bluuebunny/crossref_metadata_2025 huggingface dataset:
The Politics of Musical Standardization in Nineteenth-Century France and Britain
Authors: Gillin Edward , Gribenski Fanny
Published: February 2020

This article examines mid-nineteenth-century Anglo-French relations through the prism of musical standardization. Bringing together perspectives from musicology, history of science, and political history, it demonstrates the holistic value of musical practices for the study of processes of political integration. In 1859, Napoléon III's government determined a national pitch to which musicians should tune their instruments. The following year, Britain's Society of Arts attempted to emulate this standard. Amid tense Anglo-French relations, British audiences interpreted the French pitch as a measure of the country's autocracy, and these political anxieties materialized through a redefinition of the standard. The challenges of introducing a musical pitch within a liberal political framework encountered in 1859 were subsequently echoed in debates over the reform of weights and measures following the 1860 free trade treaty between Britain and France. Both the economic and artistic integration of these countries involved the problem of how to regulate society within a laissez-faire state. Musical standardization has received little historiographical attention, but the regulation of this art offers insights into mid-nineteenth-century Anglo-French political culture. Entangled within complex network of industrial, institutional, and social structures, musical pitch demonstrates how problems of economic and social integration were inseparable from international and socio-political contexts.
Exploring Acceptance and Commitment Therapy for parents of preterm infants
Authors: Esser Kayla , Barreira Lesley , Miller Doug , Church Paige , Major Nathalie , Cohen Eyal , Orkin Julia
Published: February 2020

The start of a parenting journey in the neonatal intensive care unit (NICU) presents many stressors to parents. Previous research has shown parents of infants admitted to the NICU experience heightened stress, anxiety, and depression. Mental health support varies across Canadian NICUs with mixed results. One promising intervention that has not been explored in the NICU is Acceptance and Commitment Therapy (ACT), a behavioural therapy that has had positive mental health-related outcomes in similar parental populations. ACT differs from previous mental health interventions such as traditional Cognitive Behavioural Therapy (CBT) as it involves mindfulness and acceptance to increase psychological flexibility. Increased psychological flexibility is linked to greater emotional well-being, a higher quality of life, and decreased stress, anxiety, and depression. There is a need for research investigating the utility of ACT in improving mental health outcomes for parents of preterm infants.
Out-of-Sample Performance of Mutual Fund Predictors
Authors: Jones Christopher S , Mo Haitao
Published: February 2020

We analyze the out-of-sample performance of variables shown to forecast future mutual fund alphas. The degree of predictability, as measured by alpha spreads from quintile sorts or cross-sectional regression slopes, falls by at least half post-sample. These declines appear to be primarily the result of changes in the level of arbitrage activity in the market, with mutual fund competition appearing to play a secondary role. We find no evidence that the declines are the result of data snooping or learning by investors or fund managers. Finally, we show that corporate bond fund performance exhibits similar dependence on measures of bond market arbitrage activity.
Lack of Multidrug Resistance-associated Protein 4 Prolongs Partial Hepatectomy-induced Hepatic Steatosis
Authors: Donepudi Ajay C , Smith Gregory J , Aladelokun Oladimeji , Lee Yoojin , Toro Steven J , Pfohl Marisa , Slitt Angela L , Wang Li , Lee Ji-Young , Schuetz John D , Manautou José E
Published: February 2020

Multidrug resistance-associated protein 4 (Mrp4) is an efflux transporter involved in the active transport of several endogenous and exogenous chemicals. Previously, we have shown that hepatic Mrp4 expression increases following acetaminophen overdose. In mice, these increases in Mrp4 expression are observed specifically in hepatocytes undergoing active proliferation. From this, we hypothesized that Mrp4 plays a key role in hepatocyte proliferation and that lack of Mrp4 impedes liver regeneration following liver injury and/or tissue loss. To evaluate the role of Mrp4 in these processes, we employed two-third partial hepatectomy (PH) as an experimental liver regeneration model. In this study, we performed PH-surgery on male wildtype (C57BL/6J) and Mrp4 knockout mice. Plasma and liver tissues were collected at 24, 48, and 72 h postsurgery and evaluated for liver injury and liver regeneration endpoints, and for PH-induced hepatic lipid accumulation. Our results show that lack of Mrp4 did not alter hepatocyte proliferation and liver injury following PH as evaluated by Ki-67 antigen staining and plasma alanine aminotransferase levels. To our surprise, Mrp4 knockout mice exhibited increased hepatic lipid content, in particular, di- and triglyceride levels. Gene expression analysis showed that lack of Mrp4 upregulated hepatic lipin1 and diacylglycerol O-acyltransferase 1 and 2 gene expression, which are involved in the synthesis of di- and triglycerides. Our observations indicate that lack of Mrp4 prolonged PH-induced hepatic steatosis in mice and suggest that Mrp4 may be a novel genetic factor in the development of hepatic steatosis.
Highland of COVID-19 outside Hubei: epidemic characteristics, control and projections of Wenzhou, China
Authors: Xu Liangde , Yuan Jian , Zhang Yaru , Zhang Guosi , Lu Fan , Su Jianzhong , Qu Jia
Published: February 2020

In late December 2019, Chinese authorities reported a cluster of pneumonia cases of unknown aetiology in Wuhan, China1. A novel strain of coronavirus named Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was isolated and identified on 2 January 20202. Human-to-human transmission have been confirmed by a study of a family cluster and have occurred in health-care workers3,4. Until 10 February 2020, 42638 cases of 2019 novel coronavirus disease (COVID-19) have been confirmed in China, of which 31728 came from Hubei Province (Figure). Wenzhou, as a southeast coastal city with the most cases outside Hubei Province, its policy control and epidemic projections have certain references for national and worldwide epidemic prevention and control. We described the epidemiologic characteristics of COVID-19 in Wenzhou and made a transmission model to predict the expected number of cases in the coming days.
Stochastic discrete epidemic modeling of COVID-19 transmission in the Province of Shaanxi incorporating public health intervention and case importation
Authors: Tang Sanyi , Tang Biao , Bragazzi Nicola Luigi , Xia Fan , Li Tangjuan , He Sha , Ren Pengyu , Wang Xia , Peng Zhihang , Xiao Yanni , Wu Jianhong
Published: February 2020

Before the lock-down of Wuhan/Hubei/China, on January 23rd 2020, a large number of individuals infected by COVID-19 moved from the epicenter Wuhan and the Hubei province due to the Spring Festival, resulting in an epidemic in the other provinces including the Shaanxi province. The epidemic scale in Shaanxi was comparatively small and with half of cases being imported from the epicenter. Based on the complete epidemic data including the symptom onset time and transmission chains, we calculate the control reproduction number (1.48-1.69) in Xi’an. We could also compute the time transition, for each imported or local case, from the latent, to infected, to hospitalized compartment, as well as the effective reproduction number. This calculation enables us to revise our early deterministic transmission model to a stochastic discrete epidemic model with case importation and parameterize it. Our model-based analyses reveal that the newly generated infections decay to zero quickly; the cumulative number of case-driven quarantined individuals via contact tracing stabilize at a manageable level, indicating that the intervention strategies implemented in the Shaanxi province have been effective. Risk analyses, important for the consideration of “resumption of work”, show that a large second outbreak is expected if the level of case importation remains at the same level as between January 10th and February 4th 2020. However, if the case importation decreases by 30%, 60% and 90%, the second outbreak if happening will be of small-scale assuming contact tracing and quarantine/isolation remain as effective as before. Finally, we consider the effects of intermittent inflow with a Poisson distribution on the likelihood of multiple outbreaks. We believe the developed methodology and stochastic model provide an important model framework for the evaluation of revising travel restriction rules in the consideration of resuming social-economic activities while managing the disease control with potential case importation.
Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project
Authors: Roman Tamara S. , Crowley Stephanie B. , Roche Myra I. , Foreman Ann Katherine M. , O’Daniel Julianne M. , Seifert Bryce A. , Lee Kristy , Brandt Alicia , Gustafson Chelsea , DeCristo Daniela M. , Strande Natasha T. , Ramkissoon Lori , Milko Laura V. , Owen Phillips , Roy Sayanty , Xiong Mai , Paquin Ryan S. , Butterfield Rita M. , Lewis Megan A. , Souris Katherine J. , Bailey Donald B. , Rini Christine , Booker Jessica K. , Powell Bradford C. , Weck Karen E. , Powell Cynthia M. , Berg Jonathan S.
Published: February 2020

Newborn screening (NBS) was established as a public health program in the 1960’s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the use of exome sequencing (ES) for NBS in theNorthCarolinaNewbornExome Sequencing forUniversalScreening (NC NEXUS) project, comparing the yield from ES used in a screening versus a diagnostic context. We enrolled healthy newborns and children with metabolic diseases or hearing loss (106 participants total). ES confirmed the participant’s underlying diagnosis in 15 out of 17 (88%) children with metabolic disorders, and in 5 out of 28 (∼18%) children with hearing loss.

We discovered actionable findings in 4 participants that would not have been detected by standard NBS. A subset of parents was eligible to receive additional information for their child about childhood-onset conditions with low or no clinical actionability, clinically actionable adult-onset conditions, and carrier status for autosomal recessive conditions. We found pathogenic variants associated with hereditary breast and/or ovarian cancer in 2 children, a likely pathogenic variant in the gene associated with Lowe syndrome in one child, and an average of 1.8 reportable variants per child for carrier results. These results highlight the benefits and limitations of using genomic sequencing for NBS and the challenges of using such technology in future precision medicine approaches.
Evaluation of the clinical characteristics of suspected or confirmed cases of COVID-19 during home care with isolation: A new retrospective analysis based on O2O
Authors: Xu Hui , Huang Sufang , Liu Shangkun , Deng Juan , Jiao Bo , Ai Ling , Xiao Yaru , Yan Li , Li Shusheng
Published: February 2020

Background

The recent outbreak of the novel coronavirus in December 2019 (COVID-19) has activated top-level response nationwide. We developed a new treatment model based on the online-to-offline (O2O) model for the home isolated patients, because in the early stages the medical staff were insufficient to cope with so many patients.

Methods

In this single-centered, retrospective study, we enrolled 48 confirmed/suspected COVID-19 patients who underwent home isolation in Wuhan between January 6 and January 31, 2020. By WeChat and online document editing all patients were treated with medical observation scale. The clinical indications such as Fever, Muscle soreness, Dyspnea and Lack of strength were collected with this system led by medical staff in management, medicine, nursing, rehabilitation and psychology.

Findings

The mean age of 48 patients was 39·08±13·88 years, 35(72·9%) were women. Compared with non-hospitalized patients, inpatients were older(≥70years, 2·4% vs 33·3%, P<0·04). All inpatients had fever, 50% inpatients had coughs and showed infiltration in both lungs at the time of diagnosis. 33·3% inpatients exhibited negative changes in their CT results at initial diagnosis. The body temperature of non-hospitalized patients with mild symptoms returned to normal by day 4-5. While dyspnea peaked on day 6 for non-hospitalized patients with mild symptoms, it persisted in hospitalized patients and exacerbated over time. The lack of strength and muscle soreness were both back to normal by day 4 for non-hospitalized patients.

Interpretation

Monitoring the trends of symptoms is more important for identifying severe cases. Excessive laboratory data and physical examination are not necessary for the evaluation of patients with mild symptoms. The system we developed is the first to convert the subjective symptoms of patients into objective scores. This type of O2O, subjective-to-objective strategy may be used in regions with similar highly infectious diseases to minimize the possibility of infection among medical staff.
Rapid Molecular Detection of SARS-CoV-2 (COVID-19) Virus RNA Using Colorimetric LAMP
Authors: Zhang Yinhua , Odiwuor Nelson , Xiong Jin , Sun Luo , Nyaruaba Raphael Ohuru , Wei Hongping , Tanner Nathan A.
Published: February 2020

The ability to detect an infectious agent in a widespread epidemic is crucial to the success of quarantine efforts in addition to sensitive and accurate screening of potential cases of infection from patients in a clinical setting. Enabling testing outside of sophisticated laboratories broadens the scope of control and surveillance efforts, but also requires robust and simple methods that can be used without expensive instrumentation. Here we report a method to identify SARS-CoV-2 (COVID-19) virus RNA from purified RNA or cell lysis using loop-mediated isothermal amplification (LAMP) using a visual, colorimetric detection. This test was additionally verified using RNA samples purified from respiratory swabs collected from COVID-19 patients in Wuhan, China with equivalent performance to a commercial RT-qPCR test while requiring only heating and visual inspection. This simple and sensitive method provides an opportunity to facilitate virus detection in the field without a requirement for complex diagnostic infrastructure.
Modelling the coronavirus disease (COVID-19) outbreak on the Diamond Princess ship using the public surveillance data from January 20 to February 20, 2020
Authors: Zhao Shi , Cao Peihua , Gao Daozhou , Zhuang Zian , Chong Marc KC , Cai Yongli , Ran Jinjun , Wang Kai , Lou Yijun , Wang Weiming , Yang Lin , He Daihai , Wang Maggie H
Published: February 2020

The novel coronavirus disease 2019 (COVID-19) outbreak on the Diamond Princess ship has caused over 634 cases as of February 20, 2020. We model the transmission process on the ship with a stochastic model and estimate the basic reproduction number at 2.2 (95%CI: 2.1-2.4). We estimate a large dispersion parameter than other coronaviruses, which implies that the virus is difficult to go extinction. The epidemic doubling time is at 4.6 days (95%CI: 3.0-9.3), and thus timely actions were crucial. The lesson learnt on the ship is generally applicable in other settings.
The Effects of “Fangcang, Huoshenshan, and Leishenshan” Hospitals and Temperature on the Mortality of COVID-19
Authors: Cai Yuwen , Huang Tianlun , Liu Xin , Xu Gaosi
Published: February 2020

Background

In December 2019, a novel coronavirus disease (COVID-19) broke out in Wuhan, China, however, the factors affecting the mortality remain unclear.

Methods

Thirty-two days of data that were shared by China National Health Commission and China Weather Net were collected using standard forms. The difference in the mortality of confirmed and severe cases before and after the use of “Fangcang, Huoshenshan, and Leishenshan” makeshift hospitals (MSHs) was tested using Mann-Whitney U test. We also studied whether air temperature (AT) could affect the above outcomes of COVID-19 cases by performing Spearman’s analysis.

Results

Eight days after the use of MSHs, the mortality of confirmed cases was significantly decreased both in Wuhan (U = 1, P < 0.001) and Hubei (U = 0, P < 0.001), while in non-Hubei regions, as a contrast, the mortality of confirmed cases remained unchanged (U = 40, P = 0.139). However, another eight days later, changes in the mortality in non-Hubei regions also became significant (U = 73, P = 0.039). Mortality of confirmed cases was found to be significantly correlated with AT both in Wuhan (r = −0.441, P = 0.012) and Hubei (r = −0.440, P = 0.012).

Conclusions

Our findings indicated that both the use of MSHs and the rise of AT were beneficial to the survival of COVID-19 cases.
Coordinated prefrontal state transition leads extinction of reward-seeking behaviors
Authors: Russo Eleonora , Ma Tianyang , Spanagel Rainer , Durstewitz Daniel , Toutounji Hazem , Köhr Georg
Published: February 2020

Extinction learning suppresses conditioned reward responses and is thus fundamental to adapt to changing environmental demands and to control excessive reward seeking. The medial prefrontal cortex (mPFC) monitors and controls conditioned reward responses. Usingin vivomultiple single-unit recordings of mPFC we studied the relationship between single-unit and population dynamics during different phases of an operant conditioning task. To examine the fine temporal relation between neural activity and behavior, we developed a model-based statistical analysis that captured behavioral idiosyncrasies. We found that single-unit responses to conditioned stimuli changed throughout the course of a session even under stable experimental conditions and consistent behavior. However, when behavioral responses to task contingencies had to be updated during the extinction phase, unit-specific modulations became coordinated across the whole population, pushing the network into a new stable attractor state. These results show that extinction learning is not associated with suppressed mPFC responses to conditioned stimuli, but is driven by single-unit coordination into population-wide transitions of the animal’s internal state.
Sex differences in clinical findings among patients with coronavirus disease 2019 (COVID-19) and severe condition
Authors: Li Jing , Zhang Yinghua , Wang Fang , Liu Bing , Li Hui , Tang Guodong , Chang Zhigang , Liu Aihua , Fu Chunyi , Gao Jing , Li Jing
Published: February 2020

Objective

To compare the sex differences in the clinical findings among patients with severe coronavirus disease 2019 (COVID-19).

Methods

We retrospectively collected data of 47 patients diagnosed as severe type of COVID-19 from February 8 to 22, 2020, including demographics, illness history, physical examination, laboratory test, management, and compared differences between men and women.

Results

Of the 47 patients, 28 (59.6%) were men. The median age was 62 years, and 30 (63.8%) had comorbidities. The initial symptoms were mainly fever (34 [72.3%]), cough (36 [76.6%]), myalgia (5 [10.6%]) and fatigue (7 [14.9%]). Procalcitonin level was higher in men than in women (0.08 vs. 0.04ng/ml, p=0.002). N-terminal-pro brain natriuretic peptide increased in 16 (57.1%) men and 5 (26.3%) women (p=0.037). Five men (17.9%) had detected positive influenza A antibody, but no women. During 2-week admission, 5 (17.9%) men and 1 (5.3%) woman were reclassified into the critical type due to deterioration. Mortality was 3.6% in men and 0 in women respectively. Four (21.1%) women and one man (3.6%) recovered and discharged from hospital.

Conclusion

Sex differences may exist in COVID-19 patients of severe type. Men are likely to have more complicated clinical condition and worse in-hospital outcomes as compared to women.
Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction
Authors: Liu Xiaoyan , Li Zhe , Liu Shuai , Chen Zhanghua , Sun Jing , Zhao Zhiyao , Huang Yi-you , Zhang Qingling , Wang Jun , Shi Yinyi , Xu Yanhui , Xian Huifang , Fang Rongli , Bai Fan , Ou Changxing , Xiong Bei , Lew Andrew M , Cui Jun , Huang Hui , Zhao Jincun , Hong Xuechuan , Zhang Yuxia , Zhou Fuling , Luo Hai-Bin
Published: February 2020

The human coronavirus HCoV-19 infection can cause acute respiratory distress syndrome (ARDS), hypercoagulability, hypertension, extrapulmonary multiorgan dysfunction. Effective antiviral and anti-coagulation agents with safe clinical profiles are urgently needed to improve the overall prognosis. We screened an FDA approved drug library and found that an anticoagulant agent dipyridamole (DIP) suppressed HCoV-19 replication at an EC50 of 100 nMin vitro. It also elicited potent type I interferon responses and ameliorated lung pathology in a viral pneumonia model. In analysis of twelve HCoV-19 infected patients with prophylactic anti-coagulation therapy, we found that DIP supplementation was associated with significantly increased platelet and lymphocyte counts and decreased D-dimer levels in comparison to control patients. Two weeks after initiation of DIP treatment, 3 of the 6 severe cases (60%) and all 4 of the mild cases (100%) were discharged from the hospital. One critically ill patient with extremely high levels of D-dimer and lymphopenia at the time of receiving DIP passed away. All other patients were in clinical remission. In summary, HCoV-19 infected patients could potentially benefit from DIP adjunctive therapy by reducing viral replication, suppressing hypercoagulability and enhancing immune recovery. Larger scale clinical trials of DIP are needed to validate these therapeutic effects.
Modeling the Epidemic Dynamics and Control of COVID-19 Outbreak in China
Authors: Zhao Shilei , Chen Hua
Published: February 2020

Background

The coronavirus disease 2019 (COVID-19) is rapidly spreading in China and more than 30 countries over last two months. COVID-19 has multiple characteristics distinct from other infectious diseases, including high infectivity during incubation, time delay between real dynamics and daily observed number of confirmed cases, and the intervention effects of implemented quarantine and control measures.

Method

We develop a Susceptible, Un-quanrantined infected, Quarantined infected, Confirmed infected (SUQC) model to characterize the dynamics of COVID-19 and explicitly parameterize the intervention effects of control measures, which is more suitable for analysis than other existing epidemic models.

Results

The SUQC model is applied to the daily released data of the confirmed infections to analyze the outbreak of COVID-19 in Wuhan, Hubei (excluding Wuhan), China (excluding Hubei) and four first-tier cities of China. We found that, before January 30th, 2020, all these regions except Beijing had a reproductive number R > 1, and after January 30th, all regions had a reproductive number R < 1, indicating that the quarantine and control measures are effective in preventing the spread of COVID-19. The confirmation rate of Wuhan estimated by our model is 0.0643, substantially lower than that of Hubei excluding Wuhan (0.1914), and that of China excluding Hubei (0.2189), but jumps to 0.3229 after Feb 12th when clinical evidence was adopted in new diagnosis guidelines. The number of un-quarantined infected cases in Wuhan on February 12, 2020 is estimated to be 3,509 and declines to 334 on February 21th, 2020. After fitting the model with data as of February 21th, 2020, we predict that the end time of COVID-19 in Wuhan and Hubei is around late March, around mid March for China excluding Hubei, and before early March 2020 for the four tier-one cities. A total of 80,511 individuals are estimated to be infected in China, among which 49,510 are from Wuhan, 17,679 from Hubei (excluding Wuhan), and the rest 13,322 from other regions of China (excluding Hubei). Note that the estimates are from a deterministic ODE model and should be interpreted with some uncertainty.

Conclusion

We suggest that rigorous quarantine and control measures should be kept before early March in Beijing, Shanghai, Guangzhou and Shenzhen, and before late March in Hubei. The model can also be useful to predict the trend of epidemic and provide quantitative guide for other countries in a high risk of outbreak, such as South Korea, Japan, Italy and Iran.
Accurate Classification of the Gut Microbiota of Patients in Intensive Care Units During the Development of Sepsis and Septic Shock
Authors: Liu Wanglin , Cheng Mingyue , Li Jinman , Zhang Peng , Fan Hang , Hu Qinghe , Han Maozhen , Su Longxiang , He Huaiwu , Tong Yigang , Ning Kang , Long Yun
Published: February 2020

The gut microbiota of intensive care unit (ICU) patients display extreme dysbiosis, which is associated with increased susceptibility to organ failure, sepsis and septic shock. However, this dysbiosis is hard to be characterized for each patient, owing to the highly dimensional complexity of gut microbiota. We thus tested whether the concept of enterotype can be applied to the gut microbiota of ICU patients, to describe the dysbiosis. We collected 131 fecal samples from a cohort of 64 ICU patients diagnosed with sepsis or septic shock, using 16S rRNA gene sequencing to dissect their gut microbiota compositions. We find that during the development of sepsis or septic shock, as well as various medical treatments, ICU patients always contain two patterns of dysbiotic microbiota named as ICU-enterotypes, which cannot be explained by the individual host properties such as age, gender and body mass index, as well as external stressors such as infection sites and antibiotic use. ICU-enterotype I comprised predominantly Bacteroides and an unclassified genus of family Enterobacteriaceae, while ICU-enterotype II comprised predominantly Enterococcus. Among more critically ill patients with acute physiology and chronic health evaluation (APACHE) II score > 18, samples of septic shock were more likely to present with ICU-enterotype I (p = 0.041). Additionally, ICU-enterotype I was correlated with high serum lactate level (p = 0.007). Therefore, different patterns of dysbiosis are correlated with different clinical outcomes, suggesting that the diagnosis of ICU-enterotypes as an independent clinical index is crucial. For this purpose, the microbial-based human index (MHI) classifier we proposed shows high precision and effectiveness in timely monitoring of ICU-enterotypes of an individual patient. Together, our work serves as the first step toward precision medicine for septic patients based on the gut microbiota profile.
Tumor-infiltrating immune cells signature predicts recurrence free survival after complete resection of localized primary gastrointestinal stromal tumors
Authors: Yi Mengshi , Zhao Rui , Wan Qianyi , Wu Xiaoting , Zhuang Wen , Yang Hanshuo , Wu Chuncheng , Xia Lin , Chen Yi , Zhou Yong
Published: February 2020

Background

Growing evidence has proposed prognostic value of immune infiltration in gastrointestinal stromal tumors (GISTs). Therefore, we aimed to develop a novel immune-based prognostic classifier (IPC) to help better stratify and predict prognosis of GISTs.

Methods

The gene expression profiles of 22 immune features of GISTs were detected from GEO dataset. The IPC was constructed using the LASSO Cox regression model and validated in a cohort including 54 patients with complete resection of localized primary GISTs via immunohistochemistry process. The performance assessment of the IPC was estimated, then compared with conventional risk prognostic criteria.

Results

The IPC was established based on 4 features: CD8, CD8/CD3, CD68, CD163/CD68 and validated to be an independent predictor of RFS for GISTs (HR 5.2, 95%CI 1.99-13.65). Significant differences were found between low- and high-IPC group in 5-year RFS (92.6% vs 48.1%, p < 0.001). Using the IPC, the high-risk group of the Modified NIH classification was split into two groups in 5-year RFS (low-IPC vs high-IPC, 85.7% vs 30.0%, p < 0.001). The IPC showed a higher net benefit than both “treat all” or “treat none” methods for the threshold probability within a range of 0-0.62 and exhibited a performance (AUC 0.842) superior to modified NIH classification (AUC 0.763).

Conclusion

The IPC was effective to predict RFS after complete resection of localized primary GISTs, adding prognostic value to the routine clinical prognostic criteria. Prospective studies are needed to further validate the analytical accuracy and practicability of the IPC in estimating prognosis of GISTs.
A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex
Authors: Smith Rebecca G. , Pishva Ehsan , Shireby Gemma , Smith Adam R. , Roubroeks Janou A.Y. , Hannon Eilis , Wheildon Gregory , Mastroeni Diego , Gasparoni Gilles , Riemenschneider Matthias , Giese Armin , Sharp Andrew J. , Schalkwyk Leonard , Haroutunian Vahram , Viechtbauer Wolfgang , van den Hove Daniel L.A. , Weedon Michael , Brokaw Danielle , Francis Paul T. , Thomas Alan J , Love Seth , Morgan Kevin , Walter Jörn , Coleman Paul D. , Bennett David A. , De Jager Philip L. , Mill Jonathan , Lunnon Katie
Published: February 2020

Epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer’s disease (N=1,453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N=1,408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further > 600 unique donors. The meta-analysis summary statistics are available in our online data resource (www.epigenomicslab.com/ad-meta-analysis/).
Future climate change promotes novel gene-climate associations in balsam poplar (Populus balsamiferaL.), a forest tree species
Authors: Gougherty Andrew V. , Keller Stephen R. , Chhatre Vikram E. , Fitzpatrick Matthew C.
Published: February 2020

A central challenge to predicting climate change effects on biodiversity is integrating information on intraspecific variation, specifically population-level local adaptation to climate. Assessing how climate change could disrupt local adaptation to climate can provide a new way of understanding population risk and vulnerability to climate change. For the wide-ranging boreal tree species, balsam poplar (Populus balsamiferaL.), we used models of existing population-level genetic differentiation to estimate three key components of population’s vulnerability to climate change: (1) predicted shifts in genetic composition with and without migration, (2) the potential for future novel gene-climate associations, and (3) the distance populations would need to migrate to minimize future maladaptation. When assessed across the range of balsam poplar, these three metrics suggest that vulnerability to climate change is greatest in the eastern portion of balsam poplar’s range, where future maladaptation peaked, migration distances to sites that minimized maladaptation were greatest, and the emergence of novel gene-climate associations were highest. Our results further suggest greater maladaptation to climate when migration distances were limited – consistent with the possibility of migration to lessen maladaptation to future climate. Our work provides a comprehensive evaluation of population’s vulnerability to climate change by simultaneously assessing population maladaptation to future climate and the distances populations would need to migrate to minimize maladaptation, in a way that goes beyond species-level bioclimatic modelling. In doing so, our work helps advance towards the long-held goal of incorporating genomic information in models of species responses to climate change.
TP53abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia
Authors: Lai Catherine , Vadakekolathu Jayakumar , Reeder Stephen , Church Sarah E. , Hood Tressa , Aldoss Ibrahim , Godwin John , Wieduwilt Matthew J. , Arellano Martha , Muth John , Ravandi Farhad , Sweet Kendra , Altmann Heidi , Foulds Gemma A. , Stölzel Friedrich , Middeke Jan Moritz , Ciciarello Marilena , Curti Antonio , Valk Peter J.M. , Löwenberg Bob , Bornhäuser Martin , DiPersio John F. , Davidson-Moncada Jan K. , Rutella Sergio
Published: February 2020

Purpose

SomaticTP53mutations and 17p deletions with genomic loss ofTP53occur in 37-46% of acute myeloid leukemia (AML) cases with adverse risk cytogenetics and are associated with primary induction failure (PIF), high risk of relapse and dismal prognosis. Herein, we aimed to characterize the immune landscape ofTP53mutated AML and to determine whetherTP53abnormalities identify a patient subgroup that may benefit from T-cell targeting immunotherapy approaches.

Experimental Design

The NanoString Pan-Cancer IO 360™ assay was used for the immune transcriptomic analysis of 64 diagnostic bone marrow (BM) samples from adults withTP53mutated AML (n=42) orTP53wild type AML (n=22), and 35 BM samples from heavily pretreated patients with relapsed/refractory (R/R) AML (11 cases withTP53mutations and/or 17p deletion with genomic loss ofTP53) who received immunotherapy with flotetuzumab, an investigational CD123×CD3 bispecific DART®molecule (NCT02152956). In silico data series included The Cancer Genome Atlas (TCGA) cohort and a Dutch–Belgian Cooperative Trial Group for Hematology–Oncology (HOVON) cohort.

Results

All TCGA cases withTP53mutations (n=13) expressed higher levels of negative immune checkpoints, inflammatory chemokines, interferon (IFN)-γ-inducible molecules, and had a higher tumor inflammation signature (TIS) score, compared with TCGA cases with other risk-defining molecular lesions. The comparison betweenTP53mutated andTP53wild type primary BM samples showed higher expression ofIFNG, FoxP3, immune checkpoints and markers of exhaustion and senescence in the former cohort and allowed the computation of a 34-gene immune classifier prognostic for overall survival.In vitromodeling experiments with AML cell lines showed heightened expression of IFN-γ and inflammation pathway genes in KG-1 cells (loss-of-function mutation ofTP53) compared with Kasumi-1 cells (gain-of-function mutation ofTP53). Finally, 5 out of 11 (45.5%) patients with R/R AML andTP53abnormalities showed evidence of anti-leukemic activity of flotetuzumab immunotherapy and had higher TIS,FoxP3, CD8 T-cell abundance, inflammatory chemokine andPD1gene expression scores at baseline compared with non-responders.

Conclusions

This study provides evidence for a correlation between IFN-γ-dominant immune subtypes andTP53abnormalities. The anti-leukemic activity with flotetuzumab encourages further study of this immunotherapeutic approach in this patient subgroup.
Super-resolved spatial transcriptomics by deep data fusion
Authors: Bergenstråhle Ludvig , He Bryan , Bergenstråhle Joseph , Andersson Alma , Lundeberg Joakim , Zou James , Maaskola Jonas
Published: February 2020

In situ RNA capturing has made it possible to record histology and spatial gene expression from the same tissue section. Here, we introduce a method that combines data from both modalities to infer super-resolved full-transcriptome expression maps. Our method unravels transcriptional heterogeneity in micrometer-scale anatomical features and enables image-based in silico spatial transcriptomics without hybridization or sequencing.
Chronic administration of a positive allosteric modulator at the α5-GABAA receptor reverses age-related dendritic shrinkage
Authors: Prevot Thomas D. , Sumitomo Akiko , Tomoda Toshifumi , Knutson Daniel E. , Li Guanguan , Cook James M. , Sibille Etienne
Published: February 2020

Over the last 15 years, worldwide life expectancy increased by 5 years jumping from 66 years to 71 years. With progress in science, medicine, and care we tend to live longer. Such extended life expectancy is still associated with age-related changes, including in the brain. The aging brain goes through various changes that can be called morphomolecular senescence. Overall, the brain volume changes, neuronal activity is modified and plasticity of the cells diminishes, sometimes leading to neuronal atrophy and death. Altogether, these changes contribute to the emergence of cognitive decline that still does not have an efficient treatment available. Many studies in the context of cognitive decline focused on pathological aging, targeting β-amyloid in Alzheimer’s disease, for example. However, β-amyloid plaques are also present in healthy adults and treatments targeting plaques have failed to improve cognitive functions. In order to improve the quality of life of aging population, it is crucial to focus on the development of novel therapies targeting different systems altered during aging, such as the GABAergic system. In previous studies, it has been shown that positive allosteric modulators (PAM) acting at the α5-containing GABA-A receptors improve cognitive performances, and that these α5-GABA-A receptors are implicated in dendritic growth of pyramidal neurons. Here, we hypothesized that targeting the α5-GABA-A receptors could contribute to the reduction of cognitive decline, directly through activity of the receptors, and indirectly by increasing neuronal morphology. Using primary neuronal culture and chronic treatment in mice, we demonstrated that an α5-PAM increased dendritic length, spine count and spine density in brain regions involved in cognitive processes (prefrontal cortex and hippocampus). We also confirmed the procognitive efficacy of the α5-PAM and showed that the washout period diminishes the precognitive effects without altering the effect on neuronal morphology. Future studies will be needed to investigate what downstream mechanisms responsible for the neurotrophic effect of the α5-PAM.
Intraspecific variation in land use-related functional traits inPlantago lanceolata
Authors: Gáspár Bence , Bossdorf Oliver , Parepa Madalin
Published: February 2020

Background and aims

Intraspecific variation in functional traits is essential for the evolutionary success of organisms. The co-variation between trait variation and environment, as well as between different traits, can help us to understand which ecological factors drive habitat adaptation, and to what extent adaptation may be constrained by trait correlations and trade-offs. In managed grasslands, plants experience a combination of competition, recurrent biomass removal and nutrient pulses. Each of these ecological challenges requires specific plant tolerances, and populations should locally adapt if intraspecific variation exists in these traits.

Methods

We studied variation in land use-related traits in the common grassland plantPlantago lanceolata. In a common environment, we quantified the competitive ability (R*), clipping tolerance and responses to a nitrogen pulse of plants from 54 populations with different land use intensities across Germany.

Key results

We found significant population differentiation in competitive ability but there was little evidence that trait variation was related to land use intensity. There was a positive relationship between competitive ability and clipping tolerance at the population level, indicating a genetic, and possibly functional, link between these two traits. In contrast, clipping tolerance and nitrogen responses were negatively correlated at the levels of plant individuals, indicating a physiological trade-off between plant responses to these two land-use processes.

Conclusions

Our results show that there is substantial intraspecific variation in some of the key functional traits for plant success in managed grasslands, and that rapid evolution and adaptation is therefore possible in these traits.
Live-cell imaging of circadian clock protein dynamics in CRISPR-generated knock-in cells
Authors: Gabriel Christian H. , del Olmo Marta , Zehtabian Amin , Reischl Silke , van Dijk Hannah , Koller Barbara , Grudziecki Astrid , Maier Bert , Ewers Helge , Herzel Hanspeter , Granada Adrian E. , Kramer Achim
Published: February 2020

The current model of the mammalian circadian oscillator is predominantly based on data from genetics and biochemistry experiments, while the cell biology of circadian clocks is still in its infancy. Here, we describe a new strategy for the efficient generation of knock-in reporter cell lines using CRISPR technology that is particularly useful for lowly or transiently expressed genes, such as those coding for circadian clock proteins. We generated single and double knock-in cells with endogenously expressed PER2 and CRY1 fused to fluorescent proteins, which allowed to simultaneously monitor the dynamics of CRY1 and PER2 proteins in live single cells. Both proteins are highly rhythmic in the nucleus of human cells with PER2 showing a much higher amplitude than CRY1. Surprisingly, CRY1 protein is nuclear at all circadian times indicating the absence of circadian gating of nuclear import. Furthermore, in the nucleus of individual cells CRY1 abundance rhythms are phase-delayed (∼5 hours), and CRY1 levels are much higher (>6 times) compared to PER2 questioning the current model of the circadian oscillator. Our knock-in strategy will allow the generation of additional single, double or triple knock-in cells for circadian clock proteins, which should greatly advance our understanding about the cell biology of circadian clocks.
A novel Ataxin-3 knock-in mouse model mimics the human SCA3 disease phenotype including neuropathological, behavioral, and transcriptional abnormalities
Authors: Haas Eva , Incebacak Rana D. , Hentrich Thomas , Maringer Yacine , Schmidt Thorsten , Zimmermann Frank , Casadei Nicolas , Mills James D. , Aronica Eleonora , Riess Olaf , Schulze-Hentrich Julia M. , Hübener-Schmid Jeannette
Published: February 2020

Background

Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide and is caused by a CAG repeat expansion in theAtaxin-3gene resulting in a polyQ expansion in the corresponding protein. The disease is characterized by neuropathological (aggregate formation, cell loss), phenotypical (gait instability, body weight reduction), and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed to gain a better understanding of the disease pathomechanism.

Methods

Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing either a heterozygous or homozygous expansion of 304 CAG/CAAs in the murineAtaxin-3locus using biochemical, behavioral, and transcriptomic approaches. Further, we compared the transcriptional changes of the knock-in mice to those found in human SCA3 patients, to evaluate the comparability of our model.

Results

The novel Ataxin-3 knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to massive aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these transcriptional changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.

Conclusion

The novel Ataxin-3 knock-in model shares neuropathological, behavioral, and transcriptomic features with human SCA3 patients and, therefore, represents an ideal model to investigate early-onset developments, therapy studies, or longitudinal biomarker alterations.
Spo0A suppressessinlocus expression inClostridioides difficile
Authors: Dhungel Babita Adhikari , Govind Revathi
Published: February 2020

Clostridioides difficileis the leading cause of nosocomial infection and is the causative agent of antibiotic-associated diarrhea. The severity of the disease is directly associated with the production of toxins, and spores are responsible for the transmission and persistence of the organism. Previously we characterizedsinlocus regulators SinR and SinR’, where SinR is the regulator of toxin production and sporulation, while the SinR’ acting as its antagonist. InBacillus subtilis, Spo0A, the master regulator of sporulation, regulates SinR, by regulating the expression of its antagonistsinI. However, the role of Spo0A in the expression ofsinRandsinR’inC. difficileis not yet reported. In this study, we testedspo0Amutants in three differentC. difficilestrains R20291, UK1, and JIR8094, to understand the role of Spo0A insinlocus expression. Western blot analysis revealed thatspo0Amutants had increased SinR levels. The qRT-PCR analysis for its expression further supported this data. By carrying out genetic and biochemical assays, we have shown that Spo0A can bind to the upstream region of this locus to regulates its expression. This study provides vital information that Spo0A regulatessinlocus, which controls critical pathogenic traits such as sporulation, toxin production, and motility inC. difficile.

IMPORTANCE

Clostridioides difficileis the leading cause of antibiotic-associated diarrheal disease in the United States. During infection,C. difficile sporesgerminate, and the vegetative bacterial cells produce toxins that damage host tissue. InC. difficile,sinlocus is known to regulate both sporulation and toxin production. In this study, we have shown that Spo0A, the master regulator of sporulation to control thesinlocus expression. We performed various genetic and biochemical experiments to show that Spo0A directly regulates the expression of this locus by binding to its upstream DNA region. This observation adds new detail to the gene regulatory network that connects sporulation and toxin production in this pathogen.
PLZF is a new substrate of CRBN with thalidomide and 5-hydroxythalidomide
Authors: Yamanaka Satoshi , Murai Hidetaka , Saito Daisuke , Abe Gembu , Tokunaga Etsuko , Iwasaki Takahiro , Takahashi Hirotaka , Takeda Hiroyuki , Suzuki Takayuki , Shibata Norio , Tamura Koji , Sawasaki Tatsuya
Published: February 2020

Thalidomide induces cereblon (CRBN)-dependent degradation of proteins. Human cytochrome P450s are thought to provide two monohydroxylated metabolites from thalidomide, and the metabolites are also considered to be involved in thalidomide effects. However, it remains unclear. We report that human PLZF/ZBTB16 is a target protein of CRBN with thalidomide and its derivatives, and that 5-hydroxythalidomide has high potential for degrading PLZF. Using a human transcription factor protein array produced by a wheat cell-free protein synthesis system, PLZF was found to bind to CRBN with thalidomide. PLZF is degraded by the CRL4CRBNcomplex with thalidomide and its derivatives. Mutagenesis analysis revealed that both 1st and 3rd zinc finger domains conserved in vertebrates are recognized for thalidomide-dependent binding and degradation by CRBN. In chicken limbs, knockdown of Plzf induced skeletal abnormalities, and Plzf was degraded after thalidomide or 5-hydroxythalidomide treatment. Our findings suggest that PLZF is a pivotal substrate involving thalidomide-induced teratogenesis.