bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-effectiveness of paediatric influenza vaccination in the Netherlands
Authors: de Boer Pieter T. , Dolk Franklin C.K. , Nagy Lisa , Wilschut Jan C. , Pitman Richard , Postma Maarten J.
Published: March 2020

Background

This study evaluates the cost-effectiveness of extending the Dutch influenza vaccination programme for elderly and clinical risk groups to include paediatric influenza vaccination, taking indirect protection into account.

Methods

An age-structured dynamic transmission model was used that was calibrated to influenza-associated GP visits over four seasons (2010/11 to 2013/14). The clinical and economic impact of different paediatric vaccination strategies were compared over 20 years, varying the targeted age range, the vaccine type for children and the vaccine type for elderly and clinical risk groups. Outcome measures include averted symptomatic infections and deaths, societal costs and quality-adjusted life years (QALYs), incremental cost-effectiveness ratios, and net health benefits (NHBs), using a willingness-to-pay threshold of €20,000 per QALY gained.

Results

At an assumed coverage of 50%, adding vaccination of 2- to 17-year-olds with quadrivalent-live-attenuated influenza vaccine (Q-LAIV) to the current influenza vaccination programme was estimated to avert on average 406,270 symptomatic cases and 83 deaths per season compared to vaccination of elderly and risk groups with trivalent inactivated vaccine (TIV), and was cost-saving (cumulative 20-year savings of 36,396 QALYs and €1,680 million; NHB: 120,411 QALYs). This strategy dominated paediatric vaccination strategies targeting 2- to 6-year-olds or 2- to 12-year-olds, or paediatric vaccination strategies with TIV. The highest NHB was obtained when 2- to 17-year-olds were vaccinated with Q-LAIV and existing target groups switched from TIV to quadrivalent inactivated vaccine (NHB: 132,907 QALYs).

Conclusion

Modelling indicates that paediatric influenza vaccination reduces the disease burden of influenza substantially and is cost-saving.
Immunodepletion with Hypoxemia: A Potential High Risk Subtype of Coronavirus Disease 2019
Authors: Yu Lilei , Tong Yongqing , Shen Gaigai , Fu Aisi , Lai Yanqiu , Zhou Xiaoya , Yuan Yuan , Wang Yuhong , Pan Yuchen , Yu Zhiyao , Li Yan , Liu Tiangang , Jiang Hong
Published: March 2020

Background

The outbreak of COVID-2019 is becoming a global public health emergency. Although its basic clinical features have been reported, the dynamic characteristics of immune system in COVID-2019 patients, especially those critical patients with refractory hypoxemia, are not yet well understood. We aim to describe the dynamic characteristics of immune system in 3 critical patients with refractory hypoxemia, and discuss the relationship between hypoxemia severity and immune cell levels, and the changes of gut microbes of COVID-2019 patient.

Methods

This is a retrospective study from 3 patients with 2019-nCoV infection admitted to Renmin Hospital of Wuhan University, a COVID-2019 designated hospital in Wuhan, from January 31 to February 6, 2020. All patients were diagnosed and classified based on the Diagnosis and Treatment of New Coronavirus Pneumonia (6th edition) published by the National Health Commission of China4. We recorded the epidemiological history, demographic features, clinical characteristics, symptoms and signs, treatment and clinical outcome in detail. Blood samples were collected and we determined the expression levels of immune cells (CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD16+56+ NK cells) in different time points. Nanopore Targeted Sequencing was used to determine the alterations of gut microbiota homeostasis.

Results

Apart from the clinical features described previously4, we found that four patients had decreased immune cells and refractory hypoxemia during the hospitalization, and the severity of hypoxemia was strongly correlated to the expression levels of immune cells. Additionally, we found that the proportion of probiotics was significantly reduced, such as Bifidobacterium, Lactobacillus, and Eubacterium, and the proportion of conditioned pathogenic bacteria was significantly increased, such as Corynebacterium of Actinobacteria and Ruthenibacterium of Firmicutes. Notably, all patients died.

Conclusions

We discussed the dynamic characteristics of host immune system and the imbalance of gut microbiota in 3 critical patients with COVID-2019. Hypoxemia severity was closely related with host immune cell levels, and the vicious circle between immune disorder and gut microbiota imbalance may be a high risk of fatal pneumonia. To the best of our knowledge, this is the first study which revealing that immunodepletion with refractory hypoxemia is a potential high risk subtype of COVID-2019 and the vicious circle between immune disorder and gut dysbiosis may be a high risk of fatal pneumonia.
Associations betweenCYP3A4, CYP3A5andSCN1APolymorphisms and Carbamazepine Metabolism in Epilepsy: A Meta-analysis
Authors: Zhao Gui-Xin , Zhang Zheng , Cai Wen-Ke , Shen Ming-Li , Wang Ping , He Gong-Hao
Published: March 2020

Background and objective

CYP3A4(rs2242480),CYP3A5(rs776746) andSCN1A(rs3812718 and rs2298771) gene polymorphisms were previously indicated to be associated with carbamazepine (CBZ) metabolism and resistance in epilepsy. However, previous studies regarding the effects of these polymorphisms still remain controversial. Therefore, we performed a meta-analysis to evaluate whether the four polymorphisms are associated with CBZ metabolism and resistance.

Methods

The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc and Wan fang Database were searched up to January 2020 for appropriate studies regarding the association of rs2242480, rs776746, rs3812718 and rs2234922 polymorphisms with metabolism and resistance to CBZ. The meta-analysis was conducted by Review Manager 5.3 software.

Results

Eighteen studies involving 2574 related epilepsy patients were included. Significant associations betweenCYP3A4rs2242480,CYP3A5rs776746 andSCN1Ars3812718 polymorphisms and plasma concentrations of CBZ were observed. Additionally,SCN1Ars3812718 polymorphism was significantly associated with CBZ resistance. However, no association was observed betweenSCN1Ars2298771 polymorphism and metabolism and resistance to CBZ.

Conclusion

TheCYP3A4rs2242480,CYP3A5rs776746 andSCN1Ars3812718 polymorphisms may play important roles in metabolism and resistance to CBZ, whileSCN1Ars2298771 polymorphism is not associated with CBZ in epilepsy. These findings would improve the individualized therapy of epileptic patients in clinics.
Acoustofluidic Assembly of 3D Neurospheroids to Model Alzheimer’s Disease
Authors: Cai Hongwei , Ao Zheng , Hu Liya , Moon Younghye , Wu Zhuhao , Lu Hui-Chen , Kim Jungsu , Guo Feng
Published: March 2020

Neuroinflammation plays a central role in the progression of many neurodegenerative diseases such as Alzheimer’s disease, and challenges remain in modeling the complex pathological or physiological processes. Here, we report an acoustofluidic 3D cell culture device that can rapidly construct 3D neurospheroids and inflammatory microenvironments for modeling microglia-mediated neuroinflammation in Alzheimer’s disease. By incorporating a unique contactless and label-free acoustic assembly, this cell culture platform can assemble dissociated embryonic mouse brain cells into hundreds of uniform 3D neurospheroids with controlled cell numbers, composition (e.g. neurons, astrocytes, and microglia), and environmental components (e.g. amyloid-β aggregates) in hydrogel within minutes. Moreover, this platform can maintain and monitor the interaction among neurons, astrocytes, microglia, and amyloid-β aggregates in real-time for several days to weeks, after the integration of a high-throughput, time-lapse cell imaging approach. We demonstrated that our engineered 3D neurospheroids can represent the amyloid-β neurotoxicity, which is one of the main pathological features of Alzheimer’s disease. Using this method, we also investigated the microglia migratory behaviors and activation in the engineered 3D inflammatory microenvironment at a high throughput manner, which is not easy to achieve in 2D neuronal cultures or animal models. Along with the simple fabrication and setup, the acoustofluidic technology is compatible with conventional Petri dishes and well-plates, supports the fine-tuning of the cellular and environmental components of 3D neurospheroids, and enables the high-throughput cellular interaction investigation. We believe our technology may be widely used as in vitro brain models for modeling neurodegenerative diseases, discovering new drugs, and testing neurotoxicity.
Low expression of ANT1 confers oncogenic properties to rhabdomyosarcoma tumor cells via modulating metabolism and death pathways
Authors: Vial J , Huchedé P , Fagault S , Basset F , Rossi M , Geoffray J , Bisaccia J , Creveaux M , Neves D , Fauvelle F , Castets P , Carré M , Weber K , Castets M
Published: March 2020

Rhabdomyosarcoma (RMS) is the most frequent form of pediatric soft-tissue sarcoma. It is divided into 2 main subtypes: ERMS (embryonal) and ARMS (alveolar). Current treatments are based on chemotherapy, surgery and radiotherapy. 5-year survival rate remains of 70% since 2000, despite several clinical trials.

RMS cells are thought to derive from muscle lineage precursors. During development, myogenesis is characterized by primary expansion of myoblasts, elimination of those in excess by cell death and the differentiation of the remaining ones into myotubes and myofibers. The idea that these processes could be hijacked by tumor cells to sustain their oncogenic transformation has emerged, while RMS is being considered as the Mister Hyde’s side of myogenesis. Thus, focusing on myogenic developmental programs could help understanding RMS molecular aetiology.

Following this idea, we decided to concentrate on ANT1, which is involved in myogenesis and is the underlying cause of genetic disorders associated with muscle degeneration. ANT1 is a mitochondrial protein, which has a functional duality, as it is involved both in metabolism via regulation of ATP/ADP release from mitochondria, but also in apoptosis as part as the mitochondria Permeability Transition Pore (mPTP). By bioinformatic analysis of transcriptomic datasets, we observed that ANT1 is expressed at low levels in RMS. Using CRISPR-Cas9 technology, we showed that decreased ANT1 expression confers selective advantages to RMS cells in terms of proliferation and resistance to stress-induced death. These effects result notably from a metabolic switch. Restoration of ANT1 expression using a Tet-On system is sufficient to prime tumor cells to death and to increase their sensitivity to chemotherapies. Thus, modulation of ANT1 activity could appear as an appealing therapeutic approach in RMS management.
AnIn VitroVascularized Micro-Tumor Model of Human Colorectal Cancer RecapitulatesIn VivoDrug Responses
Authors: Hachey Stephanie J. , Movsesyan Silva , Nguyen Quy H. , Burton-Sojo Giselle , Tankanzyan Ani , Wu Jie , Hoang Tuyen , Hatch Michaela M. , Zhao Da , Celaya Elizabeth , Gomez Samantha , Chen George T. , Davis Ryan T. , Nee Kevin , Pervolarakis Nicholas , Lawson Devon A. , Kessenbrock Kai , Lee Abraham P. , Waterman Marian L. , Hughes Christopher C.W.
Published: March 2020

Around 95% of anti-cancer drugs that show promise during preclinical study fail to gain FDA-approval for clinical use. This failure of the preclinical pipeline highlights the need for improved, physiologically-relevantin vitromodels that can better serve as reliable drug-screening tools. The vascularized micro-tumor (VMT) is a novel three-dimensional model system that recapitulates the complex human tumor microenvironment, including perfused vasculature, within a transparent microfluidic device, allowing real-time study of drug responses and tumor-stromal interactions. Here we have validated the VMT platform for the study of colorectal cancer (CRC), the second leading cause of cancer-related deaths, by showing that gene expression, tumor heterogeneity, and treatment response in the VMT more closely model CRC tumor clinicopathology than current standard drug screening modalities, including 2-dimensional (2D) monolayer culture and 3-dimensional (3D) spheroids.
Simulating future rewards: exploring the impacts of implicit context association and arithmetic booster in delay discounting
Authors: Hwang Minho , Kim Sung-Phil , Chung Dongil
Published: March 2020

People have higher preference for immediate over delayed rewards, and it is suggested that such an impulsive tendency is governed by one’s ability to simulate future rewards. Consistent with this view, recent studies have shown that enforcing individuals to focus on episodic future thoughts reduces their impulsivity. Inspired by these successful reports, we hypothesized that administration of a simple cognitive task which is linked with future thinking might also function as an effective tool for modulating individuals’ preference for immediate (or delayed) rewards. Specifically, we used one associative memory task and one working memory task that each of which was administered to intervene acquired amount of information and individuals’ ability to construct a coherent future event, respectively. Among the set of cognitive tasks, we found that only the arithmetic working memory task had a significant effect of reducing individuals’ impulsivity. However, in our follow-up experiment, this result was not replicated. Across these two independent experiments, we observed a significant main effect of repetition in individuals’ impulsivity measure, such that participants showed more patient choices at the second compared to the first assessment task. In conclusion, there was no clear evidence supporting that our suggested intervention tasks effectively reduce individuals’ impulsivity, while the current results call attention to the importance of taking into account task repetition effects in studying the impacts of cognitive training and intervention.
Why the middle ear piston prosthesis is not effective enough and how to change it?
Authors: Gambin Wiktor L.
Published: March 2020

Piston prostheses of the middle ear do not ensure sufficient audibility of high and low sounds. To find out the reason, the amplitudes of the vibrations for the stapes footplate and the piston end were compared. It was seen that for a given force that oscillates with a low frequency, the amplitude of the piston end was higher than the amplitude of the stapes footplate. This means that the stiffness of the tissue sealing up the piston in the footplate hole is lower than the stiffness of the stapes plate suspension. It was shown that as a result, for the case of the higher frequencies, the amplitude of the piston vibrations drops several times. Next, it was compared a sound propagation in the healthy ear with that in the ear after the stapedotomy. To do it, a previously prepared model of sound propagation in the ear was used. The model is simplified, but it gives all parameters of the sound wave in the cochlear fluid. According to it, a motion of the stapes footplate forms a plane wave, while the piston motion initially gives a wave similar to the spherical one. A part of the spherical wave with the front directed towards the apex forms the primary wave running in the cochlea. However, the rest of this wave has the front directed towards the stapes footplate. This wave part, after a reflection from the stapes footplate, creates a secondary wave that follows the primary wave. A splitting of the wavefront around the edge of the piston end is a source of disruptions in the sound perception. The shift of the secondary wave reduces the power of the primary wave; it disturbs the waving of the basilar membrane and may cause extra noise. To justify it, a graph of the level of the cochlear amplification for the ear with the piston prosthesis was shown. The result compared with a simulation for the healthy ear gave the values 5 dB lower. To remove these drawbacks, it was proposed to place the piston end, not inside the cochlea, but in a guide in the form of a tube ended with a funnel fixed in the hole made in the stapes footplate. The piston was suspended in a guide tube on an O-ring formed of silicone gel. It was shown that when the piston is in the guide, the level of cochlear amplification was the same as that in the healthy ear. Some design details of the new piston guide are given. It enables us to make the new piston prosthesis easily and put it into practice.
Effect of interglomerular inhibitory networks on olfactory bulb odor representations
Authors: Zavitz Daniel , Youngstrom Isaac A. , Borisyuk Alla , Wachowiak Matt
Published: March 2020

Lateral inhibition is a fundamental feature of circuits that process sensory information. In the mammalian olfactory system, inhibitory interneurons called short axon cells comprise the first network mediating lateral inhibition between glomeruli, the functional units of early olfactory coding and processing. The connectivity of this network and its impact on odor representations is not well understood. To explore this question, we constructed a computational model of the interglomerular inhibitory network using detailed characterizations of short axon cell morphologies taken from mouse olfactory bulb. We then examined how this network transformed glomerular patterns of odorant-evoked sensory input (taken from previously-published datasets) as a function of the selectivity of interglomerular inhibition. We examined three connectivity schemes: selective (each glomerulus connects to few others with heterogeneous strength), nonselective (glomeruli connect to most others with heterogenous strength) or global (glomeruli connect to all others with equal strength). We found that both selective and nonselective interglomerular networks could mediate heterogeneous patterns of inhibition across glomeruli when driven by realistic sensory input patterns, but that global inhibitory networks were unable to produce input-output transformations that matched experimental data and were poor mediators of intensity-dependent gain control. We further found that networks whose interglomerular connectivity was tuned by sensory input profile decorrelated odor representations more effectively. These results suggest that, despite their multiglomerular innervation patterns, short axon cells are capable of mediating odorant-specific patterns of inhibition between glomeruli that could, theoretically, be tuned by experience or evolution to optimize discrimination of particular odorants.

Significance Statement

Lateral inhibition is a key feature of circuitry in many sensory systems including vision, audition, and olfaction. We investigate how lateral inhibitory networks mediated by short axon cells in the mouse olfactory bulb might shape odor representations as a function of their interglomerular connectivity. Using a computational model of interglomerular connectivity derived from experimental data, we find that short axon cell networks, despite their broad innervation patterns, can mediate heterogeneous patterns of inhibition across glomeruli, and that the canonical model of global inhibition does not generate experimentally observed responses to stimuli. In addition, inhibitory connections tuned by input statistics yield enhanced decorrelation of similar input patterns. These results elucidate how the organization of inhibition between neural elements may affect computations.
CrudeNecator americanusworm extract diminishes pancreatic islets destruction in diabetic non-obese mice (NOD)
Authors: Velikkakam Teresiama , de Araujo Bruna Garzedim , Alves Érica Alessandra Rocha , Fujiwara Ricardo Toshio , Bueno Lilian Lacerda , Fiuza Jacqueline Araújo , Gaze Soraya
Published: March 2020

Hygiene hypothesis dictates that the lack of microbial interaction during the first childhood increases the chance of developing autoimmune diseases due to not proper immune system maturation. Helminthes are known by their Th2 and modulatory immune response induction. Here, it was evaluated the influence ofNecator americanusantigens during type 1 experimental mouse model (non-obese diabetic – NOD). Intraperitoneal injections for 18 weeks did not impair an inflammatory response, but induced a mixed Th1/Th2 response with presence of IL4 and IL10 from different sources. However, the induced immune response was not sufficient to decrease glucose levels but showed a change in the inflammatory infiltrate in the pancreas. It is necessary more refined studies to clarify the mechanisms of howNecator americanuscould impair diabetes progression in mice.
Do human recordings reveal drastic modulations in the discharge of striatal projection neurons in Parkinson’s disease?
Authors: Valsky Dan , Israel Zvi , Boraud Thomas , Bergman Hagai , Deffains Marc
Published: March 2020

Dopamine depletion of the striatum plays a key role in the pathophysiology of Parkinson’s disease (PD), but our understanding of the changes in the discharge rate and pattern of the striatal projection neurons (SPNs) remains limited. Here, we recorded multi-unit signals from the striatum of PD (N = 934) and dystonic (N = 718) patients undergoing deep brain stimulation surgeries. Using an innovative automated data-driven approach to classify striatal units, we showed that the SPN discharge rate is inversely proportional to the isolation quality and stationarity of the SPNs. In contrast to earlier studies in both PD patients and the non-human primate model of PD, we found no drastic changes in the spiking activity (discharge rate and pattern) of the well-isolated and stationary SPNs of PD patients compared to either dystonic patients or the normal levels of striatal activity reported in healthy animals. Moreover, cluster analysis using SPN discharge properties did not characterize two well-separated SPN subpopulations. There was therefore no specific SPN subpopulation (D1 or D2 SPNs) strongly affected by the pathological state. Instead, our results suggest that moderate changes in SPN discharge are most likely amplified by basal ganglia downstream structures, thus leading to the clinical (motor and non-motor) symptoms of PD.

Significance statement

In Parkinson’s disease (PD), the loss of the midbrain dopaminergic neurons leads to massive striatal dopamine depletion that provokes abnormal activity throughout the basal ganglia. However, the impact of dopamine depletion on neuronal activity in the striatum is still highly debated. We recorded and examined the neuronal activity in striatum of PD and dystonic patients undergoing deep brain stimulation surgeries. We found that striatal activity was not drastically higher in PD patients compared to either dystonic patients or the normal levels of striatal activity reported in animal studies. In PD, moderate changes in striatal basal activity are therefore most likely amplified by basal ganglia downstream structures.
Post-perturbational transcriptional signatures of cancer cell line vulnerabilities
Authors: Jones Andrew , Tsherniak Aviad , McFarland James M.
Published: March 2020

While chemical and genetic viability screens in cancer cell lines have identified many promising cancer vulnerabilities, simple univariate readouts of cell proliferation fail to capture the complex cellular responses to perturbations. Complementarily, gene expression profiling offers an information-rich measure of cell state that can provide a more detailed account of cellular responses to perturbations. Relatively little is known, however, about the relationship between transcriptional responses to per-turbations and the long-term cell viability effects of those perturbations. To address this question, we integrated thousands of post-perturbational transcriptional profiles from the Connectivity Map with large-scale screens of cancer cell lines’ viability response to genetic and chemical perturbations. This analysis revealed a generalized transcriptional signature associated with reduced viability across perturbations, which was consistent across post-perturbation time-points, perturbation types, and viability datasets. At a more granular level, we lay out the landscape of treatment-specific expression-viability relationships across a broad panel of drugs and genetic reagents, and we demonstrate that these post-perturbational expression signatures can be used to infer long-term viability. Together, these results help unmask the transcriptional changes that are associated with perturbation-induced viability loss in cancer cell lines.
A highly scalable method for joint whole genome sequencing and gene expression profiling of single cells
Authors: Zachariadis Vasilios , Cheng Huaitao , Andrews Nathanael J , Enge Martin
Published: March 2020

Understanding how genetic variation alters gene expression - how genotype affects phenotype - is a central challenge in biology. To address this question in complex cell mixtures, we developed Direct Nuclear Tagmentation and RNA-sequencing (DNTR-seq), which enables whole genome and mRNA sequencing jointly in single cells. When applied to biobanked leukemia samples, DNTR-seq readily identified minor subclones within patients, as well as cell-type specific gene editing such as T-cell receptor rearrangements. mRNA-seq quality is equal to RNA-only methods, and the high yield combined with low positional bias of the genomic library preparation allows detection of sub-megabase aberrations at ultra low coverage of 0.5-3M read pairs per genome. Since each cell library is individually addressable, rare subpopulations can be re-sequenced at increased depth, allowing multi-tiered study designs where depth of sequencing is informed by previous results. In addition, the direct tagmentation protocol enables coverage-independent estimation of ploidy, which can be used to unambiguously identify cell singlets. Thus, DNTR-seq directly links each cell’s state to its corresponding genome at a scale enabling routine analysis of heterogeneous tumors and other complex tissues.
Within-Family Validation of Polygenic Risk Scores and Complex Trait Prediction
Authors: Lello Louis , Raben Timothy G. , Hsu Stephen D.H.
Published: March 2020

We test a variety of polygenic predictors using tens of thousands of genetic siblings for whom we have SNP genotypes, health status, and phenotype information in late adulthood. Siblings have typically experienced similar environments during childhood, and exhibit negligible population stratification relative to each other. Therefore, the ability to predict differences in disease risk or complex trait values between siblings is a strong test of genomic prediction in humans. We compare validation results obtained using non-sibling subjects to those obtained among siblings and find that typically most of the predictive power persists in within-family designs. In the case of disease risk we test the extent to which higher polygenic risk score (PRS) identifies the affected sibling, and also compute Relative Risk Reduction as a function of risk score threshold. For quantitative traits we examine between-sibling differences in trait values as a function of predicted differences, and compare to performance in non-sibling pairs. Example results: Given 1 sibling with normal-range PRS score (<84 percentile) and 1 sibling with high PRS score (top few percentiles), the predictors identify the affected sibling about 70-90% of the time across a variety of disease conditions, including Breast Cancer, Heart Attack, Diabetes, etc. For height, the predictor correctly identifies the taller sibling roughly 80 percent of the time when the (male) height difference is 2 inches or more.
Analyzing and interpreting DNA double-strand break sequencing data
Authors: Mitra Abhishek , Dojer Norbert , Fongang Bernard , Nde Jules , Zhu Yingjie , Rowicka Maga
Published: March 2020

DNA double-strand breaks (DSBs), are a major threat to genomic stability and may lead to cancer. Several technologies to accurately detect DSBs genome-wide have been developed recently, but still lacking publicly available tools for analysis of the resulting data. Here, we present a step-by-step iSeq package (http://breakome.utmb.edu/software.html), custom designed for analysis and interpretation of DSB-sequencing data. iSeq performs barcode trimming and read counting, and identifies DSB-enriched regions by statistical test and annotate them to the desired genomic features. Applying this package, users can identify and annotate DSB-enriched regions from base pair (eg. Cas9 cleavage sites) up to megabase (eg. DNA replication stress-induced) resolution, and if possible quantify DSB frequencies per cell genome-wide by combining with qDSB-Seq. iSeq can be used for any sequencing-based DSB detection techniques. The analysis for Steps 1-19 can be performed within ~4 hours.
The gliopeptide ODN, a ligand for the benzodiazepine site of GABAAreceptors, boosts functional recovery after stroke
Authors: Lamtahri Rhita , Hazime Mahmoud , Gowing Emma K , Nagaraja Raghavendra Y. , Maucotel Julie , Alasoadura Michael , Quilichini Pascale , Lehongre Katia , Lefranc Benjamin , Gach-Janczak Katarzyna , Marcher Ann-Britt , Mandrup Susanne , Vaudry David , Clarkson Andrew N. , Leprince Jérôme , Chuquet Julien
Published: March 2020

Following stroke, the survival of neurons and their ability to re-establish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABAAreceptors (GABAAR). Conversely, in the late phase, negative allosteric modulation of GABAAR can correct the sub-optimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABAAR synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which make it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in two different paradigms of experimental stroke in mice. Furthermore, we bring evidence that during the sub-acute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity.

SIGNIFICANCE STATEMENT

Stroke remains a devastating clinical challenge because there is no efficient therapy to either minimize neuronal death with neuroprotective drugs or to enhance spontaneous recovery with neurorepair drugs. Around the brain damage, the peri-infarct cortex can be viewed as a reservoir of plasticity. However, the potential of wiring new circuits in these areas is restrained by a chronic excess of GABAergic inhibition. Here we show that an astrocyte-derived peptide (ODN), can be used as a delayed treatment, to safely correct cortical excitability and facilitate sensorimotor recovery after stroke.
Identification of potential biomarkers associated with pathogenesis of primary prostate cancer based on meta-analysis approaches
Authors: Sepahi Neda , Piran Mehrdad , Piran Mehran , Ghanbariasad Ali
Published: March 2020

Worldwide prostate cancer (PCa) is recognized as the second most common diagnosed cancer and the fifth leading cause of cancer death among men globally. Rising incidence rates of PCa have been observed over the last few decades. It is necessary to improve prostate cancer detection, diagnosis, treatment and survival. However, there are few reliable biomarkers for early prostate cancer diagnosis and prognosis. In the current study, systems biology method was applied for transcriptomic data analysis to identify potential biomarkers for primary PCa. We firstly identified differentially expressed genes (DEGs) between primary PCa and normal samples. Then the DEGs were mapped in Wikipathways and gene ontology database to conduct functional categories enrichment analysis. 1575 unique DEGs with adjusted p-value < 0.05 were achieved from two sets of DEGs. 132 common DEGs between two sets of DEGs were retrieved. The final DEGs were selected from 60 common upregulated and 72 common downregulated genes between datasets. In conclusion, we demonstrated some potential biomarkers (FOXA1, AGR2, EPCAM, CLDN3, ERBB3, GDF15, FHL1, NPY, DPP4, and GADD45A) and HIST2H2BE as a candidate one which are tightly correlated with the pathogenesis of PCa.
Targeted Esterase induced Dye loading supports Calcium Imaging in Eukaryotic Cell-Free Systems
Authors: Dhandapani Priyavathi , Dondapati Srujan Kumar , Zemella Anne , Bräuer Dennis , Wüstenhagen Doreen Anja , Kubick Stefan
Published: March 2020

Calcium imaging is an important functional tool for addressing ion channels, transporters and pumps for drug screening in living cells. Depicted eukaryotic cell-free systems utilize microsomes, derived from endoplasmic reticulum to incorporate the synthesized membrane proteins. Absence or inadequate amount of carboxylesterase in the endoplasmic reticulum of eukaryotic cells, which is necessary to cleave the acetoxymethyl ester moiety of the chemical calcium indicators, advocates the hindrance to perform calcium imaging in microsomes. In this work, we try to overcome this drawback and adapt the cell-based calcium imaging principle to a cell-free protein synthesis platform. Carboxylesterase synthesized in a Spodoptera frugiperda Sf21 lysate translation system is established as a viable calcium imaging tool and hTRPV1 is used as a model channel protein to demonstrate the realization of this concept.
Prolonged deficit of gamma oscillations in the peri-infarct cortex of mice after stroke
Authors: Hazime M , Alasoadura M , Lamtahri R , Quilichini P , Leprince J , Vaudry D , Chuquet J
Published: March 2020

Days and weeks after an ischemic stroke, the peri-infarct area adjacent to the necrotic tissue exhibits very intense synaptic reorganization aimed at regaining lost functions. In order to enhance functional recovery, it is important to understand the mechanisms supporting neural repair and neuroplasticity in the cortex surrounding the lesion. Brain oscillations of the local field potential (LFP) are rhythmic fluctuations of neuronal excitability aimed at synchronizing neuronal activity to organize information processing and plasticity. Although the oscillatory activity of the brain has been probed after stroke in both animals and humans using electroencephalography (EEG), the latter is ineffective to precisely map the oscillatory changes in the peri-infarct zone where synaptic plasticity potential is high. Here, we worked on the hypothesis that brain oscillatory system is altered in the surviving peri-infarct cortex, which may slow down functional repair and reduce the capacity to recovery. In order to document the relevance of this hypothesis, oscillatory power was measured at various distances from the necrotic core at 7 and 21 days after a permanent cortical ischemia induced in mice. Delta and theta oscillations remained at a normal power in the peri-infarct cortex, in contrast to gamma oscillations that displayed a rapid decrease, the closer we get to the lesion core. A broadband increase of power was also observed in the homotopic contralateral sites. Thus, the proximal peri-infarct cortex could become a target of therapeutic interventions aimed at correcting the oscillatory regimen. These results argue for the usefulness of therapeutic intervention aimed at boosting gamma oscillations in order to improve post-stroke functional recovery.
Evolutionary dynamics of transposable elements following a shared polyploidization event in the tribe Andropogoneae
Authors: Ramachandran Dhanushya , McKain Michael R. , Kellogg Elizabeth A. , Hawkins Jennifer S.
Published: March 2020

Both polyploidization and transposable element (TE) activity are known to be major drivers of plant genome evolution. Here, we utilize theZea-Tripsacumclade to investigate TE activity and accumulation after a recent shared polyploidization event. Comparisons of TE evolutionary dynamics in variousZeaandTripsacumspecies, in addition to two closely related diploid species,Urelytrum digitatumandSorghum bicolor, revealed existing variation in repeat content among all taxa included in the study. The repeat composition ofUrelytrumis more similar to that ofZeaandTripsacumcompared toSorghum, despite the similarity in genome size with the latter. Although the genomes of all species studied had abundant LTR-retrotransposons, we observed an expansion of thecopiasuperfamily, specifically inZ. maysandT. dactyloides, species that have adapted to more temperate environments. Additional analyses of the genomic distribution of thesecopiaelements provided evidence of biased insertions near genes involved in various biological processes including plant development, defense, and macromolecule biosynthesis. The lack ofcopiainsertions near the orthologous genes inS. bicolorsuggests that duplicate gene copies generated during polyploidization may offer novel neutral sites for TEs to insert, thereby providing an avenue for subfunctionalization via TE insertional mutagenesis.
Mechanism of BceAB-type transporter: Resistance by lipid II flipping
Authors: Zaschke-Kriesche Julia , Unsleber Sandra , Voitsekhovskaia Irina , Kulik Andreas , Behrmann Lara V. , Overbeck Nina , Stühler Kai , Stegmann Evi , Smits Sander H.J.
Published: March 2020

Treatment of bacterial infections are the great challenge of our era due to the evolved resistance mechanisms against antibiotics. The Achilles heel of bacteria is the cell wall especially during the needs of its synthesis and cell division. Here lipid II is an essential cell wall precursor component synthesized in the cytosol and flipped into the outer leaflet of the membrane prior to its incorporation into the cell wall.

Compounds targeting the cell wall or its biosynthesis precursors have been around for decades and have been used as antibiotics against bacterial infections like meningitis, pneumonia and endocarditis. Antimicrobial peptides (AMPs) have proven to be a promising weapon against multiresistant bacteria. However, theBacitracinefflux (BceAB)-type ATP binding cassette transporters expressed in the membrane of human pathogenic bacteria have been shown to confer resistance to these alternative antibiotics, thereby hampering their medical development.

InStreptococcus agalactiaeCOH1 the BceAB-type transporter NsrFP (SaNsrFP) confers high-level resistance against the antimicrobial peptide nisin, a member of the lantibiotic subfamily. We showed thatSaNsrFP provides a novel resistance mechanism by flipping lipid II back into the cytosol, thereby preventing the binding of nisin as well as other lipid II targeting compounds. This is intriguing since a relatively simple reaction mediates resistance to human pathogenic bacteria to lipid II targeting antibiotics, regardless of their structure.

Significance Statement

The ABC-transporter NsrFP fromStreptococcus agalactiae(SaNsrFP) belongs to the BceAB-type transporters. Several BceAB-type transporters are known to confer resistance against multiple antimicrobial peptides. In this study a new resistance mechanism was identified, which is based on the reduction of the number of cell wall precursor lipid II molecules on the cell surface mediated bySaNsrFP.SaNsrFP flips lipid II, which are considered to be the target for many antibiotics, back into the cytoplasm. With this newly gained knowledge about the resistance mechanism of BceAB-type transporters, novel strategies can be established to overcome or bypass this resistance in human pathogenic bacteria.
Differential roles of pyramidal and fast-spiking, GABAergic neurons in the control of glioma cell proliferation
Authors: Tantillo Elena , Vannini Eleonora , Cerri Chiara , Spalletti Cristina , Colistra Antonella , Mazzanti Chiara Maria , Costa Mario , Caleo Matteo
Published: March 2020

Recent studies have demonstrated an active role for neurons in glioma progression. Specifically, peritumoral neurons establish functional excitatory synapses with glioma cells, and optogenetic stimulation of cortical pyramidal neurons drives tumor progression. However, the specific role of different subsets of cortical neurons, such as GABAergic interneurons, remains unexplored. Here, we directly compared the effects of optogenetic stimulation of pyramidal cells vs. fast-spiking, GABAergic neurons. In mice inoculated with GL261 cells into the motor cortex, we show that optogenetic stimulation of pyramidal neurons enhances glioma cell proliferation. In contrast, optogenetic stimulation of fast-spiking, parvalbumin-positive interneurons reduces proliferation as measured by BrdU incorporation and Ki67 immunolabelling. Since both principal cells and fast-spiking interneurons are directly activated by sensory afferent input, we next placed tumors in the occipital cortex to test the impact of visual stimulation/deprivation. We report that total lack of visual input via dark rearing enhances the density of proliferating glioma cells, while daily visual stimulation by gratings of different spatial frequencies and contrast reduces tumor growth. The effects of sensory input are region-specific, as visual deprivation has no significant effect on tumor proliferation in mice with gliomas in the motor cortex. We also report that sensory stimulation combined with temozolomide administration delays the loss of visual responses in peritumoral neurons. Altogether, these data demonstrate complex effects of different neuronal subtypes in the control of glioma proliferation.

Highlights

Activity of GABAergic neurons reduces glioma cell proliferation

Levels of sensory afferent input regulate tumor proliferation

Effects of sensory input are region-specific
A porcine bimicrobial abscess model for testing interventional treatments
Authors: Wang Yak-Nam , Brayman Andrew A. , Chan Keith T. , Richmond Keith , Monsky Wayne L. , Matula Thomas J.
Published: March 2020

Background

Abscess formation is a host defense mechanism to contain the spread of infection. Abscesses can affect any part of the body and are commonsequelaeto complications of trauma, surgery, systemic infections and other disease states. Most models for abscesses are in small animals. Pursuant to the goal of developing more advanced treatments for abscesses, we sought to develop a large animal model which would reasonably mimic a fluid-filled human abscess.

Methods

Domestic swine were inoculated with a bimicrobial mixture ofBacteroides fragilis(B. fragilis) andEscherichia coli(E. coli) supplemented with an irritant (dextran). Inoculations were performed under ultrasound guidance in the muscle, subcutaneously or intradermally within the same animal. Fourteen days after inoculation, lesions were imaged with ultrasound, resected and prepared for histological evaluation.

Results

Injection of bimicrobial (aerobic and anaerobic) bacterial mixtures at multiple sites in a pig produced multiple lesions with histological features similar to encapsulated and multiloculated/multichamber abscesses often observed clinically in humans. Important salient features include the formation of a connective tissue capsule surrounding histologically nearly amorphous pus.

Conclusions

This paper provides the first description of a pig model for multiloculated abscesses. This animal model could potentially enable the evaluation of new technologies to replace or augment the current standard of care (image-guided percutaneous abscess drainage with antibiotics).
Functional delineation of tissue-resident CD8+T cell heterogeneity during infection and cancer
Authors: Milner J. Justin , Toma Clara , He Zhaoren , Kurd Nadia S. , Nguyen Quynh P. , McDonald Bryan , Quezada Lauren , Widjaja Christella E. , Witherden Deborah A. , Crowl John T. , Yeo Gene W. , Chang John T. , Omilusik Kyla D. , Goldrath Ananda W.
Published: March 2020

Unremitting defense against diverse pathogens and malignancies requires a dynamic and durable immune response. Tissue-resident memory CD8+T cells (Trm) afford robust protection against infection and cancer progression through continuous surveillance of non-lymphoid tissues. Here, we provide insight into how Trmconfer potent and persistent immunity through partitioning of distinct cellular subsets differing in longevity, effector function, and multipotency. Antigen-specific CD8+T cells localized to the epithelium of the small intestine are primarily comprised of a shorter-lived effector population most prominent early following both acute viral and bacterial infections, and a longer-lived Id3hiTrmpopulation that subsequently accumulates at later memory timepoints. We define regulatory gene-programs driving these distinct Trmstates, and further clarify roles for Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal Trmheterogeneity during infection. Further, through single-cell RNAseq analysis we demonstrate that tumor-infiltrating lymphocytes broadly differentiate into discrete populations of short-lived and long-lived Trm-like subsets, which share qualities with terminally-exhausted and progenitor-exhausted cells, respectively. As the clinical relevance of Trmcontinues to widen from acute infections to settings of chronic inflammation and malignancy, clarification of the spectrum of phenotypic and functional states exhibited by CD8+T cells that reside in non-lymphoid tissues will provide a framework for understanding their regulation and identity in diverse pathophysiological contexts.
Innate immune signalling drives loser cell elimination during stem cell competition in theDrosophilatestis
Authors: Hof-Michel Silvana , Cigoja Ljubinka , Huhn Sabina , Bökel Christian
Published: March 2020

In theDrosophilatestis, a group of stromal cells termed hub provides multiple niche signals for the surrounding germline and somatic stem cells. Stem cells of both populations compete for physical retention in the niche, and stem cell clones unable to transduce any one niche signal are rapidly eliminated by differentiation. We have recently mapped the transcriptomes of isolated somatic cyst stem cells and differentiated cyst cells, and found that the stem cells but not their differentiated progeny activate an immune response involving the NF-κB transcription factor Relish (Rel).

Here we show i) that Rel activation is not required for stemness but occurs physiologically in “losers” of stem cell competition, ii) that loss of Rel or the upstream receptor Toll suppresses loser elimination irrespective of how loser fate was induced, and iii) that clonal Rel activation is sufficient for the displacent of neutral or winner cells from the niche, even if the winners otherwise retain stem cell properties.

This generalized mechanism for the elimination of “loser” stem cells may mask the compound nature of stem cell behaviour, and instead generate the impression of a binary cell fate decision between stemness and differentiation.
Extravagant leaf display in Actinidia kolomikta attracting pollinators and maintaining photosynthetic capacity
Authors: Wang Zhen-Xing , Zhang Zishan , Li Chen , Sun Dan , Jiang Chuang-Dao , Ai Jun
Published: March 2020

The authors have withdrawn their manuscript whilst they perform additional experiments to test some of their conclusions further. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.