bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer’s disease
Authors: Condello Carlo , Lemmin Thomas , Stöhr Jan , Nick Mimi , Wu Yibing , Maxwell Alison M. , Watts Joel C. , Caro Christoffer D. , Oehler Abby , Keene C. Dirk , Bird Thomas D. , van Duinen Sjoerd G. , Lannfelt Lars , Ingelsson Martin , Graff Caroline , Giles Kurt , DeGrado William F. , Prusiner Stanley B.
Published: January 2018

Significance

An expanding body of evidence argues that the Aβ and tau proteins share important characteristics of prion propagation to cause pathogenesis in Alzheimer’s disease (AD). Aβ and tau form a number of amyloids (β-sheet–rich structures) with distinct conformations (“strains”), some of which give rise to different diseases and associated pathologies. We develop new probes of amyloid structure and use these to identify conformational strains of Aβ in heritable and sporadic forms of AD patient samples. We demonstrate that distinct strains of Aβ can be discerned in different disease types, or in different brain compartments within a given patient. Our findings may potentially explain the spectrum of clinical and pathologic features observed in AD.
Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism
Authors: Kristensen David Møbjerg , Desdoits-Lethimonier Christèle , Mackey Abigail L. , Dalgaard Marlene Danner , De Masi Federico , Munkbøl Cecilie Hurup , Styrishave Bjarne , Antignac Jean-Philippe , Le Bizec Bruno , Platel Christian , Hay-Schmidt Anders , Jensen Tina Kold , Lesné Laurianne , Mazaud-Guittot Séverine , Kristiansen Karsten , Brunak Søren , Kjaer Michael , Juul Anders , Jégou Bernard
Published: January 2018

Significance

Concern has been raised over declining male reproductive health in humans. Our study addresses this issue by extending data showing antiandrogen effects of analgesics and suggests that such compounds may be involved in adult male reproductive problems. Using a unique combination of a randomized, controlled clinical trial and ex vivo and in vitro approaches, we report a univocal depression of important aspects of testicular function, including testosterone production, after use of over-the-counter ibuprofen. The study shows that ibuprofen use results in selective transcriptional repression of endocrine cells in the human testis. This repression results in the elevation of the stimulatory pituitary hormones, resulting in a state of compensated hypogonadism, a disorder associated with adverse reproductive and physical health disorders.
Dysregulation of cotranscriptional alternative splicing underlies CHARGE syndrome
Authors: Bélanger Catherine , Bérubé-Simard Félix-Antoine , Leduc Elizabeth , Bernas Guillaume , Campeau Philippe M. , Lalani Seema R. , Martin Donna M. , Bielas Stephanie , Moccia Amanda , Srivastava Anshika , Silversides David W. , Pilon Nicolas
Published: January 2018

Significance

A timely diagnosis is key for both survival and quality of life of children with CHARGE syndrome (coloboma, heart defects, atresia of choanae, retardation of growth/development, genital abnormalities, and ear anomalies). Such diagnosis is often difficult to establish, in part because many patients test negative for mutation ofCHD7, the only gene associated with this condition to date. Identifying additional CHARGE-associated genes would not only help resolve diagnosis issues but could also help in identifying common pathogenic mechanisms, which in turn could lead to desirable curative interventions for all patients. Here,FAM172Ais reported as a new candidate gene for CHARGE syndrome. This discovery has allowed us to reveal a molecular process that is dysregulated in bothCHD7mutation-positive and -negative cases, such defect being correctable in vitro with rapamycin.
Detergent-extracted
Volvox
model exhibits an anterior–posterior gradient in flagellar Ca
2+
sensitivity
Authors: Ueki Noriko , Wakabayashi Ken-ichi
Published: January 2018

Significance

The multicellular green alga
Volvox rousseletii
displays phototaxis by changing its flagellar beating pattern in response to photoreception. However, the molecular mechanism underlying flagellar regulation is unknown. This study describes a method to demembranate whole spheroids using a nonionic detergent, with the addition of ATP reactivating flagellar motility. These reactivated spheroids swam like live spheroids. Flagellar beating direction was altered in a Ca
2+
-dependent manner, with a greater change in the anterior hemisphere than in the posterior hemisphere. These findings indicate that
V. rousseletii
has an anterior–posterior gradient of flagellar sensitivity to Ca
2+
, which likely plays a key role in
V. rousseletii
phototaxis.
IKKα inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways
Authors: Song Na-Young , Zhu Feng , Wang Zining , Willette-Brown Jami , Xi Sichuan , Sun Zhonghe , Su Ling , Wu Xiaolin , Ma Buyong , Nussinov Ruth , Xia Xiaojun , Schrump David S. , Johnson Peter F. , Karin Michael , Hu Yinling
Published: January 2018

Significance

Reactive oxygen species (ROS) can promote tumorigenesis or kill cancer cells. How different cancer-associated genetic alterations regulate ROS balance and outcome is of great importance for the design of rational cancer treatments, many of which affect ROS metabolism and sensing. Kras activation induces a ROS defense system and cell senescence, which counteract its oncogenic activity.
KRAS
-activating mutations are accompanied by IKKα loss mutations that result in elevated NOX2 but decreased expression of the NRF2 ROS defense system. Thus, IKKα ablation turns the antitumorigenic effect of Kras-induced ROS to a protumorigenic effect that enhances Kras-induced progression of lung adenocarcinoma (ADC). Restoration of IKKα activity or inhibition of the pathways activated on its loss may offer new opportunities for ADC treatment.
Glycoengineering of antibody (Herceptin) through yeast expression and in vitro enzymatic glycosylation
Authors: Liu Chiu-Ping , Tsai Tsung-I. , Cheng Ting , Shivatare Vidya S. , Wu Chung-Yi , Wu Chung-Yi , Wong Chi-Huey
Published: January 2018

Significance

The carbohydrate components of glycoproteins are known to affect the structure and function of glycoproteins, and thus it is important to develop effective tools to manipulate and optimize the glycan components of glycoproteins with therapeutic significance. This study demonstrates the discovery of endoglycosidases for the remodeling of glycans on Herceptin, a monoclonal antibody used in the treatment of breast cancer, to optimize its effector functions, especially the antibody-dependent cellular cytotoxicity (ADCC). In addition, a method has been developed for the expression of antibodies from yeast to enable the large-scale synthesis of antibodies for further manipulation of the glycan moiety, using endoglycosidases and stable transglycosylation donors to prepare a homogeneous glycoform with optimized effector functions.
Structure of the C1r–C1s interaction of the C1 complex of complement activation
Authors: Almitairi Jamal O. M. , Venkatraman Girija Umakhanth , Furze Christopher M. , Simpson-Gray Xanthe , Badakshi Farah , Marshall Jamie E. , Schwaeble Wilhelm J. , Mitchell Daniel A. , Moody Peter C. E. , Wallis Russell
Published: January 2018

Significance

C1 is a large complex that triggers the destruction of invading pathogens via lysis or by stimulation of innate and adaptive immune processes. It is composed of C1q, a protein with a bouquet-like architecture, together with a tetramer assembled from two copies each of the serine proteases C1r and C1s, which activate when C1q binds to a pathogen surface. Here we describe detailed structures that show how C1r and C1s interact via an extensive interface encompassing the N-terminal regions of both proteases. Our findings reveal how the protease tetramer is organized and suggest a mechanism for the assembly and activation of C1.
On the Renormalization Group Explanation of Universality
Authors: Franklin Alexander
Published: January 2018

It is commonly claimed that the universality of critical phenomena is explained through particular applications of the renormalization group (RG). This article has three aims: to clarify the structure of the explanation of universality, to discuss the physics of such RG explanations, and to examine the extent to which universality is thus explained. The derivation of critical exponents proceeds via a real-space or a field-theoretic approach to the RG. Building on work by Mainwood, this article argues that these approaches ought to be distinguished: while the field-theoretic approach explains universality, the real-space approach fails to provide an adequate explanation.
The Farm Economy: Future Research and Education Priorities
Authors: Featherstone Allen M
Published: January 2018

Research priorities for the U.S. farm economy include increasing the productivity and cost efficiency on current land resources while understanding production agriculture across the globe. Providing unbiased objective analysis to policymakers with regard to commodity programs, insurance markets, agricultural credit, and the production of bioenergy are important issues that directly affect not only the U.S. farm economy but other agricultural regions. The ability to manage risk, the increasing complexity of farm operations, the ability of the U.S. farm sector to be nimble to changes in individual and societal preferences, and the efficient discovery of information through efficient markets offer a wealth of research opportunities.
Long-Term Effects of an Intensive Lifestyle Intervention on Electrocardiographic Criteria for Left Ventricular Hypertrophy: The Look AHEAD Trial
Authors: Brinkley Tina E , Anderson Andrea , Soliman Elsayed Z , Bertoni Alain G , Greenway Frank , Knowler William C , Glasser Stephen P , Horton Edward S , Espeland Mark A ,   Look AHEAD Research Group
Published: January 2018

BACKGROUND

Left ventricular hypertrophy assessed by electrocardiography (ECG-LVH) is a marker of subclinical cardiac damage and a strong predictor of cardiovascular disease (CVD) events. The prevalence of ECG-LVH is increased in obesity and type 2 diabetes; however, there are no data on the long-term effects of weight loss on ECG-LVH. The purpose of this study was to determine whether an intensive lifestyle intervention (ILI) reduces ECG-LVH in overweight and obese adults with type 2 diabetes.

METHODS

Data from 4,790 Look AHEAD participants (mean age: 58.8 ± 6.8 years, 63.2% White) who were randomized to a 10-year ILI (n = 2,406) or diabetes support and education (DSE, n = 2,384) were included. ECG-LVH defined by Cornell voltage criteria was assessed every 2 years. Longitudinal logistic regression analysis with generalized estimation equations and linear mixed models were used to compare the prevalence of ECG-LVH and changes in absolute Cornell voltage over time between intervention groups, with tests of interactions by sex, race/ethnicity, and baseline CVD status.

RESULTS

The prevalence of ECG-LVH at baseline was 5.2% in the DSE group and 5.0% in the ILI group (P = 0.74). Over a median 9.5 years of follow-up, prevalent ECG-LVH increased similarly in both groups (odds ratio: 1.02, 95% confidence interval: 0.83–1.25; group × time interaction, P = 0.49). Increases in Cornell voltage during follow-up were also similar between intervention groups (group × time interaction, P = 0.57). Intervention effects were generally similar between subgroups of interest.

CONCLUSIONS

The Look AHEAD long-term lifestyle intervention does not significantly lower ECG-LVH in overweight and obese adults with type 2 diabetes.

CLINICAL TRIALS REGISTRATION

Trial Number NCT00017953 (ClinicalTrials.gov)
Statistically Convex-Cocompact Actions of Groups with Contracting Elements
Authors: Yang Wen-yuan
Published: January 2018

This paper presents a study of the asymptotic geometry of groups with contracting elements, with emphasis on a subclass of statistically convex-cocompact (SCC) actions. The class of SCC actions includes relatively hyperbolic groups, CAT(0) groups with rank-1 elements, and mapping class groups acting on Teichmüller spaces, among others. We exploit an extension lemma to prove that a group with SCC actions contains large free sub-semigroups, has purely exponential growth, and contains a class of barrier-free sets with a growth-tight property. Our study produces new results and recovers existing ones for many interesting groups through a unified and elementary approach.
An Analysis of Adverse Events in the Rehabilitation Department: Using the Veterans Affairs Root Cause Analysis System
Authors: Hagley Gregory W , Mills Peter D , Shiner Brian , Hemphill Robin R
Published: January 2018

Background

Root cause analyses (RCA) are often completed in health care settings to determine causes of adverse events (AEs). RCAs result in action plans designed to mitigate future patient harm. National reviews of RCA reports have assessed the safety of numerous health care settings and suggested opportunities for improvement. However, few studies have assessed the safety of receiving care from physical therapists, occupational therapists, or speech and language pathology pathologists.

Objective

The objective of this study was to determine the types of AEs, root causes, and action plans for risk mitigation that exist within the disciplines of rehabilitation medicine.

Design

This study is a retrospective, cross-sectional review.

Methods

A national search of the Veterans Health Administration RCA database was conducted to identify reports describing AEs associated with physical therapy, occupational therapy, or speech and language pathology services between 2009 and May 2016. Twenty-five reports met the inclusion requirements. The reports were classified by the event type, root cause, action plans, and strength of action plans.

Results

Delays in care (32.0%) and falls (28.0%) were the most common type of AE. Three AEs resulted in death. RCA teams identified deficits regarding policy and procedures as the most common root cause. Eighty-eight percent of RCA reports included strong or intermediate action plans to mitigate risk. Strong action plans included standardizing emergency terminology and implementing a dedicated line to call for an emergency response.

Limitations

These data are self-reported and only AEs that are scored as a safety assessment code 3 in the system receive a full RCA, so there are likely AEs that were not captured in this study. In addition, the RCA reports are deidentified and so do not include all patient characteristics. As the Veterans Health Administration system services mostly men, the data might not generalize to non–Veterans Health Administration systems with a different patient mix.

Conclusions

Care provided by rehabilitation professionals is generally safe, but AEs do occur. Based on this RCA review, the safety of rehabilitation services can be improved by implementing strong practices to mitigate risk to patients. Checklists should be considered to aid timely decision making when initiating an emergency response.
Ozone-Induced Vascular Contractility and Pulmonary Injury Are Differentially Impacted by Diets Enriched With Coconut Oil, Fish Oil, and Olive Oil
Authors: Snow Samantha J , Cheng Wan-Yun , Henriquez Andres , Hodge Myles , Bass Virgina , Nelson Gail M , Carswell Gleta , Richards Judy E , Schladweiler Mette C , Ledbetter Allen D , Chorley Brian , Gowdy Kymberly M , Tong Haiyan , Kodavanti Urmila P
Published: January 2018

Fish, olive, and coconut oil dietary supplementation have several cardioprotective benefits, but it is not established if they protect against air pollution-induced adverse effects. We hypothesized that these dietary supplements would attenuate ozone-induced systemic and pulmonary effects. Male Wistar Kyoto rats were fed either a normal diet, or a diet supplemented with fish, olive, or coconut oil for 8 weeks. Animals were then exposed to air or ozone (0.8 ppm), 4 h/day for 2 days. Ozone exposure increased phenylephrine-induced aortic vasocontraction, which was completely abolished in rats fed the fish oil diet. Despite this cardioprotective effect, the fish oil diet increased baseline levels of bronchoalveolar lavage fluid (BALF) markers of lung injury and inflammation. Ozone-induced pulmonary injury/inflammation were comparable in rats on normal, coconut oil, and olive oil diets with altered expression of markers in animals fed the fish oil diet. Fish oil, regardless of exposure, led to enlarged, foamy macrophages in the BALF that coincided with decreased pulmonary mRNA expression of cholesterol transporters, cholesterol receptors, and nuclear receptors. Serum microRNA profile was assessed and demonstrated marked depletion of a variety of microRNAs in animals fed the fish oil diet, several of which were of splenic origin. No ozone-specific changes were noted. Collectively, these data indicate that although fish oil offered vascular protection from ozone exposure, it increased pulmonary injury/inflammation and impaired lipid transport mechanisms resulting in foamy macrophage accumulation, demonstrating the need to be cognizant of potential off-target pulmonary effects that might offset the overall benefit of this vasoprotective supplement.
Contemporary Risk Factors and Outcomes of Transfusion-Associated Circulatory Overload*
Authors: Roubinian Nareg H. , Hendrickson Jeanne E. , Triulzi Darrell J. , Gottschall Jerome L. , Michalkiewicz Michael , Chowdhury Dhuly , Kor Daryl J. , Looney Mark R. , Matthay Michael A. , Kleinman Steven H. , Brambilla Donald , Murphy Edward L.
Published: January 2018

Objectives:

Transfusion-associated circulatory overload is characterized by hydrostatic pulmonary edema following blood transfusion. Restrictive transfusion practice may affect the occurrence and severity of transfusion-associated circulatory overload in critically ill patients. We sought to examine contemporary risk factors and outcomes for transfusion-associated circulatory overload.

Design:

Case-control study.

Setting:

Four tertiary care hospitals.

Patients:

We prospectively enrolled 200 patients with transfusion-associated circulatory overload identified by active surveillance and 405 controls matched by transfusion intensity.

Interventions:

None.

Measurements and Main Results:

Among 20,845 transfused patients who received 128,263 blood components from May 2015 until July 2016, transfusion-associated circulatory overload incidence was one case per 100 transfused patients. In addition to cardiovascular comorbidities, multivariable analysis identified the following independent predictors of transfusion-associated circulatory overload: acute kidney injury, emergency surgery, pretransfusion diuretic use, and plasma transfusion—the latter especially in females. Compared with matched controls, transfusion-associated circulatory overload cases were more likely to require mechanical ventilation (71% vs 49%; p < 0.001), experienced longer intensive care and hospital lengths of stay following transfusion, and had higher mortality (21% vs 11%; p = 0.02) even after adjustment for other potentially confounding variables.

Conclusions:

Despite restrictive transfusion practice, transfusion-associated circulatory overload remains a frequent complication of transfusion and is an independent risk factor for in-hospital morbidity and mortality. In addition to cardiovascular and renal risk factors, plasma transfusion was associated with transfusion-associated circulatory overload after controlling for other covariates. Additional research is needed to examine the benefit of reduced erythrocyte or plasma exposure in patients at high risk for transfusion-associated circulatory overload.
Predictors of Outcomes in Myocardial Infarction and Cardiogenic Shock
Authors: Acharya Deepak
Published: January 2018

Myocardial infarction (MI) complicated by cardiogenic shock (MI-CS) is a major cause of cardiovascular morbidity and mortality. Predictors of outcomes in MI-CS include clinical, laboratory, radiologic variables, and management strategies. This article reviews the existing literature on short- and long-term predictors and risk stratification in MI complicated by CS.
Speed of Language Comprehension at 18 Months Old Predicts School-Relevant Outcomes at 54 Months Old in Children Born Preterm
Authors: Marchman Virginia A. , Loi Elizabeth C. , Adams Katherine A. , Ashland Melanie , Fernald Anne , Feldman Heidi M.
Published: January 2018

Objective:

Identifying which preterm (PT) children are at increased risk of language and learning differences increases opportunities for participation in interventions that improve outcomes. Speed in spoken language comprehension at early stages of language development requires information processing skills that may form the foundation for later language and school-relevant skills. In children born full-term, speed of comprehending words in an eye-tracking task at 2 years old predicted language and nonverbal cognition at 8 years old. Here, we explore the extent to which speed of language comprehension at 1.5 years old predicts both verbal and nonverbal outcomes at 4.5 years old in children born PT.

Method:

Participants were children born PT (n = 47; ≤32 weeks gestation). Children were tested in the “looking-while-listening” task at 18 months old, adjusted for prematurity, to generate a measure of speed of language comprehension. Parent report and direct assessments of language were also administered. Children were later retested on a test battery of school-relevant skills at 4.5 years old.

Results:

Speed of language comprehension at 18 months old predicted significant unique variance (12%–31%) in receptive vocabulary, global language abilities, and nonverbal intelligence quotient (IQ) at 4.5 years, controlling for socioeconomic status, gestational age, and medical complications of PT birth. Speed of language comprehension remained uniquely predictive (5%–12%) when also controlling for children's language skills at 18 months old.

Conclusion:

Individual differences in speed of spoken language comprehension may serve as a marker for neuropsychological processes that are critical for the development of school-relevant linguistic skills and nonverbal IQ in children born PT.
Femtosecond Laser-Assisted Ipsilateral Rotational Lamellar Autokeratoplasty
Authors: Cassagne Myriam , Soler Vincent , Malecaze François , Fournié Pierre
Published: January 2018

Purpose:

To describe the surgical technique and report the outcomes of 2 patients treated with femtosecond laser-assisted ipsilateral rotational lamellar autokeratoplasty in central corneal scars.

Methods:

The corneal scar depth was mapped using preoperative optical coherence tomography. An eccentric lamellar lenticule was cut with a femtosecond laser and rotated to decenter corneal opacity and free the pupil area in 2 patients with nonprogressive central corneal scars. The surgical plan was set after simulating lenticule rotation with a digital corneal image and computer software.

Results:

In both cases, the corneal scar was decentered inferiorly, out of the pupillary area, with increased postoperative visual acuity but visual outcome limitations secondary to corneal irregularities and residual deep opacity.

Conclusions:

Femtosecond laser-assisted ipsilateral rotational lamellar autokeratoplasty is effective for shifting central corneal opacities and can be considered in appropriate cases.
Social Vulnerability in Congenital Syphilis Case Mothers: Qualitative Assessment of Cases in Indiana, 2014 to 2016
Authors: DiOrio Dawne , Kroeger Karen , Ross Amara
Published: January 2018

Background

Congenital syphilis occurs when a pregnant woman with syphilis is not diagnosed or treated and the infection is passed in utero, causing severe infant morbidity and mortality. Congenital syphilis is easily prevented if women receive timely and adequate prenatal care. Cases of congenital syphilis are considered indicators of problems in the safety net. However, maternal social and behavioral factors can impede women's care, even when providers follow guidelines.

Methods

We reviewed case interviews and maternal records for 23 congenital syphilis cases reported to the Centers for Disease Control and Prevention from Indiana between 2014 and 2016. We used qualitative methods to analyze narrative notes from maternal interviews to learn more about factors that potentially contributed to congenital syphilis cases.

Results

All providers followed Centers for Disease Control and Prevention and state recommendations for screening and treatment for pregnant women with syphilis. Twenty-one of 23 women had health insurance. The number of prenatal care visits women had was suboptimal; more than one third of women had no prenatal care. Nearly one third of women's only risk factor was sex with a primary male sex partner. The majority of women suffered social vulnerabilities, including homelessness, substance abuse, and incarceration.

Conclusions

Despite provider adherence to guidelines and health insurance availability, some pregnant women with syphilis are unlikely to receive timely diagnosis and treatment. Pregnant women at high risk for syphilis may need additional social and material support to prevent a congenital syphilis case. Additional efforts are needed to reach the male partners of vulnerable females with syphilis.
MDM2 Amplification in Intrahepatic Cholangiocarcinomas
Authors: Kim Sung Joo , Akita Masayuki , Sung You-Na , Fujikura Kohei , Lee Jae Hoon , Hwang Shin , Yu Eunsil , Otani Kyoko , Hong Seung-Mo , Zen Yoh
Published: January 2018

The present study aimed to characterize intrahepatic cholangiocarcinomas (iCCAs) with MDM2 amplification. A total of 213 cases of iCCA were examined using dual-color in situ hybridization for MDM2, immunohistochemistry for p53 and SMAD4, and gene sequencing for KRAS and IDH1/2. In situ hybridization on tissue microarrays identified MDM2 amplification in 13/213 (6%) cases. Using the recently proposed classification scheme of iCCAs (small-duct and large-duct types), all MDM2-amplified cases were of the large-duct type (13/110 cases, 12%). In whole section hybridization, MDM2 amplification appeared to be diffusely present in invasive areas. The loss of SMAD4 expression was more common in MDM2-amplified iCCAs than in those without MDM2 amplification. The relationship between MDM2 amplification and molecular alterations in p53 or KRAS was weak, with p53 overexpression and KRAS mutations only being found in 23% and 0% of cases, respectively. Overall survival was shorter in patients with MDM2-amplified iCCAs than in those with MDM2-nonamplified cancer (P=0.017); however, the lack of a prognostic impact of MDM2 amplification was confirmed in a subgroup analysis using only large-duct iCCAs. Additional studies on extrahepatic malignancies also identified MDM2 amplification in 8/68 (12%) hilar cholangiocarcinomas and 30/216 (14%) gallbladder cancers, but in 0/65 distal cholangiocarcinomas. In conclusion, MDM2 amplification in large-duct iCCAs is more common than presently considered, and it may represent a unique biliary carcinogenetic process in which KRAS and TP53 mutations are less frequent. MDM2 may become a promising drug target for not only large-duct iCCAs but also hilar and gallbladder cancers.
The Significance of Spermatic Cord Involvement by Testicular Germ Cell Tumors
Authors: Sanfrancesco Joseph M. , Trevino Karen E. , Xu Huiping , Ulbright Thomas M. , Idrees Muhammad T.
Published: January 2018

The recent 8th edition of the American Joint Committee on Cancer (AJCC) staging manual had multiple changes concerning how pathologists should stage germ cell tumors (GCTs) of the testis. A significant one concerns the impact of different types of spermatic cord involvement, specifically direct tumor extension versus discontinuous involvement by invasion through lymphovascular spaces. We compared clinicopathologic findings and outcome data between 2 cohorts with these findings to evaluate the validity of the change in the AJCC 8th edition manual. GCTs (seminomatous and nonseminomatous) of the testis were identified that had previously been staged as pT3 due to involvement of the spermatic cord. Pathologic, radiographic, and clinical findings were reviewed. Tumors were restaged based on AJCC 8th edition criteria and the cohorts were split into direct extension by tumor into the spermatic cord (pT3), spermatic cord soft tissue invasion via spread from discontinuously involved lymphovascular spaces (pT2pM1), or a combination of both (pT3pM1). One hundred cases of primary GCTs of the testis, previously classified as pT3 by the AJCC 6th or 7th cancer staging manuals from 2007 to 2015, were selected. Mixed malignant GCTs were the predominant tumor type, comprising 66% of all cases. Pure tumor morphologies included embryonal carcinoma (n=17), seminoma (n=14), teratoma (n=2), and yolk sac tumor (n=1). The tumors either directly invaded into the spermatic cord (n=78), involved the cord discontinuously via spread from lymphovascular spaces (n=18), or had both findings (n=4). Overall, 93% of patients presented at advanced clinical stage (CS). Using the AJCC 8th parameters, 12% of all tumors were upstaged. Changes included CSI (n=1) and CSII (n=11) tumors being reclassified as prognostic stage group III. Clinical and/or pathologic recurrence was identified in 19% of all patients, including 12 pT3 and 7 pM1 patients (P=0.11). Overall mean time to recurrence was 24.6 months, with a mean of 28.0 months for pT3 tumors and 18.9 months for pM1 tumors. Five patients were dead at the time of this study, including 3 (4%) with pT3 tumors and 2 (9%) in the pM1 cohort. Our findings support that seminomatous and nonseminomatous GCTs with spermatic cord invasion have a high frequency of advanced CS at presentation, regardless of involvement by direct extension or discontinuous spread via invasion from lymphovascular spaces. By designating the latter as M1, a spurious upstaging to prognostic stage group III is required by the AJCC 8th edition. We were unable to identify statistically significant difference between the 2 groups as it pertained to CS at presentation and likelihood of recurrence. Conversely, statistical trends favor that pM1 patients have more likely recurrence and worse prognosis than pT3 patients.
Erythropoietin in Treatment of Methanol Optic Neuropathy
Authors: Pakdel Farzad , Sanjari Mostafa S. , Naderi Asieh , Pirmarzdashti Niloofar , Haghighi Anousheh , Kashkouli Mohsen B.
Published: January 2018

Background:

Methanol poisoning can cause an optic neuropathy that is usually severe and irreversible and often occurs after ingestion of illicit or homemade alcoholic beverages. In this study, we evaluated the potential neuroprotective effect of erythropoietin (EPO) on visual acuity (VA) in patients with methanol optic neuropathy.

Methods:

In a prospective, noncomparative interventional case series, consecutive patients with methanol optic neuropathy after alcoholic beverage ingestion were included. All patients initially received systemic therapy including metabolic stabilization and detoxification. Treatment with intravenous recombinant human EPO consisted of 20,000 units/day for 3 successive days. Depending on clinical response, some patients received a second course of EPO. VA, funduscopy, and spectral domain optical coherence tomography were assessed during the study. Main outcome measure was VA.

Results:

Thirty-two eyes of 16 patients with methanol optic neuropathy were included. Mean age was 34.2 years (±13.3 years). The mean time interval between methanol ingestion and treatment with intravenous EPO was 9.1 days (±5.56 days). Mean follow-up after treatment was 7.5 months (±5.88 months). Median VA in the better eye of each patient before treatment was light perception (range: 3.90–0.60 logMAR). Median last acuity after treatment in the best eye was 1.00 logMAR (range: 3.90–0.00 logMAR). VA significantly increased in the last follow-up examination (P < 0.0001). Age and time to EPO treatment after methanol ingestion were not significantly related to final VA. No ocular or systemic complications occurred in our patient cohort.

Conclusions:

Intravenous EPO appears to improve VA in patients with methanol optic neuropathy and may represent a promising treatment for this disorder.
Evolutionary dynamics of the cryptocurrency market
Authors: ElBahrawy Abeer , Alessandretti Laura , Kandler Anne , Pastor-Satorras Romualdo , Baronchelli Andrea
Published: January 2018

The cryptocurrency market surpassed the barrier of $100 billion market capitalization in June 2017, after months of steady growth. Despite its increasing relevance in the financial world, a comprehensive analysis of the whole system is still lacking, as most studies have focused exclusively on the behaviour of one (Bitcoin) or few cryptocurrencies. Here, we consider the history of the entire market and analyse the behaviour of 1469 cryptocurrencies introduced between April 2013 and May 2017. We reveal that, while new cryptocurrencies appear and disappear continuously and their market capitalization is increasing (super-)exponentially, several statistical properties of the market have been stable for years. These include the number of active cryptocurrencies, market share distribution and the turnover of cryptocurrencies. Adopting an ecological perspective, we show that the so-called neutral model of evolution is able to reproduce a number of key empirical observations, despite its simplicity and the assumption of no selective advantage of one cryptocurrency over another. Our results shed light on the properties of the cryptocurrency market and establish a first formal link between ecological modelling and the study of this growing system. We anticipate they will spark further research in this direction.
Cell type-specific CLIP reveals that NOVA regulates cytoskeleton interactions in motoneurons
Authors: Yuan Yuan , Xie Shirley , Darnell Jennifer C. , Darnell Andrew J. , Saito Yuhki , Phatnani Hemali , Murphy Elisabeth , Zhang Chaolin , Maniatis Tom , Darnell Robert B.
Published: January 2018

Background

Alternative RNA processing plays an essential role in shaping cell identity and connectivity in the central nervous system (CNS). This is believed to involve differential regulation of RNA processing in various cell types. However,in vivostudy of cell-type specific post-transcriptional regulation has been a challenge. Here, we developed a sensitive and stringent method combining genetics and CLIP (crosslinking and immunoprecipitation) to globally identify regulatory interactions between NOVA and RNA in the mouse spinal cord motoneurons (MNs).

Results

We developed a means of undertaking MN-specific CLIP to explore MN-specific protein-RNA interactions relative to studies of the whole spinal cord. This allowed us to pinpoint differential RNA regulation specific to MNs, revealing major role for NOVA in regulating cytoskeleton interactions in MNs. In particular, NOVA specifically promotes the palmitoylated isoform of a cytoskeleton protein Septin 8 in MNs, which enhances dendritic arborization.

Conclusions

Our study demonstrates that cell type-specific RNA regulation is important for fine-tuning motoneuron physiology, and highlights the value of defining RNA processing regulation at single cell type resolution.
Aged blood inhibits hippocampal neurogenesis and activates microglia through VCAM1 at the blood-brain barrier
Authors: Yousef Hanadie , Czupalla Cathrin J , Lee Davis , Burke Ashley , Chen Michelle , Zandstra Judith , Berber Elisabeth , Lehallier Benoit , Mathur Vidhu , Nair Ramesh V , Bonanno Liana , Merkel Taylor , Schwaninger Markus , Quake Stephen , Butcher Eugene C , Wyss-Coray Tony
Published: January 2018

An aged circulatory environment can promote brain dysfunction and we hypothesized that the blood-brain barrier (BBB) mediates at least some of these effects. We observe brain endothelial cells (BECs) in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of Vascular Cell Adhesion Molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, the shed, soluble form of VCAM1 is prominently increased in the aged circulation of humans and mice, and aged plasma is sufficient to increase VCAM1 expression in cultured BECs and young mouse hippocampi. Systemic anti-VCAM1 antibody or genetic ablation of VCAM1 in BECs counteracts the detrimental effects of aged plasma on young brains and reverses aging aspects in old mouse brains. Thus, VCAM1 is a negative regulator of adult neurogenesis and inducer of microglial reactivity, establishing VCAM1 and the luminal side of the BBB as possible targets to treat age-related neurodegeneration.
Algebraic Shortcuts for Leave-One-Out Cross-Validation in Supervised Network Inference
Authors: Stock Michiel , Pahikkala Tapio , Airola Antti , Waegeman Willem , De Baets Bernard
Published: January 2018

Motivation

Supervised machine learning techniques have traditionally been very successful at reconstructing biological networks, such as protein-ligand interaction, protein-protein interaction and gene regulatory networks. Recently, much emphasis has been placed on the correct evaluation of such supervised models. It is vital to distinguish between using the model to either predict new interactions in a given network or to predict interactions for a new vertex not present in the original network. Specific cross-validation schemes need to be used to assess the performance in such different prediction settings.

Results

We present a series of leave-one-out cross-validation shortcuts to rapidly estimate the performance of state-of-the-art kernel-based network inference techniques.

Availability

The machine learning techniques with the algebraic shortcuts are implemented in the RLScore software package.
Power spectrum slope and motor function recovery after focal cerebral ischemia in the rat
Authors: Leemburg Susan , Gao Bo , Cam Ertugrul , Sarnthein Johannes , Bassetti Claudio L.
Published: January 2018

EEG changes across vigilance states have been observed after ischemic stroke in patients and experimental stroke models, but their relation to functional recovery remains unclear. Here, we evaluate motor function, as measured by single pellet reaching (SPR), as well as local EEG changes in NREM, REM and wakefulness during a 30-day recovery period after middle cerebral artery occlusion (MCAO) or sham surgery in rats. Small cortical infarcts resulted in poor SPR performance and induced widespread changes in EEG spectra in the ipsilesional hemisphere in all vigilance states, without causing major changes in sleep-wake architecture. Ipsilesional 1–4 Hz power was increased after stroke, whereas power in higher frequencies was reduced, resulting in a steeper slope of the power spectrum. Multielectrode array analysis of ipsilesional M1 showed that these spectral changes were present on the microelectrode level throughout M1 and were not related to increased synchronization between electrodes. Spectrum slope was significantly correlated with post-stroke motor function.
Reproductive phasiRNAs in grasses are compositionally distinct from other classes of small RNAs
Authors: Patel Parth , Mathioni Sandra , Kakrana Atul , Shatkay Hagit , Meyers Blake C.
Published: January 2018

Summary and keywords

Little is known about the characteristics and function of reproductive phased, secondary, small interfering RNAs (phasiRNAs) in the Poaceae, despite the availability of significant genomic resources, experimental data, and a growing number of computational tools. We utilized machine-learning methods to identify sequence-based and structural features that distinguish phasiRNAs in rice and maize from other small RNAs (sRNAs).

We developed Random Forest classifiers that can distinguish reproductive phasiRNAs from other sRNAs in complex sets of sequencing data, utilizing sequence-based (k-mers) and features describing position-specific sequence biases.

The classification performance attained is >80% in accuracy, sensitivity, specificity, and positive predicted value. Feature selection identified important features in both ends of phasiRNAs. We demonstrated that phasiRNAs have strand specificity and position-specific nucleotide biases potentially influencing AGO sorting; we also predicted targets to infer functions of phasiRNAs, and computationally-assessed their sequence characteristics relative to other sRNAs.

Our results demonstrate that machine-learning methods effectively identify phasiRNAs despite the lack of characteristic features typically present in precursor loci of other small RNAs, such as sequence conservation or structural motifs. The 5’-end features we identified provide insights into AGO-phasiRNA interactions; we describe a hypothetical model of competition for AGO loading between phasiRNAs of different nucleotide compositions.
Genome-wide signals of drift and local adaptation during rapid lineage divergence in a songbird
Authors: Friis Guillermo , Fandos Guillermo , Zellmer Amanda , McCormack John , Faircloth Brant , Milá Borja
Published: January 2018

The formation of independent evolutionary lineages involves neutral and selective factors, and understanding their relative roles in population divergence is a fundamental goal of speciation research. Correlations between allele frequencies and environmental variability can reveal the role of selection, yet the relative contribution of drift can be difficult to establish. Recently diversified systems such as that of the Oregon junco (Aves: Emberizidae) of western North America provide ideal scenarios to apply genetic-environment association analyses (GEA) while controlling for population structure. Genome-wide SNP loci analyses revealed marked genetic structure consisting of differentiated populations in isolated, dry southern mountain ranges, and more admixed recently expanded populations in humid northern latitudes. We used correlations between genomic and environmental variance to test for three specific modes of evolutionary divergence: (i) drift in geographic isolation, (ii) differentiation along continuous selective gradients, and (iii) isolation by adaptation. We found evidence of strong drift in southern mountains, but also signals of local adaptation in several populations, driven by temperature, precipitation, elevation and vegetation, especially when controlling for population history. We identified numerous variants under selection scattered across the genome, suggesting that local adaptation can promote rapid differentiation over short periods when acting over multiple independent loci.
Cis-directed cleavage and nonstoichiometric abundances of 21-nt reproductive phasiRNAs in grasses
Authors: Tamim Saleh , Cai Zhaoxia , Mathioni Sandra , Zhai Jixian , Teng Chong , Zhang Qifa , Meyers Blake C.
Published: January 2018

Post-transcriptional gene silencing in plants results from independent activities of diverse small RNA types. In anthers of grasses, hundreds of loci yield non-coding RNAs that are processed into 21- and 24-nt phased small interfering RNAs (phasiRNAs); these are triggered by miR2118 and miR2275.

We characterized these “reproductive phasiRNAs” from rice panicles and anthers across seven developmental stages. Our computational analysis identified characteristics of the 21-nt reproductive phasiRNAs that impact their biogenesis, stability, and potential functions.

We demonstrate that 21-nt reproductive phasiRNAs can function in cis to target their own precursors. We observed evidence of this cis regulatory activity in both rice (Oryza sativa) and maize (Zea mays). We validated this activity with evidence of cleavage and a resulting shift in the pattern of phasiRNA production.

We characterize biases in phasiRNA biogenesis, demonstrating that the Pol II-derived “top” strand phasiRNAs are consistently higher abundance than the bottom strand. The first phasiRNA from each precursor overlaps the miR2118 target site, and this impacts phasiRNA accumulation or stability, evident in the weak accumulation of this phasiRNA position. Additional influences on this first phasiRNA duplex include the sequence composition and length, and we show that these factors impact Argonaute loading.
Enhancer-gene maps in the human and zebrafish genomes using evolutionary linkage conservation
Authors: Clément Yves , Torbey Patrick , Gilardi-Hebenstreit Pascale , Crollius Hugues Roest
Published: January 2018

The spatiotemporal expression of genes is controlled by enhancer sequences that bind transcription factors. Identifying the target genes of enhancers remains difficult because enhancers regulate gene expression over long genomic distances. To address this, we used an evolutionary approach to build two genome-wide maps of enhancer-gene associations in the human and zebrafish genomes. Enhancers were identified using sequence conservation, and linked to their predicted target genes using PEGASUS, a bioinformatics method that relies on evolutionary conservation of synteny. The analysis of these maps revealed that the number of enhancers linked to a gene correlate with its expression breadth. Comparison of both maps identified hundreds of vertebrate ancestral regulatory relationships from which we could determine that enhancer-gene distances scale with genome size despite strong positional conservation. The two maps represent a resource for further studies, including the prioritisation of sequence variants in whole genome sequence of patients affected by genetic diseases.
NanoAmpli-Seq: A workflow for amplicon sequencing for mixed microbial communities on the nanopore sequencing platform
Authors: Calus Szymon T , Ijaz Umer Z , Pinto Ameet J
Published: January 2018

Background

Amplicon sequencing on Illumina sequencing platforms leverages their deep sequencing and multiplexing capacity, but is limited in genetic resolution due to short read lengths. While Oxford Nanopore or Pacific Biosciences platforms overcome this limitation, their application has been limited due to higher error rates or smaller data output.

Results

In this study, we introduce an amplicon sequencing workflow, i.e., NanoAmpli-Seq, that builds on Intramolecular-ligated Nanopore Consensus Sequencing (INC-Seq) approach and demonstrate its application for full-length 16S rRNA gene sequencing. NanoAmpli-Seq includes vital improvements to the aforementioned protocol that reduces sample-processing time while significantly improving sequence accuracy. The developed protocol includes chopSeq software for fragmentation and read orientation correction of INC-Seq consensus reads while nanoClust algorithm was designed for read partitioning-based de novo clustering and within cluster consensus calling to obtain full-length 16S rRNA gene sequences.

Conclusions

NanoAmpli-Seq accurately estimates the diversity of tested mock communities with average sequence accuracy of 99.5% for 2D and 1D2 sequencing on the nanopore sequencing platform. Nearly all residual errors in NanoAmpli-Seq sequences originate from deletions in homopolymer regions, indicating that homopolymer aware basecalling or error correction may allow for sequencing accuracy comparable to short-read sequencing platforms.