bluuebunny/crossref_metadata_2025 huggingface dataset:
Monocyte/lymphocyte ratio is related to the severity of coronary artery disease and clinical outcome in patients with non-ST-elevation myocardial infarction
Authors: Chen Hui , Li Min , Liu Lei , Dang Xiawei , Zhu Danjun , Tian Gang
Published: June 2019

Monocyte/lymphocyte ratio (MLR), a widely used inflammation maker for prognosis of cancer, tuberculosis, and autoimmune diseases, has attracted more and more attention for its application to cardiovascular disease. The aim of the present study was to investigate the relationship of MLR with the severity of coronary lesion and clinical outcomes in non-ST-elevation myocardial infarction (NSTEMI) patients.

963 consecutive NSTEMI patients (mean age, 60.77 ± 11.34; 758 male) undergoing coronary angiography were analyzed and followed in 3 groups according to the average MLR tertile (low MLR <0.23, n = 321; intermediate MLR 0.23–0.35, n = 322; high MLR >0.35, n = 320) in this study. The severity of coronary lesion was determined by Gensini score. Multiple linear regression analysis was used to examine the correlation between MLR and the severity of coronary lesion. Kaplan–Meier curve was performed to compare the long-term major adverse cardiac event (MACE)-free survival. Logistic regression analysis and Cox proportional hazard regression model were used to assess the independent predictors for in-hospital and long-term MACE.

MLR (B: 0.281, 95% confidence interval [CI]: 0.130–0.432, P < .001) and high-sensitivity C-reactive protein (B: 0.017, 95% CI: 0.010–0.024, P < .001) were both independently correlated with the severity of coronary lesion, while neutrophil/lymphocyte ratio was not. The frequencies of in-hospital MACE (1.6%, 2.2%, 4.7%, P = .016) and long-term MACE (13.3%, 16.2%, 27.2%, P < .001) both increased among the 3 groups. Kaplan–Meier curve analysis indicated that patients in high MLR group had worse long-term MACE-free survival than the patients in low MLR group (P
2 < .001) and intermediate MLR group (P
3 = .004) during a median follow-up of 22 (12–35) months. MLR was an independent predictor for in-hospital MACE (adjusted odds ratio: 2.891, 95% CI: 1.265–8.354, P = .026) and long-term MACE (adjusted hazard ratio: 1.793, 95% CI: 1.169–2.515, P = .012) in NSTEMI patients.

MLR is independently correlated with the severity of coronary lesion and has better performance to reflect the severity of coronary lesion than NLR. MLR is an independent predictor for the MACE in NSTEMI patients.
Depression and incident hip fracture
Authors: Kim So Young , Lee Joon Kyu , Oh Dong Jun , Kong Il Gyu , Choi Hyo Geun
Published: June 2019

The aim of the present study was to evaluate the risk of hip fracture in depression patients using a nationwide cohort population.

Data from the Korean National Health Insurance Service-National Sample Cohort for a population ≥50 years of age from 2002 to 2013 were collected. The 25,197 individuals with depression were matched for age, sex, income, region of residence, hypertension, diabetes, and dyslipidemia, with 100,788 individuals comprising the control group. In both the depression and control groups, history of hip fracture was evaluated. Using the International Classification of Disease-10 (ICD-10) codes, depression (F31–F39), and hip fracture (S720, S721, and S722) were investigated. The crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of hip fracture in depression patients were analyzed using a Cox proportional hazard model. Subgroup analyses were conducted according to age and sex.

In the depression group, 1.1% (277/25,197) of the subjects had hip fracture, and 0.7% (693/100,095) in the control group had hip fracture (P <.001). The depression group demonstrated a higher adjusted HR for hip fracture than the control group (adjusted HR = 1.46, 95% CI = 1.27–1.68, P <.001). This result was consistent in the ≥65 years old subgroups.

The risk of hip fracture was elevated in depression patients.
Mucosal Monosaccharide Transporter Expression in Newborns With Jejunoileal Atresia and Along the Adult Intestine
Authors: Meier Chantal Florence , Camargo Simone Mafalda Rodrigues , Hunziker Schirin , Leu Svenja , Holland‐Cunz Stefan Gerhard , Verrey François , Vuille‐dit‐Bille Raphael Nicolas
Published: June 2019

Objectives:

In newborn rodents, intestinal maturation involves delayed fructose transporter GLUT5 expression until weaning. In jejunoileal atresia (JIA), distal intestinal segments lack exposure to amniotic fluid‐containing carbohydrates. We assessed in human newborns, the impact of intestinal maturation and obstruction on mucosal monosaccharide transporter expression.

Methods:

Samples were obtained from 10 newborns operated for small intestinal atresia and from 17 adults undergoing gastroduodenoscopy and/or ileocolonoscopy. mRNA expression of the transporters SGLT1, GLUT1, GLUT2, GLUT5, and GLUT7 was measured in neonate samples proximal and distal of the atresia as well as in adult duodenum, ileum, and colon. Protein expression and localization was assessed using immunofluorescence.

Results:

Although mRNA expression of monosaccharide transporters did not significantly differ between newborn and adult samples, luminal fructose transporter GLUT5 protein was absent in 0‐ to 4‐day‐old neonates, but expressed in adults. The mRNA expression of the 5 tested monosaccharide transporters was unchanged distal from the JIA relative to proximal. Similarly, luminal sodium‐dependent glucose transporter SGLT1 and basolateral GLUT2 were expressed proximal and distal to JIA as visualized by immunofluorescence staining. With the exception of glucose transporter GLUT1 that showed highest expression levels in colon, all investigated hexose transporters showed strongest expression in duodenum, lower levels in ileum and lowest in colon.

Conclusions:

Human newborns lack small intestinal fructose transporter GLUT5 protein expression and small intestinal atresia does not affect the expression of hexose transporters.
Prediction of Thiopurine Metabolite Levels Based on Haematological and Biochemical Parameters
Authors: Hradsky Ondrej , Potuznikova Kristyna , Siroka Jitka , Lerchova Tereza , Urbanek Lubor , Mihal Vladimir , Spenerova Michaela , Velganova‐Veghova Maria , Karaskova Eva , Bronsky Jiri
Published: June 2019

Objectives:

Therapeutic drug monitoring of thiopurine erythrocyte levels is not available in all centers and it usually requires quite a long time to obtain the results. The aims of this study were to build a model predicting low levels of 6‐thioguanine and 6‐methylmercaptopurine in pediatric inflammatory bowel disease (IBD) patients and to build a model to predict nonadherence in patients treated with azathioprine (AZA).

Methods:

The study consisted of 332 observations in 88 pediatric IBD patients. Low AZA dosing was defined as 6‐thioguanine levels <125 pmol/8 × 108 erythrocytes and 6‐methylmercaptopurine levels <5700 pmol/8 × 108 erythrocytes. Nonadherence was defined as undetectable levels of 6‐thioguanine and 6‐methylmercaptopurine <240 pmol/8 × 108 erythrocytes. Data were divided into training and testing part. To construct the model predicting low 6‐thioguanine levels, nonadherence, and the level of 6‐thioguanine, the modification of random forest method with cross‐validation and resampling was used.

Results:

The final models predicting low 6‐thioguanine levels and nonadherence had area under the curve, 0.87 and 0.94; sensitivity, 0.81 and 0.82; specificity, 0.80 and 86; and distance, 0.31 and 0.21, respectively, when applied on the testing part of the dataset. When the final model for prediction of 6‐thioguanine values was applied on testing dataset, a root‐mean‐square error of 110 was obtained.

Conclusions:

Using easily obtained laboratory parameters, we constructed a model with sufficient accuracy to predict patients with low 6‐thioguanine levels and a model for prediction of AZA treatment nonadherence (web applications: https://hradskyo.shinyapps.io/6TG_prediction/ and https://hradskyo.shinyapps.io/Non_adherence/).
A Potential Role For Apparent Diffusion Coefficient in the Diagnosis of Trilateral Retinoblastoma
Authors: Farouk Sait Sameer , Haque Sofia , Karimi Sasan , Rebeiz Karim J. , Francis Jasmine H. , Marr Brian P. , Abramson David H. , Souweidane Mark M. , Dunkel Ira J.
Published: June 2019

We attempted to investigate the potential role for apparent diffusion coefficient (ADC) to diagnose trilateral retinoblastoma (TRb) by retrospectively reviewing brain magnetic resonance images of retinoblastoma patients. Observations: The median ADC measured 620.95 for TRb (n=6) and 1238.5 for normal pineal gland in bilateral retinoblastoma (n=8). Monitoring ADC trends aided in establishing the appropriate diagnoses in 3 patients (2 TRb, 1 benign pineal cyst). Conclusions: Our results provide baseline reference data and describe the importance of downward trending ADC which should prompt consideration of TRb. Unchanged high/nonrestricted values (>1000) may distinguish those with benign pineal tissue and obviate invasive neurosurgical procedures.
Effective High-dose Interferon-α Therapy in a 13-Year-Old Girl With Erdheim-Chester Disease
Authors: Tezol Ozlem , Citak Elvan Caglar , Ayhan Yavuz Selim , Balci Yuksel , Koc Zehra Pinar , Yuyucu Karabulut Yasemin
Published: June 2019

Erdheim-Chester disease (ECD) is a proliferative disorder of non-Langerhans histiocytes with a higher incidence in the fifth to seventh decades and rarer occurrence in the pediatric population. Although ECD typically involves bone, it can also affect the central nervous system, cardiovascular system, retro-orbital space, retroperitoneal space, and kidneys, lungs, and skin. A 13-year-old Syrian girl who presented with multisystemic involvement was diagnosed with ECD. The B-Raf proto-oncogene
V600E mutation was not detected in ECD lesions. Response to the high-dose interferon-α therapy was excellent in this pediatric patient. In this article, pediatric ECD case reports are also reviewed.
Spatial-Temporal Epidemiology of the Syphilis Epidemic in Relation to Neighborhood-Level Structural Factors in British Columbia, 2005–2016
Authors: Salway Travis , Gesink Dionne , Lukac Christine , Roth David , Ryan Venessa , Mak Sunny , Wang Susan , Newhouse Emily , Hayden Althea , Bharmal Aamir , Hoyano Dee , Morshed Muhammad , Grennan Troy , Gilbert Mark , Wong Jason
Published: June 2019

Background

Spatial clusters of syphilis have been observed within several jurisdictions globally; however, the degree to which they are predicted by the spatial distributions of gay, bisexual, and other men who have sex with men (GBM) and testing remains unknown. We sought to describe the spatial-temporal epidemiology of infectious syphilis and identify associations between neighborhood-level factors and rates of syphilis, in British Columbia, Canada.

Methods

We used ArcGIS to map infectious syphilis cases among men (2005 to 2016), SaTScan to detect areas with significantly elevated rates of syphilis, and spatial regression to identify associations between neighborhood-level factors and rates of syphilis.

Results

Five clusters were identified: a core in downtown Vancouver (incidence rate ratio [IRR], 18.0; 2007–2016), 2 clusters adjacent to the core (IRR, 3.3; 2012–2016; and IRR, 2.2; 2013–2016), 1 cluster east of Vancouver (IRR, 2.1; 2013–2016), and 1 cluster in Victoria (IRR, 4.3; 2015–2016). Epidemic curves were synchronized across cluster and noncluster regions. Neighborhood-level GBM population estimates and testing rates were both associated with syphilis rates; however, the spatial distribution of syphilis was not fully explained by either of these factors.

Conclusions

We identified two novel ecologic correlates of the spatial distribution of infectious syphilis—density of GBM and rates of syphilis testing—and found that these factors partially, though not entirely, explained the spatial distribution of clusters. Residual spatial autocorrelation suggests that greater syphilis testing coverage may be needed and low-barrier GBM-affirming testing should be expanded to regions outside the core.
Detectability of Malignant Lesions by Whole-Body Magnetic Resonance Imaging Using Whole-Body Integrated Positron Emission Tomography/Magnetic Resonance Imaging
Authors: Ishii Shiro , Miyajima Masayuki , Suenaga Hiroki , Sugawara Shigeyasu , Nemoto Ayaka , Ukon Naoyuki , Nambu Takeyuki , Kubo Hitoshi , Oriuchi Noboru , Ito Hiroshi
Published: June 2019

Purpose

To assess the diagnostic ability of whole-body magnetic resonance imaging (MRI) using integrated positron emission tomography/MRI(PET/MRI).

Methods

Axial T2-weighted image (T2WI), diffusion-weighted imaging (DWI), coronal T1-weighted image (T1WI), axial volumetric interpolated breath-hold examination in the lung field, and 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG–PET) were evaluated in combination with T2WI alone, T2WI + DWI, T2WI + DWI + T1WI, T2WI + DWI + T1WI + volumetric interpolated breath-hold examination (all MRI images), and all MRI + FDG-PET.

Results

A total of 370 lesions were observed in 90 (62.5%) of the 144 patients. The lesion-based sensitivities were 62%, 74%, 74%, 76%, and 94%, and the patient-based sensitivities were 70%, 77%, 77%, 77%, and 81% using T2WI, T2WI + DWI, T2WI + DWI + T1WI, all MRI, and all MRI + FDG-PET, respectively. There were significant differences in the lesion-based sensitivity between T2WI and other sequence combinations and between all MRI and all MRI + FDG-PET. No significant differences were observed between any combinations among the patient-based sensitivities.

Conclusion

The sensitivity of whole-body MRI was lower when lesion based, but almost equivalent when patient based compared with PET/MRI.
TAMIS-Flap Technique: Full-thickness Advancement Rectal Flap for High Perianal Fistulae Performed Through Transanal Minimally Invasive Surgery
Authors: Rottoli Matteo , Di Simone Massimo P. , Poggioli Gilberto
Published: June 2019

The formation of an advancement rectal flap could be technically demanding in the presence of high perianal of rectovaginal fistula, and the outcomes could be frustrated by the inadequate view, bleeding and a poor exposure through the standard transanal approach. The application of the transanal minimally invasive surgery (TAMIS) to the advancement rectal flap procedure could overcome these difficulties. In the lithotomy position, a partial fistulectomy was performed and the internal opening was closed. A full-thickness flap was mobilized initially through the classic transanal approach. Subsequently, the TAMIS port was inserted and the mobilization of the flap was carried on proximally for as long as required. The laparoscopic visualization allowed a perfect view, a proper orientation of the flap and accurate hemostasis. The TAMIS-flap procedure seems a promising technique to perform a long advancement rectal flap to treat high perianal or rectovaginal fistulae (Video, Supplemental Digital Content 1, http://links.lww.com/SLE/A208).
Description and complete genome sequence of Bradyrhizobium amphicarpaeae sp. nov., harbouring photosystem and nitrogen-fixation genes
Authors: Bromfield Eden S. P. , Cloutier Sylvie , Nguyen Hai D. T.
Published: June 2019

A bacterial strain, designated 39S1MBT, isolated from a root nodule of a soybean plant that had been inoculated with root-zone soil of Amphicarpaea bracteata (hog peanut) growing in Canada, was previously characterized and placed in a novel lineage within the genus

Bradyrhizobium

. The taxonomic status of strain 39S1MBT was verified by genomic and phenotypic analyses. Phylogenetic analyses of individual and concatenated protein-encoding gene sequences (atpD, glnII, recA, gyrB and rpoB) placed 39S1MBT in a lineage distinct from named species. Data for sequence similarities of concatenated genes relative to type strains of named species supported the phylogenetic data. Average nucleotide identity values of genome sequences (84.5–91.7 %) were well below the threshold value for bacterial species circumscription. Based on these data,

Bradyrhizobium ottawaense

OO99T and

Bradyrhizobium shewense

ERR11T are close relatives of 39S1MBT. The complete genome of 39S1MBT consists of a single 7.04 Mbp chromosome without a symbiosis island; G+C content is 64.7 mol%. Present in the genome are key photosystem and nitrogen-fixation genes, but not nodulation and type III secretion system genes. Sequence analysis of the nitrogen fixation gene, nifH, placed 39S1MBT in a novel lineage distinct from named

Bradyrhizobium

species. Data for phenotypic tests including growth characteristics and carbon source utilization supported the sequence-based analyses. Based on the data presented here, a novel species with the name

Bradyrhizobium
amphicarpaeae sp. nov. is proposed with 39S1MBT (=LMG 29934T=HAMBI 3680T) as the type strain.
Properties of a Multidimensional Landscape Model for Determining Cellular Network Thermodynamics
Authors: Hubbard Joseph B. , Halter Michael , Plant Anne L.
Published: June 2019

The steady state distributions of phenotypic responses within an isogenic population of cells result from both deterministic and stochastic characteristics of biochemical networks. A biochemical network can be characterized by a multidimensional potential landscape based on the distribution of responses and a diffusion matrix of the correlated dynamic fluctuations between N-numbers of intracellular network variables. The Boltzmann H-function defines the rate of free energy dissipation of a network system and provides a framework for determining the heat associated with the nonequilibrium steady state and its network components. We conjecture that there is an upper limit to the rate of dissipative heat produced by a biological system, and we show that the dissipative heat has a lower bound. The magnitudes of the landscape gradients and the dynamic correlated fluctuations of network variables are experimentally accessible, and through an analysis that we refer to as Thermo-Fokker-Planck (Thermo-FP), provide insight into the composition of the network and the relative thermodynamic contributions from network components. We surmise that these thermodynamic quantities allow determination of the relative importance of network components to overall network control.
Genome maintenance functions ofTrypanosoma bruceiDNA Polymerase N include telomere association and a role in antigenic variation
Authors: Leal Andrea Zurita , Schwebs Marie , Briggs Emma , Reis Helena , Lemgruber Leandro , Luko Katarina , Butter Falk , McCulloch Richard , Janzen Christian J.
Published: June 2019

Maintenance of genome integrity is critical to guarantee transfer of an intact genome from parent to offspring during cell division. DNA polymerases (Pols) provide roles in both replication of the genome and the repair of a wide range of lesions. Amongst replicative DNA Pols, translesion DNA Pols play a particular role: replication to bypass DNA damage, often at the cost of mutation. All cells express a range of translesion Pols, but little work has examined their function in parasites, including whether the enzymes might contribute to host-parasite interactions. Here, we describe a dual function of translesion PolN in African trypanosomes. Previously we demonstrated that PolN is associated with telomeric sequences and now we show that RNAi-mediated depletion of PolN results in slowed growth, altered DNA content, changes in cell morphology, and increased sensitivity to DNA damaging agents. Depletion of PolN leads to chromosome segregation defects and accumulation of DNA damage. We also show that PolN displays discrete localisation at the nuclear periphery in the absence of exogenous DNA damage. In addition, we demonstrate that PolN depletion leads to deregulation of telomeric variant surface glycoprotein genes, linking the function of this translesion DNA polymerase to host immune evasion by antigenic variation.
Computational analysis of transcriptome signature repurposes low dose trifluoperazine for the treatment of fragile X syndrome in mouse model
Authors: Ding Qi , Sethna Ferzin , Wu Xue-Ting , Miao Zhuang , Chen Ping , Zhang Yueqi , Xiao Hua , Feng Wei , Feng Yue , Li Xuan , Wang Hongbing
Published: June 2019

Fragile X syndrome (FXS), caused by mutations in fragile X mental retardation 1 gene (FMR1), is a prevailing genetic disorder of intellectual disability and autism. Currently, there is no efficacious medication for FXS. Here, we use transcriptome landscape as a holistic molecular phenotype/endpoint to identify potential therapeutic intervention. Through in silicoscreening with public gene signature database, computational analysis of transcriptome profile inFmr1knockout (KO) neurons predicts therapeutic value of an FDA-approved drug trifluoperazine. Through experimental validation, we find that systemic administration of low dose trifluoperazine at 0.05 mg/kg attenuates multiple FXS- and autism-related behavioral symptoms. Moreover, computational analysis of transcriptome alteration caused by trifluoperazine suggests a new mechanism of action against PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) activity. Consistently, trifluoperazine suppresses PI3K activity and its down-stream targets Akt (protein kinase B) and S6K1 (S6 kinase 1) in neurons. Further, trifluoperazine normalizes the aberrantly elevated activity of Akt and S6K1 and enhanced protein synthesis in FXS mouse. In conclusion, our data demonstrate promising value of gene signature-based computation in identification of therapeutic strategy and repurposing drugs for neurological disorders, and suggest trifluoperazine as a potential practical treatment for FXS.
Dancing Molecules: Rewiring Cooperative Communications within 14-3-3 ζ Docking Proteins
Authors: Davis Leroy K.
Published: June 2019

Allosteric engineering may play a key role in novel drug discovery. As allosteric interactions are often associated with disease states where protein active sites are rendered constitutively active. Due to their role in regulating signal transduction in cells, we attempted to rewire cooperative communications within the 14-3-3 ζ docking protein. To avoid disruption of evolutionarily tuned interaction networks, we attempted to do so by applying the “Fundamental Theory of the Evolution Force: FTEF”. Whereby, we reversed the motion vector of the 14-3-3 ζ C’ terminal tail. We were also able to modify low frequency vibrational modes across 14-3-3 ζ conformational ensembles. Notably, synthetic evolution by FTEF anticipated evolution of the 14-3-3 ζ docking protein. And accentuated nonrandom patterns of deformation waves resulting in a gain of function mutation characterized by increased protein flexibility. As well as allowed us to discover a genome encoded spatial arrangement of strain that promotes translation of vibrational motions through protein structural layers. We also discovered a 14-3-3 ζ evolution blueprint that predetermines evolutional fate of the docking protein. The aforementioned suggests that the evolutionary fate of cells may be encoded in the genome, thusly may be predetermined.

Significance

Allostery plays a key role in disease. Wherein, mutations redistribute conformational ensembles and render proteins constitutively active. 14-3-3 docking proteins are key signaling proteins involved in multiple signal pathways that effect cell proliferation, cell cycle and apoptosis. Saliently, the 14-3-3 ζ isoform is associated with neurodegenerative disease, cancer and glaucoma. Thusly, ability to rewire cooperative communications within 14-3-3 ζ offers opportunity for novel drug discovery.
Ammonia inhibits energy metabolism in astrocytes in a rapid and GDH2-dependent manner
Authors: Drews Leonie , Zimmermann Marcel , Poss Rebecca E. , Brilhaus Dominik , Bergmann Laura , Wiek Constanze , Piekorz Roland P. , Weber Andreas P.M. , Mettler-Altmann Tabea , Reichert Andreas S.
Published: June 2019

In hepatic encephalopathy (HE) astrocyte dysfunction is a primary factor impairing neuronal activity under hyperammonemia. We show that mitochondria in cellular HE models undergo rapid fragmentation under hyperammonemia in a reversible manner. Mitochondrial respiration and glycolysis were instantaneously hampered in a pH-independent manner. A metabolomics approach revealed a subsequent accumulation of numerous amino acids, including branched chain amino acids, and glucose. N15labeling of ammonia shows rapid incorporation of ammonia-derived nitrogen into glutamate and glutamate-derived amino acids. Downregulating humanGLUD2, encoding mitochondrial glutamate dehydrogenase 2 (GDH2), inhibiting GDH2 activity by SIRT4 overexpression, and supplementing cells with glutamate or glutamine alleviated ammonia-induced inhibition of mitochondrial respiration. Thus, under hyperammonemic conditions, GDH2 catalyzes the removal of ammonia by reductive amination of α-ketoglutarate but at the same time inhibits the TCA-cycle by depleting α-ketoglutarate. Overall, we propose a mitochondria-dependent mechanism contributing to the early steps in the pathogenesis of HE where the interplay between energy metabolism and ammonia removal plays a pivotal role.
Neuromedin U signaling regulates memory retrieval of learned salt avoidance in aC. elegansgustatory circuit
Authors: Watteyne Jan , Van der Auwera Petrus , Peymen Katleen , Borghgraef Charline , Vandewyer Elke , Rutten Iene , Lammertyn Jeroen , Jelier Rob , Schoofs Liliane , Beets Isabel
Published: June 2019

Learning and memory are regulated by neuromodulatory pathways, but the contribution and temporal requirement of most neuromodulators in a learning circuit are unknown. Here we identify the evolutionarily conserved neuromedin U (NMU) neuropeptide family as a regulator of memory retrieval inC. elegansgustatory aversive learning. The NMU homolog CAPA-1 and its receptor NMUR-1 are required for the expression of learned salt avoidance. Aversive learning depends on the release of CAPA-1 neuropeptides from sensory ASG neurons that respond to salt stimuli in an experience-dependent manner. Optogenetic silencing of CAPA-1 neurons blocks the immediate retrieval, but not the acquisition, of learned salt avoidance. CAPA-1 subsequently signals through NMUR-1 in AFD sensory neurons to modulate two navigational strategies for salt chemotaxis. Aversive conditioning thus recruits NMU signaling to eventually modulate locomotor programs for expressing learned avoidance behavior. Because NMU signaling is conserved across bilaterian animals, our findings incite further research into its function in other memory and decision-making circuits.

Graphical Abstract
GC-AG Introns Features in Long Non-coding and Protein-Coding Genes Suggest Their Role in Gene Expression Regulation
Authors: Alezz Monah Abou , Celli Ludovica , Belotti Giulia , Lisa Antonella , Bione Silvia
Published: June 2019

Long non-coding RNAs (lncRNAs) are recognized as an important class of regulatory molecules involved in a variety of biological functions. However, the regulatory mechanisms of long non-coding genes expression are still poorly understood. The characterization of the genomic features of lncRNAs is crucial to get insight into their function. In this study, we exploited recent annotations by GENCODE to characterize the genomic and splicing features of long non-coding genes in comparison with protein-coding ones, both in human and mouse. Our analysis highlighted differences between the two classes of genes in terms of their gene architecture. Significant differences in the splice sites usage were observed between long non-coding and protein-coding genes (PCG). While the frequency of non-canonical GC-AG splice junctions represents about 0.8% of total splice sites in PCGs, we identified a significant enrichment of the GC-AG splice sites in long non-coding genes, both in human (3.0%) and mouse (1.9%). In addition, we found a positional bias of GC-AG splice sites being enriched in the first intron in both classes of genes. Moreover, a significant shorter length and weaker donor and acceptor sites were found comparing GC-AG introns to GT-AG introns. Genes containing at least one GC-AG intron were found conserved in many species, more prone to alternative splicing and a functional analysis pointed toward their enrichment in specific biological processes such as DNA repair. Our study shows for the first time that GC-AG introns are mainly associated with lncRNAs and are preferentially located in the first intron. Additionally, we discovered their regulatory potential indicating the existence of a new mechanism of non-coding and PCGs expression regulation.
SilencingPHOSPHOENOLPYRUVATE CARBOXYLASE1in the Obligate Crassulacean Acid Metabolism SpeciesKalanchoë laxifloracauses Reversion to C3-like Metabolism and Amplifies Rhythmicity in a Subset of Core Circadian Clock Genes
Authors: Boxall Susanna F. , Kadu Nirja , Dever Louisa V. , Kneřová Jana , Waller Jade L. , Gould Peter J. D. , Hartwell James
Published: June 2019

Unlike C3plants, Crassulacean acid metabolism (CAM) plants fix CO2in the dark using phosphoenolpyruvate carboxylase (PPC; EC 4.1.1.31). PPC combines PEP with CO2(as HCO3−), forming oxaloacetate that is rapidly converted to malate, leading to vacuolar malic acid accumulation that peaks phased to dawn. In the light period, malate decarboxylation concentrates CO2around RuBisCO for secondary fixation. CAM mutants lacking PPC have not been described. Here, RNAi was employed to silence CAM isogenePPC1inKalanchoë laxiflora. LinerPPC1-BlackedPPC1transcripts, PPC activity, dark period CO2fixation, and nocturnal malate accumulation. Light period stomatal closure was also perturbed, and the plants displayed reduced but detectable dark period stomatal conductance, and arrhythmia of the CAM CO2fixation circadian rhythm under constant light and temperature (LL) free-running conditions. By contrast, the rhythm of delayed fluorescence was enhanced in plants lackingPPC1. Furthermore, a subset of gene transcripts within the central circadian oscillator were up-regulated and oscillated robustly. The regulation guard cell genes involved controlling stomatal movements was also altered inrPPC1-B. This provided direct evidence that altered regulatory patterns of key guard cell signaling genes are linked with the characteristic inverse pattern of stomatal opening and closing during CAM.
Scaffold subunits support associated subunit assembly in theChlamydomonasciliary nexin-dynein regulatory complex
Authors: Gui Long , Song Kangkang , Tristchler Douglas , Bower Raqual , Si Yan , Dai Aguang , Augsperger Katherine , Sakizadeh Jason , Grzemska Magdalena , Ni Thomas , Porter Mary E. , Nicastro Daniela
Published: June 2019

The nexin-dynein regulatory complex (N-DRC) in motile cilia and flagella functions as a linker between neighboring doublet microtubules, acts to stabilize the axonemal core structure, and serves as a central hub for the regulation of ciliary motility. Although the N-DRC has been studied extensively using genetic, biochemical, and structural approaches, the precise arrangement of the eleven (or more) N-DRC subunits remains unknown. Here, using cryo-electron tomography, we have compared the structure ofChlamydomonaswild-type flagella to that of strains with specific DRC subunit deletions or rescued strains with tagged DRC subunits. Our results show that DRC7 is a central linker subunit that helps connect the N-DRC to the outer dynein arms. DRC11 is required for the assembly of DRC8, and DRC8/11 form a sub-complex in the proximal lobe of the linker domain that is required to form stable contacts to the neighboring B-tubule. Gold labeling of tagged subunits determines the precise locations of the previously ambiguous N-terminus of DRC4 which is now shown to contribute to the core scaffold of the N-DRC and C-terminus of DRC5. Our results reveal the overall architecture of N-DRC, with the three subunits, DRC1/2/4 forming a core complex that serves as the scaffold for the assembly of the “functional subunits” associate, namely DRC3/5-8/11. These findings shed light on N-DRC assembly and its role in regulating flagellar beating.

Significance Statement

Cilia and flagella are small hair-like appendages in eukaryotic cells that play essential roles in cell sensing, signaling, and motility. The highly conserved nexin-dynein regulatory complex (N-DRC) is one of the key regulators for ciliary motility. At least 11 proteins (DRC1–11) have been assigned to the N-DRC, but their precise arrangement within the large N-DRC structure is not yet known. Here, using cryo-electron tomography combined with genetic approaches, we have localized DRC7, the sub-complex DRC8/DRC11, the N-terminus of DRC4, and the C-terminus of DRC5. Our results provide insights into the N-DRC structure, its function in the regulation of dynein activity, and the mechanism by whichn-drcmutations can lead to defects in ciliary motility that cause disease.
Transfer learning enables prediction ofCYP2D6haplotype function
Authors: McInnes Gregory , Dalton Rachel , Sangkuhl Katrin , Whirl-Carrillo Michelle , Lee Seung-been , Tsao Philip S. , Gaedigk Andrea , Altman Russ B. , Woodahl Erica L.
Published: June 2019

Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene whose protein product metabolizes more than 20% of clinically used drugs. Genetic variations inCYP2D6are responsible for interindividual heterogeneity in drug response that can lead to drug toxicity and ineffective treatment, makingCYP2D6one of the most important pharmacogenes. Prediction of CYP2D6 phenotype relies on curation of literature-derived functional studies to assign a functional status toCYP2D6haplotypes. As the number of large-scale sequencing efforts grows, new haplotypes continue to be discovered, and assignment of function is challenging to maintain. To address this challenge, we have trained a deep learning model to predict functional status ofCYP2D6haplotypes, called Hubble.2D6. We find that Hubble.2D6 predictsCYP2D6haplotype functional status with 88% accuracy in a held out test set and explains a significant amount of the variability inin vitrofunctional data. Hubble.2D6 may be a useful tool for assigning function to haplotypes with uncurated function, which may be used for screening individuals who are at risk of being poor metabolizers.
Mental Health, Schooling Attainment and Polygenic Scores: Are There Significant Gene-Environment Associations?
Authors: Amin Vikesh , Behrman Jere R. , Fletcher Jason M. , Flores Carlos A. , Flores-Lagunes Alfonso , Kohler Hans-Peter
Published: June 2019

It is well-established that (1) there is a large genetic component to mental health, and (2) higher schooling attainment is associated with better mental health. Given these two observations, we test the hypothesis that schooling may attenuate the genetic predisposition to poor mental health. Specifically, we estimate associations between a polygenic score (PGS) for depressive symptoms, schooling attainment and gene-environment (GxE) interactions with mental health (depressive symptoms and depression), in two distinct United States datasets at different adult ages-29 years old in the National Longitudinal Study of Adolescent Health (Add Health) and 54 years old in the Wisconsin Longitudinal Study (WLS). OLS results indicate that the association of the PGS with mental health is similar in Add Health and the WLS, but the association of schooling attainment is much larger in Add Health than in the WLS. There is some suggestive evidence that the association of the PGS with mental health is lower for more-schooled older individuals in the WLS, but there is no evidence of any significant GxE associations in Add Health. Quantile regression estimates also show that in the WLS the GxE associations are statistically significant only in the upper parts of the conditional depressive symptoms score distribution. We assess the robustness of the OLS results to omitted variable bias by using the siblings samples in both datasets to estimate sibling fixed-effect regressions. The sibling fixed-effect results must be qualified, in part due to low statistical power. However, the sibling fixed-effect estimates show that college education is associated with fewer depressive symptoms in both datasets.
MR-LDP: a two-sample Mendelian randomization for GWAS summary statistics accounting for linkage disequilibrium and horizontal pleiotropy
Authors: Cheng Qing , Yang Yi , Shi Xingjie , Yeung Kar-Fu , Yang Can , Peng Heng , Liu Jin
Published: June 2019

The proliferation of genome-wide association studies (GWAS) has prompted the use of two-sample Mendelian randomization (MR) with genetic variants as instrumental variables (IV) for drawing reliable causal relationships between health risk factors and disease outcomes. However, the unique features of GWAS demand that MR methods account for both linkage disequilibrium (LD) and ubiquitously existing horizontal pleiotropy among complex traits, which is the phenomenon wherein a variant affects the outcome through mechanisms other than exclusively through the exposure. Therefore, statistical methods that fail to consider LD and horizontal pleiotropy can lead to biased estimates and false-positive causal relationships. To overcome these limitations, we propose a probabilistic model for MR analysis to identify the casual effects between risk factors and disease outcomes using GWAS summary statistics in the presence of LD and to properly account for horizontal pleiotropy among genetic variants (MR-LDP). MR-LDP utilizes a computationally efficient parameter-expanded variational Bayes expectation-maximization (PX-VBEM) algorithm to estimate the parameter of interest and further calibrates the evidence lower bound (ELBO) for a likelihood ratio test. We then conducted comprehensive simulation studies to demonstrate the advantages of MR-LDP over the existing methods in terms of both type-I error control and point estimates. Moreover, we used two real exposure-outcome pairs (CAD-CAD and Height-Height; CAD for coronary artery disease) to validate the results from MR-LDP compared with alternative methods, showing that our method is more efficient in using all instrumental variants in LD. By further applying MR-LDP to lipid traits and body mass index (BMI) as risk factors for complex diseases, we identified multiple pairs of significant causal relationships, including a protective effect of high-density lipoprotein cholesterol (HDL-C) on peripheral vascular disease (PVD), and a positive causal effect of body mass index (BMI) on hemorrhoids.
Functional dissociation of theta oscillations in the frontal and visual cortices and their long-range network during sustained attention
Authors: Han Hio-Been , Lee Ka Eun , Choi Jee Hyun
Published: June 2019

Theta-band (4–12 Hz) activities in the frontal cortex have been thought to be a key mechanism of sustained attention and goal-related behaviors, forming a phase-coherent network with task-related sensory cortices for integrated neuronal ensembles. However, recent visual task studies found that selective attention attenuates stimulus-related theta power in the visual cortex, suggesting a functional dissociation of cortical theta oscillations. To investigate this contradictory behavior of cortical theta, a visual Go/No-Go task was performed with electroencephalogram recording in mice. During the No-Go period, transient theta oscillations were observed in both the frontal and visual cortices, but theta oscillations of the two areas were prominent in different trial epochs. By separating trial epochs based on subjects’ short-term performance, we found that frontal theta was prominent in good-performance epochs, while visual theta was prominent in bad-performance epochs, exhibiting a functional dissociation of cortical theta rhythms. Furthermore, the two theta rhythms also showed a heterogeneous pattern of phase-amplitude coupling with fast oscillations, reflecting their distinct architecture in underlying neuronal circuitry. Interestingly, in good-performance epochs, where visual theta was relatively weak, stronger fronto-visual long-range synchrony and shorter posterior-to-anterior temporal delay were found. These findings highlight a previously overlooked aspect of long-range synchrony between distinct oscillatory entities in the cerebral cortex and provide empirical evidence of a functional dissociation of cortical theta rhythms.

IN BRIEF

Previous literature emphasized the pro-cognitive role of coherent oscillatory networks between distal brain regions, such as the fronto-visual theta synchrony. However, such a conceptual framework has been challenged as recent findings revealed distinct behavioral correlates of theta oscillations found in different cortical regions, especially in the frontal and visual cortices. Here, we show that frontal and visual theta represent distinct cortical processes and that the functional connectivity between them increases during sustained attention, especially when one of the two theta rhythms is relatively suppressed. The data presented here highlight a novel aspect of neural long-range synchrony between distinct cortical oscillators with distinct functional significance in task performance.
Unprecedented biomass and fatty acid production by the newly discovered cyanobacteriumSynechococcussp. PCC 11901
Authors: Włodarczyk Artur , Selão Tiago Toscano , Norling Birgitta , Nixon Peter J.
Published: June 2019

Cyanobacteria, which use solar energy to convert carbon dioxide into biomass, are potential solar biorefineries for the sustainable production of chemicals and biofuels. However, yields obtained with current strains are still uncompetitive compared to existing heterotrophic production systems. Here we report the discovery and characterization of a new cyanobacterial strain,Synechococcussp. PCC 11901, with potential for green biotechnology. It is transformable, has a short doubling time of ≈2 hours, grows at high light intensities and a wide range of salinities and accumulates up to 18.3 g dry cell weight/L of biomass – 2-3 times more than previously described for cyanobacteria - when grown in a modified medium containing elevated nitrate, phosphate and iron. As a proof of principle, PCC 11901 engineered to produce free fatty acids did so at unprecedented levels for cyanobacteria, with final yields reaching over 6 mM (1.5 g/L), comparable to those achieved by heterotrophic organisms.
Scop3P: a comprehensive resource of human phosphosites within their full context
Authors: Ramasamy Pathmanaban , Turan Demet , Tichshenko Natalia , Hulstaert Niels , Vandermarliere Elien , Vranken Wim , Martens Lennart
Published: June 2019

Protein phosphorylation is a key post-translational modification (PTM) in many biological processes and is associated to human diseases such as cancer and metabolic disorders. The accurate identification, annotation and functional analysis of phosphosites is therefore crucial to understand their various roles. Phosphosites (P-sites) are mainly analysed through phosphoproteomics, which has led to increasing amounts of publicly available phosphoproteomics data. Several resources have been built around the resulting phosphosite information, but these are usually restricted to protein sequence and basic site metadata. What is often missing from these resources, however, is context, including protein structure mapping, experimental provenance information, and biophysical predictions. We therefore developed Scop3P: a comprehensive database of human phosphosites within their full context. Scop3P integrates sequences (UniProtKB/Swiss-Prot), structures (PDB), and uniformly reprocessed phosphoproteomics data (PRIDE) to annotate all known human phosphosites. Furthermore, these sites are put into biophysical context by annotating each phosphoprotein with perresidue structural propensity, solvent accessibility, disordered probability, and early folding information. Scop3P, available at https://iomics.ugent.be/scop3p, presents a unique resource for visualization and analysis of phosphosites, and for understanding of phosphosite structure-function relationships.
Dark diversity reveals importance of biotic resources and competition for plant diversity across broad environmental gradients
Authors: Fløjgaard Camilla , Valdez Jose W. , Dalby Lars , Moeslund Jesper Erenskjold , Clausen Kevin K. , Ejrnæs Rasmus , Pärtel Meelis , Brunbjerg Ane Kirstine
Published: June 2019

Species richness is the most commonly used metric to quantify biodiversity. However, examining dark diversity, the group of missing species which can potentially inhabit a site, can provide a more thorough understanding of the processes influencing observed biodiversity and help evaluate the restoration potential of local habitats. So far, dark diversity has mainly been studied for specific habitats or largescale landscapes while less attention has been given to variation across broad environmental gradients or as a result of local conditions and biotic interactions. In this study, we investigate the importance of local environmental conditions in determining dark diversity and observed richness in plant communities across broad environmental gradients. We use the ecospace concept to investigate how abiotic gradients (defined as position), availability of biotic resources (defined as expansion), spatiotemporal extent of habitats (defined as continuity), as well as species interactions through competition, relate to these biodiversity measures. Position variables were important for both plant richness and dark diversity, some with quadratic relationships, e.g., plant richness showing a unimodal response to soil fertility corresponding to the intermediate productivity hypothesis. Competition represented by community mean Grime C showed a negative correlation with plant richness. Besides position, organic carbon was the most important variable for dark diversity, indicating that in late succession habitats such as forests and shrubs, dark diversity is generally low. The importance of Grime C indicate that intermediate disturbance, such as grazing, may facilitate higher species richness and lower dark diversity. Comparing various biodiversity metrics and their influencing factors might reveal important drivers of biodiversity changes and result in better conservation decision-making.
New genetic sources for orange color in cucumber (Cucumis sativus L.) fruit flesh
Authors: Waters Brian M. , Kim HaeJin , Amundsen Keenan
Published: June 2019

Most cucumber varieties have fruits with white flesh, which is devoid of ß-carotene and has a low concentration of total carotenoids. Carotenoids are important nutrients for humans and animals. Thus, developing cucumber varieties with orange flesh could provide a new nutritionally enhanced food source. Some cucumbers with yellow and orange flesh have been described, but there are others that have not been studied. Here, we used three cucumber PI lines, reported to produce colored fruits, from the USDA National Plant Germplasm System to generate three F2populations. Fruits from the F2populations with colored flesh (green, yellow, or orange) were pooled, and an equal number of fruits with white flesh were pooled. RNA was isolated from the pools and used for RNA sequencing to determine gene expression differences and to identify SNPs in each pool. The orange color of the cucumber fruits was confirmed to be due to ß-carotene. There were no clear expression patterns for genes of the carotenoid biosynthesis pathway that would suggest that their expression controlled the coloration of fruits. Mutations in carotenoid biosynthesis genes also did not explain the variation. However, we detected a SNP in the homolog of theOrgene that is responsible for ß-carotene accumulation in orange cauliflower. This genetic basis is different from that of previously studied orange cucumbers, but our results suggest thatOris not the only factor. These results provide the basis for future studies for breeding orange cucumbers for commercial or home garden production.