bluuebunny/crossref_metadata_2025 huggingface dataset:
Bergamo and Covid-19: How the Dark Can Turn to Light
Authors: Perico Norberto , Fagiuoli Stefano , Di Marco Fabiano , Laghi Andrea , Cosentini Roberto , Rizzi Marco , Gianatti Andrea , Rambaldi Alessandro , Ruggenenti Piero , La Vecchia Carlo , Bertolini Guido , Paglia Stefano , Lorini Ferdinando Luca , Remuzzi Giuseppe
Published: February 2021

The novel coronavirus, SARS-CoV-2, continues to spread rapidly. Here we discuss the dramatic situation created by COVID-19 in Italy, particularly in the province of Bergamo (the most severely affected in the first wave), as an example of how, in the face of an unprecedented tragedy, acting (albeit belatedly)—including imposing a very strict lockdown—can largely resolve the situation within approximately 2 months. The measures taken here ensured that Bergamo hospital, which was confronted with rapidly rising numbers of severely ill COVID-19 patients requiring hospitalization, was able to meet the initial challenges of the pandemic. We also report that local organization and, more important, the large natural immunity against SARS-CoV-2 of the Bergamo population developed during the first wave of the epidemic, can explain the limited number of new COVID-19 cases during the more recent second wave compared to the numbers in other areas of Lombardy. Furthermore, we highlight the importance of coordinating the easing of containment measures to avoid what is currently observed in other countries, especially in the United States, Latin American and India, where this approach has not been adopted, and a dramatic resurgence of COVID-19 cases and an increase in the number of hospitalisations and deaths have been reported.
Case Report: Post-mortem Histopathological and Molecular Analyses of the Very First Documented COVID-19-Related Death in Europe
Authors: Bogdanović Milenko , Skadrić Ivan , Atanasijević Tatjana , Stojković Oliver , Popović Vesna , Savić Slobodan , Mihailović Zoran , Radnić Bojana , Aćimović Tijana , Damjanjuk Irina , Despotović Sanja , Barać Aleksandra
Published: February 2021

In Europe, the first case of coronavirus disease (COVID-19) and the first COVID-19-related death were reported in France on January 24th and February 15th, 2020, respectively. Officially, the first case of COVID-19 infection in the Republic of Serbia was registered on March 6th. Herein, we presented the first case of retrospective detection of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the post-mortem-obtained vitreous humor (VH), which took place on February 5th, 2020. This is the first death in Europe proven to be caused by COVID-19 by means of post-mortem histopathological and molecular analyses. Based on this finding, it appears that SARS-CoV-2 has been spreading faster and started spreading much earlier than it had been considered and that COVID-19 was probably the cause of the much-reported pneumonia of unknown origin in January and February 2020.
Arbuscular Mycorrhiza Mediates Efficient Recycling From Soil to Plants of Nitrogen Bound in Chitin
Authors: Bukovská Petra , Rozmoš Martin , Kotianová Michala , Gančarčíková Kateřina , Dudáš Martin , Hršelová Hana , Jansa Jan
Published: February 2021

Symbiosis between plants and arbuscular mycorrhizal (AM) fungi, involving great majority of extant plant species including most crops, is heavily implicated in plant mineral nutrition, abiotic and biotic stress tolerance, soil aggregate stabilization, as well as shaping soil microbiomes. The latter is particularly important for efficient recycling from soil to plants of nutrients such as phosphorus and nitrogen (N) bound in organic forms. Chitin is one of the most widespread polysaccharides on Earth, and contains substantial amounts of N (>6% by weight). Chitin is present in insect exoskeletons and cell walls of many fungi, and can be degraded by many prokaryotic as well as eukaryotic microbes normally present in soil. However, the AM fungi seem not to have the ability to directly access N bound in chitin molecules, thus relying on microbes in their hyphosphere to gain access to this nutrient-rich resource in the process referred to as organic N mineralization. Here we show, using data from two pot experiments, both including root-free compartments amended with 15N-labeled chitin, that AM fungi can channel substantial proportions (more than 20%) of N supplied as chitin into their plants hosts within as short as 5 weeks. Further, we show that overall N losses (leaching and/or volatilization), sometimes exceeding 50% of the N supplied to the soil as chitin within several weeks, were significantly lower in mycorrhizal as compared to non-mycorrhizal pots. Surprisingly, the rate of chitin mineralization and its N utilization by the AM fungi was at least as fast as that of green manure (clover biomass), based on direct 15N labeling and tracing. This efficient N recycling from soil to plant, observed in mycorrhizal pots, was not strongly affected by the composition of AM fungal communities or environmental context (glasshouse or outdoors, additional mineral N supply to the plants or not). These results indicate that AM fungi in general can be regarded as a critical and robust soil resource with respect to complex soil processes such as organic N mineralization and recycling. More specific research is warranted into the exact molecular mechanisms and microbial players behind the observed patterns.
Students in a Course-Based Undergraduate Research Experience Course Discovered Dramatic Changes in the Bacterial Community Composition Between Summer and Winter Lake Samples
Authors: Baker Stokes S. , Alhassan Mohamed S. , Asenov Kristian Z. , Choi Joyce J. , Craig Griffin E. , Dastidar Zayn A. , Karim Saleh J. , Sheardy Erin E. , Sloulin Salameh Z. , Aggarwal Nitish , Al-Habib Zahraa M. , Camaj Valentina , Cleminte Dennis D. , Hamady Mira H. , Jaafar Mike , Jones Marcel L. , Khan Zayan M. , Khoshaba Evileen S. , Khoshaba Rita , Ko Sarah S. , Mashrah Abdulmalik T. , Patel Pujan A. , Rajab Rabeeh , Tandon Sahil
Published: February 2021

Course-based undergraduate research experience (CURE) courses incorporate high-impact pedagogies that have been shown to increase undergraduate retention among underrepresented minorities and women. As part of the Building Infrastructure Leading to Diversity program at the University of Detroit Mercy, a CURE metagenomics course was established in the winter of 2019. Students investigated the bacterial community composition in a eutrophic cove in Lake Saint Clair (Harrison Township, MI, United States) from water samples taken in the summer and winter. The students created 16S rRNA libraries that were sequenced using next-generation sequencing technology. They used a public web-based supercomputing resource to process their raw sequencing data and web-based tools to perform advanced statistical analysis. The students discovered that the most common operational taxonomic unit, representing 31% of the prokaryotic sequences in both summer and winter samples, corresponded to an organism that belongs to a previously unidentified phylum. This result showed the students the power of metagenomics because the approach was able to detect unclassified organisms. Principal Coordinates Analysis of Bray–Curtis dissimilarity index data showed that the winter community was distinct from the summer community [Analysis of Similarities (ANOSIM) r = 0.59829, n = 18, and p < 0.001]. Dendrograms based on hierarchically clustered Pearson correlation coefficients of phyla were divided into a winter clade and a summer clade. The conclusion is that the winter bacterial population was fundamentally different from the summer population, even though the samples were taken from the same locations in a protected cove. Because of the small class sizes, qualitative as well as statistical methods were used to evaluate the course’s impact on student attitudes. Results from the Laboratory Course Assessment Survey showed that most of the respondents felt they were contributing to scientific knowledge and the course fostered student collaboration. The majority of respondents agreed or strongly agreed that the course incorporated iteration aspects of scientific investigations, such as repeating procedures to fix problems. In summary, the metagenomics CURE course was able to add to scientific knowledge and allowed students to participate in authentic research.
A Half-Day Genome Sequencing Protocol for Middle East Respiratory Syndrome Coronavirus
Authors: Kim Kwan Woo , Choi Sungmi , Shin Su-Kyoung , Lee Imchang , Ku Keun Bon , Kim Seong Jun , Kim Seil , Yi Hana
Published: February 2021

Recent coronavirus (CoV) outbreaks, including that of Middle East respiratory syndrome (MERS), have presented a threat to public health worldwide. A primary concern in these outbreaks is the extent of mutations in the CoV, and the content of viral variation that can be determined only by whole genome sequencing (WGS). We aimed to develop a time efficient WGS protocol, using universal primers spanning the entire MERS-CoV genome. MERS and synthetic Neoromicia capensis bat CoV genomes were successfully amplified using our developed PCR primer set and sequenced with MinION. All experimental and analytical processes took 6 h to complete and were also applied to synthetic animal serum samples, wherein the MERS-CoV genome sequence was completely recovered. Results showed that the complete genome of MERS-CoV and related variants could be directly obtained from clinical samples within half a day. Consequently, this method will contribute to rapid MERS diagnosis, particularly in future CoV epidemics.
Synthesis, Characterization, Antibacterial and Wound Healing Efficacy of Silver Nanoparticles From Azadirachta indica
Authors: Chinnasamy Gandhimathi , Chandrasekharan Smitha , Koh Tong Wey , Bhatnagar Somika
Published: February 2021

Bacteria are the causative agents of numerous diseases. Ever increasing number of bacterial infections has generated the need to find new antibiotic materials and new ways to combat bacterial infections. Our study investigated Azadirachta indica (AI) as an alternate source of antibiotic compounds. Phytochemical and GC-MS analysis revealed presence of flavonoids, phenolic compounds, terpenoids and terpenes. Aqueous extracts of leaves were used to synthesize silver nanoparticles (AI-AgNPs), as established by colorimetric confirmation with maximum absorbance peak at 400 nm. Optimized reaction parameters produced high yield of stable AI-AgNPs, which were characterized by UV-Vis spectroscopy, energy-dispersive X-ray spectroscopy, scanning electron microscopy, and transmission electron microscopy. Results confirmed particle diameter of 33 nm and spherical shape of AI-AgNPs. Fourier transform infrared spectroscopy inferred the presence of functional groups in bioactive constituents involved in conversion of silver ions into elemental silver by acting as capping and reducing agents during formation of AI-AgNPs. X-ray diffraction revealed their crystalline nature. Toxicity studies on Drosophila validated normal egg laying capacity and eclosion of F1 generation on AI-AgNPs (100 μg/mL). DPPH (65.17%) and ABTS (66.20%) assays affirmed strong radical scavenging effect of AI-AgNPs (500 μg/mL). The antibacterial activity of AI-AgNPs (1,000 μg/mL) was confirmed by disc diffusion assay with zone of inhibition against Bacillus cereus (17.7 mm), Escherichia coli (18.7 mm), Pseudomonas aeruginosa (10.3 mm), and Staphylococcus aureus (17.7 mm). Minimum inhibitory concentration and minimum bactericidal concentration values for AI-AgNPs ranged between 390 and 780 μg/mL. Higher bacterial suppression by AI-AgNPs in comparison with AI-extract was further divulged by prominent damage to the bacterial cell walls, disintegration of cell membranes and outflow of intercellular content as evident in SEM images. AI-AgNPs were loaded on PF127 (biocompatible-biodegradable polymer) to form a viscous, spreadable, hydrogel that demonstrated enhanced antibacterial properties in disc diffusion assay (13–18.7 mm). When topically applied on mice, AI-AgNPs-PF127 hydrogel did not show symptoms of skin irritation. Application of AI-AgNPs-PF127 hydrogel on wound sites in mice, significantly increased the wound contraction rate. Our studies present a simple green route to synthesize AI-AgNPs with enhanced antibacterial and free-radical scavenging efficacy; and AI-AgNPs-PF127 hydrogel as a low-toxic, eco-friendly delivery vehicle with potential in wound healing.
Resistance-Nodulation-Division Efflux Pump, LexABC, Contributes to Self-Resistance of the Phenazine Di-N-Oxide Natural Product Myxin in Lysobacter antibioticus
Authors: Zhao Yangyang , Liu Jiayu , Jiang Tianping , Hou Rongxian , Xu Gaoge , Xu Huiyong , Liu Fengquan
Published: February 2021

Antibiotic-producing microorganisms have developed several self-resistance mechanisms to protect them from autotoxicity. Transporters belonging to the resistance- nodulation-division (RND) superfamily commonly confer multidrug resistance in Gram-negative bacteria. Phenazines are heterocyclic, nitrogen-containing and redox-active compounds that exhibit diverse activities. We previously identified six phenazines from Lysobacter antibioticus OH13, a soil bacterium emerging as a potential biocontrol agent. Among these phenazines, myxin, a di-N-oxide phenazine, exhibited potent activity against a variety of microorganisms. In this study, we identified a novel RND efflux pump gene cluster, designated lexABC, which is located far away in the genome from the myxin biosynthesis gene cluster. We found a putative LysR-type transcriptional regulator encoding gene lexR, which was adjacent to lexABC. Deletion of lexABC or lexR gene resulted in significant increasing susceptibility of strains to myxin and loss of myxin production. The results demonstrated that LexABC pump conferred resistance against myxin. The myxin produced at lower concentrations in these mutants was derivatized by deoxidation and O-methylation. Furthermore, we found that the abolishment of myxin with deletion of LaPhzB, which is an essential gene in myxin biosynthesis, resulted in significant downregulation of the lexABC. However, exogenous supplementation with myxin to LaPhzB mutant could efficiently induce the expression of lexABC genes. Moreover, lexR mutation also led to decreased expression of lexABC, which indicates that LexR potentially positively modulated the expression of lexABC. Our findings reveal a resistance mechanism against myxin of L. antibioticus, which coordinates regulatory pathways to protect itself from autotoxicity.
Phylogenetic Revision of the Genus Aliivibrio: Intra- and Inter-Species Variance Among Clusters Suggest a Wider Diversity of Species
Authors: Klemetsen Terje , Karlsen Christian R. , Willassen Nils P.
Published: February 2021

Genus Aliivibrio is known to harbor species exhibiting bioluminescence as well as pathogenic behavior affecting the fish farming industry. Current phylogenetic understanding of Aliivibrio has largely remained dormant after reclassification disentangled it from the Vibrio genus in 2007. There is growing evidence of wider diversity, but until now the lack of genomes and selective use of type strains have limited the ability to compare and classify strains firmly. In this study, a total of 143 bacterial strains, including 51 novel sequenced strains, were used to strengthen phylogenetic relationships in Aliivibrio by exploring intra-species and inter-species relations. Multilocus sequence analysis (MLSA), applying the six housekeeping genes 16S ribosomal RNA (rRNA), gapA, gyrB, pyrH, recA, and rpoA, inferred 12 clades and a singular branch in Aliivibrio. Along with four new phylogenetic clades, the MLSA resolved prior inconsistencies circumscribing Aliivibrio wodanis and formed a unique clade we propose as the novel species Aliivibrio sp. “friggae.” Furthermore, phylogenetic assessment of individual marker genes showed gyrB, pyrH, and recA superior to the 16S rRNA gene, resolving accurately for most species clades in Aliivibrio. In this study, we provide a robust phylogenetic groundwork for Aliivibrio as a reference point to classification of species.
Microbial Derived Compounds, a Step Toward Enhancing Microbial Inoculants Technology for Sustainable Agriculture
Authors: Naamala Judith , Smith Donald L.
Published: February 2021

Sustainable agriculture remains a focus for many researchers, in an effort to minimize environmental degradation and climate change. The use of plant growth promoting microorganisms (PGPM) is a hopeful approach for enhancing plant growth and yield. However, the technology faces a number of challenges, especially inconsistencies in the field. The discovery, that microbial derived compounds can independently enhance plant growth, could be a step toward minimizing shortfalls related to PGPM technology. This has led many researchers to engage in research activities involving such compounds. So far, the findings are promising as compounds have been reported to enhance plant growth under stressed and non-stressed conditions in a wide range of plant species. This review compiles current knowledge on microbial derived compounds, taking a reader through a summarized protocol of their isolation and identification, their relevance in present agricultural trends, current use and limitations, with a view to giving the reader a picture of where the technology has come from, and an insight into where it could head, with some suggestions regarding the probable best ways forward.
Eriodictyol as a Potential Candidate Inhibitor of Sortase A Protects Mice From Methicillin-Resistant Staphylococcus aureus-Induced Pneumonia
Authors: Wang Li , Li Qianxue , Li Jiaxin , Jing Shisong , Jin Yajing , Yang Lin , Yu Hangqian , Wang Dacheng , Wang Tiedong , Wang Lin
Published: February 2021

New anti-infective approaches are urgently needed to control multidrug-resistant (MDR) pathogens, such as methicillin-resistantStaphylococcus aureus(MRSA). Sortase A (SrtA) is a membrane-bound cysteine transpeptidase that plays an essential role in the catalysis of covalent anchoring of surface proteins to the cell wall ofStaphylococcus aureus(S. aureus). The present study reports identification of a flavonoid, eriodictyol, as a reversible inhibitor of SrtA with an IC50of 2.229 ± 0.014 μg/mL that can be used as an innovative means to counter both resistance and virulence. The data indicated that eriodictyol inhibited the adhesion of the bacteria to fibrinogen and reduced the formation of biofilms and anchoring of staphylococcal protein A (SpA) on the cell wall. The results of fluorescence quenching experiments demonstrated a strong interaction between eriodictyol and SrtA. Subsequent mechanistic studies revealed that eriodictyol binds to SrtA by interacting with R197 amino acid residue. Importantly, eriodictyol reduced the adhesion-dependent invasion of A549 cells byS. aureusand showed a good therapeutic effect in a model of mouse pneumonia induced byS. aureus. Overall, the results indicated that eriodictyol can attenuate MRSA virulence and prevent the development of resistance by inhibiting SrtA, suggesting that eriodictyol may be a promising lead compound for the control of MRSA infections.
Aptamers and Aptamer-Coupled Biosensors to Detect Water-Borne Pathogens
Authors: Saad Mariam , Faucher Sebastien P.
Published: February 2021

Aptamers can serve as efficient bioreceptors for the development of biosensing detection platforms. Aptamers are short DNA or RNA oligonucleotides that fold into specific structures, which enable them to selectively bind to target analytes. The method used to identify aptamers is Systematic Evolution of Ligands through Exponential Enrichment (SELEX). Target properties can have an impact on aptamer efficiencies. Therefore, characteristics of water-borne microbial targets must be carefully considered during SELEX for optimal aptamer development. Several aptamers have been described for key water-borne pathogens. Here, we provide an exhaustive overview of these aptamers and discuss important microbial aspects to consider when developing such aptamers.
The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells
Authors: Tisi Renata , Spinelli Michela , Palmioli Alessandro , Airoldi Cristina , Cazzaniga Paolo , Besozzi Daniela , Nobile Marco S. , Mazzoleni Elisa , Arnhold Simone , De Gioia Luca , Grandori Rita , Peri Francesco , Vanoni Marco , Sacco Elena
Published: February 2021

Ras oncoproteins play a crucial role in the onset, maintenance, and progression of the most common and deadly human cancers. Despite extensive research efforts, only a few mutant-specific Ras inhibitors have been reported. We show that cmp4–previously identified as a water-soluble Ras inhibitor– targets multiple steps in the activation and downstream signaling of different Ras mutants and isoforms. Binding of this pan-Ras inhibitor to an extended Switch II pocket on HRas and KRas proteins induces a conformational change that down-regulates intrinsic and GEF-mediated nucleotide dissociation and exchange and effector binding. A mathematical model of the Ras activation cycle predicts that the inhibitor severely reduces the proliferation of different Ras-driven cancer cells, effectively cooperating with Cetuximab to reduce proliferation even of Cetuximab-resistant cancer cell lines. Experimental data confirm the model prediction, indicating that the pan-Ras inhibitor is an appropriate candidate for medicinal chemistry efforts tailored at improving its currently unsatisfactory affinity.
Metabolic Modeling to Interrogate Microbial Disease: A Tale for Experimentalists
Authors: Jean-Pierre Fabrice , Henson Michael A. , O’Toole George A.
Published: February 2021

The explosion of microbiome analyses has helped identify individual microorganisms and microbial communities driving human health and disease, but how these communities function is still an open question. For example, the role for the incredibly complex metabolic interactions among microbial species cannot easily be resolved by current experimental approaches such as 16S rRNA gene sequencing, metagenomics and/or metabolomics. Resolving such metabolic interactions is particularly challenging in the context of polymicrobial communities where metabolite exchange has been reported to impact key bacterial traits such as virulence and antibiotic treatment efficacy. As novel approaches are needed to pinpoint microbial determinants responsible for impacting community function in the context of human health and to facilitate the development of novel anti-infective and antimicrobial drugs, here we review, from the viewpoint of experimentalists, the latest advances in metabolic modeling, a computational method capable of predicting metabolic capabilities and interactions from individual microorganisms to complex ecological systems. We use selected examples from the literature to illustrate how metabolic modeling has been utilized, in combination with experiments, to better understand microbial community function. Finally, we propose how such combined, cross-disciplinary efforts can be utilized to drive laboratory work and drug discovery moving forward.
Ongoing Oscillatory Electrophysiological Alterations in Frail Older Adults: A MEG Study
Authors: Suárez-Méndez Isabel , Walter Stefan , López-Sanz David , Pasquín Natalia , Bernabé Raquel , Castillo Gallo Ernesto , Valdés Myriam , del Pozo Francisco , Maestú Fernando , Rodríguez-Mañas Leocadio
Published: February 2021

Objective: The role of the central nervous system in the pathophysiology of frailty is controversial. We used magnetoencephalography (MEG) to search for abnormalities in the ongoing oscillatory neural activity of frail individuals without global cognitive impairment.

Methods: Fifty four older (≥70 years) and cognitively healthy (Mini-Mental State Examination ≥24) participants were classified as robust (0 criterion, n = 34) or frail (≥ 3 criteria, n = 20) following Fried's phenotype. Memory, language, attention, and executive function were assessed through well-validated neuropsychological tests. Every participant underwent a resting-state MEG and a T1-weighted magnetic resonance imaging scan. We performed MEG power spectral analyses to compare the electrophysiological profiles of frail and robust individuals. We used an ensemble learner to investigate the ability of MEG spectral power to discriminate frail from robust participants.

Results: We identified increased relative power in the frail group in the mu (p < 0.05) and sensorimotor (p < 0.05) frequencies across right sensorimotor, posterior parietal, and frontal regions. The ensemble learner discriminated frail from robust participants [area under the curve = 0.73 (95% CI = 0.49–0.98)]. Frail individuals performed significantly worse in the Trail Making Test, Digit Span Test (forward), Rey-Osterrieth Complex Figure, and Semantic Fluency Test.

Interpretation: Frail individuals without global cognitive impairment showed ongoing oscillatory alterations within brain regions associated with aspects of motor control, jointly to failures in executive function. Our results suggest that some physical manifestations of frailty might partly arise from failures in central structures relevant to sensorimotor and executive processing.
A Neuromechanical Model of Multiple Network Rhythmic Pattern Generators for Forward Locomotion in C. elegans
Authors: Olivares Erick , Izquierdo Eduardo J. , Beer Randall D.
Published: February 2021

Multiple mechanisms contribute to the generation, propagation, and coordination of the rhythmic patterns necessary for locomotion inCaenorhabditis elegans. Current experiments have focused on two possibilities: pacemaker neurons and stretch-receptor feedback. Here, we focus on whether it is possible that a chain of multiple network rhythmic pattern generators in the ventral nerve cord also contribute to locomotion. We use a simulation model to search for parameters of the anatomically constrained ventral nerve cord circuit that, when embodied and situated, can drive forward locomotion on agar, in the absence of pacemaker neurons or stretch-receptor feedback. Systematic exploration of the space of possible solutions reveals that there are multiple configurations that result in locomotion that is consistent with certain aspects of the kinematics of worm locomotion on agar. Analysis of the best solutions reveals that gap junctions between different classes of motorneurons in the ventral nerve cord can play key roles in coordinating the multiple rhythmic pattern generators.
Case Report: Early-Onset Guillain–Barre Syndrome Mimicking Stroke
Authors: Sun Jing , Gao Yu , Chi Lumei , Cao Qingyang , Ning Zhijie , Nan Guangxian
Published: February 2021

Introduction: Guillain–Barre syndrome (GBS) is an acute immune-mediated inflammatory demyelinating polyneuropathy characterized by symmetrical limb weakness and areflexia. GBS can have different clinical manifestations; hence, the initial symptoms are also varied. Here, we describe a rare case of GBS presenting as hemiparesis and cranial nerve palsy, which mimic brainstem stroke.

Case Presentation: A 53-year-old man was admitted to the hospital with a 3-h history of left-arm weakness, glossolalia, and right eyelid droop. After admission, his condition suddenly worsened, with quadriplegia, bilateral peripheral facial palsy, bilateral ophthalmoplegia, and other neurological symptoms. Based on the findings from a neurological examination, MRI, cerebrospinal fluid analysis, and nerve conduction study, a diagnosis of GBS was made. He received intravenous immunoglobulin (0.4 kg/day) for 5 days. After 20 days of systematic therapy, his dysphagia, dyspnea, facial paralysis, ocular movement disorder, and leg weakness recovered almost completely, but his arms were still moderately impaired, with a power of 4/5. Fortunately, the patient recovered well without any sequelae after 2 years of follow-up.

Conclusions: In patients with an atypical presentation, the diagnosis of GBS is often delayed. With this case report, we intend to highlight the fact that some symptoms mimicking stroke may be a feature of GBS at onset; close observation and timely diagnosis are crucial for clinicians. Neuroimaging is a valuable diagnostic tool in differentiating stroke from GBS.
Reduced Regional NREM Sleep Slow-Wave Activity Is Associated With Cognitive Impairment in Parkinson Disease
Authors: Schreiner Simon J. , Imbach Lukas L. , Valko Philipp O. , Maric Angelina , Maqkaj Rina , Werth Esther , Baumann Christian R. , Baumann-Vogel Heide
Published: February 2021

Growing evidence implicates a distinct role of disturbed slow-wave sleep in neurodegenerative diseases. Reduced non-rapid eye movement (NREM) sleep slow-wave activity (SWA), a marker of slow-wave sleep intensity, has been linked with age-related cognitive impairment and Alzheimer disease pathology. However, it remains debated if SWA is associated with cognition in Parkinson disease (PD). Here, we investigated the relationship of regional SWA with cognitive performance in PD. In the present study, 140 non-demented PD patients underwent polysomnography and were administered the Montréal Cognitive Assessment (MoCA) to screen for cognitive impairment. We performed spectral analysis of frontal, central, and occipital sleep electroencephalography (EEG) derivations to measure SWA, and spectral power in other frequency bands, which we compared to cognition using linear mixed models. We found that worse MoCA performance was associated with reduced 1–4 Hz SWA in a region-dependent manner (F2, 687 =11.67, p < 0.001). This effect was driven by reduced regional SWA in the lower delta frequencies, with a strong association of worse MoCA performance with reduced 1–2 Hz SWA (F2, 687 =18.0, p < 0.001). The association of MoCA with 1–2 Hz SWA (and 1–4 Hz SWA) followed an antero-posterior gradient, with strongest, weaker, and absent associations over frontal (rho = 0.33, p < 0.001), central (rho = 0.28, p < 0.001), and occipital derivations, respectively. Our study shows that cognitive impairment in PD is associated with reduced NREM sleep SWA, predominantly in lower delta frequencies (1–2 Hz) and over frontal regions. This finding suggests a potential role of reduced frontal slow-wave sleep intensity in cognitive impairment in PD.
Vestibular Thresholds: A Review of Advances and Challenges in Clinical Applications
Authors: Kobel Megan J. , Wagner Andrew R. , Merfeld Daniel M. , Mattingly Jameson K.
Published: February 2021

Vestibular disorders pose a substantial burden on the healthcare system due to a high prevalence and the severity of symptoms. Currently, a large portion of patients experiencing vestibular symptoms receive an ambiguous diagnosis or one that is based solely on history, unconfirmed by any objective measures. As patients primarily experience perceptual symptoms (e.g., dizziness), recent studies have investigated the use of vestibular perceptual thresholds, a quantitative measure of vestibular perception, in clinical populations. This review provides an overview of vestibular perceptual thresholds and the current literature assessing use in clinical populations as a potential diagnostic tool. Patients with peripheral and central vestibular pathologies, including bilateral vestibulopathy and vestibular migraine, show characteristic changes in vestibular thresholds. Vestibular perceptual thresholds have also been found to detect subtle, sub-clinical declines in vestibular function in asymptomatic older adults, suggesting a potential use of vestibular thresholds to augment or complement existing diagnostic methods in multiple populations. Vestibular thresholds are a reliable, sensitive, and specific assay of vestibular precision, however, continued research is needed to better understand the possible applications and limitations, especially with regard to the diagnosis of vestibular disorders.
Learning to Approximate Functions Using Nb-Doped SrTiO3 Memristors
Authors: Tiotto Thomas F. , Goossens Anouk S. , Borst Jelmer P. , Banerjee Tamalika , Taatgen Niels A.
Published: February 2021

Memristors have attracted interest as neuromorphic computation elements because they show promise in enabling efficient hardware implementations of artificial neurons and synapses. We performed measurements on interface-type memristors to validate their use in neuromorphic hardware. Specifically, we utilized Nb-doped SrTiO3 memristors as synapses in a simulated neural network by arranging them into differential synaptic pairs, with the weight of the connection given by the difference in normalized conductance values between the two paired memristors. This network learned to represent functions through a training process based on a novel supervised learning algorithm, during which discrete voltage pulses were applied to one of the two memristors in each pair. To simulate the fact that both the initial state of the physical memristive devices and the impact of each voltage pulse are unknown we injected noise into the simulation. Nevertheless, discrete updates based on local knowledge were shown to result in robust learning performance. Using this class of memristive devices as the synaptic weight element in a spiking neural network yields, to our knowledge, one of the first models of this kind, capable of learning to be a universal function approximator, and strongly suggests the suitability of these memristors for usage in future computing platforms.
Online Closed-Loop Control Using Tactile Feedback Delivered Through Surface and Subdermal Electrotactile Stimulation
Authors: Dong Jian , Jensen Winnie , Geng Bo , Kamavuako Ernest Nlandu , Dosen Strahinja
Published: February 2021

Aim

Limb loss is a dramatic event with a devastating impact on a person’s quality of life. Prostheses have been used to restore lost motor abilities and cosmetic appearance. Closing the loop between the prosthesis and the amputee by providing somatosensory feedback to the user might improve the performance, confidence of the amputee, and embodiment of the prosthesis. Recently, a minimally invasive method, in which the electrodes are placed subdermally, was presented and psychometrically evaluated. The present study aimed to assess the quality of online control with subdermal stimulation and compare it to that achieved using surface stimulation (common benchmark) as well as to investigate the impact of training on the two modalities.

Methods

Ten able-bodied subjects performed a PC-based compensatory tracking task. The subjects employed a joystick to track a predefined pseudorandom trajectory using feedback on the momentary tracking error, which was conveyed via surface and subdermal electrotactile stimulation. The tracking performance was evaluated using the correlation coefficient (CORR), root mean square error (RMSE), and time delay between reference and generated trajectories.

Results

Both stimulation modalities resulted in good closed-loop control, and surface stimulation outperformed the subdermal approach. There was significant difference in CORR (86 vs 77%) and RMSE (0.23 vs 0.31) between surface and subdermal stimulation (all p < 0.05). The RMSE of the subdermal stimulation decreased significantly in the first few trials.

Conclusion

Subdermal stimulation is a viable method to provide tactile feedback. The quality of online control is, however, somewhat worse compared to that achieved using surface stimulation. Nevertheless, due to minimal invasiveness, compactness, and power efficiency, the subdermal interface could be an attractive solution for the functional application in sensate prostheses.
Dosimetry Analysis in Non-brain Tissues During TMS Exposure of Broca’s and M1 Areas
Authors: Gomez-Tames Jose , Tani Keisuke , Hayashi Kazuya , Tanaka Satoshi , Ueno Shoogo , Hirata Akimasa
Published: February 2021

For human protection, the internal electric field is used as a dosimetric quantity for electromagnetic fields lower than 5–10 MHz. According to international standards, in this frequency range, electrostimulation is the main adverse effect against which protection is needed. One of the topics to be investigated is the quantification of the internal electric field threshold levels of perception and pain. Pain has been reported as a side effect during transcranial magnetic stimulation (TMS), especially during stimulation of the Broca’s (speech) area of the brain. In this study, we designed an experiment to conduct a dosimetry analysis to quantify the internal electric field corresponding to perception and pain thresholds when targeting the Broca’s and M1 areas from magnetic stimulator exposure. Dosimetry analysis was conducted using a multi-scale analysis in an individualized head model to investigate electrostimulation in an axonal model. The main finding is that the stimulation on the primary motor cortex has higher perception and pain thresholds when compared to Broca’s area. Also, TMS-induced electric field applied to Broca’s area exhibited dependence on the coil orientation at lower electric field threshold which was found to be related to the location and thickness of pain fibers. The derived dosimetry quantities provide a scientific rationale for the development of human protection guidelines and the estimation of possible side effects of magnetic stimulation in clinical applications.
The Effects of Selective Inhibition of Histone Deacetylase 1 and 3 in Huntington’s Disease Mice
Authors: Hecklau Katharina , Mueller Susanne , Koch Stefan Paul , Mehkary Mustafa Hussain , Kilic Busra , Harms Christoph , Boehm-Sturm Philipp , Yildirim Ferah
Published: February 2021

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 alleviated transcriptional dysregulation of a number of genes, including the transcription factor genes Neurod2 and Nr4a2, and gene sets and programs, especially those that are associated to insulin-like growth factor pathway, in the striatum of R6/1 mice. RGFP109 treatment led to a modest improvement of the motor skill learning and coordination deficit on the RotaRod test, while it did not alter the locomotor and anxiety-like phenotypes in R6/1 animals. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed no significant effects. Collectively, our combined work suggests that specific HDAC1 and HDAC3 inhibition may offer benefits for alleviating the motor phenotypic deficits and transcriptional dysregulation in HD.
Downregulation of the lncRNA ASB16-AS1 Decreases LARP1 Expression and Promotes Clear Cell Renal Cell Carcinoma Progression via miR-185-5p/miR-214-3p
Authors: Li Mingzi , Yin Bingde , Chen Mulin , Peng Jingtao , Mu Xinyu , Deng Zhen , Xiao Jiantao , Li Weiguo , Fan Jie
Published: February 2021

Clear cell renal cell carcinoma (ccRCC) comprises approximately 75% of renal cell carcinomas, which is one of the most common and lethal urologic cancers, with poor quality of life for patients and is a huge economic burden to health care systems. It is imperative we find novel prognostic and therapeutic targets for ccRCC clinical intervention. In this study, we found that the expression of the long noncoding RNA (lncRNA) ASB16-AS1 was downregulated in ccRCC tissues compared with non-diseased tissues and was also associated with advanced tumor stage and larger tumors. By constructing cell and mouse models, it was found that downregulated lncRNA ASB16-AS1 enhanced cell proliferation, migration, invasion, and promoted tumor growth and metastasis. Furthermore, by performing bioinformatics analysis, biotinylated RNA pull-downs, AGO2-RIP, and luciferase reporter assays, our findings showed that downregulated ASB16-AS1 decreased La-related protein 1 (LARP1) expression by inhibiting miR-185-5p and miR-214-3p. Furthermore, it was found that overexpression of LARP1 reversed the promotive effects of downregulated ASB16-AS1 on ccRCC cellular progression. Our results revealed that downregulated ASB16-AS1 promotes ccRCC progression via a miR-185-5p-miR-214-3p-LARP1 pathway. We suggest that this pathway could be used to monitor prognosis and presents therapeutic targets for ccRCC clinical management.
The Impact of Comorbidity on Survival in Patients With Head and Neck Squamous Cell Carcinoma: A Nationwide Case-Control Study Spanning 35 Years
Authors: Ruud Kjær Eva Kristine , Jensen Jakob Schmidt , Jakobsen Kathrine Kronberg , Lelkaitis Giedrius , Wessel Irene , von Buchwald Christian , Grønhøj Christian
Published: February 2021

Background

Comorbidity is presumed to impact survival of head and neck squamous cell cancer (HNSCC) patients. However, the prevalence and prognostic impact of comorbidity in these patients is not yet well established. The aim of this study is to outline the comorbidity burden of HNSCC patients and investigate the relation to overall survival and cancer-specific mortality.

Methods

The comorbidity burden of patients registered with HNSCC in the Danish Cancer Registry between 1980 and 2014 was evaluated based on the Charlson Comorbidity Index (CCI). Patients’ risks of comorbid conditions compared to age- and gender-matched controls were estimated by odds ratios (OR). The impact of comorbidity on overall survival and cancer-specific mortality was evaluated by Cox regression and Kaplan-Meier survival analysis.

Results

A total of 25,388 HNSCC patients were included (72.5% male; mean age 63.2 years at diagnosis; median follow-up 3.0 years). CCI at diagnosis was significantly higher in patients compared to controls (p < 0.001). The most common comorbid conditions among the patients were additional non-metastatic malignancy (10.9%) and cerebrovascular disease (7.7%). Compared to controls, patients had higher odds of metastatic malignancy (OR: 4.65; 95% CI: 4.21–5.15; p < 0.001), mild liver disease (OR: 6.95; 95% CI: 6.42–7.53; p < 0.001), and moderate-severe liver disease (OR: 7.28; 95% CI: 6.14–8.65; p < 0.001). The multivariate Cox analysis revealed increasing hazard ratios with increasing CCI and in coherence the Kaplan-Meier curves showed poorer overall survival and increased cancer-specific mortality in patients with higher CCI.

Conclusion

HNSCC patients’ comorbidity burden was significantly greater compared to the general population and increased comorbidity was correlated with increased cancer-related mortality.
Long Noncoding RNA UCA1 Is Related to Autophagy and Apoptosis in Endometrial Stromal Cells
Authors: Jiang Lili , Wan Yahui , Feng Ziyi , Liu Da , Ouyang Ling , Li Yan , Liu Kuiran
Published: February 2021

Research Question

The expression of the long noncoding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) in embryonic tissues is higher than that in most cancer tissues, such as bladder cancer, indicating that RNA is a carcinoembryonic antigen. However, there are no published reports on the role of UCA1 in endometriosis (EMS). Therefore, to address this gap in knowledge, we assessed the potential role of lncRNA UCA1 in the pathogenesis and progression of EMS.

Design

To verify the expression of UCA1 in EMS, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used. RNA interference (siRNA) was used to study the biological function of UCA1 in EMS in vitro.

Results

qRT-PCR analysis showed that the expression of lncRNA UCA1 in EMS was increased (P<0.01). Knockdown of UCA1 in vitro significantly inhibited the proliferation of endometrial stromal cells (ESCs) and induced autophagy and apoptosis.

Conclusion

UCA1 is highly expressed in EMS and promotes the proliferation of ESCs but suppresses autophagy and apoptosis. In EMS, UCA1 may be a prognostic marker and therapeutic target.
The Efficacy and Safety of Anlotinib Combined With PD-1 Antibody for Third-Line or Further-Line Treatment of Patients With Advanced Non-Small-Cell Lung Cancer
Authors: Zhai Chongya , Zhang Xiaoling , Ren Lulu , You Liangkun , Pan Qin , Pan Hongming , Han Weidong
Published: February 2021

Background

Both anlotinib and programmed death 1 (PD-1) monoclonal antibody (mAb) have been approved for the third line treatment of metastatic non-small cell lung cancer (NSCLC). However, the combination of these two standard therapies has not been investigated in third-line or further-line treatment of patients with advanced NSCLC.

Methods

We reviewed 22 patients with NSCLC who received anlotinib combined with PD-1 mAb therapy from July 2018 to October 2019 at Sir Run Run Shaw Hospital. Based on the baseline characteristics, PD-L1 expression and EGFR mutation status, we retrospectively analyzed the efficacy and safety of this combination therapy by RESIST 1.1 and CTCAE 5.0.

Results

The combination treatment of anlotinib and PD-1 mAb in 22 NSCLC patients gained a median PFS of 6.8 months and a median OS of 17.3 months. The disease control rate (DCR) was 90.9%, and the objective response rate (ORR) was 36.4%, where 1 (4.6%) patient achieved complete response (CR) and 7 (31.8%) patients achieved partial response (PR). The median time to response was 3.9 months, and the median duration of the response was 6.8 months. The common grades 1–2 adverse events were fatigue 10/22 (45.5%), decreased appetite 9/22 (40.9%), hypertension 10/22 (45.5%); the common grades 3–4 adverse events were hypertension 2/22 (9.1%) and mouth ulceration 2/22 (9.1%).

Conclusion

Anlotinib combined with PD-1 mAb showed promising efficacy in third-line or further-line treatment of NSCLC, and its adverse effects is tolerable.
Sentinel Lymph-Node Biopsy in Early-Stage Cervical Cancer: The 4-Year Follow-Up Results of the Senticol 2 Trial
Authors: Favre Guillaume , Guani Benedetta , Balaya Vincent , Magaud Laurent , Lecuru Fabrice , Mathevet Patrice
Published: February 2021

Introduction

Senticol 2 is a randomized multicenter trial in the treatment of early-stage cervical cancer patients. The aim of the Senticol 2 study was to compare the effect of sentinel-lymph-node biopsy (SLNB) to that of SLNB + pelvic lymphadenectomy (PLND), and to determine the postoperative lymphatic morbidity in the two groups. Here, we report a secondary objective of this study: the follow up.

Material and Methods

In the Senticol 2 trial, patients underwent a laparoscopy with a sentinel-node-detection procedure and were randomized into two groups, namely: Group A, in which participants received SLNB, and Group B, in which participants received SLNB + PLND. Patients with an intra-operative macroscopically suspicious lymph node, were given a frozen-section evaluation and were randomized only if the results were negative. All of the patients received follow up with a clinical examination at 1, 3, and 6 months after surgery, and then every 3–4 months after that. The median follow up was 51 months (4 years and 3 months).

Results

Disease-free survival after 4 years for the SLNB group and the SLNB + PLND group were 89.51% and 93.1% (p = 0.53), respectively. The only statistical factor associated with recurrence in the univariate analysis was the adjuvant radiotherapy. No other factors, including the age of the patients, histological type, tumor size, lymph vascular space invasion (LVSI), and positive nodal status, were significant in the univariate or multivariate analyses. The overall survival rates after 4 years in the SLNB and SLNB + PLND groups were 95.2% and 96% (p = 0.97), with five and four deaths, respectively. The univariate and multivariate analyses did not find any prognostic factors.

Conclusions

This randomized study confirmed the results of the Senticol 1 study and supports the sentinel lymph node (SLN) technique as a safe technique for use in patients with early-stage cervical cancer treated with SLNB only. Disease-free survival after 4 years was similar in patients treated with SLN biopsy and patients who underwent a lymphadenectomy.