bluuebunny/crossref_metadata_2025 huggingface dataset:
ATM-TCR: TCR-Epitope Binding Affinity Prediction Using a Multi-Head Self-Attention Model
Authors: Cai Michael , Bang Seojin , Zhang Pengfei , Lee Heewook
Published: July 2022

TCR-epitope pair binding is the key component for T cell regulation. The ability to predict whether a given pair binds is fundamental to understanding the underlying biology of the binding mechanism as well as developing T-cell mediated immunotherapy approaches. The advent of large-scale public databases containing TCR-epitope binding pairs enabled the recent development of computational prediction methods for TCR-epitope binding. However, the number of epitopes reported along with binding TCRs is far too small, resulting in poor out-of-sample performance for unseen epitopes. In order to address this issue, we present our model ATM-TCR which uses a multi-head self-attention mechanism to capture biological contextual information and improve generalization performance. Additionally, we present a novel application of the attention map from our model to improve out-of-sample performance by demonstrating on recent SARS-CoV-2 data.
Single-Cell RNA Sequencing Unravels Distinct Tumor Microenvironment of Different Components of Lung Adenocarcinoma Featured as Mixed Ground-Glass Opacity
Authors: He Yu , Yu Fenglei , Tian Yi , Hu Qikang , Wang Bin , Wang Li , Hu Yan , Tao Yongguang , Chen Xiaofeng , Peng Muyun
Published: July 2022

Lung adenocarcinoma featured as mixed ground-glass opacity (mGGO) doubled its volume half of the time in comparison with that featured as pure ground-glass opacity (pGGO). The mechanisms underlying the heterogeneous appearance of mGGO remain elusive. In this study, we macro-dissected the solid (S) components and ground-glass (GG) components of mGGO and performed single-cell sequencing analyses of six paired components from three mGGO patients. A total of 19,391 single-cell profiles were taken into analysis, and the data of each patient were analyzed independently to obtain a common alteration. Cancer cells and macrophages were the dominant cell types in the S and GG components, respectively. Cancer cells in the S components, which showed relatively malignant phenotypes, were likely to originate from both the GG and S components and monitor the surrounding tumor microenvironment (TME) through an intricate cell interaction network. SPP1hi macrophages were enriched in the S components and showed increased activity of chemoattraction, while macrophages in the GG components displayed an active antimicrobial process with a higher stress-induced state. In addition, the CD47–SIRPA axis was demonstrated to be critical in the maintenance of the GG components. Taken together, our study unraveled the alterations of cell components and transcriptomic features between different components in mGGOs.
Aging Affects the Role of Myeloid-Derived Suppressor Cells in Alloimmunity
Authors: Schroeter Andreas , Roesel Maximilian J. , Matsunaga Tomohisa , Xiao Yao , Zhou Hao , Tullius Stefan G.
Published: July 2022

Myeloid-derived suppressor cells (MDSC) are defined as a group of myeloid cells with potent immunoregulatory functions that have been shown to be involved in a variety of immune-related diseases including infections, autoimmune disorders, and cancer. In organ transplantation, MDSC promote tolerance by modifying adaptive immune responses. With aging, however, substantial changes occur that affect immune functions and impact alloimmunity. Since the vast majority of transplant patients are elderly, age-specific modifications of MDSC are of relevance. Furthermore, understanding age-associated changes in MDSC may lead to improved therapeutic strategies. Here, we provide a comprehensive update on the effects of aging on MDSC and discuss potential consequences on alloimmunity.
Dramatic Efficacy of Interferon and Vemurafenib on Psychiatric Symptoms Revealing BRAFV600E-Mutated Erdheim–Chester Disease: A Case Report
Authors: Razanamahery Jérôme , Abdallahoui Maroua , Chabridon Guillaume , Fromont Agnès , Tarris Georges , Idbaih Ahmed , Comby Pierre Olivier , Godard Francois , Haroche Julien , Audia Sylvain , Bonnotte Bernard
Published: July 2022

Erdheim–Chester disease (ECD) is a rare condition with underestimated neurological involvement. Mild psychiatric symptoms such as mood swings have been rarely described in the clinical spectrum of neuro-ECD. We here describe the first patient with psychiatric manifestations of delirium revealing ECD with neurological involvement with favorable evolution under interferon followed by BRAF inhibitor monotherapy. An 81-year-old woman was referred to the hospital because of delirium and severe cognitive impairment associated with a cerebellar syndrome. Brain magnetic resonance imaging showed “FLAIR-changes” lesions in the pons and upper cerebellum peduncles. Blood and cerebrospinal fluid (CSF) analyses showed normal results except for an elevated neopterin level in the CSF. Whole-body CT scan (18FDG-PET) showed peri-nephric fat infiltration and aorta adventitia sheathing with radiotracer uptake in the pons, vessels, peri-nephric fat, and bone lesions, which was characteristic of ECD. The diagnosis was confirmed on perirenal tissue biopsy, which also showed a BRAFV600E mutation. Treatment with interferon resulted in the resolution of delirium, and treatment with BRAF inhibitor subsequently resulted in a partial remission of all active sites. This case highlights that delirium can be the first manifestation of neurodegenerative ECD. ECD should be screened in unexplained psychiatric features as interferon and targeted therapy appear to be effective in this situation.
Regulatory B Cells in Systemic Sclerosis Isolated or Concomitant With Hashimoto Thyroiditis
Authors: Capriello Silvia , Ferrari Silvia Martina , Gatto Ilenia , Santaguida Maria Giulia , Fallahi Poupak , Antonelli Alessandro , Mangino Giorgio , Romeo Giovanna , Virili Camilla , Centanni Marco
Published: July 2022

Systemic sclerosis (SSc) is a systemic autoimmune disease in which gastrointestinal disorders represent a complication in up to 90% of patients. SSc may associate with thyroid autoimmune disorders, with Hashimoto’s thyroiditis (HT) being the more prevalent worldwide. Previous studies have examined the behavior of Th17 lymphocytes and Breg cells in patients with HT and concomitant autoimmune organ-specific disorders. These immune phenotypes seem to play a significant role in the pathogenesis of both these autoimmune processes, but their behavior when these two disorders coexist has not been described. We analyzed Th17 and Breg (CD24hiCD38hi) cell subsets in 50 subjects (45F/5M; median age = 49 years): 18 were healthy donors (HD), 20 had isolated HT, and 12 had SSc, seven of whom had both HT and SSc. Breg cells’ function was also evaluated by measuring their IL-10 production when stimulated by specific activators. An increased percentage of Th17 lymphocytes characterized HT patients as compared to both HD and the whole group of SSc patients (p = 0.0018). On the contrary, the percentage of unstimulated Breg cells in SSc patients was higher (p = 0.0260), either associated or not with HT, as compared to both HT patients and HD, which, instead, showed a similar percentage of Breg cells. Following a specific stimulation with CpG, the percentages of Breg cells were increased in the whole sample of SSc patients (p < 0.001) as well as in isolated SSc and in SSc+HT ones as compared to isolated HT. However, qualitative analysis, obtained through the detection of the IL-10-producing phenotype, revealed that the percentage of CpG-stimulated CD24hiCD38hi-IL10+cells was significantly decreased in SSc patients (p < 0.0001) with no difference between isolated SSc and SSc+HT patients. The IL-10-producing phenotype was instead slightly increased in HT patients as compared to HD (4.1% vs. 2.8%). The presence of SSc seems to be characterized by an enrichment of total Breg cells but by a reduced Breg IL-10-producing phenotype, representing functional Bregs. This last finding was entirely due to the presence of SSc independently from the association with HT. This behavior is different from the ones described about the association of HT with organ-specific autoimmune disorders.
Data-Driven Prediction of Quartz Dissolution Rates at Near-Neutral and Alkaline Environments
Authors: Gong Kai , Aytas Tunahan , Zhang Shu Yang , Olivetti Elsa A.
Published: July 2022

Dissolution of silicate-based materials is important to many natural processes and engineering applications, including cement and concrete production. Here, we present a data-driven study to predict the dissolution rates of crystalline silica (i.e., quartz) in near-neutral and alkaline environments. We present a quartz dissolution database containing both dissolution rates and five major dissolution conditions (i.e., temperature, pressure, pH at the experimental temperature T (pHT), and the sodium and alumina content in the solution) via data mining from the literature. We supplement the database with experimental data of quartz dissolution rate in sodium hydroxide solutions (0–5 M) at different target temperatures (25–90°C), which are significantly less covered by the existing literature. We build two data-driven models (i.e., random forest (RF) and artificial neural network (ANN)) to predict the dissolution rate of quartz (i.e., output target) as a function of dissolution conditions (i.e., input features). The results show that both RF and ANN models exhibit high predictive capability, with R2 values of 0.97–0.98, MAPEs of 2.95–4.24% and RMSEs of ∼0.31–0.44 log (mole/m2/s) for the test set. These prediction errors are much smaller than linear regression models (RMSE of ∼1.25 log) also presented here and comparable with those achieved in previous studies using reaction models based on a smaller and less complex dataset (RMSE of ∼0.35–0.44 log). We further evaluate the interpretability and performance of the data-driven models, and the results show that the model predictions are generally consistent with literature observations, including the different impacts of input features on dissolution rate. In particular, the ANN model appears to exhibit a certain level of ability to extrapolate, i.e., making predictions in feature space not covered in the database.
Multi-Condition Temperature Field Simulation Analysis of Magnetorheological Grease Torsional Vibration Damper
Authors: Xiao Zida , Hu Hongsheng , Ouyang Qing , Shan Liyang , Su Hongbo
Published: July 2022

To reveal the transient temperature distribution pattern inside the magnetorheological grease (MRG) torsional vibration damper and explore the relationship between the current and internal temperature of the device, the transient temperature simulation analysis of the MRG device was conducted in this study. Firstly, a theoretical heat transfer model of MRG torsional vibration damper with dual heat source structural feature was established based on the Bingham constitutive model and the temperature-dependent viscosity characteristic of MRG. Then, the transient temperature field model of the MRG torsional vibration damper was developed by the finite element method, the temperature field distribution and temperature–time variation characteristics of the MRG torsional vibration damper at 0A, 1A, and 2A working conditions were analyzed, and the effects of viscosity and slip factors on the temperature rise of the device were investigated. The simulation results show that the temperature rise of MRG in the working domain is the fastest, but a gradual slowing of the temperature rise rate. The magnitude and rate of temperature rise are maximum when the 1A current is applied to the torsional vibration damper. Finally, the current–temperature curve is obtained by fitting the simulation results. The results of the analysis reveal the internal temperature distribution and temperature rise characteristics of the torsional vibration damper, which provide a theoretical basis for the structural optimization and control strategy design of the MRG torsional vibration damper considering temperature as a factor.
Design of a Wide-Angle and Polarization-Free 1-Bit Programmable Metasurface
Authors: Liu Lu , Huang Yi Fei , Zhang Hao Chi
Published: July 2022

Programmable metasurfaces have the powerful capability of controlling electromagnetic (EM) waves by coding the digital state of each meta-atom. However, conventional programmable metasurface units are difficult to maintain stable controllability under wide-angle incidence conditions, which limits the application of 1-bit programmable metasurfaces in single-beam scanning. A 1-bit dual-polarized programmable metasurface that allows oblique incidence at large angles is presented in this article. Inspired by the principle of reciprocity in the antenna theory, a wide-angle patch antenna which operates in the receiving mode and is loaded by a PIN-diode–based load circuit is designed as the basic structure of the meta-atom. Numerical simulations show that the 1-bit coding state maintains good angular stability within ±70 degrees of the incident angle for both orthogonally polarized EM waves, and single-beam scanning can be achieved at large oblique incident angles for any polarization.
Intrinsic Respiratory Gating for Simultaneous Multi-Mouse μCT Imaging to Assess Liver Tumors
Authors: Thamm Mirko , Rosenhain Stefanie , Leonardic Kevin , Höfter Andreas , Kiessling Fabian , Osl Franz , Pöschinger Thomas , Gremse Felix
Published: July 2022

Small animal micro computed tomography (μCT) is an important tool in cancer research and is used to quantify liver and lung tumors. A type of cancer that is intensively investigated with μCT is hepatocellular carcinoma (HCC). μCT scans acquire projections from different angles of the gantry which rotates X-ray source and detector around the animal. Motion of the animal causes inconsistencies between the projections which lead to artifacts in the resulting image. This is problematic in HCC research, where respiratory motion affects the image quality by causing hypodense intensity at the liver edge and smearing out small structures such as tumors. Dealing with respiratory motion is particularly difficult in a high throughput setting when multiple mice are scanned together and projection removal by retrospective respiratory gating may compromise image quality and dose efficiency. In mice, inhalation anesthesia leads to a regular respiration with short gasps and long phases of negligible motion. Using this effect and an iterative reconstruction which can cope with missing angles, we discard the relatively few projections in which the gasping motion occurs. Moreover, since gated acquisition, i.e., acquiring multiple projections from a single gantry angle is not a requirement, this method can be applied to existing scans. We applied our method in a high throughput setting in which four mice with HCC tumors were scanned simultaneously in a multi-mouse bed. To establish a ground truth, we manually selected projections with visible respiratory motion. Our automated intrinsic breathing projection selection achieved an accordance of 97% with manual selection. We reconstructed volumetric images and demonstrated that our intrinsic gating method significantly reduces the hypodense depiction at the cranial liver edge and improves the detectability of small tumors. Furthermore, we show that projection removal in a four mice scan discards only 7.5% more projections than in a single-mouse setting, i.e., four mouse scanning does not substantially compromise dose efficiency or image quality. To the best of our knowledge, no comparable method that combines multi-mouse scans for high throughput, intrinsic respiratory gating, and an available iterative reconstruction has been described for liver tumor imaging before.
The Changing Landscape of Anticoagulation in Pediatric Extracorporeal Membrane Oxygenation: Use of the Direct Thrombin Inhibitors
Authors: Neunert Cindy , Chitlur Meera , van Ommen Cornelia Heleen
Published: July 2022

Bleeding and thrombosis frequently occur in pediatric patients with extracorporeal membrane oxygenation (ECMO) therapy. Until now, most patients are anticoagulated with unfractionated heparin (UFH). However, heparin has many disadvantages, such as binding to other plasma proteins and endothelial cells in addition to antithrombin, causing an unpredictable response, challenging monitoring, development of heparin resistance, and risk of heparin-induced thrombocytopenia (HIT). Direct thrombin inhibitors (DTIs), such as bivalirudin and argatroban, might be a good alternative. This review will discuss the use of both UFH and DTIs in pediatric patients with ECMO therapy.
Impact of Air Pollution on the Ocular Surface and Tear Cytokine Levels: A Multicenter Prospective Cohort Study
Authors: Hao Ran , Zhang Mingzhou , Zhao Liming , Liu Yang , Sun Min , Dong Jing , Xu Yanhui , Wu Feng , Wei Jinwen , Xin Xiangyang , Luo Zhongping , Lv Shuxuan , Li Xuemin
Published: July 2022

Purpose

To assess air pollution-induced changes on ocular surface and tear cytokine levels.

Methods

As a prospective multicenter cohort study, 387 dry eye disease (DED) participants were recruited from five provinces in China and underwent measurements of ocular surface disease index (OSDI), Schirmer’s I test (ST), tear meniscus height (TMH), tear film break-up time (TBUT), corneal fluorescein staining (CFS), meibomian gland (MG) function, and tear cytokines. The associations between ocular surface parameters and exposure to particulate matter (PM), ozone (O3), nitrogen dioxide (NO2), and sulfur dioxide (SO2) for 1 day, 1 week, and 1 month before the examination were analyzed in single- and multi-pollutant models adjusted for confounding factors.

Results

In the multi-pollutant model, the OSDI score was positively correlated with PM with diameter ≤2.5 μm (PM2.5), O3, and SO2 exposure [PM2.5: β (1 week/month) = 0.229 (95% confidence interval (CI): 0.035–0.424)/0.211 (95% CI: 0.160–0.583); O3: β (1 day/week/month) = 0.403 (95% CI: 0.229–0.523)/0.471 (95% CI: 0.252–0.693)/0.468 (95% CI: 0.215–0.732); SO2: β (1 day/week) = 0.437 (95% CI: 0.193–0.680)/0.470 (95% CI: 0.040–0.901)]. Tear secretion was negatively correlated with O3 and NO2 exposures but positively correlated with PM2.5 levels. Air pollutants were negatively correlated with TBUT and positively related with CFS score. Besides SO2, all other pollutants were associated with aggravated MG dysfunction (MG expression, secretion, and loss) and tear cytokines increasement, such as PM2.5 and interleukin-8 (IL-8) [β (1 day) = 0.016 (95% CI: 0.003–0.029)], PM with diameter ≤10 μm (PM10) and IL-6 [β (1 day) = 0.019 (95% CI: 0.006–0.033)], NO2 and IL-6 [β (1 month) = 0.045 (95% CI: 0.018–0.072)], among others. The effects of air pollutants on DED symptoms/signs, MG functions and tear cytokines peaked within 1 week, 1 month, and 1 day, respectively.

Conclusion

Increased PM2.5, O3, and SO2 exposures caused ocular discomfort and damage with tear film instability. PM10 exposure led to tear film instability and ocular injury. PM, O3, and NO2 exposures aggravated MG dysfunction and upregulated tear cytokine levels. Therefore, each air pollutant may influence DED via different mechanisms within different time windows.
C-Terminal Extended Hexapeptides as Potent Inhibitors of the NS2B-NS3 Protease of the ZIKA Virus
Authors: Pant Suyash , Jena Nihar R.
Published: July 2022

The Zika virus (ZIKV) protease is an attractive drug target for the design of novel inhibitors to control the ZIKV infection. As the protease substrate-binding site contains acidic residues, inhibitors with basic residues can be beneficial for the inhibition of protease activities. Molecular dynamics (MD) simulation and molecular mechanics with generalized Born and surface area solvation (MM/GBSA) techniques are employed herein to design potent peptide inhibitors and to understand the nature of the basic residues that can potentially stabilize the acidic residues of the protease substrate-binding site. It is found that the inclusion of K, R, and K at P1, P2, and P3 positions, respectively, and Y at the P4 position (YKRK) would generate a highly stable tetrapeptide-protease complex with a ΔGbind of ~ −80 kcal/mol. We have also shown that the C-terminal extension of this and the second most stable tetrapeptide (YRRR) with small polar residues, such as S and T would generate even more stable hexapeptide-protease complexes. The modes of interactions of these inhibitors are discussed in detail, which are in agreement with earlier experimental studies. Thus, this study is expected to aid in the design of novel antiviral drugs against the ZIKV.
Life Within a Contaminated Niche: Comparative Genomic Analyses of an Integrative Conjugative Element ICEnahCSV86 and Two Genomic Islands From Pseudomonas bharatica CSV86T Suggest Probable Role in Colonization and Adaptation
Authors: Mohapatra Balaram , Malhotra Harshit , Phale Prashant S.
Published: July 2022

Comparative genomic and functional analyses revealed the presence of three genomic islands (GIs, >50 Kb size): ICEnahCSV86, Pseudomonas bharatica genomic island-1 (PBGI-1), and PBGI-2 in the preferentially aromatic-degrading soil bacterium, Pseudomonas bharatica CSV86T. Site-specific genomic integration at or near specific transfer RNAs (tRNAs), near-syntenic structural modules, and phylogenetic relatedness indicated their evolutionary lineage to the type-4 secretion system (T4SS) ICEclc family, thus predicting these elements to be integrative conjugative elements (ICEs). These GIs were found to be present as a single copy in the genome and the encoded phenotypic traits were found to be stable, even in the absence of selection pressure. ICEnahCSV86 harbors naphthalene catabolic (nah-sal) cluster, while PBGI-1 harbors Co-Zn-Cd (czc) efflux genes as cargo modules, whereas PBGI-2 was attributed to as a mixed-function element. The ICEnahCSV86 has been reported to be conjugatively transferred (frequency of 7 × 10–8/donor cell) to Stenotrophomonas maltophilia CSV89. Genome-wide comparative analyses of aromatic-degrading bacteria revealed nah-sal clusters from several Pseudomonas spp. as part of probable ICEs, syntenic to conjugatively transferable ICEnahCSV86 of strain CSV86T, suggesting it to be a prototypical element for naphthalene degradation. It was observed that the plasmids harboring nah-sal clusters were phylogenetically incongruent with predicted ICEs, suggesting genetic divergence of naphthalene metabolic clusters in the Pseudomonas population. Gene synteny, divergence estimates, and codon-based Z-test indicated that ICEnahCSV86 is probably derived from PBGI-2, while multiple recombination events masked the ancestral lineage of PBGI-1. Diversifying selection pressure (dN-dS = 2.27–4.31) imposed by aromatics and heavy metals implied the modular exchange-fusion of various cargo clusters through events like recombination, rearrangement, domain reshuffling, and active site optimization, thus allowing the strain to evolve, adapt, and maximize the metabolic efficiency in a contaminated niche. The promoters (Pnah and Psal) of naphthalene cargo modules (nah, sal) on ICEnahCSV86 were proved to be efficient for heterologous protein expression in Escherichia coli. GI-based genomic plasticity expands the metabolic spectrum and versatility of CSV86T, rendering efficient adaptation to the contaminated niche. Such isolate(s) are of utmost importance for their application in bioremediation and are the probable ideal host(s) for metabolic engineering.
A Dual Role of DDX3X in dsRNA-Derived Innate Immune Signaling
Authors: Kwon Juntae , Choi Hyeongjwa , Han Cecil
Published: July 2022

DEAD-Box Helicase 3 X-Linked (DDX3X) is essential for RNA metabolism and participates in various cellular processes involving RNA. DDX3X has been implicated in cancer growth and metastasis. DDX3X is involved in antiviral responses for viral RNAs and contributes to pro- or anti-microbial responses. A better understanding of how human cells regulate innate immune response against the viral “non-self” double-stranded RNAs (dsRNAs) and endogenous viral-like “self” dsRNAs is critical to understanding innate immune sensing, anti-microbial immunity, inflammation, immune cell homeostasis, and developing novel therapeutics for infectious, immune-mediated diseases, and cancer. DDX3X has known for activating the viral dsRNA-sensing pathway and innate immunity. However, accumulating research reveals a more complex role of DDX3X in regulating dsRNA-mediated signaling in cells. Here, we discuss the role of DDX3X in viral dsRNA- or endogenous dsRNA-mediated immune signaling pathways.
Activated Endolysosomal Cation Channel TRPML1 Facilitates Maturation of α-Synuclein-Containing Autophagosomes
Authors: Pollmanns Maike R. , Beer Judith , Rosignol Ines , Rodriguez-Muela Natalia , Falkenburger Björn H. , Dinter Elisabeth
Published: July 2022

Background: Protein aggregates are degraded via the autophagy-lysosome pathway and alterations in the lysosomal system leading to the accumulation of pathogenic proteins, including aggregates of α-synuclein in Parkinson’s disease (PD). The importance of the endolysosomal transient receptor potential cation channel, mucolipin subfamily 1 (TRPML1) for the lysosomal function is highlighted by the fact that TRPML1 mutations cause the lysosomal storage disease mucolipidosis type IV. In this study, we investigated the mechanism by which activation of TRPML1 affects the degradation of α-synuclein.

Methods: As a model of α-synuclein pathology, we expressed the pathogenic A53Tα-synuclein mutant in HEK293T cells. These cells were treated with the synthetic TRPML1 agonist ML-SA1. The amount of α-synuclein protein was determined by immunoblots. The abundance of aggregates and autolysosomal vesicles was determined by fluorescence microscopy and immunocytochemistry. Findings were confirmed by life-cell imaging and by application of ML-SA1 and the TRPML1 antagonist ML-SI3 to human dopaminergic neurons and human stem cell-derived neurons.

Results: ML-SA1 reduced the percentage of HEK293T cells with α-synuclein aggregates and the amount of α-synuclein protein. The effect of ML-SA1 was blocked by pharmacological and genetic inhibition of autophagy. Consistent with TRPML function, it required the membrane lipid PI(3,5)P2, and cytosolic calcium. ML-SA1 shifted the composition of autophagosomes towards a higher fraction of mature autolysosomes, also in presence of α-synuclein. In neurons, inhibition of TRPML1 by its antagonist ML-SI3 blocked autophagosomal clearance, whereas the agonist ML-SA1 shifted the composition of a-synuclein particles towards a higher fraction of acidified particles. ML-SA1 was able to override the effect of Bafilomycin A1, which blocks the fusion of the autophagosome and lysosome and its acidification.

Conclusion: These findings suggest, that activating TRPML1 with ML-SA1 facilitates clearance of α-synuclein aggregates primarily by affecting the late steps of the autophagy, i.e., by promoting autophagosome maturation. In agreement with recent work by others, our findings indicate that TRPML1 might constitute a plausible therapeutic target for PD, that warrants further validation in rodent models of α-synuclein pathology.
GPR39 Deficiency Impairs Memory and Alters Oxylipins and Inflammatory Cytokines Without Affecting Cerebral Blood Flow in a High-Fat Diet Mouse Model of Cognitive Impairment
Authors: Bah Thierno M. , Allen Elyse M. , Garcia-Jaramillo Manuel , Perez Ruby , Zarnegarnia Yalda , Davis Catherine M. , Bloom Madeline B. , Magana Armando A. , Choi Jaewoo , Bobe Gerd , Pike Martin M. , Raber Jacob , Maier Claudia S. , Alkayed Nabil J.
Published: July 2022

Vascular cognitive impairment (VCI) is the second most common cause of dementia. There is no treatment for VCI, in part due to a lack of understanding of the underlying mechanisms. The G-protein coupled receptor 39 (GPR39) is regulated by arachidonic acid (AA)-derived oxylipins that have been implicated in VCI. Furthermore, GPR39 is increased in microglia of post mortem human brains with VCI. Carriers of homozygous GPR39 SNPs have a higher burden of white matter hyperintensity, an MRI marker of VCI. We tested the hypothesis that GPR39 plays a protective role against high-fat diet (HFD)-induced cognitive impairment, in part mediated via oxylipins actions on cerebral blood flow (CBF) and neuroinflammation. Homozygous (KO) and heterozygous (Het) GPR39 knockout mice and wild-type (WT) littermates with and without HFD for 8 months were tested for cognitive performance using the novel object recognition (NOR) and the Morris water maze (MWM) tests, followed by CBF measurements using MRI. Brain tissue and plasma oxylipins were quantified with high-performance liquid chromatography coupled to mass spectrometry. Cytokines and chemokines were measured using a multiplex assay. KO mice, regardless of diet, swam further away from platform location in the MWM compared to WT and Het mice. In the NOR test, there were no effects of genotype or diet. Brain and plasma AA-derived oxylipins formed by 11- and 15-lipoxygenase (LOX), cyclooxygenase (COX) and non-enzymatically were increased by HFD and GPR39 deletion. Interleukin-10 (IL-10) was lower in KO mice on HFD than standard diet (STD), whereas IL-4, interferon γ-induced protein-10 (IP-10) and monocyte chemotactic protein-3 (MCP-3) were altered by diet in both WT and KO, but were not affected by genotype. Resting CBF was reduced in WT and KO mice on HFD, with no change in vasoreactivity. The deletion of GPR39 did not change CBF compared to WT mice on either STD or HFD. We conclude that GPR39 plays a role in spatial memory retention and protects against HFD-induced cognitive impairment in part by modulating inflammation and AA-derived oxylipins. The results indicate that GPR39 and oxylipin pathways play a role and may serve as therapeutic targets in VCI.
Galectin-3 Involvement in Cognitive Processes for New Therapeutic Considerations
Authors: Mijailović Nataša R. , Vesic Katarina , Arsenijevic Dragana , Milojević-Rakić Maja , Borovcanin Milica M.
Published: July 2022

Cognitive impairment may be a consequence of the normal aging process, but it may also be the hallmark of various neurodegenerative and psychiatric diseases. Early identification of individuals at particular risk for cognitive decline is critical, as it is imperative to maintain a cognitive reserve in these neuropsychiatric entities. In recent years, galectin-3 (Gal-3), a member of the galectin family, has received considerable attention with respect to aspects of neuroinflammation and neurodegeneration. The mechanisms behind the putative relationship between Gal-3 and cognitive impairment are not yet clear. Intrigued by this versatile molecule and its unique modular architecture, the latest data on this relationship are presented here. This mini-review summarizes recent findings on the mechanisms by which Gal-3 affects cognitive functioning in both animal and human models. Particular emphasis is placed on the role of Gal-3 in modulating the inflammatory response as a fine-tuner of microglia morphology and phenotype. A review of recent literature on the utility of Gal-3 as a biomarker is provided, and approaches to strategically exploit Gal-3 activities with therapeutic intentions in neuropsychiatric diseases are outlined.
Meta-Learning for Decoding Neural Activity Data With Noisy Labels
Authors: Xu Dongfang , Chen Rong
Published: July 2022

In neural decoding, a behavioral variable is often generated by manual annotation and the annotated labels could contain extensive label noise, leading to poor model generalizability. Tackling the label noise problem in neural decoding can improve model generalizability and robustness. We use a deep neural network based sample reweighting method to tackle this problem. The proposed method reweights training samples by using a small and clean validation dataset to guide learning. We evaluated the sample reweighting method on simulated neural activity data and calcium imaging data of anterior lateral motor cortex. For the simulated data, the proposed method can accurately predict the behavioral variable even in the scenario that 36 percent of samples in the training dataset are mislabeled. For the anterior lateral motor cortex study, the proposed method can predict trial types with F1 score of around 0.85 even 48 percent of training samples are mislabeled.
5-HT7 Receptors Regulate Excitatory-Inhibitory Balance in Mouse Spinal Cord Dorsal Horn
Authors: Comitato Antonella , Lacivita Enza , Leopoldo Marcello , Bardoni Rita
Published: July 2022

Serotonergic receptors of the 5-HT7 type (5-HT7Rs) are widely expressed in the central nervous system (CNS), where they modulate several functions, such as pain. Behavioral experiments in vivo have shown both anti- and pro-nociceptive actions of 5-HT7Rs, although an analgesic effect seems to be prevalent. In the spinal cord dorsal horn, the mechanisms involved in 5-HT7R-mediated synaptic modulation are still poorly understood, especially those regarding the control of synaptic inhibition. The present study investigated the modulation exerted by 5-HT7Rs on dorsal horn excitatory and inhibitory synaptic circuits, by performing patch-clamp recordings from lamina II neurons in mouse spinal cord slices. Our results show that applying the selective 5-HT7 agonist LP-211 facilitates glutamatergic release by enhancing the frequency of spontaneous postsynaptic currents (sEPSCs) and increasing the peak amplitude of excitatory postsynaptic currents (EPSCs) evoked by dorsal root stimulation. The effects on sEPSCs were still observed in the presence of the 5-HT1A antagonist WAY-100635, while the 5-HT7 antagonist SB-269970 blocked them. LP-211 was also able to increase the release of gamma-aminobutyric acid (GABA) and glycine, as shown by the increase of spontaneous inhibitory currents (sIPSC) frequency and evoked inhibitory postsynaptic currents (IPSC) amplitude. LP-211 was proved to be more effective in potentiating synaptic inhibition as compared to excitation: consistently, 5-HT7R activation significantly enhanced the excitability of tonic firing neurons, mainly corresponding to inhibitory interneurons. Our data bring new insights into the mechanisms of synaptic modulation mediated by 5-HT7Rs in the dorsal horn. Stronger impact on synaptic inhibition supports the hypothesis that these receptors may play an anti-nociceptive role in the spinal cord of naïve animals.
Effect of a Low-Carbohydrate Diet With or Without Exercise on Anxiety and Eating Behavior and Associated Changes in Cardiometabolic Health in Overweight Young Women
Authors: Hu Mingzhu , Shi Qingde , Sun Shengyan , Hong Hin Ieong , Zhang Haifeng , Qi Fengxue , Zou Liye , Nie Jinlei
Published: July 2022

Background

The effectiveness of low-carbohydrate diets (LCDs) on weight loss and exercise for improving cardiometabolic fitness have been well documented in the literature, but the effects of LCDs and whether adding exercise to a LCD regime could additionally benefit mental health (e. g., by lowering the level of anxiety) and associated changes in eating behavior are less clear in overweight and obese populations. Therefore, this study aimed to investigate the effects of a 4-week LCD with or without exercise on anxiety and eating behavior, and to explore the associations between changes in the psychological state and physiological parameters (i.e., body composition, aerobic fitness, blood pressure, lipid profile, and metabolic hormones).

Methods

Seventy-four overweight Chinese women [age: 20.8 ± 3.0 years, body mass index (BMI): 25.3 ± 3.3 kg·m−2] completed the 4-week randomized controlled trial, which included a LCD group (i.e., ~50 g daily carbohydrate intake) with exercise training 5 days/week (LC-EXE, n = 26), a LCD group without exercise training (LC-CON, n = 25) and a control group that did not modify their habitual diets and physical activity (CON, n = 23). Levels of anxiety, eating behavior scores and physiological parameters (i.e., body weight, V̇O2peak, blood pressure, fasting glucose, blood lipids, and serum metabolic hormones including insulin, C-peptide, leptin, and ghrelin) were measured before and after the intervention.

Results

There were significant reductions in anxiety levels in the LC-EXE compared with the LC-CON group, while no statistical changes were found in eating behaviors in any conditions after the 4-week intervention. Significant reduction in weight (~3.0 kg or 4%, p < 0.01) and decreases in insulin (~30% p < 0.01), C-peptide (~20% p < 0.01), and leptin (~40%, p < 0.01) were found in both LC-CON and LC-EXE groups, but adding exercise to a LCD regime generated no additional effects. There were significant improvements in V̇O2peak (~15% p < 0.01) and anxiety (~25% p < 0.01) in the LC-EXE compared with the LC-CON group, while no statistical differences were found between CON and LC-CON treatments. Further analysis revealed a negative association (r = −0.32, p < 0.01) between changes in levels of anxiety and changes in V̇O2peak in all participates, no other correlations were found between changes in psychological and physiological parameters.

Conclusion

Although the combination of a LCD and exercise may not induce additional reductions in body weight in overweight young females, exercise could be a useful add-on treatment along with a LCD to improve cardiometabolic health and lower anxiety levels.
Self-Confidence, Not Self-Awareness, Is Negatively Associated With Areca Nut Dependence
Authors: Hsu Chen-Yuan , Chang Pei-Chi , Yan Sheng-Lei
Published: July 2022

Areca nut is the fourth most commonly used addictive substance globally. Therefore, this study aimed to examine correlations among areca nut self-awareness, areca nut cessation self-confidence, and areca nut dependence in the Taiwanese population. This was a descriptive study in which 120 areca nut chewers who sought medical attention at a regional hospital and were residents of the Yunlin-Chiayi area, were recruited as study subjects. A structured questionnaire was used for data collection, which included demographic data, an areca nut self-awareness scale, an areca nut cessation self-confidence scale, and an areca nut dependence scale. A Pearson correlation analysis revealed that areca nut self-awareness and areca nut cessation self-confidence were not significantly correlated (r = 0.16, p = 0.069). Areca nut self-awareness and areca nut dependence also did not have a significant correlation (r = −0.06, p = 0.511). However, we found that areca nut cessation self-confidence and areca nut dependence were significantly negatively correlated (r = −0.37, p < 0.001), that is, the higher the areca nut cessation self-confidence, the lower the areca nut dependence. In addition, areca nut self-awareness showed significant correlations by age (r = 4.54, p = 0.005), occupation (r = 2.91, p = 0.02), and family support (r = 3.83, p = 0.03). Scheffe's post-hoc test revealed significant differences that subjects whose family members were extremely supportive of areca nut cessation had higher areca nut self-awareness. In conclusion, areca nut cessation self-confidence and areca nut dependence showed a significant negative correlation. Areca nut self-awareness revealed significant correlations by age, occupation, and family support. The results of this study can be used to provide a reference for implementing areca nut cessation policies in the future.
Brazilian Reference Percentiles for Bioimpedance Phase Angle of Healthy Individuals
Authors: Mattiello Rita , Mundstock Eduardo , Ziegelmann Patrícia Klarmann
Published: July 2022

Objectives

The present study was designed to estimate phase angle percentile curves for a broad age range of healthy individuals.

Methods

This is a cross-sectional study of healthy Brazilian individuals aged five to 80. InBodyS10 was used to assess phase angle. Reference curves were stratified by sex and estimated using Generalized additive models for location, scale, and shape as a continuous function of age. The phase angle determinants analyzed were physical activity, age, BMI, and SES variables.

Results

Data were analyzed from 2,146 individuals, 1,189 (55.2%) of whom were female. In both sexes, the phase angles showed a similar pattern (an increasing trend from childhood to the teenage phase, followed by stabilization during adult ages and a decrease in old adults). In female, the relationship between phase angle and age were associated with BMI and family income. In the male, the relationship between phase angle and age were associated with skin color and family income.

Conclusions

To the best of our knowledge, it is the first attempt to apply the GAMLSS technique to estimate phase angle percentiles in a healthy population covering most of the life cycle. We also showed that there are different phase angle determinants according to sex.
Flavonoid Intake From Cocoa-Based Products and Adiposity Parameters in Adolescents in Spain
Authors: Laveriano-Santos Emily P. , Arancibia-Riveros Camila , Tresserra-Rimbau Anna , Castro-Barquero Sara , Ruiz-León Ana María , Estruch Ramón , Casas Rosa , Bodega Patricia , de Miguel Mercedes , de Cos-Gandoy Amaya , Martínez-Gómez Jesús , Rodríguez Carla , Santos-Beneit Gloria , Fernández-Alvira Juan M. , Fernández-Jiménez Rodrigo , Lamuela-Raventós Rosa M.
Published: July 2022

Background

Cocoa-based products are a good source of flavonoids, which may have beneficial effects on metabolic health.

Objective

The aim of this study is to assess the relationship between flavonoids from cocoa-based products and adiposity parameters in adolescents.

Methods

A cross-sectional study was conducted involving 944 adolescents aged 11–14 years enrolled in the SI! Program for Secondary Schools trial in Spain with available baseline data from food frequency questionnaires and anthropometric measurements [weight, height, waist circumference (WC), and fat mass percentage (% FM) by bioimpedance analysis]. Fat mass index (FMI) and waist-to-height ratio (WHtR) were obtained by dividing fat mass by height and WC by height, respectively. Body mass index (BMI), WC, and FMI for age and gender z-score were calculated. Overweight/obesity was defined as BMI ≥ 85th percentile and excess adiposity as %FM or FMI ≥ 75th percentile. WC ≥ 90th percentile and WHtR with a 0.5 threshold were considered as criteria of abdominal obesity. Multilevel mixed-effect regressions were used to evaluate the association between flavonoids from cocoa-based products and adiposity parameters. Municipalities and schools were considered random effects.

Results

Participants with a higher flavonoid intake from cocoa-based products had lower WC z-score [B = −0.04, 95% CI (−0.07; −0.01), P-for trend = 0.045] and WHtR [B = −0.01, 95% CI (−0.02; −0.01), P- for trend < 0.001]. They also had lower probability of having abdominal obesity [OR 0.66, 95% CI (0.52; 0.85), P- for trend = 0.001]. Inverse associations were observed between flavonoids from cocoa powder and BMI z-score [B = −0.08, 95% CI (−0.12; −0.05), P < 0.001], WC z-score [B = −0.06, 95% CI (−0.11; −0.02), P = 0.003], WHtR [B = −0.01, 95% CI (−0.01; −0.00), P < 0.001], %FM [B = −1.11, 95% CI (−1.48; −0.75), P < 0.001], and FMI z-score [B = −0.18, 95% CI (−0.20; −0.17), P < 0.001]. Regarding dark chocolate, an inverse association only with WC z-score [B = −0.06, 95% CI (−0.08; −0.05), P < 0.001] was found. However, no association was observed between flavonoids from milk chocolate intake and anthropometric parameters.

Conclusions

A higher intake of flavonoids from cocoa-based products was associated with lower adiposity parameters and a lower probability of presenting abdominal obesity.
Dynamic Characteristics and Predictive Capability of Tumor Voxel Dose–Response Assessed Using 18F-FDG PET/CT Imaging Feedback
Authors: Chen Shupeng , Qin An , Yan Di
Published: July 2022

Purpose

Tumor voxel dose–response matrix (DRM) can be quantified using feedback from serial FDG-PET/CT imaging acquired during radiotherapy. This study investigated the dynamic characteristics and the predictive capability of DRM.

Methods

FDG-PET/CT images were acquired before and weekly during standard chemoradiotherapy with the treatment dose 2 Gy × 35 from 31 head and neck cancer patients. For each patient, deformable image registration was performed between the pretreatment/baseline PET/CT image and each weekly PET/CT image. Tumor voxel DRM was derived using linear regression on the logarithm of the weekly standard uptake value (SUV) ratios for each tumor voxel, such as SUV measured at a dose level normalized to the baseline SUV0. The dynamic characteristics were evaluated by comparing the DRMi estimated using a single feedback image acquired at the ith treatment week (i = 1, 2, 3, or 4) to the DRM estimated using the last feedback image for each patient. The predictive capability of the DRM estimated using 1 or 2 feedback images was evaluated using the receiver operating characteristic test with respect to the treatment outcome of tumor local–regional control or failure.

Results

The mean ± SD of tumor voxel SUV measured at the pretreatment and the 1st, 2nd, 3rd, 4th, and last treatment weeks was 6.76 ± 3.69, 5.72 ± 3.43, 3.85 ± 2.22, 3.27 ± 2.25, 2.5 ± 1.79, and 2.23 ± 1.27, respectively. The deviations between the DRMi estimated using the single feedback image obtained at the ith week and the last feedback image were 0.86 ± 4.87, −0.06 ± 0.3, −0.09 ± 0.17, and −0.09 ± 0.12 for DRM1, DRM2, DRM3, and DRM4, respectively. The predictive capability of DRM3 and DRM4 was significant (p < 0.001). The area under the curve (AUC) was increased with the increase in treatment dose level. The DRMs constructed using the single feedback image achieved an AUC of 0.86~1. The AUC was slightly improved to 0.94~1 for the DRMs estimated using 2 feedback images.

Conclusion

Tumor voxel metabolic activity measured using FDG-PET/CT fluctuated noticeably during the first 2 treatment weeks and obtained a stabilized reduction rate thereafter. Tumor voxel DRM constructed using a single FDG-PET/CT feedback image after the 2nd treatment week (>20 Gy) has a good predictive capability. The predictive capability improved continuously using a later feedback image and marginally improved when two feedback images were applied.