bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk of Severe Influenza Among Adults With Chronic Medical Conditions
Authors: Walker Tiffany A , Waite Ben , Thompson Mark G , McArthur Colin , Wong Conroy , Baker Michael G , Wood Tim , Haubrock Jennifer , Roberts Sally , Gross Diane K , Huang Q Sue , Newbern E Claire
Published: November 2019

Background

Severe influenza illness is presumed more common in adults with chronic medical conditions (CMCs), but evidence is sparse and often combined into broad CMC categories.

Methods

Residents (aged 18–80 years) of Central and South Auckland hospitalized for World Health Organization-defined severe acute respiratory illness (SARI) (2012–2015) underwent influenza virus polymerase chain reaction testing. The CMC statuses for Auckland residents were modeled using hospitalization International Classification of Diseases, Tenth Revision codes, pharmaceutical claims, and laboratory results. Population-level influenza rates in adults with congestive heart failure (CHF), coronary artery disease (CAD), cerebrovascular accidents (CVA), chronic obstructive pulmonary disease (COPD), asthma, diabetes mellitus (DM), and end-stage renal disease (ESRD) were calculated by Poisson regression stratified by age and adjusted for ethnicity.

Results

Among 891 276 adults, 2435 influenza-associated SARI hospitalizations occurred. Rates were significantly higher in those with CMCs compared with those without the respective CMC, except for older adults with DM or those aged <65 years with CVA. The largest effects occurred with CHF (incidence rate ratio [IRR] range, 4.84–13.4 across age strata), ESRD (IRR range, 3.30–9.02), CAD (IRR range, 2.77–10.7), and COPD (IRR range, 5.89–8.78) and tapered with age.

Conclusions

Our findings support the increased risk of severe, laboratory-confirmed influenza disease among adults with specific CMCs compared with those without these conditions.
The Impact of Sorghum Growth Stage and Resistance on Life History of Sugarcane Aphids (Hemiptera: Aphididae)
Authors: Neupane Subin B , Kerns David L , Szczepaniec Adrianna
Published: November 2019

Recent invasion of a new haplotype of sugarcane aphid (Melanaphis sacchari Zehntner) resulted in severe outbreaks of the aphids in sorghum (Sorghum bicolor L. Moench [Poales: Poaceae]) across the United States. Previous research and field observations suggested that both sorghum resistance and growth stage were important to their population dynamics in the field and hence effective and timely management to minimize economic losses associated with this pest. To explore this, we designed greenhouse experiments to quantify fecundity, prereproductive period, and longevity of sugarcane aphids across several vegetative and reproductive growth stages of a resistant (DKS 37-07) and susceptible (M77GB52 and DKS 38–88) sorghum hybrids commonly used in sorghum production. We found significant effects of sorghum resistance and growth stage on several life history traits and demographics parameters of sugarcane aphids. We did not, however, note any significant interactive effects of resistance and phenology on any of the response variables. Sugarcane aphids exposed to the susceptible sorghum produced significantly more offspring, had significantly greater intrinsic and finite rates of increase, and significantly shorter population doubling time than the aphids feeding on resistant sorghum. On the other hand, the impact of sorghum growth stage had more variable effects on life history of sugarcane aphids that were most frequently evident at the late reproductive stages. These outcomes support our hypothesis that sorghum in late stages of growth tends to be a better host for sugarcane aphids and highlight the importance of sorghum growth stage to sugarcane aphid life history and population growth potential.
Strain-accumulation mechanisms in sands under isotropic stress
Authors: Sajeva A , Capaccioli S , Cheng H
Published: November 2019

Determining the pressure dependence of dynamic moduli in unconsolidated sediments is still an open problem in applied geophysics. This is because several petrophysical parameters affect the elastic response of the granular medium during compression. Effective medium theories based on the Hertz–Mindlin contact law estimate the effective moduli from petrophysical parameters. Among them, the Pride and Berryman model assumes that new contacts between grains are progressively created during compression. Furthermore, the gaps around rattlers are distributed following a power law with distance and the global strain can change either linearly or quadratically with the local strain. This identifies two types of strain accumulation. Quadratic strain accumulation is associated with grain rotation. We simplified this model by assuming a flat distribution of gaps around rattlers and we applied this simplified model to published ultrasonic measurements. By means of these measurements, we studied how the strain-accumulation mechanism affects the coordination number during isotropic compression. The coordination numbers were estimated by applying a DEM-based correction to the average-strain model. We observe that the majority of the experimental trends lay between the linear and the quadratic accumulation trends. Based on this result, we assume that the strain accumulation is a combination of the two mechanisms and we propose a formula to estimate the contribution of each mechanism. Furthermore, we note that, in the studied datasets, rotation affects larger grains (diameter approximately 500 μm) more than smaller grains (diameter approximately 100 μm). If further validated, this correlation could guide the determination of pressure trends for sands.
Variation in Morphology and Airborne Dispersal of the Urticating Apparatus of Ochrogaster lunifer (Lepidoptera: Notodontidae), an Australian Processionary Caterpillar, and Implications for Livestock and Humans
Authors: Perkins Lynda E , Cribb Bronwen W , Pagendam Dan E , Zalucki Myron P
Published: November 2019

True setae borne on the abdominal tergites of Ochrogaster lunifer Herrich-Schӓffer caterpillars are the agents of an irritating contact dermatitis, osteomyelitis, ophthalmia, and severe allergic reactions in humans, and are the cause of Equine Amnionitis and Fetal Loss in Australia. The setae are detached and readily dislodge from the integument whereby they disperse throughout the environment. To better understand the true setae of O. lunifer as agents of medical and veterinary concern, we studied their characteristics and distance dispersed. Whereas members of the European Thaumetopoeinae have been widely studied, their southern-hemisphere counterparts such as O. lunifer are not well known despite their harmfulness and known medical and veterinary importance. The caterpillar’s investment in true setae increased with age and size, and two distinct size classes co-occurred in setae fields. A previously undescribed morphological type of true seta was found on the first abdominal segment. All true setae were calculated to travel long distances in the air even under light breeze conditions. Our results show there is a high risk of exposure to airborne urticating setae within 100 m of elevated caterpillar activity, and a likely risk of exposure for some kilometers in the direction of the prevailing breeze. This information should be used to inform management strategies in areas where urticating processionary caterpillars are active, and especially during periods of an outbreak.
Subtype-Specific Breast Cancer Incidence Rates in Black versus White Men in the United States
Authors: Sung Hyuna , DeSantis Carol , Jemal Ahmedin
Published: November 2019

Compared with white women, black women have higher incidence rates for triple-negative breast cancer but lower rates for hormone receptor (HR)–positive cancers in the United States. Whether similar racial difference occurs in male breast cancer is unclear. We examined racial differences in incidence rates of breast cancer subtypes defined by HR and human epidermal growth factor receptor 2 (HER2) by sex using nationwide data from 2010 to 2016. Among men, rates were higher in blacks than whites for all subtypes, with the black-to-white incidence rate ratios of 1.41 (95% confidence interval [CI ]= 1.32 to 1.50) for HR+/HER-, 1.65 (95% CI = 1.40 to 1.93) for HR+/HER2+, 2.62 (95% CI = 1.48 to 4.43) for HR-/HER2+, and 2.27 (95% CI = 1.67 to 3.03) for triple-negative subtype. Conversely, among women, rates in blacks were 21% lower for HR+/HER2- and comparable for HR+/HER2+ but 29% and 93% higher for HR-/HER2+ and triple-negative subtypes, respectively. Future studies are needed to identify contributing factors to the dissimilar racial patterns in breast cancer subtype incidence between men and women.
An Anatomical Site and Genetic-Based Prognostic Model for Patients With Nuclear Protein in Testis (NUT) Midline Carcinoma: Analysis of 124 Patients
Authors: Chau Nicole G , Ma Clement , Danga Kristina , Al-Sayegh Hasan , Nardi Valentina , Barrette Ryan , Lathan Christopher S , DuBois Steven G , Haddad Robert I , Shapiro Geoffrey I , Sallan Stephen E , Dhar Arindam , Nelson Jeanenne J , French Christopher A
Published: November 2019

Background

NUT midline carcinoma, renamed NUT carcinoma (NC), is an aggressive squamous cancer defined by rearrangement of the NUTM1 gene. Although a subset of patients can be cured, for the majority of patients the prognosis is grim. We sought to classify patients into risk groups based on molecular and clinicopathologic factors at the time of diagnosis.

Methods

Clinicopathologic variables and survival outcomes were extracted for a total of 141 NC patients from the NUT midline carcinoma Registry using questionnaires and medical records. Translocation type was identified by molecular analyses. Survival tree regression analysis was performed to determine risk factors associated with overall survival (OS).

Results

For 141 patients, the median age at diagnosis was 23.6 years. Fifty-one percent had thoracic origin compared with 49% nonthoracic sites (41% head and neck, 6% bone or soft tissue, 1% other). The median OS was 6.5 months (95% confidence interval [CI] = 5.8 to 9.1 months). Most patients had the BRD4-NUTM1 fusion (78%), followed by BRD3-NUTM1 (15%) and NSD3-NUTM1 (6%). Survival tree regression identified three statistically distinct risk groups among 124 patients classified by anatomical site and genetics: group A is nonthoracic primary, BRD3-, or NSD3-NUT (n = 12, median OS = 36.5 months, 95% CI = 12.5 to not reported months); group B is nonthoracic primary, BRD4-NUT (n = 45, median OS = 10 months, 95% CI = 7 to 14.6 months); and group C is thoracic primary (n = 67, median OS = 4.4 months, 95% CI = 3.5 to 5.6 months). Only groups A and B had long-term (≥3 years, n = 12) survivors.

Conclusions

We identify three risk groups defined by anatomic site and NUT fusion type. Nonthoracic primary with non-BRD4-NUT fusion confers the best prognosis, followed by nonthoracic primary with BRD4-NUT. Thoracic NC patients, regardless of the NUT fusion, have the worst survival.
Euclid-era cosmology for everyone: Neural net assisted MCMC sampling for the joint 3x2 likelihood
Authors: Manrique-Yus Andrea , Sellentin Elena
Published: November 2019

We develop a fully non-invasive use of machine learning in order to enable open research on Euclid-sized data sets. Our algorithm leaves complete control over theory and data analysis, unlike many black-box like uses of machine learning. Focusing on a ‘3x2 analysis’ which combines cosmic shear, galaxy clustering and tangential shear at a Euclid-like sky coverage, we arrange a total of 348000 data points into data matrices whose structure permits not only an easy prediction by neural nets, but it additionally permits the essential removal from the data of patterns which the neural nets could not ‘understand’. The latter provides an often lacking mechanism to control and debias the inference of physics. The theoretical backbone to our neural net training can be any conventional (deterministic) theory code, where we chose CLASS. After training, we infer the seven parameters of a wCDM cosmology by Monte Carlo Markov sampling posteriors at Euclid-like precision within a day. We publicly provide the neural nets which memorise and output all 3x2 power spectra at a Euclid-like sky coverage and redshift binning.
Projected velocity statistics of interstellar turbulence
Authors: Xu Siyao
Published: November 2019

Velocity statistics is a direct probe of the dynamics of interstellar turbulence. Its observational measurements are very challenging due to the convolution between density and velocity and projection effects. We introduce the projected velocity structure function, which can be generally applied to statistical studies of both subsonic and supersonic turbulence in different interstellar phases. It recovers the turbulent velocity spectrum from the projected velocity field in different regimes, and when the thickness of a cloud is less than the driving scale of turbulence, it can also be used to determine the cloud thickness and the turbulence driving scale. By applying it to the existing core velocity dispersion measurements of the Taurus cloud, we find a transition from the Kolmogorov to the Burgers scaling of turbulent velocities with decreasing length-scales, corresponding to the large-scale solenoidal motions and small-scale compressive motions, respectively. The latter occupy a small fraction of the volume and can be selectively sampled by clusters of cores with the typical cluster size indicated by the transition scale.
Structure–fluorescence activation relationships of a large Stokes shift fluorogenic RNA aptamer
Authors: Steinmetzger Christian , Bessi Irene , Lenz Ann-Kathrin , Höbartner Claudia
Published: November 2019

The Chili RNA aptamer is a 52 nt long fluorogen-activating RNA aptamer (FLAP) that confers fluorescence to structurally diverse derivatives of fluorescent protein chromophores. A key feature of Chili is the formation of highly stable complexes with different ligands, which exhibit bright, highly Stokes-shifted fluorescence emission. In this work, we have analyzed the interactions between the Chili RNA and a family of conditionally fluorescent ligands using a variety of spectroscopic, calorimetric and biochemical techniques to reveal key structure–fluorescence activation relationships (SFARs). The ligands under investigation form two categories with emission maxima of ∼540 or ∼590 nm, respectively, and bind with affinities in the nanomolar to low-micromolar range. Isothermal titration calorimetry was used to elucidate the enthalpic and entropic contributions to binding affinity for a cationic ligand that is unique to the Chili aptamer. In addition to fluorescence activation, ligand binding was also observed by NMR spectroscopy, revealing characteristic signals for the formation of a G-quadruplex only upon ligand binding. These data shed light on the molecular features required and responsible for the large Stokes shift and the strong fluorescence enhancement of red and green emitting RNA–chromophore complexes.
Sharing DNA-binding information across structurally similar proteins enables accurate specificity determination
Authors: Wetzel Joshua L , Singh Mona
Published: November 2019

We are now in an era where protein–DNA interactions have been experimentally assayed for thousands of DNA-binding proteins. In order to infer DNA-binding specificities from these data, numerous sophisticated computational methods have been developed. These approaches typically infer DNA-binding specificities by considering interactions for each protein independently, ignoring related and potentially valuable interaction information across other proteins that bind DNA via the same structural domain. Here we introduce a framework for inferring DNA-binding specificities by considering protein–DNA interactions for entire groups of structurally similar proteins simultaneously. We devise both constrained optimization and label propagation algorithms for this task, each balancing observations at the individual protein level against dataset-wide consistency of interaction preferences. We test our approaches on two large, independent Cys2His2 zinc finger protein–DNA interaction datasets. We demonstrate that jointly inferring specificities within each dataset individually dramatically improves accuracy, leading to increased agreement both between these two datasets and with a fixed external standard. Overall, our results suggest that sharing protein–DNA interaction information across structurally similar proteins is a powerful means to enable accurate inference of DNA-binding specificities.
Extraneural metastatic anaplastic ependymoma: a systematic review and a report of metastases to bilateral parotid glands
Authors: Umbach Gray , El Ahmadieh Tarek Y , Plitt Aaron R , Aoun Salah G , Neeley Om J , Lyon Kristopher A , Fonkem Ekokobe , Raisanen Jack M , Bishop Justin A , Wardak Zabi , Patel Toral R , Myers Larry , Mickey Bruce E
Published: November 2019

Background

Anaplastic ependymoma with extraneural metastases is associated with a poor clinical outcome. Metastatic spread to the parotid gland is a rare clinical entity that requires multidisciplinary intervention. Herein, we present a systematic review of anaplastic ependymoma with extraneural metastases and report on a case with metastases to both parotid glands.

Methods

Electronic databases were searched from their inception to February 2019. Inclusion criteria included reports of anaplastic ependymoma with extraneural metastasis. Studies were excluded if the tumor grade was not reported. A case illustration is provided.

Results

The search yielded 15 cases of anaplastic ependymoma with extraneural metastases, including the present case. Mean age at diagnosis was 15 years. The initial tumor location was predominantly supratentorial (93.3%). All cases demonstrated leptomeningeal seeding before extraneural metastasis. Mean survival from initial diagnosis was 4.5 years. Metastasis to the parotid gland occurred in 2 cases, including the present case. We present a 17-year-old female patient who underwent gross total resection of a supratentorial, paraventricular anaplastic ependymoma followed by adjuvant external beam radiation therapy. The patient developed recurrent leptomeningeal seeding, treated with Gamma Knife radiosurgery over a 5-year period. She returned with a parotid mass and cervical lymphadenopathy and underwent parotidectomy and modified radical neck dissection. She continued to experience recurrences, including the left parotid gland, and was ultimately placed in hospice care.

Conclusions

Anaplastic ependymoma with extraneural metastasis is rare. A combination of repeated surgical resection, radiation therapy, and chemotherapy can be used to manage recurrent and metastatic disease, but outcomes remain poor.
Temporoinsular Glioma Resection under Awake Mapping: 2-Dimensional Operative Video
Authors: Gong Fangyuan , Hameed N U Farrukh , Li Zeyang , Kudulaiti Nijiati , Zhang Jie , Wu Jinsong
Published: November 2019

Temporoinsular gliomas are frequently large-sized tumors that require meticulous planning to ensure maximum surgical resection and minimal neurologic deficits in patients. Here, we demonstrate our technique encompassing multi-modal imaging guidance and awake brain mapping which enables maximum safe resection of such tumors.

The patient, a 39-yr-old man, presented with depression and memory loss for 18 mo. Preoperative magnetic resonance imaging (MRI; MAGNETOM Verio, Siemens) revealed a nonenhancing lesion in the left dominant temporoinsular lobe. Three-dimensional magnetic resonance spectroscopy was used to analyze the choline/N-acetyl-aspartate index which suggested a low-grade glioma diagnosis. Informed patient consent was obtained.

After craniotomy, the mouth motor, speech arrest, and word generation areas were mapped via direct cortical stimulation under awake mapping. A strip electrode was placed across the precentral gyrus for continuous motor evoked potential monitoring. Cortical incisions were made in nonfunctional cortical areas and tumor was resected in the temporal lobe. Following this, tumor at the inferior insular zone was carefully debunked with Cavitron Ultrasonic Surgical Aspirator (Integra Lifescience) also through the temporal window. The hippocampus was preserved since it was not invaded by tumor. Subcortical mapping combined with Diffuse Tensor Imaging tractography-based navigation (Medtronic lnc.) was performed to localize the motor and language pathways. Intraoperative MRI evaluation showed tumor resection extent of 95%. Pathological and molecular analysis revealed a diagnosis of Grade II IDH-mutant oligodendroglioma. After surgery the patient was administered chemotherapy (Temozolomide). He recovered without language or motor deficits.
Returning scientists and the emergence of China’s science system
Authors: Cao Cong , Baas Jeroen , Wagner Caroline S , Jonkers Koen
Published: November 2019

China’s approach to developing a world-class science system includes a vigorous set of programmes to attract back Chinese researchers who have overseas training and work experience. No analysis is available to show the performance of these mobile researchers. This article attempts to close part of this gap. Using a novel bibliometric approach, we estimate the stocks of overseas Chinese and returnees from the perspective of their publication activities, albeit with some limitations. We show that the share of overseas Chinese scientists in the USA is considerably larger than that in the European Union. We also show that Chinese returnees publish higher impact work and continue to publish more and at the international level than domestic counterparts. Returnees not only tend to publish more, but they are instrumental in linking China into the global network. Indeed, returnees actively co-publish with researchers in their former host system, showing the importance of scientific social capital. Future research will examine the impact of length of stay, among other factors, on such impact and integration.
Faecalibacter macacae gen. nov., sp. nov., isolated from the faeces of Macaca assamensis
Authors: Chen Xiu , Li Gui-Ding , Wei Yun-Fang , Li You-Long , Yu Hua , Zhang Kun , Jiang Cheng-Lin , Jiang Yi
Published: November 2019

Huge numbers of bacteria reside in the digestive tract of most animals. During an investigation into the bacterial diversity of primates, strain YIM 102668T was isolated. When neighbour-joining phylogenetic analysis based on 16S rRNA gene sequences was conducted, strain YIM 102668T formed a cluster within the family

Flavobacteriaceae

and in a lineage not associated with any known group of previously proposed genera. Closely related genera were

Algoriella

(94.8 %),

Chishuiella

(94.8 %),

Empedobacter

(highest 94.6 %),

Moheibacter

(90.9 %) and

Weeksella

(90.6 %). In addition, strain YIM 102668T contained MK-6 as the predominant respiratory quinone and iso-C15 : 0 as the major fatty acid. The major polar lipid was phosphatidylethanolamine and the genomic DNA G+C content was 30.6 mol%. These chemotaxonomic characterizations confirmed that strain YIM 102668T belonged to the family

Flavobacteriaceae

. Supported by the results of phylogenetic, phenotypic and chemotaxonomic analyses, we propose that strain YIM 102668T represents a novel genus, for which the name Faecalibacter macacae gen. nov., sp. nov. is proposed. The type strain is YIM 102668T (=KCTC 52109T=CCTCC AB 2016016T).
Multi-omic signatures identify pan-cancer classes of tumors beyond tissue of origin
Authors: Gonzalez-Reymundez Agustin , Vazquez Ana I.
Published: November 2019

Despite recent advances in treatment, cancer continues to be one of the most lethal human maladies. One of the challenges of cancer treatment is the extreme diversity among seemingly identical tumors: while some tumors may have good prognosis and are treatable, others are quite aggressive, and may lack of effective therapies. Most of this variability comes from wide-spread mutations and epigenetic alterations. Using a novel omic-integration method, we have exploited this molecular information to re-classify tumors beyond the constraints of cell type. Eight novel tumor groups (C1-8) emerged, characterized by unique cancer signatures. C3 had better prognosis, genome stability, and immune infiltration. C2 and C5 had higher genome instability and poorer clinical outcomes. Remaining clusters were characterized by worse outcomes, along with higher genome instability. C1, C7, and C8 were upregulated for cellular and mitochondrial translation, and relatively low proliferation. C6 and C4 were also downregulated for cellular and mitochondrial translation, and had high proliferation rates. C4 was represented by copy losses on chromosome 6, and had the highest number of metastatic samples. C8 was characterized by copy losses on chromosome 11, having also the lowest lymphocytic infiltration rate. C6 had the lowest natural killer infiltration rate and was represented by copy gains of genes in chromosome 11. C7 was represented by copy gains on chromosome 6, and had the highest upregulation in mitochondrial translation. We believe that, since molecularly alike tumors could respond similarly to treatment, our results could inform therapeutic action.

Significance

Cancer has been traditionally studied as a family of different diseases from different anatomical sites. Nevertheless, regardless of the tissue of origin, cancer can be characterized by molecular alterations on mechanisms controlling cell fate and progression. In this study, we integrate 33 cancer types and show the existence of eight clusters with unique genomic signatures and clinical characteristics, beyond the site of origin of the tumor. The study and treatment of cancer, based on predominant molecular features, rather than site of origin, can potentially aid in the discovery of novel therapeutic alternatives.
Evolutionary Origins of Recurrent Pancreatic Cancer
Authors: Sakamoto Hitomi , Attiyeh Marc A. , Gerold Jeffrey M. , Makohon-Moore Alvin P. , Hayashi Akimasa , Hong Jungeui , Kappagantula Rajya , Zhang Lance , Melchor Jerry , Reiter Johannes G. , Heyde Alexander , Bielski Craig M. , Penson Alexander , Chakravarty Debyani , O’Reilly Eileen M. , Wood Laura D. , Hruban Ralph H. , Nowak Martin A. , Socci Nicholas D. , Taylor Barry S. , Iacobuzio-Donahue Christine A.
Published: November 2019

Surgery is the only curative option for Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that adjuvant or first-line platinum therapy corresponds to an increased mutational burden of recurrent disease. Recurrent disease is enriched for mutations that activate Mapk/Erk and PI3K/AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings advocate for combination therapies with immunotherapy and routine post-treatment sampling as a component of management of recurrent pancreatic cancer.
Non-Parametric Rank Statistics for Spectral Power and Coherence
Authors: Nasseroleslami Bahman , Dukic Stefan , Buxo Teresa , Coffey Amina , McMackin Roisin , Muthuraman Muthuraman , Hardiman Orla , Lowery Madeleine M. , Lalor Edmund C.
Published: November 2019

Despite advances in multivariate spectral analysis of neural signals, the statistical inference of measures such as spectral power and coherence in practical and real-life scenarios remains a challenge. The non-normal distribution of the neural signals and presence of artefactual components make it difficult to use the parametric methods for robust estimation of measures or to infer the presence of specific spectral components above the chance level. Furthermore, the bias of the coherence measures and their complex statistical distributions are impediments in robust statistical comparisons between 2 different levels of coherence. Non-parametric methods based on the median of auto-/cross-spectra have shown promise for robust estimation of spectral power and coherence estimates. However, the statistical inference based on these non-parametric estimates remain to be formulated and tested. In this report a set of methods based on non-parametric rank statistics for 1-sample and 2-sample testing of spectral power and coherence is provided. The proposed methods were demonstrated and tested using simulated neural signals in different conditions. The results show that non-parametric methods provide robustness against artefactual components. Moreover, they provide new possibilities for robust 1-sample and 2-sample testing of the complex coherency function, including both the magnitude and phase, where existing methods fall short of functionality. The utility of the methods were further demonstrated by examples on experimental neural data. The proposed approach provides a new framework for non-parametric spectral analysis of digital signals. These methods are especially suited to neuroscience and neural engineering applications, given the attractive properties such as minimal assumption on distributions, statistical robustness, and the diverse testing scenarios afforded.
The Impact of Edema and Fiber Crossing on Diffusion MRI Metrics: DBSI vs. Diffusion ODF
Authors: Ye Zezhong , Gary Sam E. , Sun Peng , Mustafi Sourajit Mitra , Glenn George Russell , Yeh Fang-Cheng , Merisaari Harri , Huang Guo-Shu , Kao Hung-Wen , Lin Chien-Yuan , Wu Yu-Chien , Jensen Jens H. , Song Sheng-Kwei
Published: November 2019

Purpose

Diffusion tensor imaging (DTI) has been employed for over two decades to noninvasively quantify central nervous system (CNS) diseases/injuries. However, DTI is an inadequate simplification of diffusion modeling in the presence of co-existing inflammation, edema, and crossing nerve fibers.

Methods

We employed a tissue phantom using fixed mouse trigeminal nerves coated with various amounts of agarose gel to mimic crossing fibers in the presence of vasogenic edema. Diffusivity measures derived by DTI and diffusion basis spectrum imaging (DBSI) were compared at increasing levels of simulated edema and degrees of fiber crossing. Further, we assessed the ability of DBSI, diffusion kurtosis imaging (DKI), generalized q-sampling imaging (GQI), q-ball imaging (QBI), and neurite orientation dispersion and density imaging (NODDI) to resolve fiber crossing, in reference to the gold standard angles measured from structural images.

Results

DTI-computed diffusivities and fractional anisotropy (FA) were significantly confounded by gelmimicked edema and crossing fibers. Conversely, DBSI calculated accurate diffusivities of individual fibers regardless of the extent of simulated edema and degrees of fiber crossing angles. Additionaly, DBSI accurately and consistently estimated crossing angles in various conditions of gel-mimicked edema when comparing with gold standard (r2=0.92, p=1.9×10−9, bias=3.9°). Small crossing angles and edema sinficantly impact dODF, making DKI, GQI and QBI less accurate in detecting and estimating fibers corrsing angles. Lastly, we demonstrate DBSI’s superiority over DTI for recovering and delineating white matter tracts in peritumoral edema for preoperative planning of surgical resection.

Conclusions

DBSI is able to separate two crossing fibers and accurately recover their diffusivities in a complex environment characterized by increasing crossing angles and amounts of gel-mimicked edema. DBSI also indicated better angular resolution capability compared with DKI, QBI and GQI.
Enhancing senior high school student engagement and academic performance using an inclusive and scalable inquiry-based program
Authors: Huyer Locke Davenport , Callaghan Neal I. , Dicks Sara , Scherer Edward , Shukalyuk Andrey I. , Jou Margaret , Kilkenny Dawn M.
Published: November 2019

The multi-disciplinary nature of science, technology, engineering and math (STEM) careers often renders difficulty for high school students navigating from classroom knowledge to post-secondary pursuits. Discrepancies between the knowledge-based high school learning approach and the experiential approach of undergraduate studies leaves some students disillusioned by STEM. We present Discovery, a semester-long inquiry-focused learning model delivered by STEM graduate students in collaboration with high school educators, in the context of biomedical engineering. Entire classes of high school STEM students representing diverse cultural and socioeconomic backgrounds engaged in iterative, problem-based learning designed to emphasize critical thinking concomitantly within the secondary school and university environments. Assessment of grades and survey data suggested positive impact of this learning model on students’ STEM pursuits, notably in under-performing cohorts, as well as repeating cohorts that engage in the program on more than one occasion. Discovery presents a scalable platform blurring the divide between secondary and post-secondary learning, providing valuable learning opportunities and capturing cohorts of students that might otherwise be under-engaged in STEM.
Hat1-Dependent Lysine Acetylation Targets Diverse Cellular Functions
Authors: Agudelo Garcia Paula A. , Nagarajan Prabakaran , Parthun Mark R.
Published: November 2019

Lysine acetylation has emerged as one of the most important post-translational modifications, regulating different biological processes. However, its regulation by lysine acetyltransferases is still unclear in most cases. Hat1 is a lysine acetyltransferase originally identified based on its ability to acetylate histones. Using an unbiased proteomics approach, we have determined how loss of Hat1 affects the mammalian acetylome. Hat1+/+and Hat1−/−mouse embryonic fibroblast (MEF) cells lines were grown in both glucose- and galactose-containing media, as Hat1 is required for growth on galactose and Hat1−/−cells exhibit defects in mitochondrial function. Following trypsin digestion of whole cell extracts, acetylated peptides were enriched by acetyllysine affinity purification and acetylated peptides were identified and analyzed by label-free quantitation. Comparison of the acetylome from Hat1+/+cells grown on galactose and glucose demonstrated that there are large carbon source-dependent changes in the mammalian acetylome where the acetylation of enzymes involved in glycolysis was the most affected. Comparisons of the acetylomes from Hat1+/+and Hat1−/−cells identified 65 proteins whose acetylation decreased by at least 2.5-fold in cells lacking Hat1. In Hat1−/−cells, acetylation of the auto regulatory loop of CBP was the most highly affected, decreasing by up to 20-fold. In addition to proteins involved in chromatin structure, Hat1-dependent acetylation was also found in a number of transcriptional regulators, including p53, and mitochondrial proteins. Hat1 mitochondrial localization suggests that it may be directly involved in the acetylation of mitochondrial proteins.
Assessment of the bovine uterus with endometritis using Doppler ultrasound
Authors: Mendonça Ribeiro Bruno Leonardo , de Souza Meira Júnior Enoch Brandão , Aleman Reyes Mario Augusto , Marques Eduardo Carvalho , de Castro Nassar Alessandra Figueiredo , Gregory Lilian
Published: November 2019

Postpartum uterine diseases such as metritis and endometritis are highly prevalent in dairy cows. These diseases negatively affect the reproductive performance and consequently economic activity. Cows in the puerperal period presenting endometritis may have alterations in the hemodynamics of the uterine tissue and the uterine arteries, which differ them from healthy cows. Therefore, this study aimed to use the Doppler ultrasonography to describe the hemodynamic changes in the uterus of cows showing endometritis diagnosed between 25 - 35 days postpartum. Eighty-nine Holstein Friesian females with 25 to 35 days postpartum were studied. Cows were assigned to two experimental groups, infected or not infected, according to the results of the endometrial cytology. Clinical examination, vaginoscopy, Doppler ultrasound and sample collection (saline solution was injected and recovered by endoscopie method aiming cytological and microbiological evaluation of the uterus) were also performed. Cows with endometritis had the cervix (P = 0.040) and the left horn (P = 0.020) increased compared to healthy cows. 78.6% of the endometritic cows showed abnormal uterine discharge, while 57.6% of healthy cows had this same condition (P = 0.0005). The spectral Doppler evaluation of the uterine arteries revealed no differences between groups. Bacillus spp., Trueperella pyogenes, Escherichia coli and Staphylococcus intermedius were the most isolated bacteria among samples. Higher score or increase of uterus vascularization of the endometrial Doppler was correlated with Trueperella pyogenes (P = 0.0003) and intrauterine heterogeneous content (P = 0.0047). Finally, mesometrial Doppler was correlated with endometrial Doppler (P < 0.001), uterine bacteria (P = 0.001) and intrauterine heterogeneous content (P = 0.049). Regarding the evolution of uterine alterations, Doppler ultrasonography provides fast results and is a lesser invasive technique such as uterus biopsie and endometrial citology and gives answers about fertility and uterus health.
Women’s brain aging: effects of sex-hormone exposure, pregnancies, and genetic risk for Alzheimer’s disease
Authors: de Lange Ann-Marie G. , Barth Claudia , Kaufmann Tobias , Maximov Ivan I. , van der Meer Dennis , Agartz Ingrid , Westlye Lars T.
Published: November 2019

Sex hormones such as estrogen fluctuate across the female lifespan, with high levels during reproductive years and natural decline during the transition to menopause. Women’s exposure to estrogen may influence their heightened risk of Alzheimer’s disease (AD) relative to men, but little is known about how it affects normal brain aging. Recent findings from the UK Biobank demonstrate less apparent brain aging in women with a history of multiple childbirths, highlighting a potential link between sex-hormone exposure and brain aging. We investigated endogenous and exogenous sex-hormone exposure, genetic risk for AD, and neuroimaging-derived biomarkers for brain aging in 16,854 middle to older-aged women. The results showed that as opposed to parity, higher cumulative sex-hormone exposure was associated with more evident brain aging, indicating that i) high levels of cumulative exposure to sex-hormones may have adverse effects on the brain, and ii) beneficial effects of pregnancies on the female brain are not solely attributable to modulations in sex-hormone exposure. In addition, for women using hormonal replacement therapy (HRT), starting treatment earlier was associated with less evident brain aging, but only in women with a genetic risk for AD. Genetic factors may thus contribute to how timing of HRT initiation influences women’s brain aging trajectories.
Characterisation of HIF-dependent alternative isoforms in pancreatic cancer
Authors: Markolin Philipp , Davidson Natalie , Hirt Christian K. , Chabbert Christophe D. , Zamboni Nicola , Schwank Gerald , Krek Wilhelm , Rätsch Gunnar
Published: November 2019

Intra-tumor hypoxia is a common feature in many solid cancers. Although transcriptional targets of hypoxia-inducible factors (HIFs) have been well characterized, alternative splicing or processing of pre-mRNA transcripts which occurs during hypoxia and subsequent HIF stabilization is much less understood. Here, we identify HIF-dependent alternative splicing events after whole transcriptome sequencing in pancreatic cancer cells exposed to hypoxia with and without downregulation of the aryl hydrocarbon receptor nuclear translocator (ARNT), a protein required for HIFs to form a transcriptionally active dimer. We correlate the discovered hypoxia-driven events with available sequencing data from pan-cancer TCGA patient cohorts to select a narrow set of putative biologically relevant splice events for experimental validation. We validate a small set of candidate HIF-dependent alternative splicing events in multiple human cancer cell lines as well as patient-derived human pancreatic cancer organoids. Lastly, we report the discovery of a HIF-dependent mechanism to produce a hypoxia-dependent, long and coding isoform of the UDP-N-acetylglucosamine transporter SLC35A3.
Effects of N-Acetyl-Leucine and its enantiomers in Niemann-Pick disease type C cells
Authors: te Vruchte Danielle , Galione Anthony , Strupp Michael , Mann Michiko
Published: November 2019

N-Acetyl-DL-Leucine is an acetylated derivative of the essential amino acid leucine and a racemate (1:1) of N-Acetyl-L-Leucine and N-Acetyl-D-Leucine enantiomers. Previous observational clinical studies have demonstrated that N-Acetyl-DL-Leucine is effective in improving ataxia in patients with Niemann-Pick disease type C (NPC), a lysosomal storage disorder characterized at the cellular level by increased relative volume of the endosomal/lysosomal system. In this study, we sought to further characterize the potential therapeutic benefit of N-acetyl-DL-leucine and its enantiomers for the treatment of NPC. We investigated the effectiveness of N-Acetyl-DL-Leucine, N-Acetyl-D-Leucine, and N-Acetyl-L-Leucine in reducing lysosomal volume in non-neuronal NPC1 cells using LysoTracker, a fluorescent dye that accumulates in acidic organelles. We report that both N-Acetyl-DL-Leucine and N-Acetyl-L-Leucine reduced relative lysosomal volume in NPC1-/- Chinese Hamster Ovary cells in a dose-dependent manner. Subsequently, we confirmed that N-Acetyl-L-Leucine was most effective at reducing relative lysosomal volumes in fibroblasts derived from NPC patients with severe disease (***p <0.001), followed by N-Acetyl-DL-Leucine (**p <0.01). Treatment with N-Acetyl-D-Leucine did not achieve statistical significance. Taken together, these results suggest that N-Acetyl-L-Leucine is the most effective enantiomer in correcting relative lysosomal volume in non-neuronal NPC cells, and support further research and development of the L-enantiomer.
Connecting omics signatures of diseases, drugs, and mechanisms of actions with iLINCS
Authors: Pilarczyk Marcin , Kouril Michal , Shamsaei Behrouz , Vasiliauskas Juozas , Niu Wen , Mahi Naim , Zhang Lixia , Clark Nicholas , Ren Yan , White Shana , Karim Rashid , Xu Huan , Biesiada Jacek , Bennett Mark F. , Davidson Sarah , Reichard John F , Roberts Kurt , Stathias Vasileios , Koleti Amar , Vidovic Dusica , Clarke Daniel J.B. , Schurer Stephan C. , Ma’ayan Avi , Meller Jarek , Medvedovic Mario
Published: November 2019

There are only a few platforms that integrate multiple omics data types, bioinformatics tools, and interfaces for integrative analyses and visualization that do not require programming skills. Among these, iLINCS is unique in scope and versatility of the data provided and the analytics facilitated. iLINCS (http://ilincs.org) is an integrative web-based platform for analysis of omics data and signatures of cellular perturbations. The platform facilitates analysis of user-submitted omics signatures of diseases and cellular perturbations in the context of a large compendium of pre-computed signatures (>200,000), as well as mining and re-analysis of the large collection of omics datasets (>12,000), pre-computed signatures, and their connections. Analytics workflows driven by user-friendly interfaces enable users with only conceptual understanding of the analysis strategy to execute sophisticated analyses of omics signatures, such as systems biology analyses and interpretation of signatures, mechanism of action analysis, and signature-driven drug repositioning. In summary, iLINCS workflows integrate vast omics data resources and a range of analytics and interactive visualization tools into a comprehensive platform for analysis of omics signatures.
The kinematics of cyclic human movement
Authors: Vieten Manfred M. , Weich Christian
Published: November 2019

Models describing cyclic movement can roughly be divided into the categories theory or data driven. Theory driven models include anatomical and physiological aspects. They are principally suitable for answering questions about the reasons for movement characteristics. But, they are complicated and substantial simplifications do not allow generally valid results. Data driven models allow answering specific questions but lack the understanding of the general movement characteristic. With this paper we try a compromise not having to rely on anatomy, neurology and muscle function. We hypothesize a general kinematic description of cyclic human motion is possible without having to specify the movement generating processes, and still getting the kinematic right. The model proposed consisting of a superposition of six contributions – subject’s attractor, morphing, short time fluctuation, transient effect, control mechanism and sensor noise -, with characterizing numbers and random contributions. We test the model with data form treadmill running and stationary biking. Applying the model in form of a simulation results in good agreement between measured data and simulation values.
Timeless couples G quadruplex detection with processing by DDX11 during DNA replication
Authors: Lerner Leticia Koch , Holzer Sandro , Kilkenny Mairi L. , Murat Pierre , Šviković Saša , Schiavone Davide , Bittleston Alice , Maman Joseph D. , Branzei Dana , Stott Katherine , Pellegrini Luca , Sale Julian E.
Published: November 2019

Regions of the genome with the potential to form secondary structure pose a frequent and significant impediment to DNA replication and must be actively managed in order to preserve genetic and epigenetic integrity. The fork protection complex (FPC), a conserved group of replisome-associated proteins including Timeless, Tipin, and Claspin, plays an important role in maintaining efficient replisome activation, ensuring optimum fork rates, sister chromatid cohesion and checkpoint function. It also helps maintain the stability of sequences prone to secondary structure formation through an incompletely understood mechanism. Here, we report a previously unappreciated DNA binding domain in the C-terminus of Timeless, which exhibits specific binding to G quadruplex (G4) structures. We show that,in vivo, both the C-terminus of Timeless and the DDX11 helicase act collaboratively to ensure processive replication of G4 structures to prevent genetic and epigenetic instability.
PKM2 ablation enhanced retinal function and survival in a preclinical model of retinitis pigmentosa
Authors: Zhang Ethan , Ryu Joseph , Levi Sarah R. , Oh Jin Kyun , Hsu Chun Wei , Lima de Carvalho Jose Ronaldo , Cui Xuan , Yang Tingting , Tsang Stephen H.
Published: November 2019

Retinitis pigmentosa (RP) is a neurodegenerative disorder that causes irreversible vision loss in over 1.5 million individuals world-wide. In this study, we demonstrate that a metabolic reprogramming can treat degeneration in a Pde6β preclinical model of RP. Pyruvate kinase M2 (PKM2) is a glycolytic enzyme that transfers phosphate from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), promoting glucose catabolism. Ablation of PKM2 resulted in enhanced photoreceptor survival and function in Pde6β-mutated mice compared with those without ablation. Electroretinogram (ERG) analyses revealed that the maximum b-wave is on average greater in Pkm2 knockout mice than in mice with Pkm2 intact. These rescue phenotypes from Pkm2 ablation in a preclinical model of RP indicate that a metabolome reprogramming may be useful in treating RP.