bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of the CIR‐ and CME‐Induced Geomagnetic Activity Effects on Mesosphere and Lower Thermospheric Temperature
Authors: Wang Ningchao , Yue Jia , Wang Wenbin , Qian Liying , Jian Lan , Zhang Jie
Published: April 2021

Neutral temperature responses in the mesosphere and lower thermosphere (MLT) to severe geomagnetic storms induced by coronal mass ejections (CMEs) are of growing interest to the space science research community. Recently, it was found that geomagnetic activities produced by the corotating interaction regions (CIRs) caused comparable effects on the Earth's upper atmosphere. In this work, we carried out a comparative study of the temperature responses in the MLT region to these two types of geomagnetic activities, using the temperature measured by the Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) instruments onboard the Thermosphere, Ionosphere, Mesosphere Energetics and Dynamics (TIMED) satellite. Our results demonstrate that CIR‐induced geomagnetic activity produced temperature variations in the MLT region and that this effect can penetrate downward to ∼100 km at high latitudes in both hemispheres. Temperature enhancements penetrated deeper during CME‐induced geomagnetic activities, but the heating effects lasted longer during CIR‐induced geomagnetic activities. There is a hemispherical asymmetry in the geomagnetical activity induced temperature changes in the MLT region. The temperature enhancements are stronger in the southern hemisphere than in the northern hemisphere during CME events.
Fault‐Valve Behavior Estimated From Intensive Foreshocks and Aftershocks of the 2017 M 5.3 Kagoshima Bay Earthquake Sequence, Kyushu, Southern Japan
Authors: Matsumoto Yoshiaki , Yoshida Keisuke , Matsuzawa Toru , Hasegawa Akira
Published: April 2021

Determining fluid migration and pore pressure change within the Earth is key to understand earthquake occurrences. We investigated the spatiotemporal characteristics of the intense foreshocks and aftershocks of the 2017 ML 5.3 earthquake in Kagoshima Bay, Kyushu, southern Japan, to examine the physical processes governing this earthquake sequence. Our relocated hypocenters show the foreshocks moved on a sharply defined plane with a steep dip. The mainshock rupture initiated at the edge of the foreshock seismic gap. The size of the foreshock seismic gap is comparable to that of the mainshock estimated from the source corner frequency, suggesting this seismic gap corresponds to the large slip region of the mainshock. The aftershocks migrated upward along several steeply dipped planes with a seismicity pattern that deviated from the typical mainshock–aftershock type. This deviation of seismicity pattern, together with the hypocenter migrations, suggests aseismic processes, such as pore pressure migration and aseismic slip, affected this earthquake sequence. We established the following hypothesis. First, fluids originating from the subducting slab migrated upward and intruded into the fault plane, reducing the fault strength and causing the foreshock sequence and potentially aseismic slip. Second, the mainshock rupture occurred due to the decreased fault strength and the increased shear stress in an area with relatively high strength. Third, pore pressure increase associated with post‐failure fluid discharge caused the upward aftershock migration. These observations are consistent with the fault‐valve model and show the importance of fluid movement at depth not only in earthquake swarms but also in foreshock–mainshock–aftershock sequences.
The Shelf Circulation of the Bellingshausen Sea
Authors: Schulze Chretien L. M. , Thompson A. F. , Flexas M. M. , Speer K. , Swaim N. , Oelerich R. , Ruan X. , Schubert R. , LoBuglio C.
Published: April 2021

Over recent decades, the West Antarctic Ice Sheet has experienced rapid thinning of its floating ice shelves as well as grounding line retreat across its marine‐terminating glaciers. The transport of warm Modified Circumpolar Deep Water (MCDW) onto the continental shelf, extensively documented along the West Antarctic Peninsula (WAP), and in the Amundsen Sea, has been identified as the key process for inducing these changes. The Bellingshausen Sea sits between the Amundsen Sea and the northern part of the WAP, but its oceanic properties remain remarkably under‐studied compared to surrounding regions. Here, we present observations collected from a hydrographic survey of the Bellingshausen Sea continental shelf in austral summer 2019. Using a combination of ship‐based and glider‐based CTD and lowered ADCP observations, we show that submarine troughs provide topographically steered pathways for MCDW from the shelf break toward deep embayments and ultimately under floating ice shelves. Warm MCDW enters the continental shelf at the deepest part of the Belgica Trough and flows onshore along the eastern side of the trough. Modification of these shoreward‐flowing waters by glacial melt is estimated by calculating meltwater fractions using an optimal multiparameter analysis. Meltwater is found to be elevated at the western edge of both the Latady and Belgica troughs. Meltwater distributions, consistent with other diagnostics, suggest a recirculation in each trough with modified waters eventually flowing westward upon leaving the Belgica Trough. Our results show that the Bellingshausen Sea is a critical part of the larger West Antarctic circulation system, linking the WAP and the Amundsen Sea.
Ocean Variability at Greenland's Largest Glacier Tongue Linked to Continental Shelf Circulation
Authors: von Albedyll Luisa , Schaffer Janin , Kanzow Torsten
Published: April 2021

Increased ocean‐to‐ice heat fluxes play a key role in the accelerated mass loss of Greenland’s marine‐terminating glaciers. Ocean current variability leads to variations in this heat flux. A year‐long time series of ocean currents at all gateways to the ocean cavity under Greenland’s largest remaining floating ice tongue at the Nioghalvfjerdsfjorden Glacier (79NG) was analyzed. The variability of the exchange flow at intra‐annual to near‐daily timescales was characterized. The currents exhibit considerable variability with standard deviations exceeding the time mean flow strength by a factor of 2. The inflow of warm Atlantic Intermediate Water into the cavity and the outflow via the northernmost calving front were directly coupled on intra‐annual timescales (periods, T > 30 days) with enhanced fluctuations in the winter months. A strong correlation between the variability of the deep inflow and currents in the subsurface boundary current on the continental shelf suggests a link between cavity and continental shelf circulation. Variability on higher frequencies (T < 30 days) in the outflow was only partly induced by the inflow variability. Two export branches of the cavity circulation were identified, which were potentially constrained by subglacial meltwater channels. The relative importance of the two export branches varies on monthly time scales. This research has provided evidence that the large intra‐annual ocean current variability at the 79NG is strongly influenced by the continental shelf circulation. Temporally varying preferred export routes increase the complexity of the cavity circulation.
Improving Air Quality in China’s Greater Bay Area
Authors: Stanley Sarah
Published: April 2021

New simulations show how reducing residential and agricultural pollution outside the Greater Bay Area could improve public health inside this megalopolis and across China.
Origin and Fate of the Chukchi Slope Current Using a Numerical Model and In‐Situ Data
Authors: Leng Hengling , Spall Michael A. , Pickart Robert S. , Lin Peigen , Bai Xuezhi
Published: April 2021

A regional coupled sea ice‐ocean model and mooring/shipboard measurements are used to investigate the origins, seasonality, and downstream fate of the Chukchi Slope Current (CSC). Three years (2013–2015) of model integration indicates that, in the mean, the model slope current transports ∼0.45 Sv of Pacific water northwestward along the Chukchi continental slope. Only 62% of this water emanates from Barrow Canyon, while the rest (38%) is fed by a westward jet extending from the southern Beaufort Sea. The jet merges with the outflow from the canyon, forming the CSC. Due to these two distinct origins, the slope current in the model has a double velocity core at times. This is consistent with the double‐core structure of the slope current seen in ship‐based observations. Seasonal changes in the volume, heat, and freshwater transports by the slope current appear to be related to the changes in the upstream flows. A tracer diagnostic in the model suggests that the part of the slope current over the upper continental slope continues westward toward the East Siberian Sea, while the portion of the current overlying deeper isobaths flows northward into the Chukchi Borderland, where it ultimately gets entrained into the Beaufort Gyre. Our study provides a detailed and complete picture of the slope current.
MRE11 promotes oral cancer progression through RUNX2/CXCR4/AKT/FOXA2 signaling in a nuclease-independent manner
Authors: Wang Yen-Yun , Chen Yuk-Kwan , Lo Steven , Chi Tsung-Chen , Chen Yi-Hua , Hu Stephen Chu-Sung , Chen Ya-Wen , Jiang Shih Sheng , Tsai Fang-Yu , Liu Wangta , Li Ruei-Nian , Hsieh Ya-Ching , Huang Chih-Jen , Yuan Shyng-Shiou F.
Published: April 2021

MRE11, the nuclease component of RAD50/MRE11/NBS1 DNA repair complex which is essential for repair of DNA double-strand-breaks in normal cells, has recently garnered attention as a critical factor in solid tumor development. Herein we report the crucial role of MRE11 in oral cancer progression in a nuclease-independent manner and delineate its key downstream effectors including CXCR4. MRE11 expression in oral cancer samples was positively associated with tumor size, cancer stage and lymph node metastasis, and was predictive of poorer patient survival and radiotherapy resistance. MRE11 promoted cell proliferation/migration/invasion in a nuclease-independent manner but enhanced radioresistance via a nuclease-dependent pathway. The nuclease independent promotion of EMT and metastasis was mediated by RUNX2, CXCR4, AKT, and FOXA2, while CXCR4 neutralizing antibody mitigated these effects in vitro and in vivo. Collectively, MRE11 may serve as a crucial prognostic factor and therapeutic target in oral cancer, displaying dual nuclease dependent and independent roles that permit separate targeting of tumor vulnerabilities in oral cancer treatment.
The role of chemotaxis and efflux pumps on nitrate reduction in the toxic regions of a ciprofloxacin concentration gradient
Authors: Alcalde Reinaldo E , Dundas Christopher M , Dong Yiran , Sanford Robert A , Keitz Benjamin Keith , Fouke Bruce W , Werth Charles J
Published: April 2021

Spatial concentration gradients of antibiotics are prevalent in the natural environment. Yet, the microbial response in these heterogeneous systems remains poorly understood. We used a microfluidic reactor to create an artificial microscopic ecosystem that generates diffusive gradients of solutes across interconnected microenvironments. With this reactor, we showed that chemotaxis toward a soluble electron acceptor (nitrate) allowed Shewanella oneidensis MR-1 to inhabit and sustain metabolic activity in highly toxic regions of the antibiotic ciprofloxacin (>80× minimum inhibitory concentration, MIC). Acquired antibiotic resistance was not observed for cells extracted from the reactor, so we explored the role of transient adaptive resistance by probing multidrug resistance (MDR) efflux pumps, ancient elements that are important for bacterial physiology and virulence. Accordingly, we constructed an efflux pump deficient mutant (∆mexF) and used resistance-nodulation-division (RND) efflux pump inhibitors (EPIs). While batch results showed the importance of RND efflux pumps for microbial survival, microfluidic studies indicated that these pumps were not necessary for survival in antibiotic gradients. Our work contributes to an emerging body of knowledge deciphering the effects of antibiotic spatial heterogeneity on microorganisms and highlights differences of microbial response in these systems versus well-mixed batch conditions.
Ibrutinib combinations in CLL therapy: scientific rationale and clinical results
Authors: Timofeeva Natalia , Gandhi Varsha
Published: April 2021

Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL). This drug irreversibly inhibits Bruton tyrosine kinase (BTK) by covalently binding to the C481 residue in the BTK kinase domain. BTK is a pivotal protein for B cell receptor signaling and tissue homing of CLL cells. Preclinical investigations have established the importance of the B cell receptor pathway in the maintenance and survival of normal and malignant B cells, underscoring the importance of targeting this axis for CLL. Clinical trials demonstrated overall and progression-free survival benefit with ibrutinib in multiple CLL subgroups, including patients with relapsed or refractory disease, patients with 17p deletion, elderly patients, and treatment-naïve patients. Consequently, ibrutinib was approved by the US Food and Drug Administration for newly diagnosed and relapsed disease. Ibrutinib has transformed the treatment of CLL; however, several limitations have been identified, including low complete remission rates, development of resistance, and uncommon substantial toxicities. Further, ibrutinib must be used until disease progression, which imposes a financial burden on patients and society. These limitations were the impetus for the development of ibrutinib combinations. Four strategies have been tested in recent years: combinations of ibrutinib with immunotherapy, chemoimmunotherapy, cell therapy, and other targeted therapy. Here, we review the scientific rationale for and clinical outcome of each strategy. Among these strategies, ibrutinib with targeted agent venetoclax results in high complete response rates and, importantly, high rates of undetectable minimal residual disease. Although we concentrate here on ibrutinib, similar combinations are expected or ongoing with acalabrutinib, tirabrutinib, and zanubrutinib, second-generation BTK inhibitors. Future investigations will focus on the feasibility of discontinuing ibrutinib combinations after a defined time; the therapeutic benefit of adding a third agent to ibrutinib-containing combinations; and profiling of resistant clones that develop after combination treatment. A new standard of care for CLL is expected to emerge from these investigations.
A deep convolutional neural network for segmentation of whole-slide pathology images identifies novel tumour cell-perivascular niche interactions that are associated with poor survival in glioblastoma
Authors: Zadeh Shirazi Amin , McDonnell Mark D. , Fornaciari Eric , Bagherian Narjes Sadat , Scheer Kaitlin G. , Samuel Michael S. , Yaghoobi Mahdi , Ormsby Rebecca J. , Poonnoose Santosh , Tumes Damon J. , Gomez Guillermo A.
Published: April 2021

Background

Glioblastoma is the most aggressive type of brain cancer with high-levels of intra- and inter-tumour heterogeneity that contribute to its rapid growth and invasion within the brain. However, a spatial characterisation of gene signatures and the cell types expressing these in different tumour locations is still lacking.

Methods

We have used a deep convolutional neural network (DCNN) as a semantic segmentation model to segment seven different tumour regions including leading edge (LE), infiltrating tumour (IT), cellular tumour (CT), cellular tumour microvascular proliferation (CTmvp), cellular tumour pseudopalisading region around necrosis (CTpan), cellular tumour perinecrotic zones (CTpnz) and cellular tumour necrosis (CTne) in digitised glioblastoma histopathological slides from The Cancer Genome Atlas (TCGA). Correlation analysis between segmentation results from tumour images together with matched RNA expression data was performed to identify genetic signatures that are specific to different tumour regions.

Results

We found that spatially resolved gene signatures were strongly correlated with survival in patients with defined genetic mutations. Further in silico cell ontology analysis along with single-cell RNA sequencing data from resected glioblastoma tissue samples showed that these tumour regions had different gene signatures, whose expression was driven by different cell types in the regional tumour microenvironment. Our results further pointed to a key role for interactions between microglia/pericytes/monocytes and tumour cells that occur in the IT and CTmvp regions, which may contribute to poor patient survival.

Conclusions

This work identified key histopathological features that correlate with patient survival and detected spatially associated genetic signatures that contribute to tumour-stroma interactions and which should be investigated as new targets in glioblastoma. The source codes and datasets used are available in GitHub:https://github.com/amin20/GBM_WSSM.
A review of acquired blepharoptosis: prevalence, diagnosis, and current treatment options
Authors: Bacharach Jason , Lee Wendy W. , Harrison Andrew R. , Freddo Thomas F.
Published: April 2021

Blepharoptosis (ptosis) is among the most common disorders of the upper eyelid encountered in both optometric and ophthalmic practice. The unilateral or bilateral drooping of the upper eyelid that characterises ptosis can affect appearance and impair visual function, both of which can negatively impact quality of life. While there are several known forms of congenital ptosis, acquired ptosis (appearing later in life, due to a variety of causes) is the predominant form of the condition. This review summarises the prevalence, causes, identification, differential diagnosis, and treatment of acquired ptosis. Particular attention is paid to the differential diagnosis of acquired ptosis and emerging treatment options, including surgical and pharmacologic approaches.
Genetic and spatial organization of the unusual chromosomes of the dinoflagellate Symbiodinium microadriaticum
Authors: Nand Ankita , Zhan Ye , Salazar Octavio R. , Aranda Manuel , Voolstra Christian R. , Dekker Job
Published: April 2021

Dinoflagellates are main primary producers in the oceans, the cause of algal blooms and endosymbionts of marine invertebrates. Much remains to be understood about their biology, including their peculiar crystalline chromosomes. We assembled 94 chromosome-scale scaffolds of the genome of the coral endosymbiont Symbiodinium microadriaticum and analyzed their organization. Genes are enriched towards the ends of chromosomes and are arranged in alternating unidirectional blocks. Some chromosomes are enriched for genes involved in specific biological processes. The chromosomes fold as linear rods and each is composed of a series of structural domains separated by boundaries. Domain boundaries are positioned at sites where transcription of two gene blocks converges and disappear when cells are treated with chemicals that block transcription, indicating correlations between gene orientation, transcription and chromosome folding. The description of the genetic and spatial organization of the S. microadriaticum genome provides a foundation for deeper exploration of the extraordinary biology of dinoflagellates and their chromosomes.
Investigating the effect of trigger delay on cardiac 31P MRS signals
Authors: Wampl Stefan , Körner Tito , Valkovič Ladislav , Trattnig Siegfried , Wolzt Michael , Meyerspeer Martin , Schmid Albrecht Ingo
Published: April 2021

The heart’s geometry and its metabolic activity vary over the cardiac cycle. The effect of these fluctuations on phosphorus (31P) magnetic resonance spectroscopy (MRS) data quality and metabolite ratios was investigated. 12 healthy volunteers were measured using a 7 T MR scanner and a cardiac 31P-1H loop coil. 31P chemical shift imaging data were acquired untriggered and at four different times during the cardiac cycle using acoustic triggering. Signals of adenosine-triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi) and 2,3-diphosphoglycerate (2,3-DPG) and their fit quality as Cramér-Rao lower bounds (CRLB) were quantified including corrections for contamination by 31P signals from blood, flip angle, saturation and total acquisition time. The myocardial filling factor was estimated from cine short axis views. The corrected signals of PCr and $$\gamma$$
γ
-ATP were higher during end-systole and lower during diastasis than in untriggered acquisitions ($$P<0.05$$

P
<
0.05

). Signal intensities of untriggered scans were between those with triggering to end-systole and diastasis. Fit quality of PCr and $$\gamma$$
γ
-ATP peaks was best during end-systole when blood contamination of ATP and Pi signals was lowest. While metabolite ratios and pH remained stable over the cardiac cycle, signal amplitudes correlated strongly with myocardial voxel filling. Triggering of cardiac 31P MRS acquisitions improves signal amplitudes and fit quality if the trigger delay is set to end-systole. We conclude that triggering to end-systole is superior to triggering to diastasis.
Zebrafish automatic monitoring system for conditioning and behavioral analysis
Authors: Barreiros Marta de Oliveira , Barbosa Felipe Gomes , Dantas Diego de Oliveira , Santos Daniel de Matos Luna dos , Ribeiro Sidarta , Santos Giselle Cutrim de Oliveira , Barros Allan Kardec
Published: April 2021

Studies using zebrafish (Danio rerio) in neuro-behavioural research are growing. Measuring fish behavior by computational methods is one of the most efficient ways to avoid human bias in experimental analyses, extending them to various approaches. Sometimes, thorough analyses are difficult to do, as fish can behave unpredictably during an experimental strategy. However, the analyses can be implemented in an automated way, using an online strategy and video processing for a complete assessment of the zebrafish behavior, based on the detection and tracking of fish during an activity. Here, a fully automatic conditioning and detailed analysis of zebrafish behavior is presented. Microcontrolled components were used to control the delivery of visual and sound stimuli, in addition to the concise amounts of food after conditioned stimuli for adult zebrafish groups in a conventional tank. The images were captured and processed for automatic detection of the fish, and the training of the fish was done in two evaluation strategies: simple and complex. In simple conditioning, the zebrafish showed significant responses from the second attempt, learning that the conditioned stimulus was a predictor of food presentation in a specific space of the tank, where the food was dumped. When the fish were subjected to two stimuli for decision-making in the food reward, the zebrafish obtained better responses to red light stimuli in relation to vibration. The behavior change was clear in stimulated fish in relation to the control group, thus, the distances traveled and the speed were greater, while the polarization was lower in stimulated fish. This automated system allows for the conditioning and assessment of zebrafish behavior online, with greater stability in experiments, and in the analysis of the behavior of individual fish or fish schools, including learning and memory studies.
Optimal ultrasonication process time remains constant for a specific nanoemulsion size reduction system
Authors: Pratap-Singh Anubhav , Guo Yigong , Lara Ochoa Sofia , Fathordoobady Farahnaz , Singh Anika
Published: April 2021

This paper theorizes the existence of a constant optimum ultrasound process time for any size-reduction operation, independent of process parameters, and dependent on product parameters. We test the concept using the case of ‘ultrasonic preparation of oil-in-water nanoemulsions’ as model system. The system parameters during ultrasonication of a hempseed oil nanoemulsion was evaluated by a response surface methodology, comprising lecithin and poloxamer-188 as surfactants. Results revealed that the particle size and emulsion stability was affected significantly (p < 0.05) by all product parameters (content of hempseed oil-oil phase, lecithin and polaxamer-surfactants); but was not significantly (p > 0.05) affected by process parameter (‘ultrasonication process time’). Next, other process parameters (emulsion volume and ultrasonic amplitude) were tested using kinetic experiments. Magnitude of particle size reduction decreased with increasing ‘ultrasonication process time’ according to a first order relationship, until a minimum particle size was reached; beyond which ultrasonication no longer resulted in detectable decrease in particle size. It was found that the optimal ultrasonication process time (defined as time taken to achieve 99% of the ‘maximum possible size reduction’) was 10 min, and was roughly constant regardless of the process parameters (sample volume and ultrasonic amplitude). Finally, the existence of this constant optimal ultrasonication process time was proven for another emulsion system (olive oil and tween 80). Based on the results of these case studies, it could be theorized that a constant optimum ultrasonication process time exists for the ultrasonication-based size-reduction processes, dependent only on product parameters.
Allostery of atypical modulators at oligomeric G protein-coupled receptors
Authors: Shivnaraine Rabindra V. , Kelly Brendan , Elmslie Gwendolynne , Huang Xi-Ping , Dong Yue John , Seidenberg Margaret , Wells James W. , Ellis John
Published: April 2021

Many G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site. Some GPCRs also possess allosteric sites, which have become a focus of drug discovery. In the M2muscarinic receptor, allosteric modulators regulate the binding and functional effects of orthosteric ligands through a mix of conformational changes, steric hindrance and electrostatic repulsion transmitted within and between the constituent protomers of an oligomer. Tacrine has been called an atypical modulator because it exhibits positive cooperativity, as revealed by Hill coefficients greater than 1 in its negative allosteric effect on binding and response. Radioligand binding and molecular dynamics simulations were used to probe the mechanism of that modulation in monomers and oligomers of wild-type and mutant M2receptors. Tacrine is not atypical at monomers, which indicates that its atypical effects are a property of the receptor in its oligomeric state. These results illustrate that oligomerization of the M2receptor has functional consequences.
Dissociation of disease onset, progression and sex differences from androgen receptor levels in a mouse model of amyotrophic lateral sclerosis
Authors: Tomas Doris , McLeod Victoria M. , Chiam Mathew D. F. , Wanniarachchillage Nayomi , Boon Wah C. , Turner Bradley J.
Published: April 2021

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder caused by loss of motor neurons. ALS incidence is skewed towards males with typically earlier age of onset and limb site of onset. The androgen receptor (AR) is the major mediator of androgen effects in the body and is present extensively throughout the central nervous system, including motor neurons. Mutations in the AR gene lead to selective lower motor neuron degeneration in male spinal bulbar muscular atrophy (SBMA) patients, emphasising the importance of AR in maintaining motor neuron health and survival. To evaluate a potential role of AR in onset and progression of ALS, we generated SOD1G93Amice with either neural AR deletion or global human AR overexpression. Using a Cre-LoxP conditional gene knockout strategy, we report that neural deletion of AR has minimal impact on the disease course in SOD1G93Amale mice. This outcome was potentially confounded by the metabolically disrupted Nestin-Cre phenotype, which likely conferred the profound lifespan extension observed in the SOD1G93Adouble transgenic male mice. In addition, overexpression of human AR produced no benefit to disease onset and progression in SOD1G93Amice. In conclusion, the disease course of SOD1G93Amice is independent of AR expression levels, implicating other mechanisms involved in mediating the sex differences in ALS. Our findings using Nestin-Cre mice, which show an inherent metabolic phenotype, led us to hypothesise that targeting hypermetabolism associated with ALS may be a more potent modulator of disease, than AR in this mouse model.
Understanding the role of aerobic fitness, spatial learning, and hippocampal subfields in adolescent males
Authors: Prathap Sandhya , Nagel Bonnie J. , Herting Megan M.
Published: April 2021

Physical exercise during adolescence, a critical developmental window, can facilitate neurogenesis in the dentate gyrus and astrogliogenesis in Cornu Ammonis (CA) hippocampal subfields of rats, and which have been associated with improved hippocampal dependent memory performance. Recent translational studies in humans also suggest that aerobic fitness is associated with hippocampal volume and better spatial memory during adolescence. However, associations between fitness, hippocampal subfield morphology, and learning capabilities in human adolescents remain largely unknown. Employing a translational study design in 34 adolescent males, we explored the relationship between aerobic fitness, hippocampal subfield volumes, and both spatial and verbal memory. Aerobic fitness, assessed by peak oxygen utilization on a high-intensity exercise test (VO2peak), was positively associated with the volumetric enlargement of the hippocampal head, and the CA1 head region specifically. Larger CA1 volumes were also associated with spatial learning on a Virtual Morris Water Maze task and verbal learning on the Rey Auditory Verbal Learning Test, but not recall memory. In line with previous animal work, the current findings lend support for the long-axis specialization of the hippocampus in the areas of exercise and learning during adolescence.
N-Demethylsinomenine, an active metabolite of sinomenine, attenuates chronic neuropathic and inflammatory pain in mice
Authors: Zhou Zhiyong , Qiu Nanqing , Ou Yuntao , Wei Qianqian , Tang Wenting , Zheng Mingcong , Xing Yaluan , Li Jie-Jia , Ling Yong , Li Junxu , Zhu Qing
Published: April 2021

Chronic pain is a significant public health problem that afflicts nearly 30% of the global population, but current pharmacotherapies are insufficient. Previous report indicated that N-demethylsinomenine, an active metabolite of sinomenine, is efficacious against postoperative pain. The present study investigated whether N-demethylsinomenine is effective for chronic painful conditions or whether repeated treatment alters its effect. Both chronic constriction injury (CCI) surgery and complete Freund’s adjuvant (CFA) intraplantar injection induced significant and reliable mechanical allodynia at least for 7 days. Acute treatment with N-demethylsinomenine (10–40 mg/kg, i.p.) dose-dependently attenuated the mechanical allodynia both in CCI-induced neuropathic pain and CFA-induced inflammatory pain in mice. The potency of N-demethylsinomenine for reducing CFA-induced mechanical allodynia was slightly higher than sinomenine. During the period of repeated treatment, N-demethylsinomenine maintained its anti-allodynic effect against both neuropathic and inflammatory pain without producing carry-over effect. Pretreatment with bicuculline, a selective γ-aminobutyric acid type A (GABAA) receptor antagonist, almost completely blocked the anti-allodynia of N-demethylsinomenine (40 mg/kg) both in CCI and CFA-treated mice. Our findings indicated that N-demethylsinomenine exhibits GABAA receptor-mediated anti-allodynic effects in mouse models of neuropathic and inflammatory pain, suggesting it may be a useful novel pharmacotherapy for the control of chronic pain.
Spectroscopic analysis of chia seeds
Authors: Mburu Monica , Paquet-Durand Olivier , Hitzmann Bernd , Zettel Viktoria
Published: April 2021

Chia seeds are becoming more and more popular in modern diets. In this contribution NIR and 2D-fluorescence spectroscopy were used to determine their nutritional values, mainly fat and protein content. 25 samples of chia seeds were analysed, whereof 9 samples were obtained from different regions in Kenya, 16 samples were purchased in stores in Germany and originated mostly from South America. For the purchased samples the nutritional information of the package was taken in addition to the values obtained for fat and protein, which were determined at the Hohenheim Core Facility. For the first time the NIR and fluorescence spectroscopy were used for the analysis of chia. For the spectral evaluation two different pre-processing methods were tested. Baseline correction with subsequent mean-centring lead to the best results for NIR spectra whereas SNV (standard normal variate transformation) was sufficient for the evaluation of fluorescence spectra. When combining NIR and fluorescence spectra, the fluorescence spectra were also multiplied with a factor to adjust the intensity levels. The best prediction results for the evaluation of the combined spectra were obtained for Kenyan samples with prediction errors below 0.2 g/100 g. For all other samples the absolute prediction error was 0.51 g/100 g for fat and 0.62 g/100 g for protein. It is possible to determine the amount of protein and fat of chia seeds by fluorescence and NIR spectroscopy. The combination of both methods is beneficial for the predictions. Chia seeds from Kenya had similar protein and lipid contents as South American seeds.
AntiTNF-alpha therapy normalizes levels of lipids and adipokines in psoriatic patients in the real-life settings
Authors: Olejniczak-Staruch Irmina , Narbutt Joanna , Ceryn Justyna , Skibińska Małgorzata , Bednarski Igor , Woźniacka Anna , Sieniawska Joanna , Kraska-Gacka Marzena , Ciążyńska Magdalena , Śmigielski Janusz , Noweta Marcin , Waszczykowski Michał , Owczarek Witold , Reich Adam , Lesiak Aleksandra
Published: April 2021

Studies have shown that the levels of pro-inflammatory adipokines in patients with psoriasis are higher than in general population. The aim of the study was to investigate the influence of 36-month therapy with TNF-α inhibitors (adalimumab, etanercept, infliximab) on the levels of adipokines (resistin, adiponectin, leptin) and lipids (TG, cholesterol, LDL, HDL) in 37 psoriasis patients and 30 healthy controls. The mean serum concentrations of adiponectin in patients from adalimumab, etanercept and infliximab group were similar to control group (p > 0.05, 142.71, 164.32, 129.35 and 174.44 μg/ml respectively). Resistin levels were higher in patients (p < 0.05, 4.48, 4.53 and 3.39 ng/ml respectively) than in controls (3.05 ng/ml). Mean leptin concentrations were significantly higher (p < 0.05) in the study group than in subjects without psoriasis (428.61, 523.24, 755.27 and 154.10 pg/ml respectively). A significant decrease in the mean resistin concentration was observed under the influence of biological therapy (p < 0.05). Decrease in serum leptin level was noted in etanercept and infliximab groups (p = 0.001 and p = 0.002 respectively). Improvement in all lipidogram parameters was noted in all examined groups (p < 0.05). Results may prove that biologic therapy affects the systemic inflammation associated with psoriasis and this effect persists with long-term therapy.
Exploring diversification drivers in golden orbweavers
Authors: Turk Eva , Kralj-Fišer Simona , Kuntner Matjaž
Published: April 2021

Heterogeneity in species diversity is driven by the dynamics of speciation and extinction, potentially influenced by organismal and environmental factors. Here, we explore macroevolutionary trends on a phylogeny of golden orbweavers (spider family Nephilidae). Our initial inference detects heterogeneity in speciation and extinction, with accelerated extinction rates in the extremely sexually size dimorphic Nephila and accelerated speciation in Herennia, a lineage defined by highly derived, arboricolous webs, and pronounced island endemism. We evaluate potential drivers of this heterogeneity that relate to organisms and their environment. Primarily, we test two continuous organismal factors for correlation with diversification in nephilids: phenotypic extremeness (female and male body length, and sexual size dimorphism as their ratio) and dispersal propensity (through range sizes as a proxy). We predict a bell-shaped relationship between factor values and speciation, with intermediate phenotypes exhibiting highest diversification rates. Analyses using SSE-class models fail to support our two predictions, suggesting that phenotypic extremeness and dispersal propensity cannot explain patterns of nephilid diversification. Furthermore, two environmental factors (tropical versus subtropical and island versus continental species distribution) indicate only marginal support for higher speciation in the tropics. Although our results may be affected by methodological limitations imposed by a relatively small phylogeny, it seems that the tested organismal and environmental factors play little to no role in nephilid diversification. In the phylogeny of golden orbweavers, the recent hypothesis of universal diversification dynamics may be the simplest explanation of macroevolutionary patterns.
Uncovering feature interdependencies in high-noise environments with stepwise lookahead decision forests
Authors: Donick Delilah , Lera Sandro Claudio
Published: April 2021

Conventionally, random forests are built from “greedy” decision trees which each consider only one split at a time during their construction. The sub-optimality of greedy implementation has been well-known, yet mainstream adoption of more sophisticated tree building algorithms has been lacking. We examine under what circumstances an implementation of less greedy decision trees actually yields outperformance. To this end, a “stepwise lookahead” variation of the random forest algorithm is presented for its ability to better uncover binary feature interdependencies. In contrast to the greedy approach, the decision trees included in this random forest algorithm, each simultaneously consider three split nodes in tiers of depth two. It is demonstrated on synthetic data and financial price time series that the lookahead version significantly outperforms the greedy one when (a) certain non-linear relationships between feature-pairs are present and (b) if the signal-to-noise ratio is particularly low. A long-short trading strategy for copper futures is then backtested by training both greedy and stepwise lookahead random forests to predict the signs of daily price returns. The resulting superior performance of the lookahead algorithm is at least partially explained by the presence of “XOR-like” relationships between long-term and short-term technical indicators. More generally, across all examined datasets, when no such relationships between features are present, performance across random forests is similar. Given its enhanced ability to understand the feature-interdependencies present in complex systems, this lookahead variation is a useful extension to the toolkit of data scientists, in particular for financial machine learning, where conditions (a) and (b) are typically met.
OptoGap is an optogenetics-enabled assay for quantification of cell–cell coupling in multicellular cardiac tissue
Authors: Boyle Patrick M. , Yu Jinzhu , Klimas Aleksandra , Williams John C. , Trayanova Natalia A. , Entcheva Emilia
Published: April 2021

Intercellular electrical coupling is an essential means of communication between cells. It is important to obtain quantitative knowledge of such coupling between cardiomyocytes and non-excitable cells when, for example, pathological electrical coupling between myofibroblasts and cardiomyocytes yields increased arrhythmia risk or during the integration of donor (e.g., cardiac progenitor) cells with native cardiomyocytes in cell-therapy approaches. Currently, there is no direct method for assessing heterocellular coupling within multicellular tissue. Here we demonstrate experimentally and computationally a new contactless assay for electrical coupling, OptoGap, based on selective illumination of inexcitable cells that express optogenetic actuators and optical sensing of the response of coupled excitable cells (e.g., cardiomyocytes) that are light-insensitive. Cell–cell coupling is quantified by the energy required to elicit an action potential via junctional current from the light-stimulated cell(s). The proposed technique is experimentally validated against the standard indirect approach, GapFRAP, using light-sensitive cardiac fibroblasts and non-transformed cardiomyocytes in a two-dimensional setting. Its potential applicability to the complex three-dimensional setting of the native heart is corroborated by computational modelling and proper calibration. Lastly, the sensitivity of OptoGap to intrinsic cell-scale excitability is robustly characterized via computational analysis.
Mixture interactions at mammalian olfactory receptors are dependent on the cellular environment
Authors: Corey Elizabeth A. , Zolotukhin Sergei , Ache Barry W. , Ukhanov Kirill
Published: April 2021

Functional characterization of mammalian olfactory receptors (ORs) remains a major challenge to ultimately understanding the olfactory code. Here, we compare the responses of the mouse Olfr73 ectopically expressed in olfactory sensory neurons using AAV gene delivery in vivo and expressed in vitro in cell culture. The response dynamics and concentration-dependence of agonists for the ectopically expressed Olfr73 were similar to those reported for the endogenous Olfr73, however the antagonism previously reported between its cognate agonist and several antagonists was not replicated in vivo. Expressing the OR in vitro reproduced the antagonism reported for short odor pulses, but not for prolonged odor exposure. Our findings suggest that both the cellular environment and the stimulus dynamics shape the functionality of Olfr73 and argue that characterizing ORs in ‘native’ conditions, rather than in vitro, provides a more relevant understanding of ligand-OR interactions.
System for quantitative evaluation of DAB&H-stained breast cancer biopsy digital images (CHISEL)
Authors: Roszkowiak Lukasz , Korzynska Anna , Siemion Krzysztof , Zak Jakub , Pijanowska Dorota , Bosch Ramon , Lejeune Marylene , Lopez Carlos
Published: April 2021

This study presents CHISEL (Computer-assisted Histopathological Image Segmentation and EvaLuation), an end-to-end system capable of quantitative evaluation of benign and malignant (breast cancer) digitized tissue samples with immunohistochemical nuclear staining of various intensity and diverse compactness. It stands out with the proposed seamless segmentation based on regions of interest cropping as well as the explicit step of nuclei cluster splitting followed by a boundary refinement. The system utilizes machine learning and recursive local processing to eliminate distorted (inaccurate) outlines. The method was validated using two labeled datasets which proved the relevance of the achieved results. The evaluation was based on the IISPV dataset of tissue from biopsy of breast cancer patients, with markers of T cells, along with Warwick Beta Cell Dataset of DAB&H-stained tissue from postmortem diabetes patients. Based on the comparison of the ground truth with the results of the detected and classified objects, we conclude that the proposed method can achieve better or similar results as the state-of-the-art methods. This system deals with the complex problem of nuclei quantification in digitalized images of immunohistochemically stained tissue sections, achieving best results for DAB&H-stained breast cancer tissue samples. Our method has been prepared with user-friendly graphical interface and was optimized to fully utilize the available computing power, while being accessible to users with fewer resources than needed by deep learning techniques.
Computational medication regimen for Parkinson’s disease using reinforcement learning
Authors: Kim Yejin , Suescun Jessika , Schiess Mya C. , Jiang Xiaoqian
Published: April 2021

Our objective is to derive a sequential decision-making rule on the combination of medications to minimize motor symptoms using reinforcement learning (RL). Using an observational longitudinal cohort of Parkinson’s disease patients, the Parkinson’s Progression Markers Initiative database, we derived clinically relevant disease states and an optimal combination of medications for each of them by using policy iteration of the Markov decision process (MDP). We focused on 8 combinations of medications, i.e., Levodopa, a dopamine agonist, and other PD medications, as possible actions and motor symptom severity, based on the Unified Parkinson Disease Rating Scale (UPDRS) section III, as reward/penalty of decision. We analyzed a total of 5077 visits from 431 PD patients with 55.5 months follow-up. We excluded patients without UPDRS III scores or medication records. We derived a medication regimen that is comparable to a clinician’s decision. The RL model achieved a lower level of motor symptom severity scores than what clinicians did, whereas the clinicians’ medication rules were more consistent than the RL model. The RL model followed the clinician’s medication rules in most cases but also suggested some changes, which leads to the difference in lowering symptoms severity. This is the first study to investigate RL to improve the pharmacological approach of PD patients. Our results contribute to the development of an interactive machine-physician ecosystem that relies on evidence-based medicine and can potentially enhance PD management.
Nanoslot metasurface design and characterization for enhanced organic light-emitting diodes
Authors: Kang Kyungnam , Im Seongmin , Lee Changhun , Kim Jungho , Kim Donghyun
Published: April 2021

We investigate bottom-emitting organic light-emitting diodes (B-OLEDs) integrated with metasurface (MS) to analyze the effect of the structural parameters on the output performance. The performance of the MS-integrated B-OLED (MIB-OLED) is evaluated by out-coupling efficiency (OCE) and reflection of the ambient light, while attention is paid mainly to dielectric capping and metal structure of MS that may influence excitation of surface plasmon (SP). The results suggest that layer thicknesses affect the performance by as much as 10% for the OCE and up to 32% for reflectance. The OCE is in general weakly affected by the structural parameters of MS. In contrast, the reflectance characteristics are found to be dominated by localized SP that is largely determined by the length and the width of a unit slot of MS. An optimization factor introduced to evaluate the performance based on out-coupling power to the radiation mode and reflectance of MIB-OLEDs confirms that integration with MS improves performance by 16% over conventional planar structure. In particular, MIB-OLED is found to enhance OCE by 51% with Lambertian-like pattern. Enhanced performance is experimentally confirmed. The findings provide insights on how to optimize the MS structure to produce MIB-OLEDs with enhanced out-coupled power and contrast ratio.