bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of Peripheral Pulmonary Artery Stenosis
Authors: Kim Chan W. , Aronow Wilbert S. , Dutta Tanya , Spevack Daniel M. , Frishman William H.
Published: February 2020

Peripheral pulmonary artery stenosis (PAS) is an abnormal narrowing of the pulmonary vasculature and can form anywhere within the pulmonary artery tree. PAS is a congenital or an acquired disease, and its severity depends on the etiology, location, and number of stenoses. Most often seen in infants and young children, some symptoms include shortness of breath, fatigue, and tachycardia. Symptoms can progressively worsen over time as right ventricular pressure increases, leading to further complications including pulmonary artery hypertension and systolic and diastolic dysfunctions. The current treatment options for PAS include simple balloon angioplasty, cutting balloon angioplasty, and stent placement. Simple balloon angioplasty is the most basic therapeutic option for proximally located PAS. Cutting balloon angioplasty is utilized for more dilation-resistant PAS vessels and for more distally located PAS. Stent placement is the most effective option seen to treat the majority of PAS; however, it requires multiple re-interventions for serial dilations and is generally reserved for PAS vessels that are resistant to angioplasty.
Cannabinoid type 2 receptor agonist JWH133 decreases blood pressure of spontaneously hypertensive rats through relieving inflammation in the rostral ventrolateral medulla of the brain
Authors: Shi He-Kai , Guo Hui-Cai , Liu Hou-Yue , Zhang Zi-Lin , Hu Mei-Yu , Zhang Yi , Li Qian
Published: February 2020

Objective:

Neuroinflammation in the rostral ventrolateral medulla (RVLM) has been reported to be associated with hypertension. The upregulation and activation of the cannabinoid type 2 (CB2) receptor may be part of the active process of limiting or downregulating the inflammatory process. This study was designed to determine the role of the CB2 receptor in blood pressure (BP) through relieving neuroinflammation in the RVLM in spontaneously hypertensive rats (SHRs).

Methods:

The long-term effects of intracerebroventricular injection of JWH133, a selective CB2 receptor agonist, on BP, heart rate (HR) and renal sympathetic nerve activity (RSNA) in SHR and Wistar–Kyoto (WKY) rats were determined. ELISA was used to measure the levels of proinflammatory cytokines, and western blotting was employed to detect protein expression of the CB2 receptor. Immunofluorescence staining was used to localize the CB2 receptor. Gene silencing of the CB2 receptor was realized by injecting adeno-associated virus (AAV) expressing CB2-specific shRNA (AAV2-r-CB2shRNA) into the RVLM.

Results:

We found that SHRs exhibited higher levels of basal BP, HR, RSNA and proinflammatory cytokines (TNFα, IL-6 and IL-1β) than those in WKY rats. The protein level of the CB2 receptor in the RVLM was robustly increased in SHRs. In addition, the CB2 receptor was mainly expressed on microglia cells of SHRs but not in WKY rats. No expression of the CB2 receptor was found on neurons of either WKY rats or SHRs. Furthermore, intracerebroventricular injection of JWH133 (1 mmol/l, 10 μl) for 28 days decreased the BP, HR, RSNA and proinflammatory cytokines significantly in SHRs, but it had no such effects in WKY rats. These effects were abolished by microinjection of 300 nl AAV2-r-CB2shRNA into the RVLM to knock down the CB2 receptor.

Conclusion:

Taken together, our results suggest that exciting the CB2 receptor relieves proinflammatory cytokine levels in the RVLM to decrease the BP, HR and RSNA in SHRs.
Stage 1 hypertension defined by the 2017 American College of Cardiology/American Heart Association guideline and risk of adverse birth outcomes in Eastern China
Authors: Liu Jieyu , Tao Linghua , Cao Yingying , Teng Haoyue , Wang Jiaxiang , Wang Min , Li Fang , Wang Yumei , Yang Luoqi , Zhao Xiaoyan , Qin Liqiang , Yin Jieyun , Zhang Yonghong
Published: February 2020

Objective:

The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline recommended a lower threshold (130/80 mmHg) for hypertension in nonpregnant adults. However, the influence of this guideline in Chinese pregnant women is not well characterized.

Methods:

Data of 32 742 and 14 479 mothers who had blood pressure (BP) less than 130/80 mmHg and no proteinuria before 20 gestational weeks and delivered live singletons between 1 January 2014 and 30 November 2019 were extracted from Taizhou and Taicang register-based cohorts, respectively. The average measured BP in the third trimester was obtained and categorized according to the 2017 ACC/AHA guideline. The association between BP and risk of adverse birth outcomes was assessed by multivariate logistic regression analysis.

Results:

In the third trimester, 331 (1.01%) and 378 (2.61%) women had mean BP at least 140/90 mmHg, but 2435 (7.44%) and 1054 (7.28%) had stage 1 hypertension (130–139/80–89 mmHg) in Taizhou and Taicang, respectively. Significant associations between stage 1 hypertension and small for gestational age [odds ratio (OR) = 1.32, 95% confidence interval (CI) = 1.14–1.52] and low birth weight (OR = 1.81, 95% CI = 1.46–2.25) were observed in the Taizhou population. Consistent results were also shown in the Taicang population [OR (95% CI), of 1.46 (1.18–1.79) and 1.50 (1.07–2.11), respectively].

Conclusion:

Stage 1 hypertension in the third trimester defined by the 2017 ACC/AHA guideline was associated with an increased risk for adverse birth outcomes in Eastern Chinese pregnant women, suggesting that this guideline may improve the detection of high BP and surveillance of adverse neonatal outcomes in China.
Health Economic Analysis in Glaucoma
Authors: Park Inhae , Gale Jesse , Skalicky Simon E.
Published: February 2020

The pressure on glaucoma services is ever-growing, and policymakers seek robust cost-effectiveness arguments in their decisions around resource allocation. The benefits of glaucoma are in preventing or delaying a future loss of vision and associated quality of life, and this expectation is quantified using a metric called utility which can be compared against other disease states. In recent clinical trials lasting up to 3 years, it has been difficult to show a difference in utility between glaucoma treatments in this limited period of time. When it comes to cost, the direct medical costs are only part of the broad range of costs that glaucoma brings to patients and communities, and the estimation of these costs can be difficult and imprecise. While the cost-effectiveness of glaucoma care, in general, is not in dispute, especially over longer time frames, the inability to measure changes in utility in shorter time frames impedes the uptake of innovations around the world. A number of approaches to improve the sensitivity and specificity of utility measurements are under investigation.
Efficacy and Safety of Monoclonal Antibodies Against Clostridioides difficile Toxins for Prevention of Recurrent Clostridioides difficile Infection
Authors: Akiyama Shintaro , Yamada Akihiro , Komaki Yuga , Komaki Fukiko , Micic Dejan , Sakuraba Atsushi
Published: February 2020

Background:

Clostridioides difficile infection is one of the most common health care-associated infections. To reduce the recurrent Clostridioides difficile infection (rCDI), monoclonal antibodies against Clostridioides difficile toxin A (actoxumab) and toxin B (bezlotoxumab) were developed. In the present study, we performed a systematic review and meta-analysis to assess their efficacy and safety.

Materials and Methods:

An electronic database was searched for relevant randomized controlled trials assessing bezlotoxumab and/or actoxumab. Outcomes included rate of rCDI and adverse events including cardiovascular and gastrointestinal events.

Results:

Four randomized controlled trials comparing antitoxin antibodies (n=1916) versus placebo (n=889) were identified. rCDI was significantly reduced by bezlotoxumab plus actoxumab (risk ratio=0.54, 95% confidence interval=0.41-0.70, P<0.001) and bezlotoxumab monotherapy (risk ratio=0.62, 95% confidence interval=0.51-0.76, P<0.001) compared with placebo. Subgroup analysis showed that bezlotoxumab plus actoxumab was remarkably preventive for patients with the following high-risk features: inpatients, vancomycin treatment, and BI/NAP/027 strain. Regarding safety, there was no difference in cardiovascular and gastrointestinal events as well as all-cause mortality between bezlotoxumab-treated patients and placebo.

Conclusions:

The results of our meta-analysis demonstrated the effectiveness and safety of bezlotoxumab for the prevention of rCDI. Bezlotoxumab may be a good therapeutic option for severe C. difficile infection rather than mild cases.
Indirectly Activated Treg Allow Dominant Tolerance to Murine Skin-grafts Across an MHC Class I Mismatch After a Single Donor-specific Transfusion
Authors: Zhang Geoff Yu , Hu Min , Watson Debbie , Wang Yuan Min , Knight John F. , Alexander Stephen I.
Published: February 2020

Background.

Tolerance induced in stringent animal transplant models using donor-specific transfusions (DST) has previously required additional immunological manipulation. Here, we demonstrate a dominant skin-allograft tolerance model induced by a single DST across an major histocompatibility class I mismatch in an unmanipulated B6 host.

Methods.

C57BL/6 (H-2b) (B6) mice were injected intravenously with splenocytes from B6.C.H-2bm1 (H-2kbm1) (bm1) or F1 (B6 × bm1) mice before skin transplantation. Mice were transplanted 7 days postinjection with donor (bm1 or F1) and third-party B10.BR (H-2k) skin grafts.

Results.

B6 hosts acutely rejected skin grafts from B6.C.H-2bm1 (bm1) and F1 (B6 × bm1) mice. A single transfusion of F1 splenocytes into B6 mice without any additional immune modulation led to permanent acceptance of F1 skin grafts. This graft acceptance was associated with persistence of donor cells long-term in vivo. The more rapid removal of DST bm1 cells than F1 cells was reduced by natural killer-cell depletion. Tolerant grafts survived an in vivo challenge with naive splenocytes. Both CD4+CD25+ and CD4+CD25− T cells from F1 DST treated B6 mice suppressed alloproliferation in vitro. Tolerance was associated with expansion of peripheral Foxp3+CD4+CD25+ regulatory T cells (Treg) and increased forkhead box P3 (Foxp3) expression in tolerant grafts. In tolerant mice, Foxp3+ Treg arises from the proliferation of indirectly activated natural Foxp3+ Treg (nTreg) and depletion of Foxp3+ Treg abrogates skin-graft tolerance.

Conclusions.

This study demonstrates that the persistence of transfused semiallogeneic donor cells mismatched at major histocompatibility class I can enhance tolerance to subsequent skin allografts through indirectly expanded nTreg leading to dominant tolerance without additional immunological manipulation.
Reclassification of Sphingomonas aeria as a later heterotypic synonym of Sphingomonas carotinifaciens based on whole-genome sequence analysis
Authors: Madhaiyan Munusamy , Saravanan Venkatakrishnan Sivaraj , Wirth Joseph S. , Whitman William B.
Published: February 2020

The 16S rRNA gene sequences of

Sphingomonas carotinifaciens

L9-754T and

Sphingomonas aeria

B093034T possess 99.71 % sequence similarity. Further studies were undertaken to clarify the taxonomic assignments of these species. Whole-genome comparisons showed that

S. aeria

B093034Tand

S. carotinifaciens

L9-754T shared 96.9 % average nucleotide identity, 98.4 % average amino acid identity and 76.1 % digital DNA–DNA hybridization values. These values exceeded or approached the recommended species delineation threshold values. Furthermore, a phylogenetic tree based on 41 of the most conserved genes provided additional evidence that

S. aeria

B093034T and

S. carotinifaciens

L9-754T are very closely related. Based on this evidence we propose the reclassification of

S. aeria

Xue et al. 2018 as a later heterotypic synonym of

S. carotinifaciens

Madhaiyan et al. 2017.
Serial interval of novel coronavirus (COVID-19) infections
Authors: Nishiura Hiroshi , Linton Natalie M. , Akhmetzhanov Andrei R.
Published: February 2020

Objective

To estimate the serial interval of novel coronavirus (COVID-19) from information on 28 infector-infectee pairs.

Methods

We collected dates of illness onset for primary cases (infectors) and secondary cases (infectees) from published research articles and case investigation reports. We subjectively ranked the credibility of the data and performed analyses on both the full dataset (n=28) and a subset of pairs with highest certainty in reporting (n=18). In addition, we adjusting for right truncation of the data as the epidemic is still in its growth phase.

Results

Accounting for right truncation and analyzing all pairs, we estimated the median serial interval at 4.0 days (95% credible interval [CrI]: 3.1, 4.9). Limiting our data to only the most certain pairs, the median serial interval was estimated at 4.6 days (95% CrI: 3.5, 5.9).

Conclusions

The serial interval of COVID-19 is shorter than its median incubation period. This suggests that a substantial proportion of secondary transmission may occur prior to illness onset. The COVID-19 serial interval is also shorter than the serial interval of severe acute respiratory syndrome (SARS), indicating that calculations made using the SARS serial interval may introduce bias.

Highlights

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The serial interval of novel coronavirus (COVID-19) infections was estimated from a total of 28 infector-infectee pairs.

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The median serial interval is shorter than the median incubation period, suggesting a substantial proportion of pre-symptomatic transmission.

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A short serial interval makes it difficult to trace contacts due to the rapid turnover of case generations.
Glycopeptide antibiotic teicoplanin inhibits cell entry of SARS-CoV-2 by suppressing the proteolytic activity of cathepsin L
Authors: Yu Fei , Pan Ting , Huang Feng , Ying Ruosu , Liu Jun , Fan Huimin , Zhang Junsong , Liu Weiwei , Lin Yingtong , Yuan Yaochang , Yang Tao , Li Rong , Zhang Xu , Lv Xi , Chen Qianyu , Liang Anqi , Zou Fan , Liu Bingfeng , Hu Fengyu , Tang Xiaoping , Li Linghua , Deng Kai , He Xin , Zhang Hui , Zhang Yiwen , Ma Xiancai
Published: February 2020

Since the outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the public health worldwide has been greatly threatened. The development of an effective treatment for this infection is crucial and urgent but is hampered by the incomplete understanding of the viral infection mechanism and the lack of specific antiviral agents. We previously reported that teicoplanin, a glycopeptide antibiotic that has been commonly used in the clinic to treat bacterial infection, significantly restrained the cell entry of Ebola virus, SARS-CoV and MERS-CoV by specifically inhibiting the activity of cathepsin L (CTSL). Here, we found that the cleavage sites of CTSL on the Spike of SARS-CoV-2 were highly conserved among all the variants. The treatment with teicoplanin suppressed the proteolytic activity of CTSL on Spike and prevented the cellular infection of different pseudotyped SARS-CoV-2 viruses. Teicoplanin potently prevented the entry of authentic SARS-CoV-2 into the cellular cytoplasm with an IC50of 2.038 μM for the Wuhan-Hu-1 reference strain and an IC50of 2.116 μM for the SARS-CoV-2 (D614G) variant. The pre-treatment of teicoplanin also prevented SARS-CoV-2 infection in hACE2 mice. In summary, our data reveal that CTSL is required for both SARS-CoV-2 and SARS-CoV infection and demonstrate the therapeutic potential of teicoplanin for universal anti-CoVs intervention.

Importance

Disease prevention and treatment are two important countermeasures to end the coronavirus disease 2019 (COVID-19). However, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, evolves all the time, resulting in the emerging of many epidemic SARS-CoV-2 mutants, which significantly impairs the effectiveness of early strain-based vaccines and antibodies. Developing universal vaccines and broad-spectrum antiviral drugs are essential to confront SARS-CoV-2 mutants including those may emerge in the future. Our study reported here showed that the cleavage sites of cellular cathepsin L (CTSL) are highly conserved among all the SARS-CoV-2 mutants and SARS-CoV. The CTSL inhibitor teicoplanin not only inhibited the cell entry of two live SARS-CoV-2 strains and various pseudotyped viruses but also prevented live virus infection in animal models. Based on our previous finding that teicoplanin also inhibited SARS-CoV and MERS-CoV infection, we believe that teicoplanin possesses the potential to become a universal anti-CoVs drug.
Evidence of recombination in coronaviruses implicating pangolin origins of nCoV-2019
Authors: Wong Matthew C. , Javornik Cregeen Sara J. , Ajami Nadim J. , Petrosino Joseph F.
Published: February 2020

A novel coronavirus (nCoV-2019) was the cause of an outbreak of respiratory illness detected in Wuhan, Hubei Province, China in December of 2019. Genomic analyses of nCoV-2019 determined a 96% resemblance with a coronavirus isolated from a bat in 2013 (RaTG13); however, the receptor binding motif (RBM) of these two genomes share low sequence similarity. This divergence suggests a possible alternative source for the RBM coding sequence in nCoV-2019. We identified high sequence similarity in the RBM between nCoV-2019 and a coronavirus genome reconstructed from a viral metagenomic dataset from pangolins possibly indicating a more complex origin for nCoV-2019.
The immune vulnerability landscape of the 2019 Novel Coronavirus, SARS-CoV-2
Authors: Zhu James , Kim Jiwoong , Xiao Xue , Wang Yunguan , Luo Danni , Jiang Shuang , Chen Ran , Xu Lin , Zhang He , Moise Lenny , Gutierrez Andres H. , De Groot Anne S. , Xiao Guanghua , Schoggins John W. , Zhan Xiaowei , Wang Tao , Xie Yang
Published: February 2020

The outbreak of the 2019 Novel Coronavirus (SARS-CoV-2) rapidly spread from Wuhan, China to more than 150 countries, areas, or territories, causing staggering numbers of infections and deaths. In this study, bioinformatics analyses were performed on 5,568 complete genomes of SARS-CoV-2 virus to predict the T cell and B cell immunogenic epitopes of all viral proteins, which formed a systematic immune vulnerability landscape of SARS-CoV-2. The immune vulnerability and genetic variation profiles of SARS-CoV were compared with those of SARS-CoV and MERS-CoV. In addition, a web portal was developed to broadly share the data and results as a resource for the research community. Using this resource, we showed that genetic variations in SARS-CoV-2 are associated with loss of B cell immunogenicity, an increase in CD4+T cell immunogenicity, and a minimum loss in CD8+T cell immunogenicity, indicating the existence of a curious correlation between SARS-CoV-2 genetic evolutions and the immunity pressure from the host. Overall, we present an immunological resource for SARS-CoV-2 that could promote both therapeutic/vaccine development and mechanistic research.
Bilateral Sequential Theta Burst Stimulation for Multiple-Therapy-Resistant Depression: a naturalistic observation study
Authors: Burhan Amer M. , Patience James A. , Teselink Johannes G.P. , Marlatt Nicole M. , Babapoor-Farokhran Sahand , Palaniyappan Lena
Published: February 2020

Depression is a significant health issue with treatment resistance reported in about one third of patients. Treatment resistance results in significant disability, impaired quality of life, and increased healthcare costs. Repetitive transcranial magnetic stimulation (rTMS) is a treatment option for treatment resistant depression (TRD) with an average response rate of around 30%. Theta-burst is a novel rTMS paradigm that has shown promise as a treatment for TRD in some preliminary studies. In a naturalistic design, we evaluated the efficacy and tolerability of bilateral sequential (right then left) prefrontal theta-burst rTMS (bsTBS) in 50 patients with TRD (600 pulses/session, 20 sessions, 100% of resting motor threshold (two patients treated at 80% due to intolerance of 100%), F4/F3 of 10-20-20 EEG localization). Data was collected over 36 months from a specialized academic TMS clinic. Patients had multiple-treatment resistance with at least two failed trials of different antidepressants with 20% also having failed electroconvulsive therapy and 66% having received professional therapy. We found a 28% remission rate (HAMD-17 score of ≤ 7) and a 52% response rate (≥ 50% reduction in HAMD-17) with a 42% reduction in average HAMD-17 score. The treatment was well tolerated, with muscle contractions, mild pain or discomfort, headache, scalp irritation, and changes to vitals being captured as occasional adverse events with two instances of syncope (0.22% of treatments). This naturalistic study shows that bsTBS is a promising paradigm for a multiple-TRD patient population with approximately one-third of treatments achieving remission and over half achieving significant response.

Previous Publication

Abstract accepted and study presented at the 2018 Canadian Psychiatric Association Annual Conference, Toronto, Ontario, Canada, September 29, 2018.
corto: a lightweight R package for Gene Network Inference and Master Regulator Analysis
Authors: Mercatelli Daniele , Lopez-Garcia Gonzalo , Giorgi Federico M.
Published: February 2020

Motivation

Gene Network Inference and Master Regulator Analysis (MRA) have been widely adopted to define specific transcriptional perturbations from gene expression signatures. Several tools exist to perform such analyses, but most require a computer cluster or large amounts of RAM to be executed.

Results

We developed corto, a fast and lightweight R package to infer gene networks and perform MRA from gene expression data, with optional corrections for Copy Number Variations (CNVs) and able to run on signatures generated from RNA-Seq or ATAC-Seq data. We extensively benchmarked it to infer context-specific gene networks in 39 human tumor and 27 normal tissue datasets.

Availability

Cross-platform and multi-threaded R package on CRAN (stable version)https://cran.rproject.org/package=cortoand Github (development release)https://github.com/federicogiorgi/corto.

Contact

federico.giorgi@unibo.it
Demonstration of resistance to satyrization behavior inAedes aegypti(Linnaeus) from La Réunion island
Authors: Maïga Hamidou , Gilles Jérémie R. L. , Lees Rosemary Susan , Yamada Hanano , Bouyer Jérémy
Published: February 2020

Aedes aegyptiandAedes albopictusare competent vectors of arboviruses such as dengue and chikungunya viruses which co-exist in some areas including La Réunion island. A kind of reproductive interference called satyrization has been described in sympatric species where a dominant species tends to control the spread of the other species. Here, we investigated satyrization in laboratory experiments to provide insights on the potential impact onAe. aegyptiof a control campaign including a sterile insect technique component againstAe. albopictus. Different mating crosses were used to test sympatric, conspecific-interspecific and allopatric effects of irradiated and non-irradiated maleAe. albopictuson femaleAe. aegypti, including in a situation of skewed male ratio. Our results suggest that there was only a low level of satyrization between sympatric populations ofAe. aegyptiandAe. albopictuscolonised from La Réunion island. A maleAe. albopictusto femaleAe. aegyptiratio of 3:1 did not increase the level of satyrization. FemaleAe. aegyptipreviously mated to maleAe. albopictuswere not prevented from being inseminated by conspecific maleAe. aegypti. A satyrization effect was not seen between allopatricAe. albopictusandAe. aegyptistrains from La Réunion Island either. The testedAe. aegyptistrain from La Réunion island has therefore developed full resistance to satyrization and so releasing sterile maleAe. albopictusmay not suppressAe. aegyptipopulations if an overflooding of irradiated maleAe. albopictusleads to similar results. The management strategy of two competent species in a sympatric area is discussed.
Telacebec for ultra-short treatment of Buruli ulcer in a mouse model
Authors: Almeida Deepak V. , Converse Paul J. , Omansen Till F. , Tyagi Sandeep , Tasneen Rokeya , Kim Jeongjun , Nuermberger Eric L.
Published: February 2020

Telacebec (Q203) is a new anti-tubercular drug with extremely potent activity againstMycobacterium ulcerans. Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture-negative in 2 weeks. Combining Q203 with rifampin resulted in relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF+clarithromycin, the current standard of care, for 4 weeks.

The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2-10 mg/kg were culture-negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2 and 10 mg/kg were culture-negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics sub-study revealed that Q203 doses of 2-10 mg/kg in mice produce plasma concentrations similar to those produced by 100-300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations.

These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for cure to ≤ 1 week (or 5 doses of 2-10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.
Differential activation of P-TEFb complexes in the development of cardiomyocyte hypertrophy following activation of distinct GPCRs
Authors: Martin Ryan D. , Sun Yalin , MacKinnon Sarah , Cuccia Luca , Pagé Viviane , Hébert Terence E. , Tanny Jason C.
Published: February 2020

Pathological cardiac hypertrophy is driven by neurohormonal activation of specific G protein-coupled receptors (GPCRs) in cardiomyocytes and is accompanied by large-scale changes in cardiomyocyte gene expression. These transcriptional changes require activity of positive transcription elongation factor b (P-TEFb), which is recruited to target genes by the bromodomain protein Brd4 or theSuperElongationComplex (SEC). Here we describe GPCR-specific regulation of these P-TEFb complexes and a novel mechanism for activating Brd4 in primary neonatal rat cardiomyocytes. The SEC was required for the hypertrophic response downstream of either the α1-adrenergic receptor (α1-AR) or the endothelin receptor (ETR). In contrast, Brd4 inhibition selectively impaired the α1-AR response. This was corroborated by the finding that activation of α1-AR, but not ETR, increased Brd4 occupancy at promoters and super enhancers of hypertrophic genes. Transcriptome analysis demonstrated that activation of both receptors initiated similar gene expression programs, but that Brd4 inhibition attenuated hypertrophic genes more robustly following α1-AR activation. Finally, we show that protein kinase A (PKA) is required for α1-AR stimulation of Brd4 chromatin occupancy. The differential role of the Brd4/P-TEFb complex in response to distinct GPCR pathways has potential clinical implications as therapies targeting this complex are currently being explored for heart failure.
Nasal high-frequency percussive ventilation versus nasal continuous positive airway pressure in term and preterm neonates exhibiting respiratory distress: a randomized controlled trial (TONIPEP; NCT 02030691)
Authors: Laurent Renesme , Eric Dumas de la Roque , Christine Germain , Agnès Chevrier , Muriel Rebola , Sophie Cramaregeas , Antoine Benard , Christophe Elleau , Olivier Tandonnet
Published: February 2020

Objective

To determine whether the use of nasal, high-frequency percussive ventilation (nHFPV) to manage neonatal respiratory distress decreases the regional cerebral oxygen saturation (rScO2) below that afforded by nasal continuous positive airway pressure (nCPAP).

Design

Monocentric, prospective, randomized, monocentric, open-label, non-inferiority crossover trial.

Patients

Newborns of gestational age (GA) ≥ 33 weeks exhibiting persistent respiratory distress after 10 min of life (Silverman score ≥ 4).

Intervention

nHFPV and nCPAP, in succession and in random order.

Main outcome measure

Mean rScO2, as revealed by near-infrared spectroscopy (NIRS) performed over the last 5 min of each ventilation mode. To show that nHFPV was not inferior to nCPAP, our a priori calculations required that the lower boundary of the bilateral 95% confidence interval (CI) of the difference between the mean rScO2 values of each ventilation mode should exceed –5.

Results

Forty-nine newborns were randomized and 46 were analyzed. The mean (± standard deviation [SD]) GA and birth weight were 36.4 ± 1.9 weeks and 2,718 ± 497 g. The diagnosis was transient tachypnea in 65% of cases and respiratory distress syndrome in 35%. The mean rScO2 difference during the last 5 min of each ventilation mode (nHFPV minus nCPAP) was – 0.7 ± 5.4% (95% CI –2.25; 0.95). Neither a period effect nor a period-treatment interaction was evident. The mean transcutaneous carbon dioxide values (n = 26) for nCPAP and nHFPV were 7.1 ± 4.8 and 7.9 ± 5.1 kPa, respectively. No harmful or unintentional effect was observed.

Conclusion

In our study on newborns of GA ≥ 33 weeks treated for respiratory distress, cerebral oxygenation via nHFPV was not inferior to nCPAP.

What is already known on the topic

Non-invasive high-frequency ventilation is feasible in preterm newborns and seems to improve ventilation compared to nasal CPAP.

We previously showed that nasal high-frequency percussive ventilation (nHFPV) was more efficient that nCPAP for respiratory distress management in newborns of gestational age (GA) ≥ 35 weeks.

The impact of mechanical ventilation, especially high-frequency modes, on cerebral blood flow in neonates is of concern.

What this study adds

nHFPV was well-tolerated and non-inferior to nasal CPAP as measured by rScO2 levels when used to manage respiratory distress at birth in newborns of GA ≥ 33 weeks.
Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCoV, in the nasal tissue
Authors: Wu Chao , Zheng Shufa , Chen Yu , Zheng Min
Published: February 2020

A novel coronavirus (2019-nCoV) was first identified in Wuhan, Hubei Province, and then spreads to the other Provinces of China. WHO decides to determine a Public Health Emergency of International Concern (PHEIC) of 2019-nCoV. 2019-nCov was reported to share the same receptor, Angiotensin-converting enzyme 2 (ACE2), with SARS-Cov. Here based on the public single-cell RNA-Seq datasets, we analyzed the ACE2 RNA expression profile in the tissues at different locations of the respiratory tract. The result indicates that the ACE2 expression appears in nasal epithelial cells. We found that the size of this population of ACE2-expressing nasal epithelial cells is comparable with the size of the population of ACE2-expression type II alveolar cells (AT2) in the Asian sample reported by Yu Zhao et al. We further detected 2019-nCoV by polymerase chain reaction (PCR) from the nasal-swab and throat-swab of seven suspected cases. We found that 2019-nCoV tends to have a higher concentration in the nasal-swab comparing to the throat-swab, which could attribute to the ACE2-expressing nasal epithelial cells. We hope this study could be informative for virus-prevention strategy development, especially the treatment of nasal mucus.
Lockdown may partially halt the spread of 2019 novel coronavirus in Hubei province, China
Authors: Shen Mingwang , Peng Zhihang , Guo Yuming , Xiao Yanni , Zhang Lei
Published: February 2020

We present a timely evaluation of the impact of lockdown on the 2019-nCov epidemic in Hubei province, China. The implementation appears to be effective in reducing about 60% of new infections and deaths, and its effect also appears to be sustainable even after its removal. Delaying its implementation reduces its effectiveness. However, the direct economic cost of such a lockdown remains to be seen and whether the model is replicable in other Chinese regions remains a matter of further investigation.
Graph neural representational learning of RNA secondary structures for predicting RNA-protein interactions
Authors: Yan Zichao , Hamilton William L. , Blanchette Mathieu
Published: February 2020

Abstract

Motivation

RNA-protein interactions are key effectors of post-transcriptional regulation. Significant experimental and bioinformatics efforts have been expended on characterizing protein binding mechanisms on the molecular level, and on highlighting the sequence and structural traits of RNA that impact the binding specificity for different proteins. Yet our ability to predict these interactionsin silicoremains relatively poor.

Results

In this study, we introduce RPI-Net, a graph neural network approach for RNA-protein interaction prediction. RPI-Net learns and exploits a graph representation of RNA molecules, yielding significant performance gains over existing state-of-the-art approaches. We also introduce an approach to rectify particular type of sequence bias present in many CLIP-Seq data sets, and we show that correcting this bias is essential in order to learn meaningful predictors and properly evaluate their accuracy. Finally, we provide new approaches to interpret the trained models and extract simple, biologically-interpretable representations of the learned sequence and structural motifs.

Availability

Source code can be accessed athttps://www.github.com/HarveyYan/RNAonGraph.

Contact

wlh@cs.mcgill.ca,blanchem@cs.mcgill.ca
PHF3 regulates neuronal gene expression through the new Pol II CTD reader domain SPOC
Authors: Appel Lisa-Marie , Franke Vedran , Bruno Melania , Grishkovskaya Irina , Kasiliauskaite Aiste , Schoeberl Ursula E. , Puchinger Martin G. , Kostrhon Sebastian , Beltzung Etienne , Mechtler Karl , Lin Gen , Vlasova Anna , Leeb Martin , Pavri Rushad , Stark Alexander , Akalin Altuna , Stefl Richard , Bernecky Carrie , Djinovic-Carugo Kristina , Slade Dea
Published: February 2020

The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) is a regulatory hub for transcription and RNA processing. Here, we identify PHD-finger protein 3 (PHF3) as a new CTD-binding factor that negatively regulates transcription and mRNA stability. The PHF3 SPOC domain preferentially binds to CTD repeats phosphorylated on Serine-2 and PHF3 tracks with Pol II across the length of genes. PHF3 competes with TFIIS for Pol II binding through its TFIIS-like domain (TLD), thus inhibiting TFIIS-mediated rescue of backtracked Pol II. PHF3 knock-out or PHF3 SPOC deletion in human cells result in gene upregulation and a global increase in mRNA stability, with marked derepression of neuronal genes. Key neuronal genes are aberrantly expressed in Phf3 knock-out mouse embryonic stem cells, resulting in impaired neuronal differentiation. Our data suggest that PHF3 is a prominent effector of neuronal gene regulation at the interface of transcription elongation and mRNA decay.
A Comprehensive Survey of Genomic Mutations in Breast Cancer Reveals Recurrent Neoantigens as Potential Therapeutic Targets
Authors: Liu Songming , Chen Chao , Zhang Xiuqing
Published: February 2020

Neoantigens are newly formed antigens generated by cancer cells but absent in normal cells. With their high specificity and immunogenicity characteristic, neoantigens are considered as an ideal target for immunotherapy. This study was aimed to investigate the signature of neoantigens in breast cancer. Somatic mutations, including SNVs and indels, were obtained from cBioPortal of 5991 breast cancer patients. For neoantigen prediction, 738 non-silent somatic variants present in at least 3 patients were selected., PIK3CA (38%), the highly mutated gene in breast cancer, can produce the highest number of neoantigens per gene. Some pan-cancer hotspot mutations, such as PIK3CA E545K (6.93%), can be recognized by at least one HLA molecule. Since there are more SNVs than indels in breast cancer, SNVs are the major source of neoantigens. Patients with hormone receptor positive or HER2 positive are more competent to produce neoantigens. Age, but not clinical stage, is a significant contributory factor of neoantigens production. We believe a detailed description of breast cancer neoantigens signatures could contribute to neoantigens based immunotherapy development.
Ant guards influence the mating system of their plant hosts by altering pollinator behaviour
Authors: Villamil Nora , Boege Karina , Stone Graham N.
Published: February 2020

Ant guards can increase plant fitness by deterring herbivores but may also reduce it by interfering with pollination, hence ant-plant interactions are ideal systems in which to study costs and benefits of mutualisms. While ant impacts on herbivory are well-studied, much less is known about impacts on pollinators and associated consequences for plant mating systems and fitness. We used field experiments to quantify the effect of ant guards on pollinator community composition, frequency and duration of flower visits, and cascading effects on plant mating system and plant fitness inTurnera velutina(Passifloraceae). Although ant patrolling did not affect pollinator community composition or visitation frequency, it decreased pollinator foraging time and flower visit duration. Such behavioural changes resulted in reduced pollen deposition on stigmas, decreasing male fitness whilst increasing outcrossing rates. This study contributes to understanding how non-pollinators, such as these defensive mutualists, can shape plant mating systems.
Identification of key proteins involved in stickleback environmental adaption with system-level analysis
Authors: Hall Martina , Kültz Dietmar , Almaas Eivind
Published: February 2020

Using abundance measurements of 1,490 proteins from four separate populations of three-spined sticklebacks, we implemented a system-level approach to correlate proteome dynamics with environmental salinity and temperature and the fish’s population and morphotype. We identified sets of robust and accurate fingerprints that predict environmental salinity, temperature, morphotype and the population sample origin, observing that proteins with specific functions are enriched in these fingerprints. Highly apparent functions represented in all fingerprints include ion transport, proteostasis, growth, and immunity, suggesting that these functions are most diversified in populations inhabiting different environments.

Applying a differential network approach, we analyzed the network of protein interactions that differs between populations. Looking at specific population combinations of differential interaction, we identify sets of connected proteins. We find that these sets and their corresponding enriched functions reflect key processes that have diverged between the four populations. Moreover, the extent of divergence, i.e. the number of enriched functions that differ between populations, is highest when all three environmental parameters are different between two populations. Key nodes in the differential interaction network signify functions that are also inherent in the fingerprints, most prominently proteostasis-related functions. However, the differential interaction network also reveals additional functions that have diverged between populations, notably cytoskeletal organization and morphogenesis.

Having such a large proteomic dataset, the strength of these analyses is that the results are purely data-driven, not based on previous findings and hypotheses about adaptation. With such an unbiased approach applied on a large proteomic dataset, we find the strongest signals given by the data, making it possible to develop more discriminatory and complex biomarkers for specific contexts of interest.
Large-scale sequence similarity analysis reveals the scope of sequence and function divergence in PilZ domain proteins
Authors: Cheang Qing Wei , Sheng Shuo , Xu Linghui , Liang Zhao-Xun
Published: February 2020

PilZ domain-containing proteins constitute a superfamily of widely distributed bacterial signalling proteins. Although studies have established the canonical PilZ domain as an adaptor protein domain evolved to specifically bind the second messenger c-di-GMP, mounting evidence suggest that the PilZ domain has undergone enormous divergent evolution to generate a superfamily of proteins that are characterized by a wide range of c-di-GMP-binding affinity, binding partners and cellular functions. The divergent evolution has even generated families of non-canonical PilZ domains that completely lack c-di-GMP binding ability. In this study, we performed a large-scale sequence analysis on more than 28,000 single- and di-domain PilZ proteins using the sequence similarity networking tool created originally to analyse functionally diverse enzyme superfamilies. The sequence similarity networks (SSN) generated by the analysis feature a large number of putative isofunctional protein clusters, and thus, provide an unprecedented panoramic view of the sequence-function relationship and function diversification in PilZ proteins. Some of the protein clusters in the networks are considered as unexplored clusters that contain proteins with completely unknown biological function; whereas others contain one, two or a few functionally known proteins, and therefore, enabling us to infer the cellular function of uncharacterized homologs or orthologs. With the ultimate goal of elucidating the diverse roles played by PilZ proteins in bacterial signal transduction, the work described here will facilitate the annotation of the vast number of PilZ proteins encoded by bacterial genome and help to prioritize functionally unknown PilZ proteins for future studies.

Importance

Although PilZ domain is best known as the protein domain evolved specifically for the binding of the second messenger c-di-GMP, divergent evolution has generated a superfamily of PilZ proteins with a diversity of ligand or protein-binding properties and cellular functions. We analysed the sequences of more than 28,000 PilZ proteins using the sequence similarity networking (SSN) tool to yield a global view of the sequence-function relationship and function diversification in PilZ proteins. The results will facilitate the annotation of the vast number of PilZ proteins encoded by bacterial genomes and help us prioritize PilZ proteins for future studies.
Integration of Brain and Behavior Measures for Identification of Data-Driven Groups Cutting Across Children with ASD, ADHD, or OCD
Authors: Jacobs Grace R. , Voineskos Aristotle N. , Hawco Colin , Stefanik Laura , Forde Natalie J. , Dickie Erin W. , Lai Meng-Chuan , Szatmari Peter , Schachar Russell , Crosbie Jennifer , Arnold Paul D. , Goldenberg Anna , Erdman Lauren , Lerch Jason P. , Anagnostou Evdokia , Ameis Stephanie H.
Published: February 2020

Autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) are clinically and biologically heterogeneous neurodevelopmental disorders (NDDs). The objective of the present study was to integrate brain imaging and behavioral measures to identify new brain-behavior subgroups cutting across these disorders. A subset of the data from the Province of Ontario Neurodevelopmental Disorder (POND) Network including participants with different NDDs (aged 6-16 years) that underwent cross-sectional T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scanning on the same 3T scanner, and behavioral/cognitive assessments was used. Similarity Network Fusion was applied to integrate cortical thickness, subcortical volume, white matter fractional anisotropy (FA), and behavioral measures in 176 children with ASD, ADHD or OCD with complete data that passed quality control. Normalized mutual information (NMI) was used to determine top contributing model features. Bootstrapping, out-of-model outcome measures and supervised machine learning were each used to examine stability and evaluate the new groups. Cortical thickness in socio-emotional and attention/executive networks and inattention symptoms comprised the top ten features driving participant similarity and differences between four transdiagnostic groups. Subcortical volumes (pallidum, nucleus accumbens, thalamus) were also different among groups, although white matter FA showed limited differences. Features driving participant similarity remained stable across resampling, and the new groups showed significantly different scores on everyday adaptive functioning. Our findings open the possibility of studying new data-driven groups that represent children with NDDs more similar to each other than others within their own diagnostic group. Such new groups can be evaluated longitudinally for prognostic utility and could be stratified for clinical trials targeted toward each group’s unique brain and behavioral profiles.
Strong inhibitory signaling underlies stable temporal dynamics and working memory in spiking neural networks
Authors: Kim Robert , Sejnowski Terrence J.
Published: February 2020

Cortical neurons process information on multiple timescales, and areas important for working memory (WM) contain neurons capable of integrating information over a long timescale. However, the underlying mechanisms for the emergence of neuronal timescales stable enough to support WM are unclear. By analyzing a spiking recurrent neural network (RNN) model trained on a WM task and activity of single neurons in the primate prefrontal cortex, we show that the temporal properties of our model and the neural data are remarkably similar. Dissecting our RNN model revealed strong inhibitory-to-inhibitory connections underlying a disinhibitory microcircuit as a critical component for long neuronal timescales and WM maintenance. We also found that enhancing inhibitory-to-inhibitory connections led to more stable temporal dynamics and improved task performance. Finally, we show that a network with such microcircuitry can perform other tasks without disrupting its pre-existing timescale architecture, suggesting that strong inhibitory signaling underlies a flexible WM network.
Differential response to cytotoxic therapy explains treatment dynamics of AML patients: insights from a mathematical modelling approach
Authors: Hoffmann H. , Thiede C. , Glauche I. , Bornhaeuser M. , Roeder I.
Published: February 2020

Disease response and durability of remission are very heterogeneous in patients with acute myeloid leukaemia (AML) patients. There is increasing evidence that the individual risk of early relapse can be predicted based on the initial treatment response. However, it is unclear how such a correlation is linked to functional aspects of AML progression and treatment. We suggest a mathematical model in which leukaemia-initiating cells and normal/healthy hematopoietic stem and progenitor cells reversibly change between an active state characterized by proliferation and chemosensitivity and a quiescent state, in which the cells do not divide, but are also insensitive to chemotherapy. Applying this model to 275 molecular time courses of NPM1-mutated patients, we conclude that the differential chemosensitivity of the leukaemia-initiating cells together with the cells’ intrinsic proliferative capacity is sufficient to reproduce both, early relapse as well as long-lasting remission. We can, furthermore, show that the model parameters associated with individual chemosensitivity and proliferative advantage of the leukemic cells are closely linked to the patients’ time to relapse. They can, therefore, be used as a measure of the aggressiveness of the disease. Early assessment of these measures and incorporation into risk stratification schemes will improve risk assessment and individual treatment in AML.