bluuebunny/crossref_metadata_2025 huggingface dataset:
Profound reductions in first and total cardiovascular events with icosapent ethyl in the REDUCE-IT trial: why these results usher in a new era in dyslipidaemia therapeutics
Authors: Boden William E , Bhatt Deepak L , Toth Peter P , Ray Kausik K , Chapman M John , Lüscher Thomas F
Published: October 2019

The aims of this clinical review are to: (i) highlight the importance of elevated baseline triglycerides (TG) in the setting of well-controlled low-density lipoprotein cholesterol (LDL-C) on statins as a major contributor to residual atherosclerotic cardiovascular disease (ASCVD) risk, particularly among patients with type 2 diabetes mellitus, metabolic syndrome, and obesity whose distinctive lipid phenotype cannot be optimally treated with LDL-C reduction therapy alone; (ii) describe the findings and clinical implications of the landmark REDUCE-IT trial in which ethyl eicosapentaenoic acid significantly improved ASCVD outcomes. While many genetic studies have shown that elevated TG are an independent causal factor for ASCVD, prior placebo-controlled trials using niacin, fibrates, omega-3 fatty acids, and dietary supplement fish oil preparations have failed to demonstrate significant CV event reduction when added to statin therapy. In contrast, the REDUCE-IT trial in 8179 participants showed convincingly that the administration of 4 g daily of icosapent ethyl (an ethyl ester of eicosapentaenoic acid) in patients at high risk for ASCVD with increased levels of baseline TG [median value, 2.44 mmol/L (216.0 mg/dL)] but well-controlled LDL-C [median value, 1.94 mmol/L (75.0 mg/dL)] reduced significantly incident events across both the trial primary endpoint and multiple prespecified secondary endpoints, including cardiovascular death, as well as both subsequent and total primary endpoint and key secondary endpoint events. Icosapent ethyl unequivocally contributed to ASCVD event reduction over and above statin therapy. The REDUCE-IT trial results should alter our approach to managing a growing population of hypertriglyceridaemic patients whose lipid phenotype requires more intensive treatment beyond LDL-C lowering alone.
Non-invasive assessment of the arrhythmogenic substrate in Brugada syndrome using signal-averaged electrocardiogram: clinical implications from a prospective clinical trial
Authors: Ciconte Giuseppe , Santinelli Vincenzo , Vicedomini Gabriele , Borrelli Valeria , Monasky Michelle M , Micaglio Emanuele , Giannelli Luigi , Negro Gabriele , Giordano Federica , Mecarocci Valerio , Mazza Beniamino C , Locati Emanuela , Anastasia Luigi , Calovic Zarko , Pappone Carlo
Published: October 2019

Aims

Brugada syndrome (BrS) represents a major cause of sudden cardiac death in young individuals. The risk stratification to forecast future life-threatening events is still controversial. Non-invasive assessment of late potentials (LPs) has been proposed as a risk stratification tool. However, their nature in BrS is still undetermined. The purpose of this study is to assess the electrophysiological determinants of non-invasive LPs.

Methods and Results

Two hundred and fifty consecutive patients with (Group 1, n = 96) and without (Group 2, n = 154) BrS-related symptoms were prospectively enrolled in the registry. Signal-averaged electrocardiogram (SAECG) was performed in all subjects before undergoing epicardial mapping. Group 1 patients exhibited larger arrhythmogenic substrates (AS; 5.8 ± 2.8 vs. 2.6 ± 2.1 cm2, P < 0.001) with more delayed potentials (220.4 ± 46.0 vs. 186.7 ± 42.3 ms, P < 0.001). Late potentials were present in 82/96 (85.4%) Group 1 and in 31/154 (20.1%) Group 2 individuals (P < 0.001). Patients exhibiting LPs had more frequently a spontaneous Type 1 pattern (30.1% vs. 10.9%, P < 0.001), SCN5A mutation (34.5% vs. 21.2%, P = 0.02), and exhibited a larger AS with longer potentials (5.8 ± 2.7 vs. 2.2 ± 1.7 cm2; 231.2 ± 37.3 vs. 213.8 ± 39.0 ms; P < 0.001, respectively). Arrhythmogenic substrate dimension was the strongest predictor of the presence of LPs (odds ratio 1.9; P < 0.001). An AS area of at least 3.5 cm2 identified patients with LPs (area under the curve 0.88, 95% confidence interval 0.843–0.931; P < 0.001) with a sensitivity of 86%, specificity 88%, positive predictive value 85%, and negative predictive value 89%.

Conclusion

The results of this study support the role of the epicardial AS as an electrophysiological determinant of non-invasive LPs, which may serve as a tool in the non-invasive assessment of the BrS substrate, as SAECG-LPs could be considered an expression of the abnormal epicardial electrical activity.

ClinicalTrials.gov number (NCT02641431; NCT03106701).
A chromosomal-level genome assembly for the giant African snail Achatina fulica
Authors: Guo Yunhai , Zhang Yi , Liu Qin , Huang Yun , Mao Guangyao , Yue Zhiyuan , Abe Eniola M , Li Jian , Wu Zhongdao , Li Shizhu , Zhou Xiaonong , Hu Wei , Xiao Ning
Published: October 2019

Background

Achatina fulica, the giant African snail, is the largest terrestrial mollusk species. Owing to its voracious appetite, wide environmental adaptability, high growth rate, and reproductive capacity, it has become an invasive species across the world, mainly in Southeast Asia, Japan, the western Pacific islands, and China. This pest can damage agricultural crops and is an intermediate host of many parasites that can threaten human health. However, genomic information of A. fulica remains limited, hindering genetic and genomic studies for invasion control and management of the species.

Findings

Using a k-mer–based method, we estimated the A. fulica genome size to be 2.12 Gb, with a high repeat content up to 71%. Roughly 101.6 Gb genomic long-read data of A. fulica were generated from the Pacific Biosciences sequencing platform and assembled to produce a first A. fulica genome of 1.85 Gb with a contig N50 length of 726 kb. Using contact information from the Hi-C sequencing data, we successfully anchored 99.32% contig sequences into 31 chromosomes, leading to the final contig and scaffold N50 length of 721 kb and 59.6 Mb, respectively. The continuity, completeness, and accuracy were evaluated by genome comparison with other mollusk genomes, BUSCO assessment, and genomic read mapping. A total of 23,726 protein-coding genes were predicted from the assembled genome, among which 96.34% of the genes were functionally annotated. The phylogenetic analysis using whole-genome protein-coding genes revealed that A. fulica separated from a common ancestor with Biomphalaria glabrata ~182 million years ago.

Conclusion

To our knowledge, the A. fulica genome is the first terrestrial mollusk genome published to date. The chromosome sequence of A. fulica will provide the research community with a valuable resource for population genetics and environmental adaptation studies for the species, as well as investigations of the chromosome-level of evolution within mollusks.
Effect of a dual enteric and respiratory pathogen challenge on swine growth, efficiency, carcass composition, and pork quality1
Authors: Outhouse Amanda C , Helm Emma T , Patterson Brian M , Dekkers Jack C M , Rauw Wendy M , Schwartz Kent J , Gabler Nicholas K , Huff-Lonergan Elisabeth , Lonergan Steven M
Published: October 2019

The objective of this study was to determine the influence of a dual respiratory and enteric pathogen challenge on growth performance, carcass composition, and pork quality of high and low feed efficient pigs. Pigs divergently selected for low and high residual feed intake (RFI, ~68 kg) from the 11th generation of Iowa State University RFI project were used to represent high and low feed efficiency. To elicit a dual pathogen challenge, half of the pigs (n = 12/line) were inoculated with Mycoplasma hyopneumoniae (Mh) and Lawsonia intracellularis (MhLI) on days post-inoculation (dpi) 0. Pigs in a separate room of the barn were not inoculated and used as controls (n = 12/RFI line). Pigs were weighed and feed intake was recorded to calculate ADG, ADFI, and G:F for the acclimation period (period 1: dpi −21 to 0), during peak infection (period 2: dpi 0 to 42), and during the remaining growth period to reach market weight (period 3: dpi 42 to harvest). At ~125 kg, pigs were harvested using standard commercial procedures. Carcasses were evaluated for composition (weight, fat free lean, loin eye area, 10th rib fat depth) and meat quality (pH decline, temperature decline, Hunter L, a, and b, subjective color and marbling, star probe, drip loss, cook loss, proximate composition, and desmin degradation). Challenged pigs had lesser ADFI than controls during period 2 (P < 0.05), but had greater ADG and G:F during period 3 (P < 0.05). Selection for feed efficiency did not result in a differential response to MhLI (P > 0.05). Loin chops from the less feed efficient, high RFI pigs, had greater drip loss, greater cook loss, lesser moisture content, greater Hunter L values, and greater Hunter b values (P < 0.05) than loin chops from low RFI pigs. Infection status did not significantly affect carcass composition or pork quality traits (P > 0.05). These results indicate that a MhLI challenge early in growth did not significantly affect ultimate carcass composition or meat quality traits. Selection for greater feed efficiency in pigs did not affect their response to pathogenic challenge.
Brassinosteroids act as a positive regulator of NBR1-dependent selective autophagy in response to chilling stress in tomato
Authors: Chi Cheng , Li Xiaomeng , Fang Pingping , Xia Xiaojian , Shi Kai , Zhou Yanhong , Zhou Jie , Yu Jingquan
Published: October 2019

Autophagy is a highly conserved and regulated catabolic process involved in the degradation of protein aggregates, which plays critical roles in eukaryotes. In plants, multiple molecular processes can induce or suppress autophagy but the mechanism of its regulation by phytohormones is poorly understood. Brassinosteroids (BRs) are steroid phytohormones that play crucial roles in plant response to stresses. Here, we investigate the role of BRs in NBR1-dependent selective autophagy in response to chilling stress in tomato. BRs and their signaling element BZR1 can induce autophagy and accumulation of the selective autophagy receptor NBR1 in tomato under chilling stress. Cold increased the stability of BZR1, which was promoted by BRs. Cold- and BR-induced increased BZR1 stability activated the transcription of several autophagy-related genes (ATGs) and NBR1 genes by directly binding to their promoters, which resulted in selective autophagy. Furthermore, silencing of these ATGs or NBR1 genes resulted in a decreased accumulation of several functional proteins and an increased accumulation of ubiquitinated proteins, subsequently compromising BR-induced cold tolerance. These results strongly suggest that BRs regulate NBR1-dependent selective autophagy in a BZR1-dependent manner in response to chilling stress in tomato.
CIRCADIAN CLOCK ASSOCIATED 1 and ATAF2 differentially suppress cytochrome P450-mediated brassinosteroid inactivation
Authors: Peng Hao , Neff Michael M
Published: October 2019

Brassinosteroids (BRs) are a group of steroid hormones regulating plant growth and development. Since BRs do not undergo transport among plant tissues, their metabolism is tightly regulated by transcription factors (TFs) and feedback loops. BAS1 (CYP734A1, formerly CYP72B1) and SOB7 (CYP72C1) are two BR-inactivating cytochrome P450s identified in Arabidopsis thaliana. We previously found that a TF ATAF2 (ANAC081) suppresses BAS1 and SOB7 expression by binding to the Evening Element (EE) and CIRCADIAN CLOCK ASSOCIATED 1 (CCA1)-binding site (CBS) on their promoters. Both the EE and CBS are known binding targets of the circadian regulatory protein CCA1. Here, we confirm that CCA1 binds the EE and CBS motifs on BAS1 and SOB7 promoters, respectively. Elevated accumulations of BAS1 and SOB7 transcripts in the CCA1 null mutant cca1-1 indicate that CCA1 is a repressor of their expression. When compared with either cca1-1 or the ATAF2 null mutant ataf2-2, the cca1-1 ataf2-2 double mutant shows higher SOB7 transcript accumulations and a stronger BR-insensitive phenotype of hypocotyl elongation in white light. CCA1 interacts with ATAF2 at both DNA–protein and protein–protein levels. ATAF2, BAS1, and SOB7 are all circadian regulated with distinct expression patterns. These results demonstrate that CCA1 and ATAF2 differentially suppress BAS1- and SOB7-mediated BR inactivation.
Engineering abiotic stress tolerance via CRISPR/ Cas-mediated genome editing
Authors: Zafar Syed Adeel , Zaidi Syed Shan-e-Ali , Gaba Yashika , Singla-Pareek Sneh Lata , Dhankher Om Parkash , Li Xueyong , Mansoor Shahid , Pareek Ashwani
Published: October 2019

Recent developments in genome editing tools have raised hopes for societal acceptance of genome-edited/modified crops. We present a critical evaluation of these tools in tackling abiotic stress, a highly complex and multigenic trait.
Hot disk of the Swift J0243.6+6124 revealed by Insight-HXMT
Authors: Doroshenko V , Zhang S N , Santangelo A , Ji L , Tsygankov S , Mushtukov A , Qu L J , Zhang S , Ge M Y , Chen Y P , Bu Q C , Cao X L , Chang Z , Chen G , Chen L , Chen T X , Chen Y , Chen Y B , Cui W , Cui W W , Deng J K , Dong Y W , Du Y Y , Fu M X , Gao G H , Gao H , Gao M , Gu Y D , Guan J , Guo C C , Han D W , Hu W , Huang Y , Huo J , Jia S M , Jiang L H , Jiang W C , Jin J , Jin Y J , Kong L D , Li B , Li C K , Li G , Li M S , Li T P , Li W , Li X , Li X B , Li X F , Li Y G , Li Z J , Li Z W , Liang X H , Liao J Y , Liu C Z , Liu G Q , Liu H W , Liu S Z , Liu X J , Liu Y , Liu Y N , Lu B , Lu F J , Lu X F , Luo T , Ma X , Meng B , Nang Y , Nie J Y , Ou G , Sai N , Song L M , Song X Y , Sun L , Tan Y , Tao L , Tuo Y L , Wang G F , Wang J , Wang W S , Wang Y S , Wen X Y , Wu B B , Wu M , Xiao G C , Xiong S L , Xu H , Xu Y P , Yang Y R , Yang J W , Yang S , Yang Y J , Zhang A M , Zhang C L , Zhang C M , Zhang F , Zhang H M , Zhang J , Zhang Q , Zhang T , Zhang W , Zhang W C , Zhang W Z , Zhang Y , Zhang Y , Zhang Y F , Zhang Y J , Zhang Z , Zhang Z L , Zhao H S , Zhao J L , Zhao X F , Zheng S J , Zhu Y , Zhu Y X , Zou C L
Published: October 2019

We report on analysis of observations of the bright transient X-ray pulsar Swift J0243.6+6124 obtained during its 2017-2018 giant outburst with Insight-HXMT, NuSTAR, and Swift observatories. We focus on the discovery of a sharp state transition of the timing and spectral properties of the source at super-Eddington accretion rates, which we associate with the transition of the accretion disk to a radiation pressure dominated (RPD) state, the first ever directly observed for magnetized neutron star. This transition occurs at slightly higher luminosity compared to already reported transition of the source from sub- to super-critical accretion regime associate with onset of an accretion column. We argue that this scenario can only be realized for comparatively weakly magnetized neutron star, not dissimilar to other ultra-luminous X-ray pulsars (ULPs), which accrete at similar rates. Further evidence for this conclusion is provided by the non-detection of the transition to the propeller state in quiescence which strongly implies compact magnetosphere and thus rules out magnetar-like fields.
Predicting fully self-consistent satellite richness, galaxy growth and starformation rates from the STastical sEmi-Empirical modeL steel.
Authors: Grylls Philip J , Shankar F , Leja J , Menci N , Moster B , Behroozi P , Zanisi L
Published: October 2019

Observational systematics complicate comparisons with theoretical models limiting understanding of galaxy evolution. In particular, different empirical determinations of the stellar mass function imply distinct mappings between the galaxy and halo masses, leading to diverse galaxy evolutionary tracks. Using our state-of-the-art STatistical sEmi-Empirical modeL, steel, we show fully self-consistent models capable of generating galaxy growth histories that simultaneously and closely agree with the latest data on satellite richness and star-formation rates at multiple redshifts and environments. Central galaxy histories are generated using the central halo mass tracks from state-of-the-art statistical dark matter accretion histories coupled to abundance matching routines. We show that too flat high-mass slopes in the input stellar-mass-halo-mass relations as predicted by previous works, imply non-physical stellar mass growth histories weaker than those implied by satellite accretion alone. Our best-fit models reproduce the satellite distributions at the largest masses and highest redshifts probed, the latest data on star formation rates and its bi-modality in the local Universe, and the correct fraction of ellipticals. Our results are important to predict robust and self-consistent stellar-mass-halo-mass relations and to generate reliable galaxy mock catalogues for the next generations of extra-galactic surveys such as Euclid and LSST.
The effect of pulsation on the near-ultraviolet spectrum of AGB stars
Authors: Guerrero Martín A , Ortiz Roberto
Published: October 2019

Pulsating and non-pulsating asymptotic giant branch (AGB) stars exhibit a variable near-ultraviolet (near-UV) spectrum, which suggest that mechanisms other than pulsation may affect their near-UV spectrum. In this work, we analyse the near-UV spectra of two groups of AGB stars: (1) regularly pulsating and (2) irregular, small-amplitude stars. Near-UV and blue spectra were obtained for 27 stars distributed into these two groups with the Isaac Newton Telescope (La Palma, Spain). Additional near-UV spectra were taken from the iue library. The occurrence of Fe ii lines depends mainly on the intensity of the stellar continuum: as it increases, Fe ii lines are gradually hampered. Balmer emission lines are pulsation driven, as they appear only among the large-amplitude pulsating stars of our sample, between −0.10 < ϕ < 0.50. Among the regularly pulsating stars, the intensity of the Mg ii λ2800 doublet is driven by pulsation, with its maximum between 0.20 < ϕ < 0.35. On the other hand, this feature is also highly variable among small-amplitude, irregularly pulsating stars. This suggests that, besides pulsation, other mechanisms may participate in the formation of this line. The spectral slope between 3000 < λ(Å)<3200 is approximately constant among small-amplitude stars, but it shows a strong correlation with the phase of the pulsation in the other group, which indicates that the origin of the continuum is chromospheric. Different phase lags between the Mg ii λ2800 and the slope of the continuum suggests that this line and its neighbouring continuum might be formed in distinct places in the chromosphere or its surroundings.
Discovery of a large H i ring around the quiescent galaxy AGC 203001
Authors: Bait Omkar , Kurapati Sushma , Duc Pierre-Alain , Cuillandre Jean-Charles , Wadadekar Yogesh , Kamphuis Peter , Barway Sudhanshu
Published: October 2019

Here we report the discovery with the Giant Metrewave Radio Telescope of an extremely large (∼115 kpc in diameter) H i ring, located around a massive quenched galaxy, AGC 203001, but off-centered, with respect to it. This ring does not have any bright extended optical counterpart unlike several other known ring galaxies. Our deep g, r, and i optical imaging of the H i ring, using the MegaCam instrument on the Canada-France-Hawaii Telescope, shows however several regions with faint optical emission at a surface brightness level of ∼28 mag/arcsec2. Such an extended H i structure is very rare with only one other case known so far – the Leo ring. Conventionally, off-centered rings have been explained by a collision with an “intruder” galaxy leading to expanding density waves of gas and stars in the form of a ring. However, in such a scenario the impact also leads to large amounts of star formation in the ring which is not observed in the ring presented in this paper. We discuss possible scenarios for the formation of such H i dominated rings.
More Arrows in the Ancient DNA Quiver: Use of Paleoepigenomes and Paleomicrobiomes to Investigate Animal Adaptation to Environment
Authors: Liu Yichen , Weyrich Laura S , Llamas Bastien
Published: October 2019

Whether and how epigenetic mechanisms and the microbiome play a role in mammalian adaptation raised considerable attention and controversy, mainly because they have the potential to add new insights into the Modern Synthesis. Recent attempts to reconcile neo-Darwinism and neo-Lamarckism in a unified theory of molecular evolution give epigenetic mechanisms and microbiome a prominent role. However, supporting empirical data are still largely missing. Because experimental studies using extant animals can hardly be done over evolutionary timescales, we propose that advances in ancient DNA techniques provide a valid alternative. In this piece, we evaluate 1) the possible roles of epigenomes and microbiomes in animal adaptation, 2) advances in the retrieval of paleoepigenome and paleomicrobiome data using ancient DNA techniques, and 3) the plasticity of either and interactions between the epigenome and the microbiome, while emphasizing that it is essential to take both into account, as well as the underlying genetic factors that may confound the findings. We propose that advanced ancient DNA techniques should be applied to a wide range of past animals, so novel dynamics in animal evolution and adaption can be revealed.
EPD in 2020: enhanced data visualization and extension to ncRNA promoters
Authors: Meylan Patrick , Dreos René , Ambrosini Giovanna , Groux Romain , Bucher Philipp
Published: October 2019

The Eukaryotic Promoter Database (EPD), available online at https://epd.epfl.ch, provides accurate transcription start site (TSS) information for promoters of 15 model organisms plus corresponding functional genomics data that can be viewed in a genome browser, queried or analyzed via web interfaces, or exported in standard formats (FASTA, BED, CSV) for subsequent analysis with other tools. Recent work has focused on the improvement of the EPD promoter viewers, which use the UCSC Genome Browser as visualization platform. Thousands of high-resolution tracks for CAGE, ChIP-seq and similar data have been generated and organized into public track hubs. Customized, reproducible promoter views, combining EPD-supplied tracks with native UCSC Genome Browser tracks, can be accessed from the organism summary pages or from individual promoter entries. Moreover, thanks to recent improvements and stabilization of ncRNA gene catalogs, we were able to release promoter collections for certain classes of ncRNAs from human and mouse. Furthermore, we developed automatic computational protocols to assign orphan TSS peaks to downstream genes based on paired-end (RAMPAGE) TSS mapping data, which enabled us to add nearly 9000 new entries to the human promoter collection. Since our last article in this journal, EPD was extended to five more model organisms: rhesus monkey, rat, dog, chicken and Plasmodium falciparum.
Follow the (ISSUE) Leader? The Leader-Led Nexus Revisited
Authors: Bodet Marc André , Dufresne Yannick , Bouchard Joanie , Gélineau François
Published: October 2019

Public opinion scholars have long debated the relationship between policy preferences, electoral candidates, and voters. While some argue that voters’ positions on the issues of the day affect the positions candidates take, others argue that relationship runs the other way. Gabriel Lenz’s 2012 book on the leader-led nexus provides an original design and provocative conclusions in a comparative context, though some have criticized the author’s findings (see, for instance, Matthews 2017). This article makes use of a multiwave voting advice application (VAA) panel dataset collected in the Canadian province of Quebec to test the generalizability of some of Lenz’s fundamental conclusions. Our results show that the influence of leaders on voters may be less important—or even reversed—where issues at stake are easy for voters to understand. The results offer evidence of issue priming and partisan influence; as well, the effect of leader influence on voters’ issue positions can vary by age group.
MOMENTS OF SPINOR L-FUNCTIONS AND SYMPLECTIC KLOOSTERMAN SUMS
Authors: Waibel Fabian
Published: October 2019

We compute the second moment of spinor $L$-functions at central points of Siegel modular forms on congruence subgroups of large prime level $N$ and give applications to non-vanishing.
BLOCKS WITH NORMAL ABELIAN DEFECT AND ABELIAN p′ INERTIAL QUOTIENT
Authors: Benson David , Kessar Radha , Linckelmann Markus
Published: October 2019

Let $k$ be an algebraically closed field of characteristic $p$, and let ${\mathcal{O}}$ be either $k$ or its ring of Witt vectors $W(k)$. Let $G$ be a finite group and $B$ a block of ${\mathcal{O}} G$ with normal abelian defect group and abelian $p^{\prime}$ inertial quotient $L$. We show that $B$ is isomorphic to its second Frobenius twist. This is motivated by the fact that bounding Frobenius numbers is one of the key steps towards Donovan’s conjecture. For ${\mathcal{O}}=k$, we give an explicit description of the basic algebra of $B$ as a quiver with relations. It is a quantized version of the group algebra of the semidirect product $P\rtimes L$.
When Investor Incentives and Consumer Interests Diverge: Private Equity in Higher Education
Authors: Eaton Charlie , Howell Sabrina T , Yannelis Constantine
Published: October 2019

We study how private equity buyouts create value in higher education, a sector with opaque product quality and intense government subsidy. With novel data on 88 private equity deals involving 994 schools, we show that buyouts lead to higher tuition and per-student debt. Exploiting loan limit increases, we find that private equity-owned schools better capture government aid. After buyouts, we observe lower education inputs, graduation rates, loan repayment rates, and earnings among graduates. Neither school selection nor student body changes fully explain the results. The results indicate that in a subsidized industry, maximizing value may not improve consumer outcomes.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Multicentric reticulohistiocytosis: the Mayo Clinic experience (1980–2017)
Authors: Sanchez-Alvarez Catalina , Sandhu Avneek Singh , Crowson Cynthia S , Wetter David A , McKenzie Gavin A , Lehman Julia S , Makol Ashima
Published: October 2019

Objectives

Multicentric reticulohistiocytosis (MRH), a rare histiocytic disease that can mimic other rheumatic conditions, may be associated with cancer and other autoimmune disorders. To better understand the disorder and its other associations, we aimed to evaluate clinical correlates and outcomes of all patients with MRH seen at Mayo Clinic, Rochester between 1980 and 2017.

Methods

A retrospective medical record review was conducted to identify all patients with MRH between 1 January 1980 and 30 April 2017.

Results

We identified 24 patients with biopsy-proven MRH (58% female, 75% Caucasian, median age at diagnosis 52 years, median follow-up of 2.3 years). All patients had cutaneous and articular involvement; 23 (96%) patients had papulonodular skin lesions (87% periungual and dorsal hand) and seven (30%) mucosal nodules; and 22 (92%) patients had arthralgias, 21 (88%) joint effusions and 13 (54%) synovitis. Most frequently used therapies included corticosteroids, cyclophosphamide, methotrexate and bisphosphonates. Biologics were used in four patients. Nine patients had symptomatic resolution at 1 year and 12 partial improvement. Radiological findings included erosive changes in three (60%) patients and arthritis mutilans in two patients (40%). Twenty-nine per cent of patients had a concomitant autoimmune disease and 25% malignancy including melanoma, endometrial, peritoneal and lung carcinoma. The 5-year survival rate was 85% (95% CI: 74, 100%).

Conclusion

To our knowledge, this is the largest single-centre series of patients with MRH highlighting the rarity of the condition and an unmet need for treatment options that can allow sustained disease remission. It also highlights the need for a high vigilance for malignancy and autoimmune diseases.
Chromosome-Level Reference Genome of Venturia effusa, Causative Agent of Pecan Scab
Authors: Winter David J. , Charlton Nikki D. , Krom Nick , Shiller Jason , Bock Clive H. , Cox Murray P. , Young Carolyn A.
Published: October 2019

Pecan scab, caused by Venturia effusa, is a devastating disease of pecan (Carya illinoinensis), which results in economic losses on susceptible cultivars throughout the southeastern United States. To enhance our understanding of pathogenicity in V. effusa, we have generated a complete telomere-to-telomere reference genome of V. effusa isolate FRT5LL7-Albino. By combining Illumina MiSeq and Oxford Nanopore MinION data, we assembled a 45.2-Mb genome represented by 20 chromosomes and containing 10,820 putative genes, of which 7,619 have at least one functional annotation. The likely causative mutation of the albino phenotype was identified as a single base insertion and a resulting frameshift in the gene encoding the polyketide synthase ALM1. This genome represents the first full chromosome-level assembly of any Venturia sp.
Corn and Soybean Host Root Endophytic Fungi with Toxicity Toward the Soybean Cyst Nematode
Authors: Strom Noah , Hu Weiming , Haarith Deepak , Chen Senyu , Bushley Kathryn
Published: October 2019

Although fungal endophytes are commonly investigated for their ability to deter microbial plant pathogens, few studies have examined the activity of fungal root endophytes against nematodes. The soybean cyst nematode (SCN; Heterodera glycines), the most severe yield-limiting pathogen of soybean (Glycine max), is commonly managed through rotation of soybean with corn (Zea mays), a nonhost of the SCN. A total of 626 fungal endophytes were isolated from surface-sterilized corn and soybean roots from experimental plots in which soybean and corn had been grown under annual rotation and under 1, 3, 5, and 35 years of continuous monoculture. Fungal isolates were grouped into 401 morphotypes, which were clustered into 108 operational taxonomic units (OTUs) based on 99% sequence similarity of the full internal transcribed spacer region. Morphotype representatives within each OTU were grown in malt extract broth and in a secondary metabolite-inducing medium buffered with ammonium tartrate, and their culture filtrates were tested for nematicidal activity against SCN juveniles. A majority of OTUs containing isolates with nematicidal culture filtrates were in the order Hypocreales, with the genus Fusarium being the most commonly isolated nematicidal genus from corn and soybean roots. Less commonly isolated taxa from soybean roots included the nematophagous fungi Hirsutella rhossiliensis, Metacordyceps chlamydosporia, and Arthrobotrys iridis. Root endophytic fungal diversity in soybean was positively correlated with SCN density, suggesting that the SCN plays a role in shaping the soybean root endophytic community.
Learning in colour: children with grapheme-colour synaesthesia show cognitive benefits in vocabulary and self-evaluated reading
Authors: Smees Rebecca , Hughes James , Carmichael Duncan A. , Simner Julia
Published: October 2019

Cognitive benefits associated with grapheme-colour synaesthesia in adults are well documented, but far less is known about whether such benefits might arise in synaesthetes as children. One previous study on a very small group of randomly sampled child synaesthetes found cognitive benefits in short-term memory and processing speed (the ability to quickly scan an array of images and discriminate between them), but was inconclusive for a test of receptive vocabulary. Using a stratified population sample (
Growing Up in Scotland
Project, Edinburgh, UK: Scottish Executive, 2007), we investigated the performance of a large cohort of child grapheme-colour synaesthetes using four literacy measures taken at age 10 years. These were three verbal comprehension measures (expressive vocabulary, receptive vocabulary and sentence comprehension) and one measure of academic self-concept in reading (plus one measure of academic self-concept in numeracy as a comparison). After controlling for demographic differences between groups, synaesthetes showed significantly enhanced performance for expressive and receptive vocabulary compared to their peers, but no benefits in sentence comprehension. Child synaesthetes also reported significantly higher academic self-concept for reading, but not for numeracy. Finally, we found that synaesthetes made significantly more progress than controls across the primary school years, although they began school with no
a priori
advantage. Our study provides powerful new evidence that children with grapheme-colour synaesthesia show vocabulary and literacy differences, which we contextualize within a theory of synaesthetic development.

This article is part of a discussion meeting issue ‘Bridging senses: novel insights from synaesthesia’.
Synaesthetic colour associations for Japanese Kanji characters: from the perspective of grapheme learning
Authors: Asano Michiko , Takahashi So-ichiro , Tsushiro Takuya , Yokosawa Kazuhiko
Published: October 2019

One of the fundamental questions about grapheme–colour synaesthesia is how specific associations between the graphemes and colours are formed. We addressed this question by focusing on the determinants of synaesthetic colours for Japanese Kanji characters (logographic characters) using a psycholinguistic approach. Study 1 explored the influence meaning has on synaesthetic colours for Kanji characters representing abstract meanings by examining synaesthetic colours for antonym pairs (i.e. characters with meanings opposed to each other) in Japanese synaesthetes. Results showed that semantic relations influenced the grapheme–colour associations for characters representing abstract meanings in the early stages of learning abstract Kanji, while the influence was reduced in the grapheme–colour associations for those learned later. Study 2 examined the effect that learning new sounds or meanings of graphemes has on synaesthetic colours for those graphemes. Japanese synaesthetes were taught new sounds or new meanings for familiar Kanji characters. Results indicated that acquiring new information for graphemes slightly but significantly reduced the test–retest grapheme–colour association consistency, suggesting that synaesthetic colours can be modulated to reflect the synaesthete's latest knowledge about graphemes. Implications of these findings are discussed from the perspective of the relationship between synaesthesia and grapheme learning.

This article is part of a discussion meeting issue ‘Bridging senses: novel insights from synaesthesia’.
Distinct colours in the ‘synaesthetic colour palette’
Authors: Rouw Romke , Root Nicholas B.
Published: October 2019

In grapheme-colour synaesthesia, particular linguistic elements evoke particular colour sensations. Interestingly, when asked, non-synaesthetes can also associate colours to letters, and previous studies show that specific letter-to-colour associations have similar biases to those of synaesthetes. However, it is an open question whether the colours reported by synaesthetes and non-synaesthetes differoverall: is there a ‘synaesthetic colour palette’? In this study, we visualize the overall distribution in colour space of colour concurrents in grapheme-colour synaesthetes, and colour associations in non-synaesthetic controls. We confirm the existence of a synaesthetic colour palette: colour concurrents in synaesthetes are different from colour associations in non-synaesthetes. We quantify three factors that distinguish the colour palette of synaesthetes and non-synaesthetes: synaesthetes have an increased over-representation of ‘pure’ (unmixed) hues, an increased presence of ‘warm’ (yellow, orange, brown) colours, and an increased presence of achromatic (grey, white, black) colours. Furthermore, we demonstrate that differences in the synaesthetic colour palette can be used to train a machine learning algorithm to reliably classify single subjects as synaesthetes versus non-synaesthetes without using test–retest consistency data. As far as we know, this is the first time an individual could be ‘diagnosed’ as a synaesthete, based only on his or her colours evoked by letters.

This article is part of a discussion meeting issue ‘Bridging senses: novel insights from synaesthesia’.
Seroprevalence of Varicella Zoster virus in China: an age-stratifed systematic review and meta-analysis
Authors: Wang Li , Sun Fu , Liu Siyang , Zhang Hongyi , Lu Bo , Shao Xiaoli , Zhang Minxin , Li Zhengwei
Published: October 2019

OBJECTIVES

the aim of this meta-analysis was pooled on the comprehensive information of the epidemiology of VZV infection and analyzed the seropositivity of VZV-IgG antibodies in different age groups in China, so as to arouse people’s attention on VZV.

DESIGN

Systematic review

DATA SOURCES

Sources included on PubMed, the China National Knowledge Infrastructure (CNKI) database, WANFANG database and the Chinese Scientific Journals Full-Text Database (CQVIP) from 1997 to 2019.

ELIGIBILITY CRITERIA

(1) the Chinese and English literatures of study on varicella-zoster virus immunization epidemics in different regions of China; (2) The literature has obvious age stratification; (3) The subjects are general people; (4) VZV sero-prevalence in the population investigated by the literature research institute. Exclusion criteria: Any study that did not contain these information was excluded.

DATA EXTRACTION AND SYNTHESIS

Two evaluators independently retrieved documents and extracted data. Information about the study design, eligible population, age and gender distribution, inclusion and exclusion criteria were checked. When they disagreed, they could solve the problem by discussion or by soliciting opinions from third parties.

RESULTS

Literatures were screened according to the inclusion criteria and 10 studies from 1997 to 2019 with a total of 11666 individuals were included. The overall VZV seroprevalence in the Chinese population was 65.80% (95% CI; 56.5% - 75.1%), and the peak prevalence was seen in the age 36-45 93.50% (95% CI; 0.917-0.953) while the VZV seroprevalence rate (82.20%, 95% CI: 0.544-1.099) was not increased in individuals of 45 and older.

CONCLUSION

The incidence of VZV increases with age, and there was no significant difference between different genders or regions. This results can provide epidemiological evidence for the prevention and treatment of VZV.

Strengths and limitations of this study

A broad search strategy and systematic review methodology were used to generate this comprehensive review on advice for prevention and treatment of VZV.

Every inclusion article was assessed with a risk of bias tool and/or a quality assessment tool.

Because of relatively small sample size, the incomplete data, and the different research objects, there are some bias in the outcomes, which limits the ability to make discrete conclusions.

There were not enough articles identified to perform a meta-analysis.
Pan-cancer single cell RNA-seq uncovers recurring programs of cellular heterogeneity
Authors: Kinker Gabriela S. , Greenwald Alissa C. , Tal Rotem , Orlova Zhanna , Cuoco Michael S. , McFarland James M. , Warren Allison , Rodman Christopher , Roth Jennifer A. , Bender Samantha A. , Kumar Bhavna , Rocco James W. , Fernandes Pedro ACM , Mader Christopher C. , Keren-Shaul Hadas , Plotnikov Alexander , Barr Haim , Tsherniak Aviad , Rozenblatt-Rosen Orit , Krizhanovsky Valery , Puram Sidharth V. , Regev Aviv , Tirosh Itay
Published: October 2019

Cultured cell lines are the workhorse of cancer research, but it is unclear to what extent they recapitulate the cellular heterogeneity observed among malignant cells in tumors, given the absence of a native tumor microenvironment. Here, we used multiplexed single cell RNA-seq to profile ~200 cancer cell lines. We uncovered expression programs that are recurrently heterogeneous within many cancer cell lines and are largely independent of observed genetic diversity. These programs of heterogeneity are associated with diverse biological processes, including cell cycle, senescence, stress and interferon responses, epithelial-to-mesenchymal transition, and protein maturation and degradation. Notably, some of these recurrent programs recapitulate those seen in human tumors, suggesting a prominent role of intrinsic plasticity in generating intra-tumoral heterogeneity. Moreover, the data allowed us to prioritize specific cell lines as model systems of cellular plasticity. We used two such models to demonstrate the dynamics, regulation and drug sensitivities associated with a cancer senescence program also observed in human tumors. Our work describes the landscape of cellular heterogeneity in diverse cancer cell lines, and identifies recurrent patterns of expression heterogeneity that are shared between tumors and specific cell lines and can thus be further explored in follow up studies.
Quantitative Visualization of Hypoxia and Proliferation Gradients Within Histological Tissue Sections
Authors: Zaidi Mark , Fu Fred , Cojocari Dan , McKee Trevor D. , Wouters Bradly G.
Published: October 2019

The formation of hypoxic microenvironments within solid tumors is known to contribute to radiation resistance, chemotherapy resistance, immune suppression, increased metastasis, and an overall poor prognosis. It is therefore crucial to understand the spatial and molecular mechanisms that contribute to tumor hypoxia formation to improve the efficacy of radiation treatment, develop hypoxia-directed therapies, and increase patient survival. The objective of this study is to present a number of complementary novel methods for quantifying tumor hypoxia and proliferation, especially in relation to the location of perfused blood vessels.

Multiplexed immunofluorescence staining can produce whole slide scanned image datasets that are amenable for computational pathology analysis. A standard marker analysis strategy is to take a positive pixel count approach, in which a threshold for positive stain is used to compute a positive area fraction for hypoxia. This work is a reassessment of that approach, utilizing not only cell segmentation but also distance to nearest blood vessel in order to incorporate spatial information into the analysis. We describe a reproducible pipeline for the visualization and quantitative analysis of hypoxia using a vessel distance analysis approach. This methodological pipeline can serve to further elucidate the relationship between vessel distance and microenvironment-linked markers such as hypoxia and proliferation, can help to quantify parameters relating to oxygen consumption and hypoxic tolerance in tissues, as well as potentially serve as a hypothesis generating tool for future studies testing hypoxia-linked markers.
Translation inhibition from a distance: the small RNA SgrS interferes with a ribosomal protein S1-dependent enhancer
Authors: Azam Muhammad S. , Vanderpool Carin K.
Published: October 2019

Many bacterial small RNAs (sRNAs) efficiently inhibit translation of target mRNAs by forming a duplex that sequesters the Shine-Dalgarno (SD) sequence or start codon and prevents formation of the translation initiation complex. There are a growing number of examples of sRNA-mRNA binding interactions distant from the SD region, but how these mediate translational regulation remains unclear. Our previous work in Escherichia coli and Salmonella identified a mechanism of translational repression of manY mRNA by the sRNA SgrS through a binding interaction upstream of the manY SD. Here, we report that SgrS forms a duplex with a uridine-rich translation-enhancing element in the manY 5’ untranslated region. Notably, we show that the enhancer is ribosome-dependent and that the small ribosomal subunit protein S1 interacts with the enhancer to promote translation of manY. In collaboration with the chaperone protein Hfq, SgrS interferes with the interaction between the translation enhancer and ribosomal protein S1 to repress translation of manY mRNA. Since bacterial translation is often modulated by enhancer-like elements upstream of the SD, sRNA-mediated enhancer silencing could be a common mode of gene regulation.
Novelty and emergent patterns in sperm: morphological diversity and evolution of spermatozoa and sperm conjugation in ground beetles (Coleoptera: Carabidae)
Authors: Gomez R. Antonio , Maddison David R.
Published: October 2019

1.

The beetle family Carabidae, with about 40,000 species, exhibits enough diversity in sperm structure and behavior to be an excellent model system for studying patterns and processes of sperm evolution. We explore their potential, documenting sperm form in 177 species of ground beetles and collecting data on 1 qualitative and 7 quantitative sperm phenotypic traits. Our sampling captures 61% of the tribal-level diversity of ground beetles. These data highlight the notable morphological diversity of sperm in ground beetles and suggest that sperm in the group have dynamic evolutionary histories with much morphological innovation and convergence. Sperm vary among species in total length from 48-3,400μm and in length and width of the sperm head. Most ground beetles make filamentous sperm with visually indistinct heads, but some or all studied members of the genusOmophron,genusTrachypachus,and tribe Dyschiriini make broad-headed sperm that show morphological differences between species. Most ground beetles package their sperm into groups of sperm, termed conjugates, and ground beetles show variation in conjugate form and in the number and arrangement of sperm in a conjugate. Most ground beetles make sperm conjugates by embedding their sperm in a non-cellular rod or spermatostyle, but some Trechitae make conjugates without a spermatostyle. The spermatostyle is remarkably variable among species and varies in length from 17-41,000μm. Several unrelated groups of ground beetles make only singleton sperm, including Nebriinae, Cicindelinae, many Trechinae, and the tribe Paussini. Given current views about ground beetle relationships, we propose preliminary hypotheses on ground beetle sperm diversification. We hypothesize that spermatostyle and conjugate traits evolve faster than sperm traits and that head width evolves more slowly than head length and sperm length. We propose that conjugation with a spermatostyle evolved early within the history of Carabidae and that it has been lost independently at least three times.

Research highlights

Ground beetle sperm is morphologically diverse.

Most species make sperm conjugates with a spermatostyle, and there is variation in sperm, spermatostyles, and conjugates.

Sperm have dynamic evolutionary histories.
Mechanophenotyping of 3D Multicellular Clusters using Displacement Arrays of Rendered Tractions
Authors: Leggett Susan E. , Patel Mohak , Valentin Thomas M. , Gamboa Lena , Khoo Amanda S. , Williams Evelyn Kendall , Franck Christian , Wong Ian Y.
Published: October 2019

Epithelial tissues mechanically deform the surrounding extracellular matrix during embryonic development, wound repair, and tumor invasion. Ex vivo measurements of such multicellular tractions within three-dimensional (3D) biomaterials could elucidate collective dissemination during disease progression, and enable preclinical testing of targeted anti-migration therapies. However, past 3D traction measurements have been low throughput due to the challenges of imaging and analyzing information-rich 3D material deformations. Here, we demonstrate a method to profile multicellular clusters in a 96-well plate format based on spatially heterogeneous contractile, protrusive, and circumferential tractions. As a case study, we profile multicellular clusters across varying states of the epithelial-mesenchymal transition, revealing a successive loss of protrusive and circumferential tractions, as well as the formation of localized contractile tractions with elongated cluster morphologies. These cluster phenotypes were biochemically perturbed using drugs, biasing towards traction signatures of different epithelial or mesenchymal states. This higher-throughput analysis is promising to systematically interrogate and perturb aberrant mechanobiology, which could be utilized with human patient samples to guide personalized therapies.