bluuebunny/crossref_metadata_2025 huggingface dataset:
Chaperone-mediated stress-sensing inMycobacterium tuberculosisenables fast activation and sustained response
Authors: Rao Satyajit D. , Datta Pratik , Gennaro Maria Laura , Igoshin Oleg A.
Published: June 2020

Dynamical properties of gene-regulatory networks are tuned to ensure bacterial survival. In mycobacteria, MprAB-σEnetwork responds to the presence of stressors, such as surfactants causing surface stress. Positive feedback loops in this network were previously predicted to cause hysteresis, i.e. different responses to identical stressor levels for pre-stressed and unstressed cells. Here we show that hysteresis does not occur in non-pathogenicMycobacterium smegmatisbut occurs inMycobacterium tuberculosis. However, the observed rapid temporal response inM. tuberculosisis inconsistent with the model predictions. To reconcile these observations, we implement a recently proposed mechanism for stress-sensing: the release of MprB from the inhibitory complex with chaperone DnaK upon the stress exposure. Using modeling and parameter fitting, we demonstrate that this mechanism can accurately describe the experimental observations. Furthermore, we predict perturbations in DnaK expression that can strongly affect dynamical properties. Experiments with these perturbations agree with model predictions, confirming the role of DnaK in fast and sustained response.

IMPORTANCE

Gene-regulatory networks controlling stress response in mycobacterial species have been linked to persistence switches enabling the bacterial dormancy within a host. However, the mechanistic basis of switching and stress sensing is not fully understood. In this paper, combining quantitative experiments and mathematical modeling, we uncover how interactions between two master regulators of stress response -- MprAB two-component system and alternative sigma factorσE– shape the dynamical properties of surface-stress network. The result show hysteresis (history dependence) in the response of pathogenic bacteriaM. tuberculosisto surface stress and lack of the hysteresis in non-pathogenicM. smegmatis. Furthermore, to resolve the apparent contradiction between the existence of hysteresis and fast activation of the response, we utilize a recently proposed role of chaperone DnaK in stress-sensing. The results leads to a novel system-level understanding of bacterial stress-response dynamics.
LILRB3 (ILT5) is a myeloid checkpoint on myeloid cells that elicits profound immununomodulation
Authors: Yeboah Muchaala , Papagregoriou Charys , Jones Des C. , Chan H.T. Claude , Hu Guangan , McPartlan Justine S. , Schiött Torbjörn , Mattson Ulrika , Mockridge C. Ian , Tornberg Ulla-Carin , Hambe Björn , Ljungars Anne , Mattsson Mikael , Tews Ivo , Glennie Martin J. , Thirdborough Stephen M. , Trowsdale John , Frendeus Björn , Chen Jianzhu , Cragg Mark S. , Roghanian Ali
Published: June 2020

Despite advances in identifying the key immunoregulatory roles of many of the human leukocyte immunoglobulin (Ig)-like receptor (LILR) family members, the function of the inhibitory molecule LILRB3 (ILT5, CD85a, LIR3) remains unclear. Studies indicate a predominant myeloid expression; however, high homology within the LILR family and a relative paucity of reagents have hindered progress for this receptor. To investigate its function and potential immunomodulatory capacity, a panel of LILRB3-specific monoclonal antibodies (mAb) was generated. LILBR3-specific mAb bound to discrete epitopes in either Ig-like domain two or four. LILRB3 ligation on primary human monocytes by agonistic mAb resulted in phenotypic and functional changes, leading to potent inhibition of immune responsesin vitro, including significant reduction in T cell proliferation. Importantly, agonizing LILRB3 in humanized mice induced tolerance and permitted efficient engraftment of allogeneic cells. Our findings reveal powerful immunosuppresive functions of LILRB3 and identify it as an important myeloid checkpoint receptor.
Cetuximab produced from a goat mammary gland expression system is equally efficacious as innovator cetuximab in model systems of cancer
Authors: Wang Qian , Gavin William , Masiello Nick , Tran Khanh B. , Laible Götz , Shepherd Peter R
Published: June 2020

Humanised monoclonal antibodies have proven a very effective mode of therapy for a wide range of conditions. With many of the monoclonal antibody drugs now coming off patent there is an increasing interest in developing biosimilar, or even biobetter, forms of these drugs. With the commercial competition associated with such generic products there is increasing demand for improved production and purification system for biosimilars. Cetuximab, also known as ‘Erbitux’, is widely used in cancer therapy, especially in advanced colorecal cancer, metastatic non-small cell lung cancer and head and neck cancer and it will come off patent in the near future. We have previously reported on a genetically engineered goat system to produce cetuximab (gCetuximab) in milk. Herein we now report on the further charactization of the gCetuximab produced utilizing additional and more sophisticated biological assays. There is similar bioactivity of the gCetuximab compared with the commercial product produced in mammalian cell culture. In particular both cetuximab antibodies selectively target EGFR and induce its internalization to down regulate EGFR signaling. Both forms have very similar half life in animals and in a HT29 colorectal cancer xenograft model have similar efficacy. We also show that the toxin MMAE can be conjugated to gCetuximab, that this targets it to cells and that this results in direct cell killing in HT29 cells. This demonstrates that the gCetuximab will also be a viable vehicle for antibody drug conjugate based therapies. Taken together, this shows that the goat milk monoclonal antibody production system is an effective way of producing a biosimilar form of cetuximab.
Three-photon imaging of synthetic dyes in deep layers of the neocortex
Authors: Liu Chao J. , Roy Arani , Simons Anthony A. , Farinella Deano M. , Kara Prakash
Published: June 2020

Multiphoton microscopy has emerged as the primary imaging tool for studying the structural and functional dynamics of neural circuits in brain tissue, which is highly scattering to light. Recently, three-photon microscopy has enabled high-resolution fluorescence imaging of neurons in deeper brain areas that lie beyond the reach of conventional two-photon microscopy, which is typically limited to ~450 μm. Three-photon imaging of neuronal calcium signals, through the genetically-encoded calcium indicator GCaMP6, has been used to successfully record neuronal activity in deeper neocortical layers and parts of the hippocampus. Bulk-loading cells in deeper cortical layers with synthetic calcium indicators could provide an alternative strategy for labelling that obviates dependence on viral tropism and promoter penetration. Here we report a strategy for visualized injection of a calcium dye, Oregon Green BAPTA-1 AM (OGB-1 AM), at 500–600 μm below the surface of the mouse visual cortex in vivo. We demonstrate successful OGB-1 AM loading of cells in cortical layers 5–6 and subsequent three-photon imaging of orientation- and direction-selective visual responses from these cells.
Multiple spatial behaviours govern social network positions in a wild ungulate
Authors: Albery Gregory F , Morris Alison , Morris Sean , Pemberton Josephine M , Clutton-Brock Tim H. , Nussey Daniel H , Firth Josh A
Published: June 2020

The structure of wild animal social systems depends on a complex combination of intrinsic and extrinsic drivers. Population structuring and spatial behaviour are key determinants of individuals’ observed social behaviour, but quantifying these spatial components alongside multiple other drivers remains difficult due to data scarcity and analytical complexity. We used a 43-year dataset detailing a wild red deer population to investigate how individuals’ spatial behaviours drive social network positioning, while simultaneously assessing other potential contributing factors. Using Integrated Nested Laplace Approximation (INLA) multi-matrix animal models, we demonstrate that social network positions are shaped by two-dimensional landscape locations, pairwise space sharing, individual range size, and spatial and temporal variation in population density, alongside smaller but detectable impacts of a selection of individual-level phenotypic traits. These results indicate strong, multifaceted spatiotemporal structuring in this society, emphasising the importance of considering multiple spatial components when investigating the causes and consequences of sociality.

Authorship Statement

GFA conceived the study, analysed the data, and wrote the manuscript, advised by JAF. AM and SM collected the data. JAF, JMP, THCB, and DN commented on the manuscript.

Data Accessibility Statement

The code used here is available athttps://github.com/gfalbery/Spocial_Deer. On acceptance, the data will be uploaded to the same repo, which will be archived on Zenodo.
A robust two-sample Mendelian Randomization method integrating GWAS with multi-tissue eQTL summary statistics
Authors: Gleason Kevin J. , Yang Fan , Chen Lin S.
Published: June 2020

In the post-genome-wide association era, two-sample Mendelian Randomization (MR) methods have been applied to detect genetically-regulated risk factors for complex diseases. Two-sample MR considers single nucleotide polymorphisms (SNPs) associated with a putative exposure as instrumental variables (IVs) to assess the effect of the exposure on an outcome by leveraging two sets of summary statistics: IV-to-exposure and IV-to-outcome statistics from existing GWASs. Traditional MR methods impose strong assumptions on the validity of IVs, and recent literature has relaxed the assumptions allowing some IVs to be invalid but generally requiring a large number of nearly independent IVs. When treating expression-quantitative-trait-loci (eQTLs) as IVs to detect gene expression levels affecting diseases, existing methods are limited in applicability since the numbers of independent eQTLs for most genes in the genome are limited. To address those challenges, we propose a robust two-sample MR framework that requires fewer IVs and allows moderate IV correlations and some IVs to be invalid. This is achieved by leveraging existing multi-tissue eQTL summary statistics (multiple sets of IV-to-exposure statistics) and GWAS statistics in a mixed model framework. We conducted simulation studies to evaluate the performance of the proposed method and apply it to detect putative causal genes for schizophrenia.
Computational assessment of transport distances in living skeletal muscle fibers studied in situ
Authors: Hansson Kenth-Arne , Solbrå Andreas Våvang , Gundersen Kristian , Bruusgaard Jo Christiansen
Published: June 2020

Transport distances in skeletal muscle fibers are mitigated by these cells having multiple nuclei. We have studied mouse living slow (soleus) and fast (extensor digitorum longus) muscle fibers in situ and determined cellular dimensions and the positions of all the nuclei within fiber segments. We modelled the effect of placing nuclei optimally and randomly using the nuclei as the origin of a transportation network. It appeared that an equidistant positioning of nuclei minimizes transport distances along the surface for both muscles. In the soleus muscle however, which were richer in nuclei, positioning of nuclei to reduce transport distances to the cytoplasm were of less importance, and these fibers exhibit a pattern not statistically different from a random positioning of nuclei. Together, these results highlight the importance of spatially distribute nuclei to minimize transport distances to the surface when nuclear density is low, while it appears that the distribution are of less importance at higher nuclear densities.
Design of a Novel Multiplex Real Time RT-PCR Assay for SARS-CoV-2 Detection
Authors: Zhen Wei , Berry Gregory J.
Published: June 2020

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 386,000 deaths globally as of June 4, 2020. In this study, we developed a novel multiplex real time reverse transcription (RT)-PCR test for detection of SARS-CoV-2, with primers designed to amplify a 108 bp target on the spike surface glycoprotein (S gene) of SARS-CoV-2 and a hydrolysis Taqman probe designed to specifically detect SARS-CoV-2. Following our design, we evaluated the Limit of detection (LOD) and clinical performance of this laboratory-developed test (LDT). A LOD study with inactivated whole virus exhibited equal performance to that seen in the modified CDC assay with a final LOD of 1,301 ± 13 genome equivalents/ml for our assay vs 1,249 ± 14 genome equivalents/ml for the modified CDC assay. In addition, a clinical evaluation with 270 nasopharyngeal (NP) swab specimens exhibited 98.5% positive percent agreement and 99.3% negative percent agreement with the modified CDC assay. The multiplex design of this assay allows the testing of 91 patients per plate, versus a maximum of 29 patients per plate on the modified CDC assay, providing the benefit of testing significantly more patients per run and saving reagents during a time when both of these parameters have been critical. Our results demonstrate that our multiplex assay performs as well as the modified CDC assay, but is more efficient and cost effective and is therefore adequate for use as a diagnostic assay and for epidemiological surveillance and clinical management of SARS-CoV-2.
The unconventional cytoplasmic sensing mechanism for ethanol chemotaxis inBacillus subtilis
Authors: Tohidifar Payman , Bodhankar Girija A. , Pei Sichong , Cassidy C. Keith , Walukiewicz Hanna E. , Ordal George W. , Stansfeld Phillip J. , Rao Christopher V.
Published: June 2020

Motile bacteria sense chemical gradients using chemoreceptors, which consist of distinct sensing and signaling domains. The general model is that the sensing domain binds the chemical and the signaling domain induces the tactic response. Here, we investigated the unconventional sensing mechanism for ethanol taxis inBacillus subtilis. Ethanol and other short-chain alcohols are attractants forB. subtilis. Two chemoreceptors, McpB and HemAT, sense these alcohols. In the case of McpB, the signaling domain directly binds ethanol. We were further able to identify a single amino-acid residue Ala431on the cytoplasmic signaling domain of McpB, that when mutated to a serine, reduces taxis to ethanol. Molecular dynamics simulations suggest ethanol binds McpB near residue Ala431and mutation of this residue to serine increases coiled-coil packing within the signaling domain, thereby reducing the ability of ethanol to bind between the helices of the signaling domain. In the case of HemAT, the myoglobin-like sensing domain binds ethanol, likely between the helices encapsulating the heme group. Aside from being sensed by an unconventional mechanism, ethanol also differs from many other chemoattractants because it is not metabolized byB. subtilisand is toxic. We propose thatB. subtilisuses ethanol and other short-chain alcohols to locate prey, namely alcohol-producing microorganisms.

Importance

Ethanol is a chemoattractant forBacillus subtiliseven though it is not metabolized and inhibits growth.B. subtilislikely uses ethanol to find ethanol-fermenting microorganisms for prey. Two chemoreceptors sense ethanol: HemAT and McpB. HemAT’s myoglobin-like sensing domain directly binds ethanol, but the heme group is not involved. McpB is a transmembrane receptor consisting of an extracellular sensing domain and a cytoplasmic signaling domain. While most attractants bind the extracellular sensing domain, we found that ethanol directly binds between inter-monomer helices of the cytoplasmic signaling domain of McpB, using a mechanism akin to those identified in many mammalian ethanol-binding proteins. Our results indicate that the sensory repertoire of chemoreceptors extends beyond the sensing domain and can directly involve the signaling domain.
Recombinant Expression of Metal-Binding Proteins (Bacterioferritin, MBP, Metallothionein, and OprF) and Pesticide-Binding Proteins (LC-Cutinase and OpdA) in Escherichia coli for Detection of Agricultural Contaminants
Authors: Hwang Kimberly , Kuo Allison , Choi Eugene , Chen Jessica , Hsu Jonathan , Clapper Jude
Published: June 2020

We consume fruits and vegetables every day without knowing whether or not agricultural residues (i.e. pesticides & heavy metals) are present on them. Current methods of agricultural residue detection are not easily accessible to the public and are inconvenient for everyday use. Thus, we want to develop a convenient visualization of agricultural residues by designing metal-binding and pesticide-binding proteins along with colored proteins that can directly interact with these residues. We worked with metal-binding proteins including Bacterioferritin, MBP, Metallothionein, and OprF. We also utilized pesticide-binding proteins LC Cutinase and OpdA. In this paper, we envision a system in which our residue-binding proteins are fused with chromoproteins to allow for the visible detection of agricultural residues on produce. Our final product can be used by consumers, distributors and farmers alike.
The Inequality of Neural Destiny: Signatures of Life course Socioeconomic Conditions in Brain Myelination and Grey Matter Volume
Authors: Loued-Khenissi Leyla , Trofimova Olga , Vollenweider Peter , Marques-Vidal Pedro , Preisig Martin , Lutti Antoine , Kliegel Matthias , Sandi Carmen , Kherif Ferhat , Stringhini Silvia , Draganski Bogdan
Published: June 2020

Socioeconomic status (SES) plays a significant role in health and disease. At the same time, early-life conditions affect neural function and structure, suggesting the brain may be a conduit for the biological embedding of SES. Here, we investigate the neural signatures of SES in a large-scale population cohort aged 45–85 years. We assess both grey matter volume (GMV) and magnetization transfer (MT) saturation, indicative of myelin content. Higher SES in childhood and adulthood associated with more GMV in several brain regions, including postcentral and temporal gyri, cuneus, and cerebellum, while low SES correlated with larger entorhinal cortex volume. High childhood SES was linked to more widespread GMV differences and higher myelin content in the sensorimotor network while low SES correlated to myelin content in the temporal lobe. Crucially, childhood SES differences in adult brains persisted even after controlling for adult SES, highlighting the unique contribution of early-life conditions to neural status in older age, independent of later changes in SES. These findings inform on the biological underpinnings of social inequality, particularly as it pertains to early-life conditions.
Prevalence and risk/protective indicators of peri-implant diseases: a university-representative cross-sectional study
Authors: Romandini Mario , Lima Cristina , Pedrinaci Ignacio , Araoz Ana , Soldini Maria Costanza , Sanz Mariano
Published: June 2020

Aim

To evaluate the prevalence of peri-implant diseases and to identify risk/protective indicators of peri-implantitis.

Materials and Methods

240 randomly selected patients from a university clinic database were invited to participate. Those who accepted, once data from their medical and dental history was collected, were examined clinically and radiographically to assess the prevalence of peri-implant health and diseases. A multilevel multivariate logistic regression analysis was carried out to identify those factors associated either positively (risk) or negatively (protective) with peri-implantitis defined as BoP/SoP and bone levels ≧2 mm.

Results

99 patients with a total of 458 dental implants were analyzed. The prevalence of preperiimplantitis and of peri-implantitis were respectively 56.6% and 31.3% at patient-level, while 27.9% and 31.7% at implant-level. The following factors were identified as risk indicators for periimplantitis: smoking (OR = 3.59; 95%CI:1.52–8.45), moderate/severe periodontitis (OR = 2.77; 95%CI:1.20–6.36), < 16 remaining teeth (OR = 2.23; 95%CI:1.05–4.73), plaque (OR = 3.49; 95%CI:1.13–10.75), implant malposition (too vestibular: OR = 2.85; 95%CI:1.17–6.93), implant brand (Nobel vs. Straumann: OR = 4.41;95% CI:1.76–11.09), restoration type (bridge: OR = 2.47; 95%CI:1.19–5.12), and trauma as reason of tooth loss (OR = 6.51;95% CI:1.45–29.26). Conversely, the following factors were identified as protective indicators: interproximal flossing/brushing (OR = 0.27; 95%CI:0.11–0.68), proton pump inhibitors (OR = 0.08; 95%CI:0.01–0.90) and anticoagulants (OR = 0.08; 95%CI:0.01–0.56).

Conclusions

Peri-implant diseases are highly prevalent among patients with dental implants in this university-based population. Several factors were identified as risk- and protective-indicators of peri-implantitis.
Cervical Spine Assessment Techniques and Neck Strength Profiles of Elite Rugby Union Players Using an Innovative Measurement Approach
Authors: McBride Lesley , Oxford Samuel W
Published: June 2020

Objectives

Neck injuries and concussion commonly occur in the sport of Rugby Union. This study analyses the current practices of medical staff in assessment of the neck and proposes a new position-specific method using a commercially available setup for the assessment of neck strength.

Methods

A survey was employed and distributed to 40 Premiership and Championship Rugby Union clubs. Thirty-eight University students (18 males and 20 females) were tested on two occasions at least 72hrs apart to determine reliability and 131 elite Rugby Union players (forwards n = 82, backs n = 49) were tested on a single occasion. Isometric neck strength was measured using a commercially available rig and digital load cell, for flexion (Flex), extension (Ext), left side flexion (LSF) and right-side flexion (RSF). Peak of three trials for each position was used for statistical analysis.

Results

Survey findings indicated no standard practice used in the assessment of the neck across the professional teams. Intra-rater reliability interclass correlation values > 0.924 when using peak neck strength across all directions, thus indicating excellent reliability. Forwards recorded significantly greater absolute values for cervical spine strength across all directions (p < 0.01) however, relative values showed no significant difference between players (p > 0.05)

Conclusion

The results show that the commercially available rig and digital load cell are a reliable tool for the assessment of isometric strength of the cervical spine and provide reference values for healthy males as well as elite Rugby Union forwards and backs.
ACE2 levels are altered in comorbidities linked to severe outcome in COVID-19
Authors: Emilsson Valur , Gudmundsson Elias F , Aspelund Thor , Jonsson Brynjolfur G , Gudjonsson Alexander , Launer Lenore J. , Lamb John R , Gudmundsdottir Valborg , Jennings Lori L , Gudnason Vilmundur
Published: June 2020

Aims

Severity of outcome in COVID-19 is disproportionately higher among the obese, males, smokers, those suffering from hypertension, kidney disease, coronary heart disease (CHD) and/or type 2 diabetes (T2D). We examined if serum levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2, were altered in these high-risk groups.

Methods

Associations of serum ACE2 levels to hypertension, T2D, obesity, CHD, smokers and males in a single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) of the elderly (mean age 75±6 years).

Results

Smokers, males, and individuals with T2D or obesity have altered serum levels of ACE2 that may influence productive infection of SARS-CoV-2 in these high-risk groups.

Conclusion

ACE2 levels are upregulated in some patient groups with comorbidities linked to COVID-19 and as such may have an emerging role as outcome in COVID-19. a circulating biomarker for severity of severity of outcome in COVID-19.

Key Points

Question

Severity of outcome in COVID-19 is disproportionately higher among the obese, males, smokers, those suffering from hypertension, kidney disease, coronary heart disease (CHD) and/or type 2 diabetes (T2D). Thus, we asked if the coronavirus SARS-CoV-2 receptor ACE2 was altered in the sera from these high-risk groups?

Findings

In a single center population-based study of 5457 Icelanders, the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), we find that ACE2 levels are significantly elevated in serum from smokers, obese and diabetic individuals, while reduced in males.

Meaning

These results demonstrate that individuals with comorbidities associated with infection of SARS-CoV-2 in these individuals. severe outcome in COVID-19 have altered serum levels of ACE2 that may influence productive
Local Aromatase Activity Alterations in Breast Cancer Tissues: A Potential Way of Decision Support for Clinicians
Authors: Tuzuner Mete Bora , Ozturk Tulin , Ilvan Sennur , Turna Hande , Yurdun Turkan , Yilmaz-Aydogan Hulya , Ozturk Oguz
Published: June 2020

Background and aims

It is becoming evident that local estrogen exposure is important in postmenopausal breast cancer patients. The microenvironment is established by breast stromal cells based on communication with tumor cells that is essential to cancer development, invasion, and metastasis. Here we investigated aromatase activity levels in both tumor and matched stromal tissues by showing their impact on the manufacturing of local estrogen and tumor progression in cases of invasive ductal carcinoma (IDC).

Methods

Tumor (T) and tumor-associated stroma (TAS) neighboring tissues were acquired from each postmenopausal patient, diagnosed with IDC, and categorized as luminal A (n = 20). The control group was formed from tumorfree breast tissue samples (N, n = 12). A microsomal-based technique was created to compare breast tissue aromatase activities using liquid chromatography – mass spectrometry.

Findings

We observed that the TAS tissues have the highest aromatase activities (p < 0.05). High progesterone receptor (PR) intensity levels were found to be decreasing the activity level in these tissues significantly (p< 0.05). Tumor tissue specific aromatase activity levels of postmenopausal patients’ were tend to be lower compared to healthy premenopausal subjects’ (3 fold, p< 0.001). In addition low activity in tumor tissues were associated with low grade and late stage cancers.

Conclusions

Early detection and personalized therapy is essential for postmenopausal breast cancer patients. Together, our inhouse tandem mass spectrometry technique has the potential for further development and standardization for the measurement of aromatase activity and may assist clinicians decide on therapy policies for postmenopausal IDC patients which could be an invaluable asset for precise and specific evaluation.
What variables can better predict the number of infections and deaths worldwide by SARS-CoV-2? Variation through time
Authors: García de Alcañíz J. G. , Romero-López J. , Martínez-Esteban R. P. , López-Rodas V. , Costas E.
Published: June 2020

Using data from 50 very different countries (which represent nearly 70% of world’s population) and by means of a regression analysis, we studied the predictive power of different variables (mobility, air pollution, health & research, economic and social & geographic indicators) over the number of infected and dead by SARS-CoV-2. We also studied if the predictive power of these variables changed during a 4 months period (March, April, May and June). We approached data in two different ways, cumulative data and non-cumulative data.

The number of deaths by Covid-19 can always be predicted with great accuracy from the number of infected, regardless of the characteristics of the country.

Inbound tourism emerged as the variable that best predicts the number of infected (and, consequently, the number of deaths) happening in the different countries. Electricity consumption and air pollution of a country (CO2emissions, nitrous oxide and methane) are also capable of predicting, with great precision, the number of infections and deaths from Covid-19. Characteristics such as the area and population of a country can also predict, although to a lesser extent, the number of infected and dead. All predictive variables remained significant through time.

In contrast, a series of variables, which in principle would seem to have a greater influence on the evolution of Covid-19 (hospital bed density, Physicians per 1000 people, Researches in R & D, urban population…), turned out to have very little - or none- predictive power.

Our results explain why countries that opted for travel restrictions and social withdrawal policies at a very early stage of the pandemic outbreak, obtained better results. Preventive policies proved to be the key, rather than having large hospital and medical resources.
HIGHER LEVELS OF CEREBROSPINAL FLUID NITRITE AND NITRATE IN LEVODOPA-INDUCED DYSKINESIAS IN PARKINSON’S DISEASE
Authors: Santos-Lobato Bruno L. , Bortolanza Mariza , Batalhão Marcelo E. , Pimentel Ângela V. , Capellari-Carnio Evelin , Del-Bel Elaine A. , Tumas Vitor
Published: June 2020

Introduction

Levodopa-induced dyskinesias (LID) in Parkinson’s disease (PD) are frequent complications, and nitric oxide has a role on its pathophysiology. The present work aims to investigate CSF levels of nitric oxide metabolites nitrite and nitrate (NOx) in patients with PD and LID.

Methods

We measured CSF NOx levels in patients with PD with and without LID, and in healthy controls. The levels of CSF NOx levels were measured by ozone-based chemiluminescence.

Results

67 participants were enrolled. CSF NOx levels were higher in patients with PD with LID than in healthy controls (Kruskal-Wallis statistics = 7.24, p = 0.02). CSF NOx levels did not correlate with other clinical variables.

Conclusion

We reported higher levels of nitric oxide in the CSF of patients with PD and LID.

Highlights

–

Nitric oxide has a role on levodopa-induced dyskinesias in Parkinson’s disease

–

We measured CSF nitrite and nitrate in Parkinson’s disease patients with dyskinesias

–

CSF nitrite and nitrate were higher in Parkinson’s disease patients with dyskinesias
Optimal Control Measures to Combat COVID 19 Spread in Sri Lanka: A Mathematical Model Considering the Heterogeneity of Cases
Authors: Wickramaarachchi WPTM , Perera SSN
Published: June 2020

The COVID 19 pandemic caused by the novel corona virus (SARS-CoV-2) has been one of the major public health concerns across the globe, currently more than 3.5 million individuals have been infected, and the number of deaths has passed 250,000. The world wide burden of the disease has been massive, and the governments are in dilemma to protect the health system of the country while safeguarding the economy. There is no vaccine or antivirus drug found against this virus while multiple research groups are actively working on a suitable candidate. The only available mode of minimizing the disease burden has been to control its transmission among the population. Since the occurrence of first COVID 19 local case on 11 March 2020, the government of Sri Lanka introduced serious social distancing and public health interventions in its fullest capacity as a developing nation to effectively combat with the disease spread. This study focuses to develop a mathematical model to investigate the dynamic of this novel disease using an extended version of an SEIR compartmental structure considering the heterogeneity of cases such as asymptomatic, symptomatic with mild indications and the cases required intensive care treatments. All the measures and interventions are in progress with a significantly large social and economic cost, thus, optimal control techniques are used to identify the most appropriate strategies to minimize this cost. The results of the simulations prove that optimal control measures can be worked out as the epidemic curves are flattened while delaying the outbreak so that the health system might not be under pressure to treat and care the patients.
The neurodevelopment of anomalous perception: Evidence in cortical folding patterns for prenatal predispositions to hallucinations in schizophrenia
Authors: Rollins Colleen P.E. , Garrison Jane R. , Arribas Maite , Seyedsalehi Aida , Li Zhi , Chan Raymond C.K. , Yang Junwei , Wang Duo , Lio Pietro , Yan Chao , Yi Zheng-hui , Cachia Arnaud , Upthegrove Rachel , Deakin Bill , Simons Jon S. , Murray Graham K. , Suckling John
Published: June 2020

Background

All perception is a construction of the brain from sensory input. Our first perceptions begin during gestation, making fetal brain development fundamental to how we experience a diverse world. Hallucinations are percepts without origin in physical reality that occur in health and disease. Despite longstanding research on the brain structures supporting hallucinations and on perinatal contributions to the pathophysiology of schizophrenia, what links these two distinct lines of research remains unclear.

Methods

We studied two independent datasets of patients with schizophrenia who underwent clinical assessment and 3T structural magnetic resonance (MR) imaging from the United Kingdom and Shanghai, China (n = 181 combined) and 63 healthy controls from Shanghai. Participants were stratified into those with (n = 79 UK; n = 22 Shanghai) and without (n = 43 UK; n = 37 Shanghai) hallucinations from the PANSS P3 scores for hallucinatory behaviour. We quantified the length, depth, and asymmetry indices of the paracingulate and superior temporal sulci (PCS, STS) from MR images and constructed cortical folding covariance matrices organized by large-scale networks.

Results

In both ethnic groups, we replicated a significantly shorter left PCS in patients with hallucinations compared to those without, and healthy controls. Reduced PCS length and STS depth corresponded to focal deviations in their geometry and to significantly increased covariance within and between areas of the salience and auditory networks.

Conclusion

The discovery of neurodevelopmental alterations contributing to hallucinations establishes testable models for these enigmatic, sometimes highly distressing, perceptions and provides mechanistic insight into the pathological consequences of prenatal origins.
Bayesian Networks in Healthcare: the chasm between research enthusiasm and clinical adoption
Authors: Kyrimi Evangelia , McLachlan Scott , Dube Kudakwashe , Fenton Norman
Published: June 2020

Problem

Bayesian Networks (BN) can address real-world decision-making problems, and there is enormous and rapidly increasing interest in their use in healthcare. Yet, despite thousands of BNs in healthcare papers published yearly, evidence of their adoption in practice is extremely limited and there is no consensus on why.

Method

A preliminary review was conducted to identify research gaps and justify the conduct of a broader scoping or systematic review of BNs in healthcare

Results

We highlight that: (1) there have been no significant attempts to systematically review the domain; (2) there are weaknesses in the way BN development processes are presented in the literature; and (3) in contrast to enthusiasm (including from clinicians) there has been negligible adoption of published BNs into clinical practice.

Conclusion

A systematic review of BNs in healthcare is needed to a) understand the chasm between research enthusiasm and clinical adoption; and b) improve clinical adoption.
The critical role of HDAC1 activates NSCLC growth by nicotine resistance Cisplatin
Authors: Peng Ching-Yi , Wu Jia-Ping
Published: June 2020

Nicotine is active in highly cisplatin-resistant cancer cells; however, there is little evidence for its resistant activity in lung cancer with cisplatin. Many mechanisms of cisplatin resistance have been proposed. The mechanisms of the nicotine treatment of cisplatin-resistant lung cancer for histone deacetylase 1 (HDAC1) activity is unknown. Nicotine was used to analyze cisplatin-resistant non-small cell lung cancer (NSCLC) cancer cell growth. Western blot was used to analyze cell cycle-related proteins. Cancer cell viability (cell survival) was measured with MTT assay. HDAC1 transfected NSCLC cells were used to analyze the direct binding between cytosol and nucleus distribution. Here, using cell viability and migration methods we firstly found nicotine regulated cisplatin-resistant NSCLC cells growth by targeting HDAC1. Expression of cisplatin was negatively correlated with HDAC1. And HDAC1 inhibitor, VPA, in the NSCLC cancer cells were predicted. Further experiments confirmed that HDAC1 directly targeted E2F and cisplatin. Besides, HDAC1 and cisplatin inhibited NSCLC cell growth and reduced expression of E2F and Cyclin E proteins. The use of nicotine compromised cisplatin-induced E2F suppression and cancer cell growth. NSCLC cancer cells co-transfected with nicotine and HDAC1 had a higher cell cycle proliferation. Taken all together, cisplatin interferes with DNA replication kills the cancer cell fastest proliferation; however, nicotine increased detoxification of cisplatin, inhibition of apoptosis and DNA repair, induced cisplatin resistance.
Negative frequency-dependent selection and asymmetrical transformation stabilise multi-strain bacterial population structures
Authors: Harrow Gabrielle L. , Lees John A. , Hanage William P. , Lipsitch Marc , Corander Jukka , Colijn Caroline , Croucher Nicholas J.
Published: June 2020

Streptococcus pneumoniaecan be split into multiple strains, each with a characteristic combination of core and accessory genome variation, able to co-circulate and compete within the same hosts. Previous analyses of epidemiological datasets suggested the short-term vaccine-associated dynamics ofS. pneumoniaestrains may be mediated through multi-locus negative frequency-dependent selection (NFDS), acting to maintain accessory loci at equilibrium frequencies. To test whether this model could explain how such multi-strain populations were generated, it was modified to incorporate recombination. The outputs of simulations featuring symmetrical recombination were compared with genomic data on locus frequencies and distributions between genotypes, pairwise genetic distances and tree shape. These demonstrated NFDS prevented the loss of variation through neutral drift, but generated unstructured populations of diverse isolates. Making recombination asymmetrical, favouring deletion of accessory loci over insertion, alongside multi-locus NFDS significantly improved the fit to genomic data. In a population at equilibrium, structuring into multiple strains was stable due to outbreeding depression, resulting from recombinants with reduced accessory genomes having lower fitness than their parental genotypes. As many bacteria inhibit the integration of insertions into their chromosomes, this combination of asymmetrical recombination and multi-locus NFDS may underlie the co-existence of strains within a single ecological niche.
How Accurate Are Circular Dichroism Based Secondary Structure Estimates?
Authors: Nagy Gabor , Grubmüller Helmut
Published: June 2020

Circular dichroism (CD) spectroscopy is highly sensitive to the secondary structure (SS) composition of proteins. Several methods exist to either estimate the SS composition of a protein or to validate existing structural models using its CD spectrum. The accuracy and precision of these methods depend on the quality of both the measured CD spectrum and the used reference structure. Using a large reference protein set with high quality CD spectra and synthetic data derived from this set, we quantified deviations from both ideal spectra and reference structures due to experimental limitations. We also determined the impact of these deviations on SS estimation, CD prediction, and SS validation methods of the SESCA analysis package. With regard to the CD spectra, our results suggest intensity scaling errors and non-SS contributions as the main causes of inaccuracies. These factors also can lead to overestimated model errors during validation. The errors of the used reference structures combine non-additively with errors caused by the CD spectrum, which increases the uncertainty of model validation. We have further shown that the effects of scaling errors in the CD spectrum can be nearly eliminated by appropriate re-scaling, and that the accuracy of model validation methods can be improved by accounting for typical non-SS contributions. These improvements have now been implemented within the SESCA package.
Cold induced chromatin compaction and nuclear retention of clock mRNAs resets the circadian rhythm
Authors: Fischl Harry , McManus David , Oldenkamp Roel , Schermelleh Lothar , Mellor Jane , Jagannath Aarti , Furger Andre
Published: June 2020

Cooling patients to sub-physiological temperatures is an integral part of modern medicine. We show that cold exposure induces temperature-specific changes to the higher-order chromatin and gene expression profiles of human cells. These changes are particularly dramatic at 18°C, a temperature synonymous with that experienced by patients undergoing controlled deep-hypothermia during surgery. Cells exposed to 18°C exhibit largely nuclear-restricted transcriptome changes. These include the nuclear accumulation of core circadian clock suppressor gene transcripts, most notablyREV-ERBα. This response is accompanied by compaction of higher-order chromatin and hindrance of mRNPs from engaging nuclear pores. Rewarming reverses chromatin compaction and releases the transcripts into the cytoplasm, triggering a pulse of suppressor gene proteins that resets the circadian clock. We show that cold-induced upregulation of REV-ERBα alone is sufficient to trigger this resetting. Our findings uncover principles of the cellular cold-response that must be considered for current and future applications involving therapeutic deep-hypothermia.
Molecular phylogenetics and micromorphology of Australasian Stipeae (Poaceae), and the interrelation of whole-genome duplication and evolutionary radiations in this grass tribe
Authors: Tkach Natalia , Nobis Marcin , Schneider Julia , Becher Hannes , Winterfeld Grit , Barkworth Mary E. , Jacobs Surrey W. L. , Röser Martin
Published: June 2020

The mainly Australian grass genusAustrostipawith ca. 64 species represents a remarkable example of an evolutionary radiation. To investigate aspects of diversification, macro- and micromorphological variation in this genus we conducted a molecular phylogenetic and scanning electron microscopy (SEM) analysis including representatives from all of its accepted subgenera.

Plastid DNA variation withinAustrostipawas low and only few lineages were resolved. Nuclear ITS andAcc1yielded comparable groupings of taxa and resolved subgeneraArbuscula,Petaurista,Bambusinain a common clade and as monophyletic. In summary, we suggest recognizing nine subgenera inAustrostipa.

Because of its taxonomic significance in Stipeae, we studied the lemma epidermal structure in 34 representatives ofAustrostipa.In most species, the lemma epidermal pattern (LEP) was relatively uniform (maize-like LEP), but in six species it was more similar to that ofStipas.str.,Neotrinia,PtilagrostisandOrthoraphium.The species representing subgeneraLobatae,Petaurista,BambusinaandA. muellerifrom subg.Tuberculataewere well-separated from all the other species included in the analysis.

Two different sequence copies ofAcc1were found in polyploidAustrostipaandAnemanthele. Each of the copy types formed a single clade. This was also true of the sampled species ofStipas.str., but their clades were strongly separated from those ofAustrostipaandAnemanthele. This underlines the statement of Tzvelev (1977) that most if not all contemporary Stipeae are of hybrid origin and demonstrates it for the first time unambiguously on the molecular level.

Chromosome number variation is surveyed and reviewed for the whole tribe Stipeae and interpreted in a molecular phylogenetic framework. The rather coherent picture of chromosome number variation underlines the phylogenetic and evolutionary significance of this character.

The closest extant relatives ofAustrostipaandAnemantheleare in the clade ofAchnatherums.str.,Celtica,OloptumandStipellula. These genera are most abundant in Central and Eastern Asia, which makes a colonization of Australian and New Zealand from this region more likely, perhaps via long-distance dispersal, than colonization of Australia from southern South America via Antarctica as previously invoked.

Supporting Informationmay be found online in the Supporting Information section at the end of the article.
Ultra-sensitive nanozyme-based chemiluminescence paper test for rapid diagnosis of SARS-CoV-2 infection
Authors: Liu Dan , Ju Chenhui , Han Chao , Shi Rui , Chen Xuehui , Duan Demin , Yan Jinghua , Yan Xiyun
Published: June 2020

The recently emerged coronavirus disease COVID-19 has now evolved into a global pandemic. Early detection is crucial for its effective control. Nucleic acid testing for viral pathogen and serological testing for host antibodies are playing important roles in current COVID-19 diagnosis. However, while nucleic acid testing is complicated, facility-restricted and time-consuming, antibody testing may result in high rates of false-negative diagnoses, especially during the early stages of viral infection. Thus, a more rapid and reliable test for both early COVID-19 diagnosis and whole-population screening is urgently needed. Here, we developed a novel nanozyme-based chemiluminescence paper assay for rapid and high-sensitive testing of SARS-CoV-2 spike antigen. Our paper test uses a newly established peroxidase-mimic Co-Fe@hemin nanozyme instead of natural HRP that catalytically amplifies the chemiluminescent signal, allowing for target concentrations to be as low as 0.1 ng/ml. Furthermore, our nanozyme-based chemiluminescence test exhibits a linear range that is 32-fold wider compared to ELISA tests. Importantly, testing is completed in less than 16 min, compared to 1-2 h required for ELISA or nucleic acid tests. Critically, signal detection is feasible using a smartphone camera. Ingredients for our test are simple and readily available, rendering overall cost considerably lower than those used in current diagnoses. In conclusion, our novel test provides a high-sensitive, point-of-care testing (POCT) approach for SARS-CoV-2 antigen detection, which should greatly increase current early screening capacities for suspected infections, and considerably lower demand for national healthcare resources.
Iron Supplementation Eliminates Antagonistic Interactions Between Root Associated Bacteria
Authors: Eng Thomas , Herbert Robin A. , Martinez Uriel , Wang Brenda , Chen Joseph , Brown Ben , Deutschbauer Adam , Bissell Mina , Mortimer Jenny C. , Mukhopadhyay Aindrila
Published: June 2020

The rhizosphere microbiome (rhizobiome) plays a critical role in plant health and development. However the processes by which the constituent microbes interact to form and maintain a community are not well understood. To investigate these molecular processes, we examined pairwise interactions between 11 different microbial isolates under selected nutrient-rich and nutrient-limited conditions. We observed that when grown with media supplemented with 56 mM glucose, 2 microbial isolates were able to inhibit the growth of 6 out of 11 other microbes tested. The interaction between microbes persisted even after the antagonistic microbe was removed, upon exposure to spent media. To probe the genetic basis for these antagonistic interactions, we used a barcoded transposon library in a proxy bacterium,Pseudomonas putida, to identify genes which showed enhanced sensitivity to the antagonistic factor(s) secreted byAcinetobactersp. 02. Iron metabolism-related gene clusters inP. putidawere implicated by this systems-level analysis. The supplementation of iron prevented the antagonistic interaction in the original microbial pair supporting the hypothesis that iron limitation drives antagonistic microbial interactions between rhizobionts. We conclude that rhizobiome community composition is influenced by competition for limiting nutrients with implications for growth and development of the plant.