bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful management of chylous ascites after pancreatoduodenectomy using etilefrine: a case report
Authors: Takahashi Yusuke , Seki Hitoshi
Published: February 2020

An 84-year-old woman underwent subtotal stomach pancreatoduodenectomy (PD) for distal cholangiocarcinoma. Over 1000 ml of serous ascites, which appeared milky after starting a high-protein, low-fat, middle-chain triglyceride diet, was discharged from the inserted drain. On postoperative day (POD) 13, she underwent right hemicolectomy for transverse colonic volvulus, which occurred on POD 9 and was refractory to conservative therapies. Following second surgery, the chylous ascites (CA) amount continued to increase. Octreotide, albumin and diuretics were administered, but the amount of ascites did not decrease. Etilefrine was administered on POD 19; the ascites amount gradually decreased. The drain was removed 3 days after etilefrine administration. She had no symptoms of abdominal distention after drain removal. Etilefrine’s effectiveness for chylothorax after esophagectomy and CA after distal pancreatectomy has been reported. We present a case of CA successfully treated by etilefrine following PD. Our case highlights etilefrine’s usefulness for CA following PD.
What Do Short Sellers Know?*
Authors: Boehmer Ekkehart , Jones Charles M , Wu Juan (Julie) , Zhang Xiaoyan
Published: February 2020

Using NYSE short-sale order data, we investigate whether short sellers’ informational advantage is related to firm earnings and analyst-related events. With a novel decomposition method, we find that while these fundamental event days constitute only 12% of sample days, they account for over 24% of the overall underperformance of heavily shorted stocks. Importantly, short sellers use both public news and private information to anticipate news regarding earnings and analysts. Shorting’s predictive ability remains significant after controlling for information in analyst actions and displays no reversal patterns, indicating that short sellers know more than analysts, and the nature of their information is long term.
Newly identified viral genomes in pangolins with fatal disease
Authors: Gao Wen-Hua , Lin Xian-Dan , Chen Yan-Mei , Xie Chun-Gang , Tan Zhi-Zhou , Zhou Jia-Jun , Chen Shuai , Holmes Edward C , Zhang Yong-Zhen
Published: February 2020

Epizootic pathogens pose a major threat to many wildlife species, particularly in the context of rapidly changing environments. Pangolins (order Pholidota) are highly threatened mammals, in large part due to the trade in illegal wildlife. During July to August 2018 four sick wild pangolins (three Manis javanica and one Manis pentadactyla) exhibiting a variety of clinical symptoms were rescued by the Jinhua Wildlife Protection Station in Zhejiang province, China. Although three of these animals died, fortunately one recovered after 2 weeks of symptomatic treatment. Using meta-transcriptomics combined with reverse transcription polymerase chain reaction (RT-PCR), we identified two novel RNA viruses in two of the dead pangolins. Genomic analysis revealed that these viruses were most closely related to pestiviruses and coltiviruses, although still highly genetically distinct, with more than 48 and 25 per cent sequence divergence at the amino acid level, respectively. We named these Dongyang pangolin virus (DYPV) and Lishui pangolin virus (LSPV) based on the sampling site and hosts. Although coltiviruses (LSPV) are known to be transmitted by ticks, we found no evidence of LSPV in ticks sampled close to where the pangolins were collected. In addition, although DYPV was present in nymph ticks (Amblyomma javanense) collected from a diseased pangolin, they were not found in the local tick population. Epidemiological investigation revealed that both novel viruses might have been imported following the illegal international trade of pangolins. Hence, these data indicate that illegal wildlife trafficking not only threatens the status of pangolin populations, but may also spread epizootic pathogens.
Atopic dermatitis and its relation to food allergy
Authors: Graham François , Eigenmann Philippe A.
Published: February 2020

Purpose of review

To present the most recent evidence on atopic dermatitis and its relation to food allergy.

Recent findings

Atopic dermatitis is a chronic inflammatory disorder of the skin characterized by impaired skin barrier because of multifactorial causes including genetic factors, immune dysregulation, and skin microbiome dysbiosis. Infants with temporary skin barrier disruption and/or persistent atopic dermatitis are particularly at risk of developing food allergy (during the so-called atopic march), with up to half of patients demonstrating positive food-specific IgE and one-third of severe cases of atopic dermatitis having positive symptoms on oral food challenge. A high proportion of children with atopic dermatitis exhibit asymptomatic sensitization to foods, and skin testing to identify potential food triggers is not recommended unless the patient has a history suggestive of food allergy and/or moderate-to-severe atopic dermatitis unresponsive to optimal topical care. Indeed, indiscriminate testing can lead to a high proportion of false-positive tests and harmful dietary evictions. Promising strategies to prevent food allergy in children with atopic dermatitis include early skincare with emollients and treatment with topical steroid, and early introduction of highly allergenic foods.

Further studies are required to identify risk factors for atopic dermatitis to help prevent the development of food allergy in this high-risk population.
New Medical Device Acquisition During Pediatric Severe Sepsis Hospitalizations
Authors: Carlton Erin F. , Donnelly John P. , Hensley Matthew K. , Cornell Timothy T. , Prescott Hallie C.
Published: February 2020

Objectives:

Severe sepsis is a significant cause of healthcare utilization and morbidity among pediatric patients. However, little is known about how commonly survivors acquire new medical devices during pediatric severe sepsis hospitalization. We sought to determine the rate of new device acquisition (specifically, tracheostomy placement, gastrostomy tube placement, vascular access devices, ostomy procedures, and amputation) among children surviving hospitalizations with severe sepsis. For contextualization, we compare this to rates of new device acquisition among three comparison cohorts: 1) survivors of all-cause pediatric hospitalizations; 2) matched survivors of nonsepsis infection hospitalizations; and 3) matched survivors of all-cause nonsepsis hospitalization with similar organ dysfunction.

Design:

Observational cohort study.

Setting:

Nationwide Readmission Database (2016), including all-payer hospitalizations from 27 states.

Patients:

Eighteen-thousand two-hundred ten pediatric severe sepsis hospitalizations; 532,738 all-cause pediatric hospitalizations; 16,173 age- and sex-matched nonsepsis infection hospitalizations; 15,025 organ dysfunction matched all-cause nonsepsis hospitalizations; and all with live discharge.

Measurements and Main Results:

Among 18,210 pediatric severe sepsis hospitalizations, 1,024 (5.6%) underwent device placement. Specifically, 3.5% had new gastrostomy, 3.1% new tracheostomy, 0.6% new vascular access devices, 0.4% new ostomy procedures, and 0.1% amputations. One-hundred forty hospitalizations (0.8%) included two or more new devices. After applying the Nationwide Readmissions Database sampling weights, there were 55,624 pediatric severe sepsis hospitalizations and 1,585,194 all-cause nonsepsis hospitalizations with live discharge in 2016. Compared to all-cause pediatric hospitalizations, severe sepsis hospitalizations were eight-fold more likely to involve new device acquisition (6.4% vs 0.8%; p < 0.001). New device acquisition was also higher in severe sepsis hospitalizations compared with matched nonsepsis infection hospitalizations (5.1% vs 1.2%; p < 0.01) and matched all-cause hospitalizations with similar organ dysfunction (4.7% vs 2.8%; p < 0.001).

Conclusions:

In this nationwide, all-payer cohort of U.S. pediatric severe sepsis hospitalizations, one in 20 children surviving severe sepsis experienced new device acquisition. The procedure rate was nearly eight-fold higher than all-cause, nonsepsis pediatric hospitalizations, and four-fold higher than matched nonsepsis infection hospitalizations.
Arrhythmias and sudden cardiac death in post-cardiac transplant patients
Authors: Eskander Michael A. , Adler Eric , Hoffmayer Kurt S.
Published: February 2020

Purpose of review

Orthotopic heart transplantation (OHT) significantly improves morbidity and mortality in patients with end-stage heart disease. Despite advances in surgical technique, immunosuppressive therapies, and patient monitoring, long-term risk of arrhythmias and sudden cardiac death (SCD) in the denervated heart remains unchanged.

Recent findings

SCD is responsible for approximately 10% of all posttransplant deaths with a pooled incidence rate of 1.30 per 100 person years and is strongly associated with cardiac allograft vasculopathy (CAV). Risk factors for SCD and CAV include higher donor age, younger recipient age, and reduced left ventricular ejection fraction. Little is known about the time course between CAV and SCD. Although some registry data establish ventricular fibrillation as a documented terminal rhythm, the arrhythmia may not be the mechanism of SCD.

In this review, we identify risk factors and general independent predictors of arrhythmia and SCD and discuss the utility of implantable cardiac defibrillators in post-cardiac transplant patients.
Concussion Symptoms Among Athletes: Preinjury Factors Predict Postinjury Factors
Authors: Sinnott Aaron M. , Kontos Anthony P. , Collins Michael W. , Ortega Justus
Published: February 2020

Objective:

Determine whether preinjury concussion symptom factors predict postinjury concussion symptom factors.

Setting:

Community concussion surveillance program between 2008 and 2017.

Participants:

A total of 290 high school and collegiate-aged athletes (n = 168, aged 14-17 years; n = 122, aged 18-21 years, respectively).

Design:

Retrospective analysis.

Main Measures:

Post-Concussion Symptom Scale scores prior to and within 7 days of sustaining a sport-related concussion.

Methods:

Post-Concussion Symptom Scale scores were aggregated into cognitive-sensory, sleep-arousal, vestibular-somatic, and affective preinjury symptom factors. These preinjury symptom factors, in conjunction with sex and previous concussion history, underwent linear regressions to predict cognitive-migraine-fatigue, somatic, sleep, and affective postinjury symptom factors.

Results:

The cognitive-sensory factor (P = .002) and female sex (P = .002) predicted the postinjury cognitive-migraine-fatigue factor in combined age group but not stratified age group models. Among the 14 to 17 years age group, and not the 18 to 21 years age group, the preinjury sleep-arousal symptom factor predicted postinjury somatic (P = .003) and sleep factors (P = .005). The affective preinjury factor predicted the affective factor (P = .001) and somatic factor (P = .008) in the 18 to 21 years age group. A history of previous concussions also predicted the postinjury somatic symptom factor (P = .005).

Conclusion:

Preinjury symptom factors predicted postinjury symptom factors and age-associated differences in symptom factors may provide clinical value in prognostic models for subsequent postinjury clinical outcomes.
Inhibitors of the blood coagulation process in patients with essential thrombocythemia
Authors: Ziołkowska Katarzyna , Boinska Joanna , Gadomska Grażyna , Wieczór Radosław , Rość Danuta
Published: February 2020

The aim of the study was to assess the activity of protein C, protein S and tissue factor pathway inhibitor in relation to the risk factors for thrombotic complications in patients with essential thrombocythemia.

The study group consisted of 45 newly diagnosed patients with essential thrombocythemia. Protein S activity was determined by chromogenic method. Activities of protein C and tissue factor pathway inhibitor (TFPI) were determined using ELISAs.

Significantly lower protein C and protein S activity but higher TFPI activity were found in patients with ET in comparison with the control group. TFPI activity was higher in women as compared to men, and in patients over 60 years of age compared with patients below 60 years of age. TFPI activity was higher in patients with leukocytes count at least 11 g/l than in patients with leukocytes count below 11 g/l and the difference almost reached statistical significance. Significantly lower protein C activity was found in patients with theJAK2V617Fmutation, in comparison with essential thrombocythemia patientsJAK2V617F(-).

The reduced protein C and protein S activity may be one of the pathogenic factors of increased prothrombotic state in essential thrombocythemia patients. The decreased protein C activity in patients with the JAK2 V617F mutation seems to confirm the significant role of this mutation in the pathogenesis of thrombotic complications in essential thrombocythemia patients. Significantly increased TFPI activity in essential thrombocythemia patients above 60 years of age and with leukocyte count above 11 g/l expresses the activation of the compensatory mechanism for increased prothrombotic activity.
Pattern of Hemolytic Anemia Among Egyptian Pediatric Emergency Department Patients
Authors: Badr Mai Saad Eldin Mahmoud , Afifi Rasha Abdel-Raouf Abdel-Aziz
Published: February 2020

Objectives

The emergency department is considered the backbone of the medical service offered in any hospital. Yet, the data on the frequency of pediatric hematological presentation is scanty. Anemia occurs in 9% to 14% of pediatric emergency department (ED) patients. Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects more than 400 million people worldwide. Unfortunately, we do not have screening program for G6PD deficiency in Egypt. The aim of this study is to assess the burden of hemolytic crisis among Egyptian children visiting ED.

Methods

This is a prospective cross-sectional study among children presenting with acute hemolytic crisis in the ED of New Children Hospital, Cairo University from March to June 2016. Cases underwent full history taking, clinical examination, and laboratory tests based on clinical judgment of the resident. We categorized the presenting hemolytic anemias into 3 groups: G6PD deficiency, acute hemolysis in previously diagnosed patients with chronic hemolytic anemia, and acute undiagnosed hemolytic anemia.

Results

Our study included 143 patients, 109 males (76.22%) and 34 females (23.76%), with a mean age 36 months (range, 3–188 months), who presented with hemolytic anemia in the ED. Seventy-six cases (53.1%) were diagnosed as G6PD deficiency, 36 (25.2%) were diagnosed as chronic hemolytic anemia, and 31 (21.7%) were diagnosed as undiagnosed acute hemolytic anemia.

Conclusions

Hemolytic anemia is very common presentation in ED. G6PD deficiency is the most common cause, representing 53.1% of the hemolytic anemia.
Determination of Parkinson Disease Laterality After Deep Brain Stimulation Using 123I FP-CIT SPECT
Authors: Park Hye Ran , Ha Seunggyun , Lee Dong Soo , Im Hyung-Jun , Paek Sun Ha
Published: February 2020

Introduction

Symptom laterality is one of the main characteristics of Parkinson disease (PD) and reported to be associated with motor and nonmotor symptom severity and prognosis. This study aimed to evaluate the changes of laterality after deep brain stimulation (DBS) and the association between dopamine transporter SPECT using 123I FP-CIT (DAT SPECT) and symptom laterality in PD before and after DBS.

Methods

Nineteen patients with PD who received bilateral subthalamic nucleus DBS were enrolled. The clinical scores including Unified Parkinson Disease Rating Scale (UPDRS) and Hoehn and Yahr were evaluated at baseline, 6 months, and 1 year after DBS. Also, the patients underwent DAT SPECT before and 6 months and 1 year after DBS. Symptom and DAT laterality indices were determined based on the UPDRS part 3 and DAT SPECT, respectively. The association between DAT and symptom laterality was assessed at baseline and 6 months and 1 year after DBS.

Results

At baseline, 11, 6, and 2 among 19 patients had left-side–dominant, right-side–dominant, and symmetric motor symptom, respectively. Among 19 patients, there were 10 patients who showed changed symptom laterality within 1 year after DBS. The agreement between symptom laterality and DAT laterality was good to excellent at baseline and 6 months and 1 year after DBS (weighted κ = 0.742, 0.736, and 0.813). Furthermore, symptom and DAT laterality indices showed significant correlation at baseline (r = 0.542, P = 0.02), 6 months (r = 0.579, P = 0.01), and 1 year after DBS (r = 0.689, P = 0.02). Symptom laterality could be determined by DAT laterality index with areas under curve of 0.833 (P = 0.045), 0.982 (P < 0.001), and 1.000 (P < 0.001) at baseline and 6 and 12 months after DBS, respectively.

Conclusions

The symptom laterality could be altered after DBS and was well correlated with laterality evaluated by DAT SPECT. An objective evaluation of laterality using DAT SPECT would be helpful for the management of patients with PD especially for adjusting the DBS programming for fine balancing of the asymmetric symptom after DBS. The large-scale study is warranted for validation of this result.
Effect of choline-phosphate cytidylyltransferase gene (pcyt-1) expression on departure of pine wood nematode,Bursaphelenchus xylophilus(Nematoda: Aphelenchoididae), fromMonochamus alternatus(Coleoptera:Cerambycidae)
Authors: Wang Yang , Chen Fengmao
Published: February 2020

In order to study the causes of pine wood nematodes (PWN),Bursaphelenchus xylophilusdeparture from its vector beetle,Monochamus alternatus, we collected PWNs which were extracted from the newly emergedM. alternatusand the 7d after emergence beetles. The total RNAs of the two groups of PWNs were extracted and transcriptomes sequencing were performed, and the genes expression differences between the two groups of PWN were analyzed. It was found that expression of choline-phosphate cytidylyltransferase gene (pcyt-1) markedly up-regulated. After inhibition ofpcyt-1expression by RNA interference, the rate of lipid degradation in PWN decreased significantly, and the motility of PWN also decreased significantly. Analysis identified that phosphatidylcholine can promote the emulsification and degradation of lipid droplets in PWN, which provide energy for PWN departure fromM. alternatus. The up-regulation of genepcyt-1is an important internal trigger for PWN departure from the beetles.
Open-source analytics tools for studying the COVID-19 coronavirus outbreak
Authors: Wu Tianzhi , Hu Erqiang , Ge Xijin , Yu Guangchuang
Published: February 2020

The COVID-19 outbreak originated at the end of 2019 from Wuhan [1, 2], a city in Hubei province in central China. According to the World Health Organization (WHO), there were 88,948 confirmed cases and 3,043 deaths from 65 countries as of March 2, 2020. In China, the outbreak has effectively confined over 1 billion people to their apartments and homes since the end of January 2020 and continues to disrupt healthcare, wellbeing, and the economy. As the situation in China appears to be stabilizing, sharp increases in confirmed cases are being reported in South Korea, Italy, Japan, and Iran.
Multiplexed drug testing of tumor slices using a microfluidic platform
Authors: Horowitz L. F. , Rodriguez A.D. , Dereli-Korkut Z. , Lin R. , Castro K. , Mikheev A. , Monnat R.J. , Folch A. , Rostomily R.C.
Published: February 2020

Current methods to assess the drug response of individual human cancers are often inaccurate, costly, or slow. Functional approaches that rapidly and directly assess the response of patient cancer tissue to drugs or small molecules offer a promising way to improve drug testing, and have the potential to identify the best therapy for individual patients. We developed a digitally-manufactured microfluidic platform for multiplexed drug testing of intact cancer slice cultures, and demonstrate the use of this platform to evaluate drug responses in slice cultures from human glioma xenografts and patient tumor biopsies. This approach retains much of the tissue microenvironment and can provide results rapidly enough, within days of surgery, to guide the choice of effective initial therapies. Our results establish a useful preclinical platform for cancer drug testing and development with the potential to improve cancer personalized medicine.
Phenotypic Noise and the Cost of Complexity
Authors: Rocabert Charles , Beslon Guillaume , Knibbe Carole , Bernard Samuel
Published: February 2020

Experimental studies demonstrate the existence of phenotypic diversity despite constant genotype and environment. Theoretical models based on a single phenotypic character predict that during an adaptation event, phenotypic noise should be positively selected far from the fitness optimum because it increases the fitness of the genotype, and then be selected against when the population reaches the optimum. It is suggested that because of this fitness gain, phenotypic noise should promote adaptive evolution. However, it is unclear how the selective advantage of phenotypic noise is linked to the rate of evolution, and whether any advantage would hold for more realistic, multi-dimensional phenotypes. Indeed, complex organisms suffer a cost of complexity, where beneficial mutations become rarer as the number of phenotypic characters increases. By using a quantitative genetics approach, we first show that for a one-dimensional phenotype, phenotypic noise promotes adaptive evolution on plateaus of positive fitness, independently from the direct selective advantage on fitness. Second, we show that for multi-dimensional phenotypes, phenotypic noise evolves to a low-dimensional configuration, with elevated noise in the direction of the fitness optimum. Such a dimensionality reduction of the phenotypic noise promotes adaptive evolution and numerical simulations show that it reduces the cost of complexity.
Multi-Approach and Multi-Scale Model of CD4+ T Cells Predicts Switch-Like and Oscillatory Emergent Behaviors in Inflammatory Response to Infection
Authors: Wertheim Kenneth Y. , Puniya Bhanwar Lal , La Fleur Alyssa , Shah Ab Rauf , Barberis Matteo , Helikar Tomáš
Published: February 2020

Immune responses rely on a complex adaptive system in which the body and infections interact at multiple scales and in different compartments. We developed a modular model of CD4+ T cells which uses four modeling approaches to integrate processes taking place at three spatial scales in different tissues. In each cell, signal transduction and gene regulation are described by a logical model, metabolism by constraint-based models. Cell population dynamics are described by an agent-based model and systemic cytokine concentrations by ordinary differential equations. A Monte Carlo simulation algorithm allows information to flow efficiently between the four modules by separating the time scales. Such modularity improves computational performance and versatility, and facilitates data integration. Our technology helps capture emergent behaviors that arise from nonlinear dynamics interwoven across three scales. Multi-scale insights added to single-scale studies allowed us to identify switch-like and oscillatory behaviors of CD4+ T cells at the population level, which are both novel and immunologically important. We envision our model and the generic framework encompassing it to become the foundation of a more comprehensive model of the human immune system.
Alignment-Integrated Reconstruction of Ancestral Sequences Improves Accuracy
Authors: Aadland Kelsey , Kolaczkowski Bryan
Published: February 2020

Ancestral sequence reconstruction (ASR) uses an alignment of extant protein sequences, a phylogeny describing the history of the protein family and a model of the molecular-evolutionary process to infer the sequences of ancient proteins, allowing researchers to directly investigate the impact of sequence evolution on protein structure and function. Like all statistical inferences, ASR can be sensitive to violations of its underlying assumptions. Previous studies have shown that, while phylogenetic uncertainty has only a very weak impact on ASR accuracy, uncertainty in the protein sequence alignment can more strongly affect inferred ancestral sequences. Here we show that errors in sequence alignment can produce errors in ASR across a range of realistic and simplified evolutionary scenarios. Importantly, sequence reconstruction errors can lead to errors in estimates of structural and functional properties of ancestral proteins, potentially undermining the reliability of analyses relying on ASR. We introduce an alignment-integrated ASR approach that combines information from many different sequence alignments. We show that integrating alignment uncertainty improves ASR accuracy and the accuracy of downstream structural and functional inferences, often performing as well as highly-accurate structure-guided alignment. Given the growing evidence that sequence alignment errors can impact the reliability of ASR studies, we recommend that future studies incorporate approaches to mitigate the impact of alignment uncertainty. Probabilistic modeling of insertion and deletion events has the potential to radically improve ASR accuracy when the model reflects the true underlying evolutionary history, but further studies are required to thoroughly evaluate the reliability of these approaches under realistic conditions.
Novel Electrodes for Reliable EEG Recordings on Coarse and Curly Hair
Authors: Etienne Arnelle , Laroia Tarana , Weigle Harper , Afelin Amber , Kelly Shawn K , Krishnan Ashwati , Grover Pulkit
Published: February 2020

EEG is a powerful and affordable brain sensing and imaging tool used extensively for the diagnosis of neurological disorders (e.g. epilepsy), brain computer interfacing, and basic neuroscience. Unfortunately, most EEG electrodes and systems are not designed to accommodate coarse and curly hair common in individuals of African descent. This can lead to poor quality data that might be discarded in scientific studies after recording from a broader population set, and for clinical diagnoses, lead to an uncomfortable and/or emotionally taxing experience, and, in the worst cases, misdiagnosis. In this work, we design a system to explicitly accommodate coarse and curly hair, and demonstrate that, across time, our electrodes, in conjunction with appropriate braiding, attain substantially (~10x) lower impedance than state-of-the-art systems. This builds on our prior work that demonstrated that braiding hair in patterns consistent with the clinical standard 10-20 arrangement leads to improved impedance with existing systems.
A mechanism for the extension and unfolding of parallel telomeric G-quadruplexes by human telomerase at single-molecule resolution
Authors: Paudel Bishnu P. , Moye Aaron Lavel , Assi Hala Abou , El-Khoury Roberto , Cohen Scott B. , Birrento Monica L. , Samosorn Siritron , Intharapichai Kamthorn , Tomlinson Christopher G. , Teulade-Fichou Marie-Paule , González Carlos , Beck Jennifer L. , Damha Masad J. , van Oijen Antoine M. , Bryan Tracy M.
Published: February 2020

Telomeric G-quadruplexes (G4) were long believed to form a protective structure at telomeres, preventing their extension by the ribonucleoprotein telomerase. Contrary to this belief, we have previously demonstrated that parallel-stranded conformations of telomeric G4 can be extended by human and ciliate telomerase. However, a mechanistic understanding of the interaction of telomerase with structured DNA remained elusive. Here, we use single-molecule fluorescence resonance energy transfer (smFRET) microscopy and bulk-phase enzymology to propose a mechanism for the resolution and extension of parallel G4 by telomerase. Binding is initiated by the RNA template of telomerase interacting with the G-quadruplex; nucleotide addition then proceeds to the end of the RNA template. It is only through the large conformational change of translocation following synthesis that the G-quadruplex structure is completely unfolded to a linear product. Surprisingly, parallel G4 stabilization with either small molecule ligands or by chemical modification does not always inhibit G4 unfolding and extension by telomerase. These data reveal that telomerase is a parallel G-quadruplex resolvase.
Immunotherapy efficacy in colorectal cancer is dependent on activation of a microbial-metabolite-immune circuit
Authors: Mager Lukas F. , Burkhard Regula , Cooke Noah C.A. , Brown Kirsty , Ramay Hena , Paik Seungil , Stagg John , Groves Ryan A. , Gallo Marco , Lewis Ian A. , Geuking Markus B. , McCoy Kathy D.
Published: February 2020

Cancer is a leading cause of death globally. Checkpoint blockade therapies offer a promising treatment for many cancers, but have been ineffective for colorectal cancers. Previous studies have shown a dependency of immunotherapies on the microbiota. Consequently, we hypothesized that specific gut bacteria promote immunotherapy for colorectal cancer. We identify three commensal bacteria and a microbial metabolite, inosine, that enhance the efficacy of immune checkpoint blockade therapy in colorectal cancer. We show that inosine interacts with the adenosine A2Areceptor on T cells resulting in intestinal Th1 cell differentiation. Decreased gut barrier function induced by immunotherapy increased the translocation of bacterial metabolites and promoted cancer protective Th1 cell activation. This microbial-metabolite-immune circuit provides a mechanism for a new class of bacteria-enhanced checkpoint blockade therapies. The efficacy of this mechanism differs among colorectal cancer subtypes and highlights the strengths as well as potential limitations of this novel bacterial co-therapy for cancer.
Resetting proteostasis with ISRIB prevents pulmonary fibrosis
Authors: Watanabe Satoshi , Markov Nikolay S. , Lu Ziyan , Aillon Raul Piseaux , Soberanes Saul , Runyan Constance E. , Ren Ziyou , Grant Rogan A. , Maciel Mariana , Abdala-Valencia Hiam , Politanska Yuliya , Nam Kiwon , Sichizya Lango , Kihshen Hermon G. , Joshi Nikita , McQuattie-Pimentel Alexandra C. , Morimoto Richard I. , Reyfman Paul A. , Budinger G.R. Scott , Misharin Alexander V.
Published: February 2020

Aging is among the most important risk factors for the development of pulmonary fibrosis. We found that a small molecule that specifically inhibits translational inhibition induced by activation of the integrated stress response (ISRIB) attenuated the severity of pulmonary fibrosis in young and old mice. The more severe fibrosis in old compared to young mice was associated with increased recruitment of pathogenic monocyte-derived alveolar macrophages. Using genetic lineage tracing and transcriptomic profiling we found that ISRIB modulates stress response signaling in alveolar epithelial cells resulting in decreased apoptosis and decreased recruitment of pathogenic monocyte-derived alveolar macrophages. These data support multicellular model of fibrosis involving epithelial cells, pathogenic monocyte-derived alveolar macrophages and fibroblasts. Inhibition of the integrated stress response in the aging lung epithelium ameliorates pulmonary fibrosis by preventing the prolonged recruitment of monocyte-derived alveolar macrophages.
Multiplexed conditional genome editing with Cas12a inDrosophila
Authors: Port Fillip , Starostecka Maja , Boutros Michael
Published: February 2020

CRISPR-Cas genome engineering has revolutionised biomedical research by enabling targeted genome modification with unprecedented ease. In the popular model organismDrosophila melanogastergene editing has so far relied exclusively on the prototypical CRISPR nuclease Cas9. The availability of additional CRISPR systems could expand the genomic target space, offer additional modes of regulation and enable the independent manipulation of genes in different cell populations of the same animal. Here we describe a platform for efficient Cas12a gene editing inDrosophila. We show that Cas12a fromLachnospiraceae bacterium, but notAcidaminococcus spec., can mediate robust gene editingin vivo. In combination with most crRNAs, LbCas12a activity is strongly suppressed at lower temperatures, enabling control of gene editing by simply modulating temperature. LbCas12a can directly utilize compact crRNAs arrays that are substantially easier to construct than Cas9 sgRNA arrays, facilitating multiplex genome engineering of several target sites in parallel. Targeting genes with arrays of three crRNAs results in the induction of loss-of function phenotypes with comparable efficiencies than a state-of-the-art Cas9 system. Lastly, we show that cell type-specific expression of LbCas12a is sufficient to mediate tightly controlled gene editing in a variety of tissues, allowing detailed analysis of gene function in this multicellular organism. Cas12a gene editing substantially expands the genome engineering toolbox in this organism and will be a powerful method for the functional annotation of theDrosophilagenome. This work also lays out principles for the development of multiplexed transgenic Cas12a genome engineering systems in other genetically tractable organisms.
Repeated morphine exposure activates synaptogenesis and other neuroplasticity-related gene networks in the prefrontal cortex of male and female rats
Authors: Liu Shirelle X. , Gades Mari S. , Harris Andrew C. , Tran Phu V. , Gewirtz Jonathan C.
Published: February 2020

Background

Opioid abuse is a chronic disorder likely involving stable neuroplastic modifications. While a number of molecules contributing to these changes have been identified, the broader spectrum of genes and gene networks that are affected by repeated opioid administration remain understudied.

Methods

We employed Next-Generation RNA-sequencing (RNA-seq) to investigate changes in gene expression in adult male and female rats’ prefrontal cortex (PFC) following daily injection of morphine (5.0 mg/kg) for 10 days. Ingenuity Pathway Analysis (IPA) was used to analyze affected molecular pathways, gene networks, and associated regulatory factors.

Results

90% of differentially expressed genes (DEGs) were upregulated in both males and females, with a 35% overlap between sexes. A substantial number of DEGs play roles in synaptic signaling and neuroplasticity. Although broadly similar, some differences were revealed in the gene ontology networks enriched in females and males (e.g., the endocannabinoid pathway in females and neuroinflammation in males).

Conclusions

Our results cohere with findings from previous studies based ona priorigene selection, while identifying broader gene networks activated by repeated opioid exposure. Our results also reveal novel genes and molecular pathways that are upregulated by repeated morphine exposure.
VC1 catalyzes a key step in the biosynthesis of vicine from GTP in faba bean
Authors: Björnsdotter Emilie , Nadzieja Marcin , Chang Wei , Escobar-Herrera Leandro , Mancinotti Davide , Angra Deepti , Khazaei Hamid , Crocoll Christoph , Vandenberg Albert , Stoddard Frederick L. , O’Sullivan Donal M. , Stougaard Jens , Schulman Alan H. , Andersen Stig U. , Geu-Flores Fernando
Published: February 2020

Faba bean is a widely adapted and high-yielding legume cultivated for its protein-rich seeds1. However, the seeds accumulate the anti-nutritional pyrimidine glucosides vicine and convicine, which can cause haemolytic anaemia—favism—in the 400 million individuals genetically predisposed by a deficiency in glucose-6-phosphate dehydrogenase2. Here, we identify the first enzyme associated with vicine and convicine biosynthesis, which we name VC1. We show thatVC1co-locates with the major QTL for vicine and convicine content and that the expression ofVC1correlates highly with vicine content across tissues. We also show that low-vicine varieties express a version ofVC1carrying a small, frame-shift insertion, and that overexpression of wild-typeVC1leads to an increase in vicine levels.VC1encodes a functional GTP cyclohydrolase II, an enzyme normally involved in riboflavin biosynthesis from the purine GTP. Through feeding studies, we demonstrate that GTP is a precursor of vicine both in faba bean and in the distantly related plant bitter gourd. Our results reveal an unexpected biosynthetic origin for vicine and convicine and pave the way for the development of faba bean cultivars that are free from these anti-nutrients, providing a safe and sustainable source of dietary protein.
TRANSITION OF PODOSOMES INTO ZIPPER-LIKE STRUCTURES IN MACROPHAGE-DERIVED MULTINUCLEATED GIANT CELLS
Authors: Balabiyev Arnat , Podolnikova Nataly P. , Mursalimov Aibek , Lowry David , Newbern Jason M. , Roberson Robert W. , Ugarova Tatiana P.
Published: February 2020

Macrophage fusion resulting in the formation of multinucleated giant cells (MGCs) is a multistage process that requires many adhesion-dependent steps and involves the rearrangement of the actin cytoskeleton. The diversity of actin-based structures and their role in macrophage fusion is poorly understood. In this study, we revealed hitherto unrecognized actin-based zipper-like structures (ZLSs) that arise between MGCs formed on the surface of implanted biomaterials. We established anin vitromodel for the induction of these structures in mouse macrophages undergoing IL-4– mediated fusion. Using this model, we show that over time MGCs develop cell-cell contacts containing ZLSs. Live-cell imaging using macrophages isolated from mRFP- or GFP-Lifeact mice demonstrated that ZLSs are dynamic formations undergoing continuous assembly and disassembly and that podosomes are precursors of these structures. Immunostaining experiments showed that vinculin, talin, integrin αMβ2, and other components of podosomes are present in ZLSs. Macrophages deficient in WASp or Cdc42, two key molecules involved in actin core organization in podosomes, as well as cells treated with the inhibitors of the Arp2/3 complex failed to form ZLSs. Furthermore, E-cadherin and nectin-2 were found between adjoining membranes, suggesting that the transition of podosomes into ZLSs is induced by bridging plasma membranes by junctional proteins.
Characterizing Trabecular Bone Properties near the Glenohumeral Joint Following Brachial Plexus Birth Injury
Authors: Fawcett Emily B. , McCormick Carolyn M. , Murray Austin F. , Crouch Dustin L. , Saul Katherine R. , Cole Jacqueline H.
Published: February 2020

Brachial plexus birth injury (BPBI) causes functional arm impairment in 30-40% of those affected due to altered loading on the glenohumeral joint. While gross morphological osseous deformities have been seen in the humerus and scapula, alterations in the underlying trabecular bone microstructure and mineralization are not clear. Using a murine model of BPBI, trabecular bone alterations were explored in the proximal humerus and distal scapula, which surround the articulating surface of the joint. Samples were scanned using micro-CT, reoriented, and analyzed for standard trabecular metrics. The regions of interest closest to the articulating surface showed the greatest detriments. In the scapula, the scapular neck region showed less robust trabecular bone in the neurectomy group with decreased BV/TV (p=0.001), BMD (p=0.001), Conn.D (p=0.006), Tb.N (p<0.0001), and DA (p=0.033), and increased Tb.Sp (p<0.0001) compared to sham. In the humerus, the epiphysis showed less robust trabecular bone in neurectomy group, but to a much lesser extent than the scapular neck. The neurectomy group showed reduced BMD (p=0.007) and Tb.N (p=0.029) compared to sham. Data suggest deformities are worse near the articulating surface, likely due to the greater amount of mechanical loading. The reduction in trabecular microstructure and mineralization may compromise bone strength of the affected limb following BPBI. Further investigation of the underlying trabecular bone deformities following injury are necessary to eventually inform better treatments to limit the development of deformities.
A Bayesian inference tool for identifying artifactual calls from differential transcript abundance analyses
Authors: Mangiola Stefano , Thomas Evan A , Modrák Martin , Papenfuss Anthony T
Published: February 2020

Relative transcript abundance has proven to be a valuable tool for inferring the phenotype of biological systems from genetic material. Several methods for the analysis of differential transcript abundance have been developed, and some of the most popular are based on negative binomial models. Although most genes are fitted reasonably well by the negative binomial distribution, the presence of outlier observations that do not fit such models can lead to artifactual identification of significant changes in transcription. Identifying those transcripts for the correct interpretation of results is extremely important. A robust and automated tool for detecting sample/transcript pairs that do not fit a negative binomial regression model is currently lacking. Here we propose ppcseq, a robust statistical framework that models hierarchically sample- and gene-wise features such as sequencing depth bias, the association between mean transcript abundance and its over-dispersion, and provides a theoretical transcript abundance distribution, on which the observed transcript abundance can be tested for outliers. We show using a publicly available data set where nearly 10% of differentially abundant transcripts had fold change inflated by the presence of outliers. This method has broad utility in filtering artifactual results of differential transcript abundance analyses based on a negative binomial framework.
Glucose-mediated expansion of a gut commensal bacterium promotesPlasmodiuminfection through alkalizing mosquito midgut
Authors: Wang Mengfei , An Yanpeng , Dong Shengzhang , Feng Yuebiao , Gao Li , Wang Penghua , Dimopoulus George , Tang Huiru , Wang Jingwen
Published: February 2020

Dietary sugar is the major energy source for mosquitoes, but its influence on mosquitoes’ capability to transmit malaria parasite remains unclear. Here we show thatPlasmodium bergheiinfection changes global metabolism ofAnopheles stephensiwith the most significant impact on glucose metabolism. Supplementation of glucose or trehalose (the main hemolymph sugar) to mosquito increasesPlasmodiuminfection by alkalizing the mosquito midgut. The glucose/trehalose diets promote rapid growth of a commensal bacterium,Asaia bogorensis, which remodels glucose metabolism and consequently increases midgut pH. The pH increase in turn promotesPlasmodiumgametogenesis. We also demonstrate the sugar composition from different natural plants influencesA. bogorensisgrowth andPlasmodiuminfection is associated with their capability to expandA. bogorensis. Altogether, our results demonstrate that dietary glucose is an important factor that determines mosquito’s competency to transmitPlasmodiumand further highlight a key role for mosquito-microbiota metabolic interactions in regulating development of malaria parasite.
Rapid evolution in managed grasslands: different land-use regimes are associated with contrasting phenotypes inPlantago lanceolata
Authors: Gáspár Bence , Durka Walter , Bossdorf Oliver
Published: February 2020

Land-use intensification is a major driver of biodiversity declines, and it is known to decrease species numbers and alter community composition of managed grasslands. An open question is whether similar impacts occur within species, i.e. whether grassland management affects also the genetic diversity of plant populations and alters their genetic composition, possibly reflecting adaptation to land use. To address these questions, we sampled 61 populations of the common grassland herbPlantago lanceolatathat covered a broad range of land use intensities in the German Biodiversity Exploratories, and we grew their offspring in a common environment to quantify variation in plant size, architecture, reproduction, and leaf economy. All measured traits harboured substantial heritable variation, and six out of nine traits showed population differentiation. Interestingly, several traits were significantly correlated with land use intensity, but with opposing trends for mowing versus grazing: Increased mowing intensity was associated with larger plant size and lower specific leaf area (SLA), which may reflect evolutionary responses to increased light competition and a lesser need for resource conservation in highly productive meadows. In contrast, increased grazing intensity tended to be associated with smaller plant size and higher SLA, a phenotype syndrome known from grazing lawns. Moreover, we found that land-use intensification also affected genetic diversity, again with opposing effects for mowing versus grazing: while increased mowing was associated with decreased levels of intrapopulation phenotypic variation, the opposite was true for increased grazing intensity. In summary, land use intensification has not only already caused rapid evolutionary changes in these grassland populations, it also affects their future evolutionary potential.
Investigating the effects of pre-stimulus cortical synchrony on behavior
Authors: van Es Mats W.J. , Gross Joachim , Schoffelen Jan-Mathijs
Published: February 2020

Rhythmic brain activity may provide a functional mechanism that facilitates dynamic interareal interactions and thereby give rise to complex behavior. It has been shown that low and high frequency oscillations propagate in opposite directions, but interactions between brain areas in various frequency bands are poorly understood. We investigated local and long-range synchrony in a brain-wide network and their relation to behavior, while human subjects executed a variant of the Simon task during MEG recording. We hypothesized that the behavioral difference for stimulus-response congruent (C) and incongruent (IC) trials is caused by differences in cortical synchrony, and that the relative behavioral benefit for trials following instances with the same stimulus-response contingency (i.e. the Gratton effect) is caused by contingency-induced changes in the state of the network. This would be achieved by temporarily upregulating the connectivity strength between behaviorally relevant network nodes. We identified regions-of-interest that differed in local synchrony during the response phase of the Simon task. Within this network, spectral power in none of the nodes in either of the studied frequencies was significantly different in the pre-cue window of the subsequent trial. Nor was there a significant difference in coherence between the task-relevant nodes that could explain the superior performance after compatible consecutive trials.
Genomic copy number predicts oesophageal cancer years before transformation
Authors: Killcoyne Sarah , Gregson Eleanor , Wedge David C. , Woodcock Dan J. , Eldridge Matthew , de la Rue Rachel , Miremadi Ahmad , Abbas Sujath , Blasko Adrienn , Januszewicz Wladyslaw , Varanou Jenkins Aikaterini , Gerstung Moritz , Fitzgerald Rebecca C.
Published: February 2020

Cancer arises through a process of somatic evolution and recent studies have shown that aneuploidies and driver gene mutations precede cancer diagnosis by several years to decades1–4Here, we address the question whether such genomic signals can be used for early detection and pre-emptive cancer treatment. To this end we study Barrett’s oesophagus, a genomic copy number driven neoplastic precursor lesion to oesophageal adenocarcinoma5. We use shallow whole genome sequencing of 777 biopsies sampled from 88 patients in surveillance for Barrett’s oesophagus over a period of up to 15 years. These data show that genomic signals exist that distinguish progressive from stable disease with an AUC of 0.87 and a sensitivity of 50% even ten years prior to histopathological disease transformation. These finding are validated on two independent cohorts of 75 and 248 patients. Compared against current patient management guidelines genomic risk classification enables earlier treatment for high risk patients as well as reduction of unnecessary treatment and monitoring for patients who are unlikely to develop cancer.