes, 1b) there would be an early peak pattern, 2a) youth athletes of both sexes would show similar frequencies of early peaks, 2b) adolescent girls would have higher early peak frequencies.

Methods

N=213 (39% boys) youth soccer and team handball athletes (phase 1) and N=35 (45% boys) with 5 year follow-up data (phase 2) were recorded performing a change of direction task with 3D motion analysis and a force plate. The time series of the first 30% of stance phase were cluster analyzed based on Euclidean distances in two steps; shape-based main clusters with a transformed time series, and magnitude based sub-clusters with body weight normalized time series. Group differences (sex, phase) in curve shape frequencies, and shape-magnitude frequencies were tested with chi-squared test.

Results

6 discrete shape-clusters and 14 magnitude based sub-clusters were formed. Phase 1 boys had higher frequencies of early peaks than phase 1 girls (38% vs 25% respectively, P<0.001 for full test). Phase 2 girls had higher frequencies of early peaks than phase 2 boys (42% vs 21% respectively, P<0.001 for full test).

Conclusions

Cluster analysis can reveal different patterns of curve shapes in biomechanical data. The early peak shape is relatable to the ACL injury mechanism as the timing of its peak moment is consistent with the timing of injury. Higher frequency of early peaks demonstrated by Phase 2 girls is consistent with their higher incidence of ACL injury.
Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing
Authors: Pararajalingam Prasath , Coyle Krysta M. , Arthur Sarah E. , Thomas Nicole , Alcaide Miguel , Meissner Barbara , Boyle Merrill , Grande Bruno M. , Slack Graham , Mungall Andrew J. , Gascoyne Randy D. , Steidl Christian , Connors Joseph , Villa Diego , Marra Marco A. , Johnson Nathalie , Scott David W. , Morin Ryan D.
Published: July 2019

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features known to contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes alongside previously published exome cohorts. To confirm our findings, we re-sequenced the genes identified in the exome cohort in 212 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association ofTP53andNOTCH1mutations and further nominate two additional genes,EWSR1andMEF2B, whose mutation respectively associated with poor and good outcome. Our sequencing revealed novel recurrent mutations including a unique missense hot spot inMEF2Band a pattern of non-coding mutations surrounding a single exon of theHNRNPH1gene. We sequenced the whole genomes of 34 MCLs to confirm the focal nature ofHNRNPH1mutations. Using RNA-seq data from 110 of these cases, we identified a functional role for recurrent non-codingHNRNPH1mutations in disrupting an auto-regulatory feedback mechanism. Overall, we identified three novel MCL-related genes with roles in RNA trafficking or splicing, namelyDAZAP1, EWSR1, andHNRNPH1. Taken together, these data strongly implicate a role for aberrant regulation of splicing in MCL pathobiology.

Key points

RNA-binding proteins with roles in regulating alternative splicing,DAZAP1, EWSR1, HNRNPH1, are frequently mutated in MCL

The majority of recurrent somaticHNRNPH1mutations are intronic and HNRNPH1 exhibits self-regulation through alternative splicing
Intestinal mucus and gut-vascular barrier: FxR-modulated entry sites for pathological bacterial translocation in liver cirrhosis
Authors: Sorribas M. , Jakob M. O. , Yilmaz B. , Li H. , Stutz D. , Noser Y. , de Gottardi A. , Moghadamrad S. , Hassan M. , Albillos A. , Francés R. , Juanola O. , Spadoni I. , Rescigno M. , Wiest R.
Published: July 2019

Background and aims

Pathological bacterial translocation (PBT) in liver cirrhosis (LC) is the hallmark for spontaneous bacterial infections increasing mortality several-fold. Factors known to contribute to PBT in LC are among others an increased intestinal permeability of which however, the mucus layer has not been addressed so far in detail. A clear route of translocation for luminal intestinal bacteria is yet to be defined but we hypothesize that the recently described gut vascular barrier (GVB) is impaired in experimental portal hypertension leading to increased accessibility of the vascular compartment for translocating bacteria.

Results

Healthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-Escherichia colifrom the small intestine to the liver whereas bile-duct-ligated (BDL) and CCl4-induced cirrhotic mice demonstrate pathological translocation which is not altered by prior thoracic-duct ligation. Mucus layer is reduced in thickness with loss of goblet-cells and Muc2-staining and expression in cirrhotic but not PPVL-mice associated with bacterial overgrowth in inner mucus layer and pathological translocation of GFP-E.colithrough the ileal epithelium. GVB is profoundly altered in BDL and CCl4-mice with Ileal extravasation of large-sized 150 kDa-FITC-dextran but only minor in PPVL-mice. This pathological endothelial permeability and accessibility in cirrhotic mice associates with an augmented expression of PV1 in intestinal vessels. OCA but not fexaramine stabilizes the GVB whereas both FXR-agonists ameliorate gut-liver-translocation of GFP-E.coli.

Conclusions

Liver cirrhosis but not portal hypertension per se grossly impairs the endothelial and muco-epithelial barriers promoting PBT to the portal-venous circulation. Both barriers appear FXR-modulated with –agonists reducing PBT via the portal-venous route.
Vaccine antigen, Factor H binding protein, is typically a non-lipidated precursor that localises to the meningococcal surface by Slam
Authors: da Silva RAG , Karlyshev AV , Oldfield NJ , Wooldridge KG , Bayliss CD , Ryan A , Griffin R
Published: July 2019

Meningococcal surface lipoprotein, Factor H binding protein (FHbp), is the sole antigen of the Trumenba vaccine (Pfizer) and one of four antigens of the Bexsero vaccine (GSK) targetingNeisseria meningitidisserogroup B isolates. Lipidation of FHbp is assumed to occur for all isolates and its surface localisation is conducted by surface lipoprotein assembly modulator, Slam.

We show in 91% of a collection of UK isolates (1742/1895) non-synonymous single nucleotide polymorphisms (SNPs) in the signal peptide of FHbp. A single SNP, common to all, alters a polar amino acid that abolishes processing, including lipidation and signal peptide cleavage. Rather than the toxic accumulation of the precursor in the periplasm as expected from disrupting the canonical processing pathway, remarkably the FHbp precursor is translocated to the outer membrane and surface-localised by Slam. Thus we show Slam is not lipoprotein-specific. In a panel of isolates expressing precursor FHbp at the surface, we investigated their binding to human factor H and their susceptibility to antibody-mediated killing. Our findings have implications for Trumenba and Bexsero and provide key insights for lipoprotein-based vaccines in development.
Reciprocity and behavioral heterogeneity govern the stability of social networks
Authors: Dakin Roslyn , Ryder T. Brandt
Published: July 2019

The dynamics of social networks can determine the transmission of information, the spread of diseases, and the evolution of behavior. Despite this broad importance, a general framework for predicting social network stability has not been proposed. Here, we present longitudinal data on the social dynamics of a cooperative bird species, the wire-tailed manakin, to evaluate the potential causes of temporal network stability. We find that when partners interact less frequently, and when the breadth of social connectedness within the network increases, the social network is subsequently less stable. Social connectivity was also negatively associated with the temporal persistence of coalition partnerships on an annual timescale. This negative association between connectivity and stability was surprising, especially given that individual manakins who were more connected also had more stable partnerships. This apparent paradox arises from a within-individual behavioral trade-off between partnership quantity and quality. Crucially, this trade-off is easily masked by behavioral variation among individuals. Using a simulation, we show that these results are explained by a simple model that combines among-individual behavioral heterogeneity and reciprocity within the network. As social networks become more connected, individuals face a trade-off between partnership quantity and maintenance. This model also demonstrates how among-individual behavioral heterogeneity, a ubiquitous feature of natural societies, can improve social stability. Together, these findings provide unifying principles that are expected to govern diverse social systems.

Significance Statement

In animal societies, social partnerships form a dynamic network that can change over time. Why are some social network structures more stable than others? We addressed this question by studying a cooperative bird species in which social behavior is important for fitness, similar to humans. We found that stable social networks are characterized by more frequent interactions, but sparser connectivity throughout the network. Using a simulation, we show how both results can be explained by a simple model of reciprocity. These findings indicate that social stability is governed by a trade-off whereby individuals can either maintain a few high-quality partners, or increase partner number. This fundamental trade-off may govern the dynamics and stability of many societies, including in humans.
West Asian sources of the Eurasian component in Ethiopians: a reassessment
Authors: Molinaro Ludovica , Montinaro Francesco , Kivisild Toomas , Pagani Luca
Published: July 2019

Previous genome-scale studies of populations living today in Ethiopia have found evidence of recent gene flow from an Eurasian source, dating to the last 3,000 years1,2,3,4. Haplotype1 and genotype data based analyses of modern2,4 and ancient data (aDNA)3,5 have considered Sardinia-like proxy2, broadly Levantine1,4 or Neolithic Levantine3 populations as a range of possible sources for this gene flow. Given the ancient nature of this gene flow and the extent of population movements and replacements that affected West Asia in the last 3000 years, aDNA evidence would seem as the best proxy for determining the putative population source. We demonstrate, however, that the deeply divergent, autochthonous African component which accounts for ∼50% of most contemporary Ethiopian genomes, affects the overall allele frequency spectrum to an extent that makes it hard to control for it and, at once, to discern between subtly different, yet important, Eurasian sources (such as Anatolian or Levant Neolithic ones). Here we re-assess pattern of allele sharing between the Eurasian component of Ethiopians (here called “NAF” for Non African) and ancient and modern proxies area after having extracted NAF from Ethiopians through ancestry deconvolution, and unveil a genomic signature compatible with population movements that affected the Mediterranean area and the Levant after the fall of the Minoan civilization.
Antinociceptive and Antioxidant Activities of Methanolic Extract of Leaves of Azadirachta Indica (Neem)
Authors: Mali Akash S , Thorat Mahesh B , Ghadge Dhairyasheel M. , Nikam Kumodini A. , Sawant Shraddha , Shaikh Farida , Vhatkar Nayana , Shinde Swapnja , Gonghade Kavyashree , Tamboli Munaf A.
Published: July 2019

Graphical abstract

Background

Azadirachta indica (Neem) is a communal plant of Meliaceae family called Neem Or Kadunimb in Maharashtra, India Neem stated anti-inflammatory through regulation of proinflammatory enzyme activities with COX and LOX enzyme. Previous studies show that Azadirachta Indica (neem) and its chief constituents play essential role in anticancer management via the modulation of different molecular pathways including NF-κB, p53, PI3K/Akt, Bcl-2, pTEN and VEGF. Many parts of the plant are traditionally used in the treatment of various pharmacological action, the analgesic activity of Neem Seed Oil has already reported but Neem Leaves.

Methods

The antinociceptive activity of Azadirachta Indica Leaves (AZIL) was examined using heat-induced-mechanical (hot-plate and tail-immersion test) and chemical-induced (acetic acid, formalin, glutamic acid, cinnamaldehyde) nociception models in mice at 50,100, and 200 mg/kg doses. ATP-sensitive K+ channel pathway, cyclic guanosine monophosphate (cGMP) pathway and involvement of opioid system was also tested using glibenclamide, methylene blue and naloxone/morphine respectively. The methanolic extract of leaves of A.Indica was assessed by using different in vitro antioxidant models of screening like scavenging of 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical, nitric oxide radical, superoxide anion radical, and hydroxyl radical.

Results

AZIL showed antinociceptive activity and antioxidant activity. In both hot plate and tail immersion tests AZIL significantly increases the latency to the thermal stimuli. In acetic acid-induced writhing test the extract repressed the number of abdominal writhing. Similarly, AZIL produced substantial dose-dependent inhibition of paw licking in both neurogenic and inflammatory pain induced by intraplanar injection of formalin. As well, AZIL also expressively withdrawn cinnamaldehyde-induced pain and the glutamate-induced pain in mice. It was also proved that pretreatment with naloxone significantly reversed the antinociception produced by AZIL in mechanical tests signifying the involvement of opioid system in its effect. Furthermore, administration of methylene blue, enhanced AZIL induced antinociception while glibenclamide, an ATP-sensitive K+ channel antagonist, could not converse antinociceptive activity induced by AZIL.

Conclusion

Based on the results of the present study it can be said that AZIL keeps significant antinociceptive activity which acts in both central and peripheral mechanisms.

Ethnopharmacological relevance

Azadiracta Indica having family Melliases is one of the common medicinal plant in United states and south Asia including India, Pakistan, Bangladesh. Various parts of the plants used in treatment of many inflammatory conditions, skin diseases, tooth protection, antidiabetic in the form of oil and herbal porridge.
An engineered serum albumin-binding AAV9 capsid achieves improved liver transduction after intravenous delivery in mice
Authors: Jin Quan , Qiao Chunping , Li Jianbin , Li Juan , Xiao Xiao
Published: July 2019

Recombinant adeno-associated viral (AAV) vectors are frequently used to deliver nucleic acids for in vivo applications and are currently the leading platform for therapeutic gene delivery in gene therapy clinical trials. Presently, there is a need for improved AAV vectors with optimized transduction efficiency in target tissues. In these studies, an engineered albumin-binding consensus domain (ABDCon) was incorporated into the AAV9 capsid via fusion to the N-terminus of the AAV9 VP2 capsid protein to generate a variant AAV9 capsid with albumin-binding properties. The variant capsid, called AAV9-ABDCon, formed viable genome-containing vector particles and exhibited binding to human serum albumin. The AAV9 capsid, on the other hand, was not found to bind to human serum albumin by the methods used in this study. Following intravenous administration, the modified AAV9-ABDCon vector was found to achieve higher levels of transduction in liver tissue compared to AAV9. These findings suggest that serum albumin-binding may be a potential method to augment AAV-mediated liver-directed gene delivery.
Comparative genomics in plant fungal pathogens (Mycosphaerellaceae): variation in mitochondrial composition due to at least five independent intron invasions
Authors: Arcila Juliana E. , Arango Rafael E. , Torres Javier M. , Arias Tatiana
Published: July 2019

Fungi provide new opportunities to study highly differentiated mitochondrial DNA. Mycosphaerellaceae is a highly diverse fungal family containing a variety of pathogens affecting many economically important crops.

Mitochondria plays a major role in fungal metabolism and fungicide resistance but up until now only two annotated mitochondrial genomes have been published in this family. We sequenced and annotated mitochondrial genomes of selected Mycosphaerellaceae species that diverged ∼66 MYA. During this time frame, mitochondrial genomes expanded significantly due to at least five independent invasions of introns into different electron transport chain genes. Comparative analysis revealed high variability in size and gene order among mitochondrial genomes even of closely related organisms, truncated extra gene copies and, accessory genes in some species. Gene order variability was common probably due to rearrangements caused by mobile intron invasion. Three threecox1copies and bicistronic transcription ofnad2-nad3andatp6-atp8inPseudocercospora fijiensiswere confirmed experimentally. Even though we found variation in mitochondrial genome composition, there was no evidence of hybridization when comparing nuclear and mitochondrial dataset sets for fungal plant pathogens analyzed here. Disentangling the causes of variation in mitochondrial genome composition in plant pathogenic fungal move us closer to understanding the molecular mechanisms responsible for vital functions in fungi ultimately aiding in controlling these diseases.
Non-sedating benzodiazepines cause contractile paralysis and tissue damage in the parasitic blood flukeSchistosoma mansoni
Authors: McCusker Paul , Mian Yeunus , Li Guanguan , Olp Michael D. , Tiruveedhula V. V. N. Phani Babu , Rashid Farjana , Golani Lalit Kumar , Smith Brian C. , Cook James M. , Chan John D.
Published: July 2019

Parasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs. In most cases, control is reliant upon praziquantel (PZQ) monotherapy. However, PZQ is ineffective against sexually immature parasites, and there have also been several concerning reports of cestode and trematode infections with poor PZQ cure-rates, emphasizing the need for alternative therapies to treat these infections. We have revisited a series of benzodiazepines, given the known anti-schistosomal activity of meclonazepam (MCLZ). MCLZ was discovered in the 1970’s but was not brought to market due to dose-limiting sedative side effects. However, in the decades since there have been advances in our understanding of the benzodiazepine GABAAreceptor sub-types that drive sedation and the development of sub-type selective, non-sedating ligands. Additionally, the sequencing of flatworm genomes reveals that parasitic trematodes and cestodes have lost GABAAR-like ligand gated anion channels, indicating that MCLZ’s anti-parasitic target is likely distinct from the human receptors that drive sedation. Therefore, we screened a library of classical and non-sedating 1,4-benzodiazepines againstSchistosoma mansoniand identified a series of imidazobenzodiazepines that immobilize wormsin vitro. One of these hits, Xhe-II-048 also disrupted the parasite tegument, causing extensive vacuole formation beneath the apical membrane. The imidazobenzodiazepine compound series identified has a dramatically lower (∼1 log) affinity for human central benzodiazepine binding site and is a promising starting point for the development of novel anti-schistosomal benzodiazepines with minimal host side-effects.

Author Summary

Over 200 million people are infected with schistosomiasis, yet there are limited therapeutic options available to treat this disease. The benzodiazepine meclonazepam is known to cure both intestinal and urinary schistosomiasis in animal and human studies, but dose-limiting sedation has been a barrier to its development. Little is known about the structure-activity relationship of meclonazepam and other benzodiazepines on schistosomes, or the identity of the parasite receptor for these compounds. However, schistosomes lack obvious homologs to the human GABAARs that cause sedation. This indicates that the parasite target of this drug is distinct from the host receptors that underpin dose-limiting side effects of meclonazepam, and raises the possibility that benzodiazepines with poor GABAAR affinity may still retain anti-parasitic effects. Here, we report anin vitroscreen of various benzodiazepines against schistosomes, and the identification of hit compounds that are active against worms yet possess reduced affinity for the human GABAARs that cause sedation.
Image-based Phenotyping and Genetic Analysis of Potato Skin Set and Color
Authors: Caraza-Harter Maria V. , Endelman Jeffrey B.
Published: July 2019

Image-based phenotyping offers new opportunities for fast, objective, and reliable measurement for breeding and genetics research. In the current study, image analysis was used to quantify potato skin color and skin set, which are critical for the marketability of new varieties. A set of 15 red potato varieties and advanced breeding lines was evaluated over two years at a single location, with two harvest times in the second year. After mechanical harvest and grading, 7-8 representative tubers per plot were photographed, and the photos were analyzed with ImageJ to measure skinning (as % surface area) and skin color using the Hue, Chroma and Lightness (HCL) representation. The plot-based heritability was consistently high (> 0.77) across traits and environments; the genetic correlation between environments was also high, ranging from 0.81 to 0.98. Significant increases in Lightness and Chroma, as well as a decrease in skinning, were observed at the late compared to early harvest, while the opposite trends for color were observed after six weeks of storage. The three color traits were unexpectedly collinear in this study, with the first principal component explaining 86% of the variation. This result may reflect the physiology of red color in potato, but the highly selected nature of the 15 genotypes may also be a factor. Image-based phenotyping offers new opportunities to advance genetic gain and understanding for tuber appearance traits that have been difficult to precisely measure in the past.
Social inhibition maintains adaptivity and consensus of foraging honeybee swarms in dynamic environments
Authors: Bidari Subekshya , Peleg Orit , Kilpatrick Zachary P
Published: July 2019

To effectively forage in natural environments, organisms must adapt to changes in the quality and yield of food sources across multiple timescales. Individuals foraging in groups act based on both their private observations and the opinions of their neighbors. How do these information sources interact in changing environments? We address this problem in the context of honeybee swarms, showing inhibitory social interactions help maintain adaptivity and consensus needed for effective foraging. Individual and social interactions of a mathematical swarm model shape the nutrition yield of a group foraging from feeders with temporally switching food quality. Social interactions improve foraging from a single feeder if temporal switching is fast or feeder quality is low. When the swarm chooses from multiple feeders, the most effective form of social interaction is direct switching, whereby bees flip the opinion of nestmates foraging at lower yielding feeders. Model linearization shows that effective social interactions increase the fraction of the swarm at the correct feeder (consensus) and the rate at which bees reach that feeder (adaptivity). Our mathematical framework allows us to compare a suite of social inhibition mechanisms, suggesting experimental protocols for revealing effective swarm foraging strategies in dynamic environments.
Associated habitat and suitability modeling of goldenseal (Hydrastis canadensisL.) in Pennsylvania: explaining and predicting species distribution in a northern edge of range state
Authors: Zuiderveen Grady H. , Chen Xin , Burkhart Eric P. , Miller Douglas A.
Published: July 2019

Goldenseal (Hydrastis canadensisL.) is a well-known perennial herb indigenous to forested areas in eastern North America. Owing to conservation concerns including wild harvesting for medicinal markets, habitat loss and degradation, and an overall patchy and often inexplicable absence in many regions, there is a need to better understand habitat factors that help determine the presence and distribution of goldenseal populations. In this study, flora and edaphic factors associated with goldenseal populations throughout Pennsylvania—a state near the northern edge of its range—were documented and analyzed to identify habitat indicators and provide possible in situ stewardship and farming (especially forest-based farming) guidance. Additionally, maximum entropy (Maxent) modeling was applied to better predict where suitable habitat might be encountered more broadly and explain species absence from regions of the state (and the northeastern states). Habitat study results identified rich, mesic, woodland sites as being suitable for goldenseal. The most prevalent overstory tree associates on such sites were tulip-poplar (Liriodendron tulipiferaL.) and sugar maple (Acer saccharumMarshall), and the most common understory associates were spicebush (Lindera benzoinL.), Virginia creeper (Parthenocissus quinquefolia(L.) Planch.), Jack-in-the-pulpit (Arisaema triphyllum(L.) Schott), mayapple (Podophyllum peltatumL.), wood fern (Drypoteris marginalis(L.) A. Gray), and rattlesnake fern (Botrypus virginianus(L.) Michx.). Loam soils were the most common textural class (average sand, silt, and clay ratio of 50:30:20) with an average pH of 6.2 and high variation in macronutrients. While such sites are widespread in the state, Maxent modeling suggested the present distribution in Pennsylvania is largely restricted by winter temperatures and bedrock type. The latter of these, in turn, is correlated in part with land use legacy (e.g., clearing for farming or livestock grazing), especially in southeast portions of the state.
Individual, but not population asymmetries, are modulated by social environment and genotype inDrosophila melanogaster
Authors: Versace Elisabetta , Caffini Matteo , Werkhoven Zach , de Bivort Benjamin L.
Published: July 2019

Theory predicts that social interactions can induce an alignment of behavioral asymmetries between individuals (i.e., population-level lateralization), but evidence for this effect is mixed. To understand how interaction with other individuals affects behavioral asymmetries, we systematically manipulated the social environment ofDrosophila melanogaster, testing individual flies and dyads (female-male, female-female and male-male pairs). In these social contexts we measured individual and population asymmetries in individual behaviors (circling asymmetry, wing use) and dyadic behaviors (relative position and orientation between two flies) in five different genotypes. We reasoned that if coordination between individuals drives alignment of behavioral asymmetries, greater alignment at the population-level should be observed in social contexts compared to solitary individuals. We observed that the presence of other individuals influenced the behavior and position of flies but had unexpected effects with respect to individual and population asymmetries: individual-level asymmetries were strong and modulated by the social context but population-level asymmetries were mild or absent. Moreover, the strength of individual-level asymmetries differed between strains, but this was not the case for population-level asymmetries. These findings suggest that the degree of social interaction found in Drosophila is insufficient to drive population-level behavioral asymmetries.
Decoding WW Domain Tandem-mediated Target Recognitions in Tissue Growth and Cell Polarity
Authors: Lin Zhijie , Yang Zhou , Xie Ruiling , Ji Zeyang , Guan Kunliang , Zhang Mingjie
Published: July 2019

WW domain tandem-containing proteins such as KIBRA, YAP, and MAGI play critical roles in cell growth and polarity via binding to and positioning target proteins in specific subcellular regions. An immense disparity exists between promiscuity of WW domain-mediated target bindings and specific roles of WW domain scaffold proteins in cell growth regulation. Here, we discovered that WW domain tandems of KIBRA and MAGI, but not YAP, bind to specific target proteins with extremely high affinity and exquisite specificity. Via systematic structural biology and biochemistry approaches, we decoded the target binding rules of WW domain tandems from cell growth regulatory proteins and uncovered a list of previously unknown WW tandem binding proteins such as β-Dystroglycan, JCAD, and PTPN21. The WW tandem-mediated target recognition mechanisms elucidated here can guide functional studies of WW domain proteins in cell growth and polarity as well as in other cellular processes including neuronal synaptic signaling.
Oxytocin increases after affiliative interactions in male Barbary macaques
Authors: Rincon Alan V. , Deschner Tobias , Schülke Oliver , Ostner Julia
Published: July 2019

Mammals living in stable social groups often mitigate the costs of group living through the formation of social bonds and cooperative relationships. The neuropeptide hormone oxytocin (OT) has been proposed to promote both bonding and cooperation although only a limited number of studies have investigated this under natural conditions. Our aim was to assess the role of OT in bonding and cooperation in male Barbary macaques (Macaca sylvanus). First we tested for an effect of affiliation - grooming and triadic male-infant-male interactions - with bond and non-bond partners on urinary OT levels. Secondly we aimed to test whether grooming interactions (and thus increased OT levels) increase a male’s general propensity to cooperate in polyadic conflicts. We collected behavioral data via full-day focal animal protocols on 14 adult males and measured endogenous OT levels from 139 urine samples collected after affiliation and non-social control periods. Urinary OT levels were higher after grooming with any partner. By contrast, OT levels after male-infant-male interactions with any partner or with bond partners were not different from controls but were higher after interactions with non-bond partners. Previous grooming did not increase the likelihood of males to support others in conflicts. Collectively, our results support research indicating that OT is involved in the regulation of adult social bonds, including in non-reproductive contexts. However, our male-infant-male interaction results go against previous studies suggesting that it is affiliation with bond rather than non-bond partners that trigger the release of OT. Alternatively, OT levels may have been elevated prior to male-infant-male interactions thus facilitating interaction between non-bond partners. The lack of an association of grooming (and by extension increased OT levels) and subsequent support speaks against an OT linked increase in the general propensity to cooperate, yet further studies are needed for a more direct test including the possibility of partner-specific contingent cooperation.
Targeted cancer cell killing by highly selective miRNA-triggered activation of a prokaryotic toxin-antitoxin system
Authors: Turnbull Alice , Bermejo-Rodríguez Camino , Preston Mark A. , Garrido-Barros María , Pimentel Belén , de la Cueva-Méndez Guillermo
Published: July 2019

Although not evolved to function in eukaryotes, prokaryotic toxin Kid induces apoptosis in human cells, and this is avoided by co-expression of its neutralizing antitoxin, Kis. Inspired by the way Kid becomes active in bacterial cells we had previously engineered a synthetic toxin-antitoxin system bearing a Kis protein variant that is selectively degraded in cells expressing viral oncoprotein E6, thus achieving highly selective killing of cancer cells transformed by human papillomavirus. Here we aimed to broaden the type of oncogenic insults, and therefore of cancer cells, that can be targeted using this approach. We show that appropriate linkage of the kis gene to a single, fully complementary, target site for an oncogenic human microRNA enables the construction of a synthetic toxin-antitoxin pair that selectively kills cancer cells overexpressing that particular microRNA. Importantly, the resulting system spares non-targeted cells from collateral damage, even when they overexpress highly homologous, though non-targeted, microRNAs.
Nestin selectively facilitates the phosphorylation of the Lissencephaly-linked protein doublecortin (DCX) by cdk5/p35 to regulate growth cone morphology and Sema3a sensitivity in developing neurons
Authors: Bott Christopher J. , McMahon Lloyd P. , Keil Jason M. , Yap Chan Choo , Kwan Kenneth Y. , Winckler Bettina
Published: July 2019

Nestin, an intermediate filament protein widely used as a marker of neural progenitors, was recently found to be expressed transiently in developing cortical neurons in culture and in developing mouse cortex. In young cortical cultures, nestin regulates axonal growth cone morphology. In addition, nestin, which is known to bind the neuronal cdk5/p35 kinase, affects responses to axon guidance cues upstream of cdk5, specifically, to Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, and changes in microtubules and actin filaments are well studied. In contrast, the roles of intermediate filament proteins in this process are poorly understood, even in cultured neurons. Here, we investigate the molecular mechanism by which nestin affects growth cone morphology and Sema3a sensitivity. We find that nestin selectively facilitates the phosphorylation of the lissencephaly-linked protein doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected by nestin. We uncover that this substrate selectivity is based on the ability of nestin to interact with DCX, but not with other cdk5 substrates. Nestin thus creates a selective scaffold for DCX with activated cdk5/p35. Lastly, we use cortical cultures derived from DCX knockout mice to show that the effects of nestin on growth cone morphology and on Sema3a sensitivity are DCX-dependent, thus suggesting a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating the intracellular kinase signaling environment in developing neurons. The sex of animal subjects is unknown.

Significance Statement

Nestin, an intermediate filament protein highly expressed in neural progenitors, was recently identified in developing neurons where it regulates growth cone morphology and responsiveness to the guidance cue Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, but the roles of intermediate filaments in this process are poorly understood. We now report that nestin selectively facilitates phosphorylation of the lissencephaly-linked doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected. This substrate selectivity is based on preferential scaffolding of DCX, cdk5, and p35 by nestin. Additionally, we demonstrate a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating intracellular kinase signaling in developing neurons.
Integrative genomics approach identifies conserved transcriptomic networks in Alzheimer’s disease
Authors: Morabito Samuel , Miyoshi Emily , Michael Neethu , Swarup Vivek
Published: July 2019

Alzheimer’s disease (AD) is a devastating neurological disorder characterized by changes in cell-type proportions and consequently marked alterations of the transcriptome. Here we use a data-driven systems biology approach across multiple cohorts of human AD, encompassing different brain regions, and integrate with multi-scale datasets comprising of DNA methylation, histone acetylation, transcriptome- and genome-wide association studies as well as quantitative trait loci to define the genetic architecture of AD. We perform co-expression network analysis across more than twelve hundred human brain samples, identifying robust AD-associated dysregulation of the transcriptome, unaltered in normal human aging. We further integrate co-expression modules with single-cell transcriptome generated from 27,321 nuclei from postmortem human brain to identify AD-specific transcriptional changes and assess cell-type proportion changes in the human AD brain. We also show that genetic variants of AD are enriched in a glial AD-associated module and identify key transcription factors regulating co-expressed modules. Additionally, we validate our results in multiple published human AD datasets which are easily accessible using our online resource (https://swaruplab.bio.uci.edu/consensusAD).
EEG power spectra and subcortical pathology in chronic disorders of consciousness
Authors: Lutkenhoff Evan S. , Nigri Anna , Sebastiano Davide Rossi , Sattin Davide , Visani Elisa , Rosazza Cristina , D’Incerti Ludovico , Bruzzone Maria Grazia , Franceschetti Silvana , Leonardi Matilde , Ferraro Stefania , Monti Martin M.
Published: July 2019

Objective

To determine (i) the association between long-term impairment of consciousness after severe brain injury, spontaneous brain oscillations, and underlying subcortical damage, and (ii) whether such data can be used to aid patient diagnosis, a process known to be susceptible to high error rates.

Methods

Cross-sectional observational sample of 116 patients with a disorder of consciousness secondary to brain injury, collected prospectively at a tertiary center between 2011 and 2013. Multimodal analyses relating clinical measures of impairment, electroencephalographic measures of spontaneous brain activity, and magnetic resonance imaging data of subcortical atrophy were conducted in 2018.

Results

In the final analyzed sample of 61 patients, systematic associations were found between electroencephalographic power spectra and subcortical damage. Specifically, the ratio of beta-to-delta relative power was negatively associated with greater atrophy in regions of the bilateral thalamus and globus pallidus (both left > right) previously shown to be preferentially atrophied in chronic disorders of consciousness. Power spectrum total density was also negatively associated with widespread atrophy in regions of the left globus pallidus, right caudate, and in brainstem. Furthermore, we showed that the combination of demographics, encephalographic, and imaging data in an analytic framework can be employed to aid behavioral diagnosis.

Conclusions

These results ground, for the first time, electroencephalographic presentation detected with routine clinical techniques in the underlying brain pathology of disorders of consciousness and demonstrate how multimodal combination of clinical, electroencephalographic, and imaging data can be employed in potentially mitigating the high rates of misdiagnosis typical of this patient cohort.

Search terms

disorders of consciousness, subcortical pathology, EEG, MRI.
Temporal regularity and stimulus control in multiple fixed interval schedules
Authors: Nepomoceno Estela B. , Cravo André M. , Reyes Marcelo B. , Caetano Marcelo S.
Published: July 2019

In multiple fixed interval schedules of reinforcement, different time intervals are signaled by different environmental stimuli which acquire control over behavior. Previous work has shown that temporal performance is controlled not only by external stimuli but also by temporal aspects of the task, depending on the order in which the different intervals are trained – intermixed across trials or in blocks of several trials. The aim of this study was to further describe the training conditions under which the stimuli acquire control over temporal performance. We manipulated the number of consecutive trials of each fixed interval (FI) per training block (Experiment I) and the number of FIs trained (Experiment II). The results suggest that when trained in blocks of several consecutive trials of the same FI, temporal performance is controlled by temporal regularities across trials and not by the visual stimuli that signal the FIs. One possible account for those data is that the temporal cues overshadow the visual stimuli for the control of temporal performance. Similar results have also been observed with humans, which suggest that temporal regularity overcomes the stimuli in the control of behavior in temporal tasks across species.