bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving the catalytic efficiency of thermostable Geobacillus stearothermophilus xylanase XT6 by single-amino acid substitution
Authors: Azouz Rasha A M , Hegazy Usama M , Said Mahmoud M , Bassuiny Roqaya I , Salem Ahmed M , Fahmy Afaf S
Published: October 2019

Directed evolution using error-prone polymerase chain reaction was employed in the current study to enhance the catalytic efficiency of a thermostable Geobacillus stearothermophilus xylanase XT6 parent. High-throughput screening identified two variants with enhanced activity. Sequencing analysis revealed the presence of a single-amino acid substitution (P209L or V161L) in each variant. The maximum activity of mutant V161L and P209L was at 85°C and 70°C, respectively. Both mutants exhibited maximum activity at pH 7. The thermal and alkaline tolerance of mutant V161L only were markedly improved. The two mutants were more resistant to ethanol inhibition than the parent. Substrate specificity of the two mutants was shifted from beechwood xylan to birchwood xylan. The potential of the two mutants to hydrolyze rice straw and sugarcane bagasse increased. Both turnover number (kcat) and catalytic efficiency (kcat/kM) increased 12.2- and 5.7-folds for variant P209L and 13- and 6.5-folds for variant V161L, respectively, towards birchwood xylan. Based on the previously published crystal structure of extracellular G. stearothermophilus xylanase XT6, V161L and P209L mutation locate on βα-loops. Conformational changes of the respective loops could potentiate the loop swinging, product release and consequently result in enhancement of the catalytic performance.
Non-removal strategy for outliers in predictive models: The PAELLA algorithm case
Authors: Castejón-limas Manuel , Alaiz-Moreton Hector , Fernández-Robles Laura , Alfonso-Cendón Javier , Fernández-Llamas Camino , Sánchez-González lidia , Pérez Hilde
Published: October 2019

This paper reports the experience of using the PAELLA algorithm as a helper tool in robust regression instead of as originally intended for outlier identification and removal. This novel usage of the algorithm takes advantage of the occurrence vector calculated by the algorithm in order to strengthen the effect of the more reliable samples and lessen the impact of those that otherwise would be considered outliers. Following that aim, a series of experiments is conducted in order to learn how to better use the information contained in the occurrence vector. Using a contrively difficult artificial data set, a reference predictive model is fit using the whole raw dataset. The second experiment reports the results of fitting a similar predictive model but discarding the samples marked as outliers by PAELLA. The third experiment uses the occurrence vector provided by PAELLA in order to classify the observations in multiple bins and fit every possible model changing which bins are considered for fitting and which are discarded in that particular model. The fourth experiment introduces a sampling process before fitting in which the occurrence vector represents the likelihood of being considered in the training data set. The fifth experiment considers the sampling process as an internal step to be performed interleaved between the training epochs. The last experiment compares our approach using weighted neural networks to a state of the art method.
Patent retrieval architecture based on document retrieval. Sketching out the Spanish patent landscape
Authors: Gil-GonzÁlez Ana B , VÁzquez-Ingelmo Andrea , de la Prieta Fernando , de Luis-Reboredo Ana , GonzÁlez-Briones Alfonso
Published: October 2019

A patent is a property granted to any new shape, configuration or arrangement of elements, of any device, tool, instrument, mechanism or other object or part thereof, that allows for a better or different operation, use or manufacture of the object that incorporates it or that provides it with some utility, advantage or technical effect that it did not have before. As a document, a patent really is a title that recognizes the right to exploit the patented invention exclusively, preventing others from making, selling or using it without the consent of the owner. The fact of making a patent is motivated by the fact of promoting creativity, hindering competition in the market as only one person holds the patent, thus protecting the initial investment and fighting against plagiarism. Patents are available to the public for dissemination and general knowledge. It is generally recognized in the specialized literature that patents can be used as an indicator to calculate the results generated by research and development activities, being a very useful indicator to measure various social, economic or technological aspects. For this reason, it is of relevant interest to have tools or systems that allow us to obtain the patents developed in a specific period of time and to carry out analyses of various economic and social factors. These analyses can serve to obtain a social perspective of society’s progress in the technological field, and this is why an analysis of patents is of our interest. This paper proposes a platform specifically designed to obtain knowledge about patents as an indicator of Spanish social, economic or technological aspects. For this purpose, the platform retrieves, analyses and visualizes functionalities that represent data on the landscape of patents obtained from the Spanish Patent and Trademark Office (OEPM) as a particular case of study.
Using the Spanish national identity card in social networks
Authors: Gayoso MartÍnez V , HernÁndez Encinas L , MartÍn MuÑoz A , DurÁn DÍaz R
Published: October 2019

The distinctive security features of the Spanish electronic national identity card, known as Documento Nacional de Identidad electrónico, allow us to propose the usage of this cryptographic smart card in an authentication framework that can be used during the registration and login phases of internet services where the validation of the user’s age and real identity are key elements, as it is the case for example of the so-called social networks. Using this mechanism with NFC-capable devices, the identity and age of the potential user can be determined, allowing or denying the access to the service based on that information.
MOBSTER – III. HD 62658: a magnetic Bp star in an eclipsing binary with a non-magnetic ‘identical twin’
Authors: Shultz M E , Johnston C , Labadie-Bartz J , Petit V , David-Uraz A , Kochukhov O , Wade G A , Pepper J , Stassun K G , Rodriguez J E , Lund M B , James D J
Published: October 2019

HD 62658 (B9p V) is a little-studied chemically peculiar star. Light curves obtained by the Kilodegree Extremely Little Telescope (KELT) and Transiting Exoplanet Survey Satellite (TESS) show clear eclipses with a period of about 4.75 d, as well as out-of-eclipse brightness modulation with the same 4.75 d period, consistent with synchronized rotational modulation of surface chemical spots. High-resolution ESPaDOnS circular spectropolarimetry shows a clear Zeeman signature in the line profile of the primary; there is no indication of a magnetic field in the secondary. PHOEBE modelling of the light curve and radial velocities indicates that the two components have almost identical masses of about 3 M⊙. The primary’s longitudinal magnetic field 〈Bz〉 varies between about +100 and −250 G, suggesting a surface magnetic dipole strength Bd = 850 G. Bayesian analysis of the Stokes V profiles indicates Bd = 650 G for the primary and Bd < 110 G for the secondary. The primary’s line profiles are highly variable, consistent with the hypothesis that the out-of-eclipse brightness modulation is a consequence of rotational modulation of that star’s chemical spots. We also detect a residual signal in the light curve after removal of the orbital and rotational modulations, which might be pulsational in origin; this could be consistent with the weak line profile variability of the secondary. This system represents an excellent opportunity to examine the consequences of magnetic fields for stellar structure via comparison of two stars that are essentially identical with the exception that one is magnetic. The existence of such a system furthermore suggests that purely environmental explanations for the origin of fossil magnetic fields are incomplete.
The Pristine Inner Galaxy Survey (PIGS) I: tracing the kinematics of metal-poor stars in the Galactic bulge
Authors: Arentsen A , Starkenburg E , Martin N F , Hill V , Ibata R , Kunder A , Schultheis M , Venn K A , Zucker D B , Aguado D , Carlberg R , González Hernández J I , Lardo C , Longeard N , Malhan K , Navarro J F , Sánchez-Janssen R , Sestito F , Thomas G , Youakim K , Lewis G F , Simpson J D , Wan Z
Published: October 2019

Our Galaxy is known to contain a central boxy/peanut-shaped bulge, yet the importance of a classical, pressure-supported component within the central part of the Milky Way is still being debated. It should be most visible at low metallicity, a regime that has not yet been studied in detail. Using metallicity-sensitive narrow-band photometry, the Pristine Inner Galaxy Survey (PIGS) has collected a large sample of metal-poor ($\rm {[Fe/H]}\, \lt -1.0$) stars in the inner Galaxy to address this open question. We use PIGS to trace the metal-poor inner Galaxy kinematics as function of metallicity for the first time. We find that the rotational signal decreases with decreasing [Fe/H] , until it becomes negligible for the most metal-poor stars. Additionally, the velocity dispersion increases with decreasing metallicity for $-3.0 \lt \rm {[Fe/H]}\, \lt -0.5$, with a gradient of −44 ± 4 km s−1 dex−1. These observations may signal a transition between Galactic components of different metallicities and kinematics, a different mapping on to the boxy/peanut-shaped bulge for former disc stars of different metallicities and/or the secular dynamical and gravitational influence of the bar on the pressure-supported component. Our results provide strong constraints on models that attempt to explain the properties of the inner Galaxy.
Semi-automated medulloblastoma segmentation and influence of molecular subgroup on segmentation quality
Authors: Dury Richard , Dineen Rob , Lourdusamy Anbarasu , Grundy Richard
Published: October 2019

Medulloblastoma is the most common malignant brain tumour in children. Segmenting the tumour itself from the surrounding tissue on MRI scans has shown to be useful for neuro-surgical planning, by allowing a better understanding of the tumour margin with 3D visualisation. However, manual segmentation of medulloblastoma is time consuming, prone to bias and inter-observer discrepancies. Here we propose a semi-automatic patient based segmentation pipeline with little sensitivity to tumour location and minimal user input.

Using SPM12 “Segment” as a base, an additional tissue component describing the medulloblastoma is included in the algorithm. The user is required to define the centre of mass and a single surface point of the tumour, creating an approximate enclosing sphere. The calculated volume is confined to the cerebellum to minimise misclassification of other intracranial structures. This process typically takes 5 minutes from start to finish.

This method was applied to 97 T2-weighted scans of paediatric medulloblastoma (7 WNT, 6 SHH, 17 Gr3, 26 Gr4, 41 unknown subtype); resulting segmented volumes were compared to manual segmentations. An average Dice coefficient of 0.85±0.07 was found, with the Group 4 subtype demonstrating a significantly higher similarity with manual segmentation than other subgroups (0.88±0.04).

When visually assessing the 10 cases with the lowest Dice coefficients, it was found that the misclassification of oedema was the most common source of error. As this method is independent of image contrast, segmentation could be improved by applying it to images that are less sensitive to oedema, such as T1.
Supratentorial and Infratentorial Ependymomas in Adult Population - A 10-year single institution case series
Authors: Acharya Shami , Ishak Athanasius , Sekhon Priya , Pedro Lavrador Jose , Malik Asfand , Tan Ronald , Gullan Richard , Vergani Francesco , Bhangoo Ranj , Ashkan Keymours
Published: October 2019

Objectives

Analyse clinical characteristics and treatment provided to an adult population diagnosed with intracranial ependymomas between 2009–2018.

Methods

Single centre retrospective cohort study. Variables reviewed: demographics, extent of resection, adjuvant oncological treatment and molecular genetics.

Results

17 patients were included (6 females, 11 males). Average age at presentation was 51.3 yrs (range 19-74yrs). 4 supratentorial (2 intraventricular, 1 temporal lobe and 1 frontal lobe) and 13 infratentorial lesions were identified.

In the supratentorial subgroup the following treatment was performed: GTR (1 patient), STR (1 patient) and Biopsy (2 patients); 2 patients underwent post-operative radiotherapy. 3 patients had a WHO grade 2 tumour (1 patient - insufficient tissue for grading). 3 recurrences were identified and 2 patients had re-debulking. 2 patients had postoperative hemiparesis, 1 patient died during treatment and 3 are currently being followed up.

In the infratentorial subgroup the following treatment was performed: GTR (5 patients), STR (7 patients) and biopsy (1 patient). 3 patients underwent post-operative radiotherapy. 1 patient was WHO grade 1, 11 patients were WHO grade 2 and 1 patient was WHO grade 3. 2 patients had tumour recurrences of which 1 was re-operated. 7 patients develop new post-operative deficits after surgery; 1 patient died and the rest are currently being followed up.

Conclusion

Even though this case series supports the good prognosis in terms of overall survival in adults with intracranial ependymomas, they represent a challenge to manage given the morbidity of optimal surgical resection and their poor response to adjuvant treatment.
The Benacerraf Problem as a Challenge for Ontic Structural Realism†
Authors: Beni Majid Davoody
Published: October 2019

Benacerraf has presented two problems for the philosophy of mathematics. These are the problem of identification and the problem of representation. This paper aims to reconstruct the latter problem and to unpack its undermining bearing on the version of Ontic Structural Realism that frames scientific representations in terms of abstract structures. I argue that the dichotomy between mathematical structures and physical ones cannot be used to address the Benacerraf problem but strengthens it. I conclude by arguing that versions of OSR that do not rely on mathematical frameworks for representational purposes need not be vulnerable to Benacerraf’s second problem.
Quantifying intralimb coordination of terrestrial ungulates with Fourier coefficient affine superimposition
Authors: Mielke Falk , Van Ginneken Chris , Aerts Peter
Published: October 2019

Many phenomena related to motor behaviour in animals are spatially and temporally periodic, making them accessible for transformation to the frequency domain via Fourier Series. Although this has been applied previously, it had not been noticed that the characteristic arrangement of Fourier coefficients in their complex-valued representation resembles landmarks in geometric morphometrics. We define a superimposition procedure in the frequency domain, which removes affine differences (mean, amplitude, phase) to reveal and compare the shape of periodic kinematic measures. This procedure is conceptually linked to dynamic similarity, which can thereby be assessed on the level of individual limb elements. We demonstrate how to make intralimb coordination accessible for large-scale, quantitative analyses. By applying this to a dataset from terrestrial ungulates, dominant patterns in forelimb coordination during walking are identified. This analysis shows that typical strides of these animals differ mostly in how much the limbs are lifted in the presence or absence of obstructive substrate features. This is shown to be independent of morphological features. Besides revealing fundamental characteristics of ungulate locomotion, we argue that the suggested method is generally suitable for the large-scale quantitative assessment of coordination and dynamics in periodic locomotor phenomena.
The signaling axis of Rac1-TFEB regulates autophagy and tumorigenesis
Authors: Ma Lijie , Ma Yuehong , Zhang Ziying , Wang Qi , Liu Xudong
Published: October 2019

Macroautophagy (hereafter referred to as autophagy) plays essential roles in cellular and organismal homeostasis. Transcription factor EB (TFEB) is a master regulator of autophagy and lysosome biogenesis. It is not fully understood how the function of TFEB in autophagy pathway is regulated. Here, we show that Rac1 GTPase is a negative modulator of autophagy by targeting TFEB. Mechanistically, Rac1 reduces autophagy flux by repressing the expressing of autophagy genes. Further investigation revealed that under nutrient-rich conditions, mammalian target of rapamycin (mTOR) phosphorylates TFEB to facilitate the interaction between Rac1 and TFEB. Biochemical dissection uncovered that guanosine 5′-triphosphate (GTP)-bound form of Rac1 selectively interacts with phosphorylated TFEB. This inhibitory interaction prevents the dephosphorylation and nucleus translocation of TFEB, which hampers the transcriptional activation of autophagy-related genes. Furthermore, Rac1-TFEB axis appeared to be important for tumorigenesis, as overexpression of dephosphorylated mutant of TFEB was able to delay the tumor growth driven by Rac1 overexpression. Together, this study not only elucidates a previously uncharacterized autophagy regulation mechanism involving Rac1 and TFEB under physiological and pathological conditions but also suggests a strategy to treat cancers that are driven by Rac1 overexpression.
Early and Late Mortality Following Discharge From the ICU: A Multicenter Prospective Cohort Study*
Authors: Rosa Regis G. , Falavigna Maicon , Robinson Caroline C. , Sanchez Evelin C. , Kochhann Renata , Schneider Daniel , Sganzerla Daniel , Dietrich Camila , Barbosa Mirceli G. , de Souza Denise , Rech Gabriela S. , dos Santos Rosa da R. , da Silva Alice P. , Santos Mariana M. , Dal Lago Pedro , Sharshar Tarek , Bozza Fernando A. , Teixeira Cassiano
Published: October 2019

Objectives:

To identify the frequency, causes, and risk factors of early and late mortality among general adult patients discharged from ICUs.

Design:

Multicenter, prospective cohort study.

Setting:

ICUs of 10 tertiary hospitals in Brazil.

Patients:

One-thousand five-hundred fifty-four adult ICU survivors with an ICU stay greater than 72 hours for medical and emergency surgical admissions or greater than 120 hours for elective surgical admissions.

Interventions:

None.

Measurements and Main Results:

The main outcomes were early (30 d) and late (31 to 365 d) mortality. Causes of death were extracted from death certificates and medical records. Twelve-month cumulative mortality was 28.2% (439 deaths). The frequency of early mortality was 7.9% (123 deaths), and the frequency of late mortality was 22.3% (316 deaths). Infections were the leading cause of death in both early (47.2%) and late (36.4%) periods. Multivariable analysis identified age greater than or equal to 65 years (hazard ratio, 1.65; p = 0.01), pre-ICU high comorbidity (hazard ratio, 1.59; p = 0.02), pre-ICU physical dependence (hazard ratio, 2.29; p < 0.001), risk of death at ICU admission (hazard ratio per 1% increase, 1.008; p = 0.03), ICU-acquired infections (hazard ratio, 2.25; p < 0.001), and ICU readmission (hazard ratio, 3.76; p < 0.001) as risk factors for early mortality. Age greater than or equal to 65 years (hazard ratio, 1.30; p = 0.03), pre-ICU high comorbidity (hazard ratio, 2.28; p < 0.001), pre-ICU physical dependence (hazard ratio, 2.00; p < 0.001), risk of death at ICU admission (hazard ratio per 1% increase, 1.010; p < 0.001), and ICU readmission (hazard ratios, 4.10, 4.17, and 1.82 for death between 31 and 60 days, 61 and 90 days, and greater than 90 days after ICU discharge, respectively; p < 0.001 for all comparisons) were associated with late mortality.

Conclusions:

Infections are the main cause of death after ICU discharge. Older age, pre-ICU comorbidities, pre-ICU physical dependence, severity of illness at ICU admission, and ICU readmission are associated with increased risk of early and late mortality, while ICU-acquired infections are associated with increased risk of early mortality.
The Cheek Interpolation Flap for Reconstruction of Auricular Mohs Defects
Authors: Norris Ivy I. , Cook Joel
Published: October 2019

BACKGROUND

Surgical reconstruction of auricular defects after Mohs surgery may prove challenging secondary to the complex topography of the ear and few options for local flap repair that do not introduce inordinate risk of anatomic distortion. The matched preauricular skin may be used to overcome these limitations.

OBJECTIVE

This study aims to examine the utility, technique, and outcomes of preauricular interpolated flaps used for auricular reconstruction. To the authors' knowledge, this study represents the only published series of cheek interpolation flaps for auricular reconstruction.

METHODS

A retrospective review of interpolated cheek flaps used for auricular reconstruction performed by one surgeon (J.C., 2000–2018) after tumor removal by Mohs micrographic surgery (MMS) at a single institution.

RESULTS

Twenty cheek interpolation flaps were identified that were used to reconstruct defects after complete removal of skin cancer on the ear. No major complications were observed.

CONCLUSION

Interpolated flaps are a useful reconstructive technique for auricular defects after MMS. Using the hairless isthmus of the preauricular cheek as the donor site for a 2-stage interpolated flap is a means of repairing the auricle when other options are not ideal.
Therapeutic Drug Monitoring in Pregnant Patients
Authors: Johnson-Davis Kamisha L. , Doyle Kelly
Published: October 2019

During pregnancy, there are several physiological changes during each trimester that can affect the absorption, distribution, metabolism, and elimination of drugs. Although there is a potential need to understand the pharmacokinetics and pharmacodynamics of drugs in pregnant patients, therapeutic drug monitoring is not well established for various drug classes due to ethical and safety concerns regarding the neonate. Potential risks from in utero drug exposure to the fetus may impact growth and development and may cause malformations or teratogenesis. The clinician must consider the benefits of drug treatment for the pregnant mother versus the risk to the fetus, before prescribing medications during pregnancy. The objective of this review is to aid clinicians, pharmacists, and laboratorians in understanding the pharmacokinetic and pharmacodynamic changes during pregnancy, to provide drug class recommendations for monitoring therapy throughout pregnancy via therapeutic drug monitoring, and to highlight the recent directives of governing agencies on maternal and fetal health.
Comparison of Neurologic Event Rates Among HeartMate II, HeartMate 3, and HVAD
Authors: Li Song , Beckman Jennifer A. , Cheng Richard , Ibeh Chinwe , Creutzfeldt Claire J. , Bjelkengren Jason , Herrington Joni , Stempien-Otero April , Lin Shin , Levy Wayne C. , Fishbein Daniel , Koomalsingh Kevin J. , Zimpfer Daniel , Slaughter Mark S. , Aliseda Alberto , Tirschwell David , Mahr Claudius
Published: October 2019

Strokes remain a leading cause of morbidity and mortality in patients with ventricular assist devices (VADs). Varying study populations, event definitions, and reporting methods make direct comparison of neurologic event risk across clinical trials and registries challenging. We aim to highlight important differences among major VAD studies and standardize rates of neurologic events to facilitate a comprehensive and objective comparison. We systematically identified and analyzed key clinical trials and registries evaluating the HeartMate II (HMII), HeartMate 3 (HM3), and HVAD devices. Reported neurologic events were nonexclusively categorized into ischemic stroke, hemorrhagic stroke, disabling stroke, fatal stroke, and other neurologic events per the studies’ definitions. Event rates were standardized to events per patient-year (EPPY) and freedom from event formats. Seven key clinical trials and registries were included in our analysis. There is significant variation and overlap in neurologic event rates for the three VAD platforms across clinical trials (all neurologic events [EPPY]: HM3 0.17–0.21; HMII 0.19–0.26; HVAD 0.16–0.28). None performs consistently better for all types of neurologic events. Furthermore, stroke rates among VAD trials correlated with baseline stroke risk factors including ischemic etiology, history of atrial fibrillation, and history of prior stroke.
Remote Intracranial Hemorrhage Secondary to Brain Tumor Surgery
Authors: Xu Tianqi , Zhang Shilei , Zhang Xiaohua , Guo Liemei
Published: October 2019

Postoperative remote intracranial hemorrhage (rICH) secondary to craniotomy surgery is an extremely rare but catastrophic complication. The present study aimed to investigate the incidence and the possible pathophysiological mechanism of rICH after brain tumor surgery. The clinical data from 9 rICH cases among 4588 patients undergoing brain tumor surgery were collected retrospectively. Remote intracranial hemorrhage occurred in 9 cases, including 6 cases of remote epidural hemorrhage (rEDH), 2 cases of remote subdural hemorrhage (rSDH), and 1 case of remote cerebellar hemorrhage (rCBH). Among the 9 cases, 2 were males and 7 were females, with an age range of 22 to 63 years (mean of 44.3 years). The incidence of rICH in the patients with ventricular system opening/drainage (4/258) was much higher than the patients without ventricular system opening/drainage (5/4330), and the difference was statistically significant (P < 0.01). Hematoma evacuation was performed in 7 patients with serious neurological status or massive hematoma. The outcome for most of the rICH cases was good, and the Glasgow outcome scale scores of 4–5 were found in 8 cases with a 3-month-long follow-up. Our results suggest that brain tumor surgery with ventricular system opening/drainage was more susceptible to rICH. Paying particlular attention to gradual reduction of intracranial pressure and avoiding excessive loss of cerebrospinal fluid may aid to prevent the occurrence of rICH. The authors suggest that a high index of suspicion, a prompt diagnosis, and emergent management is of vital importance to achieve good prognosis for rICH patients secondary to brain tumor surgery.
Orthognathic Surgery Has a Significant Positive Effect on Perceived Personality Traits and Perceived Emotional Facial Expressions in Subjects With Primary Mandibular Deficiency
Authors: Posnick Jeffrey C. , Kinard Brian E.
Published: October 2019

This study tested the hypothesis that a layperson's social perceptions of a dentofacial deformity (DFD) patient with primary mandibular deficiency (PMD) are more positive after bimaxillary orthognathic surgery.

A survey was implemented comparing layperson's social perceptions of emotional expressions and personality traits before and >6 months after orthognathic surgery when viewing standardized facial photographs. The study sample comprised 20 patients selected randomly from a larger primary mandibular deficiency database, treated by 1 surgeon after orthognathic surgery. The outcome variable was change in 6 perceived emotional expressions and 6 personality traits studied. Descriptive and bivariate statistics were computed (P < .05).

Five hundred respondents (raters) completed the survey. The respondents were 52% male with 44% aging from 25 to 34. After bimaxillary and chin orthognathic surgery, primary mandibular deficiency patients were perceived to be significantly more dominant, trustworthy, friendly, intelligent, attractive, and less threatening (P < .05). They were also perceived as happier and less angry, surprised, sad, afraid, or disgusted than before surgery (P < .05).

Laypeople consistently report improved social traits in primary mandibular deficiency patient's perceived emotional expressions and perceived personality traits after bimaxillary and chin orthognathic surgery.
Identification of E6AP-independent degradation targets of HPV E6
Authors: Vats Arushi , Thatte Jayashree , Banks Lawrence
Published: October 2019

The high-risk Human Papillomavirus (HPV) E6 oncoprotein is known to contribute to human malignancy by targeting several of its cellular substrates through the ubiquitin-mediated degradation pathway. Previous studies have revealed that E6 interacts with the E6AP ubiquitin-protein ligase and directs its ubiquitylation activity toward several specific cellular proteins, one of the most important of which is p53. However, the role of E6AP in the degradation of many other E6 substrates is still ambiguous because loss of E6AP also induces a loss of E6 expression. To examine this further, we used CRISPR-edited E6AP knockout cells to perform E6 degradation assays in the presence of a catalytically inactive mutant form of E6AP, thus ensuring the stabilization of E6 but with the ligase itself being functionally inactive. Using this system, we found that E6 can mediate the degradation of several PDZ domain-containing proteins independently of E6AP ubiquitin ligase activity. This study thus opens up ways to investigate other possible components of the cellular ubiquitin proteasome pathway that E6 might utilize to target these substrates.
Cerebral atherosclerosis contributes to Alzheimer’s dementia independently of its hallmark amyloid and tau pathologies
Authors: Wingo Aliza P. , Fan Wen , Duong Duc M. , Gerasimov Ekaterina S. , Dammer Eric B. , White Bartholomew , Thambisetty Madhav , Troncoso Juan C. , Schneider Julie A. , Lah James J. , Bennett David A. , Seyfried Nicholas T. , Levey Allan I. , Wingo Thomas S.
Published: October 2019

Cerebral atherosclerosis is a leading cause of stroke and an important contributor to dementia. However, little is known about its molecular effects on the human brain and how these alterations may contribute to dementia. Here, we investigated these questions using large-scale quantification of over 8300 proteins from 438 post-mortem brains from a discovery and replication cohort. A proteome-wide association study and protein network analysis of cerebral atherosclerosis found 114 proteins and 5 protein co-expression modules associated with cerebral atherosclerosis. Enrichment analysis of these proteins and modules revealed that cerebral atherosclerosis was associated with reductions in synaptic signaling and RNA splicing and increases in oligodendrocyte development and myelination. A subset of these proteins (n=23) and protein modules (n=2) were also associated with Alzheimer’s disease (AD) dementia, implicating a shared mechanism with AD through decreased synaptic signaling and regulation and increased myelination. Notably, neurofilament light (NEFL) and medium (NEFM) chain proteins were among these 23 proteins, and our data suggest they contribute to AD dementia through cerebral atherosclerosis. Together, our findings offer insights into effects of cerebral atherosclerosis on the human brain proteome, and how cerebral atherosclerosis contributes to dementia risk.
Identifying relationships between imaging phenotypes and lung cancer-related mutation status: EGFR and KRAS
Authors: Pinheiro Gil , Pereira Tania , Dias Catarina , Freitas Cláudia , Hespanhol Venceslau , Costa José Luis , Cunha António , Oliveira Hélder P.
Published: October 2019

EGFR and KRAS are the most frequently mutated genes in lung cancer, being active research topics in targeted therapy. Biopsy is the traditional method to genetically characterise a tumour. However, it is a risky procedure, painful for the patient, and, occasionally, the tumour might be inaccessible. This work aims to study and debate the nature of the relationships between imaging phenotypes and lung cancer-related mutation status. Until now, the literature has failed to point to new research directions, mainly consisting of results-oriented works in a field where there is still not enough available data to train clinically viable models. We intend to open a discussion about critical points and to present new possibilities for future radiogenomics studies. We conducted high-dimensional data visualisation and developed classifiers, which allowed us to analyse the results for EGFR and KRAS biological markers according to different combinations of input features. We show that EGFR mutation status might be correlated to CT scans imaging phenotypes, however, the same does not seem to hold true for KRAS mutation status. Also, the experiments suggest that the best way to approach this problem is by combining nodule-related features with features from other lung structures.
Chromosomal assembly and analyses of genome-wide recombination rates in the forest pathogenic fungusArmillaria ostoyae
Authors: Heinzelmann Renate , Rigling Daniel , Sipos György , Münsterkötter Martin , Croll Daniel
Published: October 2019

Recombination shapes the evolutionary trajectory of populations and plays an important role in the faithful transmission of chromosomes during meiosis. Levels of sexual reproduction and recombination are important properties of host-pathogen interactions because the speed of antagonistic co-evolution depends on the ability of hosts and pathogens to generate genetic variation. However, our understanding of the importance of recombination is limited because large taxonomic groups remain poorly investigated. Here, we analyze recombination rate variation in the basidiomycete fungusArmillaria ostoyae, which is an aggressive pathogen on a broad range of conifers and other trees. We constructed a dense genetic map using 198 single basidiospore progeny from a cross. Progeny were genotyped at a genome-wide set of single nucleotide polymorphism (SNP) markers using double digest restriction site associated DNA sequencing (ddRADseq). Based on a linkage map of on 11,700 SNPs spanning 1007.5 cM, we assembled genomic scaffolds into 11 putative chromosomes of a total genome size of 56.6 Mb. We identified 1984 crossover events among all progeny and found that recombination rates were highly variable along chromosomes. Recombination hotspots tended to be in regions close to the telomeres and were more gene-poor than the genomic background. Genes in proximity to recombination hotspots were encoding on average shorter proteins and were enriched for pectin degrading enzymes. Our analyses enable more powerful population and genome-scale studies of a major tree pathogen.
Nanoparticle delivery of microRNA-146a regulates mechanotransduction in lung macrophages and mitigates lung injury during mechanical ventilation
Authors: Bobba Christopher , Fei Qinqin , Shukla Vasudha , Lee Hyunwook , Patel Pragi , Putman Rachel K , Spitzer Carleen , Tsai MuChun , Wewers Mark D. , Christman John W. , Ballinger Megan N. , Ghadiali Samir , Englert Joshua A.
Published: October 2019

During mechanical ventilation, injurious biophysical forces exacerbate lung injury. These forces disrupt alveolar capillary barrier integrity, trigger proinflammatory mediator release, and differentially regulate genes and non-coding oligonucleotides such as microRNAs. In this study, we identify miR-146a as a mechanosensitive microRNA in alveolar macrophages that has therapeutic potential to mitigate lung injury during mechanical ventilation. We used humanized in-vitro systems, mouse models, and biospecimens from mechanically ventilated patients to elucidate the expression dynamics of miR-146a that might be required to decrease lung injury during mechanical ventilation. We found that the endogenous increase in miR-146a following injurious was relatively modest and not sufficient to prevent lung injury. However, when miR-146a was highly overexpressed using a nanoparticle-based delivery platform in vivo, it was sufficient to prevent lung injury. These data indicate that the endogenous increase in microRNA-146a during MV is a compensatory response that only partially limits VILI and that nanoparticle delivery approaches that significantly over-express microRNA-146a in AMs is an effective strategy for mitigating VILI.
The Intrinsically Disordered Region of ExbD is Required for Signal Transduction
Authors: Kopp Dale R. , Postle Kathleen
Published: October 2019

The TonB system actively transports vital nutrients across the unenergized outer membranes of the majority of Gram-negative bacteria. In this system, integral membrane proteins ExbB, ExbD, and TonB work together to transduce the protonmotive force (PMF) of the inner membrane to customized active transporters in the outer membrane by direct and cyclic binding of TonB to the transporters. A PMF-dependent TonB-ExbD interaction is prevented by 10-residue deletions within a periplasmic disordered domain of ExbD adjacent to the cytoplasmic membrane. Here we explored the function of the ExbD disordered domain in more detail.In vivophoto-cross-linking through sequential pBpa substitutions in the ExbD disordered domain captured five different ExbD complexes, some of which had been previously detected using in vivo formaldehyde crosslinking, a technique that lacks the residue-specific information that can be achieved through photo-cross-linking: 2 ExbB-ExbD heterodimers (one of which had not been detected previously), previously detected ExbD homodimers, previously detected PMF-dependent ExbD-TonB heterodimers, and for the first time, a predicted, ExbD-TonB PMF-independent interaction. The fact that multiple complexes were captured by the same pBpa substitution indicated the dynamic nature of ExbD interactions as the energy transduction cycle proceeded in vivo. In this study, we also discovered that a conserved motif, (V45, V47, L49, P50), within the disordered domain was required for signal transduction to TonB and to the C-terminal domain of ExbD and was the source of its essentiality.

Importance

The TonB system is a virulence factor for many Gram-negative pathogens including E-S-K-A-P-E pathogenic speciesKlebsiella pneumoniae,Acinetobacter baumannii,and Pseudomonas aeruginosa. Because the majority of protein-protein interactions in the TonB system occur in the periplasm, it is an appealing target for novel antibiotics. Understanding the molecular mechanism of the TonB system will provide valuable information for design of potential inhibitors targeting the system.
Membrane constriction and thinning by sequential ESCRT-III polymerization
Authors: Nguyen Henry C. , Talledge Nathaniel , McCullough John , Sharma Abhimanyu , Moss Frank R. , Iwasa Janet H. , Vershinin Michael D. , Sundquist Wesley I. , Frost Adam
Published: October 2019

The Endosomal Sorting Complexes Required for Transport (ESCRTs) mediate diverse membrane remodeling events. These activities typically require ESCRT-III proteins to stabilize negatively-curved membranes, although recent work has indicated that certain ESCRT-IIIs also participate in positive-curvature membrane shaping reactions. ESCRT-IIIs polymerize into membrane-binding filaments, but the structural basis for negative versus positive membrane curvature shaping by these proteins remains poorly understood. To learn how ESCRT-IIIs shape membranes, we determined structures of human membrane-bound CHMP1B-only, membrane-bound CHMP1B+IST1, and IST1-only filaments by electron cryomicroscopy. Our structures show how CHMP1B first polymerizes into a single-stranded helical filament, shaping membranes into moderate-curvature tubules. Subsequently, IST1 assembles a second strand upon the CHMP1B filament, further constricting the membrane tube and reducing its diameter nearly to the fission point. Each step of constriction, moreover, thins the underlying bilayer and lowers the barrier to membrane fission. Together, our structures reveal how a two-component, sequential polymerization mechanism drives membrane tubulation, tube constriction, and bilayer thinning.
On the correspondence of electrical and optical physiology in in vivo population-scale two-photon calcium imaging
Authors: Ledochowitsch Peter , Huang Lawrence , Knoblich Ulf , Oliver Michael , Lecoq Jerome , Reid Clay , Li Lu , Zeng Hongkui , Koch Christof , Waters Jack , de Vries Saskia E.J. , Buice Michael A.
Published: October 2019

Multiphoton calcium imaging is commonly used to monitor the spiking of large populations of neurons. Recovering action potentials from fluorescence necessitates calibration experiments, often with simultaneous imaging and cell-attached recording. Here we performed calibration for imaging conditions matching those of the Allen Brain Observatory. We developed a novel crowd-sourced, algorithmic approach to quality control. Our final data set was 50 recordings from 35 neurons in 3 mouse lines. Our calibration indicated that 3 or more spikes were required to produce consistent changes in fluorescence. Moreover, neither a simple linear model nor a more complex biophysical model accurately predicted fluorescence for small numbers of spikes (1-3). We observed increases in fluorescence corresponding to prolonged depolarizations, particularly in Emx1-IRES-Cre mouse line crosses. Our results indicate that deriving spike times from fluorescence measurements may be an intractable problem in some mouse lines.
scCancer: a package for automated processing of single cell RNA-seq data in cancer
Authors: Guo Wenbo , Wang Dongfang , Wang Shicheng , Shan Yiran , Gu Jin
Published: October 2019

Molecular heterogeneities bring great challenges for cancer diagnosis and treatment. Recent advance in single cell RNA-sequencing (scRNA-seq) technology make it possible to study cancer transcriptomic heterogeneities at single cell level. Here, we develop an R package named scCancer which focuses on processing and analyzing scRNA-seq data for cancer research. Except basic data processing steps, this package takes several special considerations for cancer-specific features. Firstly, the package introduced comprehensive quality control metrics. Secondly, it used a data-driven machine learning algorithm to accurately identify major cancer microenvironment cell populations. Thirdly, it estimated a malignancy score to classify malignant (cancerous) and non-malignant cells. Then, it analyzed intra-tumor heterogeneities by key cellular phenotypes (such as cell cycle and stemness) and gene signatures. Finally, a user-friendly graphic report was generated for all the analyses.

Availability

http://lifeome.net/software/sccancer/.

Contact

jgu@tsinghua.edu.cn
Zero-shot imputations across species are enabled through joint modeling of human and mouse epigenomics
Authors: Schreiber Jacob , Hegde Deepthi , Noble William
Published: October 2019

Recent large-scale efforts to characterize functional activity in human have produced thousands of genome-wide experiments that quantify various forms of biochemistry, such as histone modifications, protein binding, transcription, and chromatin accessibility. Although these experiments represent a small fraction of the possible experiments that could be performed, they also make human more comprehensively characterized than any other species. We propose an extension to the imputation approach Avocado that enables the model to leverage genome alignments and the large number of human genomics data sets when making imputations in other species. We found that not only does this extension result in improved imputation of mouse functional experiments, but that the extended model is able to make accurate imputations for protein binding assays that have been performed in human but not in mouse. This ability to make “zero-shot” imputations greatly increases the utility of such imputation approaches and enables comprehensive imputations to be made for species even when experimental data are sparse.

CCS CONCEPTS

• Computing methodologies → Neural networks; Factorization methods; • Applied computing → Bioinformatics; Genomics.

ACM Reference Format

Jacob Schreiber, Deepthi Hegde, and William Noble. 2020. Zero-shot imputations across species are enabled through joint modeling of human and mouse epigenomics. In ACM-BCB 2020: 11th ACM Conference on Bioinformatics, Computational Biology, and Health Informatics, Sept 21–24, 2020, Virtual. ACM, New York, NY, USA, 9 pages. https://doi.org/10.1145/1122445.1122456
miqoGraph: Fitting admixture graphs using mixed-integer quadratic optimization
Authors: Yan Julia , Patterson Nick , Narasimhan Vagheesh
Published: October 2019

Admixture graphs represent the genetic relationship between a set of populations through splits, drift and admixture. In this paper we present the Julia package miqoGraph, which uses mixed-integer quadratic optimization to fit topology, drift lengths, and admixture proportions simultaneously. Inference of topology is particularly powerful, with integer optimization automating what is usually an arduous manual process.

Availability

https://github.com/juliayyan/PhylogeneticTrees.jl

Contact

jyyan@mit.edu
Shifting spaces: which disparity or dissimilarity metrics best summarise occupancy in multidimensional spaces?
Authors: Guillerme Thomas , Puttick Mark N. , Marcy Ariel E. , Weisbecker Vera
Published: October 2019

Multidimensional analysis of traits are now a common toolkit in ecology and evolution and are based on trait-spaces in which each dimension summarise the observed trait combination (a morphospace or an ecospace). Observations of interest will typically occupy a subset of this trait-space, and researchers will apply one or more metrics to quantify the way in which organisms “inhabit” that trait-space. In macroevolution and ecology these metrics are referred to as disparity or dissimilarity metrics and can be generalised as space occupancy metrics. Researchers use these metrics to investigate how space occupancy changes through time, in relation to other groups of organisms, and in response to global environmental changes, such as global warming events or mass extinctions. However, the mathematical and biological meaning of most space occupancy metrics is vague with the majority of widely-used metrics lacking formal description.

Here we propose a broad classification of space occupancy metrics into three categories that capture changes in volume, density, or position. We analyse the behaviour of 25 metrics to study changes in trait-space volume, density and position on a series of simulated and empirical datasets.

We find no one metric describes all of trait-space but that some metrics are better at capturing certain aspects compared to other approaches and that their performance depends on both the trait-space and the hypothesis analysed. However, our results confirm the three broad categories (volume, density and position) and allow to relate changes in any of these categories to biological phenomena.

Since the choice of space occupancy metric should be specific to the data and question at had, we introduced moms, a user-friendly tool based on a graphical interface that allows users to both visualise and measure changes space occupancy for any metric in simulated or imported trait-spaces. Users are also provided with tools to transform their data in space (e.g. contraction, displacement, etc.). This tool is designed to help researchers choose the right space occupancy metrics, given the properties of their trait-space and their biological question.
Sequoia: An interactive visual analytics platform for interpretation and feature extraction from nanopore sequencing datasets
Authors: Koonchanok Ratanond , Daulatabad Swapna Vidhur , Mir Quoseena , Reda Khairi , Janga Sarath Chandra
Published: October 2019

Sequoia is a visualization tool that allows biologists to explore characteristics of signals generated by the Oxford Nanopore Technologies (ONT) in detail. From Fast5 files generated by ONT, the tool displays relative similarities between signals using the dynamic time warping and the t-SNE algorithms. Raw signals can be visualized through mouse actions while particular signals of interest can also be exported as a CSV file for further analysis. Sequoia consists of two major components: the command-line back-end that performs necessary computations using Python and the front-end that displays the visualization through a web interface. Two datasets are used to conduct a case study in order to illustrate the usability of the tool.