bluuebunny/crossref_metadata_2025 huggingface dataset:
Pseudo-pseudo Meigs’ syndrome presenting with a combination of polyserositis, elevated serum CA 125 in systemic lupus erythematosus
Authors: Gao Fei , Xu YongMei , Yang GuoWang
Published: April 2019

Rationale:

Combination of polyserositis and elevated serum CA 125 is common in tumor or infectious disease, but this clinical combination is also found in other diseases. It could be the initial manifestation of pseudo-pseudo Meigs’ syndrome (PPMS), which is characterized by the presence of polyserositis and raised CA-125 level in systemic lupus erythematosus (SLE).

Patient's concerns:

A 44-year-old Chinese female was admitted with three months history of painless abdominal distension accompanied by watery diarrhea 5–6 times daily, shortness of breath, fatigue, lower limb swelling, and 10 kg weight loss. The test results showed peripheral cytopenias, hypoproteinemia, renal dysfunction and elevated CA 125, antidouble-stranded DNA antibodies, and anti-Sjogren's syndrome A antigen antibody was positive. There is no evidence for the diagnosis of solid tumor according to the results of imaging modality and pathological examination.

Diagnosis:

The patient was diagnosed as pseudo-pseudo Meigs syndrome.

Intervention:

The patient received hormone, leflunomide, and Plaquenil therapy.

Outcomes:

The patient's symptoms were relieved and the laboratory index was improved after the treatment of hormone and immunosuppressant.

Lessons subsections as per style:

PPMS is characterized by the combination of serous effusion and elevated serum CA 125 with no evidence of tumor among SLE patients. Clinicians should be aware of the diagnosis of PPMS avoiding unnecessary anxiety or surgical interventions.
Ovarian Teratomas in Women With Anti-N-methyl-D-Aspartate Receptor Encephalitis
Authors: Nolan Amber , Buza Natalia , Margeta Marta , Rabban Joseph T.
Published: April 2019

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune syndrome in young women that is often accompanied by an ovarian teratoma (NMDAR-E teratoma). A prevailing theory implicates that the generation of autoantibodies to NMDAR on neurons in the central nervous system is triggered by neuroglial tissue in the associated teratoma. The histopathology of NMDAR-E teratomas has not been fully elucidated but limited studies have focused on alterations in neuroglial tissues and immune cell populations. We hypothesized that evidence of antibody generation in NMDAR-E teratomas could be detected by colocalized neuroglial tissue and lymphoid aggregates with germinal centers as well as by alterations in the composition and morphology of neuroglial tissues. The study compared 12 NMDAR-E teratomas (11 ovarian, 1 mediastinal) with 61 control teratomas containing neuroglial tissue from women without NMDAR-E. NMDAR-E teratomas were significantly smaller and were composed of a higher percentage of neuroglial tissue than control teratomas. Many NMDAR-E teratomas did not exhibit typical gross pathologic features of a mature cystic teratoma, but were composed of predominately solid tissue (so-called Rokitansky nodule). Colocalized neuroglial tissue and lymphoid aggregates with germinal centers were present in 11/12 NMDAR-E teratomas, predominantly within the Rokitansky nodule, but only in 4/61 control teratomas (P<0.0001). There was a relative paucity of mature neurons in NMDAR-E teratomas as well as a hypercellular astrocyte population, while there were less prominent or no differences in the presence or composition of diffuse inflammatory infiltrates, lymphoid aggregates without germinal centers, ganglion cell clusters or oligodendrocytes between NMDAR-E teratomas and control teratomas. We conclude that the presence of colocalized neuroglial tissue and lymphoid aggregates with germinal centers along with a general paucity of neurons should prompt clinical consideration for NMDAR-E even in asymptomatic women, as the symptoms may occasionally develop after an otherwise incidental oophorectomy. Tissue sampling should be directed to the Rokitansky nodule, when present, to identify neuroglial tissues; complete microscopic examination of the ovarian specimen should be considered if gross pathologic features of teratoma are not present. The significance of the altered neuroglial cell populations and potential relationship to the pathogenesis of NMDAR-E merit further study.
Differentiated Care Preferences of Stable Patients on Antiretroviral Therapy in Zambia: A Discrete Choice Experiment
Authors: Eshun-Wilson Ingrid , Mukumbwa-Mwenechanya Mpande , Kim Hae-Young , Zannolini Arianna , Mwamba Chanda P. , Dowdy David , Kalunkumya Estella , Lumpa Mwansa , Beres Laura K. , Roy Monika , Sharma Anjali , Topp Steph M. , Glidden Dave V. , Padian Nancy , Ehrenkranz Peter , Sikazwe Izukanji , Holmes Charles B. , Bolton-Moore Carolyn , Geng Elvin H.
Published: April 2019

Background:

Although differentiated service delivery (DSD) models for stable patients on antiretroviral therapy (ART) offer a range of health systems innovations, their comparative desirability to patients remains unknown. We conducted a discrete choice experiment to quantify service attributes most desired by patients to inform model prioritization.

Methods:

Between July and December 2016, a sample of HIV-positive adults on ART at 12 clinics in Zambia were asked to choose between 2 hypothetical facilities that differed across 6 DSD attributes. We used mixed logit models to explore preferences, heterogeneity, and trade-offs.

Results:

Of 486 respondents, 59% were female and 85% resided in urban locations. Patients strongly preferred infrequent clinic visits [3- vs. 1-month visits: β (ie, relative utility) = 2.84; P < 0.001]. Milder preferences were observed for waiting time for ART pick-up (1 vs. 6 hours.; β = −0.67; P < 0.001) or provider (1 vs. 3 hours.; β = −0.41; P = 0.002); “buddy” ART collection (β = 0.84; P < 0.001); and ART pick-up location (clinic vs. community: β = 0.35; P = 0.028). Urban patients demonstrated a preference for collecting ART at a clinic (β = 1.32, P < 0.001), and although most rural patients preferred community ART pick-up (β = −0.74, P = 0.049), 40% of rural patients still preferred facility ART collection.

Conclusions:

Stable patients on ART primarily want to attend clinic infrequently, supporting a focus in Zambia on optimizing multimonth prescribing over other DSD features—particularly in urban areas. Substantial preference heterogeneity highlights the need for DSD models to be flexible, and accommodate both setting features and patient choice in their design.
Cartilage Trap-Door Flap Technique for Correction of High Nasal Septum Deflection
Authors: Kim Jooyeon , Choi Gwan , Kwon Jae Hwan
Published: April 2019

Objective:

To introduce a novel cartilage trap-door flap technique in endonasal septoplasty to correct high dorsal deviation of the cartilaginous septum, and confirm its effectiveness.

Design:

Prospective observational study.

Setting:

Medical center.

Methods:

46 patients who had underwent septoplasty using the cartilage island flap technique to correct the high dorsal deviation from November 2014 to November 2015. The subjective symptoms were measured using the Nasal Obstruction Symptom Evaluation scale. The objective evaluations of the surgical results were analyzed using acoustic rhinometry. Post-operative status of the nasal septum was estimated by nasal endoscopic examination.

Results:

Among 46 patients, 32 cases (69.57%) were “complete correction”, 14cases (30.43%) were “improved” with residual deviation and there was not “no-change” or “even worse” case based on endoscopic examination. Minimal cross-sectional area in convex side of nasal cavity was significantly changed from 0.22cm2 to 0.56cm2 after the surgery, and nasal volume in narrower side of nasal cavity was significantly changed from 2.44mL to 6.22 mL. The patients’ nasal obstruction symptoms significantly reduced from 10.43 before the surgery to 1.45 after the surgery. During the follow-up period, the authors have not experienced any obvious complications such as saddle nose, septal perforation, and bleeding.

Conclusion:

The proposed cartilage trap-door flap technique provides easy and effective results for dorsal deviations of the cartilaginous septum in selected cases without significant complications.
Comparing Outcomes in Orthognathic Surgery Using Clear Aligners Versus Conventional Fixed Appliances
Authors: Kankam Hadyn , Madari Sarika , Sawh-Martinez Rajendra , Bruckman Karl C. , Steinbacher Derek M.
Published: April 2019

Purpose:

Orthognathic surgery for dentofacial deformities is typically preceded and followed by orthodontic treatment. Traditionally, orthodontic hardware is secured to the dentition to allow dental movement and stabilization. Clear-aligner therapy (eg, Invisalign) provides an aesthetic alternative, consisting of a series of transparent trays. Its use has not been described in complex triple-jaw orthognathic surgery. The purpose of this study is to evaluate perioperative outcomes and 3-dimensionally quantify postoperative edema in Invisalign patients undergoing triple-jaw orthognathic procedures, comparing this to patients treated with conventional fixed appliances. The surgical approach to patients with clear-aligners is also outlined.

Methods:

The authors conducted a retrospective chart review and 3-dimensional morphometric study of Invisalign patients undergoing triple-jaw surgery (LeFort I osteotomy, bilateral sagittal split osteotomy, and genioplasty). An identical assessment of demographically matched patients treated with conventional fixed appliances was performed and compared with the Invisalign group.

Results:

Thirty-three patients, with a mean age of 19.99 years, were included: 13 with Invisalign and 20 with conventional fixed appliances. No significant difference was observed in operating time, concurrent extraction of teeth, fat grafting, duration of hospital stay, diet advancement, and use of narcotic analgesics between the 2 groups. Nine patients had sufficient 3-dimensional images for volumetric analysis (4 with Invisalign and 5 with conventional fixed appliances). Postoperative edema was not significantly different (P = 0.712) when comparing conventional fixed appliances (44.29 ± 23.16 cm3) to Invisalign (37.36 ± 31.19 cm3).

Conclusion:

The present study demonstrates that complex multiple-jaw orthognathic procedures can be successfully performed in Invisalign patients. Perioperative and short-term clinical outcomes are not compromised.
Delayed Dural Arteriovenous Fistula at the Transverse-Sigmoid Sinus Secondary to Petroclival Meningioma Surgery Via Far Lateral Approach
Authors: Xue Xiying , Hou Yunxia , Chen Jingming , Yuan Xunhui , Sun Gaoling , Guo Liemei
Published: April 2019

Intracranial dural arteriovenous fistulas (DAVFs) are typified by pathological anastomoses between meningeal arteries and dural venous sinuses or cortical veins. There are many causes contributing to the etiology of DAVFs. Among the variable causes, acquired DAVFs secondary to craniotomy had rarely been reported, especially for delayed DAVFs at the transverse-sigmoid sinus. Till now, there are only 12 published cases of delayed DAVFs at the transverse-sigmoid sinus secondary to craniotomy. Herein, the authors describe such an extraordinary rare case secondary to petroclival meningioma resection via far lateral approach, and to the best knowledge of us, this is the first well-documented case of delayed DAVF at the transverse-sigmoid sinus following far lateral craniotomy. Furthermore, cases of delayed DAVFs at the transverse-sigmoid sinus secondary to craniotomy were reviewed and investigated, and the clinical characteristics and treatment were also broadly discussed.
Recertification Exam Performance in General Surgery is Associated With Subsequent Loss of License Actions
Authors: Jones Andrew T. , Kopp Jason P. , Malangoni Mark A.
Published: April 2019

Objectives:

To measure associations between first-time performance on the American Board of Surgery (ABS) recertification exam with subsequent state medical licensing board disciplinary actions.

Background:

Time-limited board certification has been criticized as unnecessary. Few studies have examined the relationship between recertification exam performance and outcomes.

Methods:

Retrospective analysis of loss-of-license action rates for general surgeons who were initially certified by the ABS from 1976 to 2005 and attempted to take a surgery recertification exam. Disciplinary actions from 1976 to 2016 were obtained from the Disciplinary Action Notification System through the American Board of Medical Specialties.

Results:

A total of 14,169 general surgeons attempted to pass the surgery recertification exam. The rate of loss-of-license actions was significantly higher for surgeons who failed their first exam attempt [incidence rate 3.41, 95% confidence interval (CI) 2.27–4.56] than those who passed on their first attempt (incidence rate .01, 95% CI 0.87–1.14). A Cox proportional-hazards regression model found that the adjusted hazard rate for loss-of-license actions for surgeons who failed their first recertification exam were significantly higher than those who passed their first attempt after adjusting for multiple surgeon characteristics (adjusted hazard rate 2.98, 95% CI 1.85–4.81).

Conclusions:

Failing the first recertification exam attempt was associated with a greater rate of subsequent loss-of-license actions. These results suggest that demonstrating sufficient surgical knowledge is a significant predictor of future loss-of-license actions.
Proteoliposomes as energy transferring nanomaterials: enhancing the spectral range of light-harvesting proteins using lipid-linked chromophores
Authors: Hancock Ashley M. , Meredith Sophie A. , Connell Simon D. A. , Jeuken Lars J. C. , Adams Peter G.
Published: April 2019

Biology provides a suite of optically-active nanomaterials in the form of “light harvesting” protein-chlorophyll complexes, however, these have drawbacks including their limited spectral range. We report the generation of model lipid membranes (proteoliposomes) incorporating the photosynthetic protein Light-Harvesting Complex II (LHCII) and lipid-tethered Texas Red (TR) chromophores that act as a “bio-hybrid” energy transferring nanomaterial. The effective spectral range of the protein is enhanced due to highly efficient energy transfer from the TR chromophores (up to 94%), producing a marked increase in LHCII fluorescence (up to 3x). Our self-assembly procedure offers excellent modularity allowing the incorporation of a range of concentrations of energy donors (TR) and acceptors (LHCII), allowing the energy transfer efficiency (ETE) and LHCII fluorescence to be tuned as desired. Fluorescence Lifetime Imaging Microscopy (FLIM) provides single-proteoliposome-level quantification of ETE, revealing distributions within the population and proving that functionality is maintained on a surface. Our membrane-based system acts as a controllable light harvesting nanomaterial with potential applications as thin films in photo-active devices.

Table of Contents Figure
Geothermal stickleback populations prefer cool water despite multigenerational exposure to a warm environment
Authors: Pilakouta Natalie , Killen Shaun S. , Kristjánsson Bjarni K. , Skúlason Skúli , Lindström Jan , Metcalfe Neil B. , Parsons Kevin J.
Published: April 2019

Given the threat of climate change to biodiversity, a growing number of studies are investigating the potential for organisms to adapt to rising temperatures. Earlier work has predicted that physiological adaptation to climate change will be accompanied by a shift in temperature preferences, but empirical evidence for this is lacking. Here, we test whether exposure to different thermal environments has led to changes in preferred temperatures in the wild. Our study takes advantage of a ‘natural experiment’ in Iceland, where freshwater populations of threespine sticklebacks (Gasterosteus aculeatus) are found in waters warmed by geothermal activity year-round (warm habitats), adjacent to populations in ambient-temperature lakes (cold habitats). We used a shuttle-box approach to measure temperature preferences of wild-caught sticklebacks from three warm-cold population pairs. Our prediction was that fish from warm habitats would prefer higher water temperatures than those from cold habitats. We found no support for this, as fish from both warm and cold habitats had an average preferred temperature of 13°C. Thus, our results challenge the assumption that there will be a shift in ectotherm temperature preferences in response to climate change. In addition, since warm-habitat fish can persist at relatively high temperatures despite a lower temperature preference, this suggests that preferred temperature alone may be a poor indicator of a population’s adaptive potential to a novel thermal environment.
A bifunctional ATPase drives tad pilus extension and retraction
Authors: Ellison Courtney K. , Kan Jingbo , Chlebek Jennifer L. , Hummels Katherine R. , Panis Gaёl , Viollier Patrick H. , Biais Nicolas , Dalia Ankur B. , Brun Yves V.
Published: April 2019

Molecular motors convert chemical energy directly into mechanical work1and are found in all domains of life2. These motors are critical to intracellular transport3, motility4,5, macromolecular protein assembly3,6, and many essential processes7. A wide-spread class of related bacterial motors drive the dynamic activity of extracellular fibers, such as type IV pili (T4P), that are extended and retracted using so-called secretion motor ATPases. Among these, the tightadherence (tad) pili are critical for surface sensing, surface attachment, and biofilm formation8–10. How tad pili undergo dynamic cycles of extension and retraction8despite lacking a dedicated retraction motor ATPase has remained a mystery. Here we find that a bifunctional pilus motor ATPase, CpaF, drives both activities through ATP hydrolysis. Specifically, we show that mutations within the ATP hydrolysis active site ofCaulobacter crescentusCpaF result in a correlated reduction in the rates of extension and retraction. Moreover, a decrease in the rate of ATP hydrolysis directly scales with a decrease in the force of retraction and reduced dynamics in these CpaF mutants. This mechanism of motor protein bifunctionality extends to another genus of tad-bearing bacteria. In contrast, the T4aP subclass of pili possess dedicated extension and retraction motor ATPase paralogs. We show that these processes are uncoupled using a slow ATP hydrolysis mutation in the extension ATPase of competence T4aP ofVibrio choleraethat decreases the rate of extension but has no effect on the rate of retraction. Thus, a single motor ATPase is able to drive the bidirectional processes of pilus fiber extension and retraction.
Evolution of Yin and Yang isoforms of a chromatin remodeling subunit results in the creation of two genes
Authors: Xu Wen , Long Lijiang , Zhao Yuehui , Stevens Lewis , Ellis Ronald E. , McGrath Patrick T.
Published: April 2019

Genes can encode multiple isoforms, broadening their functions and providing a molecular substrate to evolve phenotypic diversity. Evolution of isoform function is a potential route to adapt to new environments. Here we show thatde novo, beneficial alleles in thenurf-1gene fixed in two laboratory strains ofC. elegansafter isolation from the wild in 1951, before methods of cryopreservation were developed.nurf-1encodes an ortholog of BPTF, a large (>300kD) multidomain subunit of the NURF chromatin remodeling complex. Using CRISPR-Cas9 genome editing and transgenic rescue, we demonstrate that inC. elegans,nurf-1has split into two, largely non-overlapping isoforms (NURF-1.B and NURF-1.D, which we call Yin and Yang) that share only two of 26 exons. Both isoforms are essential for normal gametogenesis but have opposite effects on male/female gamete differentiation. Reproduction in hermaphrodites, which involves production of both sperm and oocytes, requires a balance of these opposing Yin and Yang isoforms. Transgenic rescue and genetic position of the fixed mutations suggest that different isoforms are modified in each laboratory strain. In a related clade ofCaenorhabditisnematodes, the shared exons have duplicated, resulting in the split of the Yin and Yang isoforms into separate genes, each containing approximately 200 amino acids of duplicated sequence that has undergone accelerated protein evolution following the duplication. Associated with this duplication event is the loss of two additionalnurf-1transcripts, including the long-form transcript and a newly identified, highly expressed transcript encoded by the duplicated exons. We propose these lost transcripts are non-functional biproducts necessary to transcribe the Yin and Yang transcripts in the same cells. Our work suggests that evolution ofnurf-1isoforms in nematodes creates adaptive conflict that can be resolved by the creation of new, independent genes.
DeepInterface: Protein-protein interface validation using 3D Convolutional Neural Networks
Authors: Balci A.T. , Gumeli C. , Hakouz A. , Yuret D. , Keskin O. , Gursoy Attila
Published: April 2019

Motivation

Protein–protein interactions are crucial in almost all biological processes. Proteins interact through their interfaces. It is important to determine how proteins interact through interfaces to understand protein binding mechanisms and to predict new protein-protein interactions.

Results

We present DeepInterface, a deep learning based method which predicts, for a given protein complex, if the interface between the proteins of a complex is a true interface or not. The model is a 3-dimensional convolutional neural networks model and the positive datasets are obtained from all complexes in the Protein Data Bank, the negative datasets are the incorrect solutions of the docking decoys. The model analyzes a given interface structure and outputs the probability of the given structure being an interface. The accuracy of the model for several interface data sets, including PIFACE, PPI4DOCK, DOCKGROUND is approximately 88% in the validation dataset and 75% in the test dataset. The method can be used to improve the accuracy of template based PPI predictions.
Single cell RNA-seq reveals cellular diversity and developmental characteristics of human infant retina
Authors: Zhong Jixing , Chen Dongsheng , Hu Fangyuan , Chen Fang , Xu Zaoxu , Fang Jian , Xu Jianjiang , Wang Shiyou , Liang Langchao , Chai Chaochao , Ding Xiangning , Zhu Jiacheng , Ding Peiwen , Xia Jun , Jiang Sanjie , Li Wei , Gao Ya , Zhang Jianguo , Li Jiankang , Xu Ping , Gao Fengjuan , Wang Dandan , Zhang Daowei , Huang Jie , Qu Shoufang , Zhang Shenghai , Wu Jihong , Sun Xinghuai
Published: April 2019

Retina, located in the innermost layer of the eye of human, holds the decisive role in visual perception. Dissecting the heterogeneity of retina is essential for understanding the mechanism of vision formation and even the development of central nervous system (CNS). Here, we performed single cell RNA-seq, analyzed 57,832 cells from human infant donors, resulting in 20 distinct clusters representing major cell types in retina: rod photoreceptors, cone photoreceptors, bipolar cells, horizontal cells, amacrine cells, Muller glia cells and microglia. We next constructed extensive networks of intercellular communication and identified ligand-receptor interactions playing crucial roles in regulating neural cell development and immune homeostasis in retina. Though re-clustering, we identified known subtypes in cone PRs and additional unreported subpopulations and corresponding markers in rod PRs as well as bipolar cells. Additionally, we linked inherited retinal disease to certain cell subtypes or subpopulations through enrichment analysis. Intriguingly, we found that status and functions of photoreceptors changed drastically between early and late retina. Overall, our study offers the first retinal cell atlas in human infants, dissecting the heterogeneity of retina and identifying the key molecules in the developmental process, which provides an important resource that will pave the way for retina development mechanism research and regenerative medicine concerning retinal biology.
Bactofilins form non-polar filaments that bind to membranes directly
Authors: Deng Xian , Gonzalez Llamazares Andres , Wagstaff James , Hale Victoria L. , Cannone Giuseppe , McLaughlin Stephen H. , Kureisaite-Ciziene Danguole , Löwe Jan
Published: April 2019

Bactofilins are small beta-helical proteins that form cytoskeletal filaments in a range of bacteria. Bactofilins have diverse functions: filaments inCaulobacter crescentusare involved in cell stalk formation whereasMyxococcus xanthusfilaments aid chromosome segregation and motility. The precise molecular architecture of bactofilin filaments has remained unclear. Here we revealed by sequence analyses and electron microscopy that in addition to wide distribution across bacteria and archaea, bactofilins are also present in a few eukaryotic cells such as oomycetes. The sole bactofilin fromThermus thermophiluswas demonstrated to form constitutive filaments and cryo-EM analysis revealed that protofilaments formed through end-to-end association of the beta-helical domains. Using a nanobody againstThermusbactofilin we determined the near-atomic filament structure, showing that the filaments are non-polar, with subunits arranged head-to-head and tail-to-tail. A polymerisation-impaired mutant F105R, that disrupts one of the two protofilament interfaces, enabled crystallisation. The crystal structure also revealed non-polar protofilaments, and the dominance of the beta-stacking interface that formed despite the inhibiting mutation. To confirm the generality of the lack of polarity, we performed co-evolutionary analysis of a large set of sequences. Finally, usingThermusbactofilin, we determined that the N-terminal disordered tail of the protein is responsible for direct binding to lipid membranes both on liposomes and by electron cryotomography inE. colicells. The tail is conserved, suggesting that membrane binding is likely a general feature of these very common but only recently discovered filaments of the prokaryotic cytoskeleton.
Mutant p53 Drives Clonal Hematopoiesis through Modulating Epigenetic Pathway
Authors: Chen Sisi , Wang Qiang , Yu Hao , Capitano Maegan L. , Vemula Sasidhar , Nabinger Sarah C. , Gao Rui , Yao Chonghua , Kobayashi Michihiro , Geng Zhuangzhuang , Fahey Aidan , Henley Danielle , Liu Stephen Z. , Wolf Eric R. , Ramdas Baskar , Cai Zhigang , Gao Hongyu , Luo Na , Sun Yang , Wong Terrence N. , Link Daniel C. , Liu Yunlong , Boswell H. Scott , Mayo Lindsey D. , Huang Gang , Kapur Reuben , Yoder Mervin C. , Broxmeyer Hal E. , Gao Zhonghua , Liu Yan
Published: April 2019

Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. WhileTP53mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. We discovered that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Further, genetic and pharmacological inhibition of EZH2 decrease the repopulating potential of p53 mutant HSPCs. Thus, we have uncovered an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies withTP53mutations.
Metabolic control of YAP via the acto-myosin system during liver regeneration
Authors: Meyer Kirstin , Morales-Navarrete Hernan , Seifert Sarah , Wilsch-Braeuninger Michaela , Dahmen Uta , Tanaka Elly M. , Brusch Lutz , Kalaidzidis Yannis , Zerial Marino
Published: April 2019

The mechanisms of organ size control remain poorly understood. A key question is how cells collectively sense the overall status of a tissue. We addressed this problem focusing on mouse liver regeneration, which is controlled by Hippo signalling. Using digital tissue reconstruction and quantitative image analysis, we found that the apical surface of hepatocytes forming the bile canalicular network expands concomitant with an increase of F-actin and phospho-Myosin, to compensate an overload of bile acids. Interestingly, these changes are sensed by the Hippo transcriptional co-activator YAP, which localizes to the apical F-actin-rich region and translocates to the nucleus in dependence of the acto-myosin system. This mechanism tolerates moderate bile acid fluctuations under tissue homeostasis, but activates YAP in response to sustained bile acid overload. Using an integrated biophysical-biochemical model of bile pressure and Hippo signalling, we explained this behaviour by the existence of a mechano-sensory mechanism that activates YAP in a switch-like manner. We propose that the apical surface of hepatocytes acts as a self-regulatory mechano-sensory system that responds to critical levels of bile acids as readout of tissue status.
A phenome-wide association and Mendelian Randomisation study of polygenic risk for depression in UK Biobank
Authors: Shen Xueyi , Howard David M , Adams Mark J ,   23andMe Research Team, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Deary Ian J , Whalley Heather C , McIntosh Andrew M
Published: April 2019

Depression is the leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Depression is known to be heritable with a polygenic architecture, and results from genome-wide associations studies are providing summary statistics with increasing polygenic signal that can be used to estimate genetic risk scores for prediction in independent samples. This provides a timely opportunity to identify traits that are associated with polygenic risk of depression in the large and consistently phenotyped UK Biobank sample. Using the Psychiatric Genomics Consortium (PGC), 23andMe and non-imaging UK Biobank datasets as reference samples, we estimated polygenic risk scores for depression (depression-PRS) in a discovery sample of 10,674 people and a replication sample of 11,214 people from the UK Biobank Imaging Study, testing for associations with 210 behavioural and 278 neuroimaging phenotypes. In the discovery sample, 93 traits were significantly associated with depression-PRS after multiple testing correction. Among these, 92 traits were in the same direction, and 69 were significant in the replication analysis. For imaging traits that replicated across samples, higher depression-PRS was associated with lower global white matter microstructure, association-fibre and thalamic-radiation microstructural integrity (absolute β: 0.023 to 0.040, PFDR: 0.045 to 3.92×10-4). Mendelian Randomisation analysis showed a causal effect of liability to depression on these structural brain measures (β: 0.125 to 0.707, pFDR<0.048). Replicated behavioural traits that positively associated with depression-PRS included sleep problems, smoking status, measures of pain and stressful life experiences, and those negatively associated with depression-PRS included subjective ratings of physical health (absolute β: 0.014 to 0.180, PFDR: 0.046 to 8.54×10-15). Effect of depression PRS on mental health in the presence of reported childhood trauma, stressful life events and those living in more socially deprived areas showed increased variance explained by 1.42 – 4.08 times (pFDR for their interaction with depression-PRS: 0.049 to 0.003). Overall, the present study revealed replicable associations between depression-PRS and white matter microstructure that appeared to be a causal consequence of liability to depression. Analyses provided further evidence that greater effects of polygenic risk of depression are found in individuals exposed to risk-conferring environments.
ADrosophilalarval premotor/motor neuron connectome generating two behaviors via distinct spatio-temporal muscle activity
Authors: Zarin Aref Arzan , Mark Brandon , Cardona Albert , Litwin-Kumar Ashok , Doe Chris Q.
Published: April 2019

Animals generate diverse motor behaviors, yet how the same motor neurons generate distinct behaviors remains an open question.Drosophilalarvae have multiple behaviors – e.g. forward crawling, backward crawling, self-righting and escape – and all of the body wall motor neurons (MNs) driving these behaviors have been identified. Despite impressive progress in mapping larval motor circuits, the role of most motor neurons in locomotion remains untested, the majority of premotor neurons (PMNs) remain to be identified, and a full understanding of proprioceptor-PMN-MN connectivity is missing. Here we report a comprehensive larval proprioceptor-PMN-MN connectome; describe individual muscle/MN phase activity during both forward and backward locomotor behaviors; identify PMN-MN connectivity motifs that could generate muscle activity phase relationships, plus selected experimental validation; identify proprioceptor-PMN connectivity that provides an anatomical explanation for the role of proprioception in promoting locomotor velocity; and identify a new candidate escape motor circuit. Finally, we generate a recurrent network model that produces the observed sequence of motor activity, showing that the identified pool of premotor neurons is sufficient to generate two distinct larval behaviors. We conclude that different locomotor behaviors can be generated by a specific group of premotor neurons generating behavior-specific motor rhythms.
Genetic divergence outpaces phenotypic divergence among threespine stickleback populations in old freshwater habitats
Authors: Currey Mark C. , Bassham Susan L. , Cresko William A.
Published: April 2019

Species such as threespine stickleback fish that are distributed across landscapes with divergent selective environments and that have diversified on different time scales can be valuable for understanding evolutionary processes. Here we synthesize high resolution genotypic and phenotypic data to explore a largely unstudied distribution of threespine stickleback populations living in marine and freshwater habitats along coastal and inland regions of northwestern Oregon. Because many inland aquatic habitats of Oregon were not glaciated during the last ice age, we hypothesized that some extant Oregon lake and river stickleback are descended from freshwater populations that were established long before the well-studied, postglacial freshwater populations of Alaska. Here we characterize the major phenotypic and genetic axes of differentiation in Oregon stickleback, and compare these patterns to their Alaska counterparts currently inhabiting regions that were covered by ice during the last glacial maximum. Phenotypic variation in Oregon stickleback is predictably partitioned between oceanic and freshwater habitats. However, we also found that genetic divergence in Oregon ecotypes is much greater than divergence among studied stickleback populations in Alaska. Additionally, we report a surprising phenotypic and genetic affinity between oceanic stickleback with freshwater populations that live far inland in two Oregon river basins.
Fitness-related traits are maximized in recently introduced, slow-growing populations of a global invasive clam
Authors: Hünicken Leandro A. , Sylvester Francisco , Bonel Nicolás
Published: April 2019

Many species are shifting their ranges being forced to rapidly respond to novel stressful environmental conditions. Colonizing individuals experience strong selective forces that favor the expression of life history traits notably affecting dispersal and reproductive rates in newly invaded habitats. Limited information is currently available on trait variation within the invasive range despite being critical for understanding ecological and evolutionary factors that drive the process of range expansion of invasive species. Here we evaluated life history shifts of the widely introduced Asian clam Corbicula, within its invaded range. Through an exhaustive literature search, we obtained data for 17 invasive Corbicula populations from different ecosystems worldwide. We tested the relationship between population and individual parameters relevant to the process of range expansion. Our main results are that recently introduced Corbicula populations were characterized by (i) low density and low rate of population increase, (ii) clams reproduced earlier in slow-growing populations, and (iii) density had no effect on population increase. All Corbicula populations analyzed in this study, which are fixed for one genotype (lineage Form A/R), experienced different selective environments in the introduced range. These findings support the perspective that adaptive phenotypic plasticity favored the expression of traits that maximize fitness in recently established populations, which faced stronger r-selective forces relative to long-established ones. We discuss the role of plasticity in facilitating rapid adaptation and increasing the likelihood of populations to overcome difficulties associated with low densities and low population increase in newly invaded areas.
An antisense oligonucleotide leads to suppressed transcriptional elongation ofHdac2and long-term memory enhancement
Authors: Poplawski Shane G. , Garbett Krassimira A. , McMahan Rebekah L. , Kordasiewicz Holly B. , Zhao Hien , Kennedy Andrew J. , Goleva Slavina B. , Sanders Teresa H. , Motley S. Timothy , Swayze Eric E. , Ecker David J. , Sweatt J. David , Michael Todd P. , Greer Celeste B.
Published: April 2019

Repression of the memory suppressor genehistonedeacetylase 2 (Hdac2) in mice elicits cognitive enhancement, and drugs that block HDAC2 catalytic activity are being investigated for treating disorders affecting memory. Currently available compounds that target HDAC2 are not specific to the HDAC2 isoform, and have short half-lives. Antisense oligonucleotides (ASOs) are a class of drugs that base pair with RNA targets and exhibit extremely long-lasting, specific inhibition relative to small molecule drugs. We utilized an ASO to reduceHdac2messenger RNA (mRNA) quantities, and explored its longevity, specificity, and mechanism of repression. A single injection of theHdac2-targeted ASO in the central nervous system diminishedHdac2mRNA levels for at least 4 months in the brain, and knockdown of this factor resulted in significant memory enhancement for 8 weeks in mice. RNA-seq analysis of brain tissues revealed that the ASO repression was specific to theHdac2isoform relative to other classicalHdacgenes, and caused alterations in levels of other memory-associated mRNAs. In cultured neurons, we observed that theHdac2-targeted ASO suppressedHdac2mRNA and anHdac2non-coding regulatory extra-coding RNA (ecRNA). The ASO not only triggered a reduction in mRNA levels, but also elicited direct transcriptional suppression of theHdac2gene through blocking RNA polymerase II elongation. These findings suggest transcriptional suppression of the target gene as a novel mechanism of action of ASOs, and opens up the possibility of using ASOs to achieve lasting gene silencing in the brain without altering the nucleotide sequence of a gene.
NK cells force cytomegalovirus to use hematopoietic cells and immune evasion for dissemination after mucosal infection
Authors: Zhang Shunchuan , Grey Finn , Snyder Christopher M.
Published: April 2019

Cytomegalovirus (CMV) infects most people in the world and causes clinically important disease in immune compromised and immune immature individuals. How the virus disseminates from the initial site of infection is poorly understood. We used an innovative approach, involving insertion of target sites for the haematopoietic specific miRNA miR-142-3p into an essential viral gene in murine cytomegalovirus. This virus was unable to disseminate to the salivary gland following intranasal infection, demonstrating a strict need for hematopoietic cells for dissemination from the natural site of infection. Viral immune evasion genes that modulate MHC-I expression and NKG2D activation were also required in this setting, as MCMV lacking these genes exhibited impaired dissemination of the viral genome to the salivary gland, and there was no detectable viral replication in the salivary gland. Depletion of T cells rescued the replication of this evasion-deficient virus in the salivary gland. Surprisingly however, the early dissemination to the salivary gland of this evasion-deficient virus, could be rescued by depletion of NK cells, but not T cells. These data are the first to show a profound loss of MCMV fitness in the absence of its MHC-I evasion genes and suggest that they protect the virus from NK cells during hematopoietic dissemination to the salivary gland, where they continued to need the three evasion genes to avoid T cell responses. Remarkably, we found that depletion of NK cells also freed the virus from the need to infect hematopoietic cells in order to reach the salivary gland. Thus, our data show that MCMV adapts to NK cell pressure after intranasal infection by using hematopoietic cells for dissemination while immune evasion genes protect the virus from NK cells during dissemination and from T cells within mucosal tissues.
An association between the gut microbiota and immune cell dynamics in humans
Authors: Schluter Jonas , Peled Jonathan U. , Taylor Bradford P. , Smith Melody , Markey Kate A. , Taur Ying , Niehus Rene , Staffas Anna , Dai Anqi , Fontana Emily , Amoretti Luigi A. , Wright Roberta J. , Morjaria Sejal , Fenelus Maly , Pessin Melissa S. , Chao Nelson J. , Lew Meagan , Bohannon Lauren , Bush Amy , Sung Anthony D. , Hohl Tobias M. , Perales Miguel-Angel , van den Brink Marcel R.M. , Xavier Joao B.
Published: April 2019

The gut microbiota influences development and homeostasis of the mammalian immune system1–3, can alter immune cell compositions in mice4–7, and is associated with responses to immunotherapy that rely on the activity of peripheral immune cells8–12. Still, our understanding of how the microbiota modulates immune cells dynamics remains limited, particularly in humans where a lack of deliberate manipulations makes inference challenging. Here we study hundreds of hospitalized—and closely monitored—patients receiving hematopoietic cell transplantation as they recover from chemotherapy and stem cell engraftment. This aggressive treatment causes large shifts in both circulatory immune cell and microbiota populations, allowing the relationships between the two to be studied simultaneously. We analyzed daily changes in white blood cells from 2,235 patients, and 10,680 longitudinal microbiota samples to identify bacteria associated with those changes. Bayesian inference and validation across patient cohorts revealed consistent associations between gut bacteria and white blood cell dynamics in the context of immunomodulatory medications, clinical metadata and homeostatic feedbacks. We contrasted the potency of fermentatively active, obligate anaerobic bacteria with that of medications with known immunomodulatory mechanism to estimate the potential of the microbiota to influence peripheral immune cell dynamics. Our analysis establishes and quantifies the link between the gut microbiota and the human immune system, with implications for microbiota-driven modulation of immunity.
Alterations of the pulmonary immunity are independent of spontaneous pneumonia in an experimental model of ischemic stroke
Authors: Farris Breanne Y. , Monaghan Kelly L. , Amend Courtney D. , Zheng Wen , Hu Heng , Coad James E. , Ren Xuefang , Wan Edwin C.K.
Published: April 2019

Stroke-associated pneumonia (SAP) is a major cause of mortality in patients who have suffered from severe ischemic stroke. Although multi-factorial in nature, stroke-induced immunosuppression plays a key role in the development of SAP. Previous studies of focal ischemic stroke induction, using a murine model of transient middle cerebral artery occlusion (tMCAO) have shown that severe brain damage results in massive apoptosis and functional defects of lymphocytes in the spleen, thymus, and peripheral blood. However, how immune alternations in remote tissues lead to a greater susceptibility to lung infections is not well-understood. Importantly, how ischemic stroke alters immune-cell fates, and the expression of cytokines and chemokines in the lungs that directly impact pulmonary immunity, has not been characterized. We report here that ischemic stroke increases the percentage of alveolar macrophages, neutrophils, and CD11b+ dendritic cells (DCs), but reduces the percentage of CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells, and eosinophils in the lungs. The depletion of immune cells in the lungs is not caused by apoptosis, cell infiltration to the brain, or spontaneous pneumonia following ischemic stroke as previously described, but correlates with a significant reduction in the levels of multiple chemokines in the lungs, including: CCL3, CCL4, CCL5, CCL17, CCL20, CCL22, CXCL5, CXCL9, and CXCL10. These findings suggest that ischemic stroke negatively impacts pulmonary immunity to become more susceptible for SAP development. Further investigation into the mechanisms that control pulmonary immune alternations following ischemic stroke may identify novel diagnostic or therapeutic targets for SAP.
Gephebase, a Database of Genotype-Phenotype Relationships for natural and domesticated variation in Eukaryotes
Authors: Courtier-Orgogozo Virginie , Arnoult Laurent , Prigent Stéphane R. , Wiltgen Séverine , Martin Arnaud
Published: April 2019

Gephebase is a manually-curated database compiling our accumulated knowledge of the genes and mutations that underlie natural, domesticated and experimental phenotypic variation in all Eukaryotes — mostly animals, plants and yeasts. Gephebase aims to compile studies where the genotype-phenotype association (based on linkage mapping, association mapping or a candidate gene approach) is relatively well supported or understood. Human disease and aberrant mutant phenotypes in laboratory model organisms are not included in Gephebase and can be found in other databases (eg. OMIM, OMIA, Monarch Initiative). Gephebase contains more than 1700 entries. Each entry corresponds to an allelic difference at a given gene and its associated phenotypic change(s) between two species or between two individuals of the same species, and is enriched with molecular details, taxonomic information, and bibliographic information. Users can easily browse entries for their topic of interest and perform searches at various levels, whether phenotypic, genetic, taxonomic or bibliographic (eg. transposable elements, cis-regulatory mutations, snakes, carotenoid content, an author name). Data can be searched using keywords and boolean operators and is exportable in spreadsheet format. This database allows to perform meta-analysis to extract general information and global trends about evolution, genetics, and the field of evolutionary genetics itself. Gephebase should also help breeders, conservationists and others to identify the most promising target genes for traits of interest, with potential applications such as crop improvement, parasite and pest control, bioconservation, and genetic diagnostic. It is freely available at www.gephebase.org.