bluuebunny/crossref_metadata_2025 huggingface dataset:
Dabigatran and Wet AMD, Results From Retinal Pigment Epithelial Cell Monolayers, the Mouse Model of Choroidal Neovascularization, and Patients From the Medicare Data Base
Authors: Akter Tanjina , Annamalai Balasubramaniam , Obert Elisabeth , Simpson Kit N. , Rohrer Bärbel
Published: June 2022

Background

Age-related macular degeneration (AMD), the leading cause of irreversible blindness in elderly Caucasian populations, includes destruction of the blood-retina barrier (BRB) generated by the retinal pigment epithelium-Bruch’s membrane complex (RPE/BrM), and complement activation. Thrombin is likely to get access to those structures upon BRB integrity loss. Here we investigate the potential role of thrombin in AMD by analyzing effects of the thrombin inhibitor dabigatran.

Material and Methods

MarketScan data for patients aged ≥65 years on Medicare was used to identify association between AMD and dabigatran use. ARPE-19 cells grown as mature monolayers were analyzed for thrombin effects on barrier function (transepithelial resistance; TER) and downstream signaling (complement activation, expression of connective tissue growth factor (CTGF), and secretion of vascular endothelial growth factor (VEGF)). Laser-induced choroidal neovascularization (CNV) in mouse is used to test the identified downstream signaling.

Results

Risk of new wet AMD diagnosis was reduced in dabigatran users. In RPE monolayers, thrombin reduced TER, generated unique complement C3 and C5 cleavage products, led to C3d/MAC deposition on cell surfaces, and increased CTGF expression via PAR1-receptor activation and VEGF secretion. CNV lesion repair was accelerated by dabigatran, and molecular readouts suggest that downstream effects of thrombin include CTGF and VEGF, but not the complement system.

Conclusions

This study provides evidence of association between dabigatran use and reduced exudative AMD diagnosis. Based on the cell- and animal-based studies, we suggest that thrombin modulates wound healing and CTGF and VEGF expression, making dabigatran a potential novel treatment option in AMD.
Derivation and Validation of a New Disease Activity Assessment Tool With Higher Accuracy for Takayasu Arteritis
Authors: Kwon Oh Chan , Park Min-Chan
Published: June 2022

Objective

To develop a new disease activity assessment tool with high accuracy for Takayasu arteritis.

Methods

Individual items from National Institute of Health (NIH) criteria and the Indian Takayasu Clinical Activity Score (ITAS2010) were tested as candidate variables to develop a new disease activity assessment tool in a derivation cohort (N = 100). Physician global assessment on disease activity was used as the gold standard. Multivariable logistic regression models were constructed and the model with the highest accuracy was identified. A formula assessing disease activity was generated using simplified β coefficients (rounded to decimal place). Diagnostic performance was evaluated through estimating the area under the curve (AUC). The new assessment tool was subsequently validated in a validation cohort (N = 46).

Results

The multivariable model yielding the highest accuracy consisted of a high erythrocyte sedimentation rate (ESR), NIH criteria 1 and 4, and carotidynia. Using simplified β coefficients, the following disease activity assessment tool was developed: high ESR (3 points), NIH criterion 1 (2 points), NIH criterion 4 (4 points), and carotidynia (3 points) (total score ≥5, active; total score <5, inactive). The new disease activity assessment tool had a higher AUC (89.37) for discriminating active and inactive diseases than NIH criteria (AUC 77.96), ITAS2010 (AUC 66.12), ITAS-ESR (AUC 75.58), and ITAS-C-reactive protein (AUC 71.34). The AUC (85.23) of the new assessment tool was similar in the validation cohort.

Conclusion

A new disease activity assessment tool that consists of high ESR, NIH criteria 1 and 4, and carotidynia had higher accuracy in discriminating active and inactive disease than currently used clinical assessment tools.
Tetraploid Ancestry Provided Atlantic Salmon With Two Paralogue Functional T Cell Receptor Beta Regions Whereof One Is Completely Novel
Authors: Grimholt Unni , Sundaram Arvind Y. M. , Bøe Cathrine Arnason , Dahle Maria K. , Lukacs Morten
Published: June 2022

Protective cellular immune responses have been difficult to study in fish, due to lack of basic understanding of their T cell populations, and tools to study them. Cellular immunity is thus mostly ignored in vaccination and infection studies compared to humoral responses. High throughput sequencing, as well as access to well assembled genomes, now advances studies of cellular responses. Here we have used such resources to describe organization of T cell receptor beta genes in Atlantic salmon. Salmonids experienced a unique whole genome duplication approximately 94 million years ago, which provided these species with many functional duplicate genes, where some duplicates have evolved new functions or sub-functions of the original gene copy. This is also the case for T cell receptor beta, where Atlantic salmon has retained two paralogue T cell receptor beta regions on chromosomes 01 and 09. Compared to catfish and zebrafish, the genomic organization in both regions is unique, each chromosomal region organized with dual variable- diversity- joining- constant genes in a head to head orientation. Sequence identity of the chromosomal constant sequences between TRB01 and TRB09 is suggestive of rapid diversification, with only 67 percent as opposed to the average 82-90 percent for other duplicated genes. Using virus challenged samples we find both regions expressing bona fide functional T cell receptor beta molecules. Adding the 292 variable T cell receptor alpha genes to the 100 variable TRB genes from 14 subgroups, Atlantic salmon has one of the most diverse T cell receptor alpha beta repertoire of any vertebrate studied so far. Perhaps salmonid cellular immunity is more advanced than we have imagined.
Neonatal Programming of Microbiota Composition: A Plausible Idea That Is Not Supported by the Evidence
Authors: Michel Catherine , Blottière Hervé M.
Published: June 2022

Underpinning the theory “developmental origins of health and disease” (DOHaD), evidence is accumulating to suggest that the risks of adult disease are in part programmed by exposure to environmental factors during the highly plastic “first 1,000 days of life” period. An elucidation of the mechanisms involved in this programming is challenging as it would help developing new strategies to promote adult health. The intestinal microbiome is proposed as a long-lasting memory of the neonatal environment. This proposal is supported by indisputable findings such as the concomitance of microbiota assembly and the first 1,000-day period, the influence of perinatal conditions on microbiota composition, and the impact of microbiota composition on host physiology, and is based on the widely held but unconfirmed view that the microbiota is long-lastingly shaped early in life. In this review, we examine the plausibility of the gut microbiota being programmed by the neonatal environment and evaluate the evidence for its validity. We highlight that the capacity of the pioneer bacteria to control the implantation of subsequent bacteria is supported by both theoretical principles and statistical associations, but remains to be demonstrated experimentally. In addition, our critical review of the literature on the long-term repercussions of selected neonatal modulations of the gut microbiota indicates that sustained programming of the microbiota composition by neonatal events is unlikely. This does not exclude the microbiota having a role in DOHaD due to a possible interaction with tissue and organ development during the critical windows of neonatal life.
Epidemiology of blaCTX-M-Positive Salmonella Typhimurium From Diarrhoeal Outpatients in Guangdong, China, 2010–2017
Authors: Jiang Qi , Ke Bi-xia , Wu De-shu , Wang Dong , Fang Liang-xing , Sun Ruan-yang , Wang Min-ge , Lei Jing-er , Shao Zheng , Liao Xiao-ping
Published: June 2022

Salmonella enterica can lead to intestinal diarrhea, and the emergence and spread of cephalosporin-resistant Salmonella have brought great challenges to clinical treatment. Therefore, this study investigated the prevalence and transmission of blaCTX-M genes among S. Typhimurium from diarrhoeal outpatients in Guangdong, China, from 2010 to 2017. A total of 221 blaCTX-M-positive isolates were recovered from 1,263 S. Typhimurium isolates from the facal samples of diarrhoea patients in 45 general hospitals from 11 cities. The most popular CTX-M gene was blaCTX-M-55 (39.6%, 72/182) in the CTX-M-1 group, followed by blaCTX-M-14 (22.5%, 41/182) and blaCTX-M-65 (19.2%, 35/182) in the CTX-M-9 group. The isolates that carried blaCTX-M-9G had significantly higher resistance rates to multiple antibacterials compared with blaCTX-M-1G (p < 0.01). Meanwhile, PFGE analysis not only showed the clonal transmission of blaCTX-M-55/14/65-positve isolates of diarrhoeal outpatients’ origins from different hospitals in Guangdong province, but also the characteristic of blaCTX-M-55/14/65-positve isolates’ bacterial persistence. Multilocus sequence typing (MLST) analysis indicated that these S. Typhimurium isolates possessed ST34 and ST19. Furthermore, genomic Beast phylogenomic analysis provided the evidence of a close relationship of blaCTX-M-positive S. Typhimurium isolates between the outpatients and pork. Most blaCTX-M-55/14/65 genes were transmitted by non-typeable or IncI1/IncFII/IncHI2 plasmids with the size of ranging from ~80 to ~280 kb. Moreover, whole-genome sequencing (WGS) analysis further revealed that blaCTX-M-55/14/65 coexisted with other 25 types of ARGs, of which 11 ARGs were highly prevalent with the detection rates >50%, and it first reported the emergence of blaTEM-141 in S. Typhimurium. This study underscores the importance of surveillance for blaCTX-M-positive microbes in diarrhea patients.
Structure and Protein-Protein Interactions of Ice Nucleation Proteins Drive Their Activity
Authors: Hartmann Susan , Ling Meilee , Dreyer Lasse S. A. , Zipori Assaf , Finster Kai , Grawe Sarah , Jensen Lasse Z. , Borck Stella , Reicher Naama , Drace Taner , Niedermeier Dennis , Jones Nykola C. , Hoffmann Søren V. , Wex Heike , Rudich Yinon , Boesen Thomas , Šantl-Temkiv Tina
Published: June 2022

Microbially-produced ice nucleating proteins (INpro) are unique molecular structures with the highest known catalytic efficiency for ice formation. Airborne microorganisms utilize these proteins to enhance their survival by reducing their atmospheric residence times. INpro also have critical environmental effects including impacts on the atmospheric water cycle, through their role in cloud and precipitation formation, as well as frost damage on crops. INpro are ubiquitously present in the atmosphere where they are emitted from diverse terrestrial and marine environments. Even though bacterial genes encoding INpro have been discovered and sequenced decades ago, the details of how the INpro molecular structure and oligomerization foster their unique ice-nucleation activity remain elusive. Using machine-learning based software AlphaFold 2 and trRosetta, we obtained and analysed the first ab initio structural models of full length and truncated versions of bacterial INpro. The modeling revealed a novel beta-helix structure of the INpro central repeat domain responsible for ice nucleation activity. This domain consists of repeated stacks of two beta strands connected by two sharp turns. One beta-strand is decorated with a TxT amino acid sequence motif and the other strand has an SxL[T/I] motif. The core formed between the stacked beta helix-pairs is unusually polar and very distinct from previous INpro models. Using synchrotron radiation circular dichroism, we validated the β-strand content of the central repeat domain in the model. Combining the structural model with functional studies of purified recombinant INpro, electron microscopy and modeling, we further demonstrate that the formation of dimers and higher-order oligomers is key to INpro activity. Using computational docking of the new INpro model based on rigid-body algorithms we could reproduce a previously proposed homodimer structure of the INpro CRD with an interface along a highly conserved tyrosine ladder and show that the dimer model agrees with our functional data. The parallel dimer structure creates a surface where the TxT motif of one monomer aligns with the SxL[T/I] motif of the other monomer widening the surface that interacts with water molecules and therefore enhancing the ice nucleation activity. This work presents a major advance in understanding the molecular foundation for bacterial ice-nucleation activity.
Reduction Kinetic of Water Soluble Metal Salts by Geobacter sulfurreducens: Fe2+/Hemes Stabilize and Regulate Electron Flux Rates
Authors: Karamash Maksym , Stumpe Michael , Dengjel Jörn , Salgueiro Carlos A. , Giese Bernd , Fromm Katharina M.
Published: June 2022

Geobacter sulfurreducens is a widely applied microorganism for the reduction of toxic metal salts, as an electron source for bioelectrochemical devices, and as a reagent for the synthesis of nanoparticles. In order to understand the influence of metal salts, and of electron transporting, multiheme c-cytochromes on the electron flux during respiration of G. sulfurreducens, the reduction kinetic of Fe3+, Co3+, V5+, Cr6+, and Mn7+ containing complexes were measured. Starting from the resting phase, each G. sulfurreducens cell produced an electron flux of 3.7 × 105 electrons per second during the respiration process. Reduction rates were within ± 30% the same for the 6 different metal salts, and reaction kinetics were of zero order. Decrease of c-cytochrome concentrations by downregulation and mutation demonstrated that c-cytochromes stabilized respiration rates by variation of their redox states. Increasing Fe2+/heme levels increased electron flux rates, and induced respiration flexibility. The kinetic effects parallel electrochemical results of G. sulfurreducens biofilms on electrodes, and might help to optimize bioelectrochemical devices.
Metagenomic Next-Generation Sequencing Is Highly Efficient in Diagnosing Pneumocystis Jirovecii Pneumonia in the Immunocompromised Patients
Authors: Wang Dongsheng , Fang Shihua , Hu Xiaowen , Xu Qixia , Chu Xinmin , Mei Xiaodong , Xie Wang
Published: June 2022

Purposes

To explore the value of metagenomic next-generation sequencing (mNGS) in diagnosing pneumocystis jiroveciipneumonia (PJP) in the immunocompromised patients.

Methods

Data of 122 patients with PJP in an immunosuppressed state and 67 non-PJP patients were collected. The diagnostic efficacy of mNGS was compared with the conventional methods, including Gomori methenamine silver (GMS) staining and serum (1,3)-β-D-glucan (BDG). Changes of anti-microbial therapy for patients with PJP based on mNGS results were also reviewed.

Results

The diagnostic sensitivity of mNGS to PJP was higher than that of GMS and BDG (100% vs. 15 and 74.5%, p < 0.001). The diagnostic specificity (91.%) was lower than that of GMS (100%), and similar with BDG (89.6%). In addition to P. jirovecii, mNGS revealed co-pathogens like human β-herpesvirus 5, human γ-pesvirus 4, and some other opportunistic pathogens. The reads of mNGS were remarkably higher in BALF than in blood samples. Initial antimicrobial treatment was modified in 89.3% patients based on the mNGS results, and 74 cases (60.7%) were treated with anti-P. jirovecii therapy.

Conclusion

mNGS is highly efficient in diagnosing PJP and good at identifying pathogens in mixed infections.
Effect of Anthropogenic Aerosol Addition on Phytoplankton Growth in Coastal Waters: Role of Enhanced Phosphorus Bioavailability
Authors: Wang Qin , Zhang Chao , Jin Haoyu , Chen Ying , Yao Xiaohong , Gao Huiwang
Published: June 2022

Atmospheric deposition can supply nutrients to induce varying responses of phytoplankton of different sizes in the upper ocean. Here, we collected surface and subsurface chlorophyll a maximum (SCM) seawaters from the Yellow Sea and East China Sea to conduct a series of onboard incubation experiments, aiming to explore the impact of anthropogenic aerosol (AR, sampled in Qingdao, a coastal city in Northern China) addition on phytoplankton growth using schemes with (unfiltered seawater, UFS) and without (filtered seawater, FS) microsized (20–200 μm) cells. We found that AR addition stimulated phytoplankton growth obviously, as indicated by chlorophyll a (Chl a) in surface incubations, and had stimulatory or no effects in SCM incubations, which was related to nutrient statuses in seawater. The high ratio of nitrogen (N) to phosphorus (P) in the AR treatments demonstrated that P became the primary limiting nutrient. The alkaline phosphatase activity (APA), which can reflect the rate at which dissolved organic P (DOP) is converted into dissolved inorganic P, was 1.3–75.5 times higher in the AR treatments than in the control, suggesting that AR addition increased P bioavailability in the incubated seawater. Dinoflagellates with the capacity to utilize DOP showed the dominant growth in the AR treatments, corresponding to the shift in phytoplankton size structure toward larger cells. Surprisingly, we found that nanosized (2–20 μm) and picosized (0.2–2 μm) Chl a concentrations in UFS were generally higher than those in FS. The APA in UFS was at least 1.6 times higher than in FS and was proportional to the contribution of microsized cells to the total Chl a, suggesting that microsized cells play an important role in the increase in APA, which contributes to the growth of nanosized and picosized phytoplankton. Current work provides new insight into the increase of P bioavailability induced by atmospheric deposition and resultant ecological effect in coastal waters.
Functional Characterization of Clostridium tyrobutyricum L319: A Promising Next-Generation Probiotic for Short-Chain Fatty Acid Production
Authors: Yang Zhihan , Amal Fatima Ezzahra , Yang Lei , Liu Yuxin , Zhu Liying , Zhu Zhengming , Jiang Ling
Published: June 2022

Probiotics contribute a lot to human health and the occurrence of diseases. Correspondingly, probiotics’ safety evaluation and probiotic properties have received increasing attention in the food industry and disease treatment. Clostridium tyrobutyricum L319 is a short-chain fatty acid (SCFA)-producing strain isolated from Grana Padano cheese with a blowing defect. Our previous study has shown its safety at the genomic level. This study focused more on the safety evaluation and probiotic properties in vitro. According to the results, this strain has no potential virulence factors or the possibility of antibiotic resistance genes propagation. It also fulfilled several criteria to be used as a probiotic, including significant hydrophobicity under an acidic condition (pH 5.0) and resistance to simulate gastric juice and intestinal juice. Additionally, this strain was found to be tolerant to the harsh conditions of the external environment, including resistance to low (20°C) and high (50°C) temperatures, high salts (3% NaCl), and low pH (pH 5.0). Finally, we found that this strain could ferment prebiotics, such as chito-oligosaccharides, to produce SCFAs. It exhibited excellent growth performance whether using chito-oligosaccharide as a sole carbon source or combining glucose as the mixed carbon source. Furthermore, chito-oligosaccharide and glucose (1:1) mixed carbon sources were the optimal strategy for the production of SCFAs. Our findings demonstrated that this strain might be considered a promising candidate for future use as a probiotic to promote health benefits.
Distinct Patterns of Rhizosphere Microbiota Associated With Rice Genotypes Differing in Aluminum Tolerance in an Acid Sulfate Soil
Authors: Xiao Xun , Wang Jia Lin , Li Jiao Jiao , Li Xiao Li , Dai Xin Jun , Shen Ren Fang , Zhao Xue Qiang
Published: June 2022

Rhizosphere microbes are important for plant tolerance to various soil stresses. Rice is the most aluminum (Al)-tolerant small grain cereal crop species, but the link between rice Al tolerance and rhizosphere microbiota remains unclear. This study aimed to investigate the microbial community structure of aluminum-sensitive and Al-tolerant rice varieties in acid sulfate soil under liming and non-liming conditions. We analyzed the rice biomass and mineral element contents of rice plants as well as the chemical properties and microbial (archaea, bacteria, and fungi) communities of rhizosphere and bulk soil samples. The results showed that the Al-tolerant rice genotype grew better and was able to take up more phosphorus from the acid sulfate soil than the Al-sensitive genotype. Liming was the main factor altering the microbial diversity and community structure, followed by rhizosphere effects. In the absence of liming effects, the rice genotypes shifted the community structure of bacteria and fungi, which accounted for the observed variation in the rice biomass. The Al-tolerant rice genotype recruited specific bacterial and fungal taxa (Bacillus, Pseudomonas, Aspergillus, and Rhizopus) associated with phosphorus solubilization and plant growth promotion. The soil microbial co-occurrence network of the Al-tolerant rice genotype was more complex than that of the Al-sensitive rice genotype. In conclusion, the bacterial and fungal community in the rhizosphere has genotype-dependent effects on rice Al tolerance. Aluminum-tolerant rice genotypes recruit specific microbial taxa, especially phosphorus-solubilizing microorganisms, and are associated with complex microbial co-occurrence networks, which may enhance rice growth in acid sulfate soil.
Exercise for Stroke Rehabilitation: A Bibliometric Analysis of Global Research From 2001 to 2021
Authors: Dong Yulin , Weng Linman , Hu Yinhu , Mao Yuxing , Zhang Yajuan , Lu Zefeng , Shi Tingting , Du Renren , Wang Wu , Wang Jinyan , Wang Xueqiang
Published: June 2022

Objective

To make a bibliometric analysis of global trends in research into exercise interventions for stroke between 2001 and 2021.

Method

This study did the systematic literature from 2001 to 2021 in Web of Science Core Collection. CiteSpace software was used to analyze the relationship of publications with countries, journals, authors, references, and keywords.

Results

A total of 3,484 publications were obtained in the bibliometric analysis. The number of publications increased gradually over the period. The United States have the most number of publications. The journal stroke had the most citations per paper (106.95) and the highest impact factor (IF 2020, 7.194). The most high frequency keywords are “stroke,” “rehabilitation,” and “recovery,” the top of burst key words are “health,” “speed,” and “aerobic exercise”.

Conclusion

These findings provide the trends of exercise for stroke s and provided the potential research frontiers in the past 20 years. It will be a useful basis for further research into focus issues, cooperators, development trends.
Linking Plasma Amyloid Beta and Neurofilament Light Chain to Intracortical Myelin Content in Cognitively Normal Older Adults
Authors: Fernandez-Alvarez Marina , Atienza Mercedes , Zallo Fatima , Matute Carlos , Capetillo-Zarate Estibaliz , Cantero Jose L.
Published: June 2022

Evidence suggests that lightly myelinated cortical regions are vulnerable to aging and Alzheimer’s disease (AD). However, it remains unknown whether plasma markers of amyloid and neurodegeneration are related to deficits in intracortical myelin content, and whether this relationship, in turn, is associated with altered patterns of resting-state functional connectivity (rs-FC). To shed light into these questions, plasma levels of amyloid-β fragment 1–42 (Aβ1–42) and neurofilament light chain (NfL) were measured using ultra-sensitive single-molecule array (Simoa) assays, and the intracortical myelin content was estimated with the ratio T1-weigthed/T2-weighted (T1w/T2w) in 133 cognitively normal older adults. We assessed: (i) whether plasma Aβ1–42 and/or NfL levels were associated with intracortical myelin content at different cortical depths and (ii) whether cortical regions showing myelin reductions also exhibited altered rs-FC patterns. Surface-based multiple regression analyses revealed that lower plasma Aβ1–42 and higher plasma NfL were associated with lower myelin content in temporo-parietal-occipital regions and the insular cortex, respectively. Whereas the association with Aβ1–42 decreased with depth, the NfL-myelin relationship was most evident in the innermost layer. Older individuals with higher plasma NfL levels also exhibited altered rs-FC between the insula and medial orbitofrontal cortex. Together, these findings establish a link between plasma markers of amyloid/neurodegeneration and intracortical myelin content in cognitively normal older adults, and support the role of plasma NfL in boosting aberrant FC patterns of the insular cortex, a central brain hub highly vulnerable to aging and neurodegeneration.
Computational Modeling of Synchrony in the Auditory Nerve in Response to Acoustic and Electric Stimulation
Authors: Goldsworthy Raymond L.
Published: June 2022

Cochlear implants are medical devices that provide hearing to nearly one million people around the world. Outcomes are impressive with most recipients learning to understand speech through this new way of hearing. Music perception and speech reception in noise, however, are notably poor. These aspects of hearing critically depend on sensitivity to pitch, whether the musical pitch of an instrument or the vocal pitch of speech. The present article examines cues for pitch perception in the auditory nerve based on computational models. Modeled neural synchrony for pure and complex tones is examined for three different electric stimulation strategies including Continuous Interleaved Sampling (CIS), High-Fidelity CIS (HDCIS), and Peak-Derived Timing (PDT). Computational modeling of current spread and neuronal response are used to predict neural activity to electric and acoustic stimulation. It is shown that CIS does not provide neural synchrony to the frequency of pure tones nor to the fundamental component of complex tones. The newer HDCIS and PDT strategies restore synchrony to both the frequency of pure tones and to the fundamental component of complex tones. Current spread reduces spatial specificity of excitation as well as the temporal fidelity of neural synchrony, but modeled neural excitation restores precision of these cues. Overall, modeled neural excitation to electric stimulation that incorporates temporal fine structure (e.g., HDCIS and PDT) indicates neural synchrony comparable to that provided by acoustic stimulation. Discussion considers the importance of stimulation rate and long-term rehabilitation to provide temporal cues for pitch perception.
Dynamical Mechanism Underlying Scale-Free Network Reorganization in Low Acetylcholine States Corresponding to Slow Wave Sleep
Authors: Czarnecki Paulina , Lin Jack , Aton Sara J. , Zochowski Michal
Published: June 2022

Sleep is indispensable for most animals’ cognitive functions, and is hypothesized to be a major factor in memory consolidation. Although we do not fully understand the mechanisms of network reorganisation driving memory consolidation, available data suggests that sleep-associated neurochemical changes may be important for such processes. In particular, global acetylcholine levels change across the sleep/wake cycle, with high cholinergic tone during wake and REM sleep and low cholinergic tone during slow wave sleep. Furthermore, experimental perturbation of cholinergic tone has been shown to impact memory storage. Through in silico modeling of neuronal networks, we show how spiking dynamics change in highly heterogenous networks under varying levels of cholinergic tone, with neuronal networks under high cholinergic modulation firing asynchronously and at high frequencies, while those under low cholinergic modulation exhibit synchronous patterns of activity. We further examined the network’s dynamics and its reorganization mediated via changing levels of acetylcholine within the context of different scale-free topologies, comparing network activity within the hub cells, a small group of neurons having high degree connectivity, and with the rest of the network. We show a dramatic, state-dependent change in information flow throughout the network, with highly active hub cells integrating information in a high-acetylcholine state, and transferring it to rest of the network in a low-acetylcholine state. This result is experimentally corroborated by frequency-dependent frequency changes observed in vivo experiments. Together, these findings provide insight into how new neurons are recruited into memory traces during sleep, a mechanism which may underlie system memory consolidation.
Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): A Review of Clinical and MRI Features, Diagnosis, and Management
Authors: Sechi Elia , Cacciaguerra Laura , Chen John J. , Mariotto Sara , Fadda Giulia , Dinoto Alessandro , Lopez-Chiriboga A. Sebastian , Pittock Sean J. , Flanagan Eoin P.
Published: June 2022

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is the most recently defined inflammatory demyelinating disease of the central nervous system (CNS). Over the last decade, several studies have helped delineate the characteristic clinical-MRI phenotypes of the disease, allowing distinction from aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) and multiple sclerosis (MS). The clinical manifestations of MOGAD are heterogeneous, ranging from isolated optic neuritis or myelitis to multifocal CNS demyelination often in the form of acute disseminated encephalomyelitis (ADEM), or cortical encephalitis. A relapsing course is observed in approximately 50% of patients. Characteristic MRI features have been described that increase the diagnostic suspicion (e.g., perineural optic nerve enhancement, spinal cord H-sign, T2-lesion resolution over time) and help discriminate from MS and AQP4+NMOSD, despite some overlap. The detection of MOG-IgG in the serum (and sometimes CSF) confirms the diagnosis in patients with compatible clinical-MRI phenotypes, but false positive results are occasionally encountered, especially with indiscriminate testing of large unselected populations. The type of cell-based assay used to evaluate for MOG-IgG (fixed vs. live) and antibody end-titer (low vs. high) can influence the likelihood of MOGAD diagnosis. International consensus diagnostic criteria for MOGAD are currently being compiled and will assist in clinical diagnosis and be useful for enrolment in clinical trials. Although randomized controlled trials are lacking, MOGAD acute attacks appear to be very responsive to high dose steroids and plasma exchange may be considered in refractory cases. Attack-prevention treatments also lack class-I data and empiric maintenance treatment is generally reserved for relapsing cases or patients with severe residual disability after the presenting attack. A variety of empiric steroid-sparing immunosuppressants can be considered and may be efficacious based on retrospective or prospective observational studies but prospective randomized placebo-controlled trials are needed to better guide treatment. In summary, this article will review our rapidly evolving understanding of MOGAD diagnosis and management.
The Seasonal Fluctuation of Fatigue in Multiple Sclerosis
Authors: Grothe Matthias , Gross Stefan , Süße Marie , Strauss Sebastian , Penner Iris Katharina
Published: June 2022

Background

Fatigue is a common symptom in patients with multiple sclerosis. Several studies suggest that outdoor temperature can impact fatigue severity, but a systematic study of seasonal variations is lacking.

Methods

Fatigue was assessed with the Fatigue Scale for Motor and Cognitive Functions (FSMC) in a temperate climatic zone with an average outdoor temperature of 8.8°C. This study included 258 patients with multiple sclerosis from 572 visits temporally distributed over the year. The data were adjusted for age, sex, cognition, depression, disease severity, and follow-up time. Linear regression models were performed to determine whether the temporal course of fatigue was time-independent, linearly time dependent, or non-linearly time dependent.

Results

Fatigue was lowest during January (mean FSMC: 49.84) and highest during August (mean FSMC: 53.88). The regression analysis showed the best fit with a model that included months + months2, which was a non-linear time dependency. Mean FSMC per month correlated significantly with the average monthly temperature (ρ = 0.972; p < 0.001).

Conclusion

In multiple sclerosis, fatigue showed a natural temporal fluctuation. Fatigue was higher during summer compared to winter, with a significant relationship of fatigue with outdoor temperature. This finding should be carefully taken into account when clinically monitoring patients over time to not interpret higher or lower scores independent of seasonal aspects.
Analysis of Clinical Symptoms of Guillain–Barré Syndrome Induced by Heat Stroke: Three Case Reports and Literature Review
Authors: Ni Xiao-xiao , Wang Cong-lin , Guo Ye-qun , Liu Zhi-feng
Published: June 2022

Background

Heat stroke is a potentially fatal condition that is caused by elevated core temperature. Guillain–Barré syndrome (GBS) induced by heat stroke is extremely rare and has only been reported in few case reports. The purpose of this case study was to evaluate the clinical symptoms, neuroelectrophysiological and imageological features of GBS after heat stroke.

Methods

We reviewed our hospital records and previously published reports to find the cases of GBS after heat stroke. The clinical, imageological, and electrophysiological profiles, treatment and prognosis were presented and analyzed.

Results

We retrieved three cases of GBS induced by heat stroke from our hospital, which presented as lesions on multiple cranial and peripheral nerves and albuminocytologic dissociation in the cerebrospinal fluid. All of these patients had disorders of consciousness at the early stage of heat stroke and a “pseudo-recovery period” after they recovered from coma after heat stroke. After immunoglobulin administration and immunoregulation therapy, these patients' neurological deficiencies were relieved significantly. But there are still disabilities and almost totally reliant on others.

Conclusions

The number of the cases of GBS induced by HS reported in this study has been the most in the recent 5 years. Clinicians should pay attention to patients with heat stroke with sustained coma and the sudden quadriplegia. Early, exact and timely diagnosis and treatment of GBS need to be performed, to accelerate recovery and improve prognosis.
Brain M-App’s Structure and Usability: A New Application for Cognitive Rehabilitation at Home
Authors: Pedroli Elisa , Mancuso Valentina , Stramba-Badiale Chiara , Cipresso Pietro , Tuena Cosimo , Greci Luca , Goulene Karine , Stramba-Badiale Marco , Riva Giuseppe , Gaggioli Andrea
Published: June 2022

Cognitive frailty is defined as a clinical condition characterized by both physical frailty and cognitive impairment, without reaching the criteria for dementia. The major goal of rehabilitation intervention is to assist patients in performing ordinary personal duties without the assistance of another person, or at the very least to remove the need for additional support, using adaptive approaches and facilities. In this regard, home-based rehabilitation allows patients to continue an intervention begun in a hospital setting while also ensuring support and assistance when access to healthcare systems is limited, such as during the present pandemic situation. We thus present Brain m-App, a tablet-based application designed for home-based cognitive rehabilitation of frail subjects, addressing spatial memory, attention, and executive functions. This app exploits the potential of 360° videos which are well-suited to home-based rehabilitation. The Brain m-app is made up of 10 days of activities that include a variety of exercises. The activities were chosen based on those patients used to do during their clinical practice in the hospital with the aim to improve their independence and autonomy in daily tasks. The preliminary usability test, which was conducted on five older people, revealed a sufficient level of usability, however, the sample size was modest. Results from the clinical study with 10 patients, revealed that Brain m-App improved especially executive functions and memory performances.
Scaling and Benchmarking an Evolutionary Algorithm for Constructing Biophysical Neuronal Models
Authors: Ladd Alexander , Kim Kyung Geun , Balewski Jan , Bouchard Kristofer , Ben-Shalom Roy
Published: June 2022

Single neuron models are fundamental for computational modeling of the brain's neuronal networks, and understanding how ion channel dynamics mediate neural function. A challenge in defining such models is determining biophysically realistic channel distributions. Here, we present an efficient, highly parallel evolutionary algorithm for developing such models, named NeuroGPU-EA. NeuroGPU-EA uses CPUs and GPUs concurrently to simulate and evaluate neuron membrane potentials with respect to multiple stimuli. We demonstrate a logarithmic cost for scaling the stimuli used in the fitting procedure. NeuroGPU-EA outperforms the typically used CPU based evolutionary algorithm by a factor of 10 on a series of scaling benchmarks. We report observed performance bottlenecks and propose mitigation strategies. Finally, we also discuss the potential of this method for efficient simulation and evaluation of electrophysiological waveforms.
Radiomics Model for Frontotemporal Dementia Diagnosis Using T1-Weighted MRI
Authors: Tafuri Benedetta , Filardi Marco , Urso Daniele , De Blasi Roberto , Rizzo Giovanni , Nigro Salvatore , Logroscino Giancarlo
Published: June 2022

Radiomics has been proposed as a useful approach to extrapolate novel morphological and textural information from brain Magnetic resonance images (MRI). Radiomics analysis has shown unique potential in the diagnostic work-up and in the follow-up of patients suffering from neurodegenerative diseases. However, the potentiality of this technique in distinguishing frontotemporal dementia (FTD) subtypes has so far not been investigated. In this study, we explored the usefulness of radiomic features in differentiating FTD subtypes, namely, the behavioral variant of FTD (bvFTD), the non-fluent and/or agrammatic (PNFA) and semantic (svPPA) variants of a primary progressive aphasia (PPA). Classification analyses were performed on 3 Tesla T1-weighted images obtained from the Frontotemporal Lobar Degeneration Neuroimaging Initiative. We included 49 patients with bvFTD, 25 patients with PNFA, 34 patients with svPPA, and 60 healthy controls. Texture analyses were conducted to define the first-order statistic and textural features in cortical and subcortical brain regions. Recursive feature elimination was used to select the radiomics signature for each pairwise comparison followed by a classification framework based on a support vector machine. Finally, 10-fold cross-validation was used to assess classification performances. The radiomics-based approach successfully identified the brain regions typically involved in each FTD subtype, achieving a mean accuracy of more than 80% in distinguishing between patient groups. Note mentioning is that radiomics features extracted in the left temporal regions allowed achieving an accuracy of 91 and 94% in distinguishing patients with svPPA from those with PNFA and bvFTD, respectively. Radiomics features show excellent classification performances in distinguishing FTD subtypes, supporting the clinical usefulness of this approach in the diagnostic work-up of FTD.
Neuropathological Mechanisms of Mild Traumatic Brain Injury: A Perspective From Multimodal Magnetic Resonance Imaging
Authors: Liu Yin , Lu Liyan , Li Fengfang , Chen Yu-Chen
Published: June 2022

Mild traumatic brain injury (mTBI) accounts for more than 80% of the total number of TBI cases. The mechanism of injury for patients with mTBI has a variety of neuropathological processes. However, the underlying neurophysiological mechanism of the mTBI is unclear, which affects the early diagnosis, treatment decision-making, and prognosis evaluation. More and more multimodal magnetic resonance imaging (MRI) techniques have been applied for the diagnosis of mTBI, such as functional magnetic resonance imaging (fMRI), arterial spin labeling (ASL) perfusion imaging, susceptibility-weighted imaging (SWI), and diffusion MRI (dMRI). Various imaging techniques require to be used in combination with neuroimaging examinations for patients with mTBI. The understanding of the neuropathological mechanism of mTBI has been improved based on different angles. In this review, we have summarized the application of these aforementioned multimodal MRI techniques in mTBI and evaluated its benefits and drawbacks.
First Metabolomic Signature of Blood-Brain Barrier Opening Induced by Microbubble-Assisted Ultrasound
Authors: Presset Antoine , Bodard Sylvie , Lefèvre Antoine , Millet Anaïs , Oujagir Edward , Dupuy Camille , Iazourène Tarik , Bouakaz Ayache , Emond Patrick , Escoffre Jean-Michel , Nadal-Desbarats Lydie
Published: June 2022

Microbubble (MB)-assisted ultrasound (US) is a promising physical method to increase non-invasively, transiently, and precisely the permeability of the blood-brain barrier (BBB) to therapeutic molecules. Previous preclinical studies established the innocuity of this procedure using complementary analytical strategies including transcriptomics, histology, brain imaging, and behavioral tests. This cross-sectional study using rats aimed to investigate the metabolic processes following acoustically-mediated BBB opening in vivo using multimodal and multimatrices metabolomics approaches. After intravenous injection of MBs, the right striata were exposed to 1-MHz sinusoidal US waves at 0.6 MPa peak negative pressure with a burst length of 10 ms, for 30 s. Then, the striata, cerebrospinal fluid (CSF), blood serum, and urine were collected during sacrifice in three experimental groups at 3 h, 2 days, and 1 week after BBB opening (BBBO) and were compared to a control group where no US was applied. A well-established analytical workflow using nuclear magnetic resonance spectrometry and non-targeted and targeted high-performance liquid chromatography coupled to mass spectrometry were performed on biological tissues and fluids. In our experimental conditions, a reversible BBBO was observed in the striatum without physical damage or a change in rodent weight and behavior. Cerebral, peri-cerebral, and peripheral metabolomes displayed specific and sequential metabolic kinetics. The blood serum metabolome was more impacted in terms of the number of perturbated metabolisms than in the CSF, the striatum, and the urine. In addition, perturbations of arginine and arginine-related metabolisms were detected in all matrices after BBBO, suggesting activation of vasomotor processes and bioenergetic supply. The exploration of the tryptophan metabolism revealed a transient vascular inflammation and a perturbation of serotoninergic neurotransmission in the striatum. For the first time, we characterized the metabolic signature following the acoustically-mediated BBBO within the striatum and its surrounding biological compartments.
Carotenoid Biosynthesis: Genome-Wide Profiling, Pathway Identification in Rhodotorula glutinis X-20, and High-Level Production
Authors: Bo Shaobo , Ni Xiaoxia , Guo Jintang , Liu Zhengyang , Wang Xiaoya , Sheng Yue , Zhang Genlin , Yang Jinfeng
Published: June 2022

Rhodotorula glutinis, as a member of the family Sporidiobolaceae, is of great value in the field of biotechnology. However, the evolutionary relationship of R. glutinis X-20 with Rhodosporidiobolus, Sporobolomyces, and Rhodotorula are not well understood, and its metabolic pathways such as carotenoid biosynthesis are not well resolved. Here, genome sequencing and comparative genome techniques were employed to improve the understanding of R. glutinis X-20. Phytoene desaturase (crtI) and 15-cis-phytoene synthase/lycopene beta-cyclase (crtYB), key enzymes in carotenoid pathway from R. glutinis X-20 were more efficiently expressed in S. cerevisiae INVSc1 than in S. cerevisiae CEN.PK2-1C. High yielding engineered strains were obtained by using synthetic biology technology constructing carotenoid pathway in S. cerevisiae and optimizing the precursor supply after fed-batch fermentation with palmitic acid supplementation. Genome sequencing analysis and metabolite identification has enhanced the understanding of evolutionary relationships and metabolic pathways in R. glutinis X-20, while heterologous construction of carotenoid pathway has facilitated its industrial application.
Effect of High-Fat and Low-Fat Dairy Products on Cardiometabolic Risk Factors and Immune Function in a Low Birthweight Swine Model of Diet-Induced Insulin Resistance
Authors: She Yongbo , Wang Kun , Makarowski Alexander , Mangat Rabban , Tsai Sue , Willing Benjamin P. , Proctor Spencer D. , Richard Caroline
Published: June 2022

Although dairy intake has been shown to have a neutral or some beneficial effect on major cardiometabolic risk factors, the impact of dairy, and especially dairy fat, on immune function remains to be investigated. To understand the effect of consuming dairy fat on cardiometabolic risk factors and immune function, we used an established low birthweight (LBW) swine model of diet-induced insulin resistance to compare high-fat and low-fat dairy products to a control high-fat diet (CHF). LBW piglets were randomized to consume one of the 3 experimental HF diets: (1) CHF, (2) CHF diet supplemented with 3 servings/day of high-fat dairy (HFDairy) and (3) CHF diet supplemented with 3 servings/day of low-fat dairy (LFDairy). As comparison groups, normal birthweight (NBW) piglets were fed a CHF (NBW-CHF) or standard pig grower diet (NBW-Chow). A total of 35 pigs completed the study and were fed for a total of 7 weeks, including 1 week of CHF transition diet. At 12 weeks of age, piglets were euthanized. Fasting blood and tissue samples were collected. Ex vivo cytokine production by peripheral blood mononuclear cells (PBMCs) stimulated with pokeweed (PWM), phytohemagglutinin (PHA) and phorbol myristate acetate-ionomycin (PMA-I) were assessed. As expected, LBW-CHF piglets showed early signs of insulin resistance (HOMA-IR, P model = 0.08). Feeding high-fat dairy products improved fasting plasma glucose concentrations more than low-fat dairy compared to LBW-CHF (P < 0.05). Irrespective of fat content, dairy consumption had neutral effect on fasting lipid profile. We have also observed lower production of IL-2 after PWM and PHA stimulation as well as lower production of TNF-α and IFN-γ after PWM stimulation in LBW-CHF than in NBW-Chow (all, P < 0.05), suggesting impaired T cell and antigen presenting cell function. While feeding high-fat dairy had minimal effect on immune function, feeding low-fat dairy significantly improved the production of IL-2, TNF-α and IFN-γ after PWM stimulation, IL-2 and IFN-γ after PHA stimulation as well as TNF-α after PMA-I stimulation compared to LBW-CHF (all, P < 0.05). These data provide novel insights into the role of dairy consumption in counteracting some obesity-related cardiometabolic and immune perturbations.