bluuebunny/crossref_metadata_2025 huggingface dataset:
Youth Baseball Pitch Counts Vastly Underestimate High-effort Throws Throughout a Season
Authors: Wahl Elizabeth P. , Pidgeon Tyler S. , Richard Marc J.
Published: February 2020

Background:

The primary purpose of this study was to compare the number of pitches thrown by youth baseball players under the official league guidelines versus the number of “high-effort” throws recorded by a validated digital sensor worn by the players during a season.

Methods:

In total, 11 and 12-year-old youth baseball players from a single league were provided an elbow sleeve and sensor to wear each time they threw a baseball for an entire baseball season. The sensor tracked total throws and pitch-equivalent high-effort throws for the season. Official pitch counts were collected at each game from the official scorekeepers.

Results:

A total of 19 players participated in the study. The sensor-determined mean total throw count (1666.2±642.2) and mean high-effort throw count (576.9±329.3) per player were both significantly higher, P<0.0001 and P=0.02, respectively, than the mean official pitch count (168.1±122.4).

Conclusions:

Our findings demonstrate that youth players make significantly more total throws and high-effort, or pitch-equivalent, throws, than what is recorded by the official pitch counts. Further research is needed to determine a safe annual “throw count” for young throwing athletes and to determine which types of throws, in addition to pitches, put youth throwers at risk for injury.

Level of Evidence:

Level IV.
Arrhythmogenic Right Ventricular Cardiomyopathy Diagnosis
Authors: Sayed Amer , Pal Suman , Poplawska Maria , Aronow Wilbert S. , Frishman William H. , Fuisz Anthon , Jacobson Jason T.
Published: February 2020

Arrhythmogenic right ventricular cardiomyopathy, formerly called “arrhythmogenic right ventricular dysplasia,” is an under-recognized clinical entity characterized by ventricular arrhythmias and a characteristic ventricular pathology. Diagnosis is often difficult due to the nonspecific nature of the disease and the broad spectrum of phenotypic variations. Therefore, consensus diagnostic criteria have been developed which combine electrocardiographic, echocardiographic, cardiac magnetic resonance imaging and histologic criteria. In 1994, an international task force first proposed the major and minor diagnostic criteria of arrhythmogenic right ventricular cardiomyopathy based on family history, arrhythmias, electrocardiographic abnormalities, tissue characterization, and structural and functional right ventricular abnormalities. In 2010, the task force criteria were revised to include quantitative abnormalities. These diagnostic modalities and the most recent task force criteria are discussed in this review.
Perspective-taking influences attentional deployment towards facial expressions of pain: an eye-tracking study
Authors: Pilch Monika , O'Hora Denis , Jennings Caroline , Caes Line , McGuire Brian E. , Kainz Veronika , Vervoort Tine
Published: February 2020

Empathetic perspective-taking (PT) may be critical in modulating attention and associated responses to another's pain. However, the differential effects of imagining oneself to be in the pain sufferer's situation (“Self-perspective”) or imagining the negative impacts on the pain sufferer's experience (“Other-perspective”) on attention have not been studied. The effects of observer PT (Self vs Other) and level of facial pain expressiveness (FPE) upon attention to another person's pain was investigated. Fifty-two adults were assigned to 1 of 3 PT conditions; they were instructed to view pairs of pain expressions and neutral faces and either (1) consider their own feelings (Self-perspective), (2) consider the feelings of the person in the picture (Other-perspective), or (3) received no further instructions (Control). Eye movements provided indices of early (probability and duration of first fixation) and later (total gaze duration) attentional deployment. Pain faces were more likely to be fixated upon first. A significant first fixation duration bias towards pain was observed, which increased with increasing levels of FPE, and was higher in the Self-PT than the Control condition. The proportion of total gaze duration on pain faces was higher in both experimental conditions than the Control condition. This effect was moderated by FPE in the Self-PT condition; there was a significant increase from low to high FPE. When observers attend to another's facial display of pain, top-down influences (such as PT) and bottom-up influences (such as sufferer's FPE) interact to control deployment and maintenance of attention.
Mechanisms of Hippo pathway in the pancreatic cancer
Authors: Xie Ruiling , Chen Rui
Published: February 2020

Pancreatic ductal adenocarcinoma (PDAC) is a lethal, aggressive, and incurable disease. The patients with PDAC are often diagnosed at the advanced stage, leading to poor overall survival because of no current effective treatment. Further exploration of the mechanism is needed urgently to provide insights on the prevention, detection, or intervention of pancreatic cancer. Oncogenic KRAS and mutated tumor suppressor genes serve essential roles in PDAC tumorigenesis. Different groups of scientists indicated that yes-associated protein and transcriptional coactivator with PDZ-binding motif, which are the main effectors of the Hippo pathway, are the center in the development of PDAC. Here, we will focus on the recent advances of the molecular mechanisms of core components in the Hippo kinases cascade and discuss their clinical implications.
Impact of Underlying Diagnosis on Speech and Quality of Life Outcomes After Cochlear Implantation for Single-Sided Deafness
Authors: Hwa Tiffany Peng , Sturm Joshua J. , Losenegger Tasher , Owen Abby , Kuhlmey Megan , Cellum Ilana , Lalwani Anil K. , Lustig Lawrence R. , Golub Justin S. , Kim Ana H.
Published: February 2020

Objective:

Our objective was to compare outcomes in speech and quality of life in those undergoing cochlear implantation for single-sided deafness (SSD), with the aim to characterize the clinical impact of underlying diagnosis in the affected ear and pre-operative hearing status.

Study Design:

Prospective case series.

Setting:

Academic Cochlear Implant Center.

Patients:

42 adult patients implanted with the diagnosis of SSD.

Interventions:

Patients were evaluated at 3-, 6-, and 12-months post-operatively using AZBio sentence and speech, and consonant-nucleus-consonant (CNC) depending on appropriate testing level. Our previously validated Comprehensive Cochlear Implant Quality of Life (CCIQ) questionnaire was administered.

Main Outcome Measures:

Speech perception, quality of life.

Results:

Subjects were stratified by the underlying diagnosis: Meniere's Disease (MD; n = 10), sudden sensorineural hearing loss (SSNHL; n = 13), and Other (eg TBI, acoustic neuroma, progressive, noise-induced; n = 19). Mean preoperative PTA of the implanted ear was 82dB ± 17; that of the nonimplanted ear was 32dB ± 17. SSNHL and MD demonstrated the highest speech perception score at 3 months (93 and 95%), and “Other” demonstrated the lowest scores at 88%. All 3 groups demonstrated nadir in speech scores at 6 months before improving at 12 months, but the “Other” diagnoses maintained the lowest speech testing across all time points. All 3 groups reported improved quality of life on CCIQ.

Conclusions:

Subjects with SSNHL and MD demonstrate excellent speech perception and quality of life outcomes after cochlear implantation for SSD. Subjects with “Other” diagnoses underlying their SSD demonstrated lower scores on speech testing but nonetheless reported improved quality of life.
The early prediction of pathological response to neoadjuvant chemotherapy and prognosis: comparison of PET Response Criteria in Solid Tumors and European Organization for Research and Treatment of Cancer criteria in breast cancer
Authors: Lian Weiling , Liu Cheng , Gu Bingxin , Zhang Jianping , Lu Linjun , Pan Herong , Yao Zhifeng , Wang Mingwei , Song Shaoli , Zhang Yingjian , Yang Zhongyi
Published: February 2020

Objective

To compare the predictive value of European Organization for Research and Treatment of Cancer (EORTC) criteria and PET Response Criteria in Solid Tumors (PERCIST), for the pathological response and prognosis of patients with breast cancer receiving neoadjuvant chemotherapy (NAC).

Methods

Consecutive PET/computed tomography scans in 128 operable female patients at baseline and after two courses of NAC were performed. Patients were categorized by complete metabolic response (CMR) and non-CMR groups using 2 PET criteria. CMR and non-CMR were used to predict pathological complete response (pCR) by diagnostic test evaluation, and to predict progression-free survival (PFS) using Kaplan–Meier plots and Cox proportional hazards regression.

Results

Ninety-two patients were finally analyzed. The sensitivity, specificity, and accuracy for pCR prediction were 69.7, 76.3, and 73.9% with EORTC criteria, and 69.7, 77.9, and 75.0% with PERCIST, respectively. Peak standardized uptake value normalized to lean body mass (SULpeak), maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and metabolic tumor volume (MTV) were pCR response with accuracy of 70.7, 60.0, 75.0, and 71.4%, respectively. CMR by the EORTC (P = 0.021) and PERCIST (P = 0.007) was significantly related to a longer PFS. The univariate and multivariate analysis suggested that CMR by PERCIST was an independent predictor of recurrence (P = 0.008).

Conclusion

EORTC criteria and PERCIST had early predictive value to long-term outcome, but moderate value for pCR. Furthermore, PERCIST might show more potential than the EORTC criteria and conventional PET-based parameters to predict prognosis in breast cancer patients following two cycles of neoadjuvant chemotherapy.

Video abstract: see http://links.lww.com/NMC/A162.
Value of 18F-FDG PET/computed tomography in predicting the simplified WHO grade of malignancy in thymic epithelial tumors
Authors: Zhao Juan , Wang Huoqiang , Li Qiang
Published: February 2020

Objective

To investigate the value of 18F-fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) in predicting the simplified WHO grade of malignancy in thymic epithelial tumors.

Materials and methods

We retrospectively reviewed 81 patients with pathologically proven thymic epithelial tumors who underwent 18F-FDG PET/CT before surgical resection. Maximum standardized uptake value (SUVmax) and SUVmax/tumor size were measured on the primary lesion. A receiver operating characteristics (ROC) curve were performed for assessing the ability of 18F-FDG PET/CT as a predictor of the simplified WHO classification.

Results

There were 43 male patients (53.1%) and 38 female patients (46.9%), and the mean age was 55.6 ± 11.9 years. The mean tumor size was 53.2 ± 21.4 mm. There were 24 low-risk thymomas (29.6%) (A, AB, and B1), 29 high-risk thymomas (35.8%) (B2 and B3), and 28 thymic carcinomas (34.6%). The SUVmax and SUVmax/tumor size were found to be predictive factors that were useful to distinguish thymomas and thymic carcinomas, and area under the ROC curve were 0.820 and 0.691, respectively (P < 0.05), and the cutoff value for discriminating thymomas and thymic carcinomas was 5.34.

Conclusion

In conclusion, a significant relationship was observed between SUVmax, SUVmax/tumor size and histological WHO classification of thymic epithelial tumors. 18F-FDG PET/CT may be useful for predicting the grade of malignancy in thymic epithelial.
Staffing Utilization and Fall Prevention With an Electronic Surveillance Video System
Authors: Daley Brittney , Fetherman Brandee , Turner Joanne
Published: February 2020

Background:

There is limited research addressing how to optimize both staffing and patient outcomes with the use of technology to reduce falls during hospitalization.

Purpose:

We compared the effects of 2 staffing patterns in conjunction with the use of an electronic surveillance system on patient falls on an inpatient medical unit.

Methods:

Study participants were randomized to receive electronic surveillance system monitoring with a dedicated rounder or electronic surveillance system without a dedicated rounder. Falls during the study period were analyzed.

Results:

Of 1032 patients, there were 8 falls during the 3-month study. Six falls occurred in the intervention group, with no rounder, and 2 occurred in the group with a dedicated rounder. The data showed no statistical significance but had clinical implications.

Conclusion:

In response to our findings, the dedicated rounder will function as a mobility technician, providing support to our nursing staff and a resource for fall risk patients.
Primary Rhinoplasty Does Not Interfere with Nasal Growth: A Long-Term Three-Dimensional Morphometric Outcome Study in Patients with Unilateral Cleft
Authors: Seo Hyung Joon , Denadai Rafael , Vamvanij Natthacha , Chinpaisarn Chatchawarn , Lo Lun-Jou
Published: February 2020

Background:

Primary rhinoplasty has not been universally adopted because the potential for nasal growth impairment remains an unsolved issue in cleft care. This study’s purpose was to assess the long-term effects of primary rhinoplasty performed by a single surgeon in a cohort of patients with a unilateral cleft lip nose deformity.

Methods:

Three-dimensional nasal morphometric measurements (linear, angular, proportional, surface area, and volume) were collected from consecutive patients (cleft group, n = 52; mean age, 19 ± 1 year) who had undergone primary rhinoplasty with the use of the Noordhoff approach between 1995 and 2002 and reached skeletal maturity. Normal age-, sex-, and ethnicity-matched subjects (control group, n = 52) were identified for comparative analyses.

Results:

No significant differences (all p > 0.05) were observed for most measures, including nasal height, alar width, nasal dorsum angle, columellar angle, columellar-labial angle, nasal tip/height ratio, nasal index, alar width/intercanthal distance ratio, nasal surface area, and nasal volume. The cleft group displayed significantly (all p < 0.05) lower nasal bridge length and nasal tip projection, and greater nasal protrusion, tip/midline deviation, nasal tip angle, nasal tip protrusion width index, and alar width/mouth ratio values than the control group.

Conclusions:

Primary rhinoplasty does not interfere with nasal growth as measured by three-dimensional photogrammetric analysis. Further imaging studies are required for the assessment of development in other anatomical nasal structures.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Evolutionary context can clarify teleosts gene names
Authors: Gasanov E.V. , Jędrychowska J. , Kuźnicki J. , Korzh V.
Published: February 2020

The initial convention to name genes relied on historical precedent, order in the human genome or mutants in model systems. However, partial duplication of genes in teleosts required naming the duplicated genes, so ohnologs adopted the ‘a’ or ‘b’ extension. Rapid advances in deciphering the zebrafish genome in relation to the human genome instituted naming genes in all other fish genomes in the convention of zebrafish. Unfortunately, some ohnologs and their resembling orthologs suffered from incorrect nomenclature, which created confusion in particular instances like establishing disease models. We sought to overcome this barrier by establishing theex silicoevolutionary-based systematic approach to naming the ohnologs in teleosts and other fish. We compared gene synteny using the spotted gar genome as the reference, which represents the unduplicated ancestral state. Using new criteria, we identified several hundreds of potentially misnamed ohnologs and validated manually several ohnologs as a proof pf principle. This may help to establish a standard naming practice resulting in the improved evolutionary-based gene nomenclature. This approach may help to identify and rename ohnologs in all relevant EMBL-EBI and NCBI databases starting from the zebrafish genome to avoid further proliferation of misleading information.
An unusual MHC molecule generates protective CD8+ T cell responses to chronic infection
Authors: Tsitsiklis A. , Bangs D.J. , Lutes L.K. , Chan S-W. , Geiger K. , Modzelewski A.J. , Labarta-Bajo L. , Wang Y. , Zuniga E.I. , Dai S. , Robey E.A.
Published: February 2020

The CD8+ T cell response to the intracellular parasiteToxoplasma gondiivaries dramatically between mouse strains, resulting in differences in control of the parasite. Protection in BALB/c mice can be attributed to an unusually strong and protective MHC-1 Ld-restricted CD8+ T cell response directed against a peptide derived from the parasite antigen GRA6. The MHC-1 Ldmolecule has limited peptide binding compared to conventional MHC molecules such as Kbor Db, which correlates with polymorphisms associated with “elite control” of HIV in humans. To investigate the link between the unusual MHC-1 molecule Ldand the generation of “elite controller” CD8+ T cell responses, we compared the GRA6-Ldspecific T cell response to the well-studied OVA-Kbspecific response, and demonstrated that GRA6-Ldspecific T cells are significantly more protective and resistant to exhaustion in chronicT. gondiiinfection. To further investigate the connection between limited peptide presentation and robust T cell responses, we used CRISPR/Cas9 to generate mice with a point mutation (W97R) in the peptide-binding groove of Ldthat results in broader peptide binding. We investigated the effect of this LdW97R mutation on another robust Ld-restricted response against the IE1 peptide during Murine Cytomegalovirus (MCMV) infection. This mutation leads to an increase in exhaustion markers in the IE1-Ldspecific CD8+ T cell response. Our results indicate that limited peptide binding by MHC-1 Ldcorrelates with the development of robust and protective CD8+ T cell responses that may avoid exhaustion during chronic infection.
Although host-related factors are important for the formation of gut microbiota, environmental factors cannot be ignored
Authors: Jung YeonGyun , Kerfahi Dorsaf , Pham Huy Quang , Son HyunWoo , Ibal Jerald Conrad , Park Min-Kyu , Park Yeong-Jun , Park Chang Eon , Choi Seung-Dae , Jo YoungJae , Kim Min-Chul , Kim Min Ji , Kang Gi Ung , Jo Hyung Woo , Yun Hyunju , Lee Bora , Park Clara Yongjoo , Kim Eun Soo , Kim Sang-Jun , Shin Jae-Ho
Published: February 2020

The gut microbiome is essential to human health. However, little is known about the influence of the environment versus host-related factors (e.g. genetic background, sex, age, and body mass) in the formation of human intestinal microflora. Here, we present evidence in support of the importance of host-related factors in the establishment and maintenance of individual gut assemblages. We collected fecal samples (n = 249) from 44 Korean naval trainees and 39 healthy people living in Korea over eight weeks and sequenced the bacterial 16S rRNA genes. The following hypotheses were tested: 1) microbiome function is linked to its diversity, community structure, and genetic host-related factors, and 2) preexisting host-related factors have a more significant effect on gut microbiome formation and composition than environmental factors. For each individual, the difference between the initial gut microbiota and that after eight weeks was negligible even though the 44 naval trainees lived in the same area and received the same diet, the same amount of exercise, and the same amount of physical stress during the study. This suggests that host-related factors, rather than environmental factors, is a key determinant of individual gut microflora. Moreover, eight weeks of physical training and experiencing the same environmental conditions resulted in an increase in the speciesBifidobacterium,Faecalibacterium, andRoseburiain most trainees, suggesting a healthier intestinal environment.

IMPORTANCE

In order to understand the role of human gut microbiome, it is important to know how individual’s gut microbiota are formed. In this study, we tested the host-related factors versus environmental factors to affect gut microbiome and found that the former have a more association. However, we also found that the controlled environment give an effect on the gut microflora as well. This study provides preliminary evidence that differences in the formation and diversity of gut microbiota within a population could be determined by host-related factors rather than environmental factors.
Epigenetic biomarkers of ageing are predictive of mortality risk in a longitudinal clinical cohort of individuals diagnosed with oropharyngeal cancer
Authors: Beynon Rhona A , Ingle Suzanne M , Langdon Ryan , May Margaret , Ness Andy , Martin Richard , Suderman Matthew , Ingarfield Kate , Marioni Riccardo , McCartney Daniel , Waterboer Tim , Pawlita Michael , Relton Caroline , Smith George Davey , Richmond Rebecca
Published: February 2020

Background

Epigenetic clocks are biomarkers of ageing derived from DNA methylation levels at a subset of CpG sites. The difference between predicted age from these clocks and chronological age (“epigenetic age acceleration”) has been shown to predict age-related disease and mortality. We aimed to assess the prognostic value of epigenetic age acceleration with all-cause mortality in a prospective clinical cohort of individuals with head and neck cancer: Head and Neck 5000.

Methods

We investigated two markers of intrinsic epigenetic age acceleration (IEAAHorvathandIEAAHannum), one marker of extrinsic epigenetic age acceleration (EEAA), one optimised to predict physiological dysregulation (AgeAccelPheno) and one optimised to predict lifespan (AgeAccelGrim). Cox regression models were first used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of epigenetic age acceleration with all-cause mortality in people with oropharyngeal cancer (n=408;105 deaths). The added prognostic value of epigenetic measures compared to a clinical model including age, gender, TNM stage and HPV status was then evaluated.

Results

IEAAHannumandAgeAccelGrimwere associated with mortality risk after adjustment for clinical and lifestyle factors [HRs per standard deviation (SD) increase in age acceleration =1.32 (95% CI=1.08, 1.61; p=0.007) and 1.39 (95% CI =1.06, 1.83; p=0.017), respectively]. There was weak evidence that the addition ofAgeAccelGrimto the clinical model improved 3-year mortality prediction (area under the receiver operating characteristic curve: 0.80 vs. 0.77; p-value for difference=0.069).

Conclusion

Our study demonstrates the potential of epigenetic age acceleration measures to enhance survival prediction in people with oropharyngeal cancer, beyond established prognostic factors.
Machine Learning Can Predict Deaths in Patients with Diverticulitis During their Hospital Stay
Authors: Ahmed Fahad Shabbir , Raza-Ul-Mustafa  , Ali Liaqat , Imad-ud-Deen  , Hameed Tahir , Ikram Asad , Bukhari Syed Ahmad Chan
Published: February 2020

Introduction

Diverticulitis is the inflammation and/or infection of small pouches known as diverticula that develop along the walls of the intestines. Patients with diverticulitis are at risk of mortality as high as 17% with abscess formation and 45% with secondary perforation, especially patients that get admitted to the inpatient services are at risk of complications including mortality. We developed a deep neural networks (DNN) based machine learning framework that could predict premature death in patients that are admitted with diverticulitis using electronic health records (EHR) to calculate the statistically significant risk factors first and then to apply deep neural network.

Methods

Our proposed framework (Deep FLAIM) is a two-phase hybrid works framework. In the first phase, we used National In-patient Sample 2014 dataset to extract patients with diverticulitis patients with and without hemorrhage with the ICD-9 codes 562.11 and 562.13 respectively and analyzed these patients for different risk factors for statistical significance with univariate and multivariate analyses to generate hazard ratios, to rank the diverticulitis associated risk factors. In the second phase, we applied deep neural network model to predict death. Additionally, we have compared the performance of our proposed system by using the popular machine learning models such as DNN and Logistic Regression (LR).

Results

A total of 128,258 patients were used, we tested 64 different variables for using univariate and multivariate (age, gender and ethnicity) cox-regression for significance only 16 factors were statistically significant for both univariate and multivariate analysis. The mortality prediction for our DNN out-performed the conventional machine learning (logistic regression) in terms of AUC (0.977 vs 0.904), training accuracy (0.931 vs 0.900), testing accuracy (0.930 vs 0.910), sensitivity (90% vs 88%) and specificity (95% vs 93%).

Conclusion

Our Deep FLAIM Framework can predict mortality in patients admitted to the hospital with diverticulitis with high accuracy. The proposed framework can be expanded to predict premature death for other disease.
Cost-effectiveness of real-world administration of chemotherapy and add-on Viscum album L. therapy compared to chemotherapy alone in the treatment of stage IV NSCLC patients
Authors: Thronicke Anja , Reinhold Thomas , von Trott Philipp , Grah Christian , Matthes Burkhard , Matthes Harald , Schad Friedemann
Published: February 2020

Background

For stage IV lung cancer patients receiving add-on Viscum album L. treatment an improved overall survival (OS) was observed. Only limited information regarding cost-effectiveness (CE) for comparisons between standard of care and standard of care plus add-on VA in stage IV lung cancer treatment is available. The present study assessed the costs and cost-effectiveness of standard of care plus VA (V) compared to standard of care alone (C) for stage IV non-small cell lung cancer (NSCLC) patients treatment in a hospital in Germany.

Methods

An observational study was conducted using data from the Network Oncology clinical registry. Patients included had stage IV lung cancer at diagnosis and received C or V treatment in a certified German Cancer Center. Cost and cost-effectiveness analyses (CEA) including the analysis of the incremental cost-effectiveness ratios (ICER) were performed from the hospital’s perspective based on routine data from financial controlling department and observed data on OS. The primary result of the analysis was tested for robustness in a bootstrap-based sensitivity analysis.

Results

118 patients (C: n=86, V: n=32) were included, mean age 63.8 years, proportion of male patients 55.1%. Adjusted hospital’s total mean costs for patients from the C and V group were €16,289 (over an adjusted mean OS time of 13.4 months) and €17,992 (over an adjusted mean OS time of 19.1 months), respectively. The costs per additional OS year gained (ICER) with the V-treatment compared to C were €3,586.

Conclusion

Based on our analysis, the assessment of inpatient costs and cost-effectiveness of IO concepts in stage IV lung cancer suggests that the combined use of chemotherapy and VA is clinically effective and was comparably cost-effective to chemotherapy alone in our analysed patient sample. Further randomized and prospective cost-effectiveness studies are mandatory to complement our findings.
A novel mechanism of HIF2-dependent PLK1-mediated metastasis and drug resistance of clear cell Renal Cell Carcinoma
Authors: Dufies Maeva , Verbiest Annelies , Cooley Lindsay S , Ndiaye Papa Diogop , Viotti Julien , He Xingkang , Nottet Nicolas , Souleyreau Wilfried , Hagege Anais , Torrino Stephanie , Parola Julien , Giuliano Sandy , Borchiellini Delphine , Schiappa Renaud , Mograbi Baharia , Zucman-Rossi Jessica , Bensalah Karim , Ravaud Alain , Auberger Patrick , Bikfalvi Andréas , Chamorey Emmanuel , Rioux-Leclercq Nathalie , Mazure Nathalie M. , Beuselinck Benoit , Cao Yihai , Bernhard Jean Christophe , Ambrosetti Damien , Pagès Gilles
Published: February 2020

Polo-Like Kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we uncover a novel hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a new HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the Plk1 promoter. In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival. Loss-of-function of Plk1 in vivo markedly attenuated ccRCC growth and metastasis. High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo and in metastatic ccRCC patients. Importantly, high Plk1 expression was defined in a subpopulation of ccRCC patients that are refractory to current therapies. Hence, we propose a therapeutic paradigm for improving outcomes of ccRCC patients.
Can increasing years of schooling reduce type 2 diabetes (T2D)?—Evidence from a Mendelian randomization of T2D and 10 of its risk factors
Authors: Adams Charleen D. , Boutwell Brian B.
Published: February 2020

A focus in recent decades has involved examining the potential causal impact of educational attainment (schooling years) on a variety of disease and life-expectancy outcomes. Numerous studies have broadly revealed a link suggesting that as years of formal schooling increase so too does health and wellbeing; however, it is unclear whether the associations are causal. Here we use Mendelian randomization, an instrumental variables technique, to probe whether more years of schooling are causally linked to type 2 diabetes (T2D) and 10 of its risk factors. The results reveal a protective effect of more schooling years against T2D (odds ratio=0.39; 95% confidence interval: 0.26, 0.58; P=3.89 × 10−06), which might be mediated in part by more years of schooling being protective against the following: having a first-degree relative with diabetes, being overweight, and having high blood pressure, higher levels of circulating triglycerides, and lower levels of HDL cholesterol. More schooling years had no effect on risk for gestational diabetes or polycystic ovarian syndrome and was associated with a decreased likelihood of moderate physical activity. These findings imply that strategies to retain adults in higher education may help reduce the risk for a major source of metabolic morbidity and mortality.
Myelin water fraction decrease in mild traumatic brain injury
Authors: Russell-Schulz Bretta , Vavasour Irene , Zhang Jing , MacKay Alex L. , Purcell Victoria , Muller Angela M. , Brucar Leyla , Torres Ivan J. , Panenka William , Virji-Babul Naznin
Published: February 2020

The increased incidence of reported traumatic brain injury (TBI) and its potentially serious long-term consequences have enormous clinical and societal impacts. The diffuse and continually evolving secondary changes after TBI make it challenging to evaluate the changes in brain-behaviour relationships. In this study we used myelin water imaging to evaluate changes in myelin water fraction (MWF) in individuals with chronic brain injury and evaluated their cognitive status using the NIH Toolbox Cognitive Battery. Twenty-two adults with mild or severe brain injury and twelve age, gender and education matched healthy controls took part in this study. We found a significant decrease in global white matter MWF in individuals with mild TBI compared to the healthy controls. Significantly lower MWF was evident in most white matter ROIs examined including the corpus callosum (separated into genu, body and splenium), minor forceps, right anterior thalamic radiation, left inferior longitudinal fasciculus; and right and left superior longitudinal fasciculus and corticospinal tract. No significant correlations were found between MWF in mild TBI and the cognitive measures. These results show for the first time the loss of myelin in chronic mild TBI.
Providing an additional electron sink by the introduction of cyanobacterial flavodiirons enhances the growth ofArabidopsis thalianain varying light
Authors: Tula Suresh , Shahinnia Fahimeh , Melzer Michael , Rutten Twan , Gómez Rodrigo , Lodeyro Anabella F. , Wirén Nicolaus von , Carrillo Néstor , Hajirezaei Mohammad R.
Published: February 2020

The ability of plants to maintain photosynthesis in a dynamically changing environment is of central importance for their growth. As their photosynthetic machinery typically cannot adapt rapidly to fluctuations in the intensity of radiation, the level of photosynthetic efficiency is not always optimal. Cyanobacteria, algae, non-vascular plants (mosses and liverworts) and gymnosperms all produce flavodiirons (Flvs), a class of proteins not represented in the angiosperms; these proteins act to mitigate the photoinhibition of photosystem I. Here, genes specifying two cyanobacterial Flvs have been expressed in the chloroplasts ofArabidopsis thalianain an attempt to improve the robustness of Photosystem I (PSI). The expression ofFlv1andFlv3together shown to enhance the efficiency of the utilization of light and to boost the plant’s capacity to accumulate biomass. Based on an assessment of the chlorophyll fluorescence in the transgenic plants, the implication was that photosynthetic activity (including electron transport flow and non-photochemical quenching during a dark-to-light transition) was initiated earlier in the transgenic than in wild type plants. The improved photosynthetic performance of the transgenics was accompanied by an increased production of ATP, an acceleration of carbohydrate metabolism and a more pronounced partitioning of sucrose into starch. The indications are that Flvs are able to establish an efficient electron sink downstream of PSI, thereby ensuring that the photosynthetic electron transport chain remains in a more oxidized state. The expression of Flvs in a plant acts to both protect photosynthesis and to control the ATP/NADPH ratio; together, their presence is beneficial for the plant’s growth potential.
Structural adaptation of oxygen tolerance in 4-hydroxybutyrl-CoA dehydratase, a key enzyme of archaeal carbon fixation
Authors: DeMirci Hasan , Tolar Bradley B. , Doukov Tzanko , Petriceks Aldis , Pal Akshaye , Yoshikuni Yasuo , Gomez Aharon , Saez David A. , Vöhringer-Martinez Esteban , Schwander Thomas , Erb Tobias J. , Francis Christopher A. , Wakatsuki Soichi
Published: February 2020

Autotrophic microorganisms that convert inorganic carbon into organic matter were key players in the evolution of life on Earth. As the early atmosphere became oxygenated, microorganisms needed to develop mechanisms for oxygen protection, especially those relying on enzymes containing oxygen-sensitive metal clusters (e.g., Fe-S). Here we investigated how 4-hydroxybutyryl-CoA dehydratase (4HBD) - the key enzyme of the 3-hydroxypropionate/4-hydroxybutyrate (HP/HB) cycle for CO2-fixation - adapted as conditions shifted from anoxic to oxic. 4HBD is found in both anaerobic bacteria and aerobic ammonia-oxidizing archaea (AOA). The oxygen-sensitive bacterial 4HBD and oxygen-tolerant archaeal 4HBD share 59 % amino acid identity. To examine the structural basis of oxygen tolerance in archaeal 4HBD, we determined the atomic resolution structure of the enzyme. Two tunnels providing access to the canonical [4Fe-4S] cluster in oxygen-sensitive bacterial 4HBD were closed with four conserved mutations found in all aerobic AOA and other archaea. Further biochemical experiments and molecular dynamics simulations support our findings that restricting access to the active site is the key to oxygen tolerance, explaining how active site evolution drove a major evolutionary transition.

Significance statement

Autotrophy (primary production) was the first life strategy on Earth. Before photosynthesis (using solar energy to fix carbon dioxide), life relied on chemical reactions for energy. These chemosynthetic reactions are present in all domains of life, including archaea possessing the most energy-efficient carbon fixation pathway - the 3-hydroxypropionate/4-hydroxybutyrate cycle. This efficiency results from enzyme modifications, including enhanced enzyme stability and catalysis of multiple reactions. We reveal the first structure of aerobic 4-hydroxybutyryl-CoA dehydratase (4HBD) from ammonia-oxidizing archaea. These archaea are among the most abundant organisms on the planet, and their 4HBD active site evolved oxygen tolerance to support aerobic metabolism. This modification can provide further insight into enzyme evolution on early earth, as photosynthesis developed and began oxygenating the atmosphere.
How important is CRISPR-Cas for protecting natural populations of bacteria against infections by mobile genetic elements?
Authors: Westra Edze , Levin Bruce
Published: February 2020

Articles on CRISPR commonly open with some variant of the phrase ‘these short-palindromic repeats and their associated endonucleases (Cas) are an adaptive immune system that exists to protect bacteria and archaea from viruses and infections with other mobile genetic elements’. There is an abundance of genomic data consistent with the hypothesis that CRISPR plays this role in natural populations of bacteria and archaea, and experimental demonstrations with a few species of bacteria and their phage and plasmids show that CRISPR-Cas systems can play this rolein vitro. Not at all clear are the ubiquity, magnitude and nature of the contribution of CRISPR-Cas systems to the ecology and evolution of natural populations of microbes, and the strength of selection mediated by different types of phage and plasmids to the evolution and maintenance of CRISPR-Cas systems. In this perspective, with the aid of heuristic mathematical-computer simulation models, we explore thea prioriconditions under which exposure to lytic and temperate phage and conjugative plasmids will select for and maintain CRISPR-Cas systems in populations of bacteria and archaea. We review the existing literature addressing these ecological and evolutionary questions and highlight the experimental and other evidence needed to fully understand the conditions responsible for the evolution and maintenance of CRISPR-Cas systems and the contribution of these systems to the ecology and evolution of bacteria, archaea and the mobile genetic elements that infect them.

Significance

There is no question about the importance and utility of CRISPR-Cas for editing and modifying genomes. On the other hand, the mechanisms responsible for the evolution and maintenance of these systems and the magnitude of their importance to the ecology and evolution of bacteria, archaea and their infectious DNAs, are not at all clear. With the aid of heuristic mathematical – computer simulation models and reviews of the existing literature, we raise questions that have to be answered to elucidate the contribution of selection – mediated by phage and plasmids – to the evolution and maintenance of this adaptive immune system and its consequences for the ecology and evolution of prokaryotes and their viruses and plasmids.
High-speed, long-term, 4Din vivolifetime imaging in intact and injured zebrafish and mouse brains by instant FLIM
Authors: Zhang Yide , Guldner Ian H. , Nichols Evan L. , Benirschke David , Smith Cody J. , Zhang Siyuan , Howard Scott S.
Published: February 2020

Traditional fluorescence microscopy is blind to molecular microenvironment information that is present in fluorescence lifetime, which can be measured by fluorescence lifetime imaging microscopy (FLIM). However, existing FLIM techniques are typically slow to acquire and process lifetime images, difficult to implement, and expensive. Here, we present instant FLIM, an analog signal processing method that allows real-time streaming of fluorescence intensity, lifetime, and phasor imaging data through simultaneous image acquisition and instantaneous data processing. Instant FLIM can be easily implemented by upgrading an existing two-photon microscope using cost-effective components and our open-source software. We further improve the functionality, penetration depth, and resolution of instant FLIM using phasor segmentation, adaptive optics, and super-resolution techniques. We demonstrate through-skull intravital 3D FLIM of mouse brains to depths of 300 μm and present the firstin vivo4D FLIM of microglial dynamics in intact and injured zebrafish and mouse brains up to 12 hours.
Quantitative single-cell interactomes in normal and virus-infected mouse lungs
Authors: Cain Margo P , Hernandez Belinda J , Chen Jichao
Published: February 2020

Mammalian organs consist of diverse, intermixed cell types that signal to each other via ligand-receptor interactions – an interactome – to ensure development, homeostasis, and injury-repair. Dissecting such intercellular interactions is facilitated by rapidly growing single-cell RNA-seq (scRNA-seq) data; however, existing computational methods are often not sufficiently quantitative nor readily adaptable by bench scientists without advanced programming skills. Here we describe a quantitative intuitive algorithm, coupled with an optimized experimental protocol, to construct and compare interactomes in control and Sendai virus-infected mouse lungs. A minimum of 90 cells per cell type compensates for the known gene dropout issue in scRNA-seq and achieves comparable sensitivity to bulk RNA-seq. Cell lineage normalization after cell sorting allows cost-efficient representation of cell types of interest. A numeric representation of ligand-receptor interactions identifies, as outliers, known and potentially new interactions as well as changes upon viral infection. Our experimental and computational approaches can be generalized to other organs and human samples.

Summary statement

An intuitive method to construct quantitative ligand-receptor interactomes using single-cell RNA-seq data and its application to normal and Sendai virus-infected mouse lungs.
mRNA stem-loops can pause the ribosome by hindering A-site tRNA binding
Authors: Bao Chen , Loerch Sarah , Ling Clarence , Korostelev Andrei A. , Grigorieff Nikolaus , Ermolenko Dmitri N.
Published: February 2020

Although the elongating ribosome is an efficient helicase, certain mRNA stem-loop structures are known to impede ribosome movement along mRNA and stimulate programmed ribosome frameshifting via mechanisms that are not well understood. Using biochemical and single-molecule Förster resonance energy transfer (smFRET) experiments, we studied how frameshift-inducing stem-loops fromE. coli dnaXmRNA and thegag-poltranscript of Human Immunodeficiency Virus (HIV) perturb translation elongation. We find that upon encountering the ribosome, the stem-loops strongly inhibit A-site tRNA binding and ribosome intersubunit rotation that accompanies translation elongation. Electron cryo-microscopy (cryo-EM) reveals that the HIV stem-loop docks into the A site of the ribosome. Our results suggest that mRNA stem-loops can transiently escape ribosome helicase by binding to the A site. Thus, the stem-loops can modulate gene expression by sterically hindering tRNA binding and inhibiting translation elongation.
Principles of dengue virus evolvability derived from genotype-fitness maps in human and mosquito cells
Authors: Dolan Patrick T. , Taguwa Shuhei , Rangel Mauricio Aguilar , Acevedo Ashley , Hagai Tzachi , Andino Raul , Frydman Judith
Published: February 2020

Dengue virus (DENV), an arbovirus infecting over 100 million annually, cycles between human and mosquito hosts1. Examining how DENV adapts to such different host environments could uncover principles of arbovirus transmission and emergence. Here we combine sequential passaging and ultra-deep sequencing to examine the sequence dynamics and fitness changes of DENV populations adapting to human and mosquito cells, identifying the contributions of beneficial and deleterious mutations in shaping the fitness landscape driving host-specific paths of viral adaptation. We find DENV phenotypic adaptation is best described by the collective fitness contributions of all the alleles present in the population. Accordingly, while increased fitness during adaptation to each host is driven by host-specific beneficial mutations, it is reduced by the consistently replenished genetic load of deleterious mutations. Of note, host-specific beneficial mutations are in discrete regions across the genome, revealing molecular mechanisms of adaptation. Some of these clusters comprise phenotypically redundant mutations that may provide evolutionary robustness to transmission bottlenecks. Our results also suggest DENV adaptation is facilitated through variation in intrinsically disordered protein regions while transmembrane and structured domains evolve under stronger biophysical constraints. Importantly, the adaptation strategies uncovered in our simple system mirror macro-evolutionary changes observed across DENV serotypes and Zika virus and may suggest general principles of evolvability in arbovirus evolution.
Phenotypic and genotypic parallel evolution in parapatric ecotypes ofSenecio
Authors: James Maddie E. , Wilkinson Melanie J. , Bernal Diana M. , Liu Huanle , North Henry L. , Engelstädter Jan , Ortiz-Barrientos Daniel
Published: February 2020

The independent and repeated adaptation of populations to similar environments often results in the evolution of similar forms. This phenomenon creates a strong correlation between phenotype and environment and is referred to as parallel evolution. However, we are still largely unaware of the dynamics of parallel evolution, as well as the interplay between phenotype and genotype within natural systems. Here, we examined phenotypic and genotypic parallel evolution in multiple parapatric Dune-Headland coastal ecotypes of an Australian wildflower,Senecio lautus. We observed a clear trait-environment association within the system, with all replicate populations having evolved along the same phenotypic evolutionary trajectory. Similar phenotypes have arisen via mutational changes occurring in different genes, although many share the same biological functions. Our results shed light on how replicated adaptation manifests at the phenotypic and genotypic levels within populations, and highlightsS. lautusas one of the most striking cases of phenotypic parallel evolution in nature.