bluuebunny/crossref_metadata_2025 huggingface dataset:
Preparation and Characterization of Cellulose Nanocrystal Extraction From Pennisetum hydridum Fertilized by Municipal Sewage Sludge via Sulfuric Acid Hydrolysis
Authors: Yu Xiaoshan , Jiang Yu , Wu Qitang , Wei Zebin , Lin Xianke , Chen Yangmei
Published: November 2021

This research focuses on the preparation of cellulose nanocrystals (CNCs) fromPennisetum hydridumfertilized by municipal sewage sludge (MSS) through sulfuric acid hydrolysis in different acid concentrations (40–65%), temperature (room temperature ∼55°C), and reaction time (50–120 min). The results showed that the obtained CNC possessed stable dispersion in water. The length of CNCs reached 272.5 nm under the condition of room temperature (RT), 65% acid concentration, and 120 min reaction time, and the diameter was within 10 nm. Furthermore, Fourier transform infrared (FTIR) showed that the CNC still kept the cellulose type I structure. The crystallinity of CNCs increased to the maximum by 18.34% compared with that of delignifiedPennisetum hydridumfibers. Thermogravimetry (TG) illustrated the thermal stability of CNCs was lower than that of delignifiedPennisetum hydridumfibers due to the introduction of sulfate groups in the cellulose. This study demonstrated thatPennisetum hydridumfertilized by MSS might be a suitable raw material for CNCs. This implies meaningful resource utilization of MSS andPennisetum hydridum.
Spatiotemporal Variability of Air Stagnation and its Relation to Summertime Ozone in the Yangtze River Delta of China
Authors: Xie Min , Zhan Chenchao , Zhan Yangzhihao , Shi Jie , Luo Yi , Zhang Ming , Liu Qian , Shen Fanhui
Published: November 2021

This paper investigates the spatiotemporal variability of air stagnation in summer as well as its relation to summer ozone (O3) over the Yangtze River Delta (YRD) region of China. Air stagnation days (ASDs) in the YRD during the summers from 2001 to 2017 range from 9 to 54 days (9.2–58.4% of the entire summer days). With the empirical orthogonal function (EOF) analysis, the dominant weather systems affecting air stagnation in the YRD are illustrated. The first three EOFs explain 68.8, 11.3, and 7.1% of the total variance of ASDs, respectively. The first EOF represents the same phase of the entire YRD, which is attributed to the East Asian summer monsoon and mainly depends on the area and the intensity of the South China Sea subtropical high. The second EOF shows significant maritime-continental contrasts, which is related to stronger near-surface winds on sea. As for the third EOF, the air stagnation in the north and the south of the YRD has the opposite phase, with a dividing line along approximately 31°N. This spatial pattern depends on the area and the intensity of the northern hemisphere polar vortex that affects the meridional circulation. O3 is the typical air pollutant in hot seasons in the YRD. It is generally at a high pollution level in summer, and has a positive trend from 2013 to 2017. Air stagnation can affect O3 pollution levels in the YRD. In ASDs, there are usually weak wind, less precipitation, low relative humidity, high temperature, strong solar radiation and high surface pressure, which are favorable to the formation of O3. More O3 pollution episodes in 2013 than 2015 can be partly attributed to more ASDs in 2013. These results show that stagnant meteorological state can lead to the hazardous air quality, and provide valuable insight into the effect of air stagnation on the changes in surface O3 during hot months.
Inflammation-Related Long Non-Coding RNA Signature Predicts the Prognosis of Gastric Carcinoma
Authors: Zhang ShuQiao , Li XinYu , Tang ChunZhi , Kuang WeiHong
Published: November 2021

Background: Gastric carcinoma (GC) is a molecularly and phenotypically highly heterogeneous disease, making the prognostic prediction challenging. On the other hand, Inflammation as part of the active cross-talk between the tumor and the host in the tumor or its microenvironment could affect prognosis.

Method: We established a prognostic multi lncRNAs signature that could better predict the prognosis of GC patients based on inflammation-related differentially expressed lncRNAs in GC.

Results: We identified 10 differently expressed lncRNAs related to inflammation associated with GC prognosis. Kaplan-Meier survival analysis demonstrated that high-risk inflammation-related lncRNAs signature was related to poor prognosis of GC. Moreover, the inflammation-related lncRNAs signature had an AUC of 0.788, proving their utility in predicting GC prognosis. Indeed, our risk signature is more precise in predicting the prognosis of GC patients than traditional clinicopathological manifestations. Immune and tumor-related pathways for individuals in the low and high-risk groups were further revealed by GSEA. Moreover, TCGA based analysis revealed significant differences in HLA, MHC class-I, cytolytic activity, parainflammation, co-stimulation of APC, type II INF response, and type I INF response between the two risk groups. Immune checkpoints revealed CD86, TNFSF18, CD200, and LAIR1 were differently expressed between lowand high-risk groups.

Conclusion: A novel inflammation-related lncRNAs (AC015660.1, LINC01094, AL512506.1, AC124067.2, AC016737.1, AL136115.1, AP000695.1, AC104695.3, LINC00449, AC090772.1) signature may provide insight into the new therapies and prognosis prediction for GC patients.
Hybrid Clustering of Single-Cell Gene Expression and Spatial Information via Integrated NMF and K-Means
Authors: Oh Sooyoun , Park Haesun , Zhang Xiuwei
Published: November 2021

Advances in single cell transcriptomics have allowed us to study the identity of single cells. This has led to the discovery of new cell types and high resolution tissue maps of them. Technologies that measure multiple modalities of such data add more detail, but they also complicate data integration. We offer an integrated analysis of the spatial location and gene expression profiles of cells to determine their identity. We propose scHybridNMF (single-cell Hybrid Nonnegative Matrix Factorization), which performs cell type identification by combining sparse nonnegative matrix factorization (sparse NMF) with k-means clustering to cluster high-dimensional gene expression and low-dimensional location data. We show that, under multiple scenarios, including the cases where there is a small number of genes profiled and the location data is noisy, scHybridNMF outperforms sparse NMF, k-means, and an existing method that uses a hidden Markov random field to encode cell location and gene expression data for cell type identification.
B Cell Recognition of Candida albicans Hyphae via TLR 2 Promotes IgG1 and IL-6 Secretion for TH17 Differentiation
Authors: Ferreira-Gomes Marta , Wich Melissa , Böde Sally , Hube Bernhard , Jacobsen Ilse D. , Jungnickel Berit
Published: November 2021

Candida albicansis usually a benign member of the human gut microbiota, but can become pathogenic under certain circumstances, for example in an immunocompromised host. The innate immune system, in particular neutrophils and macrophages, constitutes a crucial first line of defense against fungal invasion, however adaptive immunity may provide long term protection and thus allow vaccination of at risk patients. While TH1 and TH17 cells are important for antifungal responses, the role of B cells and antibodies in protection fromC. albicansinfection is less well defined. In this study, we show thatC. albicanshyphae but not yeast, as well as fungal cell wall components, directly activate B cellsviaMyD88 signaling triggered by Toll- like receptor 2, leading to increased IgG1 production. While Dectin-1 signals and specific recognition by the B cell receptor are dispensable for B cell activation in this system, TLR2/MyD88 signals cooperate with CD40 signals in promoting B cell activation. Importantly, recognition ofC. albicans viaMyD88 signaling is also essential for induction of IL-6 secretion by B cells, which promotes TH17 polarization in T-B cell coculture experiments. B cells may thus be activated directly byC. albicansin its invasive form, leading to production of antibodies and T cell help for fungal clearance.
Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study
Authors: Kim Kiwan , Gwak Ho-Shin , Han Nayoung , Hong Eun Kyung , Choi Beom K. , Lee Sangeun , Choi Soyoung , Park Ju-Hwang , Seok Ji-Hye , Jeon Yeongha , Cho Hyuntae , Lee Song-Jae , Lee Yura , Nam Ki Taek , Song Seong-Won
Published: November 2021

Background

Interleukin-13 receptor α 2 (IL13Rα2) is a promising tumor-directed antigen of malignant glioma (MG). Here, we examine the efficacy and safety of T cells containing a YYB-103 chimeric antigen receptor (CAR) that can preferentially bind to IL13Rα2 on MG cells.

Methods

IL13 was modified on the extracellular domain by substitution of amino acids with E13K, R66D, S69D, and R109K and stably transfected into human T cells using a retroviral vector. The in vitro efficacy of YYB-103 CAR T cells was tested in cell lines with differing IL13Rα1 and IL13Rα2 expression. The in vivo efficacy of intracerebroventricular (i.c.v.) and intravenous (i.v.) routes of YYB-103 CAR T-cell administration were tested in orthotopic MG mouse models. Immunohistochemical staining of MG was performed using WHO grade 3/4 surgical specimens from 53 patients. IL13Rα2 expression was quantified by H-score calculated from staining intensity and percentage of positive cells.

Results

Binding affinity assay of YYB-103 verified apparently nil binding to IL13Rα1, which was more selective than previously reported IL13 modification (E13Y). YYB-103 CAR T cells showed selective toxicity toward co-cultured U87MG (IL13Rα1+/IL13Rα2+) cells but not A431 (IL13Rα1+/IL13Rα2−) cells. Consistently, YYB-103 CAR T cells suppressed tumor growth in nude mice receiving orthotopic injection of U87 MG cells. Both i.c.v. and i.v. injections of YYB-103 CAR T cells reduced tumor volume and prolonged overall survival of tumor-bearing mice. The median H-score for IL13Rα2 in patient-derived MG tissue was 5 (mean, 57.5; SD, 87.2; range, 0 to 300).

Conclusion

This preclinical study demonstrates the efficacy of IL13Rα2-targeted YYB-103 CAR T cells against MG cells. The use of modified IL13 to construct a CAR facilitated the selective targeting of IL13Rα2-expressing MG cells while sparing IL13Rα1-expressing cells. Notably, YYB-103 CAR T cells exhibited effective blood–brain barrier crossing, suggesting compatibility with i.v. administration rather than intracranial injection. Additionally, the high H-score for IL13Rα2 in glioblastoma, especially in conjunction with the poor prognostic markers of wild-type isocitrate dehydrogenase-1 (IDH-1) and unmethylated O6-methyl guanine methyl-transferase (MGMT), could be used to determine the eligibility of patients with recurrent glioblastoma for a future clinical trial of YYB-103 CAR T cells.
Dissecting the Human Response to Staphylococcus aureus Systemic Infections
Authors: Leuzzi Rosanna , Bodini Margherita , Thomsen Isaac P. , Soldaini Elisabetta , Bartolini Erika , Muzzi Alessandro , Clemente Bruna , Galletti Bruno , Manetti Andrea Guido Oreste , Giovani Cinzia , Censini Stefano , Budroni Sonia , Spensieri Fabiana , Borgogni Erica , Rossi Paccani Silvia , Margarit Immaculada , Bagnoli Fabio , Giudice Giuseppe Del , Creech Clarence B.
Published: November 2021

Staphylococcus aureus is a common human commensal and the leading cause of diverse infections. To identify distinctive parameters associated with infection and colonization, we compared the immune and inflammatory responses of patients with a diagnosis of invasive S. aureus disease to healthy donors. We analyzed the inflammatory responses founding a pattern of distinctive cytokines significantly higher in the patients with invasive disease. The measure of antibody levels revealed a wide antibody responsiveness from all subjects to most of the antigens, with significantly higher response for some antigens in the invasive patients compared to control. Moreover, functional antibodies against toxins distinctively associated with the invasive disease. Finally, we examined the genomic variability of isolates, showing no major differences in genetic distribution compared to a panel of representative strains. Overall, our study shows specific signatures of cytokines and functional antibodies in patients with different primary invasive diseases caused by S. aureus. These data provide insight into human responses towards invasive staphylococcal infections and are important for guiding the identification of novel preventive and therapeutic interventions against S. aureus.
Multi-Antigen Outer Membrane Vesicle Engineering to Develop Polyvalent Vaccines: The Staphylococcus aureus Case
Authors: König Enrico , Gagliardi Assunta , Riedmiller Ilary , Andretta Chiara , Tomasi Michele , Irene Carmela , Frattini Luca , Zanella Ilaria , Berti Francesco , Grandi Alberto , Caproni Elena , Fantappiè Laura , Grandi Guido
Published: November 2021

Modification of surface antigens and differential expression of virulence factors are frequent strategies pathogens adopt to escape the host immune system. These escape mechanisms make pathogens a “moving target” for our immune system and represent a challenge for the development of vaccines, which require more than one antigen to be efficacious. Therefore, the availability of strategies, which simplify vaccine design, is highly desirable. Bacterial Outer Membrane Vesicles (OMVs) are a promising vaccine platform for their built-in adjuvanticity, ease of purification and flexibility to be engineered with foreign proteins. However, data on if and how OMVs can be engineered with multiple antigens is limited. In this work, we report a multi-antigen expression strategy based on the co-expression of two chimeras, each constituted by head-to-tail fusions of immunogenic proteins, in the same OMV-producing strain. We tested the strategy to develop a vaccine against Staphylococcus aureus, a Gram-positive human pathogen responsible for a large number of community and hospital-acquired diseases. Here we describe an OMV-based vaccine in which four S. aureus virulent factors, ClfAY338A, LukE, SpAKKAA and HlaH35L have been co-expressed in the same OMVs (CLSH-OMVsΔ60). The vaccine elicited antigen-specific antibodies with functional activity, as judged by their capacity to promote opsonophagocytosis and to inhibit Hla-mediated hemolysis, LukED-mediated leukocyte killing, and ClfA-mediated S. aureus binding to fibrinogen. Mice vaccinated with CLSH-OMVsΔ60 were robustly protected from S. aureus challenge in the skin, sepsis and kidney abscess models. This study not only describes a generalized approach to develop easy-to-produce and inexpensive multi-component vaccines, but also proposes a new tetravalent vaccine candidate ready to move to development.
SARS-CoV-2 and HIV-1: Should HIV-1-Infected Individuals in Sub-Saharan Africa Be Considered a Priority Group for the COVID-19 Vaccines?
Authors: Mandala Wilson Lewis , Liu Michael K. P.
Published: November 2021

Since its emergence in 2019 SARS-CoV-2 has proven to have a higher level of morbidity and mortality compared to the other prevailing coronaviruses. Although initially most African countries were spared from the devastating effect of SARS-CoV-2, at present almost every country has been affected. Although no association has been established between being HIV-1-infected and being more vulnerable to contracting COVID-19, HIV-1-infected individuals have a greater risk of developing severe COVID-19 and of COVID-19 related mortality. The rapid development of the various types of COVID-19 vaccines has gone a long way in mitigating the devastating effects of the virus and has controlled its spread. However, global vaccine deployment has been uneven particularly in Africa. The emergence of SARS-CoV-2 variants, such as Beta and Delta, which seem to show some subtle resistance to the existing vaccines, suggests COVID-19 will still be a high-risk infection for years. In this review we report on the current impact of COVID-19 on HIV-1-infected individuals from an immunological perspective and attempt to make a case for prioritising COVID-19 vaccination for those living with HIV-1 in Sub-Saharan Africa (SSA) countries like Malawi as one way of minimising the impact of COVID-19 in these countries.
Picoplankton Diel Variability and Estimated Growth Rates in Epipelagic and Mesopelagic Waters of the Central Red Sea
Authors: Al-Otaibi Najwa , García Francisca C. , Morán Xosé Anxelu G.
Published: November 2021

The diel variability of the abundance and cell size of picoplanktonic groups in the central Red Sea was monitored every 2 h in situ on 4 occasions (once per season) from 2015 to 2016. We distinguished Prochlorococcus, low (LF-Syn) and high (HF-Syn) fluorescence Synechococcus, small (Speuk) and large (Lpeuk) picoeukaryotes and two groups of heterotrophic prokaryotes of low (LNA) and high (HNA) nucleic acid content. The diel variability in abundance was less marked than in cell size and more apparent in autotrophs than heterotrophs. Specific growth rates were estimated by an empirical relationship from measurements obtained in bottle incubations of surface and deep samples collected in the winter compared with in situ variations in cell size over 24 h. Autotrophic picoplankton groups generally grew faster (0.23–0.77 d–1) than heterotrophic prokaryotes (0.12–0.50 d–1). Surface to 100 m depth-weighted specific growth rates displayed a clear seasonal pattern for Prochlorococcus, with maxima in winter (0.77 ± 0.07 d–1) and minima in fall (0.52 ± 0.07 d–1). The two groups of Synechococcus peaked in spring, with slightly higher growth rates of LF-Syn (0.57 ± 0.04 d–1) than HF-Syn (0.43 ± 0.04 d–1). Speuk and Lpeuk showed different seasonal patterns, with lower values of the former (0.27 ± 0.02 and 0.37 ± 0.04 d–1, respectively). HNA consistently outgrew LNA heterotrophic prokaryotes, with a higher growth in the epipelagic (0–200 m, 0.36 ± 0.03 d–1) than in the mesopelagic (200–700 m, 0.26 ± 0.03 d–1), while no differences were found for LNA cells (0.19 ± 0.03 d–1 and 0.17 ± 0.02 d–1, respectively). With all data pooled, the mean diel abundances of autotrophic picoplankton in the upper epipelagic and of HNA cells in the epipelagic and mesopelagic layers were significantly correlated with the specific growth rates estimated from cell size variations. Our high-resolution sampling dataset suggests that changes in growth rates underlie the noticeable seasonality of picoplankton recently described in these tropical waters.
An Efficient Track-Scale Model for Laser Powder Bed Fusion Additive Manufacturing: Part 1- Thermal Model
Authors: Tangestani Reza , Sabiston Trevor , Chakraborty Apratim , Muhammad Waqas , Yuan Lang , Martin Étienne
Published: November 2021

This is the first of two manuscripts that presents a computationally efficient full field deterministic model for laser powder bed fusion (LPBF). A new Hybrid Line (HL) heat input model integrates an exponentially decaying (ED) heat input over a portion of a laser path to significantly reduce the computational time. Experimentally measured properties of the high gamma prime nickel-based superalloy RENÉ 65 are implemented in the model to predict the in-process temperature distribution, stresses, and distortions. The model accounts for specific properties of the material as different phases. The first manuscript presents the HL heat transfer model, which is compared with the beam-scale exponentially decaying model, along with the melt pool geometry obtained experimentally by varying the laser parameters. The predicted melt pool geometry of the beam-scale ED model is shown to have good agreement with experimental measurements. While the proposed HL model exhibits lesser accuracy in predicting the melt pool geometries, it can predict the cooling rates and nodal temperatures as accurately as to the ED model. Moreover, under large time integration steps, the HL model becomes more than 1,500 times faster than the ED model.
A Systematic Review of Educational Interventions and Their Impact on Empathy and Compassion of Undergraduate Medical Students
Authors: Menezes Prianna , Guraya Salman Y. , Guraya Shaista Salman
Published: November 2021

Introduction: A compassionate and patient-centered care leads to improved clinical outcomes. Promoting empathy and compassion of medical students is a forerunner of their well-being, emotional stability, and a patient-centered care. However, there is slender evidence about best educational interventions that can inculcate empathy and compassion skills. Our objective was to conduct a systematic review of research evaluating the associations between spectrum, effectiveness, frequency of teaching modalities and their outcomes on compassion and empathy to highlight best practices.

Methods: We searched the Web of Science, PubMed, Scopus, and EBSCO Host on 22nd July 2020. We adapted our search strategy from a previously published systematic review on education for compassion and empathy. Selected studies were required to have used unique educational interventions for promoting empathy and compassion of medical students. The research questions were based on Participants (medical students), Intervention (empathy and/or compassion related teaching), Comparison, and Outcome.

Results: We analyzed 24 articles from the initial yield of 2,861. Twenty-two were quantitative studies with a mean of 12.8 on MERSQI. Twelve were randomized controlled trials while 5 measured outcomes with single group pre- and post-tests. There was no association found between duration, frequency and complexity of an educational intervention and its effectiveness. Twenty used multimodality curricula, and of those 18 reported statistically significant positive improvement in empathy, while 3 of 4 single modality were effective. Only three studies looked for long-term effects of educational interventions. Fourteen studies evaluated Kirkpatrick's level one (self-reported knowledge), 2 level three (behavior), and 6 level four (patient outcomes). We identified six major educational constructs of teaching empathy and compassion; communication, mindfulness, early clinical exposure, technology-enhanced learning, comics and arts and culture.

Discussion: Our review couldn't identify a standard teaching construct in place and highlighted that different teaching tools carry similar impact in promoting compassion and empathy and a sustainable program rather than a single training activity is essential.
Antimicrobial Peptides With Antibiofilm Activity Against Xylella fastidiosa
Authors: Moll Luís , Badosa Esther , Planas Marta , Feliu Lidia , Montesinos Emilio , Bonaterra Anna
Published: November 2021

Xylella fastidiosa is a plant pathogen that was recently introduced in Europe and is causing havoc to its agriculture. This Gram-negative bacterium invades the host xylem, multiplies, and forms biofilm occluding the vessels and killing its host. In spite of the great research effort, there is no method that effectively prevents or cures hosts from infections. The main control strategies up to now are eradication, vector control, and pathogen-free plant material. Antimicrobial peptides have arisen as promising candidates to combat this bacterium due to their broad spectrum of activity and low environmental impact. In this work, peptides previously reported in the literature and newly designed analogs were studied for its bactericidal and antibiofilm activity against X. fastidiosa. Also, their hemolytic activity and effect on tobacco leaves when infiltrated were determined. To assess the activity of peptides, the strain IVIA 5387.2 with moderate growth, able to produce biofilm and susceptible to antimicrobial peptides, was selected among six representative strains found in the Mediterranean area (DD1, CFBP 8173, Temecula, IVIA 5387.2, IVIA 5770, and IVIA 5901.2). Two interesting groups of peptides were identified with bactericidal and/or antibiofilm activity and low-moderate toxicity. The peptides 1036 and RIJK2 with dual (bactericidal–antibiofilm) activity against the pathogen and moderate toxicity stand out as the best candidates to control X. fastidiosa diseases. Nevertheless, peptides with only antibiofilm activity and low toxicity are also promising agents as they could prevent the occlusion of xylem vessels caused by the pathogen. The present work contributes to provide novel compounds with antimicrobial and antibiofilm activity that could lead to the development of new treatments against diseases caused by X. fastidiosa.
Combining Metabolomics and Interpretable Machine Learning to Reveal Plasma Metabolic Profiling and Biological Correlates of Alcohol-Dependent Inpatients: What About Tryptophan Metabolism Regulation?
Authors: Zhu Xiuqing , Huang Jiaxin , Huang Shanqing , Wen Yuguan , Lan Xiaochang , Wang Xipei , Lu Chuanli , Wang Zhanzhang , Fan Ni , Shang Dewei
Published: November 2021

Alcohol dependence (AD) is a condition of alcohol use disorder in which the drinkers frequently develop emotional symptoms associated with a continuous alcohol intake. AD characterized by metabolic disturbances can be quantitatively analyzed by metabolomics to identify the alterations in metabolic pathways. This study aimed to: i) compare the plasma metabolic profiling between healthy and AD-diagnosed individuals to reveal the altered metabolic profiles in AD, and ii) identify potential biological correlates of alcohol-dependent inpatients based on metabolomics and interpretable machine learning. Plasma samples were obtained from healthy (n = 42) and AD-diagnosed individuals (n = 43). The plasma metabolic differences between them were investigated using liquid chromatography-tandem mass spectrometry (AB SCIEX® QTRAP 4500 system) in different electrospray ionization modes with scheduled multiple reaction monitoring scans. In total, 59 and 52 compounds were semi-quantitatively measured in positive and negative ionization modes, respectively. In addition, 39 metabolites were identified as important variables to contribute to the classifications using an orthogonal partial least squares-discriminant analysis (OPLS-DA) (VIP > 1) and also significantly different between healthy and AD-diagnosed individuals using univariate analysis (p-value < 0.05 and false discovery rate < 0.05). Among the identified metabolites, indole-3-carboxylic acid, quinolinic acid, hydroxy-tryptophan, and serotonin were involved in the tryptophan metabolism along the indole, kynurenine, and serotonin pathways. Metabolic pathway analysis revealed significant changes or imbalances in alanine, aspartate, glutamate metabolism, which was possibly the main altered pathway related to AD. Tryptophan metabolism interactively influenced other metabolic pathways, such as nicotinate and nicotinamide metabolism. Furthermore, among the OPLS-DA-identified metabolites, normetanephrine and ascorbic acid were demonstrated as suitable biological correlates of AD inpatients from our model using an interpretable, supervised decision tree classifier algorithm. These findings indicate that the discriminatory metabolic profiles between healthy and AD-diagnosed individuals may benefit researchers in illustrating the underlying molecular mechanisms of AD. This study also highlights the approach of combining metabolomics and interpretable machine learning as a valuable tool to uncover potential biological correlates. Future studies should focus on the global analysis of the possible roles of these differential metabolites and disordered metabolic pathways in the pathophysiology of AD.
Characterization of Alzheimer’s Disease-Associated Excitatory Neurons via Single-Cell RNA Sequencing Analysis
Authors: Shao Fanghong , Wang Meiting , Guo Qi , Zhang Bowen , Wang Xiangting
Published: November 2021

The detailed characteristics of neuronal cell populations in Alzheimer’s disease (AD) using single-cell RNA sequencing have not been fully elucidated. To explore the characterization of neuronal cell populations in AD, this study utilized the publicly available single-nucleus RNA-sequencing datasets in the transgenic model of 5X familial Alzheimer’s disease (5XFAD) and wild-type mice to reveal an AD-associated excitatory neuron population (C3:Ex.Neuron). The relative abundance of C3:Ex.Neuron increased at 1.5 months and peaked at 4.7 months in AD mice. Functional pathways analyses showed that the pathways positively related to neurodegenerative disease progression were downregulated in the C3:Ex.Neuron at 1.5 months in AD mice. Based on the differentially expressed genes among the C3:Ex.Neuron, four subtypes (C3.1–4) were identified, which exhibited distinct abundance regulatory patterns during the development of AD. Among these subtypes, the C3.1 neurons [marked by netrin G1 (Ntng1)] exhibited a similar regulatory pattern as the C3:Ex.Neuron in abundance during the development of AD. In addition, our gene set variation analysis (GSEA) showed that the C3.1 neurons, instead of other subtypes of the C3:Ex.Neuron, possessed downregulated AD pathways at an early stage (1.5 months) of AD mice. Collectively, our results identified a previously unidentified subset of excitatory neurons and provide a potential application of these neurons to modulate the disease susceptibility.
The Effects of Acute Cardiovascular Exercise on Memory and Its Associations With Exercise-Induced Increases in Neurotrophic Factors
Authors: Kuhne Laura A. , Ksiezarczyk Anna-Maria , Braumann Klaus-Michael , Reer Rüdiger , Jacobs Thomas , Röder Brigitte , Hötting Kirsten
Published: November 2021

Due to increasing life expectancy, low-cost interventions to counteract age-related memory impairment have gained popularity. Physical activity has been shown to positively affect memory and hippocampal plasticity in rodents and humans. These effects have been proposed to be mediated by the release of neurotrophic factors. However, studies examining the effects of a single cardiovascular exercise session on human memory have yielded conflicting results. Moreover, it remains unclear whether exercise-induced memory enhancements are related to changes in peripheral neurotrophic factor concentrations. The present study tested whether one bout of cardiovascular exercise during an early phase of memory consolidation, compared to one bout of stretching and toning, positively affected memory. Furthermore, it was analyzed whether exercise-induced changes in the brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were related to memory enhancement after a single bout of physical exercise. Fifty healthy participants (20–40 years) were randomly assigned to either a cycling group (BIKE) or a stretching and toning group (STRETCH). Participants performed an implicit vocabulary learning task which was immediately followed by physical exercise. Memory for the learned vocabulary was tested 1–2 weeks later. To measure exercise-induced changes in serum neurotrophic factor levels, blood samples were collected at rest (baseline) and immediately after the exercise session. Results did not show a significant difference in memory between the BIKE group and the STRETCH group. However, in the BIKE group, a larger increase in BDNF and VEGF levels was observed than in the STRETCH group. Moreover, the increase in BDNF and memory performance tended to be positively related in the BIKE group. We speculate that the correlation between exercise-increased BDNF levels and memory in the cycling group may indicate an involvement of BDNF in mediating memory processes after acute cardiovascular exercise.
Not All That Is Gold Glitters: PV-IRES-Cre Mouse Line Shows Low Efficiency of Labeling of Parvalbumin Interneurons in the Perirhinal Cortex
Authors: Nigro Maximiliano José , Kirikae Hinako , Kjelsberg Kasper , Nair Rajeevkumar Raveendran , Witter Menno P.
Published: November 2021

The wide diversity of cortical inhibitory neuron types populating the cortex allows the assembly of diverse microcircuits and endows these circuits with different computational properties. Thus, characterizing neuronal diversity is fundamental to describe the building blocks of cortical microcircuits and probe their function. To this purpose, the mouse has emerged as a powerful tool to genetically label and manipulate specific inhibitory cell-types in the mammalian brain. Among these cell-types, the parvalbumin-expressing interneuron type (PV-INs) is perhaps the most characterized. Several mouse lines have been generated to target PV-INs. Among these mouse lines, the PV-IRES-Cre lines is the most widely used and demonstrated a high specificity and efficiency in targeting PV-INs in different cortical areas. However, a characterization of the performance across cortical regions is still missing. Here we show that the PV-IRES-Cre mouse line labels only a fraction of PV immunoreactive neurons in perirhinal cortex and other association areas. Our results point to a yet uncharacterized diversity within the PV-INs and emphasize the need to characterize these tools in specific cortical areas.
A Combined Clinical and Serum Biomarker-Based Approach May Allow Early Differentiation Between Patients With Minor Stroke and Transient Ischemic Attack as Well as Mid-term Prognostication
Authors: Pelz Johann Otto , Kubitz Katharina , Kamprad-Lachmann Manja , Harms Kristian , Federbusch Martin , Hobohm Carsten , Michalski Dominik
Published: November 2021

Background: Early differentiation between transient ischemic attack (TIA) and minor ischemic stroke (MIS) impacts on the patient's individual diagnostic work-up and treatment. Furthermore, estimations regarding persisting impairments after MIS are essential to guide rehabilitation programs. This study evaluated a combined clinical- and serum biomarker-based approach for the differentiation between TIA and MIS as well as the mid-term prognostication of the functional outcome, which is applicable within the first 24 h after symptom onset.

Methods: Prospectively collected data were used for a retrospective analysis including the neurological deficit at admission (National Institutes of Health Stroke Scale, NIHSS) and the following serum biomarkers covering different pathophysiological aspects of stroke: Coagulation (fibrinogen, antithrombin), inflammation (C reactive protein), neuronal damage in the cellular [neuron specific enolase], and the extracellular compartment [matrix metalloproteinase-9, hyaluronic acid]. Further, cerebral magnetic resonance imaging was performed at baseline and day 7, while functional outcome was evaluated with the modified Rankin Scale (mRS) after 3, 6, and 12 months.

Results: Based on data from 96 patients (age 64 ± 14 years), 23 TIA patients (NIHSS 0.6 ± 1.1) were compared with 73 MIS patients (NIHSS 2.4 ± 2.0). In a binary logistic regression analysis, the combination of NIHSS and serum biomarkers differentiated MIS from TIA with a sensitivity of 91.8% and a specificity of 60.9% [area under the curve (AUC) 0.84]. In patients with NIHSS 0 at admission, this panel resulted in a still acceptable sensitivity of 81.3% (specificity 71.4%, AUC 0.69) for the differentiation between MIS (n = 16) and TIA (n = 14). By adding age, remarkable sensitivities of 98.4, 100, and 98.2% for the prediction of an excellent outcome (mRS 0 or 1) were achieved with respect to time points investigated within the 1-year follow-up. However, the specificity was moderate and decreased over time (83.3, 70, 58.3%; AUC 0.96, 0.92, 0.91).

Conclusion: This pilot study provides evidence that the NIHSS combined with selected serum biomarkers covering pathophysiological aspects of stroke may represent a useful tool to differentiate between MIS and TIA within 24 h after symptom onset. Further, this approach may accurately predict the mid-term outcome in minor stroke patients, which might help to allocate rehabilitative resources.
Dependency in Activities of Daily Living During the First Year After Stroke
Authors: E. Wurzinger Hannah , Abzhandadze Tamar , Rafsten Lena , Sunnerhagen Katharina S.
Published: November 2021

Background: Dependency in personal activities of daily living (ADL) is a common short-term and long-term consequence of stroke and requires targeted rehabilitation. As the duration of hospital stay has become shorter in recent decades, early identification of patients who require rehabilitation has become vital. To our knowledge, no study has investigated whether ADL dependency in the very early stages after admission to the stroke unit can explain ADL dependency 3 and 12 months later. This knowledge would facilitate planning for very early discharge and patient-centered rehabilitation.

Objective: This study evaluated whether ADL dependency within 2 days after stroke could explain ADL dependency at 3 and 12 months after stroke.

Methods: This longitudinal cohort study included patients with stroke who were treated at a stroke unit in the Sahlgrenska University Hospital (Gothenburg, Sweden) between May 2011 and March 2016. The primary independent variable was ADL dependency at 36–48 h after admission to the stroke unit, which was assessed using a Barthel Index (BI) score of ≤90. The dependent variables were self-reported personal ADL dependency at 3 and 12 months after stroke. Binary logistic regression analyses were performed.

Results: Of 366 eligible patients (58% male; median age 71 years), a majority (76%) had mild stroke and 60% were ADL dependent 36–48 h after stroke. Univariable and multivariable logistic regression analyses showed that patients who were dependent within the first 2 days after stroke had higher odds for being dependent 3 months as well as 12 months after stroke.

Conclusion: The results indicated that dependency in personal ADL during the first 2 days can explain dependency at 3- and 12-month post-stroke. Therefore, early ADL assessments post-stroke can be used for understanding rehabilitation needs after stroke.
Reduced Programming Time and Strong Symptom Control Even in Chronic Course Through Imaging-Based DBS Programming
Authors: Lange Florian , Steigerwald Frank , Malzacher Tobias , Brandt Gregor Alexander , Odorfer Thorsten Michael , Roothans Jonas , Reich Martin M. , Fricke Patrick , Volkmann Jens , Matthies Cordula , Capetian Philipp D.
Published: November 2021

Objectives: Deep brain stimulation (DBS) programming is based on clinical response testing. Our clinical pilot trial assessed the feasibility of image-guided programing using software depicting the lead location in a patient-specific anatomical model.

Methods: Parkinson's disease patients with subthalamic nucleus-DBS were randomly assigned to standard clinical-based programming (CBP) or anatomical-based (imaging-guided) programming (ABP) in an 8-week crossover trial. Programming characteristics and clinical outcomes were evaluated.

Results: In 10 patients, both programs led to similar motor symptom control (MDS-UPDRS III) after 4 weeks (medicationOFF/stimulationON; CPB: 18.27 ± 9.23; ABP: 18.37 ± 6.66). Stimulation settings were not significantly different, apart from higher frequency in the baseline program than CBP (p = 0.01) or ABP (p = 0.003). Time spent in a program was not significantly different (CBP: 86.1 ± 29.82%, ABP: 88.6 ± 29.0%). Programing time was significantly shorter (p = 0.039) with ABP (19.78 ± 5.86 min) than CBP (45.22 ± 18.32).

Conclusion: Image-guided DBS programming in PD patients drastically reduces programming time without compromising symptom control and patient satisfaction in this small feasibility trial.
Chronobiology and Metabolism: Is Ketogenic Diet Able to Influence Circadian Rhythm?
Authors: Gangitano Elena , Gnessi Lucio , Lenzi Andrea , Ray David
Published: November 2021

Circadian rhythms underpin most physiological processes, including energy metabolism. The core circadian clock consists of a transcription-translation negative feedback loop, and is synchronized to light-dark cycles by virtue of light input from the retina, to the central clock in the suprachiasmatic nucleus in the hypothalamus. All cells in the body have circadian oscillators which are entrained to the central clock by neural and humoral signals. In addition to light entrainment of the central clock in the brain, it now emerges that other stimuli can drive circadian clock function in peripheral tissues, the major one being food. This can then drive the liver clock to be misaligned with the central brain clock, a situation of internal misalignment with metabolic disease consequences. Such misalignment is prevalent, with shift workers making up 20% of the working population. The effects of diet composition on the clock are not completely clarified yet. High-fat diet and fasting influence circadian expression of clock genes, inducing phase-advance and phase-delay in animal models. Ketogenic diet (KD) is able to induce a metabolic switch from carbohydrate to fatty acid oxidation, miming a fasting state. In recent years, some animal studies have been conducted to investigate the ability of the KD to modify circadian gene expression, and demonstrated that the KD alters circadian rhythm and induces a rearrangement of metabolic gene expression. These findings may lead to new approaches to obesity and metabolic pathologies treatment.
Case Report: Dual Target Deep Brain Stimulation With Externalized Programming for Post-traumatic Complex Movement Disorder
Authors: Gadot Ron , Shofty Ben , Najera Ricardo A. , Anand Adrish , Banks Garrett , Khan Abdul Basit , LoPresti Melissa A. , Vanegas Arroyave Nora , Sheth Sameer A.
Published: November 2021

Introduction: Movement disorders can be common, persistent, and debilitating sequelae of severe traumatic brain injury. Post-traumatic movement disorders are usually complex in nature, involving multiple phenomenological manifestations, and can be difficult to control with medical management alone. Deep brain stimulation (DBS) has been used to treat these challenging cases, but distorted brain anatomy secondary to trauma can complicate effective targeting. In such cases, use of diffusion tractography imaging and inpatient testing with externalized DBS leads can be beneficial in optimizing outcomes.

Case Description: We present the case of a 42-year-old man with severe, disabling post-traumatic tremor who underwent bilateral, dual target DBS to the globus pallidus internus (GPi) and a combined ventral intermediate nucleus of the thalamus (Vim)/dentato-rubro-thalamic tracts (DRTT) target. DRTT fiber tracts were reconstructed preoperatively to assist in surgical targeting given the patient’s distorted anatomy. Externalization and survey of the four leads extra-operatively with inpatient testing allowed for internalization of the leads that demonstrated benefit. Six months after surgery, the patient’s tremor and dystonic burden had decreased by 67% in the performance sub-score of The Essential Tremor Rating Scale (TETRAS).

Conclusion: A patient-tailored approach including target selection guided by individualized anatomy and tractography as well as extra-operative externalized lead interrogation was shown to be effective in optimizing clinical outcome in a patient with refractory post-traumatic tremor.
The Effects of L-Carnitine, Acetyl-L-Carnitine, and Propionyl-L-Carnitine on Body Mass in Type 2 Diabetes Mellitus Patients
Authors: Wang Dong-Dong , Wang Tian-Yun , Yang Yang , He Su-Mei , Wang You-Mei
Published: November 2021

Purpose: The study aimed to explore the effects of l-carnitine, acetyl-l-carnitine, and propionyl-l-carnitine on Body Mass in type 2 diabetes mellitus (T2DM) patients.

Methods: Randomized controlled trial (RCT) studies of l-carnitine, acetyl-l-carnitine, and propionyl-l-carnitine in T2DM patients were searched. The change rates of Body Mass index (BMI) from baseline values were used as an evaluation indicator. The maximal effect (Emax) model by non-linear mixed-effect modeling (NONMEM) was used as the evaluation method.

Results: A total of 10 RCT studies, 1239 T2DM patients were included for analysis, including eight studies of l-carnitine, one study of acetyl-l-carnitine, and one study of propionyl-l-carnitine. The study found that l-carnitine could reduce the Body Mass of T2DM patients. Based on only one study each for acetyl-l-carnitine and propionyl-l-carnitine, no significant effects were found in acetyl-l-carnitine or propionyl-l-carnitine. In addition, in order to achieve a plateau of efficacy (80% Emax), 2 g/day l-carnitine was required for at least 2 weeks.

Conclusions: Two g/day l-carnitine was required for at least 2 weeks to affect Body Mass in T2DM patients, and no significant effects were found in acetyl-l-carnitine or propionyl-l-carnitine.
Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis
Authors: Peng Ling , Lu Dafeng , Xia Yang , Hong Shaodong , Selvaggi Giovanni , Stebbing Justin , Sun Yilan , Liang Fei
Published: November 2021

Background

Targeted therapies have led to significant improvement in the management and prognosis of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). We performed a network meta-analysis of frontline treatment options of ALK-positive NSCLC to provide clinical guidance.

Methods

PubMed, Embase, ClinicalTrials.gov, and international conference databases were searched to identify relevant trials from inception to June 30, 2021. Phase III randomized controlled trials (RCTs) comparing treatments for patients with ALK-positive advanced NSCLC in the first-line setting were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcomes: progression-free survival (PFS), overall survival (OS), risk of the central nervous system (CNS) progression, adverse events (AEs) of grade (G) 3 or higher (G3 AEs), or serious AEs (SAEs). Hazard ratios (HRs) and CI for primary outcome of PFS and secondary outcome of OS and risk of CNS progression were obtained. A multivariate, consistency model, fixed-effects analysis was used in the network meta-analysis. Data on G3 AEs and SAEs were abstracted and meta-analyzed. Risk of bias (RoB) was assessed using the Cochrane Collaboration’s tool.

Results

Nine RCTs comprising 2,484 patients were included with seven treatments: alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Compared with chemotherapy, ALK-tyrosine kinase inhibitors (TKIs) significantly prolong PFS and reduced risk of CNS progression except for ceritinib. Lorlatinib appears superior at reducing risk of CNS progression. None of the ALK-TKIs have a significantly prolonged OS as compared with chemotherapy. Lorlatinib increases the risk of G3 AEs as compared with alectinib (odds ratio 4.26 [95% CrI 1.22 to 15.53]), while alectinib caused the fewest G3 AEs.

Conclusions

Lorlatinib is associated with the highest PFS benefit and lowest risk of CNS progression benefits for patients with advanced ALK-positive NSCLC, compared with other first-line treatments, but with higher toxicity. The implementation of a newer generation of ALK-TKIs in the first-line treatment of ALK-positive NSCLC into current clinical practice is evolving rapidly.