bluuebunny/crossref_metadata_2025 huggingface dataset:
A Dynamically Downscaled Ensemble of Future Projections for the California Current System
Authors: Pozo Buil Mercedes , Jacox Michael G. , Fiechter Jerome , Alexander Michael A. , Bograd Steven J. , Curchitser Enrique N. , Edwards Christopher A. , Rykaczewski Ryan R. , Stock Charles A.
Published: April 2021

Given the ecological and economic importance of eastern boundary upwelling systems like the California Current System (CCS), their evolution under climate change is of considerable interest for resource management. However, the spatial resolution of global earth system models (ESMs) is typically too coarse to properly resolve coastal winds and upwelling dynamics that are key to structuring these ecosystems. Here we use a high-resolution (0.1°) regional ocean circulation model coupled with a biogeochemical model to dynamically downscale ESMs and produce climate projections for the CCS under the high emission scenario, Representative Concentration Pathway 8.5. To capture model uncertainty in the projections, we downscale three ESMs: GFDL-ESM2M, HadGEM2-ES, and IPSL-CM5A-MR, which span the CMIP5 range for future changes in both the mean and variance of physical and biogeochemical CCS properties. The forcing of the regional ocean model is constructed with a “time-varying delta” method, which removes the mean bias of the ESM forcing and resolves the full transient ocean response from 1980 to 2100. We found that all models agree in the direction of the future change in offshore waters: an intensification of upwelling favorable winds in the northern CCS, an overall surface warming, and an enrichment of nitrate and corresponding decrease in dissolved oxygen below the surface mixed layer. However, differences in projections of these properties arise in the coastal region, producing different responses of the future biogeochemical variables. Two of the models display an increase of surface chlorophyll in the northern CCS, consistent with a combination of higher nitrate content in source waters and an intensification of upwelling favorable winds. All three models display a decrease of chlorophyll in the southern CCS, which appears to be driven by decreased upwelling favorable winds and enhanced stratification, and, for the HadGEM2-ES forced run, decreased nitrate content in upwelling source waters in nearshore regions. While trends in the downscaled models reflect those in the ESMs that force them, the ESM and downscaled solutions differ more for biogeochemical than for physical variables.
Evaluation of Polycyclic Aromatic Hydrocarbon Pollution From the HMS Royal Oak Shipwreck and Effects on Sediment Microbial Community Structure
Authors: Thomas Gareth E. , Bolam Stefan G. , Brant Jan L. , Brash Rodney , Goodsir Freya , Hynes Clare , McGenity Terry J. , McIlwaine Paul S. O. , McKew Boyd A.
Published: April 2021

Despite many shipwrecks containing oil there is a paucity of studies investigating their impact on surrounding environments. This study evaluates any potential effect the World War II shipwreck HMS Royal Oak is having on surrounding benthic sediments in Scapa Flow, Scotland. HMS (Her Majesty’s Ship) Royal Oak sank in 1939, subsequently leaked oil in the 1960s and 1990s, and is estimated to still hold 697 tonnes of fuel oil. In this study, sediments were analysed, over a 17.5 cm depth profile, along a 50–950 m cruciform transect away from the shipwreck. Analysis of polycyclic aromatic hydrocarbons (PAHs) revealed low concentrations (205.91 ± 50.15 μg kg–1 of dry sediment), which did not significantly differ with either distance from the shipwreck or sediment depth. PAH concentrations were well below the effects-range low (ERL) for the OSPAR (Oslo/Paris convention for the Protection of the Marine Environment of the North-East Atlantic) maritime area. The average Pyrogenic Index, in sediments around HMS Royal Oak, was 1.06 (±0.34), indicating PAHs were pyrogenic rather than petrogenic. Moreover, analysis of sediment microbiomes revealed no significant differences in bacterial community structure with distance from the shipwreck, with extremely low levels of obligate hydrocarbonoclastic bacteria (OHCB; 0.21% ± 0.54%). Both lines of evidence suggest that sampled sediments are not currently being impacted by petrogenic hydrocarbons and show no long-term impact by previous oil-spills from HMS Royal Oak.
Challenges to Implementing Regional Ocean Governance in the Wider Caribbean Region
Authors: Fanning Lucia , Mahon Robin , Compton Sanya , Corbin Chris , Debels Patrick , Haughton Milton , Heileman Sherry , Leotaud Nicole , McConney Patrick , Moreno Manuel Perez , Phillips Terrence , Toro Cesar
Published: April 2021

For over two decades, the countries, subregional and regional level intergovernmental organizations in the Wider Caribbean Region (WCR) have been engaged in an initiative to implement a regional governance approach for managing the shared living marine resources of the Caribbean Sea and adjacent regions. Given the inherent socio-economic and geopolitical complexity of the region, this approach has been recognized as essential to address the challenges associated with the interconnected nature of shared ecosystem goods and services upon which countries in the region depend. This paper uses a retrospective lens to shed light on the challenges confronting the region and its efforts to overcome them. It is based on the Large Marine Ecosystem Governance Framework developed specifically for the WCR in 2006 and characterized as “learning by doing.” Data were obtained for this study through desktop review of published literature documenting progress over the period 2001–2021 and insights requested from 15 key individual and institutional contributors involved in the initiative. While the lack of financial resources was an underpinning and cross-cutting issue, key constraints identified were categorized as institutional, capacity building, awareness raising, leadership, legal, political, social capital, or socio-cultural. They include national capacity to engage with regional level processes due to a variety of factors including funding, political, and institutional challenges of developing a regional coordination mechanism, engaging the broader ocean community to create the critical mass needed, the difficulty of mainstreaming ocean affairs into high level political and decision-making fora and the scarcity of local, national and regional technical and political champions. This paper advances understanding of the barriers to be overcome in highly complex socio-politically developing regions if regional ocean governance initiatives are to play the essential role identified in the 2030 Sustainable Development Agenda, reaping the sustainable benefits of a blue economy.
Model Corrected Blood Input Function to Compute Cerebral FDG Uptake Rates From Dynamic Total-Body PET Images of Rats in vivo
Authors: Massey James C. , Seshadri Vikram , Paul Soumen , Mińczuk Krzysztof , Molinos Cesar , Li Jie , Kundu Bijoy K.
Published: April 2021

Recently, we developed a three-compartment dual-output model that incorporates spillover (SP) and partial volume (PV) corrections to simultaneously estimate the kinetic parameters and model-corrected blood input function (MCIF) from dynamic 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) images of mouse heart in vivo. In this study, we further optimized this model and utilized the estimated MCIF to compute cerebral FDG uptake rates, Ki, from dynamic total-body FDG PET images of control Wistar–Kyoto (WKY) rats and compared to those derived from arterial blood sampling in vivo. Dynamic FDG PET scans of WKY rats (n = 5), fasted for 6 h, were performed using the Albira Si Trimodal PET/SPECT/CT imager for 60 min. Arterial blood samples were collected for the entire imaging duration and then fitted to a seven-parameter function. The 60-min list mode PET data, corrected for attenuation, scatter, randoms, and decay, were reconstructed into 23 time bins. A 15-parameter dual-output model with SP and PV corrections was optimized with two cost functions to compute MCIF. A four-parameter compartment model was then used to compute cerebral Ki. The computed area under the curve (AUC) and Ki were compared to that derived from arterial blood samples. Experimental and computed AUCs were 1,893.53 ± 195.39 kBq min/cc and 1,792.65 ± 155.84 kBq min/cc, respectively (p = 0.76). Bland–Altman analysis of experimental vs. computed Ki for 35 cerebral regions in WKY rats revealed a mean difference of 0.0029 min−1 (~13.5%). Direct (AUC) and indirect (Ki) comparisons of model computations with arterial blood sampling were performed in WKY rats. AUC and the downstream cerebral FDG uptake rates compared well with that obtained using arterial blood samples. Experimental vs. computed cerebral Ki for the four super regions including cerebellum, frontal cortex, hippocampus, and striatum indicated no significant differences.
Microcirculatory Response to Changes in Venoarterial Extracorporeal Membrane Oxygenation Pump Flow: A Prospective Observational Study
Authors: Wei Tzu-Jung , Wang Chih-Hsien , Chan Wing-Sum , Huang Chi-Hsiang , Lai Chien-Heng , Wang Ming-Jiuh , Chen Yih-Sharng , Ince Can , Lin Tzu-Yu , Yeh Yu-Chang
Published: April 2021

Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) pump flow is crucial for maintaining organ perfusion in patients with cardiogenic shock, but VA-ECMO pump flow optimization remains as a clinical challenge. This study aimed to investigate the response of sublingual microcirculation to changes in VA-ECMO pump flow.

Methods: Sublingual microcirculation was measured before and after changing VA-ECMO pump flow according to the treatment plan of ECMO team within 24 h and at 24-48 h after VA-ECMO placement. In clinical events of increasing VA-ECMO pump flow, those events with increased perfused vessel density (PVD) were grouped into group A, and the others were grouped into group B. In clinical events of decreasing VA-ECMO pump flow, those events with increased PVD were grouped into group C, and the others were grouped into group D.

Results: Increased PVD was observed in 60% (95% CI, 38.5–81.5%) of the events with increasing VA-ECMO pump flow. The probability of increasing PVD after increasing VA-ECMO pump flow were higher in the events with a PVD < 15 mm/mm2 at baseline than those with a PVD ≥ 15 mm/mm2 [100% (95% CI, 54.1–100%) vs. 42.9% (95% CI, 17.7–71.1%), P = 0.042]. Other microcirculatory and hemodynamic parameters at baseline did not differ significantly between group A and B or between group C and D.

Conclusion: This study revealed contradictory and non-contradictory responses of sublingual microcirculation to changes in VA-ECMO pump flow. Tandem measurements of microcirculation before and after changing VA-ECMO pump flow may help to ensure a good microcirculation.
Assessment of Biological Contribution to Natural Recovery of Anthropized Freshwater Sediments From Argentina: Autochthonous Microbiome Structure and Functional Prediction
Authors: Madueño Laura , Starevich Viviana Ayelen , Agnello Ana Carolina , Coppotelli Bibiana Marina , Laprida Cecilia , Vidal Nuria Carolina , Di Marco Pablo , Oneto Maria Elena , Del Panno Maria Teresa , Morelli Irma Susana
Published: April 2021

Monitored natural recovery (MNR) is an in situ technique of conventional remediation for the treatment of contaminated sediments that relies on natural processes to reduce the bioavailability or toxicity of contaminants. Metabarcoding and bioinformatics approaches to infer functional prediction were applied in bottom sediments of a tributary drainage channel of Río de La Plata estuary, in order to assess the biological contribution to MNR. Hydrocarbon concentration in water samples and surface sediments was below the detection limit. Surface sediments were represented with high available phosphorous, alkaline pH, and the bacterial classes Anaerolineae, Planctomycetia, and Deltaproteobacteria. The functional prediction in surface sediments showed an increase of metabolic activity, carbon fixation, methanogenesis, and synergistic relationships between Archaeas, Syntrophobacterales, and Desulfobacterales. The prediction in non-surface sediments suggested the capacity to respond to different kinds of environmental stresses (oxidative, osmotic, heat, acid pH, and heavy metals), predicted mostly in Lactobacillales order, and the capacity of Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, and Actinomyces classes to degrade xenobiotic compounds. Canonical correspondence analysis (CCA) suggests that depth, phosphate content, redox potential, and pH were the variables that structured the bacterial community and not the hydrocarbons. The characterization of sediments by metabarcoding and functional prediction approaches, allowed to assess how the microbial activity would contribute to the recovery of the site.
Genomic Characterization of Salmonella enterica Isolates From Retail Meat in Beijing, China
Authors: Lyu Na , Feng Yuqing , Pan Yuanlong , Huang Hua , Liu Yan , Xue Chenyu , Zhu Baoli , Hu Yongfei
Published: April 2021

Salmonella enterica remains one of the leading causes of foodborne bacterial disease. Retail meat is a major source of human salmonellosis. However, comparative genomic analyses of S. enterica isolates from retail meat from different sources in China are lacking. A total of 341 S. enterica strains were isolated from retail meat in sixteen districts of Beijing, China, at three different time points (January 1st, May 1st, and October 1st) in 2017. Comparative genomics was performed to investigate the genetic diversity, virulence and antimicrobial resistance gene (ARG) profiles of these isolates. The most common serotype was S. Enteritidis (203/341, 59.5%), which dominated among isolates from three different time points during the year. Laboratory retesting confirmed the accuracy of the serotyping results predicted by the Salmonella In Silico Typing Resource (SISTR) (96.5%). The pangenome of the 341 S. enterica isolates contained 13,931 genes, and the core genome contained 3,635 genes. Higher Salmonella phage 118970 sal3 (219/341, 64.2%) and Gifsy-2 (206/341, 60.4%) prevalence contributed to the diversity of the accessory genes, especially those with unknown functions. IncFII(S), IncX1, and IncFIB(S) plasmid replicons were more common in these isolates and were major sources of horizontally acquired foreign genes. The virulence gene profile showed fewer virulence genes associated with type III secretion systems in certain isolates from chicken. A total of 88 different ARGs were found in the 341 isolates. Three beta-lactamases, namely, blaCTX–M–55 (n = 15), blaCTX–M–14 (n = 11), and blaCTX–M–65 (n = 11), were more prevalent in retail meats. The emergence of qnrE1 and blaCTX–M–123 indicated a potential increase in the prevalence of retail meats. After the prohibition of colistin in China, three and four isolates were positive for the colistin resistance genes mcr-1.1 and mcr-9, respectively. Thus, we explored the evolution and genomic features of S. enterica isolates from retail meats in Beijing, China. The diverse ARGs of these isolates compromise food security and are a clinical threat.
High-Level Aminoglycoside Resistance in Human Clinical Klebsiella pneumoniae Complex Isolates and Characteristics of armA-Carrying IncHI5 Plasmids
Authors: Zhang Xueya , Li Qiaoling , Lin Hailong , Zhou Wangxiao , Qian Changrui , Sun Zhewei , Lin Li , Liu Hongmao , Lu Junwan , Lin Xi , Li Kewei , Xu Teng , Zhang Hailin , Li Changchong , Bao Qiyu
Published: April 2021

Aminoglycosides are important options for treating life-threatening infections. However, high levels of aminoglycoside resistance (HLAR) among Klebsiella pneumoniae isolates have been observed to be increasing frequently. In this study, a total of 292 isolates of the K. pneumoniae complex from a teaching hospital in China were analyzed. Among these isolates, the percentage of HLAR strains was 13.7% (40/292), and 15 aminoglycoside resistance genes were identified among the HLAR strains, with rmtB being the most dominant resistance gene (70%, 28/40). We also described an armA-carrying Klebsiella variicola strain KP2757 that exhibited a high-level resistance to all aminoglycosides tested. Whole-genome sequencing of KP2757 demonstrated that the strain contained one chromosome and three plasmids, with all the aminoglycoside resistance genes (including two copies of armA and six AME genes) being located on a conjugative plasmid, p2757-346, belonging to type IncHI5. Comparative genomic analysis of eight IncHI5 plasmids showed that six of them carried two copies of the intact armA gene in the complete or truncated Tn1548 transposon. To the best of our knowledge, for the first time, we observed that two copies of armA together with six AME genes coexisted on the same plasmid in a strain of K. variicola with HLAR. Comparative genomic analysis of eight armA-carrying IncHI5 plasmids isolated from humans and sediment was performed, suggesting the potential for dissemination of these plasmids among bacteria from different sources. These results demonstrated the necessity of monitoring the prevalence of IncHI5 plasmids to restrict their worldwide dissemination.
Infant Feeding Alters the Longitudinal Impact of Birth Mode on the Development of the Gut Microbiota in the First Year of Life
Authors: Coker Modupe O. , Laue Hannah E. , Hoen Anne G. , Hilliard Margaret , Dade Erika , Li Zhigang , Palys Thomas , Morrison Hilary G. , Baker Emily , Karagas Margaret R. , Madan Juliette C.
Published: April 2021

Cesarean-delivered (CD) infants harbor a distinct gut microbiome from vaginally delivered (VD) infants, however, during infancy, the most important driver of infant gut microbial colonization is infant feeding. Earlier studies have shown that breastfeeding is associated with higher levels of health-promoting bacteria such and Bifidobacterium and Bacteroides via modulation of the immune system, and production of metabolites. As the infant gut matures and solid foods are introduced, it is unclear whether longer duration of breast feeding restore loss of beneficial taxa within the intestinal microbiota of operatively delivered infants. Within the New Hampshire Birth Cohort Study, we evaluated the longitudinal effect of delivery mode and infant feeding on the taxonomic composition and functional capacity of developing gut microbiota in the First year of life. Microbiota of 500 stool samples collected between 6 weeks and 12 months of age (from 229 infants) were characterized by 16S ribosomal RNA sequencing. Shotgun metagenomic sequencing was also performed on 350 samples collected at either 6 weeks or 12 months of age. Among infant participants, 28% were cesarean-delivered (CD) infants and most (95%) initiated breastfeeding within the first six months of life, with 26% exclusively breastfed and 69% mixed-fed (breast milk and formula), in addition to complementary foods by age 1. Alpha (within-sample) diversity was significantly lower in CD infants compared to vaginally delivered (VD) infants (P < 0.05) throughout the study period. Bacterial community composition clustering by both delivery mode and feeding duration at 1 year of age revealed that CD infants who were breast fed for < 6 months were more dissimilar to VD infants than CD infants who breast fed for ≥ 6 months. We observed that breastfeeding modified the longitudinal impact of delivery mode on the taxonomic composition of the microbiota by 1 year of age, with an observed increase in abundance of Bacteroides fragilis and Lactobacillus with longer duration of breastfeeding among CD infants while there was an increase in Faecalibacterium for VD infants. Our findings confirm that duration of breastfeeding plays a critical role in restoring a health-promoting microbiome, call for further investigations regarding the association between breast milk exposure and health outcomes in early life.
Microbiome Sample Comparison and Search: From Pair-Wise Calculations to Model-Based Matching
Authors: Zha Yuguo , Chong Hui , Ning Kang
Published: April 2021

A huge quantity of microbiome samples have been accumulated, and more are yet to come from all niches around the globe. With the accumulation of data, there is an urgent need for comparisons and searches of microbiome samples among thousands of millions of samples in a fast and accurate manner. However, it is a very difficult computational challenge to identify similar samples, as well as identify their likely origins, among such a grand pool of samples from all around the world. Currently, several approaches have already been proposed for such a challenge, based on either distance calculation, unsupervised algorithms, or supervised algorithms. These methods have advantages and disadvantages for the different settings of comparisons and searches, and their results are also drastically different. In this review, we systematically compared distance-based, unsupervised, and supervised methods for microbiome sample comparison and search. Firstly, we assessed their accuracy and efficiency, both in theory and in practice. Then we described the scenarios in which one or multiple methods were applicable for sample searches. Thirdly, we provided several applications for microbiome sample comparisons and searches, and provided suggestions on the choice of methods. Finally, we provided several perspectives for the future development of microbiome sample comparison and search, including deep learning technologies for tracking the sources of microbiome samples.
The Interplay of HIV-1 and Macrophages in Viral Persistence
Authors: Hendricks Chynna M. , Cordeiro Thaissa , Gomes Ana Paula , Stevenson Mario
Published: April 2021

HIV-1 has evolved mechanisms to evade host cell immune responses and persist for lifelong infection. Latent cellular reservoirs are responsible for this persistence of HIV-1 despite the powerful effects of highly active antiretroviral therapies (HAART) to control circulating viral load. While cellular reservoirs have been extensively studied, much of these studies have focused on peripheral blood and resting memory CD4+ T cells containing latent HIV-1 provirus; however, efforts to eradicate cellular reservoirs have been stunted by reservoirs found in tissues compartments that are not easily accessible. These tissues contain resting memory CD4+ T cells and tissue resident macrophages, another latent cellular reservoir to HIV-1. Tissue resident macrophages have been associated with HIV-1 infection since the 1980s, and evidence has continued to grow regarding their role in HIV-1 persistence. Specific biological characteristics play a vital role as to why macrophages are latent cellular reservoirs for HIV-1, and in vitro and in vivo studies exhibit how macrophages contribute to viral persistence in individuals and animals on antiretroviral therapies. In this review, we characterize the role and evolutionary advantages of macrophage reservoirs to HIV-1 and their contribution to HIV-1 persistence. In acknowledging the interplay of HIV-1 and macrophages in the host, we identify reasons why current strategies are incapable of eliminating HIV-1 reservoirs and why efforts must focus on eradicating reservoirs to find a future functional cure.
Disbalancing Envelope Stress Responses as a Strategy for Sensitization of Escherichia coli to Antimicrobial Agents
Authors: Recacha Esther , Fox Valeria , Díaz-Díaz Sara , García-Duque Ana , Docobo-Pérez Fernando , Pascual Álvaro , Rodríguez-Martínez José Manuel
Published: April 2021

Disbalancing envelope stress responses was investigated as a strategy for sensitization of Escherichia coli to antimicrobial agents. Seventeen isogenic strains were selected from the KEIO collection with deletions in genes corresponding to the σE, Cpx, Rcs, Bae, and Psp responses. Antimicrobial activity against 20 drugs with different targets was evaluated by disk diffusion and gradient strip tests. Growth curves and time-kill curves were also determined for selected mutant-antimicrobial combinations. An increase in susceptibility to ampicillin, ceftazidime, cefepime, aztreonam, ertapenem, and fosfomycin was detected. Growth curves for Psp response mutants showed a decrease in optical density (OD) using sub-MIC concentrations of ceftazidime and aztreonam (ΔpspA and ΔpspB mutants), cefepime (ΔpspB and ΔpspC mutants) and ertapenem (ΔpspB mutant). Time-kill curves were also performed using 1xMIC concentrations of these antimicrobials. For ceftazidime, 2.9 log10 (ΔpspA mutant) and 0.9 log10 (ΔpspB mutant) decreases were observed at 24 and 8 h, respectively. For aztreonam, a decrease of 3.1 log10 (ΔpspA mutant) and 4 log1010 (ΔpspB mutant) was shown after 4–6 h. For cefepime, 4.2 log10 (ΔpspB mutant) and 2.6 log10 (ΔpspC mutant) decreases were observed at 8 and 4 h, respectively. For ertapenem, a decrease of up to 6 log10 (ΔpspB mutant) was observed at 24 h. A deficient Psp envelope stress response increased E. coli susceptibility to beta-lactam agents such as cefepime, ceftazidime, aztreonam and ertapenem. Its role in repairing extensive inner membrane disruptions makes this pathway essential to bacterial survival, so that disbalancing the Psp response could be an appropriate target for sensitization strategies.
Advances and Perspectives for Genome Editing Tools of Corynebacterium glutamicum
Authors: Wang Qingzhuo , Zhang Jiao , Al Makishah Naief H. , Sun Xiaoman , Wen Zhiqiang , Jiang Yu , Yang Sheng
Published: April 2021

Corynebacterium glutamicum has been considered a promising synthetic biological platform for biomanufacturing and bioremediation. However, there are still some challenges in genetic manipulation of C. glutamicum. Recently, more and more genetic parts or elements (replicons, promoters, reporter genes, and selectable markers) have been mined, characterized, and applied. In addition, continuous improvement of classic molecular genetic manipulation techniques, such as allelic exchange via single/double-crossover, nuclease-mediated site-specific recombination, RecT-mediated single-chain recombination, actinophages integrase-mediated integration, and transposition mutation, has accelerated the molecular study of C. glutamicum. More importantly, emerging gene editing tools based on the CRISPR/Cas system is revolutionarily rewriting the pattern of genetic manipulation technology development for C. glutamicum, which made gene reprogramming, such as insertion, deletion, replacement, and point mutation, much more efficient and simpler. This review summarized the recent progress in molecular genetic manipulation technology development of C. glutamicum and discussed the bottlenecks and perspectives for future research of C. glutamicum as a distinctive microbial chassis.
Discovery of Kasugamycin as a Potent Inhibitor of Glycoside Hydrolase Family 18 Chitinases
Authors: Qi Huitang , Jiang Xi , Ding Yi , Liu Tian , Yang Qing
Published: April 2021

Kasugamycin, a well-known aminoglycoside antibiotic, has been used widely in agriculture and medicine to combat microbial pathogens by binding the ribosome to inhibit translation. Here, kasugamycin was discovered to be a competitive inhibitor of glycoside hydrolase family 18 (GH18) chitinases from three different organisms (bacterium, insect and human). Results from tryptophan fluorescence spectroscopy and molecular docking revealed that kasugamycin binds to the substrate-binding clefts in a similar mode as the substrate. An electrostatic interaction between the amino group of kasugamycin and the carboxyl group of a conserved aspartate in GH18 chitinase (one of the catalytic triad residues) was found to be vital for the inhibitory activity. This paper not only reports new molecular targets of kasugamycin, but also expands our thinking about GH inhibitor design by using a scaffold unrelated to the substrate.
The World of Stable Ribonucleoproteins and Its Mapping With Grad-Seq and Related Approaches
Authors: Gerovac Milan , Vogel Jörg , Smirnov Alexandre
Published: April 2021

Macromolecular complexes of proteins and RNAs are essential building blocks of cells. These stable supramolecular particles can be viewed as minimal biochemical units whose structural organization, i.e., the way the RNA and the protein interact with each other, is directly linked to their biological function. Whether those are dynamic regulatory ribonucleoproteins (RNPs) or integrated molecular machines involved in gene expression, the comprehensive knowledge of these units is critical to our understanding of key molecular mechanisms and cell physiology phenomena. Such is the goal of diverse complexomic approaches and in particular of the recently developed gradient profiling by sequencing (Grad-seq). By separating cellular protein and RNA complexes on a density gradient and quantifying their distributions genome-wide by mass spectrometry and deep sequencing, Grad-seq charts global landscapes of native macromolecular assemblies. In this review, we propose a function-based ontology of stable RNPs and discuss how Grad-seq and related approaches transformed our perspective of bacterial and eukaryotic ribonucleoproteins by guiding the discovery of new RNA-binding proteins and unusual classes of noncoding RNAs. We highlight some methodological aspects and developments that permit to further boost the power of this technique and to look for exciting new biology in understudied and challenging biological models.
Strong Coupling, Hyperbolic Metamaterials and Optical Tamm States in Layered Dielectric-Plasmonic Media
Authors: Gonçalves Manuel Rodrigues
Published: April 2021

Thin films of noble metals with thickness smaller than the wavelength of light constitute one of the most investigated structures in plasmonics. The fact that surface plasmon modes can be excited in these films by different ways and the simplicity of fabrication offer ideal conditions for applications in nanophotonics. The generation of optical modes in coupled Fabry-Pérot planar cavities and their migration to hyperbolic metamaterials is investigated. Coupled Fabry-Pérot cavities behave as simple coupled resonators. When the intra-cavity media have different refractive indices in two or more coupled cavities resonance anti-crossings arise. The application of this kind of strong coupling in sensing is foreseen. Beyond the cavity modes excited by propagating waves, also long range plasmonic guided modes can be excited using emitters or evanescent waves. A periodic structure made by multiple plasmonic films and dielectrica supports bulk plasmons, of large propagation constant and increasing field amplitude. The optical response of these structures approaches that of the hyperbolic metamaterial predicted by the effective medium theory. Light can propagate with full transmission in a structure made of a photonic crystal based on quarter wavelength layers and a second photonic crystal with an overlapping forbidden band, but presenting a non-trivial topological phase achieved by band inversion. This is due to excitation of optical Tamm states at the boundary between both crystals. The extension to multiple optical Tamm states using dielectric and plasmonic materials and the symmetries of the edge states is investigated.
Rapamycin Added to Diet in Late Mid-Life Delays Age-Related Hearing Loss in UMHET4 Mice
Authors: Altschuler Richard A. , Kabara Lisa , Martin Catherine , Kanicki Ariane , Stewart Courtney E. , Kohrman David C. , Dolan David F.
Published: April 2021

Our previous study demonstrated rapamycin added to diet at 4 months of age had significantly less age-related outer hair cell loss in the basal half of the cochlea at 22 months of age compared to mice without rapamycin. The present study tested adding rapamycin to diet later in life, at 14 months of age, and added a longitudinal assessment of auditory brain stem response (ABR). The present study used UMHET4 mice, a 4 way cross in which all grandparental strains lack the Cdh23753A allele that predisposes to early onset, progressive hearing loss. UMHET4 mice typically have normal hearing until 16–17 months, then exhibit threshold shifts at low frequencies/apical cochlea and later in more basal high frequency regions. ABR thresholds at 4, 12, 24, and 48 kHz were assessed at 12, 18, and 24 months of age and compared to baseline ABR thresholds acquired at 5 months of age to determine threshold shifts (TS). There was no TS at 12 months of age at any frequency tested. At 18 months of age mice with rapamycin added to diet at 14 months had a significantly lower mean TS at 4 and 12 kHz compared to mice on control diet with no significant difference at 24 and 48 kHz. At 24 months of age, the mean 4 kHz TS in rapamycin diet group was no longer significantly lower than the control diet group, while the 12 kHz mean remained significantly lower. Mean TS at 24 and 48 kHz in the rapamycin diet group became significantly lower than in the control diet group at 24 months. Hair cell counts at 24 months showed large loss in the apical half of most rapamycin and control diet mice cochleae with no significant difference between groups. There was only mild outer hair cell loss in the basal half of rapamycin and control diet mice cochleae with no significant difference between groups. The results show that a later life addition of rapamycin can decrease age-related hearing loss in the mouse model, however, it also suggests that this decrease is a delay/deceleration rather than a complete prevention.
A Neuroscience Levels of Explanation Approach to the Mind and the Brain
Authors: Rolls Edmund T.
Published: April 2021

The relation between mental states and brain states is important in computational neuroscience, and in psychiatry in which interventions with medication are made on brain states to alter mental states. The relation between the brain and the mind has puzzled philosophers for centuries. Here a neuroscience approach is proposed in which events at the sub-neuronal, neuronal, and neuronal network levels take place simultaneously to perform a computation that can be described at a high level as a mental state, with content about the world. It is argued that as the processes at the different levels of explanation take place at the same time, they are linked by a non-causal supervenient relationship: causality can best be described in brains as operating within but not between levels. This allows the supervenient (e.g., mental) properties to be emergent, though once understood at the mechanistic levels they may seem less emergent, and expected. This mind-brain theory allows mental events to be different in kind from the mechanistic events that underlie them; but does not lead one to argue that mental events cause brain events, or vice versa: they are different levels of explanation of the operation of the computational system. This approach may provide a way of thinking about brains and minds that is different from dualism and from reductive physicalism, and which is rooted in the computational processes that are fundamental to understanding brain and mental events, and that mean that the mental and mechanistic levels are linked by the computational process being performed. Explanations at the different levels of operation may be useful in different ways. For example, if we wish to understand how arithmetic is performed in the brain, description at the mental level of the algorithm being computed will be useful. But if the brain operates to result in mental disorders, then understanding the mechanism at the neural processing level may be more useful, in for example, the treatment of psychiatric disorders.
Image Findings of Acute to Subacute Craniocervical Arterial Dissection on Magnetic Resonance Vessel Wall Imaging: A Systematic Review and Proportion Meta-Analysis
Authors: Cho Se Jin , Choi Byung Se , Bae Yun Jung , Baik Sung Hyun , Sunwoo Leonard , Kim Jae Hyoung
Published: April 2021

Background and Purpose: This systematic review and meta-analysis aimed to evaluate the pooled proportion of image findings of acute to subacute craniocervical arterial dissection (AD) direct signs on magnetic resonance vessel wall imaging (MR-VWI) and to identify factors responsible for the heterogeneity across the included studies.

Methods: A systematic literature search in the Ovid-MEDLINE and EMBASE databases was performed for studies published on the relevant topic before April 14, 2020. Pooled sensitivity and specificity values and their 95% confidence intervals (CIs) were calculated using bivariate random-effects modeling. Meta-regression analyses were also performed to determine factors influencing heterogeneity.

Results: Eleven articles with data for 209 patients with acute to subacute craniocervical AD who underwent MR-VWI were included in this systematic review and meta-analysis. The most common findings on MR-VWI were wall hematoma (84%; 95% CI, 71%−92%), abnormal enhancement (72%; 95% CI, 49%−88%), aneurysmal dilatation (71%, 95% CI, 53%−84%), and intimal flap or double lumen signs (49%; 95% CI, 29%−71%). Among the potential covariates of heterogeneity, the presence of contrast-enhanced T1-weighted imaging (CE-T1WI) within the MR-VWI sequence combination significantly affected the pooled proportion of the intimal flap or double lumen signs.

Conclusion: Wall hematoma and intimal flap or double lumen signs were the most common and least common direct sign image findings, respectively, on MR-VWI in patients with acute to subacute craniocervical AD. Furthermore, the absence of CE-T1WI in MR-VWI protocol was the cause of heterogeneity for the detection of the intimal flap or double lumen signs. This data may help improve MR-VWI interpretation and enhance the understanding of the radiologic diagnosis of craniocervical AD.
Therapeutic Use of Transcranial Direct Current Stimulation in the Rehabilitation of Prolonged Disorders of Consciousness
Authors: Aloi Davide , della Rocchetta Antonio Incisa , Ditchfield Alice , Coulborn Sean , Fernández-Espejo Davinia
Published: April 2021

Patients with Prolonged Disorders of Consciousness (PDOC) have catastrophic disabilities and very complex needs for care. Therapeutic options are very limited, and patients often show little functional improvement over time. Neuroimaging studies have demonstrated that a significant number of PDOC patients retain a high level of cognitive functioning, and in some cases even awareness, and are simply unable to show this with their external behavior - a condition known as cognitive-motor dissociation (CMD). Despite vast implications for diagnosis, the discovery of covert cognition in PDOC patients is not typically associated with a more favorable prognosis, and the majority of patients will remain in a permanent state of low responsiveness. Recently, transcranial direct current stimulation (tDCS) has attracted attention as a potential therapeutic tool in PDOC. Research to date suggests that tDCS can lead to clinical improvements in patients with a minimally conscious state (MCS), especially when administered over multiple sessions. While promising, the outcomes of these studies have been highly inconsistent, partially due to small sample sizes, heterogeneous methodologies (in terms of both tDCS parameters and outcome measures), and limitations related to electrode placement and heterogeneity of brain damage inherent to PDOC. In addition, we argue that neuroimaging and electrophysiological assessments may serve as more sensitive biomarkers to identify changes after tDCS that are not yet apparent behaviorally. Finally, given the evidence that concurrent brain stimulation and physical therapy can enhance motor rehabilitation, we argue that future studies should focus on the integration of tDCS with conventional rehabilitation programmes from the subacute phase of care onwards, to ascertain whether any synergies exist.
Microglia-Derived Interleukin 23: A Crucial Cytokine in Alzheimer's Disease?
Authors: Nitsch Louisa , Schneider Linda , Zimmermann Julian , Müller Marcus
Published: April 2021

Neuronal cell death, amyloid β plaque formation and development of neurofibrillary tangles are among the characteristics of Alzheimer's disease (AD). In addition to neurodegeneration, inflammatory processes such as activation of microglia and astrocytes are crucial in the pathogenesis and progression of AD. Cytokines are essential immune mediators of the immune response in AD. Recent data suggest a role of interleukin 23 (IL-23) and its p40 subunit in the pathogenesis of AD and corresponding animal models, in particular concerning microglia activation and amyloid β plaque formation. Moreover, in animal models, the injection of anti-p40 antibodies resulted in reduced amyloid β plaque formation and improved cognitive performance. Here, we discuss the pathomechanism of IL-23 mediated inflammation and its role in AD.
A Pre-Interventional Scale to Predict in situ Atherosclerotic Thrombosis in Acute Vertebrobasilar Artery Occlusion Patients
Authors: Zha Mingming , Wu Min , Huang Xianjun , Zhang Xiaohao , Huang Kangmo , Yang Qingwen , Cai Haodi , Ji Yachen , Lv Qiushi , Yang Dong , Dai Qiliang , Liu Rui , Liu Xinfeng
Published: April 2021

Background and Purpose: Determining the occlusion mechanism before endovascular treatment (EVT) is of great significance for acute large vessel occlusion patients. We aimed to develop and validate a simple pre-EVT scale with readily available variables for predicting in situ atherosclerotic thrombosis (ISAT) in acute vertebrobasilar artery occlusion (VBAO) patients.

Materials and Methods: Consecutive patients were retrieved from Nanjing Stroke Registry Program between January 2014 and December 2019 as a derivation cohort. Anonymous data of consecutive patients between January 2014 and December 2019 were collected from another comprehensive stroke center as an external validation cohort. Demographics, medical histories, and clinical characteristics were collected. ISAT was defined according to the following criteria: (a) detection of moderate to severe (≥50%) stenosis or stenosis with significant distal flow impairment at the occluded segment when successful reperfusion was achieved; (b) transient visualization of eccentric plaque contour or a recurrent re-occlusion tendency when reperfusion was unsuccessful. Logistic regression was taken to develop a predictive scale. The performance of the scale was assessed by area under the receiver operating characteristic curve (AUC) and Hosmer–Lemeshow test.

Results: ISAT was observed in 41 of 95 (43.2%) patients included in the derivation cohort. The ISAT predictive scale consisted of three pre-interventional predictors, including the history of hypertension, atrial fibrillation rhythm, and baseline serum glucose level ≥7.55 mmol/L. The model depicted acceptable calibration (Hosmer–Lemeshow test, P = 0.554) and good discrimination (AUC, 0.853; 95% confidence interval, 0.775–0.930). The optimal cutoff value of the ISAT scale was 1 point with 95.1% sensitivity, 64.8% specificity, and 77.9% accuracy. In the validation cohort, the discrimination ability was still promising with an AUC value of 0.800 (0.682–0.918).

Conclusion: The three-item scale comprised of the history of hypertension, atrial fibrillation rhythm, and dichotomous serum glucose level had a promising predictive value for ISAT before EVT in acute VBAO patients.
Association of Fatigue Severity With Maladaptive Coping in Multiple Sclerosis: A Data-Driven Psychodynamic Perspective
Authors: Pust Gesa E. A. , Randerath Jennifer , Goetzmann Lutz , Weierstall Roland , Korzinski Michael , Gold Stefan M. , Dettmers Christian , Ruettner Barbara , Schmidt Roger
Published: April 2021

Fatigue in persons with multiple sclerosis (PwMS) is severely disabling. However, the underlying mechanisms remain incompletely understood. Recent research suggests a link to early childhood adversities and psychological trait variables. In line with these studies, this paper took a psychodynamic perspective on MS-fatigue. It was hypothesized that fatigue could represent a manifestation of maladaptive coping with intense emotions. The schema therapeutic mode model served as a theoretical and empirically validated framework, linking psychodynamic theory and empirical research methods. The study was based on a data set of N = 571 PwMS that has also served as the basis for another publication. Data was collected online. The Schema Mode Inventory was used to quantify regulatory strategies to cope with emotionally stressful experiences. In addition, depressive symptoms (Beck's Depression Inventory - FastScreen), physical disability (Patient Determined Disease Steps), alexithymia (Toronto Alexithymia Scale-26), adverse childhood experiences (Childhood Trauma Questionnaire), and self-reported fatigue (Fatigue Scale for Motor and Cognitive Functions) were assessed. Latent profile analysis revealed three distinct groups of PwMS, based on their coping mode profiles: (1) PwMS with low maladaptive coping, (2) PwMS with avoidant/submissive coping styles, and (3) PwMS with avoidant/overcompensatory coping styles. Multivariate comparisons showed no significant difference in physical disability across the three groups. However, heightened levels of self-reported fatigue and depression symptoms occurred in PwMS with maladaptive coping styles. A path model uncovered that self-reported fatigue was robustly related to physical disability (β = 0.33) and detached/avoidant coping (Detached Protector; β = 0.34). There was no specific relation between any of the maladaptive coping modes and depression symptoms. Detached/avoidant coping was in turn predicted by childhood emotional abuse and neglect. The results indicate that childhood adversity and detached/avoidant coping styles may be associated with variability in MS-fatigue severity: PwMS that resort to detached/avoidant coping in response to negative emotions also tend to report heightened levels of fatigue, although they do not differ in their perceived disability from PwMS with low levels of fatigue and maladaptive coping. A link between MS-fatigue and the psychodynamic traumatic conversion model is discussed. The implications of these findings for therapeutic interventions require further study.