bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune Profiling to Determine Early Disease Trajectories Associated With Coronavirus Disease 2019 Mortality Rate: A Substudy from the ACTT-1 Trial
Authors: Thiede Joshua M , Gress Abigail R , Libby Samuel D , Ronayne Christine E , Matchett William E , Noren Brooke , Billings Joanne L , Menachery Vineet D , Langlois Ryan A , Kline Susan , Bold Tyler D
Published: January 2021

Coronavirus disease 2019 (COVID-19) outcomes are linked to host immune responses and may be affected by antiviral therapy. We investigated antibody and cytokine responses in ACTT-1 study participants enrolled at our center. We studied serum specimens from 19 hospitalized adults with COVID-19 randomized to treatment with remdesivir or placebo. We assessed severe acute respiratory syndrome coronavirus 2 antibody responses and identified cytokine signatures, using hierarchical clustering. We identified no clear immunologic trends attributable to remdesivir treatment. Seven participants were initially seronegative at study enrollment, and all 4 deaths occurred in this group with more recent symptom onset. We identified 3 dominant cytokine signatures, demonstrating different disease trajectories.
Application of artificial neural network for lubrication performance evaluation of rough elliptic bore journal bearing
Authors: Pradhan Sushanta Kumar , Mishra Prabhudatta , Mishra Prakash Chandra
Published: January 2021

In this study, rough elliptic bore journal bearing performance is predicted using an artificial neural network (ANN) technique. The effects of non-circularity and roughness are quantified to elliptic and isotropic in macro and micro scale, respectively. The numerically estimated performance parameters like load, friction, and flow-in at different eccentricities [0.3 (low), 0.5 (medium), and 0.8 (high)], non-circularities [0.5 (low), 1.0 (medium), and 2.0 (high)], and roughness factors [0.1 (low), 0.2 (medium), 0.3 (medium), and 0.4 (high)] are used to train and build the ANN model. The training continued until the maximum mean square error is achieved, and the best-fitting plot is generated. With a confidence level of 99.75% or an R-value of 0.99757, the results predicted are found to be satisfactory.
A need for clarification of the energy solidarity principle: what can be learned from the GeneralCourt’s judgment in the OPAL case?
Authors: Iakovenko Mykola
Published: January 2021

The EU Court of Justice General Court’s judgment in Case T-883/16 on withdrawal of the Commission’s decision on the exemptions for the OPAL pipeline (an onshore continuation of Nord Stream 1) from some of the provisions of EU legislation in gas sphere on the basis of non-compliance with the principle of energy solidarity may have a great impact on the development of EU gas market with regard to balancing different approaches to external gas supply. This case may also raise some concerns on EU energy legislation from the point of view of impact of political goals on the regulation of the market. Having regard to these issues, the article analyses this case from the perspective of EU case law on application of the solidarity principle to point out the main legal aspects of utilization of this principle and crystallize it from non-legal biases. The article also provides a holistic assessment of the general application of the solidarity principle in the energy sphere and identifying the main gaps on the example of the OPAL case judgment.
Look before you leap: are your oil patch liability clauses enforceable?: (An analysis under civil law jurisdictions with emphasis on Brazil)
Authors: Nadorff Norman , Gomes Maria Beatriz
Published: January 2021

The oil and gas industry requires huge investments involving extraordinary financial, environmental and safety risks. Dramatic images of the Deepwater Horizon (Gulf of Mexico, 2010), Alpha Piper (Scotland, 1988), P-51 (Brazil, 2001) and Campeche (Mexico, 1979) disasters offer chilling reminders of the monumental loss of life, property and environmental integrity that can quickly result from human error. With this backdrop, industry participants and their insurers learned early on that the normal fault-based approach to wellsite liability did not fit the nature and needs of the petroleum business.

This article analyzes the risks inherent in applying the laws of a civil law jurisdiction to an oil and gas wellsite contract based on common law principles, with special emphasis on Brazil. It first briefly describes the traditional common law approach to liability allocation in wellsite contracts, including “knock-for-knock” principles (“K4K”). Next, it outlines the traditional civil law approach to liability (responsbilité) through French and Brazilian prisms. The authors do not deeply discuss the pros and cons of K4K clauses nor the policy implications of anti-indemnity statutes. Rather, they assume the reader is contemplating the negotiation of a wellsite services contract subject to the laws of a civil law jurisdiction, and describe the relevant risks and possible mitigation strategies.
Organic acids: versatile stress-response roles in plants
Authors: Panchal Poonam , Miller Anthony J , Giri Jitender
Published: January 2021

Organic acids (OAs) are central to cellular metabolism. Many plant stress responses involve the exudation of OAs at the root–soil interface, which can improve soil mineral acquisition and toxic metal tolerance. Because of their simple structure, the low-molecular-weight OAs are widely studied. We discuss the conventional roles of OAs, and some newly emerging roles in plant stress tolerance. OAs are more versatile in their role in plant stress tolerance and are more efficient chelating agents than other acids, such as amino acids. Root OA exudation is important in soil carbon sequestration. These functions are key processes in combating climate change and helping with more sustainable food production. We briefly review the mechanisms behind enhanced biosynthesis, secretion, and regulation of these activities under different stresses, and provide an outline of the transgenic approaches targeted towards the enhanced production and secretion of OAs. A recurring theme of OAs in plant biology is their role as ‘acids’ modifying pH, as ‘chelators’ binding metals, or as ‘carbon sources’ for microbes. We argue that these multiple functions are key factors for understanding these molecules’ important roles in plant stress biology. Finally, we discuss how the functions of OAs in plant stress responses could be used, and identify the important unanswered questions.
Smart glass impacts stomatal sensitivity of greenhouse Capsicum through altered light
Authors: Zhao Chenchen , Chavan Sachin , He Xin , Zhou Meixue , Cazzonelli Christopher I , Chen Zhong-Hua , Tissue David T , Ghannoum Oula
Published: January 2021

Optical films that alter light transmittance may reduce energy consumption in high-tech greenhouses, but their impact on crop physiology remains unclear. We compared the stomatal responses of Capsicum plants grown hydroponically under control glass (70% diffuse light) or the smart glass (SG) film ULR-80, which blocked >50% of short-wave radiation and ~9% of photosynthetically active radiation (PAR). SG had no significant effects on steady-state (gs) or maximal (gmax) stomatal conductance. In contrast, SG reduced stomatal pore size and sensitivity to exogenous abscisic acid (ABA), thereby increasing rates of leaf water loss, guard cell K+ and Cl– efflux, and Ca2+ influx. SG induced faster stomatal closing and opening rates on transition between low (100 µmol m–2 s–1) and high PAR (1500 µmol m–2 s–1), which compromised water use efficiency relative to control plants. The fraction of blue light (0% or 10%) did not affect gs in either treatment. Increased expression of stomatal closure and photoreceptor genes in epidermal peels of SG plants is consistent with fast stomatal responses to light changes. In conclusion, stomatal responses of Capsicum to SG were more affected by changes in light intensity than spectral quality, and re-engineering of the SG should maximize PAR transmission, and hence CO2 assimilation.
RNA architecture influences plant biology
Authors: Zhu Jiaying , Li Changhao , Peng Xu , Zhang Xiuren
Published: January 2021

The majority of the genome is transcribed to RNA in living organisms. RNA transcripts can form astonishing arrays of secondary and tertiary structures via Watson–Crick, Hoogsteen, or wobble base pairing. In vivo, RNA folding is not a simple thermodynamic event of minimizing free energy. Instead, the process is constrained by transcription, RNA-binding proteins, steric factors, and the microenvironment. RNA secondary structure (RSS) plays myriad roles in numerous biological processes, such as RNA processing, stability, transportation, and translation in prokaryotes and eukaryotes. Emerging evidence has also implicated RSS in RNA trafficking, liquid–liquid phase separation, and plant responses to environmental variations such as temperature and salinity. At molecular level, RSS is correlated with splicing, polyadenylation, protein synthesis, and miRNA biogenesis and functions. In this review, we summarize newly reported methods for probing RSS in vivo and functions and mechanisms of RSS in plant physiology.
Spectroscopic study of the [O iii]λ5007 profile in Seyfert 1 galaxies
Authors: Schmidt Eduardo O , Baravalle Laura D , Rodríguez-Kamenetzky Adriana R
Published: January 2021

The spectra of active galactic nuclei usually exhibit wings in some emission lines, such as [O iii]λλ5007, 4959, with these wings generally being blueshifted and related to strong winds and outflows. The aim of this work was to analyse the [O iii] emission lines in broad-line Seyfert 1 (BLS1) galaxies in order to detect the presence of wings, and to study the [O iii] line properties and their possible connection with the central engine. In addition, we attempted to compare the black hole mass distribution in both BLS1 galaxies with symmetric and blue-asymmetric [O iii] profiles. For this purpose, we carried out a spectroscopic study of a sample of 45 nearby southern BLS1 galaxies from the Six Degree Field Galaxy survey. The [O iii] emission lines were well-fitted using a single Gaussian function in 23 galaxies, while 22 objects presented a wing component and required a double-Gaussian decomposition. By computing the radial velocity difference between the wing and core centroids (i.e. Δv), we found 18 galaxies exhibiting blueshifted wings, 2 objects presenting red wings, and 2 galaxies showing symmetric wings (Δv = 0). Moreover, Δv was slightly correlated with the black hole mass. In addition, we computed the radial velocity difference of the blue-side full extension of the wing relative to the centroid of the core component through the blue emission parameter, which revealed a correlation with black hole mass, in agreement with previous results reported for narrow-line galaxies. Finally, in our sample, similar black hole mass distributions were observed in both BLS1 galaxies with symmetric and blueshifted asymmetric [O iii] profiles.
Pneumococcal Colonization and Virulence Factors Identified Via Experimental Evolution in Infection Models
Authors: Green Angharad E , Howarth Deborah , Chaguza Chrispin , Echlin Haley , Langendonk R Frèdi , Munro Connor , Barton Thomas E , Hinton Jay C D , Bentley Stephen D , Rosch Jason W , Neill Daniel R
Published: January 2021

Streptococcus pneumoniae is a commensal of the human nasopharynx and a major cause of respiratory and invasive disease. We examined adaptation and evolution of pneumococcus, within nasopharynx and lungs, in an experimental system where the selective pressures associated with transmission were removed. This was achieved by serial passage of pneumococci, separately, in mouse models of nasopharyngeal carriage or pneumonia. Passaged pneumococci became more effective colonizers of the respiratory tract and we observed several examples of potential parallel evolution. The cell wall-modifying glycosyltransferase LafA was under strong selection during lung passage, whereas the surface expressed pneumococcal vaccine antigen gene pvaA and the glycerol-3-phosphate dehydrogenase gene gpsA were frequent targets of mutation in nasopharynx-passaged pneumococci. These mutations were not identified in pneumococci that were separately evolved by serial passage on laboratory agar. We focused on gpsA, in which the same single nucleotide polymorphism arose in two independently evolved nasopharynx-passaged lineages. We describe a new role for this gene in nasopharyngeal carriage and show that the identified single nucleotide change confers resistance to oxidative stress and enhanced nasopharyngeal colonization potential. We demonstrate that polymorphisms in gpsA arise and are retained during human colonization. These findings highlight how within-host environmental conditions can determine trajectories of bacterial evolution. Relative invasiveness or attack rate of pneumococcal lineages may be defined by genes that make niche-specific contributions to bacterial fitness. Experimental evolution in animal infection models is a powerful tool to investigate the relative roles played by pathogen virulence and colonization factors within different host niches.
Persistent Spinal Pain Syndrome: A Proposal for Failed Back Surgery Syndrome and ICD-11
Authors: Christelis Nick , Simpson Brian , Russo Marc , Stanton-Hicks Michael , Barolat Giancarlo , Thomson Simon , Schug Stephan , Baron Ralf , Buchser Eric , Carr Daniel B , Deer Timothy R , Dones Ivano , Eldabe Sam , Gallagher Rollin , Huygen Frank , Kloth David , Levy Robert , North Richard , Perruchoud Christophe , Petersen Erika , Rigoard Philippe , Slavin Konstantin , Turk Dennis , Wetzel Todd , Loeser John
Published: January 2021

Objective

For many medical professionals dealing with patients with persistent pain following spine surgery, the term Failed back surgery syndrome (FBSS) as a diagnostic label is inadequate, misleading, and potentially troublesome. It misrepresents causation. Alternative terms have been suggested, but none has replaced FBSS. The International Association for the Study of Pain (IASP) published a revised classification of chronic pain, as part of the new International Classification of Diseases (ICD-11), which has been accepted by the World Health Organization (WHO). This includes the term Chronic pain after spinal surgery (CPSS), which is suggested as a replacement for FBSS.

Methods

This article provides arguments and rationale for a replacement definition. In order to propose a broadly applicable yet more precise and clinically informative term, an international group of experts was established.

Results

14 candidate replacement terms were considered and ranked. The application of agreed criteria reduced this to a shortlist of four. A preferred option—Persistent spinal pain syndrome—was selected by a structured workshop and Delphi process. We provide rationale for using Persistent spinal pain syndrome and a schema for its incorporation into ICD-11. We propose the adoption of this term would strengthen the new ICD-11 classification.

Conclusions

This project is important to those in the fields of pain management, spine surgery, and neuromodulation, as well as patients labeled with FBSS. Through a shift in perspective, it could facilitate the application of the new ICD-11 classification and allow clearer discussion among medical professionals, industry, funding organizations, academia, and the legal profession.
Concordance of Immune-Related Markers in Lymphocytes and Prefrontal Cortex in Schizophrenia
Authors: Gatta Eleonora , Saudagar Vikram , Drnevich Jenny , Forrest Marc P , Auta James , Clark Lindsay V , Sershen Henry , Smith Robert C , Grayson Dennis R , Davis John M , Guidotti Alessandro
Published: January 2021

Schizophrenia is a severe neuropsychiatric disorder associated with a wide array of transcriptomic and neurobiochemical changes. Genome-wide transcriptomic profiling conducted in postmortem brain have provided novel insights into the pathophysiology of this disorder, and identified biological processes including immune/inflammatory-related responses, metabolic, endocrine, and synaptic function. However, few studies have investigated whether similar changes are present in peripheral tissue. Here, we used RNA-sequencing to characterize transcriptomic profiles of lymphocytes in 18 nonpsychotic controls and 19 individuals with schizophrenia. We identified 2819 differentially expressed transcripts (Pnominal < .05) in the schizophrenia group when compared to controls. Bioinformatic analyses conducted on a subset of 293 genes (Pnominal < .01 and |log2 FC| > 0.5) highlighted immune/inflammatory responses as key biological processes in our dataset. Differentially expressed genes in lymphocytes were highly enriched in gene expression profiles associated with cortex layer 5a and immune cells. Thus, we investigated whether the changes in transcripts levels observed in lymphocytes could also be detected in the prefrontal cortex (PFC, BA10) in a second replication cohort of schizophrenia subjects. Remarkably, mRNA levels detected in the PFC and lymphocytes were in strong agreement, and measurements obtained using RNA-sequencing positively correlated with data obtained by reverse transcriptase-quantitative polymerase chain reaction analysis. Collectively, our work supports a role for immune dysfunction in the pathogenesis of schizophrenia and suggests that peripheral markers can be used as accessible surrogates to investigate putative central nervous system disruptions.
Menopausal symptoms in women with premature ovarian insufficiency: prevalence, severity, and associated factors
Authors: Huang Yizhou , Qi Tongyun , Ma Linjuan , Li Die , Li Chunming , Lan Yibing , Chu Ketan , Chen Peiqiong , Xu Wenxian , Cao Yina , Ying Qian , Xu Ling , Zhou Jianhong
Published: January 2021

Objective:

To comprehensively investigate and evaluate the prevalence, severity, and associated factors of menopausal symptoms in women with premature ovarian insufficiency (POI). In this study, the specific symptomatology experienced by women with POI and women with natural menopause was also compared.

Methods:

In this cross-sectional study, 293 Chinese women with POI from an outpatient clinic were recruited between June 2014 and January 2019. The prevalence and severity of menopausal symptoms were assessed with modified Kupperman Menopausal Index. Participants completed a structured questionnaire, including medical history, menstrual characteristics, and sociodemographic data. Serum levels of reproductive hormones were measured.

Results:

Among 293 women with POI (33.76 ± 5.47 y), the most prevalent symptoms were mood swings (73.4%), insomnia (58.7%), sexual problems (58.7%), and fatigue (57.3%). Moderate-to-severe mood swings were most frequently reported (23.9%), followed by formication (17.4%) and hot flashes/sweating (17.1%). Compared with women with natural menopause, women with POI exhibited significantly higher risks for fatigue (odds ratio  = 1.42; 95% confidence interval, 1.04-1.94), melancholia (3.12; 1.94-5.01), mood swings (3.57; 2.33-5.45), insomnia (1.41; 1.02-1.96), and significantly lower risks for moderate-to-severe sexual problems (0.40; 0.23-0.69), any and moderate-to-severe muscle/joint pain (0.41; 0.27-0.62 and 0.45; 0.25-0.78, respectively). Living in urban areas and higher gravidity were independently associated with menopausal symptoms in women with POI.

Conclusions:

Women with POI experienced a high prevalence of menopausal symptoms, particularly related to psychological and sexual domains. Furthermore, women with POI tended to have more distressing menopausal symptoms compared with women with natural menopause.
The influence of gut microbiota in cardiovascular diseases—a brief review
Authors: Almeida Cátia , Barata Pedro , Fernandes Ruben
Published: January 2021

Lately, the gut microbiota has emerged as an important mediator of the development and the outcomes of certain diseases. It's well known that the gut microbiota plays an important role in maintaining human health. Still far from being completely understood and analyzed is the complexity of this ecosystem, although a close relationship between the gut microbiota and cardiovascular diseases (CVD) has been established. A loss of diversity in the microbiota will lead to physiological changes, which can improve inflammatory or infection states like atherosclerosis and hypertension, the basic pathological process of CVD. Targeting the gut microbiota and its metabolites are new and promising strategies for the treatment and prognosis of CVD.
The agent associated with blue dwarf disease in wheat represents a new phytoplasma taxon, ‘Candidatus Phytoplasma tritici’
Authors: Zhao Yan , Wei Wei , Davis Robert E. , Lee Ing-Ming , Bottner-Parker Kristi D.
Published: January 2021

Wheat blue dwarf (WBD) is one of the most economically damaging cereal crop diseases in northwestern PR China. The agent associated with the WBD disease is a phytoplasma affiliated with the aster yellows (AY) group, subgroup C (16SrI-C). Since phytoplasma strains within the AY group are ecologically and genetically diverse, it has been conceived that the AY phytoplasma group may consist of more than one species. This communication presents evidence to demonstrate that, while each of the two 16 rRNA genes of the WBD phytoplasma shares >97.5 % sequence similarity with that of the ‘CandidatusPhytoplasma asteris’ reference strain, the WBD phytoplasma clearly represents an ecologically separated lineage: the WBD phytoplasma not only has its unique transmitting vector (Psammotettix striatus) but also elicits a distinctive symptom in its predominant plant host (wheat). In addition, the WBD phytoplasma possesses molecular characteristics that further manifest its significant divergence from ‘Ca. P. asteris’. Such molecular characteristics include lineage-specific antigenic membrane proteins and a lower than 95 % genome-wide average nucleotide identity score with ‘Ca. P. asteris’. These ecological, molecular and genomic evidences justify the recognition of the WBD phytoplasma as a novel taxon, ‘CandidatusPhytoplasma tritici’.
Photorhabdus heterorhabditis subsp. aluminescens subsp. nov., Photorhabdus heterorhabditis subsp. heterorhabditis subsp. nov., Photorhabdus australis subsp. thailandensis subsp. nov., Photorhabdus australis subsp. australis subsp. nov., and Photorhabdus aegyptia sp. nov. isolated from Heterorhabditis entomopathogenic nematodes
Authors: Machado Ricardo A. R. , Muller Arthur , Ghazal Shimaa M. , Thanwisai Aunchalee , Pagès Sylvie , Bode Helge B. , Hussein Mona A. , Khalil Kamal M. , Tisa Louis S.
Published: January 2021

Three Gram-stain-negative, rod-shaped, non-spore-forming bacteria, BA1T, Q614T and PB68.1T, isolated from the digestive system of Heterorhabditis entomopathogenic nematodes, were biochemically and molecularly characterized to clarify their taxonomic affiliations. The 16S rRNA gene sequences of these strains suggest that they belong to the Gammaproteobacteria, to the family Morganellacea, and to the genus

Photorhabdus

. Deeper analyses using whole genome-based phylogenetic reconstructions suggest that BA1T is closely related to Photorhabdus akhursti, that Q614T is closely related to Photorhabdus heterorhabditis, and that PB68.1T is closely related to Photorhabdus australis. In silico genomic comparisons confirm these observations: BA1T and P. akhursti 15138T share 68.8 % digital DNA–DNA hybridization (dDDH), Q614T and

P. heterorhabditis

SF41T share 75.4 % dDDH, and PB68.1T and

P. australis

DSM 17609T share 76.6  % dDDH. Physiological and biochemical characterizations reveal that these three strains also differ from all validly described

Photorhabdus

species and from their more closely related taxa, contrary to what was previously suggested. We therefore propose to classify BA1T as a new species within the genus

Photorhabdus

, Q614T as a new subspecies within P. heterorhabditis, and PB68.1T as a new subspecies within

P. australis

. Hence, the following names are proposed for these strains: Photorhabdus aegyptia sp. nov. with the type strain BA1T(=DSM 111180T=CCOS 1943T=LMG 31957T),

Photorhabdus heterorhabditis

subsp. aluminescens subsp. nov. with the type strain Q614T (=DSM 111144T=CCOS 1944T=LMG 31959T) and

Photorhabdus australis

subsp. thailandensis subsp. nov. with the type strain PB68.1T (=DSM 111145T=CCOS 1942T). These propositions automatically create

Photorhabdus heterorhabditis

subsp. heterorhabditis subsp. nov. with SF41T as the type strain (currently classified as

P. heterorhabditis

) and

Photorhabdus australis

subsp. australis subsp. nov. with DSM17609T as the type strain (currently classified as

P. australis

).
Myroides fluvii sp. nov., isolated from the Han River, Republic of Korea
Authors: Kim Yong-Seok , Jang Seo-Hyeon , Cha Chang-Jun
Published: January 2021

A Gram-stain-negative, aerobic, short rod-shaped, pale yellow-pigmented, non-motile and gentamycin-resistant bacterial strain designated CJ210T was isolated from the Han River, Republic of Korea. Strain CJ210T grew optimally at 30 °C and pH 7.0 in the absence of NaCl on tryptic soy agar. Flexirubin-type pigments were not produced. Phylogenetic analysis based on 16S rRNA gene sequence similarity showed that strain CJ210T belonged to the genus

Myroides

within the family

Flavobacteriaceae

and was most closely related to

Myroides odoratus

KACC 14347T (98.1 % similarity), followed by

M. injenensis

KCTC 23367T (95.3 % similarity). The average nucleotide identity values between strain CJ210T and two closely related type strains

M. odoratus

KACC 14347T and

M. injenensis

KCTC 23367T were 83.7 and 73.8 %, respectively. The digital DNA–DNA hybridization results between strain CJ210T and the related type strains were 27.5 and 20.2 %, respectively. Strain CJ210T contained menaquinone 6 (MK-6) as the predominant menaquinone. The predominant polar lipids were phosphatidylethanolamine, two unidentified aminolipids and two unidentified lipids. The major fatty acids of strain CJ210T were iso-C15 : 0, iso-C17 : 0 3-OH and summed feature 9 (comprising iso-C17 : 1
 ω9c and/or C16 : 0 10-methyl). Whole genome sequencing revealed that strain CJ210T had a genome of 3.8 Mbp with 36.5 % DNA G+C content. The genome contained several antimicrobial resistance genes including an aminoglycoside-resistant gene. On the basis of the polyphasic taxonomic study, strain CJ210T represents a novel species in the genus

Myroides

, for which name Myrodies fluvii sp. nov. is proposed. The type strain is CJ210T (=KACC 19954T=JCM 33306T).
Modelling the effects of cerebral microthrombi on tissue oxygenation and cell death
Authors: Xue Yidan , El-Bouri Wahbi K. , Józsa Tamás I. , Payne Stephen J.
Published: January 2021

Thrombectomy, the mechanical removal of a clot, is the most common way to treat ischaemic stroke with large vessel occlusions. However, perfusion cannot always be restored after such an intervention. It has been hypothesised that the absence of reperfusion is due to the clot fragments that block the downstream vessels. In this paper, we present a new way of quantifying the effects of cerebral microthrombi on oxygen transport to tissue in terms of hypoxia and ischaemia. The oxygen transport was simulated with the Green’s function method on physiologically accurate microvascular cubes, which was found independent of both microvascular geometry and length scale. The microthrombi occlusions were then simulated in the microvasculature, which were extravasated over time with a new vessel extravasation model. The tissue hypoxic fraction was fitted as a sigmoidal function of vessel blockage fraction, which was then taken to be a function of time after the formation of microthrombi occlusions. A novel hypoxia-based 3-state cell death model was finally proposed to simulate the hypoxic tissue damage over time. Using the cell death model, the impact of a certain degree of microthrombi occlusions on tissue viability and microinfarct volume can be predicted over time. Quantifying the impact of microthrombi on oxygen transport and tissue death will play an important role in full brain models of ischaemic stroke and thrombectomy.
Rise-to-threshold and dynamical systems views of proactive inhibition
Authors: Rawji Vishal , Modi Sachin , Rocchi Lorenzo , Jahanshahi Marjan , Rothwell John C.
Published: January 2021

Successful models of movement should encompass the flexibility of the human motor system to execute movements under different contexts. One such context-dependent modulation is proactive inhibition, a type of behavioural inhibition concerned with responding with restraint. Whilst movement has classically been modelled as a rise-to-threshold process, there exists a lack of empirical evidence for this in limb movements. Alternatively, the dynamical systems view conceptualises activity during motor preparation as setting the initial state of a dynamical system, that evolves into the movement upon receipt of a trigger. We tested these models by measuring how proactive inhibition influenced movement preparation and execution in humans. We changed the orientation (PA: postero-anterior and AP: antero-posterior flowing currents) and pulse width (120 μs and 30 μs) of motor cortex transcranial magnetic stimulation to probe different corticospinal interneuron circuits. PA and AP interneuron circuits represent the dimensions of a state space upon which motor cortex activity unfolds during motor preparation and execution. AP30inputs were inhibited at the go cue, regardless of proactive inhibition, whereas PA120inputs scaled inversely with the probability of successful inhibition. When viewed through a rise-to-threshold model, proactive inhibition was implemented by delaying the trigger to move, suggesting that motor preparation and execution are independent. A dynamical systems perspective showed that proactive inhibition was marked by a shift in the distribution of interneuron networks (trajectories) during movement execution, despite normalisation for reaction time. Viewing data through the rise-to-threshold and dynamical systems models reveal complimentary mechanisms by which proactive inhibition is implemented.

Key points

We view proactive inhibition through the rise-to-threshold and dynamical systems models.

We change the orientation (PA: postero-anterior and AP: antero-posterior flowing currents) and pulse width (120 μs and 30 μs) of transcranial magnetic stimulation to probe interneuron networks in motor cortex during behavioural tasks employing proactive inhibition.

When viewed through a rise-to-threshold model, proactive inhibition was implemented by delaying the trigger to move, suggesting that motor preparation and execution are independent.

A dynamical systems perspective showed that despite normalisation for reaction time, the trajectory/balance between PA120and AP30interneuron inputs during movement execution depended on proactive inhibition.

Viewing data through the rise-to-threshold and dynamical systems models reveal complimentary mechanisms by which proactive inhibition is implemented.
Microfluidic Electric Egg-Laying Assay and Application toIn-vivoToxicity Screening of Microplastics usingC. elegans
Authors: Youssef Khaled , Archonta Daphne , Kubiseseki Terrance J. , Tandon Anurag , Rezai Pouya
Published: January 2021

Environmental pollutants like microplastics are posing health concerns on aquatic animals and the ecosystem. Microplastic toxicity studies usingC. elegansas a model are evolving but methodologically hindered from obtaining statistically strong data sets, detecting toxicity effects based on microplastics uptake, and correlating physiological and behavioural effects at an individual-worm level. In this paper, we report a novel microfluidic electric egg-laying assay for phenotypical assessment of multiple worms in parallel. The effects of glucose and polystyrene microplastics at various concentrations on the worms’ electric egg-laying, length, diameter, and length contraction during exposure to electric signal were studied. The device contained eight parallel worm-dwelling microchannels called electric traps, with equivalent electrical fields, in which the worms were electrically stimulated for egg deposition and fluorescently imaged for assessment of neuronal and microplastic uptake expression. A new bidirectional stimulation technique was developed, and the device design was optimized to achieve a testing efficiency of 91.25%. Exposure of worms to 100mM glucose resulted in a significant reduction in their egg-laying and size. The effects of 1μm polystyrene microparticles at concentrations of 100 and 1000 mg/L on the electric egg-laying behaviour, size, and neurodegeneration of N2 and NW1229 (expressing GFP pan-neuronally) worms were also studied. Of the two concentrations, 1000 mg/L caused severe egg-laying deficiency and growth retardation as well as neurodegeneration. Additionally, using single-worm level phenotyping, we noticed intra-population variability in microplastics uptake and correlation with the above physiological and behavioural phenotypes, which was hidden in the population-averaged results. Taken together, these results suggest the appropriateness of our microfluidic assay for toxicological studies and for assessing the phenotypical heterogeneity in response to microplastics.
Intracranial electrical stimulation alters meso-scale network integration as a function of network topology
Authors: Thompson WH , Esteban O , Oya H , Nair R , Eberhardt F , Dubois J , Poldrack RA , Adolphs R , Shine JM
Published: January 2021

Human brain dynamics are organized into a multi-scale network structure that contains multiple tight-knit, meso-scale communities. Recent work has demonstrated that many psychological capacities, as well as impairments in cognitive function secondary to damage, can be mapped onto organizing principles at this mesoscopic scale. However, we still don’t know the rules that govern the dynamic interactions between regions that are constrained by the topology of the broader network. In this preregistered study, we utilized a unique human dataset in which whole brain BOLD-fMRI activity was recorded simultaneously with intracranial electrical stimulation, to characterize the effects of direct neural stimulation on the dynamic reconfiguration of the broader network. Direct neural stimulation increased the extent to which the stimulation site’s own mesoscale community integrated with the rest of the brain. Further, we found that these network changes depended on the topological role of the stimulation site itself: stimulating regions with high participation coefficients led to global integration, whereas stimulating sites with low participation coefficients integrated that regions’ own community with the rest of the brain. These findings provide direct causal evidence for how network topology shapes and constrains inter-regional coordination, and suggest applications for targeted therapeutic interventions in patients with deep-brain stimulation.
Enhanced CICR activity reduces ER Ca2+level in cells expressing CPVT-linked mutant RyR2
Authors: Kurebayashi Nagomi , Murayama Takashi , Ohta Ryosaku , Suzuki Junji , Kanemaru Kazunori , Ohno Seiko , Horie Minoru , Iino Masamitsu , Yamashita Fumiyoshi , Sakurai Takashi
Published: January 2021

Type 2 ryanodine receptor (RyR2) is a cardiac Ca2+release channel in the endoplasmic reticulum (ER). Mutations in RyR2 are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), which is considered to be associated with enhanced spontaneous Ca2+release. This spontaneous Ca2+release tends to occur when ER Ca2+([Ca2+]ER) reaches a certain threshold level, and CPVT mutations are reported to lower this threshold. There are two explanations for this lowered threshold: the mutations increase sensitivity to luminal Ca2+or they enhance cytosolic [Ca2+] ([Ca2+]cyt)-induced Ca2+release (CICR) activity. However, no quantitative analysis of this issue has been performed so far. Here, we quantitatively explored how the change in CICR activity of RyR2 affects the threshold [Ca2+]ERexperimentally and by model-based simulation. Wild-type (WT) and CPVT-linked mutant RyR2s were expressed in HEK293 cells. [Ca2+]cytand [Ca2+]ERmeasurements with Ca2+indicators revealed that CPVT RyR2 cells showed higher oscillation frequency and lower threshold [Ca2+]ERin a mutation-specific manner compared with WT cells. The CICR activity of mutant RyR2s was assessed by Ca2+-dependent [3H]ryanodine binding and parameter analysis. CICR activity at resting [Ca2+]cyt, A7.0, was higher in CPVT mutants than in WT and a strong inverse correlation was found between threshold [Ca2+]ERand A7.0. Interestingly, lowering RyR2 expression increased threshold [Ca2+]ER, suggesting that the threshold [Ca2+]ERdepends on net Ca2+release rate via RyR2, a product of A7.0for each mutant and the density of RyR2 molecules. A model-based simulation successfully reproduced the [Ca2+]cytand [Ca2+]ERchanges. Interestingly, the CICR activity associated with specific mutations correlated well with the age of onset of the disease in CPVT patients carrying the mutations. Our data suggest that the reduction in threshold [Ca2+]ERfor spontaneous Ca2+release by CPVT mutation is explained by enhanced CICR activity without considering a change in the [Ca2+]ERsensitivity of RyR2.

CPVT-linked RyR2 mutations are prone to induce spontaneous Ca2+release from ER, which is strongly associated with arrhythmias. Kurebayashi et al. quantitatively explore how the changes in CICR activity by RyR2 mutations affect spontaneous Ca2+experimentally and by model simulation.
A Pan-Respiratory Antiviral Chemotype Targeting a Host Multi-Protein Complex
Authors: Michon Maya , Müller-Schiffmann Andreas , Lingappa Anuradha F. , Yu Shao Feng , Du Li , Deiter Fred , Broce Sean , Mallesh Suguna , Crabtree Jackelyn , Lingappa Usha F. , Macieik Amanda , Müller Lisa , Ostermann Philipp Niklas , Andrée Marcel , Adams Ortwin , Schaal Heiner , Hogan Robert J. , Tripp Ralph A. , Appaiah Umesh , Anand Sanjeev K. , Campi Thomas W. , Ford Michael J. , Reed Jonathan C. , Lin Jim , Akintunde Olayemi , Copeland Kiel , Nichols Christine , Petrouski Emma , Moreira A. Raquel , Jiang I-ting , DeYarman Nicholas , Brown Ian , Lau Sharon , Segal Ilana , Goldsmith Danielle , Hong Shi , Asundi Vinod , Briggs Erica M. , Phyo Ngwe Sin , Froehlich Markus , Onisko Bruce , Matlack Kent , Dey Debendranath , Lingappa Jaisri R. , Prasad M. Dharma , Kitaygorodskyy Anatoliy , Solas Dennis , Boushey Homer , Greenland John , Pillai Satish , Lo Michael K. , Montgomery Joel M. , Spiropoulou Christina F. , Korth Carsten , Selvarajah Suganya , Paulvannan Kumar , Lingappa Vishwanath R.
Published: January 2021

We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious virus in multiple cell culture models for all six families of viruses causing most respiratory disease in humans. In animals this chemotype has been demonstrated efficacious for Porcine Epidemic Diarrhea Virus (a coronavirus) and Respiratory Syncytial Virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral lifecycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.
Intact synapse structure and function after combined knockout of PTPδ, PTPσ and LAR
Authors: Emperador-Melero Javier , de Nola Giovanni , Kaeser Pascal S.
Published: January 2021

It has long been proposed that Leukocyte common Antigen-Related Receptor Protein Tyrosine Phosphatases (LAR-RPTPs) are cell-adhesion proteins for the control of synapse assembly. Their synaptic nanoscale localization, however, has not been established, and the fine structure of synapses after knockout of the three vertebrate genes for LAR-RPTPs (PTPδ, PTPσ and LAR) has not been tested. Here, we find that PTPδ is precisely apposed to postsynaptic scaffolds at excitatory and inhibitory synapses using superresolution microscopy. We generated triple-conditional knockout mice for PTPδ, PTPσ and LAR to test whether they are essential for synapse structure. While mild effects on synaptic vesicle clustering and active zone architecture were detected, synapse numbers and their overall structure were unaffected, membrane anchoring of the active zone persisted, and vesicle docking and release were normal. We conclude that LAR-RPTPs, despite their localization at synaptic appositions, are dispensable for the organization and function of presynaptic nerve terminals.
Local Shape Descriptors for Neuron Segmentation
Authors: Sheridan Arlo , Nguyen Tri , Deb Diptodip , Lee Wei-Chung Allen , Saalfeld Stephan , Turaga Srini , Manor Uri , Funke Jan
Published: January 2021

We present a simple, yet effective, auxiliary learning task for the problem of neuron segmentation in electron microscopy volumes. The auxiliary task consists of the prediction of Local Shape Descriptors (LSDs), which we combine with conventional voxel-wise direct neighbor affinities for neuron boundary detection. The shape descriptors are designed to capture local statistics about the neuron to be segmented, such as diameter, elongation, and direction. On a large study comparing several existing methods across various specimen, imaging techniques, and resolutions, we find that auxiliary learning of LSDs consistently increases segmentation accuracy of affinity-based methods over a range of metrics. Furthermore, the addition of LSDs promotes affinity-based segmentation methods to be on par with the current state of the art for neuron segmentation (Flood-Filling Networks, FFN), while being two orders of magnitudes more efficient—a critical requirement for the processing of future petabyte-sized datasets. Implementations of the new auxiliary learning task, network architectures, training, prediction, and evaluation code, as well as the datasets used in this study are publicly available as a benchmark for future method contributions.
A genomic perspective across Earth’s microbiomes reveals that genome size in Archaea and Bacteria is linked to ecosystem type and trophic strategy
Authors: Rodríguez-Gijón Alejandro , Nuy Julia K. , Mehrshad Maliheh , Buck Moritz , Schulz Frederik , Woyke Tanja , Garcia Sarahi L.
Published: January 2021

Our view of genome size in Archaea and Bacteria has remained skewed as the data used to paint its picture has been dominated by genomes of microorganisms that can be cultivated under laboratory settings. However, the continuous effort to catalog the genetic make-up of Earth’s microbiomes specifically propelled by recent extensive work on uncultivated microorganisms, provides a unique opportunity to revise our perspective on genome size distribution. Capitalizing on a recently released extensive catalog of tens of thousands of metagenome-assembled genomes, we provide a comprehensive overview of genome size distributions. We observe that the known phylogenetic diversity of environmental microorganisms possesses significantly smaller genomes than the collection of laboratory isolated microorganisms. Aquatic microorganisms average 3.1 Mb, host-associated microbial genomes average 3.0 Mb, terrestrial microorganism average 3.7 Mb and isolated microorganisms average 4.3 Mb. While the environment where the microorganisms live can certainly be linked to genome size, in some cases, evolutionary phylogenetic history can be a stronger predictor. Moreover, ecological strategies such as auxotrophies have a direct impact on genome size. To better understand the ecological drivers of genome size, we expand on the known and the overlooked factors that influence genome size in different environments, phylogenetic groups and trophic strategies.
Selection for feed efficiency elicits different postprandial plasma metabolite profiles in response to poor hygiene of housing conditions in growing pigs
Authors: Fraga Alícia Zem , Louveau Isabelle , Campos Paulo Henrique Reis Furtado , Hauschild Luciano , Le Floc’h Nathalie
Published: January 2021

Selection for residual feed intake (RFI), a measure of feed efficiency, may affect the ability of pigs to adapt their metabolism in response to poor environmental conditions. This study was conducted to compare postprandial plasma concentrations of insulin, energy related metabolites, and amino acids measured after a 6-week challenge consisting of exposure to good or poor hygiene of housing conditions of 24 growing pigs divergently selected for low-RFI (LRFI) and high-RFI (HRFI). Blood indicators of immune responses were assessed from samples collected before (week 0 or W0), and 3 (W3) and 6 weeks (W6) after pigs transfer to their respective housing hygiene conditions. Plasma haptoglobin concentrations and blood neutrophil granulocyte numbers were greater in poor than in good conditions at W3. Plasma concentrations of total immunoglobulin G were greater (p= 0.04) in poor than in good hygiene conditions at W6. At W6, pigs were fitted with an intravenous catheter for serial blood samplings. Low-RFI pigs had greater insulin (p< 0.001) and lower triglyceride (p= 0.04) average plasma concentrations than HRFI pigs in both conditions. In poor hygiene conditions, the peaks of insulin and glucose occured earlier and that of insulin was greater in LRFI than in HRFI pigs. Irrespective of genetic line, average plasma concentrations of histidine, isoleucine, leucine, methionine, threonine, valine, and alanine were greater in poor compared with good conditions. Only HRFI pigs had greater lysine, asparagine, proline, and tyrosine plasma concentrations in poor than in good hygiene conditions. Conversely, arginine, tryptophan, proline, and tyrosine plasma concentrations were lower only for LRFI pigs housed in poor hygiene conditions. The impact of poor hygiene of housing conditions on insulin, triglycerides, and AA profiles differed between RFI lines. More specifically, our results suggest that, contrary to HRFI, LRFI pigs increased or maintained their utilization of Trp, Arg, and Lys when housed in poor hygiene conditions. This difference may contribute to the better capacity of LRFI to cope with the poor hygiene of housing conditions.