bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence and prognosis of brain metastases in cutaneous melanoma patients: a population-based study
Authors: Zhang Dongxiao , Wang Zhe , Shang Dongping , Yu Jinming , Yuan Shuanghu
Published: October 2018

Brain metastases (BM) from cutaneous melanoma are associated with poor prognosis. Population-based data describing the associated factors of incidence and prognosis of BM from melanoma are still lacking. We identified 121 255 melanoma patients diagnosed during 2010–2015 from the Surveillance, Epidemiology, and End Results program, and identified predictive factors for incidence and survival of BM patients by using multivariable logistic and Cox’s proportional hazard regression, respectively. We identified 1547 patients with BM at the time of diagnosis of malignant cutaneous melanoma, representing 1.3% of the entire cohort and 35.4% of the subset with metastatic disease. The characteristics associated with higher BM incidence were male sex, age 40–60 years, melanoma location of face/head/neck, histologic type of nodular, higher T-stage, ulceration and extracranial metastases. The median overall survival and median cutaneous melanoma specific survival of patients with BM was 5 and 6 months, respectively. The relative factors of poor survival were older age and more extracranial metastatic sites. In summary, we provided insight into the epidemiology of BM from cutaneous melanoma. These results may provide significant help to improve the screening strategy of BM strategy and update the existing prognosis evaluation system.
Safety of Therapeutic Plasma Exchange for the Treatment of Guillain-Barré Syndrome in Polycythemia Vera
Authors: Abrams Rory M.C. , Elder Gregory A.
Published: October 2018

Polycythemia vera (PV) is a risk factor for systemic thromboses and ischemic stroke. This has been attributed to blood hyperviscosity, the result of increased blood cell production. Intravenous immunoglobulin, which is indicated for the treatment of numerous hematologic and neurological conditions also causes increased serum viscosity and has been associated with ischemic strokes in the setting of PV. Here we report a case of a 70-year-old man with prior stroke and PV who developed Guillain-Barré syndrome, an acute inflammatory demyelinating disorder of peripheral nerves causing ascending paresis, numbness, and paresthesia, who was treated safely with therapeutic plasma exchange. Plasma exchange may be preferable to administration of intravenous immunoglobulin for treatment of various medical conditions in patients with comorbid PV.
Clinical Correlations of Positive Herpes Simplex PCR in Cerebrospinal Fluid
Authors: Alessandro Lucas , Wilken Miguel , Farez Mauricio F. , Arias Cebollada Eugenia , Mora Andrea C. , Cammarota Ángel , Del Castillo Marcelo
Published: October 2018

Objectives:

Herpes simplex viruses (HSV) can produce encephalitis (HSE), which requires early detection, typically using polymerase chain reaction (PCR) in cerebrospinal fluid (CSF). However, other neurological conditions not directly caused by HSV may also present with a positive HSV PCR in the CSF (NCNHPCR+). We aimed to analyze the clinical features of both groups of patients (HSE vs. NCNHPCR+) and to consider the potential relevance of this finding in the latter.

Methods:

A retrospective analysis of clinical presentation, workup (CSF, EEG, and MRI) and outcome of patients with an HSV+ result in CSF was conducted from Jan-2007 to Sep-2015 in our institution. Patients under 18 years and those with nonencephalitic HSV associated disorders were excluded. Group comparison between HSE and NCNHPCR+ patients was conducted using parametric and nonparametric tests accordingly.

Results:

Sixteen HSE and 23 NCNHPCR+ patients were included. Patients with HSE presented a higher incidence of headache (87.5% vs. 43.5%; P=0.008), meningeal symptoms (50% vs. 17.4%; P=0.04), pleocytosis (75% vs. 18%; P=0.001), EEG abnormalities (46.67% vs. 22%; P=0.02) and typical MRI findings (50% vs. 0%; P<0.001), whereas 35% of patients with NCNHPCR+ had an underlying immunologic disorder (35% vs. 0%; P=0.012).

Conclusions:

The pathogenic role of HSV in NCNHPCR+ is uncertain. This finding must be interpreted in the appropriate clinical, EEG, and neuroimaging context. Immunocompromise and neuroinflammation states could be related to a higher presence of HSV in CSF.
Iron: an essential nutrient for Aspergillus fumigatus and a fulcrum for pathogenesis
Authors: Matthaiou Efthymia I. , Sass Gabriele , Stevens David A. , Hsu Joe L.
Published: October 2018

Purpose of review

Aspergillus fumigatus is a ubiquitous saprophytic fungus that can cause life-threatening invasive aspergillosis in immunocompromised patients. Apart from the immune status of the host only a few characterized virulence factors have been identified. In this review, we describe the role of iron in the manifestation of A. fumigatus virulence.

Recent findings

We gathered recent clinical evidence suggesting that tissue iron overload increases the risk of invasive aspergillosis occurrence. Furthermore, we summarize the mechanisms that A. fumigatus employs to achieve iron homeostasis and their importance in A. fumigatus proliferation in vitro. We describe two recent in-vivo models that clearly demonstrate the importance of iron in A. fumigatus growth and invasion.

Based on these recent findings, therapy aimed at managing A. fumigatus iron homeostasis locally could make conditions more favorable to the host.
Improved Quality of Life for Children With Beckwith–Wiedemann Syndrome Following Tongue Reduction Surgery
Authors: Harada Takeshi , Yamanishi Tadashi , Kurimoto Takayuki , Nishio Juntaro
Published: October 2018

Macroglossia is observed in the majority of patients with Beckwith–Wiedemann syndrome (BWS), a congenital condition with characteristic anomalies. In addition, sleep disordered breathing (SDB) associated with macroglossia has occasionally been noted in BWS patients, for which tongue reduction surgery is generally performed. However, macroglossia is related to various health problems, such as eating and articulation disorders, attention deficit disorder, enuresis, and thorax deformation, as well as aesthetic issues. Therefore, in addition to treating airway obstruction, tongue reduction surgery can also exert favorable effects on the overall quality of life (QOL) of patients. However, surgical indications for tongue reduction have yet to be established and reports on QOL assessments after surgery are rare. The OSA-18 questionnaire is used for screening SDB and is also useful for assessing the effect of tongue reduction surgery on QOL. We report a patient whose QOL was improved by tongue reduction surgery. On the basis of our patient's results, we recommend tongue reduction surgery in early childhood not only to treat SDB but also to improve QOL.
Aesthetic and Functional Evaluation of Large Full-Thickness Vermilion and Lower Lip Defects Reconstruction
Authors: Jun Guo , Wei Fei , Tong Liu , Yi Huang , Hao Zhou , Jun Li Shuang
Published: October 2018

Background:

It is hardly to reconstruct a huge defect of lower lip by using of partial flap which brings no mouth closing functional problem. In this study, we would like to introduce our experience in large full-thickness vermilion and lower lip/chin defects reconstruction, and also focus on the evaluation of the surgery effects.

Methods:

The large lower lip and chin (include vermilion) reconstruction were performed in Sichuan Provincial People's Hospital (2012–2015). The surgery experience was introduced in this study first. In the following section, after a statement of these basic problems, various situations involving are investigated, such as the surgical effects of aesthetic and function that were evaluated through a visual analogue scale (VAS) by doctors and patients separately. The VAS score assessments of 2 kinds of surgery were collected and compared.

Results:

A total of 7 patients use the tongue flap alone. Four patients use the combination of the free forearm flap and the anterior ventral tongue flap (COMBO flap). The VAS score of doctors group was significantly lower than the patients group (P < 0.05), and the aesthetic appearance was excellent (>90 points). Language features were not affected (>90 points). Slight mouth opening problems exist on these patients who were used COMBO flaps (>80 points; <90 points). The drooling and drumming gas problems were not observed. These 11 patients had no recurrence within 12 months after the operation.

Conclusion:

The 1:1 ratio between upper and lower lip is crucial to the design of anterior ventral tongue flap which brings with an excellent 3-dimensional morphologic and anatomic structure outcome. The bite block might become an essential operation step for vermilion reconstruction by using of tongue flap. And the COMBO flap may enhance the facial aesthetics and oral function for the reconstruction.
Tranexamic acid mediates proinflammatory and anti-inflammatory signaling via complement C5a regulation in a plasminogen activator–dependent manner
Authors: Barrett Christopher D. , Moore Hunter B. , Kong Yi-Wen , Chapman Michael P. , Sriram Ganapathy , Lim Dan , Moore Ernest E. , Yaffe Michael B.
Published: October 2018

BACKGROUND

Both tissue plasminogen activator (tPA) in the circulation and urokinase (uPA) in tissues cleave plasminogen (PLG) to plasmin to promote clot lysis. Tranexamic acid (TXA) blocks both the tPA-dependent generation of plasmin on blood clots as well as active plasmin binding to polymerized fibrin, and is commonly administered for bleeding in trauma to limit fibrinolysis. In addition to lysing clots, however, active plasmin also cleaves complement proteins, potentially enhancing inflammation. Because TXA does not block uPA-dependent plasmin generation from PLG and instead augments it, we hypothesized that administration of TXA could enhance or inhibit proinflammatory C5a formation in a PLG activator–dependent manner.

METHODS

Citrate platelet-poor plasma (PPP) and PPP depleted of complement protein C3 or PLG were obtained from healthy donors and commercial sources. Platelet-poor plasma was treated ex vivo with or without TXA and either with or without tPA or with or without uPA. Clotting was then induced by calcium and thrombin in clotted PPP experiments, while unclotted PPP experiments were treated with vehicle controls. C5a levels were measured via enzyme–linked immunosorbent assay. Data were expressed as mean ± SEM.

RESULTS

Plasmin-mediated fibrinolysis by tPA in clotted PPP led to an approximately threefold increase in C5a production (p < 0.0001), which was significantly inhibited by TXA (p < 0.001). Paradoxically, when fibrinolysis was induced by uPA, TXA treatment led to further increases in C5a production beyond uPA alone (p < 0.0001). Furthermore, clotting was not required for C5a generation from uPA + TXA. C3 depletion had no effect on C5a production, while depletion of PLG eliminated it.

CONCLUSIONS

Tranexamic acid administration can have proinflammatory or anti-inflammatory effects through regulating C5a generation by plasmin, depending on the predominating PLG activator. Tranexamic acid may cause significant inflammatory C5a elevations in injured tissues by augmenting uPA-mediated plasmin generation in a fibrin-independent manner. In contrast, TXA reduces C5a generation during tPA-mediated fibrinolysis that may reduce inflammatory responses. In vivo validation of these novel ex vivo findings is warranted and may have important clinical consequences.
Massive transfusion protocols in nontrauma patients: A systematic review and meta-analysis
Authors: Sommer Nora , Schnüriger Beat , Candinas Daniel , Haltmeier Tobias
Published: October 2018

BACKGROUND

Massive bleeding is a major cause of death both in trauma and nontrauma patients. In trauma patients, the implementation of massive transfusion protocols (MTP) led to improved outcomes. However, the majority of patients with massive bleeding are nontrauma patients.

OBJECTIVES

To assess if the implementation of MTP in nontrauma patients with massive bleeding leads to improved survival.

DATA SOURCES

National Library of Medicine's Medline database (PubMed).

STUDY ELIGIBILITY CRITERIA

Original research articles in English language investigating MTP in nontrauma patients.

PARTICIPANTS

Nontrauma patients with massive bleeding 18 years or older.

INTERVENTION

Transfusion according to MTP versus off-protocol.

STUDY APPRAISAL AND SYNTHESIS METHODS

Systematic literature review using PubMed. Outcomes assessed were mortality and transfused blood products. Studies that compared mortality of MTP and non-MTP groups were included in meta-analysis using Mantel-Haenszel random effect models.

RESULTS

A total of 252 abstracts were screened. Of these, 12 studies published 2007 to 2017 were found to be relevant to the topic, including 2,475 patients. All studies were retrospective and comprised different patient populations. Most frequent indications for massive transfusion were perioperative, obstetrical and gastrointestinal bleeding, as well as vascular emergencies. Four of the five studies that compared the number of transfused blood products in MTP and non-MTP groups revealed no significant difference. Meta-analysis revealed no significant effect of MTP on the 24-hour mortality (odds ratio 0.42; 95% confidence interval 0.01–16.62; p = 0.65) and a trend toward lower 1-month mortality (odds ratio 0.56; 95% confidence interval 0.30–1.07; p = 0.08).

LIMITATIONS

Heterogeneous patient populations and MTP in the studies included.

CONCLUSION

There is limited evidence that the implementation of MTP may be associated with decreased mortality in nontrauma patients. However, patient characteristics, as well as the indication and definition of MTP were highly heterogeneous in the available studies. Further prospective investigation into this topic is warranted.

LEVEL OF EVIDENCE

Systematic review and meta-analysis, level III.
Favorable Outcome of an Exclusively Posttransplant Prophylactic Strategy After Heart Transplantation in Recipients With High Immunological Risk
Authors: Coutance Guillaume , d’Orio Virginie , Belin Lisa , Bréchot Nicolas , Saheb Samir , Lebreton Guillaume , Bouglé Adrien , Rouvier Philippe , Gautreau Chantal , Ouldammar Salima , Chamillard Xavier , Huot Mélanie , Amour Julien , Combes Alain , Leprince Pascal , Varnous Shaida
Published: October 2018

Background.

Management of the increasing number of sensitized heart transplant candidates has become a recurrent issue. Rather than using pretransplant desensitization therapies, we used a posttransplant prophylactic strategy. Our aim was to describe outcomes in transplant recipients with preformed donor-specific anti-HLA antibodies (pfDSA) managed with this strategy.

Methods.

A posttransplant protocol was applied to patients transplanted with pfDSA, consisting of perioperative management of DSA (polyvalent immunoglobulins +/− perioperative plasmapheresis sessions, according to DSA level, as well as induction therapy) and systematic treatment of subsequent antibody-mediated rejection (AMR), even when subclinical. We performed a retrospective analysis of this prospective protocol. The study included all consecutive first recipients of a noncombined heart transplant performed between 2009 and 2015 at our center. The primary endpoint was all-cause mortality. Secondary endpoints included primary graft dysfunction, early posttransplant bleeding, rejection, and cardiac allograft vasculopathy-free survival.

Results.

A total of 523 patients were studied, including 88 (17%) and 194 (37%) transplanted with DSA mean fluorescence intensity (MFI) of 500 to 1000 and greater than 1000, respectively. The median follow-up period was 4.06 years. Survival was not significantly different between groups. Rejection-free survival was worse in patients with pfDSA MFI >1000, evidenced by a fourfold increase in the risk of antibody-mediated rejection. The incidence of primary graft dysfunction and cardiac allograft vasculopathy-free survival did not significantly differ between groups. Perioperative plasmapheresis increased the risk for transfusion of packed red blood cells.

Conclusions.

This exclusively posttransplant prophylactic strategy achieved favorable outcomes in heart transplant recipients with pfDSA.
Version 3 of the National Alzheimer’s Coordinating Center’s Uniform Data Set
Authors: Besser Lilah , Kukull Walter , Knopman David S. , Chui Helena , Galasko Douglas , Weintraub Sandra , Jicha Gregory , Carlsson Cynthia , Burns Jeffrey , Quinn Joseph , Sweet Robert A. , Rascovsky Katya , Teylan Merilee , Beekly Duane , Thomas George , Bollenbeck Mark , Monsell Sarah , Mock Charles , Zhou Xiao Hua , Thomas Nicole , Robichaud Elizabeth , Dean Margaret , Hubbard Janene , Jacka Mary , Schwabe-Fry Kristen , Wu Joylee , Phelps Creighton , Morris John C.
Published: October 2018

Introduction:

In 2015, the US Alzheimer’s Disease Centers (ADC) implemented Version 3 of the Uniform Data Set (UDS). This paper describes the history of Version 3 development and the UDS data that are freely available to researchers.

Methods:

UDS Version 3 was developed after years of coordination between the National Institute on Aging-appointed Clinical Task Force (CTF), clinicians from ∼30 ADCs, and the National Alzheimer’s Coordinating Center (NACC). The CTF recognized the need for updates to align with the state of the science in dementia research, while being flexible to the diverse needs and diseases studied at the ADCs. Version 3 also developed a nonproprietary neuropsychological battery.

Results:

This paper focuses on the substantial Version 3 changes to the UDS forms related to clinical diagnosis and characterization of clinical symptoms to match updated consensus-based diagnostic criteria. Between March 2015 and March 2018, 4820 participants were enrolled using UDS Version 3. Longitudinal data were available for 25,337 of the 37,568 total participants using all UDS versions.

Discussion:

The results from utilization of the UDS highlight the possibility for numerous research institutions to successfully collaborate, produce, and use standardized data collection instruments for over a decade.
New molecular targets in meningiomas: the present and the future
Authors: Venur Vyshak Alva , Santagata Sandro , Galanis Eva , Brastianos Priscilla K.
Published: October 2018

Purpose of review

Meningiomas, the most common primary brain tumor, have historically been managed with surgery and radiation. Traditional chemotherapy has not been effective. Fortunately, recent advances in genetic sequencing have led to an improved understanding of the molecular drivers in meningioma. This article aims to discuss the diagnostic and therapeutic implications of recently discovered genetic alterations in meningiomas.

Recent findings

Many of the recently discovered genetic alterations correlate with distinct clinical phenotypes.SMO,AKTandPIK3CAmutations are enriched in the anterior skull base.KLF4mutations are specific for secretory histology, andBAP1alterations are common in progressive rhabdoid meningiomas. Alterations inTERT,DMDandBAP1correlate with poor clinical outcomes. Importantly, the discovery of clinically actionable alterations in a number of genes, includingSMO,AKT1andPIK3CA,has opened up novel potential avenues for therapeutic management of meningiomas. Overexpression of PD-L1 in higher grade meningiomas also provides preclinical support for the investigation of checkpoint blockade.

The discovery of genetic alterations has improved our understanding of the natural history and classification of meningiomas. Clinical trials with several novel agents targeting driver mutations are currently accruing patients and they can lead to better treatment strategies.
Kinematic and biomechanical analyses in Drosophila suggests that most legged locomotion in insects can be understood within a single framework
Authors: Chun Chanwoo , Biswas Tirthabir , Bhandawat Vikas
Published: October 2018

Despite the fact that all insects have six legs, they display considerable differences in their legged locomotion. Are these differences irreconcilable, or simply different domains of the same system? In this study, we investigate walking inDrosophila. We find that despite the fact that flies walk extremely slowly relative to their size, they predominantly employ an alternating tripod gait, a gait typically associated with high-speed locomotion. The kinematics of their center of mass (CoM) is diametrically opposite to the CoM kinematics observed in insect runners such as cockroach. We resolve this tension between similar gaits, and differing kinematics in slow and high-speed locomotion by showing that the mechanics of a tripod gait naturally reduces to a simple biomechanical model which can support a range of kinematic patterns including both fly-like and cockroach-like patterns. These findings suggest that legged locomotion in different insects might represent different domains of the same system.
Early detection of cryostorage tank failure using a weight-based monitoring system
Authors: Michaelson Zahava P. , Bondalapati Sai T. , Amrane Selma , Prosser Robert W. , Hill Daniel M. , Gaur Pallavi , Recio Matt , Travassos David E. , Wolfkamp Mikaela D. , Sadowy Sasha , Thomas Colin , Forman Eric J. , Williams Zev
Published: October 2018

Object

To study the ability of custom-built, web-enabled scales to monitor liquid nitrogen (LN2) levels in cryostorage dewars.

Design

Laboratory study

Setting

A large academic fertility center in New York City.

Interventions

Cryostorage dewars were placed on top of the custom-engineered scales with continuous real-time monitoring, and weight and temperature data were recorded in the setting of slow, medium, and fast rate-loss of LN2 designed to mimic models of tank failures.

Main Outcome Measures

Weights were continuously monitored and recorded, with a calculated alarm trigger set at 10% weight loss. Temperature within the tanks was simultaneously monitored with probes placed near the top of the tanks, with calculated alarms using a −185 °C as the threshold. For the “slow rate-loss” simulations, tanks were left intact and closed in usual operating conditions, and LN2 was allowed to evaporate at the normal rate. For the “medium rate-loss” simulation, the foam core of the tank neck was removed and the insulating vacuum was eliminated by making a 1/16 inch hole in the outer tank wall. For the “fast rate-loss” simulation, a 1/16” hole was made through the outer tank wall and LN2 was released at a rate of 0.15 L/second. All simulations were performed in duplicate.

Results

With an intact and normally functioning tank, a 10% loss in LN2 occurred in 4.2-4.9 days. Warming to −185 °C occurred in 37.8 - 43.7 days, over 30 days after the weight-based alarm was triggered. Full evaporation of LN2required 36.8 days. For the medium rate-loss simulation, a 10% loss in LN2 occurred in 0.8 h. Warming to −185 °C occurred in 3.7 - 4.8 hours, approximately 3 hours after the weight-based alarm was triggered. For the fast rate-loss simulation, a 10% weight loss occurred within 15 seconds and tanks were completely depleted in under 3 minutes. Tank temperatures began to rise immediately and at a relatively constant rate of 43.9 °C/hour and 51.6 °C/hour. Temperature alarms would have sounded within 0.37 and 0.06 hours after the breech.

Conclusions

This study demonstrates that a weight-based, automated alarm system can detect tank failures prior to a temperature-based alarm system, in some cases over a month in advance. In combination with existing safety mechanisms such as temperature probes, a weight-based monitoring system could serve as a redundant safety mechanism for added protection of cryopreserved reproductive tissues.
Brain tissue segmentation based on MP2RAGE multi-contrast images in 7 T MRI
Authors: Choi Uk-Su , Kawaguchi Hirokazu , Matsuoka Yuichiro , Kober Tobias , Kida Ikuhiro
Published: October 2018

We proposed a method for segmentation of brain tissues––gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF)—using multi-contrast images, including a T1 map and a uniform T1-weighted image, from a magnetization-prepared 2 rapid acquisition gradient echoes (MP2RAGE) sequence at 7 Tesla. The proposed method was evaluated with respect to the processing time and the similarity of the segmented masks of brain tissues with those obtained using FreeSurfer, FSL, and SPM12. The processing time of the proposed method (28 ± 0 s) was significantly shorter than those of FSL and SPM12 (444 ± 4 s and 159 ± 2 s for FSL and SPM12, respectively). In the similarity assessment, the tissue mask of the brain obtained by the proposed method showed higher consistency with those obtained by FSL than with those obtained by SPM12. The proposed method misclassified the subcortical structures and large vessels since it is based on the intensities of multi-contrast images obtained using MP2RAGE, which uses a similar segmentation approach as FSL but is not based on a template image or a parcellated brain atlas, which are used for FreeSurfer and SPM12, respectively. However, the proposed method showed good segmentation in the cerebellum and WM in the medial part of the brain in comparison with the other methods. Thus, because the proposed method using different contrast images of MP2RAGE sequence showed the shortest processing time and similar segmentation ability as the other methods, it may be useful for both neuroimaging research and clinical diagnosis.
capC-MAP : A Software Package for Analysis of Capture-C data
Authors: Buckle Adam , Gilbert Nick , Marenduzzo Davide , Brackley Chris A.
Published: October 2018

We present capC-MAP, a software package for the analysis of Capture-C data. Capture-C is a “many-to-all” chromosome-conformation-capture method. We summarise the method, then detail capC-MAP, the first software specifically designed and optimised for Capture-C data. capC-MAP has been developed with ease-of-use and flexibility in mind: the entire pipe-ine can be run with a single command, or the component programs can be run individually for custom data processing, in a strategy that will suit computational as well as experimental researchers. Finally, we compare and benchmark capC-MAP against another package which can perform (though is not optimised for) analysis of Capture-C data.
Age-dependent changes in transcription factor FOXO targeting in Drosophila melanogaster
Authors: Birnbaum Allison , Wu Xiaofen , Tatar Marc , Liu Nan , Bai Hua
Published: October 2018

FOXO transcription factors have long been associated with longevity control and tissue homeostasis. Although the transcriptional regulation of FOXO have been previously characterized (especially in long-lived insulin mutants and under stress conditions), how normal aging impacts the transcriptional activity of FOXO is poorly understood. Here, we conducted a chromatin immunoprecipitation sequencing (ChIP-Seq) analysis in both young and old wild-type fruit flies, Drosophila melanogaster, to evaluate the dynamics of FOXO gene targeting during aging. Intriguingly, the number of FOXO-bound genes dramatically decreases with age (from 2617 to 224). Consistent to the reduction of FOXO binding activity, many genes targeted by FOXO in young flies are transcriptionally altered with age, either up-regulated (FOXO-repressing genes) or down-regulated (FOXO-activating genes). In addition, we show that many FOXO-bound genes in wild-type flies are unique from those in insulin receptor substrate chico mutants. Distinct from chico mutants, FOXO targets specific cellular processes (e.g., actin cytoskeleton) and signaling pathways (e.g., Hippo, MAPK) in young wild-type flies. FOXO targeting on these pathways decreases with age. Interestingly, FOXO targets in old flies are enriched in cellular processes like chromatin organization and nucleosome assembly. Furthermore, FOXO binding to core histone genes is well maintained at aged flies. Together, our findings provide new insights into dynamic FOXO targeting under normal aging and highlight the diverse and understudied regulatory mechanisms for FOXO transcriptional activity.
Identification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies
Authors: Rajendran Pradeep S. , Challis Rosemary C. , Fowlkes Charless C. , Hanna Peter , Tompkins John D. , Jordan Maria C. , Hiyari Sarah , Gabris-Weber Beth A. , Greenbaum Alon , Chan Ken Y. , Deverman Benjamin E. , Münzberg Heike , Ardell Jeffrey L. , Salama Guy , Gradinaru Viviana , Shivkumar Kalyanam
Published: October 2018

Heart rate is under the precise control of the autonomic nervous system. However, the wiring of peripheral neural circuits that regulate heart rate is poorly understood. Here, we developed a clearing-imaging-analysis pipeline to visualize innervation of intact hearts in 3D and employed a multi-technique approach to map parasympathetic and sympathetic neural circuits that control heart rate in mice. We anatomically and functionally identify cholinergic neurons and noradrenergic neurons in an intrinsic cardiac ganglion and the stellate ganglia, respectively, that project to the sinoatrial node. We also report that the heart rate response to optogenetic versus electrical stimulation of the vagus nerve displays different temporal characteristics and that vagal afferents enhance parasympathetic and reduce sympathetic tone to the heart via central mechanisms. Our findings provide new insights into neural regulation of heart rate, and our methodology to study cardiac circuits can be readily used to interrogate neural control of other visceral organs.
City-wide metagenomics uncover antibiotic resistance reservoirs in urban beach and sewage waters
Authors: Fresia Pablo , Antelo Verónica , Salazar Cecilia , Giménez Matías , D’Alessandro Bruno , Afshinnekoo Ebrahim , Mason Christopher , Gonnet Gastón H , Iraola Gregorio
Published: October 2018

Background

Microbial communities present in environmental waters constitute a reservoir for antibiotic-resistant pathogens that impact human health. For this reason a diverse variety of water environments are being analyzed using metagenomics to uncover public health threats. However, the composition of these communities along the coastal environment of a whole city where sewage and beach waters are mixed, is poorly understood.

Results

We shotgun-sequenced 20 coastal areas from the city of Montevideo (capital of Uruguay) including beach and sewage water samples to characterize bacterial communities and their virulence and antibiotic resistance repertories. We found that sewage and beach environments presented significantly different bacterial communities. Sewage waters harbored a higher prevalence and a more diverse repertory of virulence and antibiotic resistant genes mainly from well-known enterobacteria, including carbapenemases and extended-spectrum betalactamases reported in hospital infections in Montevideo. Additionally, we were able to genotype the presence of both globally-disseminated pathogenic clones as well as emerging antibiotic-resistant bacteria in sewage waters.

Conclusions

Our study represents the first in using metagenomics to jointly analyze beaches and the sewage system from an entire city, allowing us to characterize antibiotic-resistant pathogens circulating in urban waters. The data generated in this initial study represent a baseline metagenomic exploration to guide future longitudinal (time-wise) studies, whose systematic implementation will provide useful epidemiological information to improve public health surveillance.
Inference of tumor cell-specific transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection of cancer
Authors: Ulz Peter , Perakis Samantha , Zhou Qing , Moser Tina , Belic Jelena , Lazzeri Isaac , Wölfler Albert , Zebisch Armin , Gerger Armin , Pristauz Gunda , Petru Edgar , White Brandon , Roberts Charles E.S. , St. John John , Schimek Michael G. , Geigl Jochen B. , Bauernhofer Thomas , Sill Heinz , Bock Christoph , Heitzer Ellen , Speicher Michael R.
Published: October 2018

Deregulation of transcription factors (TFs) is an important driver of tumorigenesis. We developed and validated a minimally invasive method for assessing TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. We analyzed whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a newly developed bioinformatics pipeline that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns. We observed patient-specific as well as tumor-specific patterns, including accurate prediction of tumor subtypes in prostate cancer, with important clinical implications for the management of patients. Furthermore, we show that cell-free DNA TF profiling is capable of early detection of colorectal carcinomas. Our approach for mapping tumor-specific transcription factor bindingin vivobased on blood samples makes a key part of the noncoding genome amenable to clinical analysis.
The Molecular Basis of Monopolin Recruitment to the Kinetochore
Authors: Plowman Rebecca , Singh Namit , Payan Angel , Duro Eris , Corbett Kevin D. , Marston Adele L.
Published: October 2018

In budding yeast meiosis I, the kinetochores of each sister chromatid pair are fused by the monopolin complex to mediate their monoorientation on the meiosis I spindle, enabling the biorientation and segregation of homologs. Monopolin forms a V-shaped complex with binding sites for the kinetochore protein Dsn1 at the apices of the V, suggesting that monopolin forms a physical bridge between the two sister kinetochores. Here, we reveal the molecular basis of the monopolin-kinetochore interaction and identify the key interfaces required for monopolin function at the kinetochore. The disordered N-terminus of budding-yeast Dsn1 unexpectedly possesses two binding motifs for the monopolin subunit Csm1, encompassing the previously-identified “Box 1” and “Box 2-3” regions of Dsn1. Strikingly, Dsn1 Box 1 and Box 2-3 bind the same conserved hydrophobic cavity on the monopolin complex subunit Csm1, suggesting that they are mutually exclusive for Csm1 binding, yet both regions are critical for monopolin function in Saccharomyces cerevisiae meiosis I. We find that Dsn1 Box 1 is an ancestral monopolin-binding motif that is conserved throughout fungi, including in the fission yeast Schizosaccharomyces pombe. In contrast, Box 2-3 is found only in species with sequence-defined point centromeres (S. cerevisiae and its close relatives), suggesting that this region contributes specifically to sister kinetochore crosslinking in meiosis I. Finally, we propose that phosphorylation of two conserved serine residues in Box 3 may stabilize monopolin at the kinetochore, providing a potential mechanism for enforcing specific sister kinetochore crosslinking in meiosis I.
Nanopore sequencing enables high-resolution analysis of resistance determinants and mobile elements in the human gut microbiome
Authors: Bertrand Denis , Shaw Jim , Kalathiappan Manesh , Hui Qi Ng Amanda , Muthiah Senthil , Li Chenhao , Dvornicic Mirta , Soldo Janja Paliska , Koh Jia Yu , Tek Ng Oon , Barkham Timothy , Young Barnaby , Marimuthu Kalisvar , Rei Chng Kern , Sikic Mile , Nagarajan Niranjan
Published: October 2018

The analysis of information rich whole-metagenome datasets acquired from complex microbial communities is often restricted by the fragmented nature of assembly from short-read sequencing. The availability of long-reads from third-generation sequencing technologies (e.g. PacBio or Oxford Nanopore) can help improve assembly quality in principle, but high error rates and low throughput have limited their application in metagenomics. In this work, we describe the first hybrid metagenomic assembler which combines the advantages of short and long-read technologies, providing an order of magnitude improvement in contiguity compared to short read assemblies, and high base-pair level accuracy. The proposed approach (OPERA-MS) integrates a novel assembly-based metagenome clustering technique with an exact scaffolding algorithm that can efficiently assemble repeat rich sequences. Based on evaluations with defined in vitro communities and virtual gut microbiomes, we show that it is possible to assemble near complete genomes from metagenomes with as little as 9× long read coverage, thus enabling high quality assembly of lowly abundant species (<1%). Furthermore, OPERA-MS’s fine-grained clustering is able to deconvolute and assemble multiple genomes of the same species in a single sample, allowing us to study the complex dynamics of the human microbiome at the sub-species level. Applying nanopore sequencing to gut metagenomes of patients undergoing antibiotic treatment, we show that long reads can be obtained from stool samples in clinical studies to produce more meaningful metagenomic assemblies (up to 200× improvement over short-read assemblies), including the closed assembly of >80 putative plasmid/phage sequences and a 263kbp jumbo phage. Our results highlight that high-quality hybrid assemblies provide an unprecedented view of the gut resistome in these patients, including strain dynamics and identification of novel plasmid sequences.
Autistic traits, resting-state connectivity and absolute pitch in professional musicians: shared and distinct neural features
Authors: Wenhart T. , Bethlehem R.A.I. , Baron-Cohen S. , Altenmüller E.
Published: October 2018

Background

Recent studies indicate increased autistic traits in musicians with absolute pitch and a higher incidence of absolute pitch in people with autism. Theoretical accounts connect both of these with shared neural principles of local hyper- and global hypoconnectivity, enhanced perceptual functioning and a detail-focused cognitive style. This is the first study to investigate absolute pitch proficiency, autistic traits and brain correlates in the same study.

Sample and Methods

Graph theoretical analysis was conducted on resting state (eyes closed and eyes open) EEG connectivity (wPLI, weighted Phase Lag Index) matrices obtained from 31 absolute pitch (AP) and 33 relative pitch (RP) professional musicians. Small Worldness, Global Clustering Coefficient and Average Path length were related to autistic traits, passive (tone identification) and active (pitch adjustment) absolute pitch proficiency and onset of musical training using Welch-two-sample-tests, correlations and general linear models.

Results

Analyses revealed increased Path length (delta 2-4 Hz), reduced Clustering (beta 13-18 Hz), reduced Small-Worldness (gamma 30-60 Hz) and increased autistic traits for AP compared to RP. Only Clustering values (beta 13-18 Hz) were predicted by both AP proficiency and autistic traits. Post-hoc single connection permutation tests among raw wPLI matrices in the beta band (13-18 Hz) revealed widely reduced interhemispheric connectivity between bilateral auditory related electrode positions along with higher connectivity between F7-F8 and F8-P9 for AP. Pitch naming ability and Pitch adjustment ability were predicted by Path length, Clustering, autistic traits and onset of musical training (for pitch adjustment) explaining 44% respectively 38% of variance.

Conclusions

Results show both shared and distinct neural features between AP and autistic traits. Differences in the beta range were associated with higher autistic traits in the same population. In general, AP musicians exhibit a widely underconnected brain with reduced functional integration and reduced small-world-property during resting state. This might be partly related to autism-specific brain connectivity, while differences in Path length and Small-Worldness reflect other ability-specific influences. This is further evidence for different pathways in the acquisition and development of absolute pitch, likely influenced by both genetic and environmental factors and their interaction.
Adjusting for Variable Brain Coverage in Voxel-Based fMRI Meta-Analysis
Authors: Cutler Jo , Radua Joaquim , Campbell-Meiklejohn Daniel
Published: October 2018

Meta-analyses of fMRI studies are vital to establish consistent findings across the literature. However, fMRI data are susceptible to signal dropout (i.e. incomplete brain coverage), which varies across studies and brain regions. In other words, for some brain regions, only a variable subset of the studies included in an fMRI meta-analysis have data present. These missing data can mean activations in fMRI meta-analysis are underestimated (type II errors). Here we present SPM (MATLAB) code to run a novel method of adjusting random-effects models for meta-analytic averaging of a group of studies and mixed-effects models for comparison between two groups of studies. In two separate datasets, meta-analytic effect sizes and z-scores were larger in the adjusted, compared to the unadjusted analysis. Relevantly, these changes were in regions such as the ventromedial prefrontal cortex where coverage was lowest. Limitations of the method, including issues of how to threshold the adjusted maps are discussed. Code and demonstration data for the adjusted method are available at https://doi.org/10.25377/sussex.c.4223411.
On the inference speed and video-compression robustness of DeepLabCut
Authors: Mathis Alexander , Warren Richard
Published: October 2018

Pose estimation is crucial for many applications in neuroscience, biomechanics, genetics and beyond. We recently presented a highly efficient method for markerless pose estimation based on transfer learning with deep neural networks called DeepLabCut. Current experiments produce vast amounts of video data, which pose challenges for both storage and analysis. Here we improve the inference speed of DeepLabCut by up to tenfold and benchmark these updates on various CPUs and GPUs. In particular, depending on the frame size, poses can be inferred offline at up to 1200 frames per second (FPS). For instance, 278 × 278 images can be processed at 225 FPS on a GTX 1080 Ti graphics card. Furthermore, we show that DeepLabCut is highly robust to standard video compression (ffmpeg). Compression rates of greater than 1,000 only decrease accuracy by about half a pixel (for 640 × 480 frame size). DeepLabCut’s speed and robustness to compression can save both time and hardware expenses.
Eliminating effects of particle adsorption to the air/water interface in single-particle cryo-electron microscopy: Bacterial RNA polymerase and CHAPSO
Authors: Chen James , Noble Alex J. , Kang Jin Young , Darst Seth A.
Published: October 2018

Preferred particle orientation presents a major challenge for many single particle cryoelectron microscopy (cryo-EM) samples. Orientation bias limits the angular information used to generate three-dimensional maps and thus affects the reliability and interpretability of the structural models. The primary cause of preferred orientation is presumed to be due to adsorption of the particles at the air/water interface during cryo-EM grid preparation. To ameliorate this problem, detergents are often added to cryo-EM samples to alter the properties of the air/water interface. We have found that many bacterial transcription complexes suffer severe orientation bias when examined by cryo-EM. The addition of non-ionic detergents, such as NP-40, does not remove the orientation bias but the Zwitter-ionic detergent CHAPSO significantly broadens the particle orientation distributions, yielding isotropically uniform maps. We used cryoelectron tomography to examine the particle distribution within the ice layer of cryo-EM grid preparations of Escherichia coli 6S RNA/RNA polymerase holoenzyme particles. In the absence of CHAPSO, essentially all of the particles are located at the ice surfaces. CHAPSO at the critical micelle concentration eliminates particle absorption at the air/water interface and allows particles to randomly orient in the vitreous ice layer. We find that CHAPSO eliminates orientation bias for a wide range of bacterial transcription complexes containing E. coli or Mycobacterium tuberculosis RNA polymerases. Findings of this study confirm the presumed basis for how detergents can help remove orientation bias in cryo-EM samples and establishes CHAPSO as a useful tool to facilitate cryo-EM studies of baterial transcription complexes.
Bifunctional Substrate Activation via an Arginine Residue Drives Catalysis in Chalcone Isomerases
Authors: Burke Jason R. , La Clair James J. , Philippe Ryan N. , Pabis Anna , Jez Joseph M. , Cortina George A. , Kaltenbach Miriam , Bowman Marianne E. , Louie Gordon V. , Woods Katherine B. , Nelson Andrew T. , Tawfik Dan S. , Kamerlin Shina C.L. , Noel Joseph P.
Published: October 2018

Chalcone isomerases are plant enzymes that perform enantioselective oxa-Michael cyclizations of 2′-hydroxy-chalcones into flavanones. An X-ray crystal structure of an enzyme-product complex and molecular dynamics simulations reveal an enzyme mechanism wherein the guanidinium ion of a conserved arginine positions the nucleophilic phenoxide and activates the electrophilic enone for cyclization through Brønsted and Lewis acid interactions. The reaction terminates by asymmetric protonation of the carbanion intermediate syn to the guanidinium. Interestingly, bifunctional guanidine- and urea-based chemical reagents, increasingly used for asymmetric organocatalytic applications, are synthetic counterparts to this natural system. Comparative protein crystal structures and molecular dynamics simulations further demonstrate how two active site water molecules coordinate a hydrogen bond network that enables expanded substrate reactivity for 6′-deox-ychalcones in more recently evolved type-2 chalcone isomerases.
Genetic Consequences of Social Stratification in Great Britain
Authors: Abdellaoui Abdel , Hugh-Jones David , Kemper Kathryn E. , Holtz Yan , Nivard Michel G. , Veul Laura , Yengo Loic , Zietsch Brendan P. , Frayling Timothy M. , Wray Naomi , Yang Jian , Verweij Karin J.H. , Visscher Peter M.
Published: October 2018

Human DNA varies across geographic regions, with most variation observed so far reflecting distant ancestry differences. Here, we investigate the geographic clustering of genetic variants that influence complex traits and disease risk in a sample of ~450,000 individuals from Great Britain. Out of 30 traits analyzed, 16 show significant geographic clustering at the genetic level after controlling for ancestry, likely reflecting recent migration driven by socio-economic status (SES). Alleles associated with educational attainment (EA) show most clustering, with EA-decreasing alleles clustering in lower SES areas such as coal mining areas. Individuals that leave coal mining areas carry more EA-increasing alleles on average than the rest of Great Britain. In addition, we leveraged the geographic clustering of complex trait variation to further disentangle regional differences in socio-economic and cultural outcomes through genome-wide association studies on publicly available regional measures, namely coal mining, religiousness, 1970/2015 general election outcomes, and Brexit referendum results.
Elucidation of the mechanism of interaction between Klebsiella pneumoniae pullulanase and cyclodextrin
Authors: Saka Naoki , Iwamoto Hiroyuki , Malle Dominggus , Takahashi Nobuyuki , Mizutani Kimihiko , Mikami Bunzo
Published: October 2018

Crystal structures of Klebsiella pneumoniae pullulanase (KPP) in complex with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD) were refined at around 1.98–2.59 Å resolution from data collected at SPring-8. In the structures of the complexes obtained with 1 mM α-CD or γ-CD, one molecule of CD was found at carbohydrate-binding module 41 only (CBM41). In the structures of the complexes obtained with 1 mM β-CD or with 10 mM α-CD or γ-CD, two molecules of CD were found at CBM41 and in the active-site cleft, where the hydrophobic residue of Phe746 occupies the inside cavity of the CD rings. In contrast to α-CD and γ-CD, one β-CD molecule was found at the active site only in the presence of 0.1 mM β-CD. These results were coincident with the solution experiments, which showed that β-CD inhibits this enzyme more than a thousand times more potently than α-CD and γ-CD. The strong inhibition of β-CD is caused by the optimized interaction between β-CD and the side chain of Phe746. The increased K
i values of the F746A mutant for β-CD supported the importance of Phe746 in the strong interaction of pullulanase with β-CD.