bluuebunny/crossref_metadata_2025 huggingface dataset:
Left Atrial Appendage Mechanical Exclusion
Authors: Prosper Ashley , Shinbane Jerold , Maliglig Ana , Saremi Farhood , Wilcox Alison , Lee Christopher
Published: April 2020

Left atrial appendage (LAA) mechanical exclusion is being investigated for nonpharmacologic stroke risk reduction in selected patients with atrial fibrillation. There are multiple potential approaches in various stages of development and clinical application, each of which depends on specific cardiothoracic anatomic characteristics for optimal performance. Multiple imaging modalities can be utilized for application of this technology, with transesophageal echocardiography used for intraprocedural guidance. Cardiovascular computed tomographic angiography can act as a virtual patient avatar, allowing for the assessment of cardiac structures in the context of surrounding cardiac, coronary vascular, thoracic vascular, and visceral and skeletal anatomy, aiding preprocedural decision-making, planning, and follow-up. Although transesophageal echocardiography is used for intraprocedural guidance, computed tomographic angiography may be a useful adjunct for preprocedure assessment of LAA sizing and anatomic obstacles or contraindications to deployment, aiding in the assessment of optimal approaches. Potential approaches to LAA exclusion include endovascular occlusion, epicardial ligation, primary minimally invasive intercostal thoracotomy with thoracoscopic LAA ligation or appendectomy, and minimally invasive or open closure as part of cardiothoracic surgery for other indications. The goals of these procedures are complete isolation or exclusion of the entire appendage without leaving a residual appendage stump or residual flow with avoidance of acute or chronic damage to surrounding cardiovascular structures. The cardiovascular imager plays an important role in the preprocedural and postprocedural assessment of the patient undergoing LAA exclusion.
Lymphocytic Vasculitis Associated With Mild Rejection in a Vascularized Composite Allograft Recipient: A Clinicopathological Study
Authors: Roy Simon F. , Krishnan Vimal , Trinh Vincent Quoc-Huy , Collette Suzon , Dufresne Simon F. , Borsuk Daniel E. , Désy Delphine
Published: April 2020

Background.

Histologic criteria for diagnosing acute rejection in vascularized composite tissue allograft (VCA) have been established by the Banff 2007 Working Classification of Skin-Containing Composite Tissue Allograft, but the role of early vascular lesions in graft rejection warrants additional analysis.

Methods.

We performed a retrospective study of 34 skin biopsies performed over 430 d for rejection surveillance, in Canada’s first face allotransplant recipient. Three observers reviewed all biopsies to assess the nature and intensity of the inflammatory skin infiltrate. A complete histological and immunohistochemical review of the vascular components was performed with a focus on lymphocytic vasculitis, intravascular fibrin, vessel caliber, extent of injury, C4d positivity, and inflammatory cell phenotyping. We then correlated these data points to clinical and immunosuppression parameters.

Results.

Acute vascular damage in biopsies that would be classified as mild acute rejection correlates with troughs in immunosuppression and subsides when immunosuppressive tacrolimus doses are increased. Grade 0 Banff rejection and Grade I without lymphocytic vasculitis were almost indistinguishable, whereas Grade I with lymphocytic vasculitis was an easy and reproducible histologic finding.

Conclusions.

Our results highlight the possible relevance of vascular injury in the context of VCA, as its presence might underlie a more aggressive form of immune rejection. If these findings are validated in other VCA patients, vascular injury in mild rejection might warrant a different clinical approach.
Complications of Ventriculoperitoneal Shunt for Idiopathic Intracranial Hypertension: A Single-Institution Study of 32 Patients
Authors: Brune Anthony J. , Girgla Taania , Trobe Jonathan D.
Published: April 2020

Background:

Because there are no head-to-head studies of the efficacy of surgical options in the treatment of medically-intractable idiopathic intracranial hypertension (IIH), procedure selection is often based on expected complications. Cerebrospinal fluid (CSF) diversion by shunting has been reported to have a 23%–67% rate of shunt failure. But these figures derive from small cohorts or studies that do not separate the complication rates of the different shunt options—ventriculoperitoneal (VP), lumboperitoneal (LP), and ventriculoatrial (VA). The complication rate of LP shunts seems to be higher than that for VP shunts, the procedure currently in widest use. Our experience with VP shunts for IIH over the past decades suggests that the complication rate for that option is lower than reported series would suggest.

Methods:

Retrospective single-institutional study using a search engine that finds all text mentions of particular terms. We searched for the terms (“IIH” OR “Idiopathic intracranial hypertension” OR “PTC OR “pseudotumor”) AND (“VP Shunt” OR “ventriculoperitoneal”) over the period 1998 to 2018. From 490 “hits,” only 32 patients met entry criteria: diagnosis of IIH confirmed at our institution, including examination in a neuro-ophthalmology clinic showing papilledema, elevated opening pressure on lumbar puncture or a consistently elevated intraparenchymal pressure on Codman intracranial pressure (ICP) monitoring, neuroimaging and CSF studies consistent with a diagnosis of IIH, and at least 1 year of follow-up in our neuro-ophthalmology or neurosurgery clinics.

Results:

Shunt failures occurred in 6 (18.7%) of 32 patients, which included elevated ICP due to obstruction or discontinuity of the shunt, over-drainage, infection of the shunt system, or intractable abdominal pain or infection. None of these failures caused permanent worsening of vision, neurologic morbidity, or death. But they entailed considerable medical care. Placement of VP shunts also aroused patient fear of complications, precipitating 38 emergency visits in 14 patients for “false alarms.”

Conclusions:

In this series of 32 patients, the largest retrospective study of VP shunts for IIH, there was an 18.7% failure rate, lower than previously published smaller series have disclosed. But among patients who suffered complications, a saga of intensive medical care often occurred. Placement of the shunt also aroused patient fear of complications, leading to many medical encounters required to rule out complications.
Use of En Face Optical Coherence Tomography to Monitor Papilledema in Idiopathic Intracranial Hypertension: A Pilot Study
Authors: Carey Andrew R. , Bosley Thomas M. , Miller Neil R. , McCulley Timothy J. , Henderson Amanda D.
Published: April 2020

Background:

En face optical coherence tomography (OCT) uses the data acquired during OCT of the optic disc, which typically is used to determine measurements of the peripapillary retinal nerve fiber layer (ppRNFL), to generate a coronal composite fundus image rather than a cross-sectional image. En face OCT has been reported to identify retinal changes related to papilledema in idiopathic intracranial hypertension (IIH) but has not been evaluated for monitoring papilledema. This study aimed to assess the reliability and validity of en face OCT for monitoring papilledema.

Methods:

Using the Pearson correlation coefficient (R), these measurements were compared with ppRNFL thickness as well as average diameter and estimated area. Four fellowship-trained neuro-ophthalmologists were asked to qualitatively rank en face images by the area of optic disc edema while masked from all other clinical data. Rankings were compared with ppRNFL thickness as a gold standard and with en face OCT characteristics using the Pearson correlation coefficient (R).

Results:

Experts were able to correctly identify an increase in average ppRNFL thickness >10 µm with a mean (SD) of 91% (±7%) accuracy. A ranking error among experts corresponded to a mean (standard error) change in the ppRNFL thickness of 6 (±6) µm. The mean Pearson correlation coefficient by the area of disc edema among experts was 0.92 (±0.13).

Conclusions:

Multiple objective parameters of en face OCT of optic disc edema have an excellent correlation with ppRNFL thickness. These results suggest that en face OCT is a valid clinical tool for monitoring papilledema in IIH.
Unmasking Anxiety in Autism: Explicit and Implicit Threatening Face Stimuli Dissociate Amygdala-centered Functional Connectivity
Authors: Chen Yu-Chun , Chen Chenyi , Martínez Róger Marcelo , Fan Yang-Tang , Liu Chia-Chien , Cheng Yawei
Published: April 2020

Background

Anxiety is the most prevalent comorbidity in individuals diagnosed with autism spectrum disorder (ASD). Amygdala reactivity to explicit and implicit threat processing is predictive of anxiety-related symptomatology. The neural mechanisms underlying the link between anxiety and ASD remains elusive.

Methods

In this fMRI study, we recruited young adults with ASD (N = 31) and matched them with controls, then proceeded to assess their autistic and anxiety traits by the use of the Autism-Spectrum Quotient (AQ) and the State-Trait Anxiety Inventory (STAI-S), respectively; and scanned their hemodynamic responses, including amygdala, in response to explicit and implicit (backwardly masked) perception of threatening faces.

Results

As compared to controls, the amygdala reactivity in ASD subjects was significantly lower to explicit threat, but comparable for implicit threat. The correlations of the amygdala reactivity with the AQ and STAI-S were dissociated depending on threat processing (explicit or implicit). Furthermore, the amygdala in ASD relative to controls had a more negative functional connectivity with the superior parietal cortex, fusiform gyrus, and hippocampus for explicit threat, whereas a more positive connectivity with the medial prefrontal cortex, temporal pole, and hippocampus for implicit threat.

Conclusion

In ASD, the transmission of socially relevant information along dorsal and ventral neural pathways centered on the amygdala is dissociated depending on explicit and implicit threat processing. This dissociation, ascribed to their failure to compromise pre-existing hyperarousal, might contribute to anxiety in ASD.
The potential of low molecular weight heparin to mitigate cytokine storm in severe COVID-19 patients: a retrospective clinical study
Authors: Shi Chen , Wang Cong , Wang Hanxiang , Yang Chao , Cai Fei , Zeng Fang , Cheng Fang , Liu Yihui , Zhou Taotao , Deng Bin , Vlodavsky Israel , Li Jin-Ping , Zhang Yu
Published: April 2020

Background

On March 11, 2020, the World Health Organization declared its assessment of COVID-19 as a global pandemic. However, specific antiviral drugs are still unavailable, and pateints are managed by multiple complementary treatments.

Methods

The electronic medical records of COVID-19 patients where basic information, complete blood count, coagulation profile, inflammatory cytokines and serum biochemical indicators in 42 patients with COVID-19 (21 of whom were treated with low molecular weight heparin (LMWH), and 21 without LMWH) that were retrospectively analyzed to compare and evaluate the effect of LMWH treatment on disease progression.

Findings

42 patients with COVID-19 treated at the hospital between February 1 and March 15, 2020, were selected for the study, of which 21 underwent LMWH treatment (LMWH group), and 21 did not (Control), during hospitalization. Changes in the percentage of lymphocytes in the LMWH group before and after LMWH treatment were significantly different from those in the control group (11·10±9·50 vs. 3·08±9·66,p=0·011, respectively). Changes in the levels of D-dimer and fibrinogen degradation products (FDP) in the LMWH group before and after LMWH treatment were significantly different from those in the control group (-2·85±3·90, -0·05±0.85,p=0·002; -9·05±13·14, -1·78±3·15,p=0·035). Strikingly, in the LMWH group, IL-6 levels were significantly reduced after LMWH treatment (47·47±58·86, 15·76±25·71,p=0·006). Besides, the changes in IL-6 levels in the LMWH group before and after LMWH treatment were significantly different from those in the control group (-32·46±65·97, 14·96±151·09,p=0·031).

Interpretation

LMWH improves the coagulation dysfunction of COVID-19 patients and exerts anti-inflammatory effects by reducing IL-6 and increasing lymphocyte %. It appears that LMWH can be used as a potential therapeutic drug for the treatment of COVID-19, paving the way for a subsequent well-controlled clinical trial.

Funding

National Natural Science Foundation of China (No. 81603037 to SC) and the National Key Research and Development Plan of China(2017YFC0909900).
Combined prophylactic and therapeutic use maximizes hydroxychloroquine anti-SARS-CoV-2 effectsin vitro
Authors: Clementi Nicola , Criscuolo Elena , Diotti Roberta Antonia , Ferrarese Roberto , Castelli Matteo , Burioni Roberto , Clementi Massimo , Mancini Nicasio
Published: April 2020

While the SARS-CoV-2 pandemic is hardly hitting the world, it is of extreme importance that significantin vitroobservations guide the quick set up of clinical trials. In this study, we evidence that the anti-SARS-CoV2 activity of a clinically achievable hydroxychloroquine concentration is maximized only when administered before and after the infection of Vero E6 cells. This strongly suggests that only a combined prophylactic and therapeutic use of hydroxychloroquine may be effective in limiting viral replication in patients.
Stochastic Compartmental Modelling of SARS-CoV-2 with Approximate Bayesian Computation
Authors: Chandra Vedant
Published: April 2020

In this proof-of-concept study, we model the spread of SARS-CoV-2 in various environments with a stochastic susceptible-infectious-recovered (SIR) compartmental model. We fit this model to the latest epidemic data with an approximate Bayesian computation (ABC) technique. Within this SIR-ABC framework, we extrapolate long-term infection curves for several regions and evaluate their steepness. We propose several applications and extensions of the SIR-ABC technique.
Transmission Dynamics and Control Methodology of COVID-19: a Modeling Study
Authors: Zhu Hongjun , Li Yan , Jin Xuelian , Huang Jiangping , Liu Xin , Qian Ying , Tan Jindong
Published: April 2020

The coronavirus disease 2019 (COVID-19) has grown up to be a pandemic within a short span of time. To investigate transmission dynamics and then determine control methodology, we took epidemic in Wuhan as a study case. Unfortunately, to our best knowledge, the existing models are based on the common assumption that the total population follows a homogeneous spatial distribution, which is not the case for the prevalence occurred both in the community and in hospital due to the difference in the contact rate. To solve this problem, we propose a novel epidemic model called SEIR-HC, which is a novel epidemic model with two different social circles. Using the model alongside the exclusive optimization algorithm, the spread process of COVID-19 epidemic in Wuhan city is reproduced and then the propagation characteristics and unknown data are estimated. Furthermore, the control measures implemented in Wuhan are assessed and the control methodology of COVID-19 is discussed to provide guidance for limiting the epidemic spread.
Susceptibility of ferrets, cats, dogs, and different domestic animals to SARS-coronavirus-2
Authors: Shi Jianzhong , Wen Zhiyuan , Zhong Gongxun , Yang Huanliang , Wang Chong , Liu Renqiang , He Xijun , Shuai Lei , Sun Ziruo , Zhao Yubo , Liang Libin , Cui Pengfei , Wang Jinliang , Zhang Xianfeng , Guan Yuntao , Chen Hualan , Bu Zhigao
Published: April 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the infectious disease COVID-19, which was first reported in Wuhan, China in December, 2019. Despite the tremendous efforts to control the disease, COVID-19 has now spread to over 100 countries and caused a global pandemic. SARS-CoV-2 is thought to have originated in bats; however, the intermediate animal sources of the virus are completely unknown. Here, we investigated the susceptibility of ferrets and animals in close contact with humans to SARS-CoV-2. We found that SARS-CoV-2 replicates poorly in dogs, pigs, chickens, and ducks, but efficiently in ferrets and cats. We found that the virus transmits in cats via respiratory droplets. Our study provides important insights into the animal reservoirs of SARS-CoV-2 and animal management for COVID-19 control.
A2E induces the transactivation of RARs, PPARs and RXRs and its effects are counteracted by norbixin in retinal pigment epithelium cellsin vitro
Authors: Fontaine Valérie , Fournié Mylène , Monteiro Elodie , Boumedine Thinhinane , Balducci Christine , Guibout Louis , Latil Mathilde , Dilda Pierre J. , Sahel José-Alain , Veillet Stanislas , Lafont René , Camelo Serge
Published: April 2020

N-retinylidene-N-retinylethanolamine (A2E) plays a central role in age-related macular degeneration (AMD) by inducing apoptosis, angiogenesis and inflammation. It has been proposed that A2E effects are mediated at least partly via the retinoic acid receptor (RAR)-α. Here we show that A2E binds and transactivates not only RARs, but also peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs). Norbixin, which protects retinal pigment epithelium (RPE) cells against apoptosis induced by combined blue light illumination and A2E exposure, is also a ligand of these nuclear receptors (NRs) but does not induce their transactivation. Norbixin inhibits RXRs and PPARs but enhances RARs transactivation induced by A2E. Norbixin also inhibits PPAR-γ transactivation induced by its high affinity ligand troglitazone. Photoprotection of RPE cells by norbixin correlates with maintained levels of the antiapoptotic B-cell lymphoma 2 (Bcl2) protein. Moreover, norbixin reduces protein kinase B (AKT) phosphorylation, NF-κB and activator protein 1 (AP-1) transactivation, and the mRNA expression of the inflammatory interleukins (IL) 6 and 8 and of vascular endothelial growth factor (VEGF) that are enhanced by A2E. By contrast, norbixin increases matrix metalloproteinase 9 (MMP9) and C-C motif chemokine ligand 2 (CCL2) mRNA expression but has neither effect on extracellular signal-regulated kinase (ERK) phosphorylation, nor on IL-18 mRNA expression in response to A2E. Altogether, we show for the first time that A2E deleterious biological effects appear to be mediated through RARs, PPARs and RXRs. Moreover, we report that the modulation of these NRs by norbixin may open new avenues for the treatment of AMD.
Mechanism of auxin and GA crosstalk in diploid strawberry fruit initiation
Authors: Zhou Junhui , Sittmann John , Guo Lei , Huang Xiaolong , Pulapaka Anuhya , Liu Zhongchi
Published: April 2020

Strawberry, a high value fruit crop, has recently become amenable for genetic studies due to genomic resources and CRISPR/CAS9 tools. Unlike ovary-derived botanical fruits, strawberry is an accessory fruit derived from receptacle, the stem tip subtending floral organs. Although both botanical and accessory fruits initiate development in response to auxin and GA released from seeds, the downstream auxin and GA signaling mechanisms underlying accessory fruit development remain unknown. Using wild strawberry, we performed in depth molecular characterizations of accessory fruit development. We show that auxin signaling proteins FveARF8/FveARF6 are bound and hence inhibited by FveIAA4 and FveRGA1, repressors in auxin and GA signaling pathways. This inhibition is relieved post-fertilization or by the application of GA or auxin. Mutants ofFveRGA1developed parthenocarpic fruit suggesting a conserved function of DELLA proteins in fruit set. Further, FveARF8 was found to repress the expression of a GA receptor gene GID1c to control fruit’s sensitivity to GA, revealing a novel crosstalk mechanism. We demonstrate that consensus co-expression network provides a powerful tool for non-model species in the selection of interacting genes for functional studies. These findings will facilitate the improvement of strawberry fruit productivity and quality by guiding future production of parthenocarpic fruit.

One sentence summary

Genome editing and network analysis are applied to investigating the mechanism of accessory fruit initiation in the wild strawberry, revealing conserved as well as novel crosstalk mechanisms.

The author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (www.plantcell.org) is: Zhongchi Liu (zliu@umd.edu)
Nuclease-mediated depletion biases in ribosome footprint profiling libraries
Authors: Zinshteyn Boris , Wangen Jamie R , Hua Boyang , Green Rachel
Published: April 2020

Ribosome footprint profiling is a high throughput sequencing based technique that provides detailed and global views of translation in living cells. An essential part of this technology is removal of unwanted, normally very abundant, ribosomal RNA sequences that dominate libraries and increase sequencing costs. The most effective commercial solution (Ribo-Zero) has been discontinued and a number of new, experimentally distinct commercial applications have emerged on the market. Here we evaluated several commercially available alternatives designed for RNA-seq of human samples and find them unsuitable for ribosome footprint profiling. We instead recommend the use of custom-designed biotinylated oligos, which were widely used in early ribosome profiling studies. Importantly, we warn that depletion solutions based on targeted nuclease cleavage significantly perturb the high-resolution information that can be derived from the data, and thus do not recommend their use for any applications that require precise determination of the ends of RNA fragments.
Alignment free identification of clones in B cell receptor repertoires
Authors: Lindenbaum Ofir , Nouri Nima , Kluger Yuval , Kleinstein Steven H.
Published: April 2020

Following pathogenic challenge, activated B cells rapidly expand and undergo somatic hypermutation, yielding groups of clonally related B-cells with diversified immunoglobulin receptors. Inference of clonal relationships based on the receptor sequence is an essential step in many adaptive immune receptor repertoire sequencing studies. These relationships are typically identified by a multi-step process that involves: (1) grouping sequences based on shared V and J gene assignments, and junction lengths, and (2) clustering these sequences using a junction-based distance. However, this approach is sensitive to the initial V(D)J gene assignments, which are error-prone, and fails to identify clonal relatives whose junction length has changed through accumulation of indels. Through defining a translation-invariant feature space in which we cluster the sequences, we develop an alignment-free clonal identification method that does not require gene assignments and is not restricted to a fixed junction length. This alignment-free approach has higher sensitivity compared to a typical junction-based distance method without loss of specificity and PPV. While the alignment-free procedure identifies clones that are broadly consistent with the junction-based distance method, it also identifies clones with characteristics (multiple V or J gene assignments or junction lengths) that are not detectable with thejunction based distancemethod.
The Institutional and Cultural Context of Cross-National Variation in COVID-19 Outbreaks
Authors: Messner Wolfgang
Published: April 2020

Background

The COVID-19 pandemic poses an unprecedented and cascading threat to the health and economic prosperity of the world’s population.

Objectives

To understand whether the institutional and cultural context influences the COVID-19 outbreak.

Methods

At the ecological level, regression coefficients are examined to figure out contextual variables influencing the pandemic’s exponential growth rate across 96 countries.

Results

While a strong institutional context is negatively associated with the outbreak (B = −0.55 … −0.64, p < 0.001), the pandemic’s growth rate is steeper in countries with a quality education system (B = 0.33, p < 0.001). Countries with an older population are more affected (B = 0.46, p < 0.001). Societies with individualistic (rather than collectivistic) values experience a flatter rate of pathogen proliferation (B = −0.31, p < 0.001), similarly for higher levels of power distance (B = −0.32, p < 0.001). Hedonistic values, that is seeking indulgence and not enduring restraints, are positively related to the outbreak (B = 0.23, p = 0.001).

Conclusions

The results emphasize the need for public policy makers to pay close attention to the institutional and cultural context in their respective countries when instigating measures aimed at constricting the pandemic’s growth.
Modeling social distancing strategies to prevent SARS-CoV2 spread in Israel- A Cost-effectiveness analysis
Authors: Shlomai Amir , Leshno Ari , Sklan Ella H. , Leshno Moshe
Published: April 2020

Objectives

While highly effective in preventing SARS-CoV-2 spread, national lockdowns come with an enormous economic price. Few countries have adopted an alternative “testing, tracing, and isolation” approach to selectively isolate people at high exposure risk, thereby minimizing the economic impact. To assist policy makers, we performed a cost-effectiveness analysis of these two strategies.

Methods

A modified Susceptible, Exposed, Infectious, Recovered and Deceased (SEIRD) model was employed to assess the situation in Israel, a small country with ~9 million people. The incremental cost-effectiveness ratio (ICER) of these strategies, as well as the expected number of infected individuals and deaths were calculated.

Results

A nationwide lockdown is expected to save on average 274 (median 124, interquartile range (IQR): 71-221) lives compared to the “testing, tracing, and isolation” approach. However, the ICER will be on average $45,104,156 (median $ 49.6 million, IQR: 22.7-220.1) to prevent one case of death.

Conclusions

A national lockdown has a moderate advantage in saving lives with tremendous costs and possible overwhelming economic effects. These findings should assist decision-makers dealing with additional waves of this pandemic.

Highlights

Drastic measures of national lockdowns are taken by many countries to slow-down SARS-CoV-2 spread. However, these measures have detrimental economic effects.

Here we compare two strategies to control the epidemic using a modified SEIRD model: 1. Global national lockdown 2. Focused isolation of people at high exposure risk, following detailed epidemiological investigations.

We show that strategy 1 is modestly superior in saving lives compared to strategy 2, but with tremendous costs to prevent one case of death. This might result in overwhelming economic effects that are expected to increase future death toll.
Forecasting the CoViD–19 Diffusion in Italy and the Related Occupancy of Intensive Care Units
Authors: Fenga Livio
Published: April 2020

This paper provides a model–based method for the forecast of the total number of currently CoVoD-19 positive individuals and of the occupancy of the available Intensive Care Units in Italy. The predictions obtained – for a time horizon of 10 days starting from March 29th – will be provided at a national as well as at a more disaggregate levels, following a criterion based on the magnitude of the phenomenon. While the Regions which have been hit the most by the pandemic have been kept separated, the less affected ones have been aggregated into homogeneous macro-areas. Results show that – within the forecast period considered (March 29th - April 7th) – all of the Italian regions will show a decreasing number of CoViD-19 positive people. Same for the number of people who will need to be hospitalized in a Intensive Care Unit (ICU). These estimates are valid under constancy of the Government’s current containment policies. In this scenario, Northern Regions will remain the most affected ones and no significant outbreak are foreseen in the southern regions.
Deep analysis of the USP18-dependent ISGylome and proteome unveils important roles for USP18 in tumour cell antigenicity and radiosensitivity
Authors: Pinto-Fernandez Adan , Salio Mariolina , Partridge Tom , Chen Jianzhou , Vere George , Greenwood Helene , Olie Cyriel Sebastiaan , Damianou Andreas , Scott Hannah Claire , Pegg Henry Jack , Chiarenza Alessandra , Díaz-Saez Laura , Smith Paul , Gonzalez-Lopez Claudia , Patel Bhavisha , Anderton Emma , Jones Neil , Hammonds Tim R. , Huber Kilian , Muschel Ruth , Borrow Persephone , Cerundolo Vincenzo , Kessler Benedikt M.
Published: April 2020

The deubiquitylating enzyme USP18 is a major negative regulator of the interferon (IFN) signalling cascade. IFN pathways contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy and are often deregulated in cancer. USP18 is the predominant human protease that cleaves interferon-stimulated gene ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteinsin vivo. In this study, using advanced proteomic techniques, we have expanded the USP18-dependent ISGylome and proteome in a chronic myeloid leukaemia (CML)-derived cell line (HAP1) treated with type I IFN. Novel ISGylation targets were characterised that modulate the sensing of innate ligands, antigen presentation and secretion of cytokines. Consequently, CML USP18-deficient cells are more antigenic, driving increased activation of cytotoxic T lymphocytes (CTLs) and are more susceptible to irradiation. Our results suggest USP18 as a pharmacological target in cancer immunotherapy and radiotherapy.
Computational tools for serial block EM reveal differences in plasmodesmata distributions and wall environments
Authors: Paterlini Andrea , Belevich Ilya , Jokitalo Eija , Helariutta Ykä
Published: April 2020

Plasmodesmata are small channels that connect plant cells. While recent technological advances have facilitated the analysis of the ultrastructure of these channels, there are limitations to efficiently addressing their presence over an entire cellular interface. Here, we highlight the value of serial block electron microscopy for this purpose. We developed a computational pipeline to study plasmodesmata distributions and we detect presence/absence of plasmodesmata clusters, pit fields, at the phloem unloading interfaces ofArabidopsis thalianaroots. Pit fields can be visualised and quantified. As the wall environment of plasmodesmata is highly specialised we also designed a tool to extract the thickness of the extracellular matrix at and outside plasmodesmata positions. We show and quantify clear wall thinning around plasmodesmata with differences between genotypes, namely in the recently publishedplm-2sphingolipid mutant. Our tools open new avenues for quantitative approaches in the analysis of symplastic trafficking.

Sentence summary

We developed computational tools for serial block electron microscopy datasets to extract information on the spatial distribution of plasmodesmata over an entire cellular interface and on the wall environment the plasmodesmata are in.
Periprotein lipidomes ofSaccharomyces cerevisiaeprovide a flexible environment for conformational changes of membrane proteins
Authors: van ’t Klooster Joury S , Cheng Tan-Yun , Sikkema Hendrik R , Jeucken Aike , Moody D. Branch , Poolman Bert
Published: April 2020

Yeast tolerates a low pH and high solvent concentrations. The permeability of the plasma membrane (PM) for small molecules is low and lateral diffusion of proteins is slow. These findings suggest a high degree of lipid order, which raises the question of how membrane proteins function in such an environment. The yeast PM is segregated into the Micro-Compartment-of-Can1 (MCC) and Pma1 (MCP), which have different lipid compositions. We extracted proteins from these microdomains via stoichiometric capture of lipids and proteins in styrene-maleic-acid-lipid-particles (SMALPs). We purified SMALP-lipid-protein complexes by chromatography and quantitatively analyzed periprotein lipids located within the diameter defined by one SMALP. Phospholipid and sterol concentrations are similar for MCC and MCP, but sphingolipids are enriched in MCP. Ergosterol is depleted from this periprotein lipidome, whereas phosphatidylserine is enriched relative to the bulk of the plasma membrane. Direct detection of PM lipids in the ‘periprotein space’ supports the conclusion that proteins function in the presence of a locally disordered lipid state.
Automated Feature Extraction from Population Wearable Device Data Identified Novel Loci Associated with Sleep and Circadian Rhythms
Authors: Li Xinyue , Zhao Hongyu
Published: April 2020

Wearable devices have been increasingly used in research to provide continuous physical activity monitoring, but how to effectively extract features remains challenging for researchers. To analyze the generated actigraphy data in large-scale population studies, we developed computationally efficient methods to derive sleep and activity features through a Hidden Markov Model-based sleep/wake identification algorithm, and circadian rhythm features through a Penalized Multi-band Learning approach adapted from machine learning. Unsupervised feature extraction is useful when labeled data are unavailable, especially in large-scale population studies. We applied these two methods to the UK Biobank wearable device data and used the derived sleep and circadian features as phenotypes in genome-wide association studies. We identified 53 genetic loci with p<5×10-8including genes known to be associated with sleep disorders and circadian rhythms as well as novel loci associated with Body Mass Index, mental diseases and neurological disorders, which suggest shared genetic factors of sleep and circadian rhythms with physical and mental health. Further cross-tissue enrichment analysis highlights the important role of the central nervous system and the shared genetic architecture with metabolism-related traits and the metabolic system. Our study demonstrates the effectiveness of our unsupervised methods for wearable device data when additional training data cannot be easily acquired, and our study further expands the application of wearable devices in population studies and genetic studies to provide novel biological insights.
Convergence and novelty in adaptation to whole genome duplication in three independent polyploids
Authors: Bray Sian M. , Wolf Eva M. , Zhou Min , Busoms Silvia , Bohutínská Magdalena , Paajanen Pirita , Monnahan Patrick , Koch Jordan , Fischer Sina , Koch Marcus A. , Yant Levi
Published: April 2020

Convergent evolution is observed broadly across the web of life, but the degree of evolutionary constraint during adaptation of core intracellular processes is not known. High constraint has been assumed for conserved processes, such as cell division and DNA repair, but reports of nimble evolutionary shifts in these processes have confounded this expectation. Whole genome duplication (WGD) necessitates the concerted adjustment of a wide range of fundamental intracellular functions but nevertheless has been repeatedly survived in all kingdoms. Given this repeated adaptation to WGD despite obvious intracellular challenges to core processes such as meiosis, we asked: how do lineages not only survive WGD, but sometimes ultimately thrive? Are the solutions employed constrained or diverse? Here we detect genes and processes under selection following WGD in theCochleariaspecies complex by performing a scan for selective sweeps following WGD in a large-scale survey of 73 resequenced individuals from 23 populations across Europe. We then contrast our results from two independent WGDs inArabidopsis arenosaandCardamine amara.We find that while WGD does require the adaptation of particular functional processes in all three cases, the specific genes recruited to respond are highly flexible. We also observe evidence of varying degrees of convergence between different cases. Our results point to a polygenic basis for the distributed adaptive systems that control meiotic crossover number, ionomic rewiring, cell cycle control, and nuclear regulation. Given the sheer number of loci under selection post-WGD, we surmise that this polygenicity may explain the general lack of convergence between these species that are ~30 million years diverged. Based on our results, we speculate that adaptive processes themselves – such as the rate of generation of structural genomic variants—may be altered by WGD in nascent autopolyploids, contributing to the occasionally spectacular adaptability of autopolyploids observed across kingdoms.
Laser capture microdissection in combination with mass spectrometry: Approach to characterization of tissue-specific proteomes ofEudiplozoon nipponicum(Monogenea, Polyopisthocotylea)
Authors: Roudnický Pavel , Potěšil David , Zdráhal Zbyněk , Gelnar Milan , Kašný Martin
Published: April 2020

Eudiplozoon nipponicum(Goto, 1891) is a hematophagous monogenean ectoparasite which inhabits the gills of the common carp (Cyprinus carpio). Heavy infestation can lead to anemia and in conjunction with secondary bacterial infections cause poor health and eventual death of the host.

This study is based on an innovative approach to protein localization which has never been used in parasitology before. Using laser capture microdissection, we dissected particular areas of the parasite body without contaminating the samples by surrounding tissue, and in combination with analysis by mass spectrometry obtained tissue-specific proteomes of tegument, intestine, and parenchyma of our model organism,E. nipponicum. We successfully verified the presence of certain functional proteins (e.g. cathepsin L) in tissues where their presence was expected (intestine) and confirmed that there were no traces of these proteins in other tissues (tegument and parenchyma). Additionally, we identified a total of 2,059 proteins, including 72 peptidases and 33 peptidase inhibitors. As expected, the greatest variety was found in the intestine and the lowest variety in the parenchyma.

Our results are significant on two levels. Firstly, we demonstrated how one can localize all proteins in one analysis and without using laboratory animals (antibodies for immunolocalization of single proteins). Secondly, this study offers the first complex proteomic data on not only theE. nipponicumbut within the whole class of Monogenea, which was from this point of view until recently neglected.
Multiscale Co-Expression in the Brain
Authors: Harris Benjamin D. , Crow Megan , Fischer Stephan , Gillis Jesse
Published: April 2020

Single-cell RNA-sequencing (scRNAseq) data can reveal co-regulatory relationships between genes that may be hidden in bulk RNAseq due to cell type confounding. Using the primary motor cortex data from the Brain Initiative Cell Census Network (BICCN), we study cell type specific co-expression across 500,000 cells. Surprisingly, we find that the same gene-gene relationships that differentiate cell types are evident at finer and broader scales, suggesting a consistent multiscale regulatory landscape.
The ModelSEED Database for the integration of metabolic annotations and the reconstruction, comparison, and analysis of metabolic models for plants, fungi, and microbes
Authors: Seaver Samuel M. D. , Liu Filipe , Zhang Qizhi , Jeffryes James , Faria José P. , Edirisinghe Janaka N. , Mundy Michael , Chia Nicholas , Noor Elad , Beber Moritz E. , Best Aaron A. , DeJongh Matthew , Kimbrel Jeffrey A. , D’haeseleer Patrik , Pearson Erik , Canon Shane , Wood-Charlson Elisha M. , Cottingham Robert W. , Arkin Adam P. , Henry Christopher S.
Published: April 2020

For over ten years, ModelSEED has been a primary resource for the construction of draft genome-scale metabolic models based on annotated microbial or plant genomes. Now being released, the biochemistry database serves as the foundation of biochemical data underlying ModelSEED and KBase. The biochemistry database embodies several properties that, taken together, distinguish it from other published biochemistry resources by: (i) including compartmentalization, transport reactions, charged molecules and proton balancing on reactions;; (ii) being extensible by the user community, with all data stored in GitHub; and (iii) design as a biochemical “Rosetta Stone” to facilitate comparison and integration of annotations from many different tools and databases. The database was constructed by combining chemical data from many resources, applying standard transformations, identifying redundancies, and computing thermodynamic properties. The ModelSEED biochemistry is continually tested using flux balance analysis to ensure the biochemical network is modeling-ready and capable of simulating diverse phenotypes. Ontologies can be designed to aid in comparing and reconciling metabolic reconstructions that differ in how they represent various metabolic pathways. ModelSEED now includes 33,978 compounds and 36,645 reactions, available as a set of extensible files on GitHub, and available to search athttps://modelseed.organd KBase.
Brain Network Organization During Mindful Acceptance of Emotions
Authors: Dixon Matthew Luke , Girn Manesh , Christoff Kalina
Published: April 2020

Individuals use various strategies to cope with challenging emotions such as anxiety. Mindful acceptance involves broadening attentional scope and fully experiencing present moment sensory feelings (whether pleasant or unpleasant) without judgment or elaboration. In contrast, narrative-evaluation involves focusing on a narrow band of sensory experience and generating an elaborate narrative about the meaning and desirability of one’s emotional feelings. The current study examined brain network organization during these strategies using graph theoretic analyses. We used a naturalistic task paradigm in which participants reflected on an anxiety-provoking issue from their personal lives and adopted each strategy in different blocks. Compared to narrative-evaluation, mindful acceptance was associated with: (i) increased global network connectivity; (ii) greater integration of interoceptive regions (mid and posterior insula) into large-scale networks; (iii) reorganization of motivational circuits including a shift in the striatum’s network assignment from the default network to the salience network; and (iv) a shift from default network to frontoparietal control network (FPCN) regions as central hubs that coordinate information flow. Functional connectivity patterns within the left FPCN were associated with acceptance reports. Thus, broadening attentional scope during mindful acceptance is supported by a more globally interconnected neural landscape, as well as greater information flow through FPCN regions that underlie metacognitive awareness and cognitive control.
The quorum-sensing systems ofVibrio campbelliiDS40M4 and BB120 are genetically and functionally distinct
Authors: Simpson Chelsea A. , Petersen Blake D. , Haas Nicholas W. , Geyman Logan J. , Lee Aimee H. , Podicheti Ram , Pepin Robert , Brown Laura C. , Rusch Douglas B. , Manzella Michael P. , Papenfort Kai , van Kessel Julia C.
Published: April 2020

Vibrio campbelliiBB120 (previously classified asVibrio harveyi) is a fundamental model strain for studying quorum sensing in vibrios. A phylogenetic evaluation of sequencedVibriostrains in Genbank revealed that BB120 is closely related to the environmental isolateV. campbelliiDS40M4. We exploited DS40M4’s competence for exogenous DNA uptake to rapidly generate >30 isogenic strains with deletions of genes encoding BB120 quorum-sensing system homologs. Our results show that the quorum-sensing circuit of DS40M4 is distinct from BB120 in three ways: 1) DS40M4 does not produce an acyl homoserine lactone autoinducer but encodes an active orphan LuxN receptor, 2) the quorum regulatory small RNAs (Qrrs) are not solely regulated by autoinducer signaling through the response regulator LuxO, and 3) the DS40M4 quorum-sensing regulon is much smaller than BB120 (~100 genes vs ~400 genes, respectively). Using comparative genomics to expand our understanding of quorum-sensing circuit diversity, we observe that conservation of LuxM/LuxN proteins differs widely both between and withinVibriospecies. These strains are also phenotypically distinct: DS40M4 exhibits stronger interbacterial cell killing, whereas BB120 forms more robust biofilms and is bioluminescent. These results underscore the need to examine wild isolates for a broader view of bacterial diversity in the marine ecosystem.

Originality-Significance Statement

Wild bacterial isolates yield important information about traits that vary within species. Here, we compare environmental isolateVibrio campbelliiDS40M4 to its close relative, the model strain BB120 that has been a fundamental strain for studying quorum sensing for >30 years. We examine several phenotypes that define this species, including quorum sensing, bioluminescence, and biofilm formation. Importantly, DS40M4 is naturally transformable with exogenous DNA, which allows for the rapid generation of mutants in a laboratory setting. By exploiting natural transformation, we genetically dissected the functions of BB120 quorum-sensing system homologs in the DS40M4 strain, including two-component signaling systems, transcriptional regulators, and small RNAs.
The C-terminus is critical for the degradation of substrates by thePseudomonas aeruginosaCtpA protease
Authors: Chung Sammi , Darwin Andrew J.
Published: April 2020

Bacterial carboxyl-terminal processing proteases (CTPs) are widely conserved and have been linked to important processes including signal transduction, cell wall metabolism, and virulence. However, the features that target proteins for CTP-dependent cleavage are unclear. Studies of theEscherichia coliCTP Prc suggested that it cleaves proteins with non-polar and/or structurally unconstrained C-termini, but it is not clear if this applies broadly.Pseudomonas aeruginosahas a divergent CTP, CtpA, which is required for virulence. CtpA works in complex with the outer membrane lipoprotein LbcA to degrade cell wall hydrolases. Here, we investigated if the C-termini of two non-homologous CtpA substrates are important for their degradation. We determined that these substrates have extended C-termini, compared to their closestE. colihomologs. Removing seven amino acids from these extensions was sufficient to inhibit their degradation by CtpA bothin vivoandin vitro. Degradation of one truncated substrate was restored by adding the C-terminus from the other, but not by adding an unrelated sequence. However, modification of the C-terminus of non-substrates, by adding the C-terminal amino acids from a substrate, did not cause their degradation by CtpA. Therefore, the C-termini of CtpA substrates are required but not sufficient for degradation. Although C-terminal truncated substrates were not degraded, they still associated with the LbcA•CtpA complexin vivo. Therefore, degradation of a protein by CtpA requires a C-terminal-independent interaction with the LbcA•CtpA complex, followed by C-terminal-dependent degradation, perhaps because CtpA must initiate cleavage at a specific C-terminal site.

IMPORTANCE

Carboxyl-terminal processing proteases (CTPs) are found in all three domains of life, but exactly how they work is poorly understood, including how they recognize substrates. Bacterial CTPs have been associated with virulence, including CtpA ofPseudomonas aeruginosa, which works in complex with the outer membrane lipoprotein LbcA to degrade potentially dangerous peptidoglycan hydrolases. We report an important advance by revealing that degradation by CtpA requires at least two separable phenomena, and that one of them depends on information encoded in the substrate C-terminus. A C-terminal-independent association with the LbcA•CtpA complex is followed by C-terminal-dependent cleavage by CtpA. Increased understanding of how CTPs target proteins is significant, due to their links to virulence, peptidoglycan remodeling, and other important processes.