bluuebunny/crossref_metadata_2025 huggingface dataset:
Production of Labile Protein-Like Dissolved Organic Carbon Associated With Anaerobic Methane Oxidization in the Haima Cold Seeps, South China Sea
Authors: Hu Tingcang , Luo Min , Xu Yunping , Gong Shanggui , Chen Duofu
Published: December 2021

Cold seeps where methane-rich fluids escape from the seafloor generally support enormous biomass of chemosynthetic organisms and associated fauna. In addition to transporting a great amount of methane toward the seafloor, cold seeps also contribute to the aged, dissolved organic carbon (DOC) pool in the deep ocean. Here, two sediment cores from the “Haima cold seeps,” northern South China Sea and a nearby reference core were analyzed for pore-water sulfate and DOC concentrations, δ13C of DOC, and optical properties of dissolved organic matter (DOM). High DOC concentrations (0.9–3.7 mM) accompanied by extremely low δ13C values (−43.9 to −76.2‰) suggest the conversion of methane into sedimentary DOC pool in the seep sediments. Parallel factor analysis (PARAFAC) of the fluorescence excitation-emission matrices shows higher fluorescent intensities of labile protein-like components (C2 and C4) and lower fluorescent intensities of refractory humic-like components (C1 and C3) in the seep cores compared to the reference core. The intensity of C2 is positively correlated with DOC concentrations and δ13C-DOC in the seep sediments, suggesting that the labile protein-like DOM was produced by the anaerobic oxidation of methane (AOM). Moreover, low humification index (HIX) and high biological index (BIX) values also indicate intensified production of relatively labile DOM with lower degradation degree in the seep cores compared to the reference core. Hence, we highlight that methane-derived DOC may serve as important carbon and energy sources for heterotrophic microbial communities due to its relatively labile nature.
Findings by an International Collaboration on SJS/TEN With Severe Ocular Complications
Authors: Ueta Mayumi
Published: December 2021

Stevens-Johnson Syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, e.g., the ocular surface, oral cavity, and genitals. In patients with extensive skin detachment and a poor prognosis, the condition is called toxic epidermal necrolysis (TEN). Not all, but some patients with SJS/TEN manifest severe ocular lesions. Approximately 50% of SJS/TEN patients diagnosed by dermatologists and in burn units suffer from severe ocular complications (SOC) such as severe conjunctivitis with pseudomembrane and ocular surface epithelial defects in the acute stage. In the chronic stage, this results in sequelae such as severe dry eye and visual disturbance. Before 2005, our group of Japanese scientists started focusing on ophthalmic SJS/TEN with SOC. We found that cold medicines were the main causative drugs of SJS/TEN with SOC and that in Japanese patients,HLA-A*02:06andHLA-B*44:03were significantly associated with cold medicine-related SJS/TEN with SOC (CM-SJS/TEN with SOC). We expanded our studies and joined scientists from Korea, Brazil, India, Taiwan, Thailand, and the United Kingdom in an international collaboration to detect the genetic predisposition for SJS/TEN with SOC. This collaboration suggested that in Japanese patients, cold medicines, including NSAIDs, were the main causative drugs, and thatHLA-A*02:06was implicated in Japanese and Korean patients andHLA-B*44:03in Japanese-, Indian-, and European ancestry Brazilian patients. Our joint findings reveal that there are ethnic differences in the HLA types associated with SJS/TEN with SOC.
Serum Phosphorus and Albumin in Patients Undergoing Peritoneal Dialysis: Interaction and Association With Mortality
Authors: Huang Naya , Li Huiyan , Fan Li , Zhou Qian , Fu Dongying , Guo Lin , Yi Chunyan , Yu Xueqing , Mao Haiping
Published: December 2021

Hyperphosphatemia and hypoalbuminemia confer worse clinical outcomes, whether these risk factors interact to predispose to mortality is unclear. In this prospective cohort study, 2,118 patients undergoing incident continuous ambulatory peritoneal dialysis (CAPD) were enrolled and categorized into four groups based on the changing point regarding mortality at 1.5 mmol/L for serum phosphorus and 35 g/L for serum albumin. Risks of all-cause and cardiovascular mortality were examined independently and interactively in overall and subgroups. There was no association between serum phosphorus with all-cause and cardiovascular mortality, but significant interactions (p = 0.02) between phosphorus and albumin existed in overall population. Patients in subgroup with high phosphorus and low albumin were at greater risk of all-cause (HR 1.95, 95%CI 1.27–2.98, p = 0.002) but not cardiovascular mortality (HR 0.37, 95%CI 0.10–1.33, p = 0.13), as compared to those with low phosphorus and high albumin. In contrast, patients with both low parameters had a higher risk of all-cause (HR 1.75, 95%CI 1.22–2.50, p = 0.002) and cardiovascular mortality (HR 1.92, 95%CI 1.07–3.45, p = 0.03). Notably, an elevated risk of both all-cause and cardiovascular mortality was observed in those with low serum albumin, irrespective of phosphorus levels, suggesting low albumin may be useful to identify a higher-risk subgroup of patients undergoing CAPD with different serum phosphorus levels.
New Syphilis Cases in Older Adults, 2004–2019: An Analysis of Surveillance Data From South China
Authors: Wang Cheng , Zhao Peizhen , Xiong Mingzhou , Tucker Joseph D. , Ong Jason J. , Hall Brian J. , Sami Mojgan , Zheng Heping , Yang Bin
Published: December 2021

Background: Sexual health among older adults is a major public health concern globally. The syphilis burden is increasing in older adults in China. This study aimed to describe factors associated with syphilis infection and diagnosis among older adults in China during a 16 year period.

Methods: Using 16 years of data (2004–2019) from the syphilis case report system of Guangdong, China, we compared data from older adults (aged ≥50 years) with those from younger people (aged 15–49 years). We compared the two age group with the Chi-square test for difference, and Joinpoint regression models to assess the temporal trends.

Results: During the study period, 242,115 new syphilis diagnoses were reported in older adults. The mean notification rate of new diagnoses was 64.1 per 100,000 population across the entire 16-year period, which significantly increased over time (average annual percent change [AAPC] 16.2%, 95% CI 13.7–18.7). Syphilis diagnoses increased significantly over time among less developed cities and older women. In 2019, compared with younger adults, newly diagnosed older adults were more likely to be male, native to reporting city, had unknown transmission routes, and were diagnosed late.

Conclusion: Our findings call for an urgent need to deliver more targeted prevention interventions for older adults, such as strengthen awareness among health care providers, and integration of syphilis services and primary health care for older adults.
Clinical Characteristics and Management of Patients With Clinical Amyopathic Dermatomyositis: A Retrospective Study of 64 Patients at a Tertiary Dermatology Department
Authors: Tang Keyun , Zhang Hanlin , Jin Hongzhong
Published: December 2021

Background: Clinical amyopathic dermatomyositis (CADM) represents a subtype of 5–20% of patients with dermatomyositis (DM), which can be categorized into amyopathic dermatomyositis (ADM) and hypomyopathic dermatomyositis (HDM). The characteristics of patients with CADM are still limited in English literature.

Objective: To investigate clinical features, cutaneous findings, diagnostic accuracy, and treatment regimen of CADM patients.

Methods: Sixty-four patients diagnosed with CADM at Peking Union Medical College Hospital by dermatologists were retrospectively analyzed. Data were recorded in the electronic database at each offline clinical consultation and directly extracted from medical records. 2017 EULAR/ACR criteria for idiopathic inflammatory myositis (IIM) classification was used to identify and classify patients with CADM. Published studies were searched to extract relevant data of CADM patients.

Results: This cohort included 38 ADM patients and 26 HDM patients. 2017 EULAR/ACR criteria classified 67.2% of patients with CADM into probable or definite DM. Antimalarials were given to a majority of CADM patients (72.6%, n = 45). However, 68.8% (31 out of 45) required at least one aggressive agent combined with hydroxychloroquine due to insufficient response or side effects. The median of systemic treatments in HDM was significantly higher than ADM (p = 0.007). The number of ADM patients using antimalarials as monotherapy was significantly higher than that of HDM patients (p = 0.031), while the number of HDM patients receiving steroids combined with immunosuppressants was significantly higher (p = 0.025). The median of Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) score improvement was 11.5 and 10.5 for ADM and HDM after a median follow-up of 31.5 and 32.5 months, respectively. Six patients with normal muscle strength developed muscle weakness after a median of 10.5 months (IQR 9-13), and elevated inflammatory markers at initial visit might indicate their muscle weakness development.

Conclusions: 32.8% of patients may be overlooked using the three skin variables of 2017 EULAR/ACR criteria. The response rate to single hydroxychloroquine in our cohort was 68.8%. Detailed treatment modalities were different among ADM and HDM. Long-term monitoring for the development of myositis in patients with CADM, especially those with elevated inflammatory markers at initial visit, may be warranted.
Soluble Urokinase Plasminogen Activator Receptor (suPAR) Independently Predicts Severity and Length of Hospitalisation in Patients With COVID-19
Authors: Enocsson Helena , Idoff Cornelia , Gustafsson Annette , Govender Melissa , Hopkins Francis , Larsson Marie , Nilsdotter-Augustinsson Åsa , Sjöwall Johanna
Published: December 2021

Background: Efficient healthcare based on prognostic variables in hospitalised patients with COVID-19 could reduce the risk of complications and death. Recently, soluble urokinase Plasminogen Activator Receptor (suPAR) was shown to predict respiratory failure, kidney injury, and clinical outcome in patients with SARS-CoV-2 infection. The aim of this study was to investigate the value of suPAR as a prognostic tool, in comparison with other variables, regarding disease severity and length of hospital stay in patients with COVID-19.

Patients and Methods: Individuals hospitalised with COVID-19 (40 males, 20 females; median age 57.5 years) with a median symptom duration of 10 days and matched, healthy controls (n = 30) were included. Admission levels of suPAR were measured in serum by enzyme-linked immunosorbent assay. Blood cell counts, C-reactive protein (CRP) levels, lactate dehydrogenase (LDH), plasma creatinine and estimated glomerular filtration rates were analysed and oxygen demand, level of care and length of hospitalisation recorded.

Results: Patients had significantly higher suPAR levels compared to controls (P < 0.001). Levels were higher in severely/critically (median 6.6 ng/mL) compared with moderately ill patients (median 5.0 ng/mL; P = 0.002). In addition, suPAR levels correlated with length of hospitalisation (rho = 0.35; P = 0.006). Besides suPAR, LDH, CRP, neutrophil count, neutrophil-to-monocyte and neutrophil-to-lymphocyte ratio, body mass index and chronic renal failure were discriminators of COVID-19 severity and/or predictors of length of hospitalisation.

Conclusion: Admission levels of suPAR were higher in patients who developed severe/critical COVID-19 and associated with length of hospital stay. In addition, we showed that suPAR functioned as an independent predictor of COVID-19 disease severity.
LncRNA MSC-AS1 Is a Diagnostic Biomarker and Predicts Poor Prognosis in Patients With Gastric Cancer by Integrated Bioinformatics Analysis
Authors: Yang Wei , Ge Fusheng , Lu Shuaibing , Shan Zhiming , Peng Liangqun , Chai Junhui , Liu Hongxing , Li Baodong , Zhang Zhandong , Huang Jinxi , Hua Yawei , Zhang Yonglei
Published: December 2021

Numerous studies have shown that long uncoded RNA (lncRNA) MSC-AS1 may play an important role in the occurrence and development of some types of cancer. However, its role in gastric cancer has rarely been discussed. This study aimed to clarify the association between lncRNA MSC-AS1 and gastric cancer using The Cancer Genome Atlas (TCGA) database. We determined the expression of MSC-AS1 using the Wilcoxon rank sum test; in addition, logistic regression was applied to evaluate the association between MSC-AS1 and clinicopathological characteristics. Also, Kaplan-Meier and Cox regression were used to evaluate the relationship between MSC-AS1 and survival. A nomogram was conducted to predict the impact of MSC-AS1 on prognosis. Moreover, Gene Set enrichment analysis (GSEA) was performed to annotate the biological function of MSC-AS1. Quantitative analysis of immune infiltration was carried out by single-set GSEA (ssGSEA). The MSC-AS1 level was elevated in gastric cancer tissues. An increased MSC-AS1 level was significantly correlated with T stage (odds ratio [OR] = 2.55 for T3 and T4 vs. T1 and T2), histological type (OR = 5.28 for diffuse type vs. tubular type), histological grade (OR = 3.09 for grade 3 vs. grades 1 and 2), TP53 status (OR = 0.55 for mutated vs. wild type), and PIK3CA status (OR = 0.55 for mutated vs. wild type) (all p < 0.05) by univariate logistic regression. Kaplan-Meier survival analysis showed high MSC-AS1 expression had a poor overall survival [hazard ratio (HR) = 1.75; 95% confidence interval (CI): 1.25–2.45; p = 0.001] and progression-free interval (HR = 1.47; 95% CI: 1.03–2.10; p = 0.034). Multivariate survival analysis revealed that MSC-AS1 expression (HR = 1.681; 95% CI: 1.057–2.673; p = 0.028) was independently correlated with overall survival. GSEA demonstrated that the P38/MAPK pathway, the VEGF pathway, the cell adhesion molecules cams, the NOD-like receptor signaling pathway were differentially enriched in the high MSC-AS1 expression phenotype. SsGSEA and Spearman correlation revealed the relationships between MSC-AS1 and macrophages, NK cells, and Tems were the strongest. Coregulatory proteins were included in the PPI network. Upregulated lncRNA MSC-AS1 might be a potential biomarker for the diagnosis and prognosis of gastric cancer.
Antimicrobial Activity of Nanoconjugated Glycopeptide Antibiotics and Their Effect on Staphylococcus aureus Biofilm
Authors: Berini Francesca , Orlandi Viviana Teresa , Gamberoni Federica , Martegani Eleonora , Armenia Ilaria , Gornati Rosalba , Bernardini Giovanni , Marinelli Flavia
Published: December 2021

In the era of antimicrobial resistance, the use of nanoconjugated antibiotics is regarded as a promising approach for preventing and fighting infections caused by resistant bacteria, including those exacerbated by the formation of difficult-to-treat bacterial biofilms. Thanks to their biocompatibility and magnetic properties, iron oxide nanoparticles (IONPs) are particularly attractive as antibiotic carriers for the targeting therapy. IONPs can direct conjugated antibiotics to infection sites by the use of an external magnet, facilitating tissue penetration and disturbing biofilm formation. As a consequence of antibiotic localization, a decrease in its administration dosage might be possible, reducing the side effects to non-targeted organs and the risk of antibiotic resistance spread in the commensal microbiota. Here, we prepared nanoformulations of the ‘last-resort’ glycopeptides teicoplanin and vancomycin by conjugating them to IONPs via surface functionalization with (3-aminopropyl) triethoxysilane (APTES). These superparamagnetic NP-TEICO and NP-VANCO were chemically stable and NP-TEICO (better than NP-VANCO) conserved the typical spectrum of antimicrobial activity of glycopeptide antibiotics, being effective against a panel of staphylococci and enterococci, including clinical isolates and resistant strains. By a combination of different methodological approaches, we proved that NP-TEICO and, although to a lesser extent, NP-VANCO were effective in reducing biofilm formation by three methicillin-sensitive or resistant Staphylococcus aureus strains. Moreover, when attracted and concentrated by the action of an external magnet, NP-TEICO exerted a localized inhibitory effect on S. aureus biofilm formation at low antibiotic concentration. Finally, we proved that the conjugation of glycopeptide antibiotics to IONPs reduced their intrinsic cytotoxicity toward a human cell line.
Tea Plants With Gray Blight Have Altered Root Exudates That Recruit a Beneficial Rhizosphere Microbiome to Prime Immunity Against Aboveground Pathogen Infection
Authors: Wang Qiaomei , Yang Ruijuan , Peng Wenshu , Yang Yanmei , Ma Xiaoling , Zhang Wenjie , Ji Aibing , Liu Li , Liu Pei , Yan Liang , Hu Xianqi
Published: December 2021

Tea gray blight disease and its existing control measures have had a negative impact on the sustainable development of tea gardens. However, our knowledge of safe and effective biological control measures is limited. It is critical to explore beneficial microbial communities in the tea rhizosphere for the control of tea gray blight. In this study, we prepared conditioned soil by inoculating Pseudopestalotiopsis camelliae-sinensis on tea seedling leaves. Thereafter, we examined the growth performance and disease resistance of fresh tea seedlings grown in conditioned and control soils. Next, the rhizosphere microbial community and root exudates of tea seedlings infected by the pathogen were analyzed. In addition, we also evaluated the effects of the rhizosphere microbial community and root exudates induced by pathogens on the performance of tea seedlings. The results showed that tea seedlings grown in conditioned soil had lower disease index values and higher growth vigor. Soil microbiome analysis revealed that the fungal and bacterial communities of the rhizosphere were altered upon infection with Ps. camelliae-sinensis. Genus-level analysis showed that the abundance of the fungi Trichoderma, Penicillium, and Gliocladiopsis and the bacteria Pseudomonas, Streptomyces, Bacillus, and Burkholderia were significantly (p < 0.05) increased in the conditioned soil. Through isolation, culture, and inoculation tests, we found that most isolates from the induced microbial genera could inhibit the infection of tea gray blight pathogen and promote tea seedling growth. The results of root exudate analysis showed that infected tea seedlings exhibited significantly higher exudate levels of phenolic acids and flavonoids and lower exudate levels of amino acids and organic acids. Exogenously applied phenolic acids and flavonoids suppressed gray blight disease by regulating the rhizosphere microbial community. In summary, our findings suggest that tea plants with gray blight can recruit beneficial rhizosphere microorganisms by altering their root exudates, thereby improving the disease resistance of tea plants growing in the same soil.
Single Molecule Measurements of the Accessibility of Molecular Surfaces
Authors: Dey Arpan , Vishvakarma Vicky , Das Anirban , Kallianpur Mamata , Dey Simli , Joseph Roshni , Maiti Sudipta
Published: December 2021

An important measure of the conformation of protein molecules is the degree of surface exposure of its specific segments. However, this is hard to measure at the level of individual molecules. Here, we combine single molecule photobleaching (smPB, which resolves individual photobleaching steps of single molecules) and fluorescence quenching techniques to measure the accessibility of individual fluorescently labeled protein molecules to quencher molecules in solution. A quencher can reduce the time a fluorophore spends in the excited state, increasing its photostability under continuous irradiation. Consequently, the photo-bleaching step length would increase, providing a measure for the accessibility of the fluorophore to the solvent. We demonstrate the method by measuring the bleaching step-length increase in a lipid, and also in a lipid-anchored peptide (both labelled with rhodamine-B and attached to supported lipid bilayers). The fluorophores in both molecules are expected to be solvent-exposed. They show a near two-fold increase in the step length upon incubation with 5 mM tryptophan (a quencher of rhodamine-B), validating our approach. A population distribution plot of step lengths before and after addition of tryptophan show that the increase is not always homogenous. Indeed there are different species present with differential levels of exposure. We then apply this technique to determine the solvent exposure of membrane-attached N-terminus labelled amylin (h-IAPP, an amyloid associated with Type II diabetes) whose interaction with lipid bilayers is poorly understood. hIAPP shows a much smaller increase of the step length, signifying a lower level of solvent exposure of its N-terminus. Analysis of results from individual molecules and step length distribution reveal that there are at least two different conformers of amylin in the lipid bilayer. Our results show that our method (“Q-SLIP”, Quenching-induced Step Length increase in Photobleaching) provides a simple route to probe the conformational states of membrane proteins at a single molecule level.
Transcriptomic Changes Highly Similar to Alzheimer’s Disease Are Observed in a Subpopulation of Individuals During Normal Brain Aging
Authors: Peng Shouneng , Zeng Lu , Haure-Mirande Jean-Vianney , Wang Minghui , Huffman Derek M. , Haroutunian Vahram , Ehrlich Michelle E. , Zhang Bin , Tu Zhidong
Published: December 2021

Aging is a major risk factor for late-onset Alzheimer’s disease (LOAD). How aging contributes to the development of LOAD remains elusive. In this study, we examined multiple large-scale transcriptomic datasets from both normal aging and LOAD brains to understand the molecular interconnection between aging and LOAD. We found that shared gene expression changes between aging and LOAD are mostly seen in the hippocampal and several cortical regions. In the hippocampus, the expression of phosphoprotein, alternative splicing and cytoskeleton genes are commonly changed in both aging and AD, while synapse, ion transport, and synaptic vesicle genes are commonly down-regulated. Aging-specific changes are associated with acetylation and methylation, while LOAD-specific changes are more related to glycoprotein (both up- and down-regulations), inflammatory response (up-regulation), myelin sheath and lipoprotein (down-regulation). We also found that normal aging brain transcriptomes from relatively young donors (45–70 years old) clustered into several subgroups and some subgroups showed gene expression changes highly similar to those seen in LOAD brains. Using brain transcriptomic datasets from another cohort of older individuals (>70 years), we found that samples from cognitively normal older individuals clustered with the “healthy aging” subgroup while AD samples mainly clustered with the “AD similar” subgroups. This may imply that individuals in the healthy aging subgroup will likely remain cognitively normal when they become older and vice versa. In summary, our results suggest that on the transcriptome level, aging and LOAD have strong interconnections in some brain regions in a subpopulation of cognitively normal aging individuals. This supports the theory that the initiation of LOAD occurs decades earlier than the manifestation of clinical phenotype and it may be essential to closely study the “normal brain aging” to identify the very early molecular events that may lead to LOAD development.
Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons
Authors: Morales-Rosales Sandra Lizbeth , Santín-Márquez Roberto , Posadas-Rodriguez Pedro , Rincon-Heredia Ruth , Montiel Teresa , Librado-Osorio Raúl , Luna-López Armando , Rivero-Segura Nadia Alejandra , Torres Claudio , Cano-Martínez Agustina , Silva-Palacios Alejandro , Cortés-Hernández Paulina , Morán Julio , Massieu Lourdes , Konigsberg Mina
Published: December 2021

The decline in brain function during aging is one of the most critical health problems nowadays. Although senescent astrocytes have been found in old-age brains and neurodegenerative diseases, their impact on the function of other cerebral cell types is unknown. The aim of this study was to evaluate the effect of senescent astrocytes on the mitochondrial function of a neuron. In order to evaluate neuronal susceptibility to a long and constant senescence-associated secretory phenotype (SASP) exposure, we developed a model by using cellular cocultures in transwell plates. Rat primary cortical astrocytes were seeded in transwell inserts and induced to premature senescence with hydrogen peroxide [stress-induced premature senescence (SIPS)]. Independently, primary rat cortical neurons were seeded at the bottom of transwells. After neuronal 6 days in vitro (DIV), the inserts with SIPS-astrocytes were placed in the chamber and cocultured with neurons for 6 more days. The neuronal viability, the redox state [reduced glutathione/oxidized glutathione (GSH/GSSG)], the mitochondrial morphology, and the proteins and membrane potential were determined. Our results showed that the neuronal mitochondria functionality was altered after being cocultured with senescent astrocytes. In vivo, we found that old animals had diminished mitochondrial oxidative phosphorylation (OXPHOS) proteins, redox state, and senescence markers as compared to young rats, suggesting effects of the senescent astrocytes similar to the ones we observed in vitro. Overall, these results indicate that the microenvironment generated by senescent astrocytes can affect neuronal mitochondria and physiology.
Transitions in the Cognitive Frailty States in Community-Living Older Adults: A 6-Year Prospective Cohort Study
Authors: Tang Huiyu , Zhu Huan , Sun Qianqian , Qin Hai , Wang Shuang
Published: December 2021

Background: Frailty is a multidimensional concept, including physical, cognitive, social, sensorial, psychological, and nutritional phenotypes. Among these phenotypes, cognitive frailty is the most widely investigated, which is related to many adverse health outcomes in older individuals. Whether cognitive frailty is dynamic or how these frail phenotypes interact remains an open issue. We studied the rate of these changes over time and their associated factors in a 6-year follow-up cohort.

Methods: A total of 426 Chinese community-living older adults in Dujiangyan aged 65 years or older were involved and followed up in three visits 6 years apart. Frailty and cognitive function were assessed using the FRAIL scale and the Mini-Mental State Examination scale. Demographic information, geriatric syndrome, and social interaction status were studied. Rates of transitions in cognitive frailty states and associated risk factors were studied. We used the stepwise logistic regression model to analyze risk factors.

Results: At baseline, 18.8% of participants were only in the physical frailty (PF) or mild cognitive impairment (MCI) group, and 0.09% of participants were in the cognitive frailty group. By the end of 6 years, 62 (14.5%) participants had died, and the rates of only PF or MCI group and cognitive frailty group increased to 36.2 and 3.3%, respectively. Also, 199 (46.7%) participants had deteriorated compared with the baseline. The multivariate regression analysis showed that older (OR = 1.12, 95% CI = 1.07 − 1.16, P < 0.001), smoker (OR = 2.15, 95% CI = 1.37 − 3.39, P = 0.001), poor self-evaluation health status (OR = 1.93, 95% CI = 1.06 − 3.51, P = 0.033), and malnutrition (OR = 2.07, 95% CI = 1.21 − 3.52, P = 0.008) were risk factors for worsening, whereas willing to make new friends (OR = 0.61, 95% CI = 0.38 − 0.96, P = 0.032) was associated with 39% lower chance of deterioration.

Conclusion: Cognitive frailty is a dynamically changing state, where transitions may be influenced by multidimensions. Multidimensional monitoring of a wide range of events occurring in aging may be the best way to act early. We hope our study may serve as a starting point for redefining the definition of cognitive frailty by covering different frailty domains.
Applications of Scanning Electron Microscopy Using Secondary and Backscattered Electron Signals in Neural Structure
Authors: Koga Daisuke , Kusumi Satoshi , Shibata Masahiro , Watanabe Tsuyoshi
Published: December 2021

Scanning electron microscopy (SEM) has contributed to elucidating the ultrastructure of bio-specimens in three dimensions. SEM imagery detects several kinds of signals, of which secondary electrons (SEs) and backscattered electrons (BSEs) are the main electrons used in biological and biomedical research. SE and BSE signals provide a three-dimensional (3D) surface topography and information on the composition of specimens, respectively. Among the various sample preparation techniques for SE-mode SEM, the osmium maceration method is the only approach for examining the subcellular structure that does not require any reconstruction processes. The 3D ultrastructure of organelles, such as the Golgi apparatus, mitochondria, and endoplasmic reticulum has been uncovered using high-resolution SEM of osmium-macerated tissues. Recent instrumental advances in scanning electron microscopes have broadened the applications of SEM for examining bio-specimens and enabled imaging of resin-embedded tissue blocks and sections using BSE-mode SEM under low-accelerating voltages; such techniques are fundamental to the 3D-SEM methods that are now known as focused ion-beam SEM, serial block-face SEM, and array tomography (i.e., serial section SEM). This technical breakthrough has allowed us to establish an innovative BSE imaging technique called section-face imaging to acquire ultrathin information from resin-embedded tissue sections. In contrast, serial section SEM is a modern 3D imaging technique for creating 3D surface rendering models of cells and organelles from tomographic BSE images of consecutive ultrathin sections embedded in resin. In this article, we introduce our related SEM techniques that use SE and BSE signals, such as the osmium maceration method, semithin section SEM (section-face imaging of resin-embedded semithin sections), section-face imaging for correlative light and SEM, and serial section SEM, to summarize their applications to neural structure and discuss the future possibilities and directions for these methods.
Glia-Driven Brain Circuit Refinement Is Altered by Early-Life Adversity: Behavioral Outcomes
Authors: Milbocker Katrina A. , Campbell Taylor S. , Collins Nicholas , Kim SuHyeong , Smith Ian F. , Roth Tania L. , Klintsova Anna Y.
Published: December 2021

Early-life adversity (ELA), often clinically referred to as “adverse childhood experiences (ACE),” is the exposure to stress-inducing events in childhood that can result in poor health outcomes. ELA negatively affects neurodevelopment in children and adolescents resulting in several behavioral deficits and increasing the risk of developing a myriad of neuropsychiatric disorders later in life. The neurobiological mechanisms by which ELA alters neurodevelopment in childhood have been the focus of numerous reviews. However, a comprehensive review of the mechanisms affecting adolescent neurodevelopment (i.e., synaptic pruning and myelination) is lacking. Synaptic pruning and myelination are glia-driven processes that are imperative for brain circuit refinement during the transition from adolescence to adulthood. Failure to optimize brain circuitry between key brain structures involved in learning and memory, such as the hippocampus and prefrontal cortex, leads to the emergence of maladaptive behaviors including increased anxiety or reduced executive function. As such, we review preclinical and clinical literature to explore the immediate and lasting effects of ELA on brain circuit development and refinement. Finally, we describe a number of therapeutic interventions best-suited to support adolescent neurodevelopment in children with a history of ELA.
A Novel Hydrogen Sulfide Donor Reduces Pilocarpine-Induced Status Epilepticus and Regulates Microglial Inflammatory Profile
Authors: Liu Zhongrui , Zhu Ziting , He Yan , Kang Qiyun , Li Fei , Zhang Wenlong , He Yuehua , Lin Yuwan , Huang Baoyi , Mo Mingshu , Xu Pingyi , Zhu Xiaoqin
Published: December 2021

Although epilepsy is one of the most common neurologic disorders, there is still a lack of effective therapeutic drugs for it. Recently, we synthesized a novel hydrogen sulfide (H2S) donor, which is found to reduce seizures in animal models effectively. But it remains to be determined for its mechanism. In the present study, we found that the novel H2S donor could reduce pilocarpine-induced seizures in mice. It alleviated the epileptic behavior, the hippocampal electroencephalography (EEG) activity of seizures, and the damage of hippocampal neurons in status epilepticus mice. In addition, the novel H2S donor could reduce microglial inflammatory response. It not only reduced the upregulation of pro-inflammatory markers [inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2)] in status epilepticus mice, but also increased the levels of microglial anti-inflammatory marker arginase-1 (Arg-1). In lipopolysaccharide-treated microglia BV2 cells, administration of the H2S donor also significantly reduced the lipopolysaccharide-induced upregulation of the expression of the pro-inflammatory markers and increased the expression of the anti-inflammatory markers. Thus, the novel H2S donor regulates microglial inflammatory profile in status epilepticus mice and in vitro. These results suggested that the novel H2S donor can reduce seizures and regulate microglial inflammatory profile, which may be a novel mechanism and potential therapeutic strategy of the H2S donor anti-seizures.
Use of Batroxobin in Central and Peripheral Ischemic Vascular Diseases: A Systematic Review
Authors: Lan Duo , Song Siying , Liu Yunhuan , Jiao Baolian , Meng Ran
Published: December 2021

Background and Purpose: The mechanism of action of Batroxobin included the decomposition of the fibrinogen to fibrin degradation products (FDPs) and D-dimer and mobilization of endothelial cells to release endogenous nt-PA and to promote thrombolysis. This review aims to summarize current study findings about batroxobin on correcting cerebral arterial, venous, and peripheral vascular diseases, to explore the mechanism of batroxobin on anti-thrombosis process.

Methods: A thorough literature search was conducted utilizing the PubMed Central (PMC) and EMBASE databases to identify studies up to June 2021. Data from clinical studies and animal experiments about batroxobin were extracted, integrated and analyzed based on Cochrane handbook for systematic reviews of interventions approach and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), including the condition of subjects, the usage and dosage, research observation index and main findings.

Results: A total of 62 studies were enrolled in this systematic review, including 26 clinical studies and 36 animal experiments. The 26 clinical studies involved 873 patients with arterial ischemic events, 92 cases with cerebral venous thrombosis, 13 cases with cerebral cortical vein thrombosis, and 1,049 cases with peripheral vascular diseases. These patients included 452 males and 392 females aged 65.6 ± 5.53 years. The results revealed that batroxobin had broad effects, including improving clinical prognosis (n = 12), preventing thrombosis (n = 7), promoting thrombolysis (n = 6), and improving vascular cognitive dysfunction (n = 1). The effects of batroxobin on reducing neuronal apoptosis (n = 8),relieving cellular edema (n = 4), improving spatial memory (n = 3), and promoting thrombolysis (n = 13) were concluded in animal experiments. The predominant mechanisms explored in animal experiments involved promoting depolymerization of fibrinogen polymers (n = 6), regulating the expression of related molecules (n = 9); such as intercellular adhesion molecule, heat shock proteins, tumor necrosis factor), reducing oxidative stress (n = 5), and reducing inflammation response (n = 4).

Conclusion: Batroxobin can correct both arterial and venous ischemic diseases by promoting depolymerization of fibrinogen polymers, regulating the expression of related molecules, reducing oxidative stress, and reducing the inflammation response.
Longitudinal, Quantitative, Multimodal MRI Evaluation of Patients With Intracerebral Hemorrhage Over the First Year
Authors: Haque Muhammad E. , Boren Seth B. , Arevalo Octavio D. , Gupta Reshmi , George Sarah , Parekh Maria A. , Zhao Xiurong , Aronowski Jaraslow , Savitz Sean I.
Published: December 2021

In most patients with intracerebral hemorrhage (ICH), the hematoma and perihematomal area decrease over the subsequent months but patients continue to exhibit neurological impairments. In this serial imaging study, we characterized microstructural and neurophysiological changes in the ICH-affected brain tissues and collected the National Institute of Health Stroke Scale (NIHSS) and modified Rankin Score (mRS), two clinical stroke scale scores. Twelve ICH patients were serially imaged on a 3T MRI at 1, 3, and 12 months (M) after injury. The hematoma and perihematomal volume masks were created and segmented using FLAIR imaging at 1 month which were applied to compute the susceptibilities (χ), fractional anisotropy (FA), mean diffusivity (MD), and cerebral blood flow (CBF) in the same tissues over time and in the matching contralesional tissues. At 3 M, there was a significant (p < 0.001) reduction in hematoma and perihematomal volumes. At 1 M, the χ, FA, and CBF were decreased in the perihematomal tissues as compared to the contralateral side, whereas MD increased. In the hematomal tissues, the χ increased whereas FA, MD, and CBF decreased as compared to the contralesional area at 1 M. Temporally, CBF in the hematoma and perihematomal tissues remained significantly (p < 0.05) lower compared with the contralesional areas whereas MD in the hematoma and χ in the perihematomal area increased. The NIHSS and mRS significantly correlated with hematoma and perihematomal volume but not with microstructural integrity. Our serial imaging studies provide new information on the long-term changes within the brain after ICH and our findings may have clinical significance that warrants future studies.
Thenar Muscle Motor Imagery Increases Spinal Motor Neuron Excitability of the Abductor Digiti Minimi Muscle
Authors: Bunno Yoshibumi , Suzuki Toshiaki
Published: December 2021

When a person attempts intended finger movements, unintended finger movement also occur, a phenomenon called “enslaving”. Given that motor imagery (MI) and motor execution (ME) share a common neural foundation, we hypothesized that the enslaving effect on the spinal motor neuron excitability occurs during MI. To investigate this hypothesis, electromyography (EMG) and F-wave analysis were conducted in 11 healthy male volunteers. Initially, the EMG activity of the left abductor digiti minimi (ADM) muscle during isometric opposition pinch movement by the left thumb and index finger at 50% maximal effort was compared with EMG activity during the Rest condition. Next, the F-wave and background EMG recordings were performed under the Rest condition, followed by the MI condition. Specifically, in the Rest condition, subjects maintained relaxation. In the MI condition, they imagined isometric left thenar muscle activity at 50% maximal voluntary contraction (MVC). During ME, ADM muscle activity was confirmed. During the MI condition, both F-wave persistence and the F-wave/M-wave amplitude ratio obtained from the ADM muscle were significantly increased compared with that obtained during the Rest condition. No difference was observed in the background EMG between the Rest and MI conditions. These results suggest that MI of isometric intended finger muscle activity at 50% MVC facilitates spinal motor neuron excitability corresponding to unintended finger muscle. Furthermore, MI may induce similar modulation of spinal motor neuron excitability as actual movement.
A Toolbox and Crowdsourcing Platform for Automatic Labeling of Independent Components in Electroencephalography
Authors: Soghoyan Gurgen , Ledovsky Alexander , Nekrashevich Maxim , Martynova Olga , Polikanova Irina , Portnova Galina , Rebreikina Anna , Sysoeva Olga , Sharaev Maxim
Published: December 2021

Independent Component Analysis (ICA) is a conventional approach to exclude non-brain signals such as eye movements and muscle artifacts from electroencephalography (EEG). A rejection of independent components (ICs) is usually performed in semiautomatic mode and requires experts’ involvement. As also revealed by our study, experts’ opinions about the nature of a component often disagree, highlighting the need to develop a robust and sustainable automatic system for EEG ICs classification. The current article presents a toolbox and crowdsourcing platform for Automatic Labeling of Independent Components in Electroencephalography (ALICE) available via link http://alice.adase.org/. The ALICE toolbox aims to build a sustainable algorithm to remove artifacts and find specific patterns in EEG signals using ICA decomposition based on accumulated experts’ knowledge. The difference from previous toolboxes is that the ALICE project will accumulate different benchmarks based on crowdsourced visual labeling of ICs collected from publicly available and in-house EEG recordings. The choice of labeling is based on the estimation of IC time-series, IC amplitude topography, and spectral power distribution. The platform allows supervised machine learning (ML) model training and re-training on available data subsamples for better performance in specific tasks (i.e., movement artifact detection in healthy or autistic children). Also, current research implements the novel strategy for consentient labeling of ICs by several experts. The provided baseline model could detect noisy IC and components related to the functional brain oscillations such as alpha and mu rhythm. The ALICE project implies the creation and constant replenishment of the IC database, which will improve ML algorithms for automatic labeling and extraction of non-brain signals from EEG. The toolbox and current dataset are open-source and freely available to the researcher community.
Providing Evidence for the Null Hypothesis in Functional Magnetic Resonance Imaging Using Group-Level Bayesian Inference
Authors: Masharipov Ruslan , Knyazeva Irina , Nikolaev Yaroslav , Korotkov Alexander , Didur Michael , Cherednichenko Denis , Kireev Maxim
Published: December 2021

Classical null hypothesis significance testing is limited to the rejection of the point-null hypothesis; it does not allow the interpretation of non-significant results. This leads to a bias against the null hypothesis. Herein, we discuss statistical approaches to ‘null effect’ assessment focusing on the Bayesian parameter inference (BPI). Although Bayesian methods have been theoretically elaborated and implemented in common neuroimaging software packages, they are not widely used for ‘null effect’ assessment. BPI considers the posterior probability of finding the effect within or outside the region of practical equivalence to the null value. It can be used to find both ‘activated/deactivated’ and ‘not activated’ voxels or to indicate that the obtained data are not sufficient using a single decision rule. It also allows to evaluate the data as the sample size increases and decide to stop the experiment if the obtained data are sufficient to make a confident inference. To demonstrate the advantages of using BPI for fMRI data group analysis, we compare it with classical null hypothesis significance testing on empirical data. We also use simulated data to show how BPI performs under different effect sizes, noise levels, noise distributions and sample sizes. Finally, we consider the problem of defining the region of practical equivalence for BPI and discuss possible applications of BPI in fMRI studies. To facilitate ‘null effect’ assessment for fMRI practitioners, we provide Statistical Parametric Mapping 12 based toolbox for Bayesian inference.
Enriched Rehabilitation Improves Gait Disorder and Cognitive Function in Parkinson’s Disease: A Randomized Clinical Trial
Authors: Wang Xin , Chen LanLan , Zhou Hongyu , Xu Yao , Zhang Hongying , Yang Wenrui , Tang XiaoJia , Wang Junya , Lv Yichen , Yan Ping , Peng Yuan
Published: December 2021

Background: Studies on non-pharmacological strategies for improving gait performance and cognition in Parkinson’s disease (PD) are of great significance. We aimed to investigate the effect of and mechanism underlying enriched rehabilitation as a potentially effective strategy for improving gait performance and cognition in early-stage PD.

Methods: Forty participants with early-stage PD were randomly assigned to receive 12 weeks (2 h/day, 6 days/week) of enriched rehabilitation (ER; n = 20; mean age, 66.14 ± 4.15 years; 45% men) or conventional rehabilitation (CR; n = 20; mean age 65.32 ± 4.23 years; 50% men). In addition, 20 age-matched healthy volunteers were enrolled as a control (HC) group. We assessed the general motor function using the Unified PD Rating Scale—Part III (UPDRS-III) and gait performance during single-task (ST) and dual-task (DT) conditions pre- and post-intervention. Cognitive function assessments included the Montreal Cognitive Assessment (MoCA), the Symbol Digit Modalities Test (SDMT), and the Trail Making Test (TMT), which were conducted pre- and post-intervention. We also investigated alteration in positive resting-state functional connectivity (RSFC) of the left dorsolateral prefrontal cortex (DLPFC) in participants with PD, mediated by ER, using functional magnetic resonance imaging (fMRI).

Results: Compared with the HC group, PD participants in both ER and CR groups performed consistently poorer on cognitive and motor assessments. Significant improvements were observed in general motor function as assessed by the UPDRS-III in both ER and CR groups post-intervention. However, only the ER group showed improvements in gait parameters under ST and DT conditions post-intervention. Moreover, ER had a significant effect on cognition, which was reflected in increased MoCA, SDMT, and TMT scores post-intervention. MoCA, SDMT, and TMT scores were significantly different between ER and CR groups post-intervention. The RSFC analysis showed strengthened positive functional connectivity between the left DLPFC and other brain areas including the left insula and left inferior frontal gyrus (LIFG) post-ER.

Conclusion: Our findings indicated that ER could serve as a potentially effective therapy for early-stage PD for improving gait performance and cognitive function. The underlying mechanism based on fMRI involved strengthened RSFC between the left DLPFC and other brain areas (e.g., the left insula and LIFG).