bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic Insights Into the Genetic Structure and Natural Selection of Mongolians
Authors: Yang Xiaomin , Sarengaowa  , He Guanglin , Guo Jianxin , Zhu Kongyang , Ma Hao , Zhao Jing , Yang Meiqing , Chen Jing , Zhang Xianpeng , Tao Le , Liu Yilan , Zhang Xiu-Fang , Wang Chuan-Chao
Published: December 2021

Mongolians dwell at the Eastern Eurasian Steppe, where is the agriculture and pasture interlaced area, practice pastoral subsistence strategies for generations, and have their own complex genetic formation history. There is evidence that the eastward expansion of Western Steppe herders transformed the lifestyle of post-Bronze Age Mongolia Plateau populations and brought gene flow into the gene pool of Eastern Eurasians. Here, we reported genome-wide data for 42 individuals from the Inner Mongolia Autonomous Region of North China. We observed that our studied Mongolians were structured into three distinct genetic clusters possessing different genetic affinity with previous studied Inner Mongolians and Mongols and various Eastern and Western Eurasian ancestries: two subgroups harbored dominant Eastern Eurasian ancestry from Neolithic millet farmers of Yellow River Basin; another subgroup derived Eastern Eurasian ancestry primarily from Neolithic hunter-gatherers of North Asia. Besides, three-way/four-way qpAdm admixture models revealed that both north and southern Western Eurasian ancestry related to the Western Steppe herders and Iranian farmers contributed to the genetic materials into modern Mongolians. ALDER-based admixture coefficient and haplotype-based GLOBETROTTER demonstrated that the former western ancestry detected in modern Mongolian could be recently traced back to a historic period in accordance with the historical record about the westward expansion of the Mongol empire. Furthermore, the natural selection analysis of Mongolians showed that the Major Histocompatibility Complex (MHC) region underwent significantly positive selective sweeps. The functional genes, alcohol dehydrogenase (ADH) and lactase persistence (LCT), were not identified, while the higher/lower frequencies of derived mutations were strongly correlated with the genetic affinity to East Asian/Western Eurasian populations. Our attested complex population movement and admixture in the agriculture and pasture interlaced area played an important role in the formation of modern Mongolians.
Screening for Active Compounds Targeting Human Natural Killer Cell Activation Identifying Daphnetin as an Enhancer for IFN-γ Production and Direct Cytotoxicity
Authors: Yao Baige , Yang Qinglan , Yang Yao , Li Yana , Peng Hongyan , Wu Shuting , Wang Lili , Zhang Shuju , Huang Minghui , Wang Erqiang , Xiong Peiwen , Luo Ting , Li Liping , Jia Sujie , Deng Yafei , Deng Youcai
Published: December 2021

Natural killer (NK) cells are a potent weapon against tumor and viral infection. Finding active compounds with the capacity of enhancing NK cell effector functions will be effective to develop new anti-cancer drugs. In this study, we initially screened 287 commercially available active compounds by co-culturing with peripheral blood mononuclear cells (PBMCs). We found that five compounds, namely, Daphnetin, MK-8617, LW6, JIB-04, and IOX1, increased the IFN-γ+ NK cell ratio in the presence of IL-12. Further studies using purified human primary NK cells revealed that Daphnetin directly promoted NK cell IFN-γ production in the presence of IL-12 but not IL-15, while the other four compounds acted on NK cells indirectly. Daphnetin also improved the direct cytotoxicity of NK cells against tumor cells in the presence of IL-12. Through RNA-sequencing, we found that PI3K-Akt-mTOR signaling acted as a central pathway in Daphnetin-mediated NK cell activation in the presence of IL-12. This was further confirmed by the finding that both inhibitors of PI3K-Akt and its main downstream signaling mTOR, LY294002, and rapamycin, respectively, can reverse the increase of IFN-γ production and cytotoxicity in NK cells promoted by Daphnetin. Collectively, we identify a natural product, Daphnetin, with the capacity of promoting human NK cell activation via PI3K-Akt-mTOR signaling in the presence of IL-12. Our current study opens up a new potential application for Daphnetin as a complementary immunomodulator for cancer treatments.
Antibodies to Full-Length Agrin Protein in Chinese Patients With Myasthenia Gravis
Authors: Wang Shumin , Yang Haonan , Guo Rongjing , Wang Lulu , Zhang Yingna , Lv Jie , Zhao Xue , Zhang Jing , Fang Hua , Zhang Qingyong , Zhang Yunke , Yang Junhong , Cui Xinzheng , Gao Peiyang , Chang Ting , Gao Feng
Published: December 2021

This study aimed to establish a cell-based assay (CBA) for the detection of agrin antibodies (Agrin-Ab) to explore the clinical features of agrin antibody-positive Chinese patients with myasthenia gravis (Agrin-MG). We developed a CBA based on the human full-length agrin protein expressed in HEK293T cells for the reliable and efficient detection of Agrin-Ab. Clinical data and serum samples were collected from 1948 MG patients in 26 provinces in China. The demographic and clinical features of Agrin-MG patients were compared with those of other MG patient subsets. Eighteen Agrin-MG cases were identified from 1948 MG patients. Nine patients were Agrin-Ab positive, and nine were AChR-Ab and Agrin-Ab double-positive (Agrin/AChR-MG). Eleven (61.11%) patients were males older than 40 years of age. The initial symptom in 13 (81.25%) cases was ocular weakness. Occasionally, the initial symptom was limb-girdle weakness (two cases) or bulbar muscle weakness (one case). Agrin-MG patients demonstrated slight improvement following treatment with either acetylcholinesterase inhibitor or prednisone; however, the combination of the two drugs could effectively relieve MG symptoms. In China, Agrin-MG demonstrated seropositivity rates of 0.92%. These patients were commonly middle-aged or elderly men. The patients usually presented weakness in the ocular, bulbar, and limb muscles, which may be combined with thymoma. These patients have more severe diseases, although the combination of pyridostigmine and prednisone was usually effective in relieving symptoms.
Single-Cell Transcriptome Analysis Reveals RGS1 as a New Marker and Promoting Factor for T-Cell Exhaustion in Multiple Cancers
Authors: Bai Yunmeng , Hu Meiling , Chen Zixi , Wei Jinfen , Du Hongli
Published: December 2021

T-cell exhaustion is one of the main reasons of tumor immune escape. Using single-cell transcriptome data of CD8+ T cells in multiple cancers, we identified different cell types, in which Pre_exhaust and exhausted T cells participated in negative regulation of immune system process. By analyzing the coexpression network patterns and differentially expressed genes of Pre_exhaust, exhausted, and effector T cells, we identified 35 genes related to T-cell exhaustion, whose high GSVA scores were associated with significantly poor prognosis in various cancers. In the differentially expressed genes, RGS1 showed the greatest fold change in Pre_exhaust and exhausted cells of three cancers compared with effector T cells, and high expression of RGS1 was also associated with poor prognosis in various cancers. Additionally, RGS1 protein was upregulated significantly in tumor tissues in the immunohistochemistry verification. Furthermore, RGS1 displayed positive correlation with the 35 genes, especially highly correlated with PDCD1, CTLA4, HAVCR2, and TNFRSF9 in CD8+ T cells and cancer tissues, indicating the important roles of RGS1 in CD8+ T-cell exhaustion. Considering the GTP-hydrolysis activity of RGS1 and significantly high mRNA and protein expression in cancer tissues, we speculated that RGS1 potentially mediate the T-cell retention to lead to the persistent antigen stimulation, resulting in T-cell exhaustion. In conclusion, our findings suggest that RGS1 is a new marker and promoting factor for CD8+ T-cell exhaustion and provide theoretical basis for research and immunotherapy of exhausted cells.
The Role of E3 Ubiquitin Ligases and Deubiquitinases in Inflammatory Bowel Disease: Friend or Foe?
Authors: Zou Min , Zeng Qi-Shan , Nie Jiao , Yang Jia-Hui , Luo Zhen-Yi , Gan Hua-Tian
Published: December 2021

Inflammatory bowel disease (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), exhibits a complex multifactorial pathogenesis involving genetic susceptibility, imbalance of gut microbiota, mucosal immune disorder and environmental factors. Recent studies reported associations between ubiquitination and deubiquitination and the occurrence and development of inflammatory bowel disease. Ubiquitination modification, one of the most important types of post-translational modifications, is a multi-step enzymatic process involved in the regulation of various physiological processes of cells, including cell cycle progression, cell differentiation, apoptosis, and innate and adaptive immune responses. Alterations in ubiquitination and deubiquitination can lead to various diseases, including IBD. Here, we review the role of E3 ubiquitin ligases and deubiquitinases (DUBs) and their mediated ubiquitination and deubiquitination modifications in the pathogenesis of IBD. We highlight the importance of this type of posttranslational modification in the development of inflammation, and provide guidance for the future development of targeted therapeutics in IBD.
Immune Modulatory Properties of Collagen in Cancer
Authors: Rømer Anne Mette Askehøj , Thorseth Marie-Louise , Madsen Daniel Hargbøl
Published: December 2021

During tumor growth the extracellular matrix (ECM) undergoes dramatic remodeling. The normal ECM is degraded and substituted with a tumor-specific ECM, which is often of higher collagen density and increased stiffness. The structure and collagen density of the tumor-specific ECM has been associated with poor prognosis in several types of cancer. However, the reason for this association is still largely unknown. Collagen can promote cancer cell growth and migration, but recent studies have shown that collagens can also affect the function and phenotype of various types of tumor-infiltrating immune cells such as tumor-associated macrophages (TAMs) and T cells. This suggests that tumor-associated collagen could have important immune modulatory functions within the tumor microenvironment, affecting cancer progression as well as the efficacy of cancer immunotherapy. The effects of tumor-associated collagen on immune cells could help explain why a high collagen density in tumors is often correlated with a poor prognosis. Knowledge about immune modulatory functions of collagen could potentially identify targets for improving current cancer therapies or for development of new treatments. In this review, the current knowledge about the ability of collagen to influence T cell activity will be summarized. This includes direct interactions with T cells as well as induction of immune suppressive activity in other immune cells such as macrophages. Additionally, the potential effects of collagen on the efficacy of cancer immunotherapy will be discussed.
Metabolic Adaptations During Staphylococcus aureus and Candida albicans Co-Infection
Authors: Eichelberger Kara R. , Cassat James E.
Published: December 2021

Successful pathogens require metabolic flexibility to adapt to diverse host niches. The presence of co-infecting or commensal microorganisms at a given infection site can further influence the metabolic processes required for a pathogen to cause disease. The Gram-positive bacterium Staphylococcus aureus and the polymorphic fungus Candida albicans are microorganisms that asymptomatically colonize healthy individuals but can also cause superficial infections or severe invasive disease. Due to many shared host niches, S. aureus and C. albicans are frequently co-isolated from mixed fungal-bacterial infections. S. aureus and C. albicans co-infection alters microbial metabolism relative to infection with either organism alone. Metabolic changes during co-infection regulate virulence, such as enhancing toxin production in S. aureus or contributing to morphogenesis and cell wall remodeling in C. albicans. C. albicans and S. aureus also form polymicrobial biofilms, which have greater biomass and reduced susceptibility to antimicrobials relative to mono-microbial biofilms. The S. aureus and C. albicans metabolic programs induced during co-infection impact interactions with host immune cells, resulting in greater microbial survival and immune evasion. Conversely, innate immune cell sensing of S. aureus and C. albicans triggers metabolic changes in the host cells that result in an altered immune response to secondary infections. In this review article, we discuss the metabolic programs that govern host-pathogen interactions during S. aureus and C. albicans co-infection. Understanding C. albicans-S. aureus interactions may highlight more general principles of how polymicrobial interactions, particularly fungal-bacterial interactions, shape the outcome of infectious disease. We focus on how co-infection alters microbial metabolism to enhance virulence and how infection-induced changes to host cell metabolism can impact a secondary infection.
Effect of Extreme Heatwaves on the Mortality and Cellular Immune Responses of Purplish Bifurcate Mussel Mytilisepta virgata (Wiegmann, 1837) (=Septifer virgatus) in Indoor Mesocosm Experiments
Authors: Hong Hyun-Ki , Kim Chang Wan , Kim Jeong-Hwa , Kajino Nobuhisa , Choi Kwang-Sik
Published: December 2021

In the rocky intertidal environment, the frequency and duration of heatwaves have increased over the last decade, possibly due to global climate change. Heatwaves often result in lethal or sub-lethal disturbances in benthic animals by changing their metabolic activities. In this study, we investigated the impacts of extreme heatwave stress on the hemocyte functions of Mytilisepta virgata and subsequent mortality to gain a better understanding of the potential causes and consequences of mass mortality events in this mussel during summer. We discriminated three types of hemocytes in the hemolymph, granulocytes, hyalinocytes, and blast-like cells, using flow cytometry and revealed that granulocytes were the major hemocyte involved in cellular defensive activities, such as phagocytosis and reactive oxygen species (ROS) production. For the experiment, mussels were exposed to a 40°C air temperature for 12 h per day over 5 days under laboratory conditions as a simulated semi-diurnal tidal cycle. Mortality began to occur within 3 days after beginning the experiment, and all mussels had died by the end of the experiment. Flow cytometry indicated that the mussels exposed to high air temperatures produced significantly more ROS than did the control mussels within 2 days after the onset of the experiment, which may have caused oxidative stress. Such high levels of ROS in the hemolymph increased DNA damage in hemocytes after 3 days of exposure and decreased the phagocytosis of hemocytes 4 days after the experiment began. The observed mortality and decline in immune capacity suggested that an extreme heat event occurring in the rocky intertidal ecosystem during summer could exert sublethal to lethal impacts on macrobenthic animals.
Combination of Early Allograft Dysfunction and Protein Expression Patterns Predicts Outcome of Liver Transplantation From Donation After Cardiac Death
Authors: Wei Qiang , Zhou Junbin , Wang Kun , Zhang Xuanyu , Chen Junli , Lu Di , Wei Xuyong , Zheng Shusen , Xu Xiao
Published: December 2021

Early allograft dysfunction (EAD) after liver transplantation (LT) accompanies poor prognosis. This study aims to explore the relationship between pretransplant intrahepatic proteins and the incidence of EAD, and the value of combined EAD and protein profiles for predicting recipient and graft survival prognosis. Liver biopsy specimens of 105 pretransplant grafts used for LT were collected and used for immunohistochemistry analysis of 5 proteins. And matched clinical data of donor, recipient, transplantation, and prognosis were analyzed. The incidence of EAD was 41.9% (44/105) in this cohort. Macrovesicular steatosis (P = 0.016), donor body mass index (P = 0.013), recipients' pretransplant serum creatinine (P = 0.036), and intrahepatic expression of heme oxygenase 1 (HO1) (P = 0.015) and tumor necrosis factor α (TNF-α) (P = 0.039) were independent predictors of EAD. Inferior graft and recipient prognosis were observed in patients who experienced EAD (P = 0.028 and 0.031) or received grafts with higher expression of sirtuin 1 (P = 0.005 and 0.013). The graft and recipient survival were worst in patients with both EAD and high expression of sirtuin 1 (P = 0.001 and 0.004). In conclusion, pretransplant intrahepatic expression of HO1 and TNF-α are associated with the incidence of EAD. The combination of EAD and EAD-unrelated proteins showed superiority in distinguishing recipients with worse prognosis.
Multistage Classification of Current Density Distribution Maps of Various Heart States Based on Correlation Analysis and k-NN Algorithm
Authors: Udovychenko Yevhenii , Popov Anton , Chaikovsky Illya
Published: December 2021

Magnetocardiography is a modern method of registration of the magnetic component of electromagnetic field, generated by heart activity. Magnetocardiography results are a useful source for the diagnosis of various heart diseases and states, but their usage is still undervalued in the cardiology community. In this study, a two-stage classification by correlation analysis using a k-Nearest Neighbor (k-NN) algorithm is applied for the binary classification of myocardium current density distribution maps (CDDMs). Fourteen groups of CDDMs from patients with different heart states, healthy volunteers, sportsmen, patients with negative T-peak, patients with myocardial damage, male and female patients with microvascular disease, patients with ischemic heart disease, and patients with left ventricular hypertrophy, divided into five and three different groups depending on the degree of pathology, were compared. Selection of best metric, used in classifier and number of neighbors, was performed to define the classifier with best performance for each pair of heart states. Accuracy, specificity, sensitivity, and precision values dependent on the number of neighbors are obtained for each class. The proposed method allows to obtain a value of average accuracy equal to 96%, 70% sensitivity, 98% specificity, and 70% precision.
Distinguishing Relapse From Reinfection With Whole-Genome Sequencing in Recurrent Pulmonary Tuberculosis: A Retrospective Cohort Study in Beijing, China
Authors: Du Jian , Li Qing , Liu Min , Wang Yufeng , Xue Zhongtan , Huo Fengmin , Zhang Xuxia , Shang Yuanyuan , Li Shanshan , Huang Hairong , Pang Yu
Published: December 2021

Background: Tuberculosis recurrence is still a major problem for the control of tuberculosis, and the cause of the recurrence is still unclear.

Methods: We retrospectively recruited 68 pairs of samples of Mycobacterium tuberculosis (MTB) from recurrent TB cases in Beijing Chest Hospital between January 2008 and December 2019. The whole-genome sequencing was conducted to analyze single-nucleotide polymorphism (SNP) and to identify whether recurrent disease was due to relapse or reinfection. The BACTEC MGIT was performed to compare differences in drug susceptibility profiles between two episodes.

Results: 62 (91.2%) out of 68 confirmed recurrence were due to relapse, whereas the remaining six (8.8%) were due to reinfection. And there was a strong association between earlier relapse and underlying chronic diseases. In addition, the MTB isolates from non-diabetic patients had a higher mutation rate than those from diabetic patients. A community transmission was also identified in our cohort. Levofloxacin resistance was the most frequently observed drug resistance for 12.9% relapse cases.

Conclusion: The relapse of a previous episode in Beijing. The underlying chronic diseases are associated with an earlier TB relapse. MTB isolates were more prone to develop levofloxacin resistance than moxifloxacin resistance after FQ exposure. The patients at high-risk for relapses deserve more careful investigation.
Ontology-Enriched Specifications Enabling Findable, Accessible, Interoperable, and Reusable Marine Metagenomic Datasets in Cyberinfrastructure Systems
Authors: Blumberg Kai L. , Ponsero Alise J. , Bomhoff Matthew , Wood-Charlson Elisha M. , DeLong Edward F. , Hurwitz Bonnie L.
Published: December 2021

Marine microbial ecology requires the systematic comparison of biogeochemical and sequence data to analyze environmental influences on the distribution and variability of microbial communities. With ever-increasing quantities of metagenomic data, there is a growing need to make datasets Findable, Accessible, Interoperable, and Reusable (FAIR) across diverse ecosystems. FAIR data is essential to developing analytical frameworks that integrate microbiological, genomic, ecological, oceanographic, and computational methods. Although community standards defining the minimal metadata required to accompany sequence data exist, they haven’t been consistently used across projects, precluding interoperability. Moreover, these data are not machine-actionable or discoverable by cyberinfrastructure systems. By making ‘omic and physicochemical datasets FAIR to machine systems, we can enable sequence data discovery and reuse based on machine-readable descriptions of environments or physicochemical gradients. In this work, we developed a novel technical specification for dataset encapsulation for the FAIR reuse of marine metagenomic and physicochemical datasets within cyberinfrastructure systems. This includes using Frictionless Data Packages enriched with terminology from environmental and life-science ontologies to annotate measured variables, their units, and the measurement devices used. This approach was implemented in Planet Microbe, a cyberinfrastructure platform and marine metagenomic web-portal. Here, we discuss the data properties built into the specification to make global ocean datasets FAIR within the Planet Microbe portal. We additionally discuss the selection of, and contributions to marine-science ontologies used within the specification. Finally, we use the system to discover data by which to answer various biological questions about environments, physicochemical gradients, and microbial communities in meta-analyses. This work represents a future direction in marine metagenomic research by proposing a specification for FAIR dataset encapsulation that, if adopted within cyberinfrastructure systems, would automate the discovery, exchange, and re-use of data needed to answer broader reaching questions than originally intended.
Effects of Clostridium butyricum on Growth Performance, Gut Microbiota and Intestinal Barrier Function of Broilers
Authors: Li Wenjia , Xu Bin , Wang Linyi , Sun Quanyou , Deng Wen , Wei Fengxian , Ma Huihui , Fu Chen , Wang Gaili , Li Shaoyu
Published: December 2021

This study was conducted to evaluate the effects of Clostridium butyricum dietary supplementation on the growth, antioxidant, immune response, gut microbiota, and intestinal barrier function of broilers under high stocking density (HSD) stress. A total of 324 1-day-old Arbor Acres male broilers were randomly assigned to three treatments with six replicates, each replicate including 18 chickens (18 birds/m2). The experiment lasted 6 weeks. The three treatments were basal diet (control, CON), basal diet supplemented with 1 × 109 colony forming units (cfu)/kg C. butyricum (CB), and basal diet supplemented with 10 mg/kg virginiamycin (antibiotic, ANT). The results showed that the body weight (BW) and average daily gain (ADG) of broilers in the CB group were significantly higher than those in the CON group in three periods (p < 0.05). The total antioxidant capacity (T-AOC) and the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity in serum of the CB group were significantly increased compared with those in the CON and ANT groups at 42 days (p < 0.05). At 42 days, the serum immunoglobulin M (IgM) and immunoglobulin G (IgG) levels of the CB group were significantly higher than those of the CON group. Compared with the CON group, interleukin-1β (IL-1β) in the CB group was significantly decreased in the starter and grower stages (p < 0.05), but there was no significant difference between the two treatment groups (p > 0.05). C. butyricum significantly decreased the high stocking density-induced expression levels of IL-1β and tumor necrosis factor-α (TNF-α) in the ileum of broilers at different stages. Additionally, C. butyricum could increase the expressions of claudin-1 and zonula occludens-1 (ZO-1) in intestinal tissue. Moreover, C. butyricum significantly increased the Sobs and Shannon indices in the CB group compared with the ANT group (p < 0.05), while the Ace index in the CB group was significantly higher than that of the CON group (p < 0.05). Furthermore, by using 16S rRNA gene sequencing, the proportion of Bacteroides in the CB group was increased compared to those in the CON and ANT groups at the genus level. In conclusion, C. butyricum supplemented into feed could improve the growth performance and feed utilization of broilers by promoting immune and intestinal barrier function and benefiting the cecal microflora.
Bacillus anthracis Phylogeography: New Clues From Kazakhstan, Central Asia
Authors: Shevtsov Alexandr , Lukhnova Larissa , Izbanova Uinkul , Vernadet Jean-Philippe , Kuibagarov Marat , Amirgazin Asylulan , Ramankulov Yerlan , Vergnaud Gilles
Published: December 2021

This article describes Bacillus anthracis strains isolated in Kazakhstan since the 1950s until year 2016 from sixty-one independent events associated with anthrax in humans and animals. One hundred and fifty-four strains were first genotyped by Multiple Locus VNTR (variable number of tandem repeats) Analysis (MLVA) using 31 VNTR loci. Thirty-five MLVA31 genotypes were resolved, 28 belong to the A1/TEA group, five to A3/Sterne-Ames group, one to A4/Vollum and one to the B clade. This is the first report of the presence of the B-clade in Kazakhstan. The MLVA31 results and epidemiological data were combined to select a subset of seventy-nine representative strains for draft whole genome sequencing (WGS). Strains from Kazakhstan significantly enrich the known phylogeny of the Ames group polytomy, including the description of a new branch closest to the Texas, United States A.Br.Ames sublineage stricto sensu. Three among the seven currently defined branches in the TEA polytomy are present in Kazakhstan, “Tsiankovskii”, “Heroin”, and “Sanitary Technical Institute (STI)”. In particular, strains from the STI lineage are largely predominant in Kazakhstan and introduce numerous deep branching STI sublineages, demonstrating a high geographic correspondence between “STI” and Kazakhstan, Central Asia. This observation is a strong indication that the TEA polytomy emerged after the last political unification of Asian steppes in the fourteenth century of the Common Era. The phylogenetic analysis of the Kazakhstan data and of currently available WGS data of worldwide origin strengthens our understanding of B. anthracis geographic expansions in the past seven centuries.
Functionally Assessing the Age-Related Decline in the Detection Rate of Photons by Cone Photoreceptors
Authors: Braham chaouche Asma , Rezaei Maryam , Silvestre Daphné , Arleo Angelo , Allard Rémy
Published: December 2021

Age-related decline in visual perception is usually attributed to optical factors of the eye and neural factors. However, the detection of light by cones converting light into neural signals is a crucial intermediate processing step of vision. Interestingly, a novel functional approach can evaluate many aspects of the visual system including the detection of photons by cones. This approach was used to investigate the underlying cause of age-related visual decline and found that the detection rate of cones was considerably affected with healthy aging. This functional test enabling to evaluate the detection of photons by cones could be particularly useful to screen for retinal pathologies affecting cones such as age-related macular degeneration. However, the paradigm used to functionally measure the detection of photons was complex as it was evaluating many other properties of the visual system. The aim of the current mini review is to clarify the underlying rationale of functionally evaluating the detection of photons by cones, describe a simpler approach to evaluate it, and review the impact of aging on the detection rate of cones.
Psychographic Segmentation: Another Lever for Precision Population Brain Health
Authors: Smith Erin , Ibanez Agustin , Lavretsky Helen , Berk Michael , Eyre Harris A.
Published: December 2021

Dementia prevention interventions that address modifiable risk factors for dementia require extensive lifestyle and behavior changes. Strategies are needed to enhance engagement and personalization of the experience at a population level. Precision Population Brain Health aims to improve brain health across the lifespan at a population level. Psychographic segmentation is a core component of Precision Population Brain Health with untapped potential. Psychographic segmentation applies behavioral and social sciences to understanding people’s motivations, values, priorities, decision making, lifestyles, personalities, communication preferences, attitudes, and beliefs. Integrating psychographic segmentation into dementia care could provide a more personalized care experience and increased patient engagement, leading to improved health outcomes and reduced costs. Psychographic segmentation can enhance patient engagement for dementia and shift the clinical paradigm from “What is the matter?” to “What matters to you?” Similar benefits of psychographic segmentation can be provided for dementia caregivers. Developing dementia prevention programs that integrate psychographic segmentation could become the basis for creating a shared framework for prevention of non-communicable diseases and brain health disorders at a population level. Integrating psychographic segmentation into digital health tools for dementia prevention programs is especially critical to overcome current suboptimal approaches. Applying psychographic segmentation to dementia prevention has the potential to help people feel a sense of empowerment over their health and improve satisfaction with their health experience—creating a culture shift in the way brain health is approached and paving the way toward Precision Population Brain Health.
The Locus Coeruleus Noradrenaline System in Delirium
Authors: Hansen Niels , Rediske Alina Isabel
Published: December 2021

Delirium is a brain state involving severe brain dysfunction affecting cognitive and attentional capacities. Our opinion statement review aims to elucidate the relationship between abnormal arousal and locus coeruleus (LC) activity in cognitive dysfunction and inattention in delirium states. We propose (1) that enhanced noradrenaline release caused by altered arousal in hyperactive delirium states leads to increased noradrenergic transmission within the LC and subcortical and cortical brain regions including the prefrontal cortex and hippocampus, thus affecting how attention and cognition function. In hypoactive delirium states, however, we are presuming (2) that less arousal will cause the release of noradrenaline to diminish in the LC, followed by reduced noradrenergic transmission in cortical and subcortical brain areas concentrated within the prefrontal cortex and hippocampus, leading to deficient attention and cognitive processing. Studies addressing the measurement of noradrenaline and its derivatives in biomaterial probes regarding delirium are also covered in this article. In conclusion, the LC-NA system plays a crucial role in generating delirium. Yet there have been no large-scale studies investigating biomarkers of noradrenaline to help us draw conclusions for improving delirium’s diagnosis, treatment, and prognosis, and to better understand its pathogenesis.
The Occurrence of Alzheimer’s Disease and Parkinson’s Disease in Individuals With Osteoporosis: A Longitudinal Follow-Up Study Using a National Health Screening Database in Korea
Authors: Kwon Mi Jung , Kim Joo-Hee , Kim Ji Hee , Cho Seong Jin , Nam Eun Sook , Choi Hyo Geun
Published: December 2021

Background: Public health concerns regarding the potential link between osteoporosis and the increased occurrence of Alzheimer’s disease (AD) and Parkinson’s disease (PD) have been raised, but the results remain inconsistent and require further validation. Here, we investigated the long-term relationship of osteoporosis with the occurrence of AD/PD using data from a large-scale nationwide cohort.

Methods: This longitudinal follow-up study included 78,994 patients with osteoporosis and 78,994 controls from the Korean National Health Insurance Service-Health Screening Cohort database (2002–2015) who were matched using propensity score matching at a 1:1 ratio based on age, sex, income, and residential area. A Cox proportional hazard model was used to assess the association between osteoporosis and the occurrence of AD/PD after adjusting for multiple covariates.

Results: During the follow-up period, AD occurred in 5,856 patients with osteoporosis and 3,761 controls (incidence rates: 10.4 and 6.8 per 1,000 person-years, respectively), and PD occurred in 1,397 patients and 790 controls (incidence rates: 2.4 and 1.4 per 1,000 person-years, respectively). The incidences of AD and PD were significantly higher in the osteoporosis group than in the matched control group. After adjustment, the osteoporosis group exhibited 1.27-fold and 1.49-fold higher occurrences of AD (95% confidence interval (CI) = 1.22–1.32) and PD (95% CI = 1.36–1.63) than the controls, respectively. The results of subgroup analyses supported the increased occurrence of AD and PD in patients with osteoporosis, independent of income, residential area, obesity, smoking, alcohol consumption, hyperlipidemia, hypertension, or blood glucose level.

Conclusion: Our results indicate that the presence of osteoporosis may increase the likelihood of developing two common neurodegenerative diseases in adults aged ≥40 years.
PTSD as an Endothelial Disease: Insights From COVID-19
Authors: Sfera Adonis , Osorio Carolina , Rahman Leah , Zapata-Martín del Campo Carlos Manuel , Maldonado Jose Campo , Jafri Nyla , Cummings Michael Allen , Maurer Steve , Kozlakidis Zisis
Published: December 2021

Graphical Abstract 1

Covid-19 triggers endothelial cell (EC) senescence and dysfunction, likely predisposing to PTSD by increasing microvascular permeability that enables the extravasation of stress molecules into the brain trauma-processing networks in amygdala, hippocampus and the medial prefrontal cortex. The virus upregulates host angiotensin II (ANG II) (via S1 antigen), usurps furin/plasmin (via S2 antigen), mitochondria (via ORF9b), and Sigma-1 receptors (Sig-1Rs) via NSP6. These structures, previously associated with PTSD, link the SARS-CoV-2 virus to increased susceptibility for stress related disorders. As ECs are major producers of brain derived neurotrophic factor (BDNF), a neurotrophin altered in PTSD, senescent ECs lower this molecule further, predisposing to stress related disorders.
Tacrolimus-Induced Neurotrophic Differentiation of Adipose-Derived Stem Cells as Novel Therapeutic Method for Peripheral Nerve Injury
Authors: Yao Xiangyun , Yan Zhiwen , Li Xiaojing , Li Yanhao , Ouyang Yuanming , Fan Cunyi
Published: December 2021

Peripheral nerve injuries (PNIs) are frequent traumatic injuries across the globe. Severe PNIs result in irreversible loss of axons and myelin sheaths and disability of motor and sensory function. Schwann cells can secrete neurotrophic factors and myelinate the injured axons to repair PNIs. However, Schwann cells are hard to harvest and expand in vitro, which limit their clinical use. Adipose-derived stem cells (ADSCs) are easily accessible and have the potential to acquire neurotrophic phenotype under the induction of an established protocol. It has been noticed that Tacrolimus/FK506 promotes peripheral nerve regeneration, despite the mechanism of its pro-neurogenic capacity remains undefined. Herein, we investigated the neurotrophic capacity of ADSCs under the stimulation of tacrolimus. ADSCs were cultured in the induction medium for 18 days to differentiate along the glial lineage and were subjected to FK506 stimulation for the last 3 days. We discovered that FK506 greatly enhanced the neurotrophic phenotype of ADSCs which potentiated the nerve regeneration in a crush injury model. This work explored the novel application of FK506 synergized with ADSCs and thus shed promising light on the treatment of severe PNIs.
Temporally Targeted Interactions With Pathologic Oscillations as Therapeutical Targets in Epilepsy and Beyond
Authors: Földi Tamás , Lőrincz Magor L. , Berényi Antal
Published: December 2021

Self-organized neuronal oscillations rely on precisely orchestrated ensemble activity in reverberating neuronal networks. Chronic, non-malignant disorders of the brain are often coupled to pathological neuronal activity patterns. In addition to the characteristic behavioral symptoms, these disturbances are giving rise to both transient and persistent changes of various brain rhythms. Increasing evidence support the causal role of these “oscillopathies” in the phenotypic emergence of the disease symptoms, identifying neuronal network oscillations as potential therapeutic targets. While the kinetics of pharmacological therapy is not suitable to compensate the disease related fine-scale disturbances of network oscillations, external biophysical modalities (e.g., electrical stimulation) can alter spike timing in a temporally precise manner. These perturbations can warp rhythmic oscillatory patterns via resonance or entrainment. Properly timed phasic stimuli can even switch between the stable states of networks acting as multistable oscillators, substantially changing the emergent oscillatory patterns. Novel transcranial electric stimulation (TES) approaches offer more reliable neuronal control by allowing higher intensities with tolerable side-effect profiles. This precise temporal steerability combined with the non- or minimally invasive nature of these novel TES interventions make them promising therapeutic candidates for functional disorders of the brain. Here we review the key experimental findings and theoretical background concerning various pathological aspects of neuronal network activity leading to the generation of epileptic seizures. The conceptual and practical state of the art of temporally targeted brain stimulation is discussed focusing on the prevention and early termination of epileptic seizures.
Psychiatric Symptoms and Parental Stress in Children and Adolescents With Epilepsy
Authors: Operto Francesca Felicia , Pastorino Grazia Maria Giovanna , Pippa Federica , Padovano Chiara , Vivenzio Valentina , Scuoppo Chiara , Pistola Ilaria , Coppola Giangennaro
Published: December 2021

Introduction:The aim of this study was to identify the presence of emotional and behavioral symptoms in children and adolescents with epilepsy, to measure the stress levels in their parents, and to determine if and how parental stress was linked to emotional and behavioral symptoms of their children.

Methods:We conducted a cross-sectional observational study including 103 children and adolescents with different form of epilepsy and 93 sex-/age-matched controls. Parental stress and emotional and behavioral symptoms were assessed through two standardized questionnaires: the Parenting Stress Index (PSI) and the Child Behavior Checklist (CBCL), respectively. We also considered the following variables: age, sex, maternal education level, family history of psychiatric disorders, duration of epilepsy, seizure frequency, seizure type, and number of antiseizure medications.

Results:The statistical comparison showed that the epilepsy group obtained significantly higher scores than controls in almost all the CBCL and the PSI scales (p< 0.05). The correlation analysis revealed a significant relationship between the PSI Total Stress scale and the following CBCL scales: total problems, internalizing problems, and externalizing problems (p< 0.05). An earlier age of seizure onset was related to a greater presence of externalizing problems, total problems, and total stress (p< 0.05).

Conclusion:In the epilepsy group, we found higher levels of parental stress and higher presence of emotional and behavioral symptoms compared to controls, mainly represented by internalizing problems (anxiety and depression symptoms). Therefore, it is important to precociously detect these symptoms and monitor them over time, in order to prevent psychiatric problems. In addition, parents of children with epilepsy should be offered psychological support to cope with parental stress and to improve the relationship with their children.
The Differential Effects of Acute Right- vs. Left-Sided Vestibular Deafferentation on Spatial Cognition in Unilateral Labyrinthectomized Mice
Authors: Nguyen Thanh Tin , Nam Gi-Sung , Kang Jin-Ju , Han Gyu Cheol , Kim Ji-Soo , Dieterich Marianne , Oh Sun-Young
Published: December 2021

This study aimed to investigate the disparity in locomotor and spatial memory deficits caused by left- or right-sided unilateral vestibular deafferentation (UVD) using a mouse model of unilateral labyrinthectomy (UL) and to examine the effects of galvanic vestibular stimulation (GVS) on the deficits over 14 days. Five experimental groups were established: the left-sided and right-sided UL (Lt.-UL and Rt.-UL) groups, left-sided and right-sided UL with bipolar GVS with the cathode on the lesion side (Lt.-GVS and Rt.-GVS) groups, and a control group with sham surgery. We assessed the locomotor and cognitive-behavioral functions using the open field (OF), Y maze, and Morris water maze (MWM) tests before (baseline) and 3, 7, and 14 days after surgical UL in each group. On postoperative day (POD) 3, locomotion and spatial working memory were more impaired in the Lt.-UL group compared with the Rt.-UL group (p< 0.01, Tamhane test). On POD 7, there was a substantial difference between the groups; the locomotion and spatial navigation of the Lt.-UL group recovered significantly more slowly compared with those of the Rt.-UL group. Although the differences in the short-term spatial cognition and motor coordination were resolved by POD 14, the long-term spatial navigation deficits assessed by the MWM were significantly worse in the Lt.-UL group compared with the Rt.-UL group. GVS intervention accelerated the vestibular compensation in both the Lt.-GVS and Rt.-GVS groups in terms of improvement of locomotion and spatial cognition. The current data imply that right- and left-sided UVD impair spatial cognition and locomotion differently and result in different compensatory patterns. Sequential bipolar GVS when the cathode (stimulating) was assigned to the lesion side accelerated recovery for UVD-induced spatial cognition, which may have implications for managing the patients with spatial cognitive impairment, especially that induced by unilateral peripheral vestibular damage on the dominant side.
Current Response in CaV1.3–/– Mouse Vestibular and Cochlear Hair Cells
Authors: Manca Marco , Yen Piece , Spaiardi Paolo , Russo Giancarlo , Giunta Roberta , Johnson Stuart L. , Marcotti Walter , Masetto Sergio
Published: December 2021

Signal transmission by sensory auditory and vestibular hair cells relies upon Ca2+-dependent exocytosis of glutamate. The Ca2+ current in mammalian inner ear hair cells is predominantly carried through CaV1.3 voltage-gated Ca2+ channels. Despite this, CaV1.3 deficient mice (CaV1.3–/–) are deaf but do not show any obvious vestibular phenotype. Here, we compared the Ca2+ current (ICa) in auditory and vestibular hair cells from wild-type and CaV1.3–/– mice, to assess whether differences in the size of the residual ICa could explain, at least in part, the two phenotypes. Using 5 mM extracellular Ca2+ and near-body temperature conditions, we investigated the cochlear primary sensory receptors inner hair cells (IHCs) and both type I and type II hair cells of the semicircular canals. We found that the residual ICa in both auditory and vestibular hair cells from CaV1.3–/– mice was less than 20% (12–19%, depending on the hair cell type and age investigated) compared to controls, indicating a comparable expression of CaV1.3 Ca2+ channels in both sensory organs. We also showed that, different from IHCs, type I and type II hair cells from CaV1.3–/– mice were able to acquire the adult-like K+ current profile in their basolateral membrane. Intercellular K+ accumulation was still present in CaV1.3–/– mice during IK,L activation, suggesting that the K+-based, non-exocytotic, afferent transmission is still functional in these mice. This non-vesicular mechanism might contribute to the apparent normal vestibular functions in CaV1.3–/– mice.
Polarity Sensitivity of Human Auditory Nerve Fibers Based on Pulse Shape, Cochlear Implant Stimulation Strategy and Array
Authors: Heshmat Amirreza , Sajedi Sogand , Schrott-Fischer Anneliese , Rattay Frank
Published: December 2021

Neural health is of great interest to determine individual degeneration patterns for improving speech perception in cochlear implant (CI) users. Therefore, in recent years, several studies tried to identify and quantify neural survival in CI users. Among all proposed techniques, polarity sensitivity is a promising way to evaluate the neural status of auditory nerve fibers (ANFs) in CI users. Nevertheless, investigating neural health based on polarity sensitivity is a challenging and complicated task that involves various parameters, and the outcomes of many studies show contradictory results of polarity sensitivity behavior. Our computational study benefits from an accurate three-dimensional finite element model of a human cochlea with realistic human ANFs and determined ANF degeneration pattern of peripheral part with a diminishing of axon diameter and myelination thickness based on degeneration levels. In order to see how different parameters may impact the polarity sensitivity behavior of ANFs, we investigated polarity behavior under the application of symmetric and asymmetric pulse shapes, monopolar and multipolar CI stimulation strategies, and a perimodiolar and lateral CI array system. Our main findings are as follows: (1) action potential (AP) initiation sites occurred mainly in the peripheral site in the lateral system regardless of stimulation strategies, pulse polarities, pulse shapes, cochlear turns, and ANF degeneration levels. However, in the perimodiolar system, AP initiation sites varied between peripheral and central processes, depending on stimulation strategies, pulse shapes, and pulse polarities. (2) In perimodiolar array, clusters formed in threshold values based on cochlear turns and degeneration levels for multipolar strategies only when asymmetric pulses were applied. (3) In the perimodiolar array, a declining trend in polarity (anodic threshold/cathodic threshold) with multipolar strategies was observed between intact or slight degenerated cases and more severe degenerated cases, whereas in the lateral array, cathodic sensitivity was noticed for intact and less degenerated cases and anodic sensitivity for cases with high degrees of degeneration. Our results suggest that a combination of asymmetric pulse shapes, focusing more on multipolar stimulation strategies, as well as considering the distances to the modiolus wall, allows us to distinguish the degeneration patterns of ANFs across the cochlea.