bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer in General Responders Participating in World Trade Center Health Programs, 2003–2013
Authors: Shapiro Moshe Z , Wallenstein Sylvan R , Dasaro Christopher R , Lucchini Roberto G , Sacks Henry S , Teitelbaum Susan L , Thanik Erin S , Crane Michael A , Harrison Denise J , Luft Benjamin J , Moline Jacqueline M , Udasin Iris G , Todd Andrew C
Published: October 2019

Background

Following the September 11, 2001, attacks on the World Trade Center (WTC), thousands of workers were exposed to an array of toxins known to cause adverse health effects, including cancer. This study evaluates cancer incidence in the WTC Health Program General Responder Cohort occurring within 12 years post exposure.

Methods

The study population consisted of 28 729 members of the General Responder Cohort enrolled from cohort inception, July 2002 to December 31, 2013. Standardized incidence ratios (SIRs) were calculated with cancer case inclusion and follow-up starting post September 11, 2001 (unrestricted) and, alternatively, to account for selection bias, with case inclusion and follow-up starting 6 months after enrollment in the WTC Health Program (restricted). Case ascertainment was based on linkage with six state cancer registries. Under the restricted criterion, hazard ratios were estimated using multivariable Cox proportional hazards models for all cancer sites combined and for prostate cancer.

Results

Restricted analyses identified 1072 cancers in 999 responders, with elevations in cancer incidence for all cancer sites combined (SIR = 1.09, 95% confidence interval [CI] = 1.02 to 1.16), prostate cancer (SIR = 1.25, 95% CI = 1.11 to 1.40), thyroid cancer (SIR = 2.19, 95% CI = 1.71 to 2.75), and leukemia (SIR = 1.41, 95% CI = 1.01 to 1.92). Cancer incidence was not associated with any WTC exposure index (composite or individual) for all cancer sites combined or for prostate cancer.

Conclusion

Our analyses show statistically significant elevations in cancer incidence for all cancer sites combined and for prostate and thyroid cancers and leukemia. Multivariable analyses show no association with magnitude or type of exposure.
The Fungal PCR Initiative's evaluation of in-house and commercial Pneumocystis jirovecii qPCR assays: Toward a standard for a diagnostics assay
Authors: Gits-Muselli Maud , White P Lewis , Mengoli Carlo , Chen Sharon , Crowley Brendan , Dingemans Gijs , Fréalle Emilie , L Gorton Rebecca , Guiver Malcom , Hagen Ferry , Halliday Catriona , Johnson Gemma , Lagrou Katrien , Lengerova Martina , Melchers Willem J G , Novak-Frazer Lily , Rautemaa-Richardson Riina , Scherer Emeline , Steinmann Joerg , Cruciani Mario , Barnes Rosemary , Donnelly J Peter , Loeffler Juergen , Bretagne Stéphane , Alanio Alexandre
Published: October 2019

Quantitative real-time PCR (qPCR) is increasingly used to detect Pneumocystis jirovecii for the diagnosis of Pneumocystis pneumonia (PCP), but there are differences in the nucleic acids targeted, DNA only versus whole nucleic acid (WNA), and also the target genes for amplification. Through the Fungal PCR Initiative, a working group of the International Society for Human and Animal Mycology, a multicenter and monocenter evaluation of PCP qPCR assays was performed. For the multicenter study, 16 reference laboratories from eight different countries, performing 20 assays analyzed a panel consisting of two negative and three PCP positive samples. Aliquots were prepared by pooling residual material from 20 negative or positive- P. jirovecii bronchoalveolar lavage fluids (BALFs). The positive pool was diluted to obtain three concentrations (pure 1:1; 1:100; and 1:1000 to mimic high, medium, and low fungal loads, respectively). The monocenter study compared five in-house and five commercial qPCR assays testing 19 individual BALFs on the same amplification platform. Across both evaluations and for all fungal loads, targeting WNA and the mitochondrial small sub-unit (mtSSU) provided the earliest Cq values, compared to only targeting DNA and the mitochondrial large subunit, the major surface glycoprotein or the beta-tubulin genes. Thus, reverse transcriptase-qPCR targeting the mtSSU gene could serve as a basis for standardizing the P. jirovecii load, which is essential if qPCR is to be incorporated into clinical care pathways as the reference method, accepting that additional parameters such as amplification platforms still need evaluation.
A galaxy’s accretion history unveiled from its integrated spectrum
Authors: Boecker Alina , Leaman Ryan , van de Ven Glenn , Norris Mark A , Mackereth J Ted , Crain Robert A
Published: October 2019

We present a new method of quantifying a galaxy’s accretion history from its integrated spectrum alone. Using full spectral fitting and calibrated regularization techniques we show how we can accurately derive a galaxy’s mass distribution in age-metallicity space and further separate this into stellar populations from different chemical enrichment histories. By exploiting the fact that accreted lower mass galaxies will exhibit an offset to lower metallicities at fixed age compared to the in-situ stellar population, we quantify the fraction of light that comes from past merger events, that are long since mixed in phase-space and otherwise indistinguishable. Empirical age-metallicity relations (AMRs) parameterized for different galaxy masses are used to identify the accreted stellar populations and link them back to the progenitor galaxy’s stellar mass. This allows us to not only measure the host galaxy’s total ex-situ mass fraction (facc), but also quantify the relative amount of accreted material deposited by satellite galaxies of different masses, i.e. the accreted satellite mass function in analogy to the subhalo mass function. Using mock spectra of present-day, early-type galaxies with total stellar mass ∼109 − 1012 M⊙ from the EAGLE simulation suite we demonstrate that our method can recover the total accreted fraction to within $\approx 38 \%$, the stellar mass of the most massive accreted subhalo to within $\approx 56 \%$ and the slope of the accreted satellite mass function to within $\approx 17 \%$ of the true values from the EAGLE merger trees. Future application of this method to observations could potentially provide us accretion histories of hundreds of individual galaxies, for which deep integrated light spectroscopy is available.
Stellar proton event-induced surface radiation dose as a constraint on the habitability of terrestrial exoplanets
Authors: Atri Dimitra
Published: October 2019

The discovery of terrestrial exoplanets orbiting in habitable zones around nearby stars has been one of the significant developments in modern astronomy. More than a dozen such planets, like Proxima Centauri b and TRAPPIST-1 e, are in close-in configurations and their proximity to the host star makes them highly sensitive to stellar activity. Episodic events such as flares have the potential to cause severe damage to close-in planets, adversely impacting their habitability. Flares on fast-rotating young M stars occur up to 100 times more frequently than on G-type stars, which makes their planets even more susceptible to stellar activity. Stellar energetic particles emanating from stellar proton events (SPEs) cause atmospheric damage (erosion and photochemical changes), and produce secondary particles, which in turn results in enhanced radiation dosage on planetary surfaces. We explore the role of SPEs and planetary factors in determining planetary surface radiation doses. These factors include SPE fluence and spectra, and planetary column density and magnetic field strength. Taking particle spectra from 70 major solar events (observed between 1956 and 2012) as proxy, we use the geant4 Monte Carlo model to simulate SPE interactions with exoplanetary atmospheres, and we compute surface radiation dose. We demonstrate that in addition to fluence, SPE spectrum is also a crucial factor in determining the surface radiation dose. We discuss the implications of these findings in constraining the habitability of terrestrial exoplanets.
Effect of BRCA1 missense variants on gene reversion in DNA double-strand break repair mutants and cell cycle-arrested cells of Saccharomyces cerevisiae
Authors: Lodovichi Samuele , Bellè Francesca , Cervelli Tiziana , Lorenzoni Alessandra , Maresca Luisa , Cozzani Cristina , Caligo Maria Adelaide , Galli Alvaro
Published: October 2019

Evaluation of the functional impact of germline BRCA1 variants that are likely to be associated to breast and ovarian cancer could help to investigate the mechanism of BRCA1 tumorigenesis. Expression of pathogenic BRCA1 missense variants increased homologous recombination (HR) and gene reversion (GR) in yeast. We thought to exploit yeast genetics to shed light on BRCA1-induced genome instability and tumorigenesis. We determined the effect on GR of several neutral and pathogenic BRCA1 variants in the yeast strain RSY6wt and its isogenic DSB repair mutants, such as mre11∆, rad50∆ and rad51∆. In the RSY6wt, four out of five pathogenic and two out of six neutral variants significantly increased GR; rad51∆ strain, the pathogenic variants C61G and A1708E induced a weak but significant increase in GR. On the other hand, in rad50∆ mutant expressing the pathogenic variants localised at the BRCT domain, a further GR increase was seen. The neutral variant N132K and the VUS A1789T induced a weak GR increase in mre11∆ mutant. Thus, BRCA1 missense variants require specific genetic functions and presumably induced GR by different mechanisms. As DNA repair is regulated by cell cycle, we determined the effect on GR of BRCA1 variants in cell cycle-arrested RSYwt cells. GR is highly BRCA1-inducible in S-phase-arrested cells as compared to G1 or G2. Sequence analysis of genomic DNA from ILV1 revertant clones showed that BRCA1-induced ilv1-92 reversion by base substitution when GR is at least 6-fold over the control. Our study demonstrated that BRCA1 may interfere with yeast DNA repair functions that are active in S-phase causing high level of GR. In addition, we confirmed here that yeast could be a reliable model to investigate the mechanism and genetic requirements of BRCA1-induced genome instability. Finally, developing yeast-based assays to characterise BRCA1 missense variants could be useful to design more precise therapies.
EnhancerAtlas 2.0: an updated resource with enhancer annotation in 586 tissue/cell types across nine species
Authors: Gao Tianshun , Qian Jiang
Published: October 2019

Enhancers are distal cis-regulatory elements that activate the transcription of their target genes. They regulate a wide range of important biological functions and processes, including embryogenesis, development, and homeostasis. As more and more large-scale technologies were developed for enhancer identification, a comprehensive database is highly desirable for enhancer annotation based on various genome-wide profiling datasets across different species. Here, we present an updated database EnhancerAtlas 2.0 (http://www.enhanceratlas.org/indexv2.php), covering 586 tissue/cell types that include a large number of normal tissues, cancer cell lines, and cells at different development stages across nine species. Overall, the database contains 13 494 603 enhancers, which were obtained from 16 055 datasets using 12 high-throughput experiment methods (e.g. H3K4me1/H3K27ac, DNase-seq/ATAC-seq, P300, POLR2A, CAGE, ChIA-PET, GRO-seq, STARR-seq and MPRA). The updated version is a huge expansion of the first version, which only contains the enhancers in human cells. In addition, we predicted enhancer–target gene relationships in human, mouse and fly. Finally, the users can search enhancers and enhancer–target gene relationships through five user-friendly, interactive modules. We believe the new annotation of enhancers in EnhancerAtlas 2.0 will facilitate users to perform useful functional analysis of enhancers in various genomes.
American Indian/Alaska Native Smokers’ Utilization of a Statewide Tobacco Quitline: Engagement and Quitting Behaviors From 2008 to 2018
Authors: Lienemann Brianna A , Cummins Sharon E , Tedeschi Gary J , Wong Shiushing , Zhu Shu-Hong
Published: October 2019

Introduction

The objective of this study was to examine access, engagement, and quitting behaviors of American Indian/Alaska Native (AIAN) callers to the California Smokers’ Helpline. Telephone counseling is the primary function of the quitline. The overarching theoretical framework for California’s quitline is social cognitive theory, although it also utilizes motivational interviewing and cognitive-behavioral strategies.

Aims and Methods

AIAN (n = 16 089) and White (n = 173 425) California quitline callers from 2009 to 2018 were compared on their characteristics, engagement, and quitting behaviors. Quitline callers responded to a telephone survey at intake. A random selection was called for evaluation 7 months later (White n = 8194, AIAN n = 764). Data from the 2009 to 2017 California Health Interview Survey (CHIS) were used as a reference point for AIANs (AIAN n = 1373).

Results

The quitline and CHIS had similar proportions of AIANs (4.6% vs. 4.3%, respectively). AIAN smokers were more likely than White smokers to report physical (53.6% vs. 44.9%) and mental (65.7% vs. 57.8%) health conditions at intake. AIANs were more likely to participate in counseling than White callers (67.1% vs. 65.7%). Among those who received counseling, AIANs had greater odds than White smokers of making a quit attempt (adjusted odds ratio = 1.39 [1.06, 1.81]) and similar odds of quitting for 180 days (adjusted odds ratio = 0.95 [0.69, 1.31]).

Conclusions

Rates of access, engagement, and quitting suggest that individualized quitline counseling was as effective with AIANs as it was with White smokers. Increasing efforts to refer AIANs to existing state quitlines can help more smokers quit.

Implications

This study showed that AIAN smokers were well represented among California quitline callers, even without a targeted campaign. It also found that AIAN smokers engaged in quitline services and were as able to quit as their White counterparts were, even after adjusting for other baseline characteristics. One implication is that public health programs can promote quitlines using broad-based campaigns knowing that they will still motivate AIAN smokers to seek help. Another implication is that a standard, individualized counseling protocol delivered by culturally competent quitline staff can effectively help AIAN smokers to quit.
Clostridioides difficile Enteritis in Patients Following Total Colectomy—a Rare but Genuine Clinical Entity
Authors: Ulrich Robert J , Bott Jonathan , Imlay Hannah , Lopez Kerri , Cinti Sandro , Rao Krishna
Published: October 2019

Clostridioides difficile enteritis (CDE) after colectomy is an understudied infectious syndrome. We reviewed 20 years of post-colectomy data and found CDE in 44/855 (5.1%) patients, usually within one year of surgery. Risk factors include acid suppression, inflammatory bowel disease, and antibiotics with enteral feeds. Clostridioides difficile enteritis often presents with severe disease requiring hospitalization.
Upper limb motor improvement in chronic stroke after combining botulinum toxin A injection and multi-joints robot-assisted therapy: a case report
Authors: Martino Cinnera Alex , Pucello Alessandra , Lupo Alessandro , Gimigliano Francesca , Mammucari Elisa , Cicero Dario Lo , Iosa Marco , Paolucci Stefano , Morone Giovanni
Published: October 2019

Spasticity is one of the major complications after stroke. Botulinum toxin type A (BoNT-A) injection is commonly used to manage focal spasticity. However, it is uncertain whether BoNT-A can improve activities of daily living function of paretic arm. The recovery of functions of the affected arm is also the aim of robotic upper limb (UL) therapy. The motorized exoskeleton assists the patient in a large 3D work environment by promoting movement for the UL (shoulder, elbow, wrist, hand). The combination of the BoNT-A injection and the robotic therapy might enhance functional recovery after stroke. We reported the case of a chronic stroke patient in which the injection of BoNT-A was combined with multi-joint exoskeleton training. The patient showed improvement in the motor control of the UL, supporting the feasibility of this approach.
Antiretroviral-responsive confluent and reticulated papillomatosis: a case report of an unusual association
Authors: Ballout Rami A , Helou Gilbert , Maatouk Ismael
Published: October 2019

This is the case of a 29-year-old male newly diagnosed with advanced HIV (CD4 < 35cells/mm3), presenting to us with hyperpigmented and scaly non-pruritic macules over his chest and upper abdomen of several weeks duration. Woodlamp examination was negative, but a skin biopsy suggested confluent and reticulated papillomatosis (CRP). Given his lack of any of the condition’s identifiable triggers and the unusually rapid resolution of his lesions shortly after antiretroviral therapy initiation, an immunodeficiency-related etiology for his CRP was entertained. Autoimmune disorders and atopic conditions have been well reported previously as possible triggers of CRP. However, in this report, we raise immunodeficiency as a possible trigger of CRP as well, such that immune dysregulation overall (autoimmunity or immunodeficiency) can contribute to CRP ontogenesis. To our best knowledge, this is the first report to date suggesting a possible association between CRP, a rare dermatological condition, and acquired immunodeficiency syndrome.
Nonalcoholic fatty liver disease as a risk factor for Clostridium difficile-associated diarrhea
Authors: Nseir W B , Hussein S H H , Farah R , Mahamid M N , Khatib H H , Mograbi J M , Peretz A , Amara A E
Published: October 2019

Aims

Clostridium difficile is the most common cause of infectious nosocomial diarrhea among adults in developed countries. Nonalcoholic fatty liver disease (NAFLD) is considered the most common chronic liver disease and it is associated with bacterial infections. Our goal was to assess whether NAFLD considered a risk factor for C. difficile-associated diarrhea (CDAD).

Methods

We conducted a retrospective study of patients admitted with CDAD at Baruch Padeh Medical Center, Poria, Israel during a period of four years. Data on demographic characteristics, clinical signs, underlying conditions, presence of fatty liver based on computed tomography/ultrasonography imaging and several risk factors for CDI were collected. The control group included patients with diarrhea who were negative for CDT and had been hospitalized during the same period. The controls were matched for age (±5 years) and gender.

Results

Totally, 115/164 patients with CDAD met the inclusion criteria. The control group was consisted of 115 hospitalized patients with non-CDAD. The mean age of all the participants (230) was 69.57 ± 18 years. NAFLD was found in 76/115 (66%) patients with CDAD vs. 35/115 (30.4%) in the control group, P < 0.001. Moreover, we found significant associations between CDAD group and metabolic syndrome, prior use of antibiotic in the last 3 months, NAFLD and high serum levels of C-reactive protein. Multivariate analysis showed that NAFLD, odds ratio 1.51, 95% confidence interval 1.2–1.95, P = 0.05 was significantly associated with CDAD.

Conclusions

This retrospective study showed that NAFLD is a risk factor for CDAD. Moreover, metabolic syndrome and high serum levels of C-reactive protein were significantly associated with the risk of CDAD.
Hardy Spaces on Homogeneous Groups and Littlewood-Paley Functions
Authors: Sato Shuichi
Published: October 2019

We establish a characterization of the Hardy spaces on the homogeneous groups in terms of the Littlewood–Paley functions. The proof is based on vector-valued inequalities shown by applying the Peetre maximal function.
Normal versus extraordinary societal impact: how to understand, evaluate, and improve research activities in their relations to society?
Authors: Sivertsen Gunnar , Meijer Ingeborg
Published: October 2019

Societal impact of research does not occur primarily as unexpected extraordinary incidents of particularly useful breakthroughs in science. It is more often a result of normal everyday interactions between organizations that need to create, exchange, and make use of new knowledge to further their goals. We use the distinctions between normal and extraordinary societal impact and between organizational- and individual-level activities and responsibilities to discuss how science–society relations can better be understood, evaluated, and improved by focusing on the organizations that typically interact in a specific domain of research.
OPTIMIZATION OF RADIATION DOSE IN CT IMAGING: ESTABLISHING THE INSTITUTIONAL DIAGNOSTIC REFERENCE LEVELS AND PATIENT DOSE AUDITING
Authors: Razali Mohd Amir Syahmi Mat , Ahmad Muhamad Zabidi , Shuaib Ibrahim Lutfi , Osman Noor Diyana
Published: October 2019

The aim of this study was to propose local diagnostic reference levels (LDRLs) for the most common computed tomography (CT) examinations (including contrast and non-contrast scan phase) performed at Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia (USM), Malaysia. A retrospective CT dose survey of 1488 subjects from January 2015 until December 2018 was performed at AMDI USM, Malaysia. The proposed DRLs were established at 50th and 75th percentile of dose distribution for all dose metrics (CT dose index [CTDI]; CTDIvol, CTDIw and dose–length product). The proposed LDRLs were compared with national DRLs and other established DRLs. The 10 most common CT examinations at AMDI were thorax–abdomen–pelvis (TAP) CT (46%), followed by pelvis CT (17%), abdomen–pelvis CT (10%), brain/head CT (9%) and other CT protocols. The local DRLs were established using the third quartile values of dose distribution and were categorized based on CT region protocols. Most of the proposed DRLs were exceeded the national DRLs (63%) and other international DRLs (67%). From the dose auditing, almost half of the recent dose data (for year 2018) exceeded the proposed local DRLs and the unusual dose were observed in TAP, brain/head and pelvis CT examinations. The unusual higher dose could be due to higher mAs settings, higher number of scan phase for contrast study and higher pitch factor. The local DRLs should be established for dose optimization and reduction of the occurrence of excessive radiation exposure to the patients. The establishment of the Ads and LDRLs should also consider all the factors that affect the variation in DRLs such as CT technology, scanning protocols and population characteristics. The local dose distribution should always be revised for improvement of the current local practice.
Normalizing the Abnormal: Do Antipsychotic Drugs Push the Cortex Into an Unsustainable Metabolic Envelope?
Authors: Turkheimer Federico E , Selvaggi Pierluigi , Mehta Mitul A , Veronese Mattia , Zelaya Fernando , Dazzan Paola , Vernon Anthony C
Published: October 2019

The use of antipsychotic medication to manage psychosis, principally in those with a diagnosis of schizophrenia or bipolar disorder, is well established. Antipsychotics are effective in normalizing positive symptoms of psychosis in the short term (delusions, hallucinations and disordered thought). Their long-term use is, however, associated with side effects, including several types of movement (extrapyramidal syndrome, dyskinesia, akathisia), metabolic and cardiac disorders. Furthermore, higher lifetime antipsychotic dose-years may be associated with poorer cognitive performance and blunted affect, although the mechanisms driving the latter associations are not well understood. In this article, we propose a novel model of the long-term effects of antipsychotic administration focusing on the changes in brain metabolic homeostasis induced by the medication. We propose here that the brain metabolic normalization, that occurs in parallel to the normalization of psychotic symptoms following antipsychotic treatment, may not ultimately be sustainable by the cerebral tissue of some patients; these patients may be characterized by already reduced oxidative metabolic capacity and this may push the brain into an unsustainable metabolic envelope resulting in tissue remodeling. To support this perspective, we will review the existing data on the brain metabolic trajectories of patients with a diagnosis of schizophrenia as indexed using available neuroimaging tools before and after use of medication. We will also consider data from pre-clinical studies to provide mechanistic support for our model.
Why Do We Do What We Do? The Values of the Social History of Medicine
Authors: McKay Richard A
Published: October 2019

At the Society for the Social History of Medicine (SSHM)’s biennial conference in Liverpool in July 2018, members gathered to discuss a short working paper developed by the Society’s executive committee to articulate the values underpinning the SSHM’s mission. The occasion marked the first public discussion of this document, in development since 2015, which was intended to encourage disciplinary self-awareness and engagement, to give a sense of the breadth and importance of work carried out in our field and to spark broader discussion. To further these aims as the Society celebrates its fiftieth anniversary, the working paper appears here, accompanied by a foreword from the Society’s Policy Development Officer and the lightly revised invited responses shared that day by five members at different career stages.
Model-Based Species Delimitation: Are Coalescent Species Reproductively Isolated?
Authors: Campillo Luke C , Barley Anthony J , Thomson Robert C
Published: October 2019

A large and growing fraction of systematists define species as independently evolving lineages that may be recognized by analyzing the population genetic history of alleles sampled from individuals belonging to those species. This has motivated the development of increasingly sophisticated statistical models rooted in the multispecies coalescent process. Specifically, these models allow for simultaneous estimation of the number of species present in a sample of individuals and the phylogenetic history of those species using only DNA sequence data from independent loci. These methods hold extraordinary promise for increasing the efficiency of species discovery but require extensive validation to ensure that they are accurate and precise. Whether the species identified by these methods correspond to the species that would be recognized by alternative species recognition criteria (such as measurements of reproductive isolation) is currently an open question and a subject of vigorous debate. Here, we perform an empirical test of these methods by making use of a classic model system in the history of speciation research, flies of the genus Drosophila. Specifically, we use the uniquely comprehensive data on reproductive isolation that is available for this system, along with DNA sequence data, to ask whether Drosophila species inferred under the multispecies coalescent model correspond to those recognized by many decades of speciation research. We found that coalescent based and reproductive isolation-based methods of inferring species boundaries are concordant for 77% of the species pairs. We explore and discuss potential explanations for these discrepancies. We also found that the amount of prezygotic isolation between two species is a strong predictor of the posterior probability of species boundaries based on DNA sequence data, regardless of whether the species pairs are sympatrically or allopatrically distributed. [BPP; Drosophila speciation; genetic distance; multispecies coalescent.]
Fluorescent Reporter Zebrafish Line for Estrogenic Compound Screening Generated Using a CRISPR/Cas9-Mediated Knock-in System
Authors: Abdelmoneim Ahmed , Clark Cedric L , Mukai Motoko
Published: October 2019

An increasing number of compounds in our diet and environment are being identified as estrogenic, causing serious and detrimental effects on human, animal, and ecosystem health. Time- and cost-effective biological tools to detect and screen these compounds with potential high-throughput capabilities are in ever-growing demand. We generated a knock-in zebrafish transgenic line with enhanced green fluorescent protein (EGFP) driven by the regulatory region upstream of vitellogenin 1 (vtg1), a well-studied biomarker for estrogenic exposure, using CRISPR/Cas9 technology. Exposure to 17β-estradiol (E2: 0–625 nM) starting at 4-h post-fertilization in dechorionated embryos resulted in the significant induction of hepatic EGFP with ≥5 nM E2 as early as 3-days post-fertilization. Concentration- and time-dependent increase in the percentage of hepatic EGFP-positive larvae and extent of fluorescence expression, categorized into 3 expression levels, were observed with E2 exposure. A strong correlation between the levels of EGFP mRNA, vtg1 mRNA, and EGFP fluorescence levels were detected. Image analysis of the area and intensity of hepatic EGFP fluorescence resulted in high-fidelity quantitative measures that could be used in automated screening applications. In addition, exposure to bisphenol A (0–30 μM) resulted in quantitative responses showing promise for the use of this transgenic line to assess estrogenic activity of endocrine-disrupting chemicals. These results demonstrate that this novel knock-in zebrafish reporter allows for distinct screening of in vivo estrogenic effects, endpoints of which can be used for laboratory testing of samples for estimation of possible human and environmental risks.
Proximal Tubular Vacuolization and Hypersensitivity to Drug-Induced Nephrotoxicity in Male Mice With Decreased Expression of the NADPH-Cytochrome P450 Reductase
Authors: Ding Liang , Li Lei , Liu Senyan , Bao Xiaochen , Dickman Kathleen G , Sell Stewart S , Mei Changlin , Zhang Qing-Yu , Gu Jun , Ding Xinxin
Published: October 2019

The effect of variations in the expression of cytochrome P450 reductase (CPR or POR) is determined in mice with decreased POR expression to identify potential vulnerabilities in people with low POR expression. There is an age-dependent appearance of increasing vacuolization in the proximal tubules of the renal cortex in 4- to 9-month-old male (but not female) Cpr-low (CL) mice. These mice have low POR expression in all cells of the body and upregulation of lysosome-associated membrane protein 1 expression in the renal cortex. Vacuolization is also seen in extrahepatic CL and extrarenal CL male mice, but not in mice with tissue-specific Por deletion in liver, intestinal epithelium, or kidney. The occurrence of vacuolization is accompanied by increases in serum blood-urea-nitrogen levels. Male CL mice are hypersensitive to cisplatin- and gentamicin-induced renal toxicity at 3 months of age, before proximal tubular (PT) vacuoles are detectable. At doses that do not cause renal toxicity in wild-type mice, both drugs cause substantial increases in serum blood-urea-nitrogen levels and PT vacuolization in male but not female CL mice. The hypersensitivity to drug-induced renal toxicity is accompanied by increases in circulating drug levels. These novel findings demonstrate deficiency of renal function in mice with globally reduced POR expression and suggest that low POR expression may be a risk factor for drug-induced nephrotoxicity in humans.
Adiponectin links maternal metabolism to uterine contractility
Authors: Vyas Vibhuti , Guerra Damian D. , Bok Rachael , Powell Theresa , Jansson Thomas , Hurt K. Joseph
Published: October 2019

Adiponectin is secreted by adipose tissue and promotes insulin sensitivity. Low circulating adiponectin is associated with increased risk for preterm labor, but the influence of adiponectin on uterine myometrial physiology is unknown. We hypothesized that adiponectin receptors (AdipoRs) decrease myometrial contractility via AMPK to promote uterine quiescence in pregnancy. Using quantitative RT‐PCR, we found that nonpregnant or pregnant human and mouse myometrium express AdipoR1 and AdipoR2 mRNAs. We confirmed AdipoR2 protein expression in human and mouse myometrium, with increased abundance in late mouse pregnancy. Both recombinant adiponectin and a pharmacologic AdipoR agonist, AdipoRon, potently inhibited uterine myometrial strip contractions in physiologic organ bath. The relaxation was independent of contractile stimulus (oxytocin, KCl, U46619). AdipoR agonists increased AMPK phosphorylation in pregnant mouse myometrium, and the direct AMPK activator A769662 also relaxed myometrial strips. However, the AMPK inhibitor dorsomorphin (compound C) blocked AMPK phosphorylation but did not abolish relaxation with either AdipoRon or A769662. In summary, adiponectin inhibits myometrial contractility consistent with the possibility that it is a previously unrecognized link between maternal metabolism and pregnancy maintenance. We also identify a separate role for AMPK regulating myometrial contractions that may influence labor onset.—Vyas, V., Guerra, D. D., Bok, R., Powell, T., Jansson, T., Hurt, K. J. Adiponectin links maternal metabolism to uterine contractility. FASEB J. 33, 14588‐14601 (2019). www.fasebj.org
Saccharospirillum alexandrii sp. nov., isolated from the toxigenic marine dinoflagellate Alexandrium catenella LZT09
Authors: Yang Qiao , Jiang Zhiwei , Zhou Xin , Xie Zhangxian , Wang Ying , Wang Dongfang , Feng Lijuan , Yang Guangfeng , Ge Yaming , Zhang Xiaoling
Published: October 2019

A Gram-stain-negative, strictly aerobic, non-motile and non-pigmented spirillum, designated strain LZ-5T, was isolated from cultures of the paralytic shellfish poisoning (PSP) toxin-producing marine dinoflagellate Alexandrium catenella LZT09 collected from the Zhoushan sea area in the East China Sea during an algal bloom. The isolate grew at 4–40 °C (optimum, 25–33 °C) and pH 5.0–9.0 (optimum, 7.5) in the presence of 0.5–10 % (w/v) NaCl (optimum, 4.0 %). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain LZ-5T clearly belonged to the genus

Saccharospirillum

of the family

Saccharospirillaceae

. Strain LZ-5T shared highest 16S rRNA gene sequence similarity with

Saccharospirillum impatiens

EL-105T (98.9 %),

Saccharospirillum mangrovi

HK-33T (97.2 %), Saccharospirillum correiae CPA1T (96.8 %),

Saccharospirillum salsuginis

YIM-Y25T (96.8 %) and

Saccharospirillum aestuarii

IMCC 4453T (95.1 %). The average nucleotide identity and in silico DNA–DNA hybridization between strain LZ-5T and the two most closely related

Saccharospirillum

strains,

S. impatiens

EL-105T and

S. mangrovi

HK-33T, were 82.2 and 19.3 %, and 72.2 and 13.2 %, respectively. The predominant respiratory quinone of strain LZ-5T was Q-8, and the major fatty acids were summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c), summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c) and C16 : 0. The polar lipids of strain LZ-5T were diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), phosphatidylcholine (PC), glycolipid (GL), two unidentified glycophospholipids (GPLs), three unidentified aminophospholipids (APLs) and two unidentified lipids. The genomic DNA G+C content was 57.2 mol%. On the basis of this polyphasic characterization, strain LZ-5T represents a novel species of the genus

Saccharospirillum

, for which the name Saccharospirillum alexandrii sp. nov. is proposed. The type strain is LZ-5T (=KCTC 62460T=CCTCC AB2017232T).
Associations between outdoor temperature and bright sunlight with metabolites in two population-based European cohorts
Authors: Eveleens Maarse Boukje C , Loh Nellie Y. , Karpe Fredrik , Rosendaal Frits R , van Heemst Diana , Mook-Kanamori Dennis O , van Dijk Ko Willems , Rensen Patrick CN , Kooijman Sander , Christodoulides Constantinos , Noordam Raymond
Published: October 2019

Context: Outdoor temperature and bright sunlight may directly and/or indirectly modulate systemic metabolism.

Objective: We assessed the associations between outdoor temperature and bright sunlight duration with metabolomics.

Design: meta-analysis of two cross-sectional studies.

Setting: Two population-based European cohort studies.

Patients or other participants: Non-diabetic individuals from the Oxford BioBank (OBB; N=6,368; mean age 47.0 years, males 44%) and the Netherlands Epidemiology of Obesity (NEO; N=5,916; mean age 55.6 years, males 43%) studies.

Intervention(s): Data on mean outdoor bright sunlight and temperature collected from local weather stations in the week prior to blood sampling.

Main Outcome Measure(s): Serum levels of 148 metabolites measured using NMR spectroscopy, including 14 lipoprotein subclasses.

Statistical analyses: Multivariable linear regression analyses adjusted for age, sex, body mass index, season and either outdoor temperature or bright sunlight. Summary statistics from the OBB and NEO cohorts were combined using fixed-effect meta-analyses.

Results: A higher mean outdoor temperature was associated with increased concentrations of lipoprotein (sub)particles and certain amino acids such as phenylalanine and leucine. In contrast, longer mean hours of bright sunlight were specifically associated with lower concentrations of very low density lipoprotein (sub)particles. The direction of effects was consistent between the OBB and NEO, although effect sizes were generally larger in the OBB.

Conclusions: Increased bright sunlight duration is associated with an improved metabolic profile whilst higher outdoor temperature may adversely impact cardiometabolic health.
A single-sample circadian biomarker that performs across populations and platforms
Authors: Wu Gang , Ruben Marc D. , Francey Lauren J. , Smith David F. , Sherrill Joseph D. , Oblong John E. , Mills Kevin J. , Hogenesch John B.
Published: October 2019

Background

For circadian medicine to influence health, such as when to take a drug or undergo a procedure, a practical way to measure body time is needed. Recent machine learning algorithms show that gene expression data from blood and skin can provide reliable estimates of body time. However, for clinical viability, a biomarker must be easily measured and generalizable to a broad population. It is not clear that any circadian biomarker yet satisfies these criteria.

Results

We analyzed 24 h molecular rhythms in human dermis and epidermis at three distinct body sites, leveraging both longitudinal and population data. Circadian clock function was strongest in the epidermis, regardless of body site. We identified a 12-gene biomarker set that reported circadian phase to within 3 hours from a single sample of epidermis—the skin’s most superficial layer. This set performed well across body sites, ages, sexes, and detection platforms.

Conclusions

This research shows that the clock in epidermis is more robust than dermis regardless of body site. To encourage ongoing validation of this biomarker in diverse populations, diseases, and experimental designs, we developed SkinPhaser—a user-friendly app to test biomarker performance in datasets (https://github.com/gangwug/SkinPhaser).
Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility
Authors: Korn Clio , Akam Thomas , Jensen Kristian HR , Vagnoni Cristiana , Huber Anna , Tunbridge Elizabeth M , Walton Mark E
Published: October 2019

Dopamine plays a crucial role in adaptive behavior, and dysfunctional dopamine is implicated in multiple psychiatric conditions characterized by inflexible or inconsistent choices. However, the precise relationship between dopamine and flexible decision making remains unclear. One reason is that, while many studies have focused on the activity of dopamine neurons, efficient dopamine signaling also relies on clearance mechanisms, notably the dopamine transporter (DAT), which predominates in striatum, and catechol-O-methyltransferase (COMT), which predominates in cortex. The exact locus, extent, and timescale of the effects of DAT and COMT are uncertain. Moreover, there is limited data on how acute disruption of either mechanism affects flexible decision making strategies mediated by cortico-striatal networks. To address these issues, we combined pharmacological modulation of DAT and COMT with electrochemistry and behavior in mice. DAT blockade, but not COMT inhibition, regulated sub-second dopamine release in the nucleus accumbens core, but surprisingly neither clearance mechanism affected evoked release in prelimbic cortex. This was not due to a lack of sensitivity, as both amphetamine and atomoxetine changed the kinetics of sub-second release. In a multi-step decision making task where mice had to respond to reversals in either reward probabilities or the choice sequence to reach the goal, DAT blockade selectively impaired, and COMT inhibition improved, performance after reward reversals, but neither manipulation affected the adaptation of choices after actionstate transition reversals. Together, our data suggest that DAT and COMT shape specific aspects of behavioral flexibility by regulating striatal and cortical dopamine, respectively, at fast and slow timescales.
Messenger RNAs with large numbers of upstream ORFs are translated via leaky scanning and reinitiation in the asexual stages ofPlasmodium falciparum
Authors: Kaur Chhaminder , Kumar Mayank , Patankar Swati
Published: October 2019

The genome ofPlasmodium falciparumhas one of the most skewed base pair compositions of any eukaryote, with an AT content of 80-90%. As start and stop codons are AT-rich, the probability of finding upstream open reading frames (uORFs) in messenger RNAs (mRNAs) is high and parasite mRNAs have an average of 10 uORFs in their leader sequences. Similar to other eukaryotes, uORFs repress the translation of the downstream gene (dORF) inP. falciparum, yet the parasite translation machinery is able to bypass these uORFs and reach the dORF to initiate translation. This can happen by leaky scanning and/or reinitiation.

In this report, we assessed leaky scanning and reinitiation by studying the effect of uORFs on the translation of a dORF, in this case the luciferase reporter gene, and showed that both mechanisms are employed in the asexual blood stages ofP. falciparum. Furthermore, in addition to codon usage of the uORF, translation of the dORF is governed by the Kozak sequence and length of the uORF, and inter-cistronic distance between the uORF and dORF. Based on these features whole genome data was analyzed to uncover classes of genes that might be regulated by uORFs. This study indicates that leaky scanning and reinitiation appear to be widespread in asexual stages ofP. falciparum, which may require modifications of existing factors that are involved in translation initiation in addition to novel, parasite-specific proteins.
Tumor neoantigen heterogeneity thresholds provide a time window for combination immunotherapy
Authors: Aguadé-Gorgorió Guim , Solé Ricard
Published: October 2019

Following the advent of immunotherapy as a possible cure for cancer, remarkable insight has been gained on the role of mutational load and neoantigens as key ingredients in T cell recognition of malignancies. However, not all highly mutational tumors react to immune therapies, and even initial success is often followed by eventual relapse. Recent research points out that high heterogeneity in the neoantigen landscape of a tumor might be key in understanding the failure of immune surveillance. In this work we present a mathematical framework able to describe how neoantigen distributions shape the immune response. Modeling T cell reactivity as a function of antigen dominancy and distribution across a tumor indicates the existence of a diversity threshold beyond which T cells fail at controling heterogeneous cancer growth. Furthemore, an analytical estimate for the evolution of average antigen clonality indicates rapid increases in epitope heterogeneity in early malignancy growth. In this scenario, we propose that therapies targeting the tumor prior to immunotherapy can reduce neoantigen heterogeneity, and postulate the existence of a time window, before tumor relapse due to de novo resistance, rendering immunotherapy more effective.

Major Findings

Genetic heterogeneity affects the immune response to an evolving tumor by shaping the neoantigen landscape of the cancer cells, and highly heterogeneous tumors seem to escape T cell recognition. Mathematical modeling predicts the existence of a well defined neoantigen diversity threshold, beyond which lymphocites are not able to counteract the growth of a population of highly heterogeneous subclones. Furthermore, evolutionary dynamics predict a fast decay of neoantigen clonality, rendering advanced tumors hard to attack at the time of immunotherapy. Within this mathematical framework we propose that targeted therapy forcing a selective pressure for resistance might as well increase neoantigen homogeneity, providing a novel possibility for combination therapy.
Interconversion between Anticipatory and Active GID E3 Ubiquitin Ligase Conformations via Metabolically Driven Substrate Receptor Assembly
Authors: Qiao Shuai , Langlois Christine R. , Chrustowicz Jakub , Sherpa Dawafuti , Karayel Ozge , Hansen Fynn M. , Beier Viola , von Gronau Susanne , Bollschweiler Daniel , Schäfer Tillman , Alpi Arno F. , Mann Matthias , Prabu J. Rajan , Schulman Brenda A.
Published: October 2019

Cells respond to environmental changes by toggling metabolic pathways, preparing for homeostasis, and anticipating future stresses. For example, inSaccharomyces cerevisiae, carbon stress-induced gluconeogenesis is terminated upon glucose availability, a process that involves the multiprotein E3 ligase, GIDSR4, recruiting N-termini and catalyzing ubiquitylation of gluconeogenic enzymes. Here, genetics, biochemistry, and cryo electron microscopy define molecular underpinnings ofglucose-induceddegradation. Unexpectedly, carbon stress induces an inactive anticipatory complex (GIDAnt), which awaits a glucose-induced substrate receptor to form the active GIDSR4. Meanwhile, other environmental perturbations elicit production of an alternative substrate receptor assembling into a related E3 ligase complex. The intricate structure of GIDAntenables anticipating and ultimately binding various N-degron targeting (i.e. “N-end rule”) substrate receptors, while the GIDSR4E3 forms a clamp-like structure juxtaposing substrate lysines with the ubiquitylation active site. The data reveal evolutionarily conserved GID complexes as a family of multisubunit E3 ubiquitin ligases responsive to extracellular stimuli.
SECNVs: A Simulator of Copy Number Variants and Whole-Exome Sequences from Reference Genomes
Authors: Xing Yue , Dabney Alan R. , Li Xiao , Wang Guosong , Gill Clare A. , Casola Claudio
Published: October 2019

Copy number variants are insertions and deletions of 1 kb or larger in a genome that play an important role in phenotypic changes and human disease. Many software applications have been developed to detect copy number variants using either whole-genome sequencing or whole-exome sequencing data. However, there is poor agreement in the results from these applications. Simulated datasets containing copy number variants allow comprehensive comparisons of the operating characteristics of existing and novel copy number variant detection methods. Several software applications have been developed to simulate copy number variants and other structural variants in whole-genome sequencing data. However, none of the applications reliably simulate copy number variants in whole-exome sequencing data. We have developed and tested SECNVs (Simulator of Exome Copy Number Variants), a fast, robust and customizable software application for simulating copy number variants and whole-exome sequences from a reference genome. SECNVs is easy to install, implements a wide range of commands to customize simulations, can output multiple samples at once, and incorporates a pipeline to output rearranged genomes, short reads and BAM files in a single command. Variants generated by SECNVs are detected with high sensitivity and precision by tools commonly used to detect copy number variants. SECNVs is publicly available at https://github.com/YJulyXing/SECNVs.