bluuebunny/crossref_metadata_2025 huggingface dataset:
Infratentorial Supracerebellar Approach for Resection of Midbrain Cavernous Malformation: 3-Dimensional Operative Video
Authors: Patel Krunal , Budohoski Karol P , Olijnyk Leonardo Desessards , Bulstrode Harry , Santarius Thomas , Kirollos Ramez W , Trivedi Rikin A
Published: June 2019

Cavernous malformations (cavernomas) of the brain stem with recurrent hemorrhage may be amenable to microsurgical resection if they are present close to the surface. The risks of surgery need to be balanced with the natural history of the lesion and the accumulation of neurological deficits and risk to life with multiple hemorrhages. In this 3D operative video, we illustrate the technique for the resection of a dorsally located midbrain cavernous malformation.

Informed consent was obtained for this procedure. The cavernoma is accessed with the use of a supracerebellar infratentorial approach. The infratentorial craniotomy and coagulation of the superior vermian veins is shown. A description is provided of the use of hemosiderin staining and the intercollicular relative “safe zone”
1
as landmarks for the neurotomy. The technique of cavernoma dissection from the surrounding gliotic plane is shown and described.

In this case, the patient required prolonged rehabilitation but fully recovered without residual deficit 1 yr following surgery.
Financial Frictions and the Great Productivity Slowdown
Authors: Duval Romain , Hong Gee Hee , Timmer Yannick
Published: June 2019

We study the role of financial frictions for productivity. Using a rich cross-country firm-level data, we exploit variation in preexisting exposure to the 2008 global financial crisis to study the post-crisis productivity slowdown. Firms with weaker precrisis balance sheets experienced a highly persistent decline in post-crisis total factor productivity growth relative to their less vulnerable counterparts, accounting for about one-third of the within-firm productivity slowdown. This decline was larger for firms that faced a more severe tightening of credit conditions. Financially fragile firms cut back on innovation activities, one channel through which financial frictions weakened post-crisis productivity growth.
q-LAMP Assays for the Detection of Botryosphaeria dothidea Causing Chinese Hickory Canker in Trunk, Water, and Air Samples
Authors: Wang Q. W. , Zhang C. Q.
Published: June 2019

Trunk canker disease caused by Botryosphaeria dothidea with a prolonged latent infection phase poses a serious threat to Chinese hickory production. To further understand the epidemiological characteristics and develop reasonable management techniques, a quantitative loop-mediated isothermal amplification (q-LAMP) assay was developed to quantitatively monitor B. dothidea in hickory plants, water, and air samples. Specific primers were designed based on the different sites of the β-tubulin sequence between B. dothidea and other fungi commonly found on Chinese hickory. At the optimum reaction temperature of 65.9°C, this loop-mediated isothermal amplification (LAMP) assay can specifically distinguish B. dothidea from other tested fungi. The limit of detection of LAMP assays for B. dothidea was 0.001 ng/µl of pure genomic DNA and 10 spores per 1 ml of water. The q-LAMP assay enables rapid detection of B. dothidea within 60 min in hickory trunk, water in hickory forests, and spores captured on tapes. These results provide a powerful and convenient tool for monitoring B. dothidea, which could be applied widely in epidemiology, forecast, and management of tree canker disease.
Habitat preference modulates trans-oceanic dispersal in a terrestrial vertebrate
Authors: Blom Mozes P. K. , Matzke Nicholas J. , Bragg Jason G. , Arida Evy , Austin Christopher C. , Backlin Adam R. , Carretero Miguel A. , Fisher Robert N. , Glaw Frank , Hathaway Stacie A. , Iskandar Djoko T. , McGuire Jimmy A. , Karin Benjamin R. , Reilly Sean B. , Rittmeyer Eric N. , Rocha Sara , Sanchez Mickaël , Stubbs Alexander L. , Vences Miguel , Moritz Craig
Published: June 2019

The importance of long-distance dispersal (LDD) in shaping geographical distributions has been debated since the nineteenth century. In terrestrial vertebrates, LDD events across large water bodies are considered highly improbable, but organismal traits affecting dispersal capacity are generally not taken into account. Here, we focus on a recent lizard radiation and combine a summary-coalescent species tree based on 1225 exons with a probabilistic model that links dispersal capacity to an evolving trait, to investigate whether ecological specialization has influenced the probability of trans-oceanic dispersal.
Cryptoblepharus
species that occur in coastal habitats have on average dispersed 13 to 14 times more frequently than non-coastal species and coastal specialization has, therefore, led to an extraordinarily widespread distribution that includes multiple continents and distant island archipelagoes. Furthermore, their presence across the Pacific substantially predates the age of human colonization and we can explicitly reject the possibility that these patterns are solely shaped by human-mediated dispersal. Overall, by combining new analytical methods with a comprehensive phylogenomic dataset, we use a quantitative framework to show how coastal specialization can influence dispersal capacity and eventually shape geographical distributions at a macroevolutionary scale.
Conserving evolutionary history does not result in greater diversity over geological time scales
Authors: Cantalapiedra J. L. , Aze T. , Cadotte M. W. , Dalla Riva G. V. , Huang D. , Mazel F. , Pennell M. W. , Ríos M. , Mooers A. Ø.
Published: June 2019

Alternative prioritization strategies have been proposed to safeguard biodiversity over macroevolutionary time scales. The first prioritizes the most distantly related species—maximizing phylogenetic diversity (PD)—in the hopes of capturing at least some lineages that will successfully diversify into the future. The second prioritizes lineages that are currently speciating, in the hopes that successful lineages will continue to generate species into the future. These contrasting schemes also map onto contrasting predictions about the role of slow diversifiers in the production of biodiversity over palaeontological time scales. We consider the performance of the two schemes across 10 dated species-level palaeo-phylogenetic trees ranging from Foraminifera to dinosaurs. We find that prioritizing PD for conservation generally led to fewer subsequent lineages, while prioritizing diversifiers led to modestly more subsequent diversity, compared with random sets of lineages. Importantly for conservation, the tree shape when decisions are made cannot predict which scheme will be most successful. These patterns are inconsistent with the notion that long-lived lineages are the source of new species. While there may be sound reasons for prioritizing PD for conservation, long-term species production might not be one of them.
Ancestral chytrid pathogen remains hypervirulent following its long coevolution with amphibian hosts
Authors: Fu Minjie , Waldman Bruce
Published: June 2019

Many amphibian species around the world, except in Asia, suffer morbidity and mortality when infected by the emerging infectious pathogenBatrachochytrium dendrobatidis(Bd). A lineage of the amphibian chytrid fungus isolated from South Korean amphibians (BdAsia-1) is evolutionarily basal to recombinant global pandemic lineages (BdGPL) associated with worldwide amphibian population declines. In Asia, the Bd pathogen and its amphibian hosts have coevolved over 100 years or more. Thus, resilience of Asian amphibian populations to infection might result from attenuated virulence of endemic Bd lineages, evolved immunity to the pathogen or both. We compared susceptibilities of an Australasian amphibian,Litoria caerulea, known to lack resistance to BdGPL, with those of three Korean species,Bufo gargarizans,Bombina orientalisandHyla japonica, after inoculation with BdAsia-1, BdGPL or a blank solution. Subjects became infected in all experimental treatments but Korean species rapidly cleared themselves of infection, regardless of Bd lineage. They survived with no apparent secondary effects. By contrast,L. caerulea, after infection by either BdAsia-1 or BdGPL, suffered deteriorating body condition and carried progressively higher Bd loads over time. Subsequently, most subjects died. Comparing their effects onL. caerulea, BdAsia-1 induced more rapid disease progression than BdGPL. The results suggest that genomic recombination with other lineages was not necessary for the ancestral Bd lineage to evolve hypervirulence over its long period of coevolution with amphibian hosts. The pathogen's virulence may have driven strong selection for immune responses in endemic Asian amphibian host species.
Domain-invariant features for mechanism of action prediction in a multi-cell-line drug screen
Authors: Boyd Joseph C. , Pinheiro Alice , Del Nery Elaine , Reyal Fabien , Walter Thomas
Published: June 2019

High Content Screening is an important tool in drug discovery and characterisation. Often, high content drug screens are performed on one single cell line. Yet, a single cell line cannot be thought of as a perfect disease model. Many diseases feature an important molecular heterogeneity. Consequently, a drug may be effective against one molecular subtype of a disease, but less so against another. To characterise drugs with respect to their effect not only on one cell line but on a panel of cell lines is therefore a promising strategy to streamline the drug discovery process. The contribution of this paper is twofold. First, we investigate whether we can predict drug mechanism of action (MOA) at the molecular level without optimisation of the MOA classes to the screen specificities. To this end, we benchmark a set of algorithms within a conventional pipeline, and evaluate their MOA prediction performance according to a statistically rigorous framework. Second, we extend this conventional pipeline to the simultaneous analysis of multiple cell lines, each manifesting potentially different morphological baselines. For this, we propose multitask autoencoders, including a domain-adaptive model used to construct domain-invariant feature representations across cell lines. We apply these methods to a pilot screen of two triple negative breast cancer cell lines as models for two different molecular subtypes of the disease.
methylSCOPA and META-methylSCOPA: software for the analysis and aggregation of epigenome-wide association studies of multiple correlated phenotypes
Authors: Draisma Harmen , Liu Jun , Pupko Igor , Demirkan Ayşe , Balkhiyarova Zhanna , Morris Andrew P , Magi Reedik , Wielscher Matthias , Hassan Saqib , van Duijn Cornelia M. , Sebert Sylvain , Jarvelin Marjo-Riitta , Kaakinen Marika , Prokopenko Inga
Published: June 2019

Background

Multi-phenotype genome-wide association studies (MP-GWAS) of correlated traits have greater power to detect genotype–phenotype associations than single-trait GWAS. However, no multi-phenotype analysis method exists for epigenome-wide association studies (EWAS).

Results

We extended the SCOPA approach developed by us to “methylSCOPA” software in C++ by ‘reversely’ regressing DNA hyper/hypo-methylation information on a linear combination of phenotypes. We evaluated two models of association between DNA methylation and fasting glucose (FG) and insulin (FI) levels: Model 1, including FG, FI, and three measured potential confounders (body mass index [BMI], fasting serum triglyceride levels [TG], and waist/hip ratio [WHR]), and Model 2, including FG and FI corrected for the effects of BMI, TG, and WHR. Both models were additionally corrected for participant sex and smoking status (current/ever/never). We meta-analyzed the cohort-specific MP-EWAS results with our novel software META-methylSCOPA, mapped genomic locations to CGCh37/hg19, and adoptedP<1×10−7to denote epigenome-wide significance. We used the Illumina Infinium HumanMethylation450K BeadChip array data from the Northern Finland Birth Cohorts (NFBC) 1966/1986. We quality-controlled the data, regressed out the effects of measured potential confounders, and normalized the methylation signal intensity and FI data. The MP-EWAS included data for 643/457 individuals from NFBC1966 and NFBC1986, respectively (total N=1,100).

In Model 1, we detected epigenome-wide significant association in the MP-EWAS meta-analysis at cg13708645 (chr12:121,974,305;P=1.2×10−8) withinKDM2Bgene. Single-trait effects withinKDM2Bwere on FI, BMI, and WHR. Model with effect on BMI and WHR showed the strongest association at this locus, while effect on FI in single-phenotype analysis was driven by the effect of adiposity. In Model 2, the strongest association was at cg05063096 (chr3:143,689,810;P=2.3×10−7) annotated toC3orf58with strongest effect on FI in single-trait analysis and multi-phenotype effect on FI and WHI within Model 1.

We characterized the effects of established EWAS loci for diabetes and its risk factors and detected suggestive (p<0.01) associations at six markers includingPHGDH, TXNIP, SLC7A11, CPT1A, MYO5CandABCG1, through the dissection of the multi-phenotype effects in Model 1.

Conclusions

We implemented MP-EWAS in methylSCOPA and demonstrated its enhanced power over single-trait EWAS for correlated phenotypes in large-scale data.
Phenotypic plasticity as a mechanism of cave colonization and adaptation
Authors: Bilandžija Helena , Hollifield Breanna , Steck Mireille , Meng Guanliang , Ng Mandy , Koch Andrew D. , Gračan Romana , Ćetković Helena , Porter Megan L. , Renner Kenneth J. , Jeffery William R.
Published: June 2019

A widely accepted model for the evolution of cave animals posits colonization by surface ancestors followed by the acquisition of adaptations over many generations. However, the speed of cave adaptation in some species suggests mechanisms operating over shorter timescales. To address these mechanisms, we used Astyanax mexicanus, a teleost with ancestral surface morphs (surface fish, SF) and derived cave morphs (cavefish, CF). We exposed SF to completely dark conditions and identified numerous altered traits at both the gene expression and phenotypic levels. Remarkably, most of these alterations mimicked CF phenotypes. Our results indicate that cave-related traits can appear within a single generation by phenotypic plasticity. In the next generation, plasticity can be further refined. The initial plastic responses are random in adaptive outcome but may determine the subsequent course of evolution. Our study suggests that phenotypic plasticity contributes to the rapid evolution of cave-related traits in A. mexicanus.
Enhanced efficacy of vaccination with vaccinia virus in old versus young mice
Authors: Shmeleva Evgeniya V. , Smith Geoffrey L. , Ferguson Brian J.
Published: June 2019

Immunosenescence is believed to be responsible for poor vaccine efficacy in the elderly. To overcome this difficulty, research into vaccination strategies and the mechanisms of immune responses to vaccination is required. By analyzing the innate and adaptive immune responses to vaccination with vaccinia virus (VACV) in mice of different age groups, we found that immune cell recruitment, production of cytokines/chemokines and control of viral replication at the site of intradermal vaccination were preserved in aged mice and were comparable with younger groups. Analysis of cervical draining lymph nodes (dLN) collected after vaccination showed that numbers of germinal center B cells and follicular T helper cells were similar across different age groups. The number of VACV-specific CD8 T cells in the spleen and the levels of serum neutralizing antibodies 1 month after vaccination were also comparable across all age groups. However, following intranasal challenge of vaccinated mice, body weight loss was lower and virus was cleared more rapidly in aged mice than in younger animals. In conclusion, vaccination with VACV can induce an effective immune response and stronger protection in elderly animals. Thus, the development of recombinant VACV-based vaccines against different infectious diseases should be considered as a strategy for improving vaccine immunogenicity and efficacy in the elderly.
Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis
Authors: Liu Xinquan , Ghosh Debadyuti
Published: June 2019

The RAS family of oncogenes (KRAS, HRAS, NRAS) are the most frequent mutations in cancers and regulate key signaling pathways that drive tumor progression. As a result, drug delivery targeting RAS-driven tumors has been a long-standing challenge in cancer therapy. Mutant RAS activates cancer cells to actively take up nutrients, including glucose, lipids, and albumin, via macropinocytosis to fulfill their energetic requirements to survive and proliferate. Here, we exploit this mechanism to deliver nanoparticles in cancer cells harboring activating KRAS mutations. We have synthesized stable albumin nanoparticles that demonstrate significantly greater uptake in cancer cells with activating mutations of KRAS than monomeric albumin (i.e. dissociated form of clinically-used nab-paclitaxel). From pharmacological inhibition and semi-quantitative fluorescent microscopy studies, these nanoparticles exhibit significantly increased uptake in mutant KRAS cancer cells than wild-type KRAS cells by macropinocytosis. Importantly, we demonstrate that their uptake is driven by KRAS. This nanoparticle-based strategy targeting RAS-driven macropinocytosis is a facile approach towards improved delivery into KRAS-driven cancers.
Reconsidering electrophysiological markers of response inhibition in light of trigger failures in the stop-signal task
Authors: Skippen P , Fulham W. R , Michie P.T , Matzke D , Heathcote A , Karayanidis F
Published: June 2019

We investigate the neural correlates underpinning response inhibition using a parametric ex-Gaussian model of stop-signal task performance, fit with hierarchical Bayesian methods, in a large healthy sample (N=156). The parametric model accounted for trigger failure (i.e., failures to initiate the inhibition process) and returned an SSRT estimate (SSRTEXG3) that was attenuated by ≈65ms compared to traditional non-parametric SSRT estimates (SSRTint). The amplitude and latency of the N1 and P3 event related potential components were derived for both stop-success and stop-failure trials and compared to behavioural estimates derived from traditional (SSRTint) and parametric (SSRTEXG3, trigger failure) models. Both the fronto-central N1 and P3 peaked earlier and were larger for stop-success than stop-failure trials. For stop-failure trials only, N1 peak latency correlated with both SSRT estimates as well as trigger failure and temporally coincided with SSRTEXG3, but not SSRTint. In contrast, P3 peak and onset latency were not associated with any behavioural estimates of inhibition for either trial type. While overall the N1 peaked earlier for stop-success than stop-failure trials, this effect was not found in poor task performers (i.e., high trigger failure/slow SSRT). These findings are consistent with attentional modulation of both the speed and reliability of the inhibition process, but not for poor performers. Together with the absence of any P3 onset latency effect, our findings suggest that attentional mechanisms are important in supporting speeded and reliable inhibition processes required in the stop-signal task.
Highly precise base editing with CC context-specificity using engineered human APOBEC3G-nCas9 fusions
Authors: Liu Zhiquan , Chen Siyu , Shan Huanhuan , Chen Mao , Song Yuning , Lai Liangxue , Li Zhanjun
Published: June 2019

Cytidine base editors, composed of a cytidine deaminase fused to Cas9 nickase, enable efficient C-to-T conversion in various organisms. However, current base editors can induce unwanted bystander C-to-T conversions when more than one C is present in the activity window of cytidine deaminase, which negatively affects the precision. Here, we develop a new base editor with CC context-specificity using rationally engineered human APOBEC3G, thus significantly reduce unwanted bystander activities. In addition, efficient C-to-T conversion that can further recognize relaxed NG PAMs is achieved by combining an engineered SpCas9-NG variant. These novel base editors with improved precision and targeting scope will expand the toolset for precise gene modification in organisms.
Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver
Authors: Wang Jianye , Hu Bian , Zhao Zhicong , Zhang Haiyan , Zhang He , Zhao Zhenjun , Ma Xiong , Shen Bin , Sun Beicheng , Huang Xingxu , Hou Jiajie , Xia Qiang
Published: June 2019

Endoplasmic reticulum (ER) stress-associated cell death is prevalent in various liver diseases. However, the determinant mechanism how hepatocytes survive unresolved stress was still unclear. Interleukin-24 (IL-24) was previously found to promote ER stress-mediated cell death, and yet its expression and function in the liver remained elusive. Here we identified an anti-apoptotic role of IL-24, which transiently accumulated within ER-stressed hepatocytes in a X-box binding protein 1 (XBP1)-dependent manner. Disruption of IL-24 increased cell death in the CCL4- or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2α (eIF2α) or genetical ablation of C/EBP homologous protein (CHOP) restored hepatocyte function in the absence of IL-24. In a clinical setting, patients with acute liver failure manifested a profound decrease of hepatic IL-24 expression, which was associated with disease progression. In conclusion, intrinsic hepatocyte IL-24 maintains ER homeostasis by restricting the eIF2α-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.
An improved encoding of genetic variation in a Burrows-Wheeler transform
Authors: Büchler Thomas , Ohlebusch Enno
Published: June 2019

Motivation

In resequencing experiments, a high-throughput sequencer produces DNA-fragments (called reads) and each read is then mapped to the locus in a reference genome at which it fits best. Currently dominant read mappers (Li and Durbin, 2009; Langmead and Salzberg, 2012) are based on the Burrows-Wheeler transform (BWT). A read can be mapped correctly if it is similar enough to a substring of the reference genome. However, since the reference genome does not represent all known variations, read mapping tends to be biased towards the reference and mapping errors may thus occur. To cope with this problem, Huang et al. (2013) encoded SNPs in a BWT by the IUPAC nucleotide code (Cornish-Bowden, 1985). In a different approach, Maciuca et al. (2016) provided a ‘natural encoding’ of SNPs and other genetic variations in a BWT. However, their encoding resulted in a significantly increased alphabet size (the modified alphabet can have millions of new symbols, which usually implies a loss of efficiency). Moreover, the two approaches do not handle all known kinds of variation.

Results

In this article, we propose a method that is able to encode many kinds of genetic variation (SNPs, MNPs, indels, duplications, transpositions, inversions, and copy-number variation) in a BWT. It takes the best of both worlds: SNPs are encoded by the IUPAC nucleotide code as in (Huang et al., 2013) and the encoding of the other kinds of genetic variation relies on the idea introduced in (Maciuca et al., 2016). In contrast to Maciuca et al. (2016), however, we use only one additional symbol. This symbol marks variant sites in a chromosome and delimits multiple variants, which are added at the end of the ‘marked chromosome’. We show how the backward search algorithm, which is used in BWT-based read mappers, can be modified in such a way that it can cope with the genetic variation encoded in the BWT. We implemented our method and compared it to BWBBLE (Huang et al., 2013) and gramtools (Maciuca et al., 2016).

Availability

https://www.uni-ulm.de/in/theo/research/seqana/

Contact:Enno.Ohlebusch@uni-ulm.de
Preadaptation of pandemic GII.4 noroviruses in hidden virus reservoirs years before emergence
Authors: Ruis Christopher , Lindesmith Lisa C. , Mallory Michael L. , Brewer-Jensen Paul D. , Bryant Josephine M. , Costantini Veronica , Monit Christopher , Vinjé Jan , Baric Ralph S. , Goldstein Richard A. , Breuer Judith
Published: June 2019

The control of pandemic pathogens depends on early prediction of pandemic variants and, more generally, understanding origins of such variants and factors that drive their global spread. This is especially important for GII.4 norovirus, where vaccines under development offer promise to prevent hundreds of millions of annual gastroenteritis cases. Previous studies have suggested that new GII.4 pandemic viruses evolve from previous pandemic variants through substitutions in the antigenic region of the VP1 protein that enable evasion of host population immunity, leading to global spread. In contrast, we show here that the acquisition of new genetic and antigenic characteristics is not the proximal driver of new pandemics. Instead, pandemic GII.4 viruses circulate undetected for years before causing a new pandemic, during which time they diversify and spread over wide geographical areas. Serological data demonstrate that by 2003, some nine years before it emerged as a new pandemic, the ancestral 2012 pandemic strain had already acquired the antigenic characteristics that allowed it to evade prevailing population immunity against the previous 2009 pandemic variant. These results provide strong evidence that viral genetic changes are necessary but not sufficient for GII.4 pandemic spread. Instead, we suggest that it is changes in host population immunity that enable pandemic spread of an antigenically-preadapted GII.4 variant. These results indicate that predicting future GII.4 pandemic variants will require surveillance of currently unsampled reservoir populations. Furthermore, a broadly acting GII.4 vaccine will be critical to prevent future pandemics.

Significance

Norovirus pandemics and their associated public health and economic costs could be prevented by effective vaccines. However, vaccine development and distribution will require identification of the sources and drivers of new pandemics. We here use phylogenetics and serological experiments to develop and test a new hypothesis of pandemic norovirus emergence. We find that pandemic noroviruses preadapt, diversify and spread worldwide years prior to emergence, strongly indicating that genetic changes are necessary but not sufficient to drive a new pandemic. We instead suggest that changes in population immunity enable pandemic emergence of a pre-adapted low-level variant. These findings indicate that prediction of new pandemics will require surveillance of under-sampled virus reservoirs and that norovirus vaccines will need to elicit broad immunity.
A gall-forming insect manipulates hostplant phytohormone synthesis, concentrations, and signaling
Authors: Body Mélanie J. A. , Appel Heidi M. , Edger Patrick P. , Schultz Jack C.
Published: June 2019

Insect galls are highly specialized plant organs formed by an intimate biochemical interaction between the plant and a gall-inducing insect. Galls provide the insect enhanced nutrition and protection against natural enemies and environmental stresses. Because galls are plant organs, their development is likely to be governed by native phytohormones that function in organogenesis. We characterized concentrations of both growth and stress phytohormones in ungalled leaves and the leaf galls of Daktulosphaira vitifoliae on wild grape Vitis riparia at 4 different developmental stages. We found clear evidence of hormone manipulation by phylloxera during gall initiation and development. Phylloxera suppressed accumulation of of gibberellins, auxin, and jasmonates during the first two gall stages while absiscic acid concentrations were suppressed throughout development. Concentrations of 3 cytokinins and salicylate were greatly elevated during the earliest gall stage and declined sharply thereafter. We found no evidence of expression of cytokinin biosynthesis genes during the first gall stage, which strongly suggests that phylloxera supplied those phytohormones. High salicylate concentrations could have been caused by cytokinins, a response to microbes, or both. Our results suggest a central role for cytokinins in gall initiation and indicate the importance of the insect’s ability to manipulate other hormones.
Benefits of commitment in hierarchical inference
Authors: Qiu Cheng , Luu Long , Stocker Alan A.
Published: June 2019

Humans have the tendency to commit to a single interpretation of what has caused some observed evidence rather than considering all possible alternatives. This tendency can explain various forms of confirmation and reference biases. However, committing to a single high-level interpretation seems short-sighted and irrational, and thus it is unclear why humans seem motivated to pursue such strategy.

In a first step toward answering this question, we systematically quantified how this strategy affects estimation accuracy at the feature level in the context of two universal hierarchical inference tasks, categorical perception and causal cue combination. Using model simulations, we demonstrate that although estimation is generally impaired when conditioned on only a single high-level inter-pretation, the impairment is not uniform across the entire feature range. On the contrary, compared to a full inference strategy that considers all high-level interpretations, accuracy is actually better for feature values for which the probability of an incorrect categorical/structural commitment is relatively low. That is to say, if an observer is reasonably certain about the high-level interpretation of the feature, it is advantageous to condition subsequent feature inference only on that particular interpretation. We also show that this benefit of commitment is substantially amplified if late noise corrupts information processing (e.g., during retention in working memory). Our results suggest that top-down inference strategies that solely rely on the most likely high-level interpretation can be favorable and at least locally outperform a full inference strategy.
Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3
Authors: Huang Kerui , Miao Ting , Chang Kai , Kang Ping , Jiang Qiuhan , Simmonds Andrew J. , Cara Francesca Di , Bai Hua
Published: June 2019

Age is a major risk factor for cardiovascular diseases. Currently, the non-autonomous regulation of age-related cardiac dysfunction is poorly understood. In the present study, we discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes (hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is significantly up-regulated (52-fold) in aged oenocytes. Oenocyte-specific knockdown of Upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of Upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates aging- and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.
Suppression of store-operated calcium entry causes dilated cardiomyopathy of the Drosophila heart
Authors: Petersen Courtney E. , Wolf Matthew J. , Smyth Jeremy T.
Published: June 2019

Store-operated Ca2+ entry (SOCE) is an essential Ca2+ signaling and homeostatic mechanism present in nearly all animal cells. SOCE refers to influx of Ca2+ into cells that is activated by depletion of endoplasmic or sarcoplasmic reticulum stores (ER/SR) Ca2+ stores. In the SOCE pathway, STIM proteins function as Ca2+ sensors in the ER, and upon ER Ca2+ store depletion STIM rearranges to ER-plasma membrane junctions where it activates Orai Ca2+ influx channels. Multiple studies have implicated STIM and Orai mediated SOCE in the pathogenesis of cardiac hypertrophy. Importantly however, the functional roles of SOCE in normal heart physiology have not been well defined. We have addressed this in Drosophila melanogaster, a powerful animal model of cardiac development and physiology. We show that heart specific suppression of Drosophila Stim and Orai resulted in reduced contractility consistent with dilated cardiomyopathy, characterized by increased end diastolic and end systolic dimensions and decreased fractional shortening. Reduced contractility was apparent in larval hearts and became more pronounced in adults. Myofibers were disorganized and more widely spaced in larval and adult hearts with Stim and Orai RNAi as compared to controls, possibly reflecting decompensation or upregulated stress response signaling due to altered Ca2+ homeostasis. Lastly, we show that reduced heart function significantly affected animal health and viability, as animals with heart specific Stim and Orai suppression exhibited significant delays in post-embryonic development and adults died significantly earlier than controls. Collectively, our results demonstrate that SOCE is essential for normal heart physiology and establish Drosophila as an important model for delineation of functional SOCE roles in cardiomyocytes.
A mouse model of recurrent myocardial infarction reports diminished emergency hematopoiesis and cardiac inflammation
Authors: Cremer Sebastian , Schloss Maximilian J. , Vinegoni Claudio , Zhang Shuang , Rohde David , Feruglio Paolo Fumene , Schmidt Stephen , Wojtkiewicz Greg , Weissleder Ralph , Swirski Filip K. , Nahrendorf Matthias
Published: June 2019

Recurrent MI is common in patients with coronary artery disease and associates with high mortality. Here we developed a surgical mouse model in which two subsequent MIs affect different left ventricular regions in the same mouse. Recurrent MI was induced by ligating the left circumflex followed by the left anterior descending branch of the coronary artery. We characterized the resulting ischemia by whole-heart fluorescent coronary angiography after optical organ clearing and by cardiac MRI. We report that a first MI induces bone marrow “memory” via a circulating signal, thereby affecting hematopoietic factor expression in bone marrow macrophages. This altered the organism’s reaction to subsequent events. Inspite at least similar extent of injury reported by blood troponin, recurrent MI caused reduced emergency hematopoiesis and less leukocytosis than a first MI. Consequently, fewer leukocytes migrated to the ischemic myocardium. The hematopoietic response to lipopolysaccharide was also mitigated after a previous MI. Our data suggest that hematopoietic and innate immune responses are shaped by a preceding MI.
Microbial community-level features linked to divergent carbon flows during early litter decomposition in a constant environment
Authors: Johansen Renee , Albright Michaeline , Lopez Deanna , Gallegos-Graves La Verne , Runde Andreas , Mueller Rebecca , Washburne Alex , Yoshida Thomas , Dunbar John
Published: June 2019

During plant litter decomposition in soils, carbon has two general fates: return to the atmosphere via microbial respiration or transport into soil where long-term storage may occur. Discovering microbial community features that drive carbon fate from litter decomposition may improve modeling and management of soil carbon. This concept assumes there are features (or underlying processes) that are widespread among disparate communities, and therefore amenable to modeling. We tested this assumption using an epidemiological approach in which two contrasting patterns of carbon flow in laboratory microcosms were delineated as functional states and diverse microbial communities representing each state were compared to discover shared features linked to carbon fate. Microbial communities from 206 soil samples from the southwestern United States were inoculated on plant litter in microcosms, and carbon flow was measured as cumulative carbon dioxide (CO2) and dissolved organic carbon (DOC) after 44 days. Carbon flow varied widely among the microcosms, with a 2-fold range in cumulative CO2efflux and a 5-fold range in DOC quantity. Bacteria, not fungi, were the strongest drivers of DOC variation. The most significant community-level feature linked to DOC abundance was bacterial richness—the same feature linked to carbon fate in human-gut microbiome studies. This proof-of-principle study under controlled conditions suggests common features driving carbon flow in disparate microbial communities can be identified, motivating further exploration of underlying mechanisms that may influence carbon fate in natural ecosystems.
Distinct neural mechanisms for the prosocial and rewarding properties of MDMA
Authors: Heifets Boris D. , Salgado Juliana S. , Taylor Madison D. , Hoerbelt Paul , Cardozo Pinto Daniel F. , Steinberg Elizabeth E. , Walsh Jessica J. , Sze Ji Y. , Malenka Robert C.
Published: June 2019

The extensively abused recreational drug MDMA has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA’s prosocial effect. MDMA’s acute rewarding properties, in contrast, require dopaminergic signaling. MDMA’s prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA’s prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.

One Sentence Summary

MDMA, which has both therapeutic and abuse potential, engages a brain region-specific serotonergic pathway to produce its prosocial effect.
Identification of peptide coatings that enhance diffusive transport of nanoparticles through the tumor microenvironment
Authors: Mohanty Rashmi P. , Liu Xinquan , Kim Jae Y. , Peng Xiujuan , Bhandari Sahil , Leal Jasmim , Arasappan Dhivya , Wylie Dennis , Dong Tony , Ghosh Debadyuti
Published: June 2019

In solid tumors, increasing drug penetration promotes their regression and improves the therapeutic index of compounds. However, the heterogeneous extracellular matrix (ECM) acts a steric and interaction barrier that hinders effective transport of therapeutics, including nanomedicines. Specifically, the interactions between the ECM and surface physicochemical properties of nanomedicines (e.g. charge, hydrophobicity) impedes their diffusion and penetration. To address the challenges using existing surface chemistries, we used peptide-presenting phage libraries as a high-throughput approach to screen and identify peptides as coatings with desired physicochemical properties that improve diffusive transport through the tumor microenvironment. Through iterative screening against the ECM and identification by next-generation DNA sequencing and analysis, we selected individual clones and measured their transport by diffusion assays. Here, we identified a net-neutral charge, hydrophilic peptide P4 that facilitates significantly higher diffusive transport of phage than negative control through in vitro tumor ECM. Through alanine mutagenesis, we confirmed that the hydrophilicity, charge, and their spatial ordering impact diffusive transport. P4 phage clone exhibited almost 200-fold improved uptake in ex vivo pancreatic tumor xenografts compared to the negative control. Nanoparticles coated with P4 exhibited ∼40-fold improvement in diffusivity in pancreatic tumor tissues, and P4-coated particles demonstrated less hindered diffusivity through the ECM compared to particles functionalized with gold standard poly(ethylene) glycol or iRGD peptide ligand. By leveraging the power of molecular diversity using phage display, we can greatly expand the chemical space of surface chemistries that can improve the transport of nanomedicines through the complex tumor microenvironment to ultimately improve their efficacy.

Abstract Figure
M13 phage display to identify a permeating peptide against hyperconcentrated mucin
Authors: Leal Jasmim , Dong Tony , Gao Feng , Soto Melissa , Smyth Hugh D.C. , Ghosh Debadyuti
Published: June 2019

Mucus is an impregnable barrier for drug delivery across the epithelia for treatment of mucosal-associated diseases. While current carriers are promising for mucus penetration, their surface chemistries do not possess chemical complexity to probe and identify optimal physicochemical properties desired for mucus penetration. As initial study, we use M13 phage display presenting random peptides to select peptides that can facilitate permeation through hyperconcentrated mucin. Here, a net-neutral charge, hydrophilic peptide was identified to facilitate transport of phage and fluorophore conjugates through mucin barrier compared to controls. This initial finding warrants further study to understand how composition and spatial distribution of physicochemical properties of peptides can be optimized to improve transport across the mucus barrier.
Divide and Conquer: Real-time maximum likelihood fitting of multiple emitters for super-resolution localization microscopy
Authors: Li Luchang , Xin Bo , Kuang Weibing , Zhou Zhiwei , Huang Zhen-Li
Published: June 2019

Multi-emitter localization has great potential for maximizing the imaging speed of super-resolution localization microscopy. However, the slow image analysis speed of reported multi-emitter localization algorithms limits their usage in mostly off-line image processing with small image size. Here we adopt the well-known divide and conquer strategy in computer science and present a fitting-based method called QC-STORM for fast multi-emitter localization. Using simulated and experimental data, we verify that QC-STORM is capable of providing real-time full image processing on raw images with 100 µm × 100 µm field of view and 10 ms exposure time, with comparable spatial resolution as the popular fitting-based ThunderSTORM and the up-to-date non-iterative WindSTORM. This study pushes the development and practical use of super-resolution localization microscopy in high-throughput or high-content imaging of cell-to-cell differences or discovering rare events in a large cell population.
Adaptive laboratory evolution ofEscherichia coliunder acid stress
Authors: Du Bin , Olson Connor A. , Sastry Anand V. , Fang Xin , Phaneuf Patrick V. , Chen Ke , Wu Muyao , Szubin Richard , Xu Sibei , Gao Ye , Hefner Ying , Feist Adam M. , Palsson Bernhard O.
Published: June 2019

The ability ofEscherichia colito tolerate acid stress is important for its survival and colonization in the human digestive tract. Here, we performed adaptive laboratory evolution of the laboratory strainE. coliK-12 MG1655 at pH 5.5 in glucose minimal medium. By 800 generations, six independent populations under evolution reached 18.0% higher growth rates than their starting strain at pH 5.5, while maintaining comparable growth rates to the starting strain at pH 7. We characterized the evolved strains to find that: (1) whole genome sequencing of isolated clones from each evolved population revealed mutations inrpoCappearing in 5 of 6 sequenced clones; (2) gene expression profiles revealed different strategies to mitigate acid stress, that are related to amino acid metabolism and energy production and conversion. Thus, a combination of adaptive laboratory evolution, genome resequencing, and expression profiling reveals, on a genome-scale, the strategies thatE. colideploys to mitigate acid stress.
The activity-dependent transcription factor Npas4 regulates IQSEC3 expression in somatostatin interneurons to mediate anxiety-like behavior
Authors: Kim Seungjoon , Park Dongseok , Kim Jinhu , Lee Dongsoo , Kim Dongwook , Kim Hyeonho , Hong Sookyung , Jeon Jongcheol , Kim Jaehoon , Cheong Eunji , Um Ji Won , Ko Jaewon
Published: June 2019

Organization of mammalian inhibitory synapses is thought to be crucial for normal brain functions, but the underlying molecular mechanisms have been still incompletely understood. IQSEC3 (IQ motif and Sec7 domain 3) is a guanine nucleotide exchange factor for ADP-ribosylation factor (ARF-GEF) that directly interacts with gephyrin. Here, we show that GABAergic synapse-specific transcription factor, Npas4 (neuronal PAS domain protein 4) directly binds to the promoter of Iqsec3 and regulates its transcription. Strikingly, an enriched environment (EE) induced Npas4 upregulation and concurrently increased IQSEC3 protein levels specifically in mouse CA1 stratum oriens layer somatostatin (SST)-expressing GABAergic interneurons, which are compromised in Npas4-knockout (KO) mice. Moreover, expression of wild-type (WT) IQSEC3, but not a dominant-negative (DN) ARF-GEF–inactive mutant, rescued the decreased GABAergic synaptic transmission in Npas4-deficient SST interneurons. Concurrently, expression of IQSEC3 WT normalized the altered GABAergic synaptic transmission in dendrites, but not soma, of Npas4-deficient CA1 pyramidal neurons. Furthermore, expression of IQSEC3 WT, but not IQSEC3 DN, in SST-expressing interneurons in CA1 SST Npas4-KO mice rescued the altered anxiety-like behavior. Collectively, our results suggest that IQSEC3 is a key GABAergic synapse component that is directed by Npas4 activity- and ARF activity-dependent gene programs in SST-expressing interneurons to orchestrate the functional excitation-to-inhibition balance.
A DNA-based synthetic apoptosome
Authors: Rosier Bas J.H.M. , Markvoort Albert J. , Gumí-Audenis Berta , Roodhuizen Job A.L. , den Hamer Anniek , Brunsveld Luc , de Greef Tom F.A.
Published: June 2019

Living cells are able to regulate key cellular processes by physically assembling signaling components on dedicated molecular platforms. The spatial organization of proteins in these higher-order signaling complexes facilitates proximity-driven activation and inhibition events, allowing tight regulation of the flow of information. Here, we employ the programmability and modularity of DNA origami as a controllable molecular platform for studying protein-protein interactions involved in intracellular signaling. Specifically, we engineer a synthetic, DNA origami-based version of the apoptosome, a large multi-protein signaling complex that regulates apoptosis by co-localization of multiple caspase-9 monomers. Ourin vitrocharacterization using both wildtype caspase-9 monomers and inactive mutants tethered to a DNA origami platform directly demonstrates that enzymatic activity is induced by proximity-driven dimerization with asymmetric, half-of-sites reactivity. Additionally, experimental results supported by a detailed thermodynamic model reveal a multivalent activity enhancement in tethered caspase-9 oligomers of three and four enzymes, partly originating from a statistical increase in the number of active catalytic units in higher-order enzyme clusters. Our results offer fundamental insights in caspase-9 activity regulation and demonstrate that DNA origami provides a modular platform to construct and characterize higher-order signaling complexes. The engineered DNA-based protein assembly platform has the potential to be broadly applied to inform the function of other important multi-enzyme assemblies involved in inflammation, innate immunity, and necrosis.