bluuebunny/crossref_metadata_2025 huggingface dataset:
Optical Coherence Tomography Neuro-Toolbox for the Diagnosis and Management of Papilledema, Optic Disc Edema, and Pseudopapilledema
Authors: Sibony Patrick A. , Kupersmith Mark J. , Kardon Randy H.
Published: September 2020

Background:

Distinguishing optic disc edema from pseudopapilledema is a common, sometimes challenging clinical problem. Advances in spectral-domain optical coherence tomography (SD-OCT) of the optic nerve head (ONH) has proven to be a cost effective, noninvasive, outpatient procedure that may help. At its core are tools that quantify the thickness of the retinal nerve fiber layer (RNFL) and ganglion cell–inner plexiform layer (GC-IPL). The SD-OCT also provides a set of tools that may be qualitatively interpreted in the same way that we read an MRI. They include the transverse axial, en face, and circular tomogram. Our goal is to describe a practical office-based set of tools using SD-OCT in the diagnosis and monitoring of papilledema, optic disc edema, and pseudopapilledema.

Evidence Acquisition:

Searches on PubMed were performed using combinations of the following key words: OCT, papilledema, pseudopapilledema, optic disc drusen, retinal folds (RF), and choroidal folds (CF).

Results:

The principal elements of SD-OCT analysis of the ONH are the RNFL and GC-IPL thickness; however, these metrics have limitations when swelling is severe. Qualitative interpretation of the transverse axial SD-OCT aids in assessing peripapillary shape that may help distinguish papilledema from pseudopapilledema, evaluate atypical optic neuropathies, diagnose shunt failures, and identify outer RF and CF. There is a consensus that the SD-OCT is the most sensitive way of identifying buried optic disc drusen. En face SD-OCT is especially effective at detecting peripapillary wrinkles and outer retinal creases, both of which are common and distinctive signs of optic disc edema that rule out pseudopapilledema. Mechanically stressing the ONH in the adducted eye position, in patients with papilledema, may expose folds and peripapillary deformations that may not be evident in primary position. We also discuss how to optimize the acquisition and registration of SD-OCT images.

Conclusions:

The SD-OCT is not a substitute for a complete history and a careful examination. It is, however, a convenient ancillary test that aids in the diagnosis and management of papilledema, optic disc edema, and pseudopapilledema. It is particularly helpful in monitoring changes over the course of time and distinguishing low-grade papilledema from buried drusen. The application of the SD-OCT toolbox depends on optimizing the acquisition of images, understanding its limitations, recognizing common artifacts, and accurately interpreting images in the context of both history and clinical findings.
Computing and optimizing over all fixed-points of discrete systems on large networks
Authors: Riehl James R. , Zimmerman Maxwell I. , Singh Matthew F. , Bowman Gregory R. , Ching ShiNung
Published: September 2020

Equilibria, or fixed points, play an important role in dynamical systems across various domains, yet finding them can be computationally challenging. Here, we show how to efficiently compute all equilibrium points of discrete-valued, discrete-time systems on sparse networks. Using graph partitioning, we recursively decompose the original problem into a set of smaller, simpler problems that are easy to compute, and whose solutions combine to yield the full equilibrium set. This makes it possible to find the fixed points of systems on arbitrarily large networks meeting certain criteria. This approach can also be used without computing the full equilibrium set, which may grow very large in some cases. For example, one can use this method to check the existence and total number of equilibria, or to find equilibria that are optimal with respect to a given cost function. We demonstrate the potential capabilities of this approach with examples in two scientific domains: computing the number of fixed points in brain networks and finding the minimal energy conformations of lattice-based protein folding models.
Uncertainty quantification reveals the physical constraints on pumping by peristaltic hearts
Authors: Waldrop Lindsay D. , He Yanyan , Battista Nicholas A. , Neary Peterman Tess , Miller Laura A.
Published: September 2020

Most biological functional systems are complex, and this complexity is a fundamental driver of diversity. Because input parameters interact in complex ways, a holistic understanding of functional systems is key to understanding how natural selection produces diversity. We present uncertainty quantification (UQ) as a quantitative analysis tool on computational models to study the interplay of complex systems and diversity. We investigate peristaltic pumping in a racetrack circulatory system using a computational model and analyse the impact of three input parameters (Womersley number, compression frequency, compression ratio) on flow and the energetic costs of circulation. We employed two models of peristalsis (one that allows elastic interactions between the heart tube and fluid and one that does not), to investigate the role of elastic interactions on model output. A computationally cheaper surrogate of the input parameter space was created with generalized polynomial chaos expansion to save computational resources. Sobol indices were then calculated based on the generalized polynomial chaos expansion and model output. We found that all flow metrics were highly sensitive to changes in compression ratio and insensitive to Womersley number and compression frequency, consistent across models of peristalsis. Elastic interactions changed the patterns of parameter sensitivity for energetic costs between the two models, revealing that elastic interactions are probably a key physical metric of peristalsis. The UQ analysis created two hypotheses regarding diversity: favouring high flow rates (where compression ratio is large and highly conserved) and minimizing energetic costs (which avoids combinations of high compression ratios, high frequencies and low Womersley numbers).
Flagellar kinematics reveals the role of environment in shaping sperm motility
Authors: Guasto Jeffrey S. , Estrada Jonathan B. , Menolascina Filippo , Burton Lisa J. , Patel Mohak , Franck Christian , Hosoi A. E. , Zimmer Richard K. , Stocker Roman
Published: September 2020

Swimming spermatozoa from diverse organisms often have very similar morphologies, yet different motilities as a result of differences in the flagellar waveforms used for propulsion. The origin of these differences has remained largely unknown. Using high-speed video microscopy and mathematical analysis of flagellar shape dynamics, we quantitatively compare sperm flagellar waveforms from marine invertebrates to humans by means of a novel phylokinematic tree. This new approach revealed that genetically dissimilar sperm can exhibit strikingly similar flagellar waveforms and identifies two dominant flagellar waveforms among the deuterostomes studied here, corresponding to internal and external fertilizers. The phylokinematic tree shows marked discordance from the phylogenetic tree, indicating that physical properties of the fluid environment, more than genetic relatedness, act as an important selective pressure in shaping the evolution of sperm motility. More broadly, this work provides a physical axis to complement morphological and genetic studies to understand evolutionary relationships.
Frontal plane dynamics of the centre of mass during quadrupedal locomotion on a split-belt treadmill
Authors: Latash E. M. , Barnett W. H. , Park H. , Rider J. M. , Klishko A. N. , Prilutsky B. I. , Molkov Y. I.
Published: September 2020

Our previous study of cat locomotion demonstrated that lateral displacements of the centre of mass (COM) were strikingly similar to those of human walking and resembled the behaviour of an inverted pendulum (Parket al.2019J. Exp. Biol.222, 14. (doi:10.1242/jeb.198648)). Here, we tested the hypothesis that frontal plane dynamics of quadrupedal locomotion are consistent with an inverted pendulum model. We developed a simple mathematical model of balance control in the frontal plane based on an inverted pendulum and compared model behaviour with that of four cats locomoting on a split-belt treadmill. The model accurately reproduced the lateral oscillations of cats' COM vertical projection. We inferred the effects of experimental perturbations on the limits of dynamic stability using data from different split-belt speed ratios with and without ipsilateral paw anaesthesia. We found that the effect of paw anaesthesia could be explained by the induced bias in the perceived position of the COM, and the magnitude of this bias depends on the belt speed difference. Altogether, our findings suggest that the balance control system is actively involved in cat locomotion to provide dynamic stability in the frontal plane, and that paw cutaneous receptors contribute to the representation of the COM position in the nervous system.
Do infants and preschoolers quantify probabilities based on proportions?
Authors: Placì Sarah , Fischer Julia , Rakoczy Hannes
Published: September 2020

Most statistical problems encountered throughout life require the ability to quantify probabilities based on proportions. Recent findings on the early ontogeny of this ability have been mixed: For example, when presented with jars containing preferred and less preferred items, 12-month-olds, but not 3- and 4-years-olds, seem to rely on the proportions of objects in the jars to predict the content of samples randomly drawn out of them. Given these contrasting findings, it remains unclear what the probabilistic reasoning abilities of young children are and how they develop. In our study, we addressed this question and tested, with identical methods across age groups and similar methods to previous studies, whether 12-month-olds and 3- and 4-years-olds rely on proportions of objects to estimate probabilities of random sampling events. Results revealed that neither infants nor preschoolers do. While preschoolers' performance is in line with previous findings, infants' performance is difficult to interpret given their failure in a control condition in which the outcomes happened with certainty rather than a graded probability. More systematic studies are needed to explain why infants succeeded in a previous study but failed in our study.
Centre of pressure versus centre of mass stabilization strategies: the tightrope balancing case
Authors: Morasso Pietro
Published: September 2020

This study proposes a generalization of the ankle and hip postural strategies to be applied to the large class of skills that share the same basic challenge of defeating the destabilizing effect of gravity on the basis of the same neuromotor control organization, adapted and specialized to a variable number of degrees of freedom, different body parts, different muscles and different sensory feedback channels. In all the cases, we can identify two crucial elements (the CoP, centre of pressure and the CoM, centre of mass) and the central point of the paper is that most balancing skills can be framed in the CoP–CoM interplay and can be modelled as a combination/alternation of two basic stabilization strategies: the standard well-investigated
COPS
(or CoP stabilization strategy, the default option), where the CoM is the controlled variable and the CoP is the control variable, and the less investigated
COMS
(or CoM stabilization strategy), where CoP and CoM must exchange their role because the range of motion of the CoP is strongly constrained by environmental conditions. The paper focuses on the tightrope balancing skill where sway control in the sagittal plane is modelled in terms of the
COPS
while the more challenging sway in the coronal plane is modelled in terms of the
COMS,
with the support of a suitable balance pole. Both stabilization strategies are implemented as state-space intermittent, delayed feedback controllers, independent of each other. Extensive simulations support the degree of plausibility, generality and robustness of the proposed approach.
Composite amine mixed matrix membranes for high-pressure CO
2
-CH
4
separation: synthesis, characterization and performance evaluation
Authors: Fauzan Nur Aqilah Bt , Mukhtar Hilmi , Nasir Rizwan , Mohshim Dzeti Farhah Bt , Arasu Naviinthiran , Man Zakaria , Mannan Hafiz Abdul
Published: September 2020

The key challenge in the synthesis of composite mixed matrix membrane (MMMs) is the incompatible membrane fabrication using porous support in the dry–wet phase inversion technique. The key objective of this research is to synthesize thin composite ternary (amine) mixed matrix membranes on microporous support by incorporating 10 wt% of carbon molecular sieve (CMS) and 5–15 wt% of diethanolamine (DEA) in polyethersulfone (PES) dope solution for the separation of carbon dioxide (CO
2
) from methane (CH
4
) at high-pressure applications. The developed membranes were evaluated for their morphological structure, thermal and mechanical stabilities, functional groups, as well as for CO
2
-CH
4
separation performance at high pressure (10–30 bar). The results showed that the developed membranes have asymmetric structure, and they are mechanically strong at 30 bar. This new class of PES/CMS/DEA composite MMMs exhibited improved gas permeance compared to pure PES composite polymeric membrane. CO
2
-CH
4
perm-selectivity enhanced from 8.15 to 16.04 at 15 wt% of DEA at 30 bar pressure. The performance of amine composite MMMs is theoretically predicted using a modified Maxwell model. The predictions were in good agreement with experimental data after applying the optimized values with AARE % = ∼less than 2% and
R
2
= 0.99.
Synthesis of a novel aluminium salt of nitrogen-containing alkylphosphinate with high char formation to flame retard acrylonitrile–butadiene–styrene
Authors: Yang Xue , Wang Hao , Liu Xueqing , Liu Jiyan
Published: September 2020

A novel nitrogen-containing alkylphosphinate salt—aluminium β-(p-nitrobenzamide) ethyl methyl phosphinate (AlNP) was synthesized and used to flame retard acrylonitrile–butadiene–styrene copolymer (ABS). The Fourier transform infrared spectrometry,
1
H,
13
C and
31
P nuclear magnetic resonance and X-ray fluorescent spectroscopy (XRF) were applied to characterize the structure and composition of products. The flame retardancy performance, thermal properties and mechanical strength of the ABS/AlNP with respect to AlNP loading were investigated. AlNP was stable before 330°C and decomposed very slowly with residues high up to 56.1% at 700°C. Adding 25–30 wt% of AlNP alone can make ABS to pass V0 rating in the vertical burning tests (UL 94). The results according to the micro combustion calorimeter, thermogravimetric analysis showed that AlNP can depress the heating release and retard the thermal degradation of the ABS. Scanning electron microscopy observation of the residues from LOI test indicated that AlNP formed the condensed and tough residues layer during combustion; XRF analysis showed that the residues contained phosphorus and aluminium element and nitrogen element was not detected. The compact phosphorus/aluminium-rich substance acted as a barrier to enhance flame-retardant properties of the ABS.
Effect of
p
-TsOH pretreatment on separation of bagasse components and preparation of nanocellulose filaments
Authors: Feng Chengqi , Du Juan , Wei Shuai , Qin Chengrong , Liang Chen , Yao Shuangquan
Published: September 2020

The efficient separation of bagasse components was achieved by
p
-toluenesulfonic acid (
p
-TsOH) pretreatment. The effects of
p
-TsOH dosage, reaction temperature and reaction time on cellulose, hemicellulose and lignin contents were studied. Eighty-five per cent of lignin was dissolved, whereas the cellulose loss was minimal (less than 8.1%). Cellulose-rich water-insoluble residual solids were obtained. The degree of polymerization of cellulose decreased slightly, but the crystallinity index (CrI) increased from 52.0% to 68.1%. It indicated that the highly efficient delignification of bagasse was achieved by
p
-TsOH pretreatment. The nanocellulose filaments (CNFs) were produced by the treated samples. The physico-chemical properties of CNFs were characterized by transmission electron microscopy and thermogravimetric analysis. The results show that the CNFs have smaller average size and higher thermal stability. It provides a new method for CNFs.
Enhancing the expression of
ARK1
genes in poplar leads to multiple branches and transcriptomic changes
Authors: Liu Xiaozhen , Zhang Zhiming , Bian Wen , Duan Anan , Zhang Hanyao
Published: September 2020

The
ARBORKNOX1
(
ARK1
) gene is an important gene for regulating plant growth and development; however, transcriptomic responses of enhancing expression of
ARK1
gene in poplar are poorly investigated. To provide insight into the gene function of the
ARK1
gene in poplar, the
ARK1
transgenic poplar ‘717' and ‘84 K' lines were obtained, the morphology of transgenic plants was observed, and transcriptome profiles were compared. The results showed that there were multiple branches in
ARK1
transgenic seedlings compared with non-transgenic seedlings. The results of transcriptome analysis showed that there were significant differences in transcriptome profiles between the transgenic lines of ‘717' and ‘84 K', and between non-transgenic lines (CK) and transgenic plants. The real-time quantitative polymerase chain reaction (RT-qPCR) analysis confirmed the expression levels of the genes involved in the pathway of zeatin biosynthesis and brassinosteroid biosynthesis. The increase in expression levels of
AHP
and
CYCD3
was related to multiple branches. Enhancing the expression of the
ARK1
gene in poplar seedlings leads to multiple branches and transcriptomic changes.
Varroa destructor
infestation impairs the improvement of landing performance in foraging honeybees
Authors: Muijres Florian T. , van Dooremalen Coby , Lankheet Martin , Lugt Heleen , de Vries Lana J. , Van Langevelde Frank
Published: September 2020

The parasitic mite
Varroa destructor
is an important contributor to the high losses of western honeybees. Forager bees from
Varroa
-infested colonies show reduced homing and flight capacity; it is not known whether flight manoeuvrability and related learning capability are also affected. Here, we test how honeybees from
Varroa
-infested and control colonies fly in an environment that is unfamiliar at the beginning of each experimental day. Using stereoscopic high-speed videography, we analysed 555 landing manoeuvres recorded during 12 days of approximately 5 h in length. From this, we quantified landing success as percentage of successful landings, and assessed how this changed over time. We found that the forager workforce of
Varroa
-infested colonies did not improve their landing success over time, while for control bees landing success improved with approximately 10% each hour. Analysis of the landing trajectories showed that control bees improved landing success by increasing the ratio between in-flight aerodynamic braking and braking at impact on the landing platform; bees from
Varroa
-infested colonies did not increase this ratio over time. The
Varroa
-induced detriment to this landing skill-learning capability might limit forager bees from
Varroa
-infested colonies to adapt to new or challenging conditions; this might consequently contribute to
Varroa
-induced mortality of honeybee colonies.
Oxidative costs of cooperation in cooperatively breeding Damaraland mole-rats
Authors: Mendonça Rute , Vullioud Philippe , Katlein Nathan , Vallat Armelle , Glauser Gaétan , Bennett Nigel C. , Helfenstein Fabrice
Published: September 2020

Within cooperatively breeding societies, individuals adjust cooperative contributions to maximize indirect fitness and minimize direct fitness costs. Yet, little is known about the physiological costs of cooperation, which may be detrimental to direct fitness. Oxidative stress, the imbalance between reactive oxygen species (by-products of energy production) and antioxidant protection, may represent such a cost when cooperative behaviours are energetically demanding. Oxidative stress can lead to the accumulation of cellular damage, compromising survival and reproduction, thus mediating the trade-off between these competing life-history traits. Here, we experimentally increased energetically demanding cooperative contributions in captive Damaraland mole-rats (Fukomys damarensis). We quantified oxidative stress-related effects of increased cooperation on somatic and germline tissues, and the trade-off between them. Increased cooperative contributions induced oxidative stress in females and males, without increasing somatic damage. Males accumulated oxidative damage in their germline despite an increase in antioxidant defences. Finally, oxidative damage accumulation became biased towards the germline, while antioxidant protection remained biased towards the soma, suggesting that males favour the maintenance of somatic tissues (i.e. survival over reproduction). Our results show that heightened cooperative contributions can ultimately affect direct fitness through oxidative stress costs, which may represent a key selective pressure for the evolution of cooperation.
Reproducibility of leftward planum temporale asymmetries in two genetically isolated populations of chimpanzees (
Pan troglodytes
)
Authors: Spocter Muhammad A. , Sherwood Chet C. , Schapiro Steven J. , Hopkins William D.
Published: September 2020

Once considered a hallmark of human uniqueness, brain asymmetry has emerged as a feature shared with several other species, including chimpanzees, one of our closest living relatives. Most notable has been the discovery of asymmetries in homologues of cortical language areas in apes, particularly in the planum temporale (PT), considered a central node of the human language network. Several lines of evidence indicate a role for genetic mechanisms in the emergence of PT asymmetry; however, the genetic determinants of cerebral asymmetries have remained elusive. Studies in humans suggest that there is heritability of brain asymmetries of the PT, but this has not been explored to any extent in chimpanzees. Furthermore, the potential influence of non-genetic factors has raised questions about the reproducibility of earlier observations of PT asymmetry reported in chimpanzees. As such, the present study was aimed at examining both the heritability of phenotypic asymmetries in PT morphology, as well as their reproducibility. Using magnetic resonance imaging, we evaluated morphological asymmetries of PT surface area (mm
2
) and mean depth (mm) in captive chimpanzees (
n
= 291) derived from two genetically isolated populations. Our results confirm that chimpanzees exhibit a significant population-level leftward asymmetry for PT surface area, as well as significant heritability in the surface area and mean depth of the PT. These results conclusively demonstrate the existence of a leftward bias in PT asymmetry in chimpanzees and suggest that genetic mechanisms play a key role in the emergence of anatomical asymmetry in this region.
Lack of protective effect of chloroquine derivatives on COVID-19 disease in a Spanish sample of chronically treated patients
Authors: Laplana Marina , Yuguero Oriol , Fibla Joan
Published: September 2020

Background

The search for a SARS-CoV-2 treatment has emerged as a worldwide priority. We evaluated the role of chloroquine and its derivatives in COVID-19 in Spanish individuals.

Methods

We performed a survey addressed to patients regularly taking chloroquine and its derivatives for the control of their autoimmune diseases. The survey was distributed with special attention to Spanish patient associations centred on autoimmune diseases and rheumatology and to the general population. A sample of untreated subjects was matched to the treated group according to sex, age range and incidence region. COVID-19 disease prevalence was compared between treated and untreated-matched control sample.

Results

A total of 319 surveys of patients regularly taking chloroquine and its derivatives were recovered for further analysis. The prevalence of declared COVID-19 status in the treated group was 5.3% and the mean prevalence among the untreated-matched groups was 3.4%. A community exposition to COVID-19 was associated with a greater prevalence of COVID-19 in both, treated (17.0% vs. 3.2%; p-value<0.001) and untreated groups (13.4% vs. 1.1%; p-value=0.027).

Conclusion

We did not find differences of reported COVID-19 cases between treated and untreated groups, indicating a lack of protection by regular administration of chloroquine and its derivative drugs on COVID-19 infection. Of relevance, data indicates that patients that regularly take chloroquine derivatives are exposed to SARS-CoV-2 infection and must take the same protection measures as the general population.
The use of germicidal ultraviolet light, vaporised hydrogen peroxide and dry heat to decontaminate face masks and filtering respirators contaminated with an infectious norovirus
Authors: Wielick Constance , Ludwig-Begall Louisa F. , Dams Lorène , Razafimahefa Ravo M. , Demeuldre Pierre-Francois , Napp Aurore , Laperre Jan , Haubruge Eric , Thiry Etienne
Published: September 2020

In the context of the SARS-CoV-2 pandemic, reuse of surgical masks and filtering facepiece respirators has been recommended. Their reuse necessitates procedures to inactivate contaminating human respiratory and oral pathogens. We previously demonstrated decontamination of masks and respirators contaminated with an infectious SARS-CoV-2 surrogate via ultraviolet germicidal irradiation, vaporised hydrogen peroxide, and use of dry heat. Here, we show that these same methods efficiently inactivate a more resistant, non-enveloped oral virus; decontamination of infectious murine norovirus-contaminated masks and respirators reduced viral titres by over four orders of magnitude on mask or respirator coupons.
Real Time and Delayed Effects of Subcortical Low Intensity Focused Ultrasound
Authors: Cain Joshua A. , Visagan Shakthi , Johnson Micah A. , Crone Julia , Blades Robin , Spivak Norman M. , Shattuck David W. , Monti Martin M.
Published: September 2020

Deep brain nuclei are integral components of large-scale circuits mediating important cognitive and sensorimotor functions. However, because they fall outside the domain of conventional non-invasive neuromodulatory techniques, their study has been primarily based on neuropsychological models, limiting the ability to fully characterize their role and to develop interventions in cases where they are damaged. To address this gap, we used the emerging technology of non-invasive low-intensity focused ultrasound (LIFU) to directly modulate left lateralized basal ganglia structures in healthy volunteers. During sonication, we observed local and distal decreases in blood oxygenation level dependent (BOLD) signal in the targeted left globus pallidus (GP) and in large-scale cortical networks. We also observed a generalized decrease in relative perfusion throughout the cerebrum following sonication. These results show, for the first time using functional MRI data, the ability to modulate deep-brain nuclei using LIFU while measuring its local and global consequences, opening the door for future applications of subcortical LIFU.
Shifts in mutation spectra enhance access to beneficial mutations
Authors: Sane Mrudula , Diwan Gaurav D , Bhat Bhoomika A , Wahl Lindi M , Agashe Deepa
Published: September 2020

Biased mutation spectra are pervasive, with wide variation in the magnitude of mutational biases that influence genome evolution and adaptation. How do such diverse biases evolve? Our experiments show that changing the mutation spectrum allows populations to sample previously under-sampled mutational space, including beneficial mutations. The resulting shift in the distribution of fitness effects is advantageous: beneficial mutation supply and beneficial pleiotropy both increase, while deleterious load reduces. More broadly, simulations indicate that reducing or reversing the direction of a long-term bias is always selectively favoured. Such changes in mutation bias can occur easily via altered function of DNA repair genes. A phylogenetic analysis shows that these genes are repeatedly gained and lost in bacterial lineages, leading to frequent bias shifts in opposite directions. Thus, shifts in mutation spectra may evolve under selection, and can directly alter the outcome of adaptive evolution by facilitating access to beneficial mutations.

SIGNIFICANCE STATEMENT

Mutations are important because they provide raw material for evolution. Some types of mutations occur more often than others, and the strength of such mutational bias varies across species. It is not clear how this variation arises. We experimentally measured the immediate effects of changing the mutation bias ofE. coli, and used simulations to understand the long-term effects. Altering mutational bias is beneficial whenever the new bias increases sampling of mutational classes that were previously under-sampled. We also show that historically, bacteria have often experienced such beneficial bias switches. Our work thus demonstrates the importance of mutational biases in evolution. By allowing exploration of new mutational space, altered mutation biases could drive rapid adaptation.
Drug connectivity mapping and functional analysis reveals therapeutic small molecules that differentially modulate myelination
Authors: Pieropan F , Rivera AD , Williams G , Calzolari F , Butt AM , Azim K
Published: September 2020

Oligodendrocytes are the myelin forming cells of the central nervous system (CNS) and are generated from oligodendrocyte progenitor cells (OPCs). Disruption or loss of oligodendrocytes and myelin has devastating effects on CNS function and integrity, which occurs in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer’s disease (AD) and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular regulatory pathways. Here, we have used a combined drug connectivity systems biology and neurobiological approach to identify compounds that exert positive and negative effects on oligodendroglia, depending on concentration. Notably, LY294002, a potent inhibitor of PI3K/Akt signalling, was the most highly ranked small molecule for both pro- and anti-oligodendroglial effects. We validated thesein silicofindings in multiplein vivoandex vivoneurobiological models and demonstrate that low and high doses of LY294002 have a profoundly bipartite effect on the generation of OPCs and their differentiation into myelinating oligodendrocytes. Finally, we employed transcriptional profiling and signalling pathway activity assays to determine cell-specific mechanisms of action of LY294002 on oligodendrocytes and resolve optimalin vivoconditions required to promote myelin repair. These results demonstrate the power of multifactorial neurobiological andin silicostrategies in determining the therapeutic potential of small molecules in neurodegenerative disorders.

One-sentence summary

Drug discovery and CNS myelination
The impact of work loss on mental and physical health during the COVID-19 pandemic: Findings from a prospective cohort study
Authors: Griffiths Daniel , Sheehan Luke , van Vreden Caryn , Petrie Dennis , Grant Genevieve , Whiteford Peter , R Sim Malcolm , Collie Alex
Published: September 2020

Objective

To determine if losing work during the COVID-19 pandemic is associated with mental and physical health. To determine if social interactions and financial resources moderate the relationship between work loss and health.

Design

Baseline data from a prospective longitudinal cohort study.

Setting

Australia, 27th March to 12th June 2020.

Participants

Australians aged 18+ years, employed in a paid job prior to the COVID-19 pandemic who responded to an online or telephone survey.

Main Outcome Measures

Kessler-6 score > 18 indicating high psychological distress. Short Form 12 (SF-12) mental health or physical health component score < = 45 indicating poor mental or physical health.

Results

2,603 respondents including groups who had lost their job (N = 541), were not working but remained employed (N = 613), were working less (N = 789) and whose work was unaffected (N = 789). Three groups experiencing work loss had greater odds of high psychological distress (AOR = 2.22–3.66), poor mental (AOR = 1.78–2.27) and physical health (AOR = 2.10–2.12) than the unaffected work group. Poor mental health was more common than poor physical health. The odds of high psychological distress (AOR = 5.43–8.36), poor mental (AOR = 1.92–4.53) and physical health (AOR = 1.93–3.90) were increased in those reporting fewer social interactions or less financial resources.

Conclusion

Losing work during the COVID-19 pandemic is associated with mental and physical health problems, and this relationship is moderated by social interactions and financial resources. Responses that increase financial security and enhance social connections may partially alleviate the health impacts of work loss.

Registration

Australian New Zealand Clinical Trials Registry: ACTRN12620000857909.
A novel and potent thrombolytic fusion protein consisting of anti-insoluble fibrin antibody and mutated urokinase
Authors: Hanaoka Shingo , Saijou Shinji , Matsumura Yasuhiro
Published: September 2020

Because the risk of thromboembolism increases with age, as well as due to infectious diseases, safer and more effective thrombolytic agents are in greater demand. Tissue plasminogen activator (tPA) is currently used clinically because it has higher binding specificity for insoluble fibrin (IF) than urokinase (UK), but even pro-tPA has catalytic activity in places other than IF. Meanwhile, UK has the advantage that it is specifically activated on IF, but it only binds IF weakly. Unlike the anti-IF monoclonal antibody (mAb) established in the past, our anti-IF mAb recognizes a pit structure formed only in IF. Here, we developed a new mAb against the pit, 1101, that does not affect coagulation or fibrinolysis, and prepared a fusion protein of UK with humanized 1101 Fab to transport UK selectively to IF. In IF-containing lesions, UK is cleaved by plasmin at two sites, Lys158/Ile159 and Lys135/Lys136. Cleavage of the former leads to activation of UK; however, because activated UK is linked by S-S bonds before and after cleavage, it is not released from the fusion. Cleavage at the latter site causes UK to leave the fusion protein; hence, we mutated Lys135/Lys136 to Gly135/Gly136 to prevent release of UK. This engineered UK-antibody fusion, AMU1114, significantly decreased the systemic side effects of UKin vivo. In a mouse thrombus formation experiment, the vascular patency rate was 0% (0/10) in the control, 50% (5/10) in the tPA, and 90% (9/10) in the AMU1114 treatment group. These data support future clinical development of AMU1114.
Celastrol directly inhibits PFKM to induce weight loss and leptin sensitization
Authors: Wang Kang , Wu Xiaobo , Zhuang Yinghua , Sun Huan , Wang Fengchao , Wang Tao , Zhang Zhiyuan
Published: September 2020

Despite the prevalence of obesity and related health consequences around the globe, effective treatments for inducing healthy weight loss are still lacking. Celastrol is a pentacyclic triterpene that was recently identified as a potent anti-obesity agent. Celastrol increases sensitivity to leptin, but the molecular target of celastrol is unknown. Therefore, the mechanisms by which this agent exerts its anti-obesity effect remain elusive. Using tissue-specific ABPP (activity-based protein profiling), we found that PFKM, a rate-limiting enzyme for glycolysis in skeletal muscle, is a direct target of celastrol. Celastrol inhibited PFKM enzymatic activity, andPfkmknockout mice were resistant to a high fat diet, were hypersensitive to exogenous leptin, and were unresponsive to celastrol. PFKM inhibition led to activation of AMPK and inactivation of ACC in cultured myotubes and mouse skeletal muscle. Specific loss of AMPK in muscle significantly attenuated the anti-obesity effects of celastrol. Further, PFKM inhibition and subsequent activation of the AMPK/ACC signaling pathway reduced levels of free fatty acids by switching energy expenditure and consequently decreasing levels of SOCS1 expression, which are both required for leptin sensitization in 293t/hLepRb cells and mice. Finally, using a high throughput compound screen we identified an alternative PFKM inhibitor, 3-79, which exhibits a strong anti-obesity effect and non-covalent binding capacity. This compound is a promising agent for treating obesity in the clinic.
EARLY VIRAL CLEARANCE AMONG COVID-19 PATIENTS WHEN GARGLING WITH POVIDONE-IODINE AND ESSENTIAL OILS – A CLINICAL TRIAL
Authors: Mohamed Nurul Azmawati , Baharom Nizam , Sulaiman Wan Shahida Wan , Rashid Zetti Zainol , Ken Wong Kon , Ali Umi Kalsom , Othman Siti Norlia , Samat Muttaqillah Najihan , Kori Najma , Periyasamy Petrick , Zakaria Nor Azizan , Sugurmar Agni Nhirmal Kumar , Kazmin Nur Ezzaty Mohammad , Khee Cheong Xiong , Saniman Siti Mariyam , Isahak Ilina
Published: September 2020

Background

Gargling had been reported to have significant roles in the prevention and treatment of respiratory tract infections. The purpose of this study was to assess the ability of regular gargling to eliminate SARS-CoV-2 in the oropharynx and nasopharynx.

Methodology

This pilot, open labeled, randomized, parallel study compared the effect of 30 seconds, 3 times/day gargling using 1% povidone-iodine (PVP-I), essential oils and tap water on SARS-CoV-2 viral clearance among COVID-19 patients in a tertiary hospital in Kuala Lumpur. Progress was monitored by day 4,6 and 12 PCR (Ct value), gargling and symptoms diary as well as clinical observations.

Results

Five confirmed Stage 1 COVID-19 patients were recruited for each arm. The age range was from 22 to 56 years old. The majority were males. Two respondents had co-morbidities, which were asthma and obesity. Viral clearance was achieved at day 6 in 100%, 80%, 20% and 0% for 1% PVP-I, essential oils, tap water and control group respectively. Analysis of 1% PVP-I group versus control group showed significant p-value for comparison of PCR results on Day 4, Day 6 and Day 12.

Conclusions

This preliminary study showed that gargling with 1% PVP-I and essential oils show great potential to be part of the treatment and management of Stage 1 COVID-19. Larger studies are required to ascertain the benefit of gargling for different stages of COVID-19 patients. This study was registered in clinicaltrial.gov (NCT04410159).
Implementing a program to improve handoffs and reduce adverse events in Paediatric Intensive Care Units in Argentina: a stepped wedge trial
Authors: Facundo Jorro-Barón , Inés Suarez-Anzorena , Rodrigo Burgos-Pratx , Noelia Demaio , Matias Penazzi , Gisela Rodriguez , Paula Rodriguez Ana , Daniel Velardez , Silvina Ábalos , Silvina Lardone , Joaquín Olivieri , Rocío Gallagher , Rocio Rodriguez , Luz Gibbons , Martin Landry Luis , Ezequiel Garcia-Elorrio
Published: September 2020

Introduction

An effective and standardized communication anticipates and limits the appearance of possible adverse events.

Objective

To evaluate the effect of the implementation of a handoff program in reducing the frequency of adverse events (AE) in Paediatric Intensive Care Units (PICUs).

Methods

Facility-based, cluster randomised stepped wedge trial in six Argentine PICUs, with more than 20 admissions per month. The intervention comprised a Spanish version on the I-PASS Handoff Bundle consisting of a written and verbal handoff using mnemonics, an introductory workshop with teamwork training, an advertising campaign, simulation exercises and observation and standardized feedback of handoffs.

Results

We recruited 6 cluster PICUs in 5 hospitals. We reviewed 1465 medical records (MR). We did not observed differences in the rates of preventable AE per 1000 days of hospitalization (control 60.4 [37.5 - 97.4] vs. intervention 60.4 [33.2 - 109.9], p = 0.3568, RR:1.21 [CI95%:0.80 - 1.83]), and no changes in the categories or types of AE. We evaluated 847 handoffs. Compliance with all items in verbal and written handoff was significantly higher in the intervention group. We observed a longer time per patient to complete the handoff in the intervention group (7.29 minutes [5.77 - 8.81] vs. 5.96 [4.69 - 7.23]; p < 0.0002, RR:1.33 [CI95%:0.64 - 2.02]), without changes in the whole time used for handoff (control: 35.7 [29.6 - 41.8] vs. intervention: 34.7 [26.5 - 42.1]; p = 0.4900, RR:1.43 [CI95%:-2.63 - 5.49]). Perception of improved communication from provider didn’t show changes.

Conclusions

After the implementation of the I-PASS bundle, improvement in the quality of handoffs was observed. Nevertheless, no differences were observed in the frequency of AE, nor in the perception of improved communication.
Blood neurofilament light concentration at admittance: a potential prognostic marker in COVID-19
Authors: Aamodt Anne Hege , Høgestøl Einar August , Popperud Trine Haug , Holter Jan Cato , Dyrhol-Riise Anne Ma , Tonby Kristian , Stiksrud Birgitte , Quist-Paulsen Else , Berge Tone , Barratt-Due Andreas , Aukrust Pål , Heggelund Lars , Blennow Kaj , Zetterberg Henrik , Harbo Hanne Flinstad
Published: September 2020

Objective

To test the hypotheses that blood concentrations of neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAp) can serve as biomarkers for disease severity in COVID-19 patients.

Methods

Forty-seven inpatients with confirmed COVID-19 had blood samples drawn on admission for assessing serum biomarkers of CNS injury by Single molecule array (Simoa). Concentrations of NfL and GFAp were analyzed in relation to symptoms, clinical signs, inflammatory biomarkers and clinical outcomes. We used multivariate linear models to test for differences in biomarker concentrations in the subgroups, accounting for confounding effects.

Results

In total, 21 % (n = 10) of the patients were admitted to an intensive care unit, whereas the overall mortality rate was 13 % (n = 6). Non-survivors had higher serum concentrations of NfL than patients who were discharged alive both in adjusted analyses (p = 2.6 × 10−7) and unadjusted analyses (p = 0.001). Serum concentrations of GFAp were significantly higher in non-survivors than survivors in adjusted analyses (p = 0.02). The NfL concentrations in non-survivors increased over repeated measurements, whereas the concentrations in survivors were stable. Significantly higher concentrations of NfL were found in patients reporting fatigue, while reduced concentrations were found in patients experiencing cough, myalgia and joint pain.

Conclusion

Increased concentrations of NfL and GFAp in COVID-19 patients on admission may indicate increased mortality risk. Measurement of blood biomarkers for nervous system injury can be useful to detect and monitor CNS injury in COVID-19.
Care dependency among older women in Austrian nursing homes: The role of outdoor temperatures
Authors: Schuettengruber Gerhilde , Grossschaedl Franziska , Hoedl Manuela
Published: September 2020

The aim of this study was to investigate the associations between outdoor temperatures and care dependency degree among female nursing home residents. A secondary data analysis of data from a cluster-randomized controlled trial was conducted. Data from 345 female nursing home residents in two federal states in southern Austria were collected. Data on the degree of care dependency, dementia and age were collected from the participating female residents. Outdoor temperature data were provided by the Austrian Central Institute for Meteorology and Geodynamics. The results of the regression analysis show that the outdoor temperatures significantly affect the degree of care dependency. As the outdoor temperature decreases, the CDS score increases, which indicates that the number of independent woman enhance. For nursing home practice, we strongly recommend establishing heat plans. Representative prospective studies need to be carried out to investigate the causality between temperature and the degree of care dependency.
Cholesteryl Ester Transfer Protein as a Drug Target for Cardiovascular Disease
Authors: Schmidt Amand F , Hunt Nicholas B , Gordillo-Marañón Maria , Charoen Pimphen , Drenos Fotios , Casas Juan-Pablo , Kivimaki Mika , Lawlor Deborah A , Giambartolomei Claudia , Papacosta Olia , Chaturvedi Nishi , Bis Joshua C ,   UCLEB consortium, O’Donnell Christopher , Wannamethee Goya , Wong Andrew , Price Jackie F , Hughes Alun D , Gaunt Tom R , Franceschini Nora , Mook-Kanamori Dennis O , Zwierzyna Magdalena , Sofat Reecha , Hingorani Aroon D , Finan Chris
Published: September 2020

Drug development of cholesteryl ester transfer protein (CETP) inhibition to prevent coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and Mendelian randomization (MR) results. Findings from meta-analyses of CETP inhibitor trials (≥ 24 weeks follow-up) were used to judge between-compound heterogeneity in treatment effects. Genetic data were extracted on 190+ pharmacologically relevant outcomes; spanning 480,698-21,770 samples and 74,124-4,373 events. Drug target MR of protein concentration was used to determine the on-target effects of CETP inhibition and compared to that of PCSK9 modulation. Fifteen eligible CETP inhibitor trials of four compounds were identified, enrolling 79,961 participants. There was a high degree of heterogeneity in effects on lipids, lipoproteins, blood pressure, and clinical events. For example, dalcetrapib and evacetrapib showed a neutral effect, torcetrapib increased, and anacetrapib decreased cardiovascular disease (CVD); heterogeneity p-value < 0.001. In drug target MR analysis, lower CETP concentration (per μg/ml) was associated with CHD (odds ratio 0.95; 95%CI 0.91; 0.99), heart failure (0.95; 95%CI 0.92; 0.99), chronic kidney disease (0.94 95%CI 0.91; 0.98), and age-related macular degeneration (1.69; 95%CI 1.44; 1.99). Lower PCSK9 concentration was associated with a lower risk of CHD, heart failure, atrial fibrillation and stroke, and increased risk of Alzheimer’s disease and asthma. In conclusion, previous failures of CETP inhibitors are likely compound related. CETP inhibition is expected to reduce risk of CHD, heart failure, and kidney disease, but potentially increase risk of age-related macular disease.