bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery and Characterization of a Bilirubin Inducible Green Fluorescent Protein From the Moray Eel Gymnothorax zonipectis
Authors: Guarnaccia Andrew M. , Krivoshik Sara Rose , Sparks John S. , Gruber David F. , Gaffney Jean P.
Published: September 2021

Since the initial discovery of Aqueoria victoria’s green fluorescence off the coast of Washington’s Puget Sound, biofluorescent marine organisms have been found across the globe. The variety of colors of biofluorescence as well as the variability in the organisms that exhibit this fluorescence is astounding. The mechanisms of biofluorescence in marine organisms are also variable. To fluoresce, some organisms use fluorescent proteins, while others use small molecules. In eels, green biofluorescence was first identified in Anguilla japonica. The green fluorescence in A. japonica was discovered to be caused by a fatty acid binding protein (UnaG) whose fluorescence is induced by the addition of bilirubin. Members of this class of proteins were later discovered in Kaupichthys eels (Chlopsid FP I and Chlopsid FP II). Here, we report the discovery and characterization of the first member of this class of green fluorescent fatty acid binding proteins from the moray eel Gymnothorax zonipectis. This protein, GymFP, is 15.6 kDa with a fluorescence excitation at 496 nm and an emission maximum at 532 nm upon addition of bilirubin. GymFP is 61% homologous to UnaG and 47% homologous to Chlopsid FP I. Here, we report de novo transcriptome assembly, protein expression, and fluorescence spectroscopic characterization of GymFP. These findings extend the fluorescent fatty acid binding proteins into a third family of true eels (Anguilliformes).
Seasonal Fishery Closure in the Northern Bay of Bengal Causes Immediate but Contrasting Ecological and Socioeconomic Impacts
Authors: Islam Mohammad Mahmudul , Begum Amany , Rahman Syed Mohammad Aminur , Ullah Hadayet
Published: September 2021

Bangladesh has introduced a monsoonal fishery closure in the Bay of Bengal to ensure the conservation of fish stocks and productive breeding grounds. While the fishing ban has likely supported this goal, it has also sparked protest and resentment among small-scale fishers. This study investigated fishers’ perceptions of the 65-day fishing ban between May and July in the Bay of Bengal. We collected both qualitative and quantitative data from five coastal fishing communities. Data were analyzed to explore fishers’ perceptions of the socioeconomic and ecological impacts of the closure. While most respondents agreed that the closure produced positive ecological outcomes, they felt that their income and food security had been negatively affected. Importantly, crew members perceived their losses to be more extreme than the boat skipper or owner due to their overreliance on the fishery and lack of alternative skills and occupations. These fishers cannot forfeit their livelihoods and food security needs, as they are already living on the margins of subsistence. This social ramification emphasizes the necessity of understanding the interconnection between fishers’ socioeconomic conditions and conservation needs. Social-ecological trade-offs and inequalities raise the question of social equity and environmental justice, which could ultimately compromise management and conservation effectiveness and legitimacy. The involvement of local communities in the decision-making process for future fishery interventions could enhance both the livelihood opportunities and the positive ecological outcomes in the Bay of Bengal marine ecosystem.
Two New M23 Peptidoglycan Hydrolases With Distinct Net Charge
Authors: Wysocka Alicja , Jagielska Elżbieta , Łężniak Łukasz , Sabała Izabela
Published: September 2021

Bacterial peptidoglycan hydrolases play an essential role in cell wall metabolism during bacterial growth, division, and elongation (autolysins) or in the elimination of closely related species from the same ecological niche (bacteriocins). Most studies concerning the peptidoglycan hydrolases present in Gram-positive bacteria have focused on clinically relevant Staphylococcus aureus or the model organism Bacillus subtilis, while knowledge relating to other species remains limited. Here, we report two new peptidoglycan hydrolases from the M23 family of metallopeptidases derived from the same staphylococcal species, Staphylococcus pettenkoferi. They share modular architecture, significant sequence identity (60%), catalytic and binding residue conservation, and similar modes of activation, but differ in gene distribution, putative biological role, and, strikingly, in their isoelectric points (pIs). One of the peptides has a high pI, similar to that reported for all M23 peptidases evaluated to date, whereas the other displays a low pI, a unique feature among M23 peptidases. Consequently, we named them SpM23_B (Staphylococcus pettenkoferi M23 “Basic”) and SpM23_A (Staphylococcus pettenkoferi M23 “Acidic”). Using genetic and biochemical approaches, we have characterized these two novel lytic enzymes, both in vitro and in their physiological context. Our study presents a detailed characterization of two novel and clearly distinct peptidoglycan hydrolases to understand their role in bacterial physiology.
Application of Machine Learning Techniques to an Agent-Based Model of Pantoea
Authors: Chen Serena H. , Londoño-Larrea Pablo , McGough Andrew Stephen , Bible Amber N. , Gunaratne Chathika , Araujo-Granda Pablo A. , Morrell-Falvey Jennifer L. , Bhowmik Debsindhu , Fuentes-Cabrera Miguel
Published: September 2021

Agent-based modeling (ABM) is a powerful simulation technique which describes a complex dynamic system based on its interacting constituent entities. While the flexibility of ABM enables broad application, the complexity of real-world models demands intensive computing resources and computational time; however, a metamodel may be constructed to gain insight at less computational expense. Here, we developed a model in NetLogo to describe the growth of a microbial population consisting of Pantoea. We applied 13 parameters that defined the model and actively changed seven of the parameters to modulate the evolution of the population curve in response to these changes. We efficiently performed more than 3,000 simulations using a Python wrapper, NL4Py. Upon evaluation of the correlation between the active parameters and outputs by random forest regression, we found that the parameters which define the depth of medium and glucose concentration affect the population curves significantly. Subsequently, we constructed a metamodel, a dense neural network, to predict the simulation outputs from the active parameters and found that it achieves high prediction accuracy, reaching an R2 coefficient of determination value up to 0.92. Our approach of using a combination of ABM with random forest regression and neural network reduces the number of required ABM simulations. The simplified and refined metamodels may provide insights into the complex dynamic system before their transition to more sophisticated models that run on high-performance computing systems. The ultimate goal is to build a bridge between simulation and experiment, allowing model validation by comparing the simulated data to experimental data in microbiology.
Peptides Derived From S and N Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 Induce T Cell Responses: A Proof of Concept for T Cell Vaccines
Authors: Lee Yu-Sun , Hong So-Hee , Park Hyo-Jung , Lee Ho-Young , Hwang Ji-Yeon , Kim Seo Yeon , Park Jun Won , Choi Kang-Seuk , Seong Je Kyung , Park Sang-In , Lee Sang-Myeong , Hwang Kyung-Ah , Yun Jun-Won , Nam Jae-Hwan
Published: September 2021

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that escape vaccine-induced neutralizing antibodies has indicated the importance of T cell responses against this virus. In this study, we highlight the SARS-CoV-2 epitopes that induce potent T cell responses and discuss whether T cell responses alone are adequate to confer protection against SARS-CoV-2 and describe the administration of 20 peptides with an RNA adjuvant in mice. The peptides have been synthesized based on SARS-CoV-2 spike and nucleocapsid protein sequences. Our study demonstrates that immunization with these peptides significantly increases the proportion of effector memory T cell population and interferon-γ (IFN-γ)-, interleukin-4 (IL-4)-, tumor necrosis factor-α (TNF-α)-, and granzyme B-producing T cells. Of these 20 peptides, four induce the generation of IFN-γ-producing T cells, elicit CD8+ T cell (CTL) responses in a dose-dependent manner, and induce cytotoxic T lymphocytes that eliminate peptide-pulsed target cells in vivo. Although it is not statistically significant, these peptide vaccines reduce viral titers in infected hamsters and alleviate pulmonary pathology in SARS-CoV-2-infected human ACE2 transgenic mice. These findings may aid the design of effective SARS-CoV-2 peptide vaccines, while providing insights into the role of T cells in SARS-CoV-2 infection.
Influence of New Compound Disinfectant From N-Dodecyl-2-(Piridin-1-Ium)Acetamide Chloride on Pathogenic Microorganisms in Poultry Houses
Authors: Chen Nannan , Qin Pingwei , Liu Yu , Yang Ying , Wen Hairuo , Jia Lihua , Li Jing , Zhu Zhanbo
Published: September 2021

With the development of large-scale and intensive poultry farming, environmental disinfection has become particularly important, and the effectiveness of disinfection depends upon the performance of the disinfectants. Quaternate ammonium salt is a group of positively charged polyatomic ions with both antibacterial and antiviral activities. In order to prepare an ideal disinfectant for poultry farms, we combined a quaternate ammonium salt N-dodecyl-2-(piridin-1-ium)acetamide chloride with two other disinfectants (chlorhexidine acetate and glutaraldehyde), respectively. The antimicrobial activity, mutagenicity, and safety of the compound disinfectants were assessed by the European Standard methods using ATCC strains and clinical isolates. The results showed that both compound disinfectants meet the requirements of microbial reduction, and their effectiveness was not affected by organic matter. Quaternary ammonium disinfectant resistance genes were not detected in the strains tested indicating that bacteria are less likely to develop resistance to these compound disinfectants. Ames test showed that there was no detectable mutagenicity in the strains treated with the compound disinfectants. In vivo experiment showed that both compound disinfectants did not have significant pathological effect in mice. The bactericidal effect of the compound disinfectants was not significantly different among strains of different sources (p>0.05). Clinical tests showed that compound disinfectant had a good bactericidal effect on the air and ground of poultry farms. These results show that quaternary ammonium salts in combination with other compounds can enhance the bactericidal effect and can be used safely in poultry feedlots. This study provides a technical reference for the development of a new quaternate ammonium compound disinfectant with strong disinfection effect and low irritation.
Phosphate-Solubilizing Bacterium Acinetobacter pittii gp-1 Affects Rhizosphere Bacterial Community to Alleviate Soil Phosphorus Limitation for Growth of Soybean (Glycine max)
Authors: He Donglan , Wan Wenjie
Published: September 2021

Phosphorus (P) availability is a major restriction to crop production, and phosphate-solubilizing bacteria (PSBs) in soils are responsible for P turnover. However, it remains unknown whether the application of PSB can facilitate both inorganic and organic P transformation and enhance function of plant rhizosphere bacteria. In this study, we applied Illumina MiSeq sequencing, plate-colony counting, quantitative PCR, and multiple ecological analyses. We found that the inoculation of PSB Acinetobacter pittii gp-1 significantly promoted the growth of soybean represented by better vegetation properties (e.g., plant height and root P) and increased activities of phosphatase (4.20–9.72 μg/g/h) and phytase (0.69–1.53 μmol/g/day) as well as content of indole acetic acid (5.80–40.35 μg/g/h). Additionally, the application of strain A. pittii gp-1 significantly increased abundances of both inorganic and organic P-cycling-related genes (i.e., phoD, bpp, gcd, and pstS). More importantly, the application of A. pittii gp-1 could increase the function represented by P-cycling-related enzymes (e.g., phosphotransferase) of rhizosphere bacterial community based on functional profiling. To our knowledge, this is the first report that the application of PSB A. pittii promotes inorganic and organic P utilization and increases the function of rhizosphere bacterial community. Therefore, the PSB A. pittii gp-1 could be a good candidate for the promotion of soybean growth.
Inhibition of Quorum Sensing and Biofilm Formation of Esculetin on Aeromonas Hydrophila
Authors: Sun Bing , Luo Huaizhi , Jiang Huan , Wang Zhennan , Jia Aiqun
Published: September 2021

Quorum sensing (QS) and biofilm formation inhibition activity of esculetin on Aeromonas hydrophila SHAe 115 were evaluated. Exposure to esculetin at 25, 50, and 100μg/ml significantly inhibited the production of protease and hemolysin, the formation of biofilms and attenuated the swarming motility of A. hydrophila SHAe 115. Biofilm forming inhibition was also observed through confocal laser scanning microscopy and scanning electron microscope. Quantitative real-time PCR analysis indicated that genes positively related to QS and biofilm formation were downregulated to varying degrees, while gene (litR) negatively related to biofilm formation was significantly upregulated. The phenotypic results were in good agreement with gene expression levels. These results indicated that esculetin would be a potential QS inhibitor for A. hydrophila.
Lactiplantibacillus plantarum Reduced Renal Calcium Oxalate Stones by Regulating Arginine Metabolism in Gut Microbiota
Authors: Liu Yu , Jin Xi , Tian Lei , Jian Zhongyu , Ma Yucheng , Cheng Liang , Cui Yaqian , Li Hong , Sun Qun , Wang Kunjie
Published: September 2021

Renal calcium oxalate (CaOx) stones are a common kidney disease. There are few methods for reducing the formation of these stones. However, the potential of probiotics for reducing renal stones has received increasing interest. We previously isolated a strain of Lactiplantibacillus plantarum N-1 from traditional cheese in China. This study aimed to investigate the effects of N-1 on renal CaOx crystal deposition. Thirty rats were randomly allocated to three groups: control group (ddH2O by gavage), model group [ddH2O by gavage and 1% ethylene glycol (EG) in drinking water], and Lactiplantibacillus group (N-1 by gavage and 1% EG in drinking water). After 4 weeks, compared with the model group, the group treated with N-1 exhibited significantly reduced renal crystals (P < 0.05). In the ileum and caecum, the relative abundances of Lactobacillus and Eubacterium ventriosum were higher in the control group, and those of Ruminococcaceae UCG 007 and Rikenellaceae RC9 were higher in the N-1-supplemented group. In contrast, the relative abundances of Staphylococcus, Corynebacterium 1, Jeotgalicoccus, Psychrobacter, and Aerococcus were higher in the model group. We also predicted that the arginase level would be higher in the ileal microbiota of the model group than in the N-1-supplemented group with PICRUSt2. The arginase activity was higher, while the level of arginine was lower in the ileal contents of the model group than in the N-1-supplemented group. The arginine level in the blood was also higher in the N-1-supplemented group than in the model group. In vitro studies showed that exposure to arginine could reduce CaOx crystal adhesion to renal epithelial HK-2 cells. Our findings highlighted the important role of N-1 in reducing renal CaOx crystals by regulating arginine metabolism in the gut microbiota. Probiotics containing L. plantarum N-1 may be potential therapies for preventing renal CaOx stones.
Opportunities and Challenges of Bacterial Glycosylation for the Development of Novel Antibacterial Strategies
Authors: Yakovlieva Liubov , Fülleborn Julius A. , Walvoort Marthe T. C.
Published: September 2021

Glycosylation is a ubiquitous process that is universally conserved in nature. The various products of glycosylation, such as polysaccharides, glycoproteins, and glycolipids, perform a myriad of intra- and extracellular functions. The multitude of roles performed by these molecules is reflected in the significant diversity of glycan structures and linkages found in eukaryotes and prokaryotes. Importantly, glycosylation is highly relevant for the virulence of many bacterial pathogens. Various surface-associated glycoconjugates have been identified in bacteria that promote infectious behavior and survival in the host through motility, adhesion, molecular mimicry, and immune system manipulation. Interestingly, bacterial glycosylation systems that produce these virulence factors frequently feature rare monosaccharides and unusual glycosylation mechanisms. Owing to their marked difference from human glycosylation, bacterial glycosylation systems constitute promising antibacterial targets. With the rise of antibiotic resistance and depletion of the antibiotic pipeline, novel drug targets are urgently needed. Bacteria-specific glycosylation systems are especially promising for antivirulence therapies that do not eliminate a bacterial population, but rather alleviate its pathogenesis. In this review, we describe a selection of unique glycosylation systems in bacterial pathogens and their role in bacterial homeostasis and infection, with a focus on virulence factors. In addition, recent advances to inhibit the enzymes involved in these glycosylation systems and target the bacterial glycan structures directly will be highlighted. Together, this review provides an overview of the current status and promise for the future of using bacterial glycosylation to develop novel antibacterial strategies.
Force and Stepwise Movements of Gliding Motility in Human Pathogenic Bacterium Mycoplasma pneumoniae
Authors: Mizutani Masaki , Sasajima Yuya , Miyata Makoto
Published: September 2021

Mycoplasma pneumoniae, a human pathogenic bacterium, binds to sialylated oligosaccharides and glides on host cell surfaces via a unique mechanism. Gliding motility is essential for initiating the infectious process. In the present study, we measured the stall force of an M. pneumoniae cell carrying a bead that was manipulated using optical tweezers on two strains. The stall forces of M129 and FH strains were averaged to be 23.7 and 19.7 pN, respectively, much weaker than those of other bacterial surface motilities. The binding activity and gliding speed of the M129 strain on sialylated oligosaccharides were eight and two times higher than those of the FH strain, respectively, showing that binding activity is not linked to gliding force. Gliding speed decreased when cell binding was reduced by addition of free sialylated oligosaccharides, indicating the existence of a drag force during gliding. We detected stepwise movements, likely caused by a single leg under 0.2-0.3 mM free sialylated oligosaccharides. A step size of 14-19 nm showed that 25-35 propulsion steps per second are required to achieve the usual gliding speed. The step size was reduced to less than half with the load applied using optical tweezers, showing that a 2.5 pN force from a cell is exerted on a leg. The work performed in this step was 16-30% of the free energy of the hydrolysis of ATP molecules, suggesting that this step is linked to the elementary process of M. pneumoniae gliding. We discuss a model to explain the gliding mechanism, based on the information currently available.
Kidney Function in Patients With Neuromuscular Disease: Creatinine Versus Cystatin C
Authors: Screever Elles M. , Kootstra-Ros Jenny E. , Doorn Joyce , Nieuwenhuis Jellie A. , Meulenbelt Henk E. J. , Meijers Wouter C. , de Boer Rudolf A.
Published: September 2021

Background: Accurate measurement of kidney function in patients with neuromuscular disorders is challenging. Cystatin C, a marker not influenced by skeletal muscle degradation, might be of clinical value in these patients.

Methods: We consecutively enrolled 39 patients with neuromuscular disorders. We investigated the association of the eGFR, based on plasma creatinine and Cystatin C, with clinical and biochemical variables associated with kidney function, namely age and galectin-3.

Results: Creatinine-based eGFR was 242 (±80) and Cystatin C-based eGFR was 110 (±23) mL/min/1.73 m2. Cystatin C-based eGFR was associated with age (β −0.63 p < 0.0001) and galectin-3 levels (β −0.43 p < 0.01), while creatinine-based eGFR was not (β −0.22 p = 0.20; β −0.28 p = 0.10). Sensitivity analyses in Duchenne and Becker patients revealed the same results: Cystatin C-based eGFR was associated with age (β −0.61 p < 0.01) and galectin-3 levels (β −0.43 p = 0.05), while creatinine-based eGFR was not (β −0.32 p = 0.13; β −0.34 p = 0.14).

Conclusions: These data indicate that estimation of renal function in patients with neuromuscular disorders cannot reliably be achieved with creatinine, while Cystatin C appears a reasonable alternative. Since a large proportion of patients with neuromuscular disorders develops heart failure, and requires heart failure medication, adequate monitoring of renal function is warranted.
At the Intersection of Gut Microbiome and Stroke: A Systematic Review of the Literature
Authors: Sharma Vishakha , Sharma Vaibhav , Shahjouei Shima , Li Jiang , Chaudhary Durgesh , Khan Ayesha , Wolk Donna M. , Zand Ramin , Abedi Vida
Published: September 2021

Background: Ischemic and hemorrhagic stroke are associated with a high rate of long-term disability and death. Recent investigations focus efforts to better understand how alterations in gut microbiota composition influence clinical outcomes. A key metabolite, trimethylamine N-oxide (TMAO), is linked to multiple inflammatory, vascular, and oxidative pathways. The current biochemical underpinnings of microbial effects on stroke remain largely understudied. The goal of our study is to explore the current literature to explain the interactions between the human gut microbiome and stroke progression, recovery, and outcome. We also provide a descriptive review of TMAO.

Methods: A systematic literature search of published articles between January 1, 1990, and March 22, 2020, was performed on the PubMed database to identify studies addressing the role of the microbiome and TMAO in the pathogenesis and recovery of acute stroke. Our initial investigation focused on human subject studies and was further expanded to include animal studies. Relevant articles were included, regardless of study design. The analysis included reviewers classifying and presenting selected articles by study design and sample size in a chart format.

Results: A total of 222 titles and abstracts were screened. A review of the 68 original human subject articles resulted in the inclusion of 24 studies in this review. To provide further insight into TMAO as a key player, an additional 40 articles were also reviewed and included. Our findings highlighted that alterations in richness and abundance of gut microbes and increased plasma TMAO play an important role in vascular events and outcomes. Our analysis revealed that restoration of a healthy gut, through targeted TMAO-reducing therapies, could provide alternative secondary prevention for at-risk patients.

Discussion: Biochemical interactions between the gut microbiome and inflammation, resulting in metabolic derangements, can affect stroke progression and outcomes. Clinical evidence supports the importance of TMAO in modulating underlying stroke risk factors. Lack of standardization and distinct differences in sample sizes among studies are major limitations.
Trend of Sudden Unexpected Death in Epilepsy Incidence Rate in Rural West China
Authors: Wang Haijiao , Chen Deng , He Jun , He Yujin , Liu Ling , Zhou Dong
Published: September 2021

Objectives: To explore the trend of sudden unexpected death in epilepsy (SUDEP) incidence rate over time in rural west China.

Methods: We scanned probable SUDEP patients from the epilepsy program between 2010 and 2019 in rural West China and performed a verbal autopsy for each eligible patient. We calculated the crude and sex-adjusted incidence rate of SUDEP per person-year over a calendar year and the year of follow-up. We calculated the incidence rate ratio with the Poisson model in STATA 12.0 and calculated the annual percentage change (APC) and average annual percentage change in Joinpoint Trend Analysis Software 4.8.0.1 to analyze the trend of SUDEP incidence rate.

Results: In 2010–2019, 44 probable SUDEPs were identified from 10,128 patients with a total person-year of 31,347. The crude and sex-adjusted incidence rates of SUDEP were 1.40 and 1.45%0. Twenty-five (56.8%) of the 44 probable SUDEPs had no generalized tonic-clonic seizure 3 months before their death. The incidence of probable SUDEP decreased significantly in the calendar year [APC = −11.7, 95% confidence interval (CI): −21.7 to −0.3] and in time of follow-up (average annual percentage change = −21.2, 95% CI: −34.3 to −5.4). Comparing the first 5 years in follow-up with the subsequent 3 years, the incidence rate of SUDEP decreased significantly (estimated incidence rate ratio = 0.4, 95% CI: 0.2 to 0.8).

Significance: SUDEP happened to 1.4 cases per thousand patient-years in convulsive epilepsy in rural west China between 2010 and 2019. The incidence rate of SUDEP presented a downward trend over the time of follow-up.
Measurement of Human Semicircular Canal Spatial Attitude
Authors: Wu Shuzhi , Lin Ping , Zheng Yanyan , Zhou Yifei , Liu Zhaobang , Yang Xiaokai
Published: September 2021

Located deep in the temporal bone, the semicircular canal is a subtle structure that requires a spatial coordinate system for measurement and observation. In this study, 55 semicircular canal and eyeball models were obtained by segmentation of MRI data. The spatial coordinate system was established by taking the top of the common crus and the bottom of the eyeball as the horizontal plane. First, the plane equation was established according to the centerline of the semicircular canals. Then, according to the parameters of the plane equation, the plane normal vectors were obtained. Finally, the average unit normal vector of each semicircular canal plane was obtained by calculating the average value of the vectors. The standard normal vectors of the and left posterior semicircular canal, superior semicircular canal and lateral semicircular canal were [−0.651, 0.702, 0.287], [0.749, 0.577, 0.324], [−0.017, −0.299, 0.954], [0.660, 0.702, 0.266], [−0.739, 0.588, 0.329], [0.025, −0.279, 0.960]. The different angles for the different ways of calculating the standard normal vectors of the right and left posterior semicircular canal, superior semicircular canal and lateral semicircular canal were 0.011, 0.028, 0.008, 0.011, 0.024, and 0.006 degrees. The technology for measuring the semicircular canal spatial attitudes in this study are reliable, and the measurement results can guide vestibular function examinations and help with guiding the diagnosis and treatment of BPPV.
Modulating Cortical Instrument Representations During Auditory Stream Segregation and Integration With Polyphonic Music
Authors: Hausfeld Lars , Disbergen Niels R. , Valente Giancarlo , Zatorre Robert J. , Formisano Elia
Published: September 2021

Numerous neuroimaging studies demonstrated that the auditory cortex tracks ongoing speech and that, in multi-speaker environments, tracking of the attended speaker is enhanced compared to the other irrelevant speakers. In contrast to speech, multi-instrument music can be appreciated by attending not only on its individual entities (i.e., segregation) but also on multiple instruments simultaneously (i.e., integration). We investigated the neural correlates of these two modes of music listening using electroencephalography (EEG) and sound envelope tracking. To this end, we presented uniquely composed music pieces played by two instruments, a bassoon and a cello, in combination with a previously validated music auditory scene analysis behavioral paradigm (Disbergen et al., 2018). Similar to results obtained through selective listening tasks for speech, relevant instruments could be reconstructed better than irrelevant ones during the segregation task. A delay-specific analysis showed higher reconstruction for the relevant instrument during a middle-latency window for both the bassoon and cello and during a late window for the bassoon. During the integration task, we did not observe significant attentional modulation when reconstructing the overall music envelope. Subsequent analyses indicated that this null result might be due to the heterogeneous strategies listeners employ during the integration task. Overall, our results suggest that subsequent to a common processing stage, top-down modulations consistently enhance the relevant instrument’s representation during an instrument segregation task, whereas such an enhancement is not observed during an instrument integration task. These findings extend previous results from speech tracking to the tracking of multi-instrument music and, furthermore, inform current theories on polyphonic music perception.
Relaxation Degree Analysis Using Frontal Electroencephalogram Under Virtual Reality Relaxation Scenes
Authors: Zhang Yue , Zhang Lulu , Hua Haoqiang , Jin Jianxiu , Zhu Lingqing , Shu Lin , Xu Xiangmin , Kuang Feng , Liu Yunhe
Published: September 2021

Increasing social pressure enhances the psychological burden on individuals, and the severity of depression can no longer be ignored. The characteristics of high immersion and interactivity enhance virtual reality (VR) application in psychological therapy. Many studies have verified the effectiveness of VR relaxation therapy, although a few have performed a quantitative study on relaxation state (R-state). To confirm the effectiveness of VR relaxation and quantitatively assess relaxation, this study confirmed the effectiveness of the VR sightseeing relaxation scenes using subjective emotion scale and objective electroencephalogram (EEG) data from college students. Moreover, some EEG features with significant consistent differences after they watched the VR scenes were detected including the energy ratio of the alpha wave, gamma wave, and differential asymmetry. An R-state regression model was then built using the model stacking method for optimization, of which random forest regression, AdaBoost, gradient boosting (GB), and light GB were adopted as the first level, while linear regression and support vector machine were applied at the second level. The leave-one-subject-out method for cross-validation was used to evaluate the results, where the mean accuracy of the framework achieved 81.46%. The significantly changed features and the R-state model with over 80% accuracy have laid a foundation for further research on relaxation interaction systems. Moreover, the VR relaxation therapy was applied to the clinical treatment of patients with depression and achieved preliminary good results, which might provide a possible method for non-drug treatment of patients with depression.
Case Report: Embedding “Digital Chronotherapy” Into Medical Devices—A Canine Validation for Controlling Status Epilepticus Through Multi-Scale Rhythmic Brain Stimulation
Authors: Zamora Mayela , Meller Sebastian , Kajin Filip , Sermon James J. , Toth Robert , Benjaber Moaad , Dijk Derk-Jan , Bogacz Rafal , Worrell Gregory A. , Valentin Antonio , Duchet Benoit , Volk Holger A. , Denison Timothy
Published: September 2021

Circadian and other physiological rhythms play a key role in both normal homeostasis and disease processes. Such is the case of circadian and infradian seizure patterns observed in epilepsy. However, these rhythms are not fully exploited in the design of active implantable medical devices. In this paper we explore a new implantable stimulator that implements chronotherapy as a feedforward input to supplement both open-loop and closed-loop methods. This integrated algorithm allows for stimulation to be adjusted to the ultradian, circadian and infradian patterns observed in patients through slowly-varying temporal adjustments of stimulation and algorithm sub-components, while also enabling adaption of stimulation based on immediate physiological needs such as a breakthrough seizure or change of posture. Embedded physiological sensors in the stimulator can be used to refine the baseline stimulation circadian pattern as a “digital zeitgeber,” i.e., a source of stimulus that entrains or synchronizes the subject's natural rhythms. This algorithmic approach is tested on a canine with severe drug-resistant idiopathic generalized epilepsy exhibiting a characteristic diurnal pattern correlated with sleep-wake cycles. Prior to implantation, the canine's cluster seizures evolved to status epilepticus (SE) and required emergency pharmacological intervention. The cranially-mounted system was fully-implanted bilaterally into the centromedian nucleus of the thalamus. Using combinations of time-based modulation, thalamocortical rhythm-specific tuning of frequency parameters as well as fast-adaptive modes based on activity, the canine experienced no further SE events post-implant as of the time of writing (7 months). Importantly, no significant cluster seizures have been observed either, allowing the reduction of rescue medication. The use of digitally-enabled chronotherapy as a feedforward signal to augment adaptive neurostimulators could prove a useful algorithmic method in conditions where sensitivity to temporal patterns are characteristics of the disease state, providing a novel mechanism for tailoring a more patient-specific therapy approach.
An Adaptive STDP Learning Rule for Neuromorphic Systems
Authors: Gautam Ashish , Kohno Takashi
Published: September 2021

The promise of neuromorphic computing to develop ultra-low-power intelligent devices lies in its ability to localize information processing and memory storage in synaptic circuits much like the synapses in the brain. Spiking neural networks modeled using high-resolution synapses and armed with local unsupervised learning rules like spike time-dependent plasticity (STDP) have shown promising results in tasks such as pattern detection and image classification. However, designing and implementing a conventional, multibit STDP circuit becomes complex both in terms of the circuitry and the required silicon area. In this work, we introduce a modified and hardware-friendly STDP learning (named adaptive STDP) implemented using just 4-bit synapses. We demonstrate the capability of this learning rule in a pattern recognition task, in which a neuron learns to recognize a specific spike pattern embedded within noisy inhomogeneous Poisson spikes. Our results demonstrate that the performance of the proposed learning rule (94% using just 4-bit synapses) is similar to the conventional STDP learning (96% using 64-bit floating-point precision). The models used in this study are ideal ones for a CMOS neuromorphic circuit with analog soma and synapse circuits and mixed-signal learning circuits. The learning circuit stores the synaptic weight in a 4-bit digital memory that is updated asynchronously. In circuit simulation with Taiwan Semiconductor Manufacturing Company (TSMC) 250 nm CMOS process design kit (PDK), the static power consumption of a single synapse and the energy per spike (to generate a synaptic current of amplitude 15 pA and time constant 3 ms) are less than 2 pW and 200 fJ, respectively. The static power consumption of the learning circuit is less than 135 pW, and the energy to process a pair of pre- and postsynaptic spikes corresponding to a single learning step is less than 235 pJ. A single 4-bit synapse (capable of being configured as excitatory, inhibitory, or shunting inhibitory) along with its learning circuitry and digital memory occupies around 17,250 μm2 of silicon area.
The Role of Extracellular Vesicles in the Developing Brain: Current Perspective and Promising Source of Biomarkers and Therapy for Perinatal Brain Injury
Authors: Gamage Teena K. J. B. , Fraser Mhoyra
Published: September 2021

This comprehensive review focuses on our current understanding of the proposed physiological and pathological functions of extracellular vesicles (EVs) in the developing brain. Furthermore, since EVs have attracted great interest as potential novel cell-free therapeutics, we discuss advances in the knowledge of stem cell- and astrocyte-derived EVs in relation to their potential for protection and repair following perinatal brain injury. This review identified 13 peer-reviewed studies evaluating the efficacy of EVs in animal models of perinatal brain injury; 12/13 utilized mesenchymal stem cell-derived EVs (MSC-EVs) and 1/13 utilized astrocyte-derived EVs. Animal model, method of EV isolation and size, route, timing, and dose administered varied between studies. Notwithstanding, EV treatment either improved and/or preserved perinatal brain structures both macroscopically and microscopically. Additionally, EV treatment modulated inflammatory responses and improved brain function. Collectively this suggests EVs can ameliorate, or repair damage associated with perinatal brain injury. These findings warrant further investigation to identify the optimal cell numbers, source, and dosage regimens of EVs, including long-term effects on functional outcomes.
Treatment With Nepicastat Decreases Contextual Traumatic Memories Persistence in Post-traumatic Stress Disorder
Authors: Martinho Raquel , Correia Gabriela , Seixas Rafaela , Oliveira Ana , Silva Soraia , Serrão Paula , Fernandes-Lopes Carlos , Costa Cristina , Moreira-Rodrigues Mónica
Published: September 2021

Post-traumatic stress disorder (PTSD) is a common anxiety mental disorder and can be manifested after exposure to a real or perceived life-threatening event. Increased noradrenaline and adrenaline in plasma and urine have been documented in PTSD. Dopamine-β-hydroxylase (DBH) catalyzes the conversion of dopamine to noradrenaline and consequently, DBH inhibition reduces catecholamines. Our aim was to evaluate if nepicastat treatment decreases PTSD signs in an animal model. Wild-type (129x1/SvJ) female mice were submitted to PTSD induction protocol. DBH-inhibitor nepicastat (30 mg/kg) or vehicle (0.2% HPMC) were administered once daily since day 0 until day 7 or 12. The percentage of freezing was calculated on days 0, 1, 2, and 7, and behavioral tests were performed. Quantification of nepicastat in plasma and DBH activity in the adrenal gland was evaluated. Catecholamines were quantified by HPLC with electrochemical detection. mRNA expression ofNpas4andBdnfin hippocampus was evaluated by qPCR.Mice in the PTSD-group and treated with nepicastat showed a decrease in freezing, and an increase in the time spent and entries in open arms in elevated plus maze test. In mice treated with nepicastat, adrenal gland DBH activity was decreased, and catecholamines were also decreased in plasma and tissues. On day 7, in mice treated with nepicastat, there was an increase ofNpas4andBdnfmRNA expression in the hippocampus.In conclusion, DBH inhibitor nepicastat has an effect consistent with a decrease in the persistence of traumatic memories and anxiety-like behavior in this PTSD mice model. The disruption of traumatic memories through interference with the formation, consolidation, retrieval, and/or expression processes may be important to decrease PTSD symptoms and signs. The increase inNpas4andBdnfmRNA expression in the hippocampus may be important to develop a weaker traumatic contextual memory after nepicastat treatment.
Rehabilitation Needs of Head and Neck Cancer Patients and Stakeholders: Case Study
Authors: Karampela Maria , Porat Talya , Mylonopoulou Vasiliki , Isomursu Minna
Published: September 2021

Background

The incidents of Head and Neck Cancer (HNC) are rising worldwide, suggesting that this type of cancer is becoming more common. The foreseen growth of incidents signifies that future rehabilitation services will have to meet the needs of a wider population.

Objective

The aim of this paper is to explore the needs of patients, caregivers and healthcare professionals during HNC rehabilitation.

Methods

This paper reports the empirical findings from a case study that was conducted in a cancer rehabilitation center in Copenhagen to elicit the needs of HNC cancer patients, informal caregivers and healthcare professionals.

Results

Four areas of needs during the rehabilitation process were identified: service delivery, emotional, social and physical needs. Service delivery needs and emotional needs have been identified as the most prevalent.

Conclusions

Stakeholders’ needs during the rehabilitation process were found to be interrelated. All stakeholders faced service delivery challenges in the form of provision and distribution of information, including responsibilities allocation between municipalities, hospitals and rehabilitation services. Emotional and social needs have been reported by HNC patients and informal caregivers, underlining the importance of inclusion of all actors in the design of future healthcare interventions. Connected Health (CH) solutions could be valuable in provision and distribution of information.
The Prognostic Significance of the Continuous Administration of Anti-PD-1 Antibody via Continuation or Rechallenge After the Occurrence of Immune-Related Adverse Events
Authors: Fujisaki Toshiya , Watanabe Satoshi , Ota Takeshi , Kushiro Kohei , Sato Yusuke , Takahashi Miho , Ohtsubo Aya , Shoji Satoshi , Nozaki Koichiro , Ichikawa Kosuke , Hokari Satoshi , Kondo Rie , Miyabayashi Takao , Abe Tetsuya , Miura Satoru , Tanaka Hiroshi , Okajima Masaaki , Terada Masaki , Matsumoto Naoya , Ishida Takashi , Iwashima Akira , Sato Kazuhiro , Yoshizawa Hirohisa , Aoki Nobumasa , Hayashi Masachika , Ohshima Yasuyoshi , Koya Toshiyuki , Kikuchi Toshiaki
Published: September 2021

Objectives

Although immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs.

Methods

We retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors.

Results

Of 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) vs. not reached (95% CI: 22.4–NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) vs. not reached (95% CI: 8.4–NE); p = 0.031].

Conclusion

The current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.
Lymph Node Dissections for T3T4 Stage Penile Cancer Patients Without Preoperatively Detectable Lymph Node Metastasis Bring More Survival Benefits: A Propensity Matching Analysis
Authors: Li Han , Ma Yucheng , Jian Zhongyu , Jin Xi , Xiang Liyuan , Li Hong , Wang Kunjie
Published: September 2021

Background and Aims

The current guidelines for the treatment of penile cancer patients with clinically non-invasive normal inguinal lymph nodes are still broad, so the purpose of this study is to determine which patients are suitable for lymph node dissection (LND).

Methods

Histologically confirmed penile cancer patients (primary site labeled as C60.9-Penis) from 2004 to 2016 in the Surveillance, Epidemiology, and Results database were included in this analysis. Univariate and multivariate Cox regression analyses were applied to determine an overall estimate of LND on overall survival and cancer-specific survival. A 1:1 propensity matching analysis (PSM) was applied to enroll balanced baseline cohort, and further Kaplan–Meier (KM) survival analysis was used to get more reliable results.

Results

Out of 4,458 histologically confirmed penile cancer patients with complete follow-up information, 1,052 patients were finally enrolled in this analysis. Age, pathological grade, T stage, and LND were identified as significant predictors for overall survival (OS) in the univariate Cox analysis. In the multivariate Cox regression, age, pathological grade, T stage, and LND were found significant. The same results were also found in the univariate and multivariate Cox regression analyses for cancer-specific survival (CSS). After the successful PSM, further KM analysis revealed that LND could bring significant OS and CSS benefits for T3T4 patients without lymph node metastasis.

Conclusion

Lymph node dissection may bring survival benefits for penile cancer patients without preoperatively detectable lymph node metastasis, especially for T3T4 stage patients. Further randomized control trial is needed.
Establishment and Characterization of a Novel Multidrug Resistant Human Ovarian Cancer Cell Line With Heterogenous MRP7 Overexpression
Authors: Wang Jing-Quan , Wu Zhuo-Xun , Yang Yuqi , Li Jin-Sui , Yang Dong-Hua , Fan Ying-Fang , Chen Zhe-Sheng
Published: September 2021

Ovarian cancer is one of the leading female malignancies which accounts for the highest mortality rate among gynecologic cancers. Surgical cytoreduction followed by chemotherapy is the mainstay of treatment. However, patients with recurrent ovarian cancer are likely to exhibit resistance to chemotherapy due to reduced sensitivity to chemotherapeutic drugs. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters have been extensively studied as multidrug resistance (MDR) mediators since they are responsible for the efflux of various anticancer drugs. Multidrug resistance protein 7 (MRP7, or ABCC10) was discovered in 2001 and revealed to transport chemotherapeutic drugs. Till now, only limited knowledge was obtained regarding its roles in ovarian cancer. In this study, we established an MRP7-overexpressing ovarian cancer cell line SKOV3/MRP7 via transfecting recombinant MRP7 plasmids. The SKOV3/MRP7 cell line was resistant to multiple anticancer drugs including paclitaxel, docetaxel, vincristine and vinorelbine with a maximum of 8-fold resistance. Biological function of MRP7 protein was further determined by efflux-accumulation assays. Additionally, MTT results showed that the drug resistance of the SKOV3/MRP7 cells was reversed by cepharanthine, a known inhibitor of MRP7. Moreover, we also found that the overexpression of MRP7 enhanced the migration and epithelial-mesenchymal transition (EMT) induction. In conclusion, we established an in vitro model of MDR in ovarian cancer and suggested MRP7 overexpression as the leading mechanism of chemoresistance in this cell line. Our results demonstrated the potential relationship between MRP7 and ovarian cancer MDR.