bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimizing Sequencing Resources in Genotyped Livestock Populations Using Linear Programming
Authors: Cheng Hao , Xu Keyu , Li Jinghui , Abraham Kuruvilla Joseph
Published: October 2021

Low-cost genome-wide single-nucleotide polymorphisms (SNPs) are routinely used in animal breeding programs. Compared to SNP arrays, the use of whole-genome sequence data generated by the next-generation sequencing technologies (NGS) has great potential in livestock populations. However, sequencing a large number of animals to exploit the full potential of whole-genome sequence data is not feasible. Thus, novel strategies are required for the allocation of sequencing resources in genotyped livestock populations such that the entire population can be imputed, maximizing the efficiency of whole genome sequencing budgets. We present two applications of linear programming for the efficient allocation of sequencing resources. The first application is to identify the minimum number of animals for sequencing subject to the criterion that each haplotype in the population is contained in at least one of the animals selected for sequencing. The second application is the selection of animals whose haplotypes include the largest possible proportion of common haplotypes present in the population, assuming a limited sequencing budget. Both applications are available in an open source program LPChoose. In both applications, LPChoose has similar or better performance than some other methods suggesting that linear programming methods offer great potential for the efficient allocation of sequencing resources. The utility of these methods can be increased through the development of improved heuristics.
ERAP, KIR, and HLA-C Profile in Recurrent Implantation Failure
Authors: Piekarska Karolina , Radwan Paweł , Tarnowska Agnieszka , Wiśniewski Andrzej , Radwan Michał , Wilczyński Jacek R. , Malinowski Andrzej , Nowak Izabela
Published: October 2021

The mother’s uterine immune system is dominated by uterine natural killer (NK) cells during the first trimester of pregnancy. These cells express killer cell immunoglobulin-like receptors (KIRs) of inhibitory or activating function. Invading extravillous trophoblast cells express HLA-C molecules, and both maternal and paternal HLA-C allotypes are presented to KIRs. Endoplasmic reticulum aminopeptidase 1 (ERAP1) and 2 (ERAP2) shape the HLA class I immunopeptidome. The ERAPs remove N-terminal residues from antigenic precursor peptides and generate optimal-length peptides to fit into the HLA class I groove. The inability to form the correct HLA class I complexes with the appropriate peptides may result in a lack of immune response by NK cells. The aim of this study was to investigate the role of ERAP1 and ERAP2 polymorphisms in the context of KIR and HLA-C genes in recurrent implantation failure (RIF). In addition, for the first time, we showed the results of ERAP1 and ERAP2 secretion into the peripheral blood of patients and fertile women. We tested a total of 881 women. Four hundred ninety-six females were patients who, together with their partners, participated in in vitro fertilization (IVF). A group of 385 fertile women constituted the control group. Women positive for KIR genes in the Tel AA region and HLA-C2C2 were more prevalent in the RIF group than in fertile women (p/pcorr. = 0.004/0.012, OR = 2.321). Of the ERAP polymorphisms studied, two of them (rs26653 and rs26618) appear to affect RIF susceptibility in HLA-C2-positive patients. Moreover, fertile women who gave birth in the past secreted significantly more ERAP1 than IVF women and control pregnant women (p < 0.0001 and p = 0.0005, respectively). In the case of ERAP2, the opposite result was observed; i.e., fertile women secreted far less ERAP2 than IVF patients (p = 0.0098). Patients who became pregnant after in vitro fertilization embryo transfer (IVF-ET) released far less ERAP2 than patients who miscarried (p = 0.0032). Receiver operating characteristic (ROC) analyses indicate a value of about 2.9 ng/ml of ERAP2 as a point of differentiation between patients who miscarried and those who gave birth to a healthy child. Our study indicates that both ERAP1 and ERAP2 may be involved in processes related to reproduction.
CRAC Channel Controls the Differentiation of Pathogenic B Cells in Lupus Nephritis
Authors: Li Xue , Zeng Qin , Wang Shuyi , Li Mengyuan , Chen Xionghui , Huang Yuefang , Chen Binfeng , Zhou Mianjing , Lai Yimei , Guo Chaohuan , Zhao Siyuan , Zhang Hui , Yang Niansheng
Published: October 2021

Store-operated Ca2+ release-activated Ca2+ (CRAC) channel is the main Ca2+ influx pathway in lymphocytes and is essential for immune response. Lupus nephritis (LN) is an autoimmune disease characterized by the production of autoantibodies due to widespread loss of immune tolerance. In this study, RNA-seq analysis revealed that calcium transmembrane transport and calcium channel activity were enhanced in naive B cells from patients with LN. The increased expression of ORAI1, ORAI2, and STIM2 in naive B cells from patients with LN was confirmed by flow cytometry and Western blot, implying a role of CRAC channel in B-cell dysregulation in LN. For in vitro study, CRAC channel inhibition by YM-58483 or downregulation by ORAI1-specific small-interfering RNA (siRNA) decreased the phosphorylation of Ca2+/calmodulin-dependent protein kinase2 (CaMK2) and suppressed Blimp-1 expression in primary human B cells, resulting in decreased B-cell differentiation and immunoglobulin G (IgG) production. B cells treated with CaMK2-specific siRNA showed defects in plasma cell differentiation and IgG production. For in vivo study, YM-58483 not only ameliorated the progression of LN but also prevented the development of LN. MRL/lpr lupus mice treated with YM-58483 showed lower percentage of plasma cells in the spleen and reduced concentration of anti-double-stranded DNA antibodies in the sera significantly. Importantly, mice treated with YM-58483 showed decreased immune deposition in the glomeruli and alleviated kidney damage, which was further confirmed in NZM2328 lupus mice. Collectively, CRAC channel controlled the differentiation of pathogenic B cells and promoted the progression of LN. This study provides insights into the pathogenic mechanisms of LN and that CRAC channel could serve as a potential therapeutic target for LN.
Evaluating the Efficacy of Acoustic Metrics for Understanding Baleen Whale Presence in the Western North Atlantic Ocean
Authors: Pegg Nicole , Roca Irene T. , Cholewiak Danielle , Davis Genevieve E. , Van Parijs Sofie M.
Published: October 2021

Soundscape analyses provide an integrative approach to studying the presence and complexity of sounds within long-term acoustic data sets. Acoustic metrics (AMs) have been used extensively to describe terrestrial habitats but have had mixed success in the marine environment. Novel approaches are needed to be able to deal with the added noise and complexity of these underwater systems. Here we further develop a promising approach that applies AM with supervised machine learning to understanding the presence and species richness (SR) of baleen whales at two sites, on the shelf and the slope edge, in the western North Atlantic Ocean. SR at both sites was low with only rare instances of more than two species (out of six species acoustically detected at the shelf and five at the slope) vocally detected at any given time. Random forest classification models were trained on 1-min clips across both data sets. Model outputs had high accuracy (>0.85) for detecting all species’ absence in both sites and determining species presence for fin and humpback whales on the shelf site (>0.80) and fin and right whales on the slope site (>0.85). The metrics that contributed the most to species classification were those that summarized acoustic activity (intensity) and complexity in different frequency bands. Lastly, the trained model was run on a full 12 months of acoustic data from on the shelf site and compared with our standard acoustic detection software and manual verification outputs. Although the model performed poorly at the 1-min clip resolution for some species, it performed well compared to our standard detection software approaches when presence was evaluated at the daily level, suggesting that it does well at a coarser level (daily and monthly). The model provided a promising complement to current methodologies by demonstrating a good prediction of species absence in multiple habitats, species presence for certain species/habitat combinations, and provides higher resolution presence information for most species/habitat combinations compared to that of our standard detection software.
Smart Chimeric Lysin ClyC Loaded Alginate Hydrogel Reduces Staphylococcus aureus Induced Bone Infection
Authors: Yao Fangfang , Wu Xinyu , Liao Yilin , Yan Qi , Li Yuhong
Published: October 2021

Staphylococcus aureus (S. aureus) is the most common cause of hospital and community-acquired infections. The current clinical treatment is limited by the emergence of drug-resistant strains. We previously developed a chimeric ClyC that effectively inhibited S. aureus strains. Nonetheless, an efficient delivery system to provide sustained release of ClyC to infected site is needed. Thus, we engineered a chimeric ClyC loaded alginate hydrogel (ClyC-AH) to improve the therapeutic outcomes against S. aureus. ClyC-AH retained the stability and activity of ClyC while providing a sustained release of ClyC and a continuous antibacterial effect against S. aureus. Compared to ClyC alone, the use of ClyC-AH was relatively safe, as there was no significant cytotoxicity to BHK-21 cells at a ClyC concentration≤250 μg/ml. Furthermore, in a S. aureus infected mouse model of osteomyelitis, ClyC-AH reduced bacterial burden in the femur and surrounding tissues, with a reduction of 2 log10 (CFU/ml) in viable bacterial number. Based on these results, hydrogel-delivered chimeric lysin ClyC provides a promising future in the S.aureus targeting therapy.
Florescence Intensity Ratio Thermometer in the First Biological Window Based on Non-Thermally Coupled Energy Levels of Tm3+ and Ho3+ Ions
Authors: Li Liang , Hao Haoyue
Published: October 2021

In this study, the up-conversion luminescence and optical temperature sensing properties of Ho3+/Tm3+/Yb3+-co-doped NaLuF4 phosphors were investigated. The visible (475, 540, and 650 nm) and near-infrared light (692 and 800 nm) radiated from 1Ho3+/4Tm3+/Yb3+-co-doped NaLuF4 phosphors were obvious enough for subsequent detection. The slopes in the lnI–lnP plot of the emissions located in the first biological window (650, 692, and 800 nm) were both ∼1.5, which mean that the power had little effect on the three fluorescence peak ratios. Based on the florescence intensity ratios (FIRs) of 650 and 692 nm, the relative sensing sensitivity reaches 0.029 K−1 (476 K). The relative sensing sensitivity based on the FIRs of 800 and 692 nm reaches 0.0076 K−1 (476 K). The results reveal that 1Ho3+/4Tm3+/Yb3+-co-doped NaLuF4 phosphors have potential applications in FIR-based temperature sensing in biological tissue for their high sensing sensitivity. In addition, the emission colors of the sample stabilize in the white light region as the temperature increased from 303 to 467 K, implying that it can also be used in white display.
Revisited Hyperoxia Pathophysiology in the Perioperative Setting: A Narrative Review
Authors: Busani Stefano , Sarti Marco , Serra Francesco , Gelmini Roberta , Venturelli Sophie , Munari Elena , Girardis Massimo
Published: October 2021

The widespread use of high-dose oxygen, to avoid perioperative hypoxemia along with WHO-recommended intraoperative hyperoxia to reduce surgical site infections, is an established clinical practice. However, growing pathophysiological evidence has demonstrated that hyperoxia exerts deleterious effects on many organs, mainly mediated by reactive oxygen species. The purpose of this narrative review was to present the pathophysiology of perioperative hyperoxia on surgical wound healing, on systemic macro and microcirculation, on the lungs, heart, brain, kidneys, gut, coagulation, and infections. We reported here that a high systemic oxygen supply could induce oxidative stress with inflammation, vasoconstriction, impaired microcirculation, activation of hemostasis, acute and chronic lung injury, coronary blood flow disturbances, cerebral ischemia, surgical anastomosis impairment, gut dysbiosis, and altered antibiotics susceptibility. Clinical studies have provided rather conflicting results on the definitions and outcomes of hyperoxic patients, often not speculating on the biological basis of their results, while this review highlighted what happens when supranormal PaO2 values are reached in the surgical setting. Based on the assumptions analyzed in this study, we may suggest that the maintenance of PaO2 within physiological ranges, avoiding unnecessary oxygen administration, may be the basis for good clinical practice.
Process Evaluation of an Online SUpport PRogram for Older Hearing Aid Users Delivered in a Cluster Randomized Controlled Trial
Authors: Meijerink Janine F. J. , Pronk Marieke , Lissenberg-Witte Birgit I. , Jansen Vera , Kramer Sophia E.
Published: October 2021

Objectives: To evaluate the process of implementing a web-based support program (SUPR) for hearing aid users in the Dutch dispensing setting in order to allow interpretation of the randomized controlled trial's results (positive effects on hearing-aid related outcomes; no effects on psychosocial outcomes).

Design: Measures: context of implementation, recruitment, SUPR's: reach, implementation fidelity, dose delivered, dose received, satisfaction, and benefit. Data collection: quantitative and qualitative.

Study Sample: One hundred thirty-eight clients (mean age 68.1 years; 60% male) and 44 dispensers completed questionnaires. Five clients and 6 dispensers participated in interviews and focus groups.

Results: Clients and dispensers were generally satisfied with SUPR's usefulness. SUPR-videos were watched by 7–37% of the clients. Around half of the dispensers encouraged clients to watch them or informed them about SUPR. Some clients found the SUPR-materials suboptimal, and changes in personnel and limited dispenser-training were barriers acting on a contextual level.

Conclusions: This study identified several factors that contributed to the success of SUPR. Others factors, acting on various levels (e.g., intervention material, dispensers, and implementation context), were suboptimal and may explain the absent psychosocial effects. The identified factors are important to consider in further development of SUPR, and in other web-based support programs.
Emerging Adaptive Strategies Under Temperature Fluctuations in a Laboratory Evolution Experiment of Escherichia Coli
Authors: Lambros Maryl , Pechuan-Jorge Ximo , Biro Daniel , Ye Kenny , Bergman Aviv
Published: October 2021

Generalists and specialists are types of strategies individuals can employ that can evolve in fluctuating environments depending on the extremity and periodicity of the fluctuation. To evaluate whether the evolution of specialists or generalists occurs under environmental fluctuation regimes with different levels of periodicity, 24 populations of Escherichia coli underwent laboratory evolution with temperatures alternating between 15 and 43°C in three fluctuation regimes: two periodic regimes dependent on culture's cell density and one random (non-periodic) regime with no such dependency, serving as a control. To investigate contingencies on the genetic background, we seeded our experiment with two different strains. After the experiment, growth rate measurements at the two temperatures showed that the evolution of specialists was favored in the random regime, while generalists were favored in the periodic regimes. Whole genome sequencing demonstrated that several gene mutations were selected in parallel in the evolving populations with some dependency on the starting genetic background. Given the genes mutated, we hypothesized that the driving force behind the observed adaptations is the restoration of the internal physiology of the starting strains' unstressed states at 37°C, which may be a means of improving fitness in the new environments. Phenotypic array measurements supported our hypothesis by demonstrating a tendency of the phenotypic response of the evolved strains to move closer to the starting strains' response at the optimum of 37°C, especially for strains classified as generalists.
Seed-Transmitted Bacteria and Fungi Dominate Juvenile Plant Microbiomes
Authors: Johnston-Monje David , Gutiérrez Janneth P. , Lopez-Lavalle Luis Augusto Becerra
Published: October 2021

Plant microbiomes play an important role in agricultural productivity, but there is still much to learn about their provenance, diversity, and organization. In order to study the role of vertical transmission in establishing the bacterial and fungal populations of juvenile plants, we used high-throughput sequencing to survey the microbiomes of seeds, spermospheres, rhizospheres, roots, and shoots of the monocot crops maize (B73), rice (Nipponbare), switchgrass (Alamo), Brachiaria decumbens, wheat, sugarcane, barley, and sorghum; the dicot crops tomato (Heinz 1706), coffee (Geisha), common bean (G19833), cassava, soybean, pea, and sunflower; and the model plants Arabidopsis thaliana (Columbia-0) and Brachypodium distachyon (Bd21). Unsterilized seeds were planted in either sterile sand or farm soil inside hermetically sealed jars, and after as much as 60 days of growth, DNA was extracted to allow for amplicon sequence-based profiling of the bacterial and fungal populations that developed. Seeds of most plants were dominated by Proteobacteria and Ascomycetes, with all containing operational taxonomic units (OTUs) belonging to Pantoea and Enterobacter. All spermospheres also contained DNA belonging to Pseudomonas, Bacillus, and Fusarium. Despite having only seeds as a source of inoculum, all plants grown on sterile sand in sealed jars nevertheless developed rhizospheres, endospheres, and phyllospheres dominated by shared Proteobacteria and diverse fungi. Compared to sterile sand-grown seedlings, growth on soil added new microbial diversity to the plant, especially to rhizospheres; however, all 63 seed-transmitted bacterial OTUs were still present, and the most abundant bacteria (Pantoea, Enterobacter, Pseudomonas, Klebsiella, and Massilia) were the same dominant seed-transmitted microbes observed in sterile sand-grown plants. While most plant mycobiome diversity was observed to come from soil, judging by read abundance, the dominant fungi (Fusarium and Alternaria) were also vertically transmitted. Seed-transmitted fungi and bacteria appear to make up the majority of juvenile crop plant microbial populations by abundance, and based on occupancy, there seems to be a pan-angiosperm seed-transmitted core bacterial microbiome. Further study of these seed-transmitted microbes will be important to understand their role in plant growth and health, as well as their fate during the plant life cycle and may lead to innovations for agricultural inoculant development.
Unique Terminal Regions and Specific Deletions of the Segmented Double-Stranded RNA Genome of Alternaria Alternata Virus 1, in the Proposed Family Alternaviridae
Authors: Wu Chien-Fu , Aoki Nanako , Takeshita Naoki , Fukuhara Toshiyuki , Chiura Hiroshi X. , Arie Tsutomu , Kotta-Loizou Ioly , Okada Ryo , Komatsu Ken , Moriyama Hiromitsu
Published: October 2021

Alternaria alternata virus 1 (AaV1) has been identified in the saprophytic fungus Alternaria alternata strain EGS 35–193. AaV1 has four genomic double-stranded (ds)RNA segments (dsRNA1–4) packaged in isometric particles. The 3' end of each coding strand is polyadenylated (36–50nt), but the presence of a cap structure at each 5' end has not previously been investigated. Here, we have characterized the AaV1 genome and found that it has unique features among the mycoviruses. We confirmed the existence of cap structures on the 5' ends of the AaV1 genomic dsRNAs using RNA dot blots with anti-cap antibodies and the oligo-capping method. Polyclonal antibodies against purified AaV1 particles specifically bound to an 82kDa protein, suggesting that this protein is the major capsid component. Subsequent Edman degradation indicated that the AaV1 dsRNA3 segment encodes the major coat protein. Two kinds of defective AaV1 dsRNA2, which is 2,794bp (844 aa) in length when intact, appeared in EGS 35–193 during subculturing, as confirmed by RT-PCR and northern hybridization. Sequence analysis revealed that one of the two defective dsRNA2s contained a 231bp deletion, while the other carried both the 231bp deletion and an additional 465bp deletion in the open reading frame. Both deletions occurred in-frame, resulting in predicted proteins of 767 aa and 612 aa. The fungal isolates carrying virions with the defective dsRNA2s showed impaired growth and abnormal pigmentation. To our best knowledge, AaV1 is the first dsRNA virus to be identified with both 5' cap and 3'poly(A) structures on its genomic segments, as well as the specific deletions of dsRNA2.
Multimodal Exercise Effects in Older Adults Depend on Sleep, Movement Biography, and Habitual Physical Activity: A Randomized Controlled Trial
Authors: Vogel Oliver , Niederer Daniel , Vogt Lutz
Published: October 2021

Background: The promotion of healthy aging is one of the major challenges for healthcare systems in current times. The present study investigates the effects of a standardized physical activity intervention for older adults on cognitive capacity, self-reported health, fear of falls, balance, leg strength and gait under consideration of movement biography, sleep duration, and current activity behavior.

Methods: This single-blinded, randomized controlled trial included 49 community-dwelling older adults (36 women; 82.9 ± 4.5 years of age (Mean [M] ± SD); intervention group = 25; control group = 24). Movement biography, sleep duration, cognitive capacity, self-reported health status, and fear of falls were assessed by means of questionnaires. Leg strength, gait, and current activity levels were captured using a pressure plate, accelerometers, and conducting the functional-reach and chair-rising-test. The multicomponent intervention took place twice a week for 45 min and lasted 16 weeks. Sub-cohorts of different sleep duration were formed to distinguish between intervention effects and benefits of healthy sleep durations. Change scores were evaluated in univariate analyses of covariances (ANCOVAs) between groups and sub-cohorts of different sleep duration in both groups. Changes in cognitive capacity, self-reported health, fear of falls, balance, leg strength, and gait were investigated using the respective baseline values, movement biography, and current activity levels as covariates. Analysis was by intention-to-treat (ITT).

Results: We found sub-cohort differences in cognitive capacity change scores [F(3,48) = 5.498, p = 0.003, ηp2 = 0.287]. Effects on fear of falls [F(1,48) = 12.961, p = 0.001, ηp2 = 0.240] and balance change scores F(1,48) = 4.521, p = 0.040, ηp2 = (0.099) were modified by the level of current activity. Effects on gait cadence were modified by the movement biography [F(1,48) = 4.545; p = 0.039, ηp2 = 0.100].

Conclusions: Unlike for functional outcomes, our multicomponent intervention in combination with adequate sleep duration appears to provide combinable beneficial effects for cognitive capacity in older adults. Trainability of gait, fear of falls, and flexibility seems to be affected by movement biography and current physical activity levels.

Trial registration: This study was registered at the DRKS (German Clinical Trials Register) on November 11, 2020 with the corresponding trial number: DRKS00020472.
Recommendations to Optimize the Use of Volumetric MRI in Huntington's Disease Clinical Trials
Authors: Kinnunen Kirsi M. , Mullin Ariana P. , Pustina Dorian , Turner Emily C. , Burton Jackson , Gordon Mark F. , Scahill Rachael I. , Gantman Emily C. , Noble Simon , Romero Klaus , Georgiou-Karistianis Nellie , Schwarz Adam J.
Published: October 2021

Volumetric magnetic resonance imaging (vMRI) has been widely studied in Huntington's disease (HD) and is commonly used to assess treatment effects on brain atrophy in interventional trials. Global and regional trajectories of brain atrophy in HD, with early involvement of striatal regions, are becoming increasingly understood. However, there remains heterogeneity in the methods used and a lack of widely-accessible multisite, longitudinal, normative datasets in HD. Consensus for standardized practices for data acquisition, analysis, sharing, and reporting will strengthen the interpretation of vMRI results and facilitate their adoption as part of a pathobiological disease staging system. The Huntington's Disease Regulatory Science Consortium (HD-RSC) currently comprises 37 member organizations and is dedicated to building a regulatory science strategy to expedite the approval of HD therapeutics. Here, we propose four recommendations to address vMRI standardization in HD research: (1) a checklist of standardized practices for the use of vMRI in clinical research and for reporting results; (2) targeted research projects to evaluate advanced vMRI methodologies in HD; (3) the definition of standard MRI-based anatomical boundaries for key brain structures in HD, plus the creation of a standard reference dataset to benchmark vMRI data analysis methods; and (4) broad access to raw images and derived data from both observational studies and interventional trials, coded to protect participant identity. In concert, these recommendations will enable a better understanding of disease progression and increase confidence in the use of vMRI for drug development.
Consilience in the Peripheral Sensory Adaptation Response
Authors: Wong Willy
Published: October 2021

Measurements of the peripheral sensory adaptation response were compared to a simple mathematical relationship involving the spontaneous, peak, and steady-state activities. This relationship is based on the geometric mean and is found to be obeyed to good approximation in peripheral sensory units showing a sustained response to prolonged stimulation. From an extensive review of past studies, the geometric mean relationship is shown to be independent of modality and is satisfied in a wide range of animal species. The consilience of evidence, from nearly 100 years of experiments beginning with the work of Edgar Adrian, suggests that this is a fundamental result of neurophysiology.
Unraveling the Interconnections Between Statistical Learning and Dyslexia: A Review of Recent Empirical Studies
Authors: Singh Sonia , Conway Christopher M.
Published: October 2021

One important aspect of human cognition involves the learning of structured information encountered in our environment, a phenomenon known as statistical learning. A growing body of research suggests that learning to read print is partially guided by learning the statistical contingencies existing between the letters within a word, and also between the letters and sounds to which the letters refer. Research also suggests that impairments to statistical learning ability may at least partially explain the difficulties experienced by individuals diagnosed with dyslexia. However, the findings regarding impaired learning are not consistent, perhaps partly due to the varied use of methodologies across studies – such as differences in the learning paradigms, stimuli used, and the way that learning is assessed – as well as differences in participant samples such as age and extent of the learning disorder. In this review, we attempt to examine the purported link between statistical learning and dyslexia by assessing a set of the most recent and relevant studies in both adults and children. Based on this review, we conclude that although there is some evidence for a statistical learning impairment in adults with dyslexia, the evidence for an impairment in children is much weaker. We discuss several suggestive trends that emerge from our examination of the research, such as issues related to task heterogeneity, possible age effects, the role of publication bias, and other suggestions for future research such as the use of neural measures and a need to better understand how statistical learning changes across typical development. We conclude that no current theoretical framework of dyslexia fully captures the extant research findings on statistical learning.
Severe and Regionally Widespread Increases in Tissue Urea in the Human Brain Represent a Novel Finding of Pathogenic Potential in Parkinson’s Disease Dementia
Authors: Scholefield Melissa , Church Stephanie J. , Xu Jingshu , Patassini Stefano , Roncaroli Federico , Hooper Nigel M. , Unwin Richard D. , Cooper Garth J. S.
Published: October 2021

Widespread elevations in brain urea have, in recent years, been reported in certain types of age-related dementia, notably Alzheimer’s disease (AD) and Huntington’s disease (HD). Urea increases in these diseases are substantive, and approximate in magnitude to levels present in uraemic encephalopathy. In AD and HD, elevated urea levels are widespread, and not only in regions heavily affected by neurodegeneration. However, measurements of brain urea have not hitherto been reported in Parkinson’s disease dementia (PDD), a condition which shares neuropathological and symptomatic overlap with both AD and HD. Here we report measurements of tissue urea from nine neuropathologically confirmed regions of the brain in PDD and post-mortem delay (PMD)-matched controls, in regions including the cerebellum, motor cortex (MCX), sensory cortex, hippocampus (HP), substantia nigra (SN), middle temporal gyrus (MTG), medulla oblongata (MED), cingulate gyrus, and pons, by applying ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Urea concentrations were found to be substantively elevated in all nine regions, with average increases of 3–4-fold. Urea concentrations were remarkably consistent across regions in both cases and controls, with no clear distinction between regions heavily affected or less severely affected by neuronal loss in PDD. These urea elevations mirror those found in uraemic encephalopathy, where equivalent levels are generally considered to be pathogenic, and those previously reported in AD and HD. Increased urea is a widespread metabolic perturbation in brain metabolism common to PDD, AD, and HD, at levels equal to those seen in uremic encephalopathy. This presents a novel pathogenic mechanism in PDD, which is shared with two other neurodegenerative diseases.
Contribution of GlyR α3 Subunits to the Sensitivity and Effect of Ethanol in the Nucleus Accumbens
Authors: San Martin Loreto S. , Armijo-Weingart Lorena , Araya Anibal , Yévenes Gonzalo E. , Harvey Robert J. , Aguayo Luis G.
Published: October 2021

The glycine receptor (GlyR), a ligand-gated ion channel, is critical for inhibitory neurotransmission in brainstem, spinal cord, and in supraspinal regions. Recent data from several laboratories have shown that GlyRs are expressed in the brain reward circuitry and that α1 and α2 are the principal subunits expressed in the nucleus accumbens (nAc). In the present study, we studied the sensitivity to ethanol of homomeric and heteromeric α3 GlyR subunits in HEK293 cells and dissociated neurons from the nAc. Finally, we explored ethanol-related behaviors in aGlra3knockout mouse (Glra3–/–). Studies in HEK293 cells showed that while homomeric α3 GlyR subunits were insensitive to ethanol, heteromeric α3β GlyR subunits showed higher sensitivity to ethanol. Additionally, using electrophysiological recordings in dissociated accumbal neurons, we found that the glycine current density increased inGlra3–/–mice and the GlyRs were less affected by ethanol and picrotoxin. We also examined the effect of ethanol on sedation and drinking behavior inGlra3–/–mice and found that the duration in the loss of righting reflex (LORR) was unchanged compared to wild-type (WT) mice. On the other hand, using the drinking in the dark (DID) paradigm, we found thatGlra3–/–mice have a larger ethanol consumption compared to WT mice, and that this was already high during the first days of exposure to ethanol. Our results support the conclusion that heteromeric α3β, but not homomeric α3, GlyRs are potentiated by ethanol. Also, the increase in GlyR and GABAAR mediated current densities in accumbal neurons in the KO mice support the presence of compensatory changes to α3 knock out. The increase in ethanol drinking in theGlra3–/–mice might be associated to the reduction in β and compensatory changes in other subunits in the receptor arrangement.
Evaluation of Directed Causality Measures and Lag Estimations in Multivariate Time-Series
Authors: Heyse Jolan , Sheybani Laurent , Vulliémoz Serge , van Mierlo Pieter
Published: October 2021

The detection of causal effects among simultaneous observations provides knowledge about the underlying network, and is a topic of interests in many scientific areas. Over the years different causality measures have been developed, each with their own advantages and disadvantages. However, an extensive evaluation study is missing. In this work we consider some of the best-known causality measures i.e., cross-correlation, (conditional) Granger causality index (CGCI), partial directed coherence (PDC), directed transfer function (DTF), and partial mutual information on mixed embedding (PMIME). To correct for noise-related spurious connections, each measure (except PMIME) is tested for statistical significance based on surrogate data. The performance of the causality metrics is evaluated on a set of simulation models with distinct characteristics, to assess how well they work in- as well as outside of their “comfort zone.” PDC and DTF perform best on systems with frequency-specific connections, while PMIME is the only one able to detect non-linear interactions. The varying performance depending on the system characteristics warrants the use of multiple measures and comparing their results to avoid errors. Furthermore, lags between coupled variables are inherent to real-world systems and could hold essential information on the network dynamics. They are however often not taken into account and we lack proper tools to estimate them. We propose three new methods for lag estimation in multivariate time series, based on autoregressive modelling and information theory. One of the autoregressive methods and the one based on information theory were able to reliably identify the correct lag value in different simulated systems. However, only the latter was able to maintain its performance in the case of non-linear interactions. As a clinical application, the same methods are also applied on an intracranial recording of an epileptic seizure. The combined knowledge from the causality measures and insights from the simulations, on how these measures perform under different circumstances and when to use which one, allow us to recreate a plausible network of the seizure propagation that supports previous observations of desynchronisation and synchronisation during seizure progression. The lag estimation results show absence of a relationship between connectivity strength and estimated lag values, which contradicts the line of thinking in connectivity shaped by the neuron doctrine.
LncRNA LGALS8-AS1 Promotes Breast Cancer Metastasis Through miR-125b-5p/SOX12 Feedback Regulatory Network
Authors: Zhai Duanyang , Li Tianfu , Ye Runyi , Bi Jiong , Kuang Xiaying , Shi Yawei , Shao Nan , Lin Ying
Published: October 2021

Background

Metastasis is a major factor weakening the long-term survival of breast cancer patients. Increasing evidence revealed that long non-coding RNAs (lncRNAs) were involved in the occurrence and development of breast cancer. In this study, we aimed to investigate the role of LGALS8-AS1 in the metastatic progression of breast cancer cells and its potential mechanisms.

Results

The lncRNA LGALS8-AS1 was highly expressed in breast cancer and associated with poor survival. LGALS8-AS1 functioned as an oncogenic lncRNA that promoted the metastasis of breast cancer both in vitro and in vivo. It upregulated SOX12 via competing as a competing endogenous RNA (ceRNA) for sponging miR-125b-5p and acted on the PI3K/AKT signaling pathway to promote the metastasis of breast cancer. Furthermore, SOX12, in turn, activated LGALS8-AS1 expression via direct recognition of its sequence binding enrichment motif on the LGALS8-AS1 promoter, thereby forming a positive feedback regulatory loop.

Conclusion

This study manifested a novel mechanism of LGALS8-AS1 facilitating the metastasis of breast cancer. The LGALS8-AS1/miR-125b-5p/SOX12 reciprocal regulatory loop dyscrasia promoted the migration and invasion of breast cancer cells. This signaling axis could be applicable to the design of novel therapeutic strategies against this malignancy.
Bio-Conjugated Quantum Dots for Cancer Research: Detection and Imaging
Authors: Liang Zhengyan , Khawar Muhammad Babar , Liang Jingyan , Sun Haibo
Published: October 2021

Ultrasound, computed tomography, magnetic resonance, and gamma scintigraphy-based detection and bio-imaging technologies have achieved outstanding breakthroughs in recent years. However, these technologies still encounter several limitations such as insufficient sensitivity, specificity and security that limit their applications in cancer detection and bio-imaging. The semiconductor quantum dots (QDs) are a kind of newly developed fluorescent nanoparticles that have superior fluorescence intensity, strong resistance to photo-bleaching, size-tunable light emission and could produce multiple fluorescent colors under single-source excitation. Furthermore, QDs have optimal surface to link with multiple targets such as antibodies, peptides, and several other small molecules. Thus, QDs might serve as potential, more sensitive and specific methods of detection than conventional methods applied in cancer molecular targeting and bio-imaging. However, many challenges such as cytotoxicity and nonspecific uptake still exist limiting their wider applications. In the present review, we aim to summarize the current applications and challenges of QDs in cancer research mainly focusing on tumor detection, bio-imaging, and provides opinions on how to address these challenges.
Natural Products: A Promising Therapeutics for Targeting Tumor Angiogenesis
Authors: Li Ruyi , Song Xin , Guo Yanan , Song Peng , Duan Dongzhu , Chen Zhe-Sheng
Published: October 2021

Tumor-associated angiogenesis is a key target for anti-cancer therapy. The imbalance between pro-angiogenic and anti-angiogenic signals elicited by tumor cells or tumor microenvironment always results in activating “angiogenic switch”. Tumor angiogenesis functions in multi-aspects of tumor biology, including endothelial cell apoptosis, tumor metastasis, and cancer stem cell proliferation. Numerous studies have indicated the important roles of inexpensive and less toxic natural products in targeting tumor angiogenesis-associated cytokines and apoptotic signaling pathways. Our current knowledge of tumor angiogenesis is based mainly on experiments performed on cells and animals, so we summarized the well-established models for angiogenesis both in vitro and in vivo. In this review, we classified and summarized the anti-angiogenic natural agents (Polyphenols, Polysaccharides, Alkaloids, Terpenoids, Saponins) in targeting various tumor types according to their chemical structures at present, and discussed the mechanistic principles of these natural products on regulating angiogenesis-associated cytokines and apoptotic signaling pathways. This review is to help understanding the recent progress of natural product research for drug development on anti-tumor angiogenesis.
Evaluation of MRI Features and Neurodevelopmental Outcomes for Prenatally Diagnosed Periventricular Pseudocysts
Authors: Sun Cong , Zhang Xinjuan , Chen Xin , Wei Xinhong , Chen Yufan , Yang Aocai , Zhu Jinxia , Wang Guangbin
Published: October 2021

Objectives: This study aimed to evaluate the morphologic features and neurodevelopmental outcomes of individuals prenatally diagnosed with a periventricular pseudocyst (PVPC).

Methods: Pregnant women with a fetus prenatally diagnosed with PVPC by MRI were enrolled in this retrospective study. The fetuses with PVPCs were divided into group 1 (isolated PVPC) and group 2 (PVPC with additional findings). The surviving infants underwent brain MRI examinations and the Gesell Developmental Scale (GDS) test after birth. Independent sample t-tests were used to compare the differences in the developmental quotient (DQ) between group 1 and group 2. We also analyzed the correlations among the DQ, location (unilateral/bilateral), size (diameter), and number (single/multiple) of the PVPCs in group 1 using Lasso regression.

Results: In total, 131 infants (group 1: 78 infants, group 2: 53 infants) underwent MRI examinations after birth, and 97 infants (group 1: 59 infants, group 2: 38 infants) underwent the GDS test. Upon follow-up, the sizes of the cysts had become smaller or disappeared after birth. The average DQ in group 2 was lower than that in group 1 (all with p < 0.001). In group 1, the location (unilateral/bilateral), size (diameter), and number (single/multiple) of the PVPC did not affect the DQ.

Conclusions: The PVPCs became smaller or disappeared after birth. Isolated PVPCs usually have a normal presentation after birth regardless of the location, number, or size. For PVPCs with additional findings, the neurodevelopmental outcomes were inferior to those in isolated PVPCs.
Case Report: An Anomalous Left Hepatic Venous Connection in a Patient With Unexpected Cyanosis
Authors: Luo Fanyan , Bu Haisong
Published: October 2021

An anomalous left hepatic venous (LHV) connection is an extremely rare cardiac malformation, and left hepatic venous route abnormalities not associated with other cardiac lesions do not require surgical treatment because they are physiologically benign. However, when venous route abnormalities exist with associated cardiac lesions, the conduct of the cardiac surgical repair must accommodate the abnormal venous anatomy, especially in total cavopulmonary connection patients. Herein, we present a rare case of a 7-year-old Chinese boy about 1 year post bilateral superior vena cava pulmonary anastomosis who presented with severe cyanosis and was referred to our department. However, the patient showed an unexpected gradual decrease in blood oxygen saturation to 60–70% after the extracardiac total cavopulmonary connection (ETCPC) operation. Emergency echocardiography and computed tomography confirmed that the LHV entered the right atrium. Subsequently, the patient undergone completion of a staged TCPC with intra-atrial tunnel technique. This illustrative report highlights the essence of improving the preoperative accurate diagnosis to avoid unplanned reoperation in China, especially for the remote rural areas of eastern countries where the level of health care and services is relatively backward. Failure to identify anomalous LHV connection, in this case, will delay effective treatment past the optimal treatment time.
Repurposing Cefazolin-Avibactam for the Treatment of Drug Resistant Mycobacterium tuberculosis
Authors: Srivastava Shashikant , Gumbo Tawanda , Thomas Tania
Published: October 2021

Background: While tuberculosis (TB) is curable and preventable, the most effective first-line antibiotics cannot kill multi-drug resistant (MDR) Mycobacterium tuberculosis (Mtb). Therefore, effective drugs are needed to combat MDR-TB, especially in children. Our objective was to repurpose cefazolin for MDR-TB treatment in children using principles of pharmacokinetic/pharmacodynamics (PK/PD).

Methods: Cefazolin minimum inhibitory concentration (MIC) was identified in 17 clinical Mtb strains, with and without combination of the β-lactamase inhibitor, avibactam. Next, dose-ranging studies were performed using the intracellular hollow fiber model of TB (HFS-TB) to identify the optimal cefazolin exposure. Monte Carlo experiments were then performed in 10,000 children for optimal dose identification based on cumulative fraction of response (CFR) and Mtb susceptibility breakpoint in three age-groups.

Results: Avibactam reduced the cefazolin MICs by five tube dilutions. Cefazolin-avibactam demonstrated maximal kill of 4.85 log10 CFU/mL in the intracellular HFS-TB over 28 days. The % time above MIC associated with maximal effect (EC80) was 46.76% (95% confidence interval: 43.04–50.49%) of dosing interval. For 100 mg/kg once or twice daily, the CFR was 8.46 and 61.39% in children <3 years with disseminated TB, 9.70 and 84.07% for 3–5 years-old children, and 17.20 and 76.13% for 12–15 years-old children. The PK/PD-derived susceptibility breakpoint was dose dependent at 1–2 mg/L.

Conclusion: Cefazolin-avibactam combination demonstrates efficacy against both drug susceptible and MDR-TB clinical strains in the HFS-TB and could potentially be used to treat children with tuberculosis. Clinical studies are warranted to validate our findings.
Polarization Label-Free Microscopy Imaging of Biological Samples by Exploiting the Zeeman Laser Emission
Authors: Callegari Fabio , Le Gratiet Aymeric , Zunino Alessandro , Mohebi Ali , Bianchini Paolo , Diaspro Alberto
Published: October 2021

Mueller Matrix Microscopy exploits the generation and the analysis of polarized light to create label-free contrast in biological images. However, when dealing with Optical Scanning Microscopy, it is required a fast generation of the polarization states in order to obtain a good Signal-to-Noise Ratio at the pixel-dwell time rate. In this work, we propose a microscopy system based on a scanning beam architecture that is exploiting the simultaneous emission of orthogonal polarization states from a Zeeman laser to provide Mueller Matrix images. This approach is based on the detection of an interference signal that allows to time-encode polarization states directly from the laser source, without the need for further active components for the management of the polarization states. We provide the theoretical model behind this approach and we apply our new method to the imaging of biological samples. Our Mueller Matrix imaging setup enables high-speed scanning microscopy, while preserving compactness and simplicity of construction. Our findings may lead to more effective dissemination of label-free techniques and their use by biological researchers.