bluuebunny/crossref_metadata_2025_split huggingface dataset:
Revisiting the reduction of stochastic models of genetic feedback loops with fast promoter switching
Authors: Holehouse J. , Grima R. 
Published: June 2019

AbstractPropensity functions of the Hill-type are commonly used to model transcriptional regulation in stochastic models of gene expression. This leads to an effective reduced master equation for the mRNA and protein dynamics only. Based on deterministic considerations, it is often stated or tacitly assumed that such models are valid in the limit of rapid promoter switching. Here, starting from the chemical master equation describing promoter-protein interactions, mRNA transcription, protein translation and decay, we prove that in the limit of fast promoter switching, the distribution of protein numbers is different than that given by standard stochastic models with Hill-type propensities. We show the differences are pronounced whenever the protein-DNA binding rate is much larger than the unbinding rate, a special case of fast promoter switching. Furthermore we show using both theory and simulations that use of the standard stochastic models leads to drastically incorrect predictions for the switching properties of positive feedback loops and that these differences decrease with increasing mean protein burst size. Our results confirm that commonly used stochastic models of gene regulatory networks are only accurate in a subset of the parameter space consistent with rapid promoter switching.Statement of SignificanceA large number of models of gene regulatory networks in the literature assume that since promoter switching is fast then transcriptional regulation can be effectively modeled using Hill functions. While this approach can be rigorously justified for deterministic models, it is presently unclear if it is also the case for stochastic models. In this article we prove that this is not the case, i.e. stochastic models of gene regulatory systems, namely those with feedback loops, describing transcriptional regulation using Hill functions are only valid in a subset of parameter conditions consistent with fast promoter switching. We identify parameter regimes where these models are correct and where their predictions cannot be trusted.
Pervasive off-target and double-stranded DNA nicking by CRISPR-Cas12a
Authors: Murugan Karthik , Seetharam Arun S. , Severin Andrew J. , Sashital Dipali G. 
Published: June 2019

AbstractCas12a (formerly Cpf1) is an RNA-guided endonuclease in the CRISPR-Cas immune system that can be easily programmed for genome editing. Cas12a can bind and cut dsDNA targets with high specificity in vivo, making it an ideal candidate for precise genome editing applications. This specificity is contradictory to the natural role of Cas12a as an immune effector against rapidly evolving phages. However, the native cleavage specificity and activity remains to be fully understood. We employed high-throughput in vitro cleavage assays to determine and compare the native specificities of three Cas12a orthologs. Surprisingly, we observed pervasive nicking of randomized target libraries, with strong nicking activity observed against targets with up to four mismatches. Nicking and cleavage activities are dependent on mismatch type and position, and vary depending on the Cas12a ortholog and crRNA sequence. Our high-throughput and biochemical analysis further reveal that Cas12a has robust activated non-specific nicking and weak non-specific dsDNA degradation activity in trans. Together, our findings reveal Cas12a cleavage activities that could be beneficial in the context of bacterial CRISPR-Cas immunity but may be detrimental for genome editing technology.
Minimum epistasis interpolation for sequence-function relationships
Authors: Zhou Juannan , McCandlish David M. 
Published: June 2019

AbstractMassively parallel phenotyping assays have provided unprecedented insight into how multiple mutations combine to determine biological function. While these assays can measure phenotypes for thousands to millions of genotypes in a single experiment, in practice these measurements are not exhaustive, so that there is a need for techniques to impute values for genotypes whose phenotypes are not directly assayed. Here we present a method based on the idea of inferring the least epistatic possible sequence-function relationship compatible with the data. In particular, we infer the reconstruction in which mutational effects change as little as possible across adjacent genetic backgrounds. Although this method is highly conservative and has no tunable parameters, it also makes no assumptions about the form that genetic interactions take, resulting in predictions that can behave in a very complicated manner where the data require it but which are nearly additive where data is sparse or absent. We apply this method to analyze a fitness landscape for protein G, showing that our technique can provide a substantially less epistatic fit to the landscape than standard methods with little loss in predictive power. Moreover, our analysis reveals that the complex structure of epistasis observed in this dataset can be well-understood in terms of a simple qualitative model consisting of three fitness peaks where the landscape is locally additive in the vicinity of each peak.
Lifetime marijuana use in relation to insulin resistance in lean, overweight, and obese US adults
Authors: Ngueta Gerard , Ndjaboue Ruth 
Published: June 2019

AbstractBackgroundObese individuals are more likely to show insulin resistance (IR). However, limited population studies on marijuana use with markers of IR have yielded mixed results. The aim of this study was to examine the association of marijuana use with IR in US adults with different body mass index (BMI) status.MethodsData from the 2009 to 2016 National Health and Nutrition Examination Survey (NHANES) were abstracted. Minimal lifetime marijuana use was estimated using the duration of regular exposure and frequency of use. The association of marijuana use with both fasting insulin (FINS) and homeostasis model assessment of insulin resistance (HOMA‐IR) was determined in lean, overweight, and obese individuals separately using generalized linear models. Interview weight years of data were used to account for the unequal probability of sampling and non‐response.ResultsOf all 129 509 adults aged 18 to 59 years, 50.3% were women. In current obese marijuana consumers, mean FINS in those with less than four uses per month was 52% (95% confidence interval [CI] 19%‐71%) lower than in never users. In former obese consumers with eight or more uses per month and who stopped marijuana use <12 months ago, mean FINS was 47% (95% CI 18%‐66%) lower than in never users. Mean FINS in those who quit marijuana 12 to 119 and 120 months and more prior the survey was 36% (95% CI 7%‐57%) and 36% (95% CI 10%‐54%) lower, respectively.ConclusionsMarijuana use is associated with lower FINS and HOMA‐IR in obese but not non‐obese adults, even at low frequency of less than four uses per month. Former marijuana consumers with high lifetime use had significantly lower FINS levels that persisted, independent of the duration of time since last use.
Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy
Authors: Hatakeyama Keiichi , Nagashima Takeshi , Ohshima Keiichi , Ohnami Sumiko , Ohnami Shumpei , Shimoda Yuji , Serizawa Masakuni , Maruyama Koji , Naruoka Akane , Akiyama Yasuto , Urakami Kenichi , Kusuhara Masatoshi , Mochizuki Tohru , Yamaguchi Ken 
Published: June 2019

AbstractTumor mutational burden (TMB) and mutational signatures reflect the process of mutation accumulation in cancer. However, the significance of these emerging characteristics remains unclear. In the present study, we used whole‐exome sequencing to analyze the TMB and mutational signature in solid tumors of 4046 Japanese patients. Eight predominant signatures—microsatellite instability, smoking, POLE, APOBEC, UV, mismatch repair, double‐strand break repair, and Signature 16—were observed in tumors with TMB higher than 1.0 mutation/Mb, whereas POLE and UV signatures only showed moderate correlation with TMB, suggesting the extensive accumulation of mutations due to defective POLE and UV exposure. The contribution ratio of Signature 16, which is associated with hepatocellular carcinoma in drinkers, was increased in hypopharynx cancer. Tumors with predominant microsatellite instability signature were potential candidates for treatment with immune checkpoint inhibitors such as pembrolizumab and were found in 2.8% of cases. Furthermore, based on microarray analysis, tumors with predominant signatures were classified into 2 subgroups depending on the expression of immune‐related genes reflecting differences in the immune context of the tumor microenvironment. Tumor subpopulations differing in the content of infiltrating immune cells might respond differently to immunotherapeutics. An understanding of cancer characteristics based on TMB and mutational signatures could provide new insights into mutation‐driven tumorigenesis.
Jarid1b promotes epidermal differentiation by mediating the repression of Ship1 and activation of the AKT/Ovol1 pathway
Authors: Sun Xuewei , Li Zhiyuan , Niu Yanfang , Zhao Lijuan , Huang Yichuan , Li Qiang , Zhang Shengnan , Chen Ting , Fu Tao , Yang Tao , An Xiaofei , Jiang Yan , Zhang Jisheng 
Published: June 2019

AbstractObjectivesTerminally differentiated stratified squamous epithelial cells play an important role in barrier protection of the skin. The integrity of epidermal cells is maintained by tight regulation of proliferation and differentiation. The aim of this study was to investigate the role of epigenetic regulator H3K4me3 and its demethylase Jarid1b in the control of epithelial cell differentiation.Materials and methodsRT‐qPCR, Western blotting and IHC were used to detect mRNA and protein levels. We analysed cell proliferation by CCK8 assay and cell migration by wound healing assay. ChIP was used to measure H3K4me3 enrichment. A chamber graft model was established for epidermal development.ResultsOur studies showed that H3K4me3 was decreased during epidermal differentiation. The H3K4me3 demethylase Jarid1b positively controlled epidermal cell differentiation in vitro and in vivo. Mechanistically, we found that Jarid1b substantially increased the expression of mesenchymal‐epithelial transition (MET)‐related genes, among which Ovol1 positively regulated differentiation gene expression. In addition, Ovol1 expression was repressed by PI3K‐AKT pathway inhibitors and overexpression (O/E) of the PI3K‐AKT pathway suppressor Ship1. Knockdown (KD) of Ship1 activated downstream PI3K‐AKT pathway and enhanced Ovol1 expression in HaCaT. Importantly, we found that Jarid1b negatively regulated Ship1 expression, but not that of Pten, by directly binding to its promoter to modulate H3K4me3 enrichment.ConclusionOur results identify an essential role of Jarid1b in the regulation of the Ship1/AKT/Ovol1 pathway to promote epithelial cell differentiation.
The plus‐tip tracking and microtubule stabilizing activities of Javelin‐like regulate microtubule organization and cell polarity
Authors: Baskar Raju , Bahkrat Anna , Otani Tetsuhisa , Wada Housei , Davidov Geula , Pandey Himanshu , Gheber Larisa , Zarivach Raz , Hayashi Shigeo , Abdu Uri 
Published: June 2019

Cell polarity is essential for building cell asymmetry in all eukaryotic cells. Drosophila oocyte and bristle development require the newly characterized Spn‐F protein complex, which includes Spn‐F, IKKε, and Javelin‐like (Jvl), to establish polarity. Jvl is a novel microtubule (MT)‐associated protein; however, the mechanism by which it regulates MT organization is still unknown. We found that overexpression of Jvl stabilizes MTs and that jvl is needed for stable MT arrangement at the bristle tip and organization of the dynamic MT throughout the bristle shaft. At low levels of expression in cultured cells, Jvl behaved as a microtubule plus‐end tracking protein. We demonstrated that Jvl physically interacts with the highly conserved MT end‐binding protein 1 (EB1) using yeast two‐hybrid and GST pull‐down assays. This interaction is, however, dispensable for Jvl function in oocyte and bristle development. In addition, using a MT‐binding assay, we saw that Jvl‐C terminus directly binds to MTs. We also revealed that oocyte developmental arrest caused by Jvl overexpression in the germline can be rescued by mutations in its partners, spn‐F and ikkε, suggesting that complex formation with Spn‐F and IKKε is required for Jvl function in vivo. In summary, our results show that the microtubule plus‐end tracking and stabilizing activities of Jvl are central for controlling cell polarity of oocytes and bristles.
Cross‐country spillovers of fiscal consolidations in the euro area
Authors: Poghosyan Tigran 
Published: June 2019

AbstractThis paper revisits the issue of cross‐country spillovers from fiscal consolidations using an innovative empirical methodology. We find evidence in support of fiscal spillovers in ten euro area countries. Fiscal consolidation in one country not only reduces domestic output (direct effect) but also reduces the output of other member countries (indirect/spillover effect). Fiscal spillovers are larger for (a) more closely located and economically integrated countries, and (b) fiscal shocks originating from relatively larger countries. On average, 1% of gross domestic product fiscal consolidation in ten euro area countries reduces the combined output by 0.6% on impact, out of which half is driven by indirect effects from fiscal spillovers. The impact peters out and becomes insignificant over the medium term. It is largely driven by tax measures, which have a relatively stronger effect on output compared to expenditure measures. The results are robust to alternative measures of bilateral links across countries.
End stage scurvy in the developed world: A diagnostic conundrum but not to be mistaken for pyoderma gangrenosum
Authors: Le Stephanie T. , Wang Jenny Z. , Alexanian Claire C. , Johng Stephanie Y. , Patel Forum B. , Wang Elizabeth A. , Ma Chelsea , Wilken Reason , Cheng Michelle Y. , Maverakis Emanual 
Published: June 2019

AbstractScurvy is a clinical syndrome, resulting from ascorbic acid deficiency. Prevalence of the condition is now extremely low in the Western population and its diagnosis can be challenging without a high index of suspicion. When cases do present, they are often misdiagnosed initially. Therefore, a thorough history, physical exam, and laboratory evaluation are key to showing this now rare but extremely well‐known disease. We report a case of scurvy manifesting as persistent non‐healing lower‐extremity ulcerations, initially mistaken for pyoderma gangrenosum. The patient responded to appropriate replacement therapy, but ulcers were slow to heal. As was the case in our patient, symptom reversal may require additional nutritional replacement. We encourage physicians to consider nutritional deficiencies in their differential diagnoses and highlight the incidence of malnutrition in the proper clinical setting to avoid diagnostic delay.
Association between periodontitis and cognitive impairment: Analysis of national health and nutrition examination survey (NHANES) III
Authors: Sung Cheng‐En , Huang Ren‐Yeong , Cheng Wan‐Chien , Kao Tung‐Wei , Chen Wei‐Liang 
Published: June 2019

AbstractObjectivesPeriodontitis has been hypothesized as being one of the most common potential risk factors for the development of dementia and cognitive impairment. In order to investigate the relationship between periodontitis and cognition impairment, the National Health and Nutrition Examination Survey (NHANES) database was analysed after adjusting for potential confounding factors, including age and other systemic co‐morbidities.Materials and MethodsIn total, 4,663 participants aged 20–59 years who had received full‐mouth periodontal examination and undergone the cognitive functional test were enrolled. The grade of periodontal disease was categorized into severe, moderate, and mild. Cognitive function examinations, including the simple reaction time test (SRTT), symbol digit substitution test (SDST), and serial digit learning test (SDLT), were adopted for the evaluation of cognitive impairment.ResultsThe subjects with mild and moderate to severe periodontitis had higher SDLT and SDST scores, which indicated decreased cognitive function, compared with the healthy group. After adjusting for demographic factors, education, smoking, cardiovascular diseases, and laboratory data, periodontitis was significantly correlated with elevated SDST and SDLT scores (p values for trend = 0.014 and 0.038, respectively) by generalized linear regression models.ConclusionOur study highlighted that periodontal status was associated with cognitive impairment in a nationally representative sample of US adults.
Comparison of periodontitis patients’ classification in the 2018 versus 1999 classification
Authors: Graetz Christian , Mann Lucas , Krois Joachim , Sälzer Sonja , Kahl Maren , Springer Claudia , Schwendicke Falk 
Published: June 2019

AbstractObjectivesWe aimed to assess how the 2018 and 1999 classifications of periodontal diseases reflect (a) patients’ characteristics, (b) disease severity/extent/progression and (c) tooth loss (TL) during observation period.MethodsA total of 251 patients were followed over 21.8 ± 6.2 years. For the 1999 classification, using clinical attachment level (CAL), patients were classified as localized/generalized, mild/moderate/severe and aggressive/chronic periodontitis. For the 2018 classification, patients were staged according to their CAL or bone loss (BL) and the number of lost teeth (stages I–IV). Further factors like probing pocket depths (PPD) or furcation involvement modified the stage. The extent was sub‐classified as generalized/localized. Patients were graded according to the BL/age index, smoking and/or diabetes.ResultsAccording to the 1999 classification, most patients suffered from generalized severe chronic periodontitis (203/251) or generalized aggressive periodontitis (45/251). Patients with aggressive periodontitis were younger and less often female or smokers. They showed similar TL (0.25 ± 0.22 teeth/patient*year) as generalized severe chronic periodontitis patients (0.23 ± 0.25 teeth/patient*year). According to the 2018 classification, most patients were classified as generalized III‐C (140/251), III‐B (31/251) or IV‐C (64/251). Patients’ age, smoking status, CAL, PPD and BL were well reflected. TL differed between IV‐C (0.36 ± 0.47), generalized III‐C (0.21 ± 0.24) and localized forms (0.10–0.15).ConclusionsPatients’ characteristics, disease severity/extent/progression and TL were well reflected by the 2018 classification.
Cassava brown streak virus Ham1 protein hydrolyses mutagenic nucleotides and is a necrosis determinant
Authors: Tomlinson Katie R. , Pablo‐Rodriguez José Luis , Bunawan Hamidun , Nanyiti Sarah , Green Patrick , Miller Josie , Alicai Titus , Seal Susan E. , Bailey Andy M. , Foster Gary D. 
Published: June 2019

SummaryCassava brown streak disease (CBSD) is a leading cause of cassava losses in East and Central Africa, and is currently having a severe impact on food security. The disease is caused by two viruses within the Potyviridae family: Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV), which both encode atypical Ham1 proteins with highly conserved inosine triphosphate (ITP) pyrophosphohydrolase (ITPase) domains. ITPase proteins are widely encoded by plant, animal, and archaea. They selectively hydrolyse mutagenic nucleotide triphosphates to prevent their incorporation into nucleic acid and thereby function to reduce mutation rates. It has previously been hypothesized that U/CBSVs encode Ham1 proteins with ITPase activity to reduce viral mutation rates during infection. In this study, we investigate the potential roles of U/CBSV Ham1 proteins. We show that both CBSV and UCBSV Ham1 proteins have ITPase activities through in vitro enzyme assays. Deep‐sequencing experiments found no evidence of the U/CBSV Ham1 proteins providing mutagenic protection during infections of Nicotiana hosts. Manipulations of the CBSV_Tanza infectious clone were performed, including a Ham1 deletion, ITPase point mutations, and UCBSV Ham1 chimera. Unlike severely necrotic wild‐type CBSV_Tanza infections, infections of Nicotiana benthamiana with the manipulated CBSV infectious clones do not develop necrosis, indicating that that the CBSV Ham1 is a necrosis determinant. We propose that the presence of U/CBSV Ham1 proteins with highly conserved ITPase motifs indicates that they serve highly selectable functions during infections of cassava and may represent a euphorbia host adaptation that could be targeted in antiviral strategies.
Spectral characteristics of visible light‐induced pigmentation and visible light protection factor
Authors: Kohli Indermeet , Nahhas Amanda F. , Braunberger Taylor L. , Chaowattanapanit Suteeraporn , Mohammad Tasneem F. , Nicholson Cynthia L. , Kollias Nikiforos , Lim Henry W. , Hamzavi Iltefat H. 
Published: June 2019

AbstractSolar radiation is a major contributor to the development of skin cancer. Recent studies have shown that visible light (VL), a major portion of solar spectrum, induces biologic effects on the skin. Ultraviolet filters in currently available broad‐spectrum sunscreens do not offer protection against VL. This study was designed to identify the spectral characteristics of the skin responses induced by VL, which can be utilized for time efficient in vivo VL testing. Thirty‐one subjects were irradiated with a light source emitting visible light with less than 0.5% long wavelength UVA1 (VL + UVA1, 370‐700 nm), and 41 subjects were irradiated with pure visible light (pure VL, 400‐700 nm). Assessments including clinical photography, investigator's global assessment of pigmentation and erythema, and diffuse reflectance spectroscopy (DRS) performed immediately and seven days after irradiation. Clinical and spectroscopic data showed that VL + UVA1 spectral output induced significantly darker and persistent skin responses as compared to those induced by pure VL. Spectroscopic signatures of skin responses induced by both radiation sources were identified. The signatures were found to be specific to the radiation source and time of collection. A method to evaluate VL protection factor, using quantitative information from the spectral signatures obtained, was proposed.