bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors Associated With Emergency Department Health Professionals' Attitudes Toward Family Presence During Adult Resuscitation in 9 Greek Hospitals
Authors: Bellali Thalia , Manomenidis Georgios , Platis Charalampos , Kourtidou Eleni , Galanis Petros
Published: July 2020

Background

Different cultural context results in variability in health professionals' attitude toward family presence in the emergency department (ED) during resuscitation. Knowledge about emergency department health professionals' (EDHPs') attitude toward family presence during resuscitation (FPDR) in Greece can contribute to the understanding of cultural and value-related obstacles and opportunities to implement this practice. It would be useful for Greek health professionals when they have to care for citizens from other countries in which guidelines for FPDR exist to understand their difference in behavior and reaction and be more tolerant.

Objectives

To explore Greek EDHPs' experiences, concerns, and benefits regarding FPDR and determine the contributing factors that are associated with their positive or negative attitude about the process.

Methods

A convenience sample of 305 health professionals working in the ED of 9 general hospitals of the National Healthcare System in northern Greece participated in a cross-sectional study (response rate, 87.6%).

Results

Positive experience of FPDR was encountered in 65.9% of EDHPs. Only 2.3% reported that they work in EDs where FPDR is allowed. Hospital regional location, previous positive experience of FPDR, and competency in supporting family members during FPDR were independently associated with a positive attitude toward FPDR.

Conclusions

Greek EDHPs are not ready to accept FPDR practice. The establishment of formal policy similarly to resuscitation guidelines and family-centered training courses are needed to mitigate negative beliefs. Attempts to enhance positive attitude should include educational interventions providing knowledge on the benefits of FPDR.
The Arts Unique to Critical Care Nursing: Hard to Measure But Breathtakingly Manifest in a Pandemic
Authors: Harvey Maurene A.
Published: July 2020

This commentary begins as a question and makes a call for action. The question is: “Are ICU (intensive care unit) patients' outcomes related to the degree to which the patients' nurses practice the art of nursing unique to critical care?” When nurses address patients' basic human needs as opposed to tending solely to tasks, it likely affects the patients' vital signs, need for analgesia or sedation, adverse effects of stress, and short- and long-term outcomes. These factors are often collected in studies of the critically ill. The level of practice reflecting the art of critical care nursing can be an unrecognized confounding variable influencing results. The call for action is “create a tool to measure and study the effect of the art of nursing unique to the ICU on patient outcomes.” The current COVID crisis has created tremendous visibility and awareness illuminating the role of the nurses and other health care providers. It is quite fitting, as this is also the year of the nurse and the midwife, that we celebrate and articulate much of what is unique to the art of our practice.
Possible Coronavirus Disease 2019 Pandemic and Pregnancy: Vertical Transmission Is Not Excluded
Authors: Marzollo Roberto , Aversa Salvatore , Prefumo Federico , Saccani Barbara , Perez Carmen Rodriguez , Sartori Enrico , Motta Mario
Published: July 2020

Coronavirus disease 2019 outbreak has a growing impact on global health; vertical transmission of severe acute respiratory syndrome coronavirus 2 infection is still controversial. In this article, we describe a case of vertical transmission of severe acute respiratory syndrome coronavirus 2 in a newborn with respiratory and gastrointestinal symptoms.
Results of Treatment of the Multiple Ligament Injured (Dislocated) Knee
Authors: James Evan W. , Wolfe Isabel , Marx Robert G.
Published: July 2020

Knee dislocations leading to multiligament knee injuries are associated with a wide variety of bony, ligamentous, soft tissue, and neurovascular injury patterns. Numerous management strategies have been proposed including nonoperative treatment and surgical repair or reconstruction. In recent years, an emphasis has been placed on anatomic repair and reconstruction principles, which have shown superior outcomes compared with older techniques. However, despite these advances, clinical outcomes continue to vary widely, with many patients experiencing chronic pain, stiffness, loss of range of motion, instability, and failure to return to work or sports. The purpose of this chapter is to review clinical outcomes following combined anterior and posterior cruciate ligament, medial collateral ligament, and posterolateral corner injuries sustained during a knee dislocation. Understanding the available treatment options and reported outcomes will allow surgeons to individualize management to address each patient’s specific injury pattern and functional goals.
Regulation of Angiopoietin-2 Before and After Mechanical Circulatory Support Therapy
Authors: Nakamura Makiko , Imamura Teruhiko , Hori Masakazu , Nakagaito Masaki , Ueno Hiroshi , Yokoyama Shigeki , Doi Toshio , Fukahara Kazuaki , Kinugawa Koichiro
Published: July 2020

Gastrointestinal bleeding (GIB) during mechanical circulatory support (MCS) is a major unsolved comorbidity. Inadequate activation of angiopoietin-2-related systems is considered as a major cause of GIB. However, the regulation of angiopoietin-2 remains unknown. Consecutive 20 patients who received continuous-flow MCS therapy (MCS group) and 12 with advanced heart failure (HF; HF group) were prospectively enrolled and their angiopoetin-2 levels were compared. Angiopoietin-2 level had a moderate correlation with log10 B-type natriuretic peptide (BNP; r = 0.39, p < 0.001). The MCS group had significantly higher angiopoietin-2 level divided by log10 BNP compared with the HF group (2.80 ± 0.20 vs. 1.88 ± 0.17, p < 0.001). Angiopoetin-2 had a moderate correlation with central venous pressure and C-reactive protein during the MCS support (r = 0.51 and r = 0.45, respectively). Higher angiopoietin-2 level divided by log10 BNP (> 4.3) was significantly associated with the occurrence of GIB with a hazard ratio of 296 (95% confidence interval 2.24–38620, p = 0.0224). Angiopoietin-2 was already elevated in the HF cohort and more elevated following MCS initiation. Among the MCS cohort, angiopoietin-2 was particularly elevated in patients with systemic congestion and inflammation and was associated with higher incidence of GIB.
The Impact of a High-risk Psychosocial Assessment on Outcomes After Durable Mechanical Circulatory Support
Authors: Kittleson Michelle M. , Barone Heather , Cole Robert M. , Olman Megan , Fishman Alisa , Olanisa Linda , Runyan Carmelita , Hajj Jennifer , Huie Newman , Lindsay Michael , Sun Nancy , Luong Eric , Cheng Susan , Passano Elizabeth , Kobashigawa Jon A. , Esmailian Fardad , Ramzy Danny , Moriguchi Jaime D.
Published: July 2020

Patient adherence is vital to the success of durable mechanical circulatory support (MCS), and the pre-MCS assessment of adherence by the multidisciplinary advanced heart failure team is a critical component of the evaluation. We assessed the impact of a high-risk psychosocial assessment before durable MCS implantations on post-MCS outcomes. Between January 2010 and April 2018, 319 patients underwent durable MCS at our center. We excluded those who died or were transplanted before discharge. The remaining 203 patients were grouped by pre-MCS psychosocial assessment: high-risk (26; 12.8%) versus acceptable risk (177; 87.2%). We compared clinical characteristics, nonadherence, and outcomes between groups. High-risk patients were younger (48 vs. 56; p = 0.006) and more often on extracorporeal membrane oxygenation at durable MCS placement (26.9% vs. 9.0%; p = 0.007). These patients had a higher incidence of post-MCS nonadherence including missed clinic appointments, incorrect medication administration, and use of alcohol and illicit drugs. After a mean follow-up of 15.3 months, 100% of high-risk patients had unplanned hospitalizations compared with 76.8% of acceptable-risk patients. Per year, high-risk patients had a median of 2.9 hospitalizations per year vs. 1.2 hospitalizations per year in acceptable-risk patients. While not significant, there were more driveline infections over the follow-up period in high-risk patients (27% vs. 14.7%), deaths (27% vs. 18%), and fewer heart transplants (53.8% vs. 63.8%).The pre-MCS psychosocial assessment is associated with post-MCS evidence of nonadherence and unplanned hospitalizations. Attention to pre-MCS assessment of psychosocial risk factors is essential to optimize durable MCS outcomes.
Reactivation of Cytomegalovirus Following Left Ventricular Assist Device Implantation: A Case–Control Study
Authors: Lundgren Scott W. , Florescu Diana F. , Zolty Ronald
Published: July 2020

While cytomegalovirus (CMV) reactivation occurs in immunocompetent patients who are critically ill and has been associated with worse outcomes, very few cases of CMV reactivation have been reported following left ventricular assist device (LVAD) implantation. We aimed to evaluate the incidence and risk factors for CMV reactivation following LVAD implantation. Retrospective chart review of patients who had undergone LVAD implantation between July 2004 and December 2018 was performed. Cases with CMV reactivation post-LVAD were randomly matched (1:2) by sex, LVAD type, and implant year with controls utilizing SAS macros. Fisher’s exact and paired sample t-tests were performed to evaluate for differences between categorical and continuous variables, respectively. Days to reactivation post-LVAD implantation were calculated in cases, and the corresponding times post-LVAD implantation were determined in control patients for variable comparisons. Survival analysis was performed using the Kaplan–Meier method. Of the 349 patients reviewed, 208 (59.6%) patients were seropositive for CMV before LVAD implantation. Of these 208 patients, eight (3.8%) had CMV reactivation following LVAD implantation. The median time to CMV reactivation following LVAD implantation was 21.5 days (range, 6–177). Six (75%) patients had CMV viremia, and the other two had colitis and pneumonia without viremia. In comparison to controls, patients with CMV had higher creatinine levels (p = 0.039) and higher RDW (p = 0.05) and were more likely to have received steroids within the previous week (p = 0.028) and to have concurrent bacterial infection (p = 0.001). CMV reactivation following LVAD implantation is more frequent than expected. Early testing, diagnosis, and treatment in at-risk patients (i.e., renal failure, steroid use, elevated RDW) might improve clinical outcomes.
Incentivizing Fruits and Vegetables in the Farm Bill
Authors: Wiese Gretchen N. , Ramakrishnan Monica , Clark Camille , Savaiano Dennis
Published: July 2020

Almost all US adults fail to consume the 5 servings of fruit and vegetables recommended by the Dietary Guidelines for Americans, with those living near or below the poverty line consuming even less. Fruit and vegetable producers, and consumers participating in nutrition assistance programs are supported in the 2018 Farm Bill. We discuss current and potential strategies that reduce barriers for both consumers and producers in the Farm Bill. We argue that future Farm Bills should further incentivize the production and consumption of fruits and vegetables by increasing (1) support for nutrition assistance programs, (2) funding research that focuses on specialty crops, and (3) specialty crop insurance.
Age-Based Percentiles of Measured Mean Arterial Pressure in Pediatric Patients in a Hospital Setting
Authors: Roberts Joan S. , Yanay Ofer , Barry Dwight
Published: July 2020

Objectives:

To develop and validate age-specific percentile curves of measured mean arterial pressure for children in a hospital setting.

Design:

Retrospective observational study of electronic records.

Setting:

Tertiary care, freestanding pediatric hospital in Seattle, WA.

Patients:

Nonpremature children, birth to 18 years old, evaluated in the emergency room, or admitted to either acute care or critical care units.

Interventions:

Oscillometric blood pressure data collected from February 2012 to June 2016 were examined for documentation of systolic, diastolic, and mean arterial pressure values. Quantile curves were developed using restricted cubic splines and validated with two sets of patient data. The effects of birth sex and behavioral state on the curves were examined. The frequency of values less than 5th percentile for mean arterial pressure within a population was compared with four published criteria for hypotension.

Measurements and Main Results:

Eighty-five–thousand two-hundred ninety-eight patients (47% female) provided 2,385,122 mean arterial pressure readings to develop and validate age-based distributions to create percentile curves and a reference table. The behavior state of patients affected the curves, with disturbed behavior state more prevalent in toddler-aged patients. There was no clinical difference between females and males within age brackets. Mean arterial pressure quantiles identified additional hypotensive episodes as compared with systolic blood pressure thresholds and predicted mean arterial pressure values. Code and data available at: https://osf.io/upqtv/.

Conclusions:

This is the first study reporting age-specific quantiles of measured mean arterial pressure in children in a hospital setting. The percentile curves may guide care in illnesses when perfusion pressure is critical and serve as parameter for bedside and electronic record-based response to clinical change. Future work to correlate threshold mean arterial pressure values with outcomes would be feasible based on quantile curves.
Rapid Diagnostic Tests for Meningitis and Encephalitis—BioFire
Authors: Fleischer Eduardo , Aronson Paul L.
Published: July 2020

Meningitis and encephalitis (ME) are important causes of morbidity and mortality worldwide. Patients suspected of having ME are often hospitalized and started on empiric antimicrobial treatment, because of the potential adverse consequences of delaying the diagnosis or treatment. Multiplexed polymerase chain reaction panels are one of several rapid diagnostic technologies that have the potential to overcome some of the limitations of conventional diagnostic methods for ME. The BioFire FilmArray Meningitis/Encephalitis Panel was the first Food and Drug Administration–cleared multiplex polymerase chain reaction for the evaluation of cerebrospinal fluid samples, able to identify 14 organisms in a single test reaction. This newer rapid diagnostic tool has an overall high sensitivity and specificity for the diagnosis of ME with a fast turnaround time and has the potential to improve resource utilization for patients presenting with suspicion of ME. However, further research is needed to determine its optimal use in the evaluation of patients with suspected ME.
Division of the genus Chryseobacterium: Observation of discontinuities in amino acid identity values, a possible consequence of major extinction events, guides transfer of nine species to the genus Epilithonimonas, eleven species to the genus Kaistella, and three species to the genus Halpernia gen. nov., with description of Kaistella daneshvariae sp. nov. and Epilithonimonas vandammei sp. nov. derived from clinical specimens
Authors: Nicholson Ainsley C. , Gulvik Christopher A. , Whitney Anne M. , Humrighouse Ben W. , Bell Melissa E. , Holmes Barry , Steigerwalt Arnie G. , Villarma Aaron , Sheth Mili , Batra Dhwani , Rowe Lori A. , Burroughs Mark , Pryor Jessica C. , Bernardet Jean-François , Hugo Celia , Kämpfer Peter , Newman Jeffrey D. , McQuiston John R.
Published: July 2020

The genus

Chryseobacterium

in the family

Weeksellaceae

is known to be polyphyletic. Amino acid identity (AAI) values were calculated from whole-genome sequences of species of the genus Chryseobacterium, and their distribution was found to be multi-modal. These naturally-occurring non-continuities were leveraged to standardise genus assignment of these species. We speculate that this multi-modal distribution is a consequence of loss of biodiversity during major extinction events, leading to the concept that a bacterial genus corresponds to a set of species that diversified since the Permian extinction. Transfer of nine species (

Chryseobacterium arachidiradicis

, Chryseobacterium bovis, Chryseobacterium caeni, Chryseobacterium hispanicum, Chryseobacterium hominis, Chryseobacterium hungaricum﻿,, Chryseobacterium pallidum and

Chryseobacterium zeae

) to the genus

Epilithonimonas

and eleven (

Chryseobacterium anthropi

,

Chryseobacterium antarcticum

,

Chryseobacterium carnis

,

Chryseobacterium chaponense

, Chryseobacterium haifense, Chryseobacterium jeonii,

Chryseobacterium montanum

,

Chryseobacterium palustre

,

Chryseobacterium solincola

,

Chryseobacterium treverense

and

Chryseobacterium yonginense

) to the genus

Kaistella

is proposed. Two novel species are described: Kaistella daneshvariae sp. nov. and Epilithonimonas vandammei sp. nov. Evidence is presented to support the assignment of

Planobacterium taklimakanense

to a genus apart from Chryseobacterium, to which Planobacterium salipaludis comb nov. also belongs. The novel genus Halpernia is proposed, to contain the type species Halpernia frigidisoli comb. nov., along with Halpernia humi comb. nov., and Halpernia marina comb. nov.
The final step of 40S ribosomal subunit maturation is controlled by a dual key lock
Authors: Plassart Laura , Shayan Ramtin , Montellese Christian , Rinaldi Dana , Larburu Natacha , Pichereaux Carole , Lebaron Simon , O’Donohue Marie-Françoise , Kutay Ulrike , Marcoux Julien , Gleizes Pierre-Emmanuel , Plisson-Chastang Célia
Published: July 2020

Preventing premature interaction of preribosomes with the translation apparatus is essential to translation accuracy. Hence, the final maturation step releasing functional 40S ribosomal subunits, namely processing of the 18S ribosomal RNA 3’ end, is safeguarded by protein DIM2, which both interacts with the endoribonuclease NOB1 and masks the rRNA cleavage site. To elucidate the control mechanism that unlocks NOB1 activity, we performed cryo-EM analysis of late human pre-40S particles purified using a catalytically-inactive form of ATPase RIO1. These structures, together with in vivo and in vitro functional analyses, support a model in which ATP-loaded RIO1 cooperates with ribosomal protein RPS26/eS26 to displace DIM2 from the 18S rRNA 3’ end, thereby triggering final cleavage by NOB1; release of ADP then leads to RIO1 dissociation from the 40S subunit. This dual key lock mechanism requiring RIO1 and RPS26 guarantees the precise timing of pre-40S particle conversion into translation-competent ribosomal subunits.
Mucin-type O-glycosylation Landscapes of SARS-CoV-2 Spike Proteins
Authors: Zhang Yong , Zhao Wanjun , Mao Yonghong , Chen Yaohui , Zhu Jingqiang , Hu Liqiang , Gong Meng , Cheng Jingqiu , Yang Hao
Published: July 2020

The densely glycosylated spike (S) proteins that are highly exposed on the surface of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) facilitate viral attachment, entry, and membrane fusion. We have previously reported all the 22N-glycosites and site-specificN-glycans in the S protein protomer. Herein, we report the comprehensive and precise site-specific O-glycosylation landscapes of SARS-CoV-2 S proteins, which were characterized using high-resolution mass spectrometry. Following digestion using trypsin and trypsin/Glu-C, and de-N-glycosylation using PNGase F, we determined the mucin-type (GalNAc-type) O-glycosylation pattern of S proteins, including unambiguousO-glycosites and the 6 most commonO-glycans occupying them, via Byonic identification and manual validation. Finally, 43O-glycosites were identified in the insect cell-expressed S protein. Most glycosites were modified by non-sialylatedO-glycans such as HexNAc(1) and HexNAc(1)Hex(1). In contrast, 30O-glycosites were identified in the human cell-expressed S protein S1 subunit. Most glycosites were modified by sialylatedO-glycans such as HexNAc(1)Hex(1)NeuAc(1) and HexNAc(1)Hex(1)NeuAc(2). Our results are the first to reveal that the SARS-CoV-2 S protein is a mucin-type glycoprotein; clusteredO-glycans often occur in the N- and the C-termini of the S protein, and theO-glycosite andO-glycan compositions vary with the host cell type. These site-specific O-glycosylation landscapes of the SARS-CoV-2 S protein are expected to provide novel insights into the viral binding mechanism and present a strategy for the development of vaccines and targeted drugs.
Whole genome sequencing based differentiation between re-infection and relapse in Indian patients with tuberculosis recurrence, with and without HIV co-infection
Authors: Shanmugam Sivakumar , Bachmann Nathan L , Martinez Elena , Menon Ranjeeta , Narendran Gopalan , Narayanan Sujantha , Tripathy Srikanth , Devi K R Uma , Sawleshwarkar Shailendra , Marais Ben , Sintchenko Vitali
Published: July 2020

Differentiation between relapse and reinfection in cases with tuberculosis (TB) recurrence has important implications for public health, especially in patients with human immunodeficiency virus (HIV) co-infection. Forty-one pairedM. tuberculosisisolates collected from 20 HIV-positive and 21 HIV-negative patients, who experienced TB recurrence after previous successful treatment, were subjected to whole genome sequencing (WGS) in addition to spoligotyping and mycobacterial interspersed repeat unit (MIRU) typing. Comparison ofM. tuberculosisgenomes indicated that 95% of TB recurrences in the HIV-negative cohort were due to relapse, while the majority of TB recurrences (75%) in the HIV-positive cohort was due to re-infection (P=0.0001). Drug resistance conferring mutations were documented in four pairs (9%) of isolates associated with relapse. The high contribution of re-infection to TB among HIV patients warrants further study to explore risk factors for TB exposure in the community.
Critical Mobility, a practical criterion and early indicator for regional COVID-19 resurgence
Authors: Freitag Marcus O. , Schmude Johannes , Siebenschuh Carlo , Stolovitzky Gustavo , Hamann Hendrik F. , Lu Siyuan
Published: July 2020

The sharp reduction of human mobility in March 2020, as observed by anonymized cellphone data, has played an important role in thwarting a runaway COVID-19 pandemic. As the world is reopening, the risks of new flare-ups are rising. We report a data-driven approach, grounded in strong correlation between mobility and growth in COVID-19 cases two weeks later, to establish a spatial-temporal model of “critical mobility” maps that separate relatively safe mobility levels from dangerous ones. The normalized difference between the current and critical mobility has predictive power for case trajectories during the “opening-up” phases. For instance, actual mobility has risen above critical mobility in many southern US counties by the end of May, foreshadowing the latest virus resurgence. Encouragingly, critical mobility has been rising throughout the USA, likely due to face mask-wearing and social distancing measures. However, critical mobility is still well below pre-COVID mobility levels in most of the country suggesting continued mobility-reduction is still necessary.
Impact of low-frequency coding variants on human facial shape
Authors: Liu Dongjing , Alhazmi Nora , Matthews Harold , Lee Myoung Keun , Li Jiarui , Hecht Jacqueline T. , Wehby George L. , Moreno Lina M. , Heike Carrie L. , Roosenboom Jasmien , Feingold Eleanor , Marazita Mary L. , Claes Peter , Liao Eric C. , Weinberg Seth M. , Shaffer John R.
Published: July 2020

The contribution of low-frequency variants to the genetic architecture of normal-range facial traits is unknown. We studied the influence of low-frequency coding variants (MAF < 1%) on multi-dimensional facial shape phenotypes in 2329 healthy Europeans. We used MultiSKAT o scan the exome for face-associated low-frequency variants in a gene-based manner. Seven genes (AR, CARS2, FTSJ1, HFE, LTB4R, TELO2, NECTIN1) were significantly associated with shape variation of the cheek, chin, nose and mouth areas. These genes displayed a wide range of phenotypic effects, with some impacting the full face and others affecting localized regions. The missense variant rs142863092 inNECTIN1had a significant effect on chin morphology, and was predicted bioinformatically to be deleterious.NECTIN1is an established craniofacial gene that underlies a human syndrome that includes a mandibular phenotype. We further showed thatnectin1amutations can affect zebrafish craniofacial development, with the size and shape of the mandibular cartilage altered in mutant animals. These Findings highlighted the role of low-frequency coding variants in normal-range facial variation.
Genomic prediction for malting quality traits in practical barley breeding programs
Authors: Sarup Pernille , Edriss Vahid , Kristensen Nanna Hellum , Jensen Jens Due , Orabi Jihad , Jahoor Ahmed , Jensen Just
Published: July 2020

Genomic prediction can be advantageous in barley breeding for traits such as yield and malting quality to increase selection accuracy and minimize expensive phenotyping. In this paper, we investigate the possibilities of genomic selection for malting quality traits using a limited training population. The size of the training population is an important factor in determining the prediction accuracy of a trait. We investigated the potential for genomic prediction of malting quality within breeding cycles with leave one out (LOO) cross-validation, and across breeding cycles with leave set out (LSO) cross-validation. In addition, we investigated the effect of training population size on prediction accuracy by random two, four, and ten-fold cross-validation. The material used in this study was a population of 1329 spring barley lines from four breeding cycles. We found medium to high narrow sense heritabilities of the malting traits (0.31 to 0.65). Accuracies of predicting breeding values from LOO tests ranged from 0.6 to 0.9 making it worth the effort to use genomic prediction within breeding cycles. Accuracies from LSO tests ranged from 0.39 to 0.70 showing that genomic prediction across the breeding cycles were possible as well. Accuracy of prediction increased when the size of the training population increased. Therefore, prediction accuracy might be increased both within and across breeding cycle by increasing size of the training population
PTPN11/SHP2 negatively regulates growth in breast epithelial cells: implications on tumorigenesis
Authors: Chakladar Madhumita , Nair Madhumathy G , Prabhu Jyothi S , Sridhar T S , Kelkar Devaki , Kulkarni Madhura , Shashidhara LS
Published: July 2020

PTPN11/SHP2, a non-receptor protein tyrosine phosphatase is a prominent target of the receptor tyrosine kinase that participates in positive feedback signalling of the human epidermal growth factor receptors and helps in growth and migration. PTPN11/SHP2 is widely believed to be an oncoprotein, although it’s possible tumor-suppressor role is also reported. Our analysis of breast cancer metadata shows, PTPN11/SHP2 copy number loss in luminal A subtype is correlated to poor disease-specific survival and late-stage cancer at diagnosis. Analysis of the level 4 Reverse Phase Protein Array (RPPA) data available on the TCGA database resulted in positive correlations between the lower expression levels of constitutively active variant, the phospho-SHP2-Y542, of PTPN11/SHP2 and larger tumor size and lymph node positivity. We experimentally examined possible negative regulation of growth by PTPN11/SHP2 using MCF10A, a normal breast epithelial cell line. Knock-down of PTPN11/SHP2 resulted in increased cell migration, cell shape changes to mesenchymal morphology, and increased survival in cells treated with epirubicin, a DNA-damaging drug. However, it did not alter the rate of cell proliferation. It is possible that PTPN11/SHP2 might function as a tumor suppressor by potentiating proliferating cells with increased cell migration and resistance to apoptosis.

Statement of Significance

Molecules likePTPN11/SHP2, among many others that show dual specificity in tumorigenesis in the same tissue depending on the upstream signaling cues, present challenges in the field of targeted drug therapy. This study puts forth the importance of understanding the mechanism of one of the two outcomes and thereby helps better clinical management of a subgroup of cancer.
Exploration of theNeisseriaresistome reveals resistance mechanisms in commensals that may be acquired byN. gonorrhoeaethrough horizontal gene transfer
Authors: Fiore Michael A. , Raisman Jordan C. , Wong Narayan H. , Hudson André O. , Wadsworth Crista B.
Published: July 2020

Non-pathogenicNeisseriahave repeatedly been demonstrated to transfer antibiotic resistance genes to their pathogenic relative,Neisseria gonorrhoeae.However, the resistance genotypes and subsequent phenotypes of non-pathogens within the genus have been studied and described less frequently. Here, we use Etests to characterize the minimum inhibitory concentrations (MICs) of a panel ofNeisseria(n=26) – including several commensal species – acquired from the CDC & FDA’s Antibiotic Resistance (AR) Isolate Bank to a suite of diverse antibiotics. We furthermore use whole genome sequencing and the Comprehensive Antibiotic Resistance Database (CARD) Resistance Gene Identifier (RGI) platform to predict possible causal resistance-encoding mutations. Within this panel, resistant isolates to all tested antimicrobials including penicillin (n=5/26), ceftriaxone (n=2/26), cefixime (n=3/26), tetracycline (n=10/26), azithromycin (n=11/26), and ciprofloxacin (n=4/26) were found. In total we identify 63 distinct mutations predicted by RGI to be involved in resistance. The presence of several of these mutations had clear associations with increases in MIC such as: DNA gyrase subunit A (gyrA) (S91F) and ciprofloxacin, tetracycline resistance protein (tetM) and 30S ribosomal protein S10 (rpsJ) (V57M) and tetracycline, and TEM-type β-lactamases and penicillin. However, mutations with strong associations to macrolide and cephalosporin resistance were not conclusive. This work serves as an initial exploration into the resistance-encoding mutations harbored by non-pathogenicNeisseria,which will ultimately aid in prospective surveillance for novel resistance mechanisms that may be rapidly acquired byN. gonorrhoeae.
miR-100-5p downregulates mTOR to suppress the proliferation, migration and invasion of prostate cancer cells
Authors: Li Su-Liang , Ye Yun , Wang Jian-Jun
Published: July 2020

Background

Previous studies have shown that miR-100-5p expression is abnormal in prostate cancer. However, the role and regulatory mechanism of miR-100-5p requires further investigation. Thus, the aim of this study was to observe the effects of miR-100-5p on the proliferation, migration and invasion of prostate cancer (PCa) cells and to explore the potential related regulatory mechanism.

Methods

Differential miRNA expression analysis was performed using next-generation sequencing (NGS) in the PCa cell line LNCaP and the normal prostatic epithelial cell line RWPE-1. The expression levels of miR-100-5pwere detected using real-time fluorescence quantitative PCR (qRT-PCR). LNCaP cells were transfected with NC-mimics or miR-100-5p mimics by using liposome transfection. Moreover, the CCK-8 proliferation assay, cell scratch assay and Transwell assay were used to detect the effects of miR-100-5p on cell proliferation, migration and invasion. In addition, the potential target gene of miR-100-5p was predicted, and the influence of miR-100-5p on the expression of mTOR mRNA by qRT-PCR and the expression of mTOR protein was detected by western blot and immunohistochemical staining.

Results

Differential expression analysis of high-throughput sequencing data showed low expression of miR-100-5p in the PCa cell line LNCaP. It was further confirmed by qRT-PCR that the expression of miR-100-5p in LNCaP cells was significantly lower than that in RWPE-1 cells (P<0.01). miR-100-5p expression in LNCaP cells was markedly upregulated after transfection with miR-100-5p mimics (P<0.01), while cell proliferation, migration and invasion capacities were clearly reduced (P<0.01), and mTOR mRNA and protein expression was also substantially lowered (P<0.01). Finally, we further confirmed by immunohistochemical staining that miR-100-5p regulated the expression of mTOR.

Conclusion

miR-100-5p is expressed at low levels in LNCaP cells, and it can suppress LNCaP cell proliferation, migration and invasion, the mechanism of which is related to downregulating the expression of mTOR.
RIP140 inhibits glycolysis-dependent proliferation of breast cancer cells by regulating GLUT3 expression through transcriptional crosstalk between hypoxia induced factor and p53
Authors: Jacquier Valentin , Gitenay Delphine , Fritsch Samuel , Bonnet Sandrine , Győrffy Balázs , Jalaguier Stéphan , Linares Laetitia K. , Cavaillès Vincent , Teyssier Catherine
Published: July 2020

Cancer cells with uncontrolled proliferation preferentially depend on glycolysis to grow, even in the presence of oxygen. The transcriptional co-regulator RIP140 represses the activity of transcription factors that drive cell proliferation and metabolism and plays a role in mammary tumorigenesis. Here we use cell proliferation and metabolic assays to demonstrate that RIP140-deficiency causes a glycolysis-dependent increase in breast tumor growth. We further demonstrate that RIP140 reduces the transcription of the glucose transporter GLUT3 gene, by inhibiting the transcriptional activity of hypoxia inducible factor HIF-2α in cooperation with p53. Interestingly, RIP140 expression was significantly associated with good prognosis only for breast cancer patients with tumors expressing low GLUT3, low HIF-2α and high p53, thus confirming the mechanism of RIP140 anti-tumor activity provided by our experimental data. Overall, our work establishes RIP140 as a critical modulator of the p53/HIF cross-talk to inhibit breast cancer cell glycolysis and proliferation.
Novel mechanistic insights into the role of Mer2 as the keystone of meiotic DNA break formation
Authors: Rousova Dorota , Nivsarkar Vaishnavi , Altmannova Veronika , Funk Saskia K. , Raina Vivek B. , Liedtke David , Janning Petra , Müller Franziska , Reichle Heidi , Vader Gerben , Weir John R.
Published: July 2020

In meiosis, DNA double strand break (DSB) formation by Spo11 initiates recombination and enables chromosome segregation. Numerous factors are required for Spo11 activity, and couple the DSB machinery to the development of a meiosis-specific ?axis-tethered loop? chromosome organization. Through in vitro reconstitution and budding yeast genetics we here provide architectural insight into the DSB machinery by focussing on a foundational DSB factor, Mer2. We characterise the interaction of Mer2 with the histone reader Spp1, and show that Mer2 directly associates to nucleosomes, likely highlighting a contribution of Mer2 to tethering DSB factors to chromatin. We reveal the biochemical basis of Mer2 association with Hop1, a HORMA domain-containing chromosomal axis factor. Finally, we identify a conserved region within Mer2 crucial for DSB activity, and show that this region of Mer2 establishes an interaction with the DSB factor Mre11. In combination with previous work, we establish Mer2 as a keystone of the DSB machinery by bridging key protein complexes involved in the initiation of meiotic recombination.
Biochemical Patterns of Antibody Polyreactivity Revealed Through a Bioinformatics-Based Analysis of CDR Loops
Authors: Boughter Christopher T. , Borowska Marta T. , Guthmiller Jenna J. , Bendelac Albert , Wilson Patrick C. , Roux Benoit , Adams Erin J.
Published: July 2020

Antibodies are critical components of adaptive immunity, binding with high affinity to pathogenic epitopes. Antibodies undergo rigorous selection to achieve this high affinity, yet some maintain an additional basal level of low affinity, broad reactivity to diverse epitopes, a phenomenon termed “polyreactivity”. While polyreactivity has been observed in antibodies isolated from various immunological niches, the biophysical properties that allow for promiscuity in a protein selected for high affinity binding to a single target remain unclear. Using a database of nearly 1,500 polyreactive and non-polyreactive antibody sequences, we created a bioinformatic pipeline to isolate key determinants of polyreactivity. These determinants, which include an increase in inter-loop crosstalk and a propensity for an “inoffensive” binding surface, are sufficient to generate a classifier able to identify polyreactive antibodies with over 75% accuracy. The framework from which this classifier was built is generalizable, and represents a powerful, automated pipeline for future immune repertoire analysis.
MOLECULAR DETERMINANTS OF THE ENDOCYTIC PROTEIN EPSIN CONTROLLING ITS LOCALIZATION AND FUNCTION IN CANCER CELL MIGRATION AND INVASION
Authors: Madhivanan Kayalvizhi , Cao Lingyan , Staiger Chris J. , Aguilar R. Claudio
Published: July 2020

Epsins are endocytic adaptor proteins with signaling and endocytic functions. The three mammalian epsin paralogs are made of an Epsin N-Terminal Homology (ENTH) domain and an unstructured C-terminal region. The highly conserved ENTH domain plays a role in signaling by blocking RhoGAP activity and is required for cell migration in mammalian cells. However, our lab has previously shown that only epsin full length overexpression can enhance cell migration, but the ENTH domain alone cannot. Among the three Epsin paralogs, epsin 3 followed by epsin 2 were able to substantially enhance cell migration. This study is the first one to systematically and comprehensibly address the contribution of different motifs within the epsin C-terminus to enhance protein localization and cell migration. We show that is not the lipid-binding ENTH domain, but the C-terminus of epsin the one playing a major role in epsin association with sites of endocytosis. Further, we dissected the contribution of individual C-terminal endocytic (clathrin-, AP2-, Ubiquitin- and EH domain-binding) motifs for epsin localization. We found that while all motifs show a degree of synergism, the clathrin-binding motifs are the most important for epsin localization. Our study also showed that, these motifs (particularly the clathrin binding site) play an important role in sustaining endocytic site dynamics and cell migration.
Zinc Metabolic Defect of Aging Alveolar Progenitors in Progressive Pulmonary Fibrosis
Authors: Liang Jiurong , Huang Guanling , Liu Xue , Taghavifar Forough , Liu Ningshan , Wang Yizhou , Deng Nan , Yao Changfu , Burman Ankita , Xie Ting , Rowan Simon , Weigt S. Samuel , Belperio John , Stripp Barry , Parks William C. , Jiang Dianhua , Noble Paul W.
Published: July 2020

Idiopathic pulmonary fibrosis (IPF) is a fatal form of interstitial lung disease and aging has been identified as a risk factor to the disease. Alveolar type II cells (AEC2s) function as progenitor cells in the lung. Growing evidences indicate that IPF results from repeating AEC2 injury and inadequate epithelial repair. We previously reported that there was a significant loss of alveolar progenitors in the lungs of patients with IPF. In our current study, we performed single cell RNA-seq of epithelial cells from lungs of patients with IPF and healthy donors as well as epithelial cells from old and young mouse lungs with bleomycin injury. We identified a defect of zinc metabolism of AEC2s from IPF lungs and bleomycin-injured old mouse lungs. We further discovered that a specific zinc transporter ZIP8 was down regulated in IPF AEC2s and AEC2s from aged mice. Loss of ZIP8 expression is associated with impaired AEC2 renewal through sirtuin signaling in aging and IPF. Targeted deletion of Zip8 in murine AEC2 compartment led to reduced AEC2 renewal capacity, impaired AEC2 recovery, and worsened lung fibrosis after bleomycin injury. In summary, we have identified novel metabolic defects of AEC2s during aging and in IPF which contribute to the pathogenesis of lung fibrosis. Therapeutic strategies to restore critical components of these metabolic programs could improve AEC2 progenitor activity and mitigate ongoing fibrogenesis.

In Brief

Liang et al. performed single cell RNA-seq (scRNA-seq) of epithelial cells in IPF and in mice and discovered a zinc metabolic defect of alveolar progenitor cells (AEC2) in IPF and injured old mice characterized by down-regulation of a specific zinc transporter ZIP8. Manipulation of ZIP8 and zinc in 3D organoid culture of AEC2 in vitro and targeted deletion of Zip8 in AEC2s in vivo demonsrated a role of ZIP8 in promoting AEC2 progenitor function.

Highlights

ScRNA-seq revealed dysregulation of zinc metabolism in AEC2s and decreased stem cell signaling in IPF

ReducedSLC39A8and related gene expression of IPF AEC2s and aged mouse AEC2s

ZIP8-dependent zinc metabolism is required for AEC2 renewal

Targeted deletion ofSlc39a8impaired AEC2 renewal and promoted lung fibrosis
Mapping the adaptive landscape of a major agricultural pathogen reveals evolutionary constraints across heterogeneous environments
Authors: Dutta Anik , Hartmann Fanny E. , Francisco Carolina Sardinha , McDonald Bruce A. , Croll Daniel
Published: July 2020

The adaptive potential of pathogens in novel or heterogeneous environments underpins the risk of disease epidemics. Antagonistic pleiotropy or differential resource allocation among life-history traits can constrain pathogen adaptation. However, we lack understanding how the genetic architecture of individual traits can generate trade-offs. Here, we report a large-scale study based on 145 global strains of the fungal wheat pathogenZymoseptoria triticifrom four continents. We measured 50 life-history traits, including virulence and reproduction on 12 different wheat hosts and growth responses to several abiotic stressors. To elucidate the genetic basis of adaptation, we used multi-trait genome-wide association mapping. We show that most traits are governed by polygenic architectures and are highly heritable suggesting that adaptation proceeds mainly through allele frequency shifts at many loci. We identified numerous pleiotropic SNPs with conflicting effects on host colonization and survival in stressful environments. Such genetic constraints are likely limiting the pathogen’s ability to cause host damage and could be exploited for pathogen control. In contrast, adaptation to abiotic stress factors was likely facilitated by synergistic pleiotropy. Our study illustrates how comprehensive mapping of life-history trait architectures across diverse environments allows to predict evolutionary trajectories of pathogens confronted with environmental perturbations.
Subcellular mRNA localization and local translation ofArhgap11ain radial glial cells regulates cortical development
Authors: Pilaz Louis-Jan , Joshi Kaumudi , Liu Jing , Tsunekawa Yuji , Alsina Fernando C. , Sethi Sahil , Suzuki Ikuo K. , Vanderhaeghen Pierre , Polleux Franck , Silver Debra L.
Published: July 2020

mRNA localization and local translation enable exquisite spatial and temporal control of gene expression, particularly in highly polarized and elongated cells. These features are especially prominent in radial glial cells (RGCs), which serve as neural and glial precursors of the developing cerebral cortex, and scaffolds for migrating neurons. Yet the mechanisms by which distinct sub-cellular compartments of RGCs accomplish their diverse functions are poorly understood. Here, we demonstrate that subcellular RNA localization and translation of the RhoGAP Arhgap11a controls RGC morphology and mediates cortical cytoarchitecture.Arhgap11amRNA and protein exhibit conserved localization to RGC basal structures in mice and humans, conferred by a 5′UTR cis-element. Proper RGC morphology relies upon activeArhgap11amRNA transport and localization to basal structures, where ARHGAP11A is locally synthesized. Thus, RhoA activity is spatially and acutely activated via local translation in RGCs to promote neuron positioning and cortical cytoarchitecture. Altogether, our study demonstrates that mRNA localization and local translation mediate compartmentalization of neural progenitor functions to control brain development.

Highlights

Arhgap11a in radial glia non-cell autonomously promotes neuronal migration and lamination

Arhgap11amRNA localizes to radial glial endfeet via a 5’ UTR cis element

ARHGAP11A expression in basal process and endfeet depends upon its localized mRNA

Localized mRNA and RhoA-GAP activity in endfeet control radial glial morphology
Thalamic encoding of lexical status is lateralized during reading aloud
Authors: Wang Dengyu , Lipski Witold J. , Bush Alan , Chrabaszcz Anna , Dastolfo-Hromack Christina , Dickey Michael W. , Fiez Julie A. , Richardson R. Mark
Published: July 2020

To explore whether the thalamus participates in lexical status encoding, local field potentials were recorded in patients undergoing deep brain stimulation lead implantation while they read aloud single-syllable words and nonwords. Bilateral decreases in thalamic beta (12-30Hz) activity were preferentially locked to stimulus presentation, and these decreases were greater when nonwords were read. Increased broadband gamma (70-150Hz) activity also was locked preferentially to speech onset bilaterally, but greater nonword-related increases in this activity were observed only on the left, demonstrating lateralization of thalamic gamma selectivity for lexical status. In addition, this lexical status effect was strongest in more anterior thalamic locations, regions which are more likely to receive pallidal than cerebellar afferents. These results provide evidence from intracranial thalamic recordings for the lateralization and topography of subcortical lexical status processing.
The versatile X-ray beamline of the Munich Compact Light Source: design, instrumentation and applications
Authors: Günther Benedikt , Gradl Regine , Jud Christoph , Eggl Elena , Huang Juanjuan , Kulpe Stephanie , Achterhold Klaus , Gleich Bernhard , Dierolf Martin , Pfeiffer Franz
Published: July 2020

Inverse Compton scattering provides means to generate low-divergence partially coherent quasi-monochromatic, i.e. synchrotron-like, X-ray radiation on a laboratory scale. This enables the transfer of synchrotron techniques into university or industrial environments. Here, the Munich Compact Light Source is presented, which is such a compact synchrotron radiation facility based on an inverse Compton X-ray source (ICS). The recent improvements of the ICS are reported first and then the various experimental techniques which are most suited to the ICS installed at the Technical University of Munich are reviewed. For the latter, a multipurpose X-ray application beamline with two end-stations was designed. The beamline's design and geometry are presented in detail including the different set-ups as well as the available detector options. Application examples of the classes of experiments that can be performed are summarized afterwards. Among them are dynamic in vivo respiratory imaging, propagation-based phase-contrast imaging, grating-based phase-contrast imaging, X-ray microtomography, K-edge subtraction imaging and X-ray spectroscopy. Finally, plans to upgrade the beamline in order to enhance its capabilities are discussed.
3-(2,2-Dioxo-3,4-dihydrobenzo[e][1,2,3]oxathiazin-4-yl)-3-fluoro-1-phenylindolin-2-one
Authors: Wu Mei-Fang , Chen Ling-Yan , Li Ya
Published: July 2020

The title compound, C21H15FN2O4S, contains two chiral carbon centres, but crystal symmetry generates a racemic mixture. The crystal structure features N—H...O hydrogen bonding. The sulfonate group is disordered with an occupancy ratio of 0.933 (4):0.067 (4).