bluuebunny/crossref_metadata_2025 huggingface dataset:
Profile and Functional Prediction of Plasma Exosome-Derived CircRNAs From Acute Ischemic Stroke Patients
Authors: Yang Jie , Hao Junli , Lin Yapeng , Guo Yijia , Liao Ke , Yang Min , Cheng Hang , Yang Ming , Chen Kejie
Published: March 2022

Stroke is one of the major causes of death and long-term disability, of which acute ischemic stroke (AIS) is the most common type. Although circular RNA (circRNA) expression profiles of AIS patients have been reported to be significantly altered in blood and peripheral blood mononuclear cells, the role of exosome-containing circRNAs after AIS is still unknown. Plasma exosomes from 10 AIS patients and 10 controls were isolated, and through microarray and bioinformatics analysis, the profile and putative function of circRNAs in the plasma exosomes were studied. A total of 198 circRNAs were differentially quantified (|log2 fold change| ≥ 1.00, p < 0.05) between AIS patients and controls. The levels of 12 candidate circRNAs were verified by qRT-PCR, and the quantities of 10 of these circRNAs were consistent with the data of microarray. The functions of host genes of differentially quantified circRNAs, including RNA and protein process, focal adhesion, and leukocyte transendothelial migration, were associated with the development of AIS. As a miRNA sponge, differentially quantified circRNAs had the potential to regulate pathways related to AIS, like PI3K-Akt, AMPK, and chemokine pathways. Of 198 differentially quantified circRNAs, 96 circRNAs possessing a strong translational ability could affect cellular structure and activity, like focal adhesion, tight junction, and endocytosis. Most differentially quantified circRNAs were predicted to bind to EIF4A3 and AGO2—two RNA-binding proteins (RBPs)—and to play a role in AIS. Moreover, four of ten circRNAs with verified levels by qRT-PCR (hsa_circ_0112036, hsa_circ_0066867, hsa_circ_0093708, and hsa_circ_0041685) were predicted to participate in processes of AIS, including PI3K-Akt, AMPK, and chemokine pathways as well as endocytosis, and to be potentially useful as diagnostic biomarkers for AIS. In conclusion, plasma exosome-derived circRNAs were significantly differentially quantified between AIS patients and controls and participated in the occurrence and progression of AIS by sponging miRNA/RBPs or translating into proteins, indicating that circRNAs from plasma exosomes could be crucial molecules in the pathogenesis of AIS and promising candidates as diagnostic biomarkers and therapeutic targets for the condition.
IL25 Enhanced Colitis-Associated Tumorigenesis in Mice by Upregulating Transcription Factor GLI1
Authors: Liu Junxi , Qian Bingxiu , Zhou Lin , Shen Gang , Tan Yandan , Liu Siqi , Zhao Zewei , Shi Jianglin , Qi Weiwei , Zhou Ti , Yang Xia , Gao Guoquan , Yang Zhonghan
Published: March 2022

Interleukin-25 (IL17E/IL25) plays a critical role in colitis and intestinal homeostasis. However, the expression and biological role of IL25 in colorectal cancer is not properly understood. In this study, we show that IL25 is mainly expressed by cancer stem cells in the colorectal cancer microenvironment. Genetic deletion of IL25 inhibited tumor formation and growth and prolonged survival in AOM/DSS-treated mice. IL25 stimulated cancer organoid and cancer cells sphere formation and prevented the tumor from chemotherapy-induced apoptosis. Mechanistically, IL25 upregulated stem cell genes LGR5, CD133, and ABC transporters via activating the Hedgehog signaling pathway. IL25 inhibited phosphorylation of AMPK and promoted GLI1 accumulation to maintain cancer stem cells. Moreover, IL25 expression was associated with poor survival in patients with metastatic colorectal cancer. Taken together, our work reveals an immune-associated mechanism that intrinsically confers cancer cell stemness properties. Our results first demonstrated that IL25, as a new potent endogenous Hedgehog pathway agonist, could be an important prognostic factor and therapeutic target for CRC.
Autoantibodies Against Proteins Previously Associated With Autoimmunity in Adult and Pediatric Patients With COVID-19 and Children With MIS-C
Authors: Burbelo Peter D. , Castagnoli Riccardo , Shimizu Chisato , Delmonte Ottavia M. , Dobbs Kerry , Discepolo Valentina , Lo Vecchio Andrea , Guarino Alfredo , Licciardi Francesco , Ramenghi Ugo , Rey-Jurado Emma , Vial Cecilia , Marseglia Gian Luigi , Licari Amelia , Montagna Daniela , Rossi Camillo , Montealegre Sanchez Gina A. , Barron Karyl , Warner Blake M. , Chiorini John A. , Espinosa Yazmin , Noguera Loreani , Dropulic Lesia , Truong Meng , Gerstbacher Dana , Mató Sayonara , Kanegaye John , Tremoulet Adriana H. ,   Pediatric Emergency Medicine Kawasaki Group, Eisenstein Eli M. , Su Helen C. , Imberti Luisa , Poli Maria Cecilia , Burns Jane C. , Notarangelo Luigi D. , Cohen Jeffrey I.
Published: March 2022

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren’s syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.
Feasibility of the Sabellarid Reef Habitat Restoration
Authors: Franzitta Giulio , Colletti Alberto , Savinelli Beatrice , Lo Martire Marco , Corinaldesi Cinzia , Musco Luigi
Published: March 2022

Polychaetes of the genus Sabellaria (Annelida, Sabellariidae) are gregarious bioconstructors that build reefs by assembling rigid tubes with sand grains in shallow waters. Sabellarid bioconstructions provide important ecosystem services such as sediment stabilization, water filtration and the mitigation of coastal erosion as well as nursery areas, shelter and feeding grounds for several marine species. Moreover, sabellarid reefs are exposed to both natural and anthropogenic disturbance and are therefore listed by international directives among the marine habitats deserving protection. We conducted a pilot study to assess the feasibility of habitat restoration with the sabellarid reef through a novel transplantation method. Fragments of S. spinulosa reef were collected at 1 m depth, fixed using epoxy putty into terracotta vases and then attached on the landward side of the two breakwaters in a coastal marine area enclosed in a Site of National Interest (SNI) of the central-western Adriatic (Mediterranean Sea). Overall, 14 of the 24 transplanted fragments (54.2%) survived during the study period (17 months). The total area of the transplanted reef fragments reduced during the early phase, appearing stable toward the end of the experiment. The transplantation method resulted effective given the survival rate observed, however, we did not observe the expected increase in the reef surface. Small-scale variation in environmental conditions such as organic load, sediment granulometry and hydrodynamics might have affected the growth capacity of the transplanted reef fragments. Further studies considering the microscale environmental requirements of this species are needed to better understand the feasibility of sabellarid reef restoration and its large-scale implementation.
A Numerical Model for Determining Deep Methane Flux Linked to the Free Gas Zone: Application to the Ocean Drilling Program Site 995 and Implications for Regional Deep Methane Flux at the Blake Ridge
Authors: Zheng Zihan , Cao Yuncheng , Xu Wenyue , Chen Duofu
Published: March 2022

The lack of the quantification of deep dissolved methane flux prevents us from accurately understanding hydrate accumulation and distribution at a given geologic setting where vertically upward methane advection dominates the hydrate system. The upward deep methane flux was usually applied as an assumed value in many previous studies. Considering the deep methane flux changes the methane concentration in the pore water and further affects the phase transfer between the gas and aqueous phases depending on the in situ methane concentration, we link gas bubbles distribution to deep dissolved methane flux. Here, we constructed a numerical model to quantify the dissolved methane flux from depth based on the parameters related to gas bubble distribution, including the residual gas saturation in sediments and the free gas zone (FGZ) thickness. We then applied our model to ODP Site 995 at the Blake Ridge where methane was sourced from deep layers. Our model results predict an upward deep methane flux of 0.0231 mol/m2/a and the occurrence of another gas interval in deeper sediments, which are consistent with seismic data. We further explored the influence of upward methane flux on hydrate accumulation and found that the thin hydrate occurrence zone at nearby Site 994 likely resulted from a small deep methane flux. Combined with the previous conclusion of high deep methane flux at Site 997, we showed that along the Blake Ridge drilling transect the estimated deep methane fluxes decrease with increasing distance from the crest of the ridge. This approach for quantifying deep methane flux is complementary to the current hydrate accumulation model and provides new insights into the regional methane flux estimation at the Blake Ridge.
Ergodic Structural Diversity Predicts Dynamics in Amorphous Materials
Authors: Yang Zeng-Yu , Wang Yun-Jiang
Published: March 2022

Identification of flexible local environments from a disordered medium has been a long-standing challenge. Here, we introduce a time-relevant structural Shannon entropy as a unique feature of the atomic-scale environment in glass, which is based on a metric of the time-invariant, or ergodic, and Voronoi structural diversity that an atom experiences during a sufficiently long-time thermal fluctuation. This new concept of time-relevant Shannon entropy simultaneously integrates the static topology and the vibrational feature such that it potentially probes all the possible configurational space in a sub-basin of the local potential energy landscape. This structural representation is not only capable of predicting the energy barrier of an elementary structural excitation but also demonstrates a robust correlation with the boson peak in metallic glasses, although the physical entity is defined from a purely structural aspect. The proposition, therefore, represents a successful demonstration of the physics-informed structure–property relationship in amorphous materials.
Combined Estrogen Alpha and Beta Receptor Expression Has a Prognostic Significance for Colorectal Cancer Patients
Authors: Topi Geriolda , Ghatak Souvik , Satapathy Shakti Ranjan , Ehrnström Roy , Lydrup Marie-Louise , Sjölander Anita
Published: March 2022

We reported that high estrogen receptor beta (ERβ) expression is independently associated with better prognosis in female colorectal cancer (CRC) patients. However, estrogen receptor alpha (ERα) is expressed at very low levels in normal colon mucosa, and its prognostic role in CRC has not been explored. Herein, we investigated the combined role of ERα and ERβ expression in the prognosis of female patients with CRC, which, to the best of our knowledge, is the first study to investigate this topic. A total number of 306 primary CRCs were immunostained for ERα and ERβ expression. A Cox regression model was used to evaluate overall survival (OS) and disease-free survival (DFS). The combined expression of high ERβ + negative ERα correlates with longer OS (HR = 0.23; 95% CI: 0.11–0.45, P <0.0001) and DFS (HR = 0.10; 95% CI: 0.03–0.26, P < 0.0001) and a more favorable tumor outcome, as well as significantly higher expression of antitumorigenic proteins than combined expression of low ERβ + positive ERα. Importantly, we found that low ERβ expression was associated with local recurrence of CRC, whereas ERα expression was correlated with liver metastasis. Overall, our results show that the combined high ERβ + negative ERα expression correlated with a better prognosis for CRC patients. Our results suggest that the combined expression of ERα and ERβ could be used as a predictive combination marker for CRC patients, especially for predicting DFS.
Transcutaneous Electrical Acupoint Stimulation Decreases the Incidence of Postoperative Nausea and Vomiting After Laparoscopic Non-gastrointestinal Surgery: A Multi-Center Randomized Controlled Trial
Authors: Gao Wei , Zhang Linzhong , Han Xuechang , Wei Lai , Fang Jie , Zhang Xiaqing , Zhang Jiaqiang , Wang Haiyun , Zhou Qi , Wang Chenggang , Chen Wenting , Ni Xinli , Yang Lan , Du Ruini , Wang Ge , Liu Bingyu , Li Yajuan , Zhang Shanshan , Wang Qiang
Published: March 2022

Importance

Postoperative nausea and vomiting (PONV) gives patients a bad experience and negates their good recovery from surgery.

Objective

This trial aims to assess the preventive effectiveness of transcutaneous electrical acupoint stimulation (TEAS) on the incidence of PONV in high-risk surgical patients.

Design

The large sample size, multicenter, evaluator-blinded, and randomized controlled study was conducted between September 3, 2019 to February 6, 2021.

Setting

The 12 hospitals were from different Chinese provinces.

Participants

After obtaining ethics approval and written informed consent, 1,655 patients with Apfel score ≥ 3 points were enrolled for selective laparoscopic non-gastrointestinal surgery under general anesthesia.

Interventions

Patients were randomly allocated into the TEAS and Sham group with a 1:1 ratio. The TEAS group was stimulated on bilateral Neiguan and Zusanli acupoints after recovery from anesthesia on the surgical day and the next morning for 30 min, while the Sham group received an identical setting as TEAS but without currents delivered. Electronic patient self-reported scale was used to evaluate and record the occurrence of PONV.

Main Outcomes and Measures

Primary clinical end point is the incidence of PONV which was defined as at least one incidence of nausea, retching, or vomiting after operation within postoperative 24 h.

Results

Compared with the Sham treatment, the TEAS lowered the PONV incidence by 4.8% (29.4 vs. 34.2%, P = 0.036) and vomiting incidence by 7.4% (10.4 vs. 17.8%, P < 0.001). TEAS also lowered persistent nausea incidence and PONV scores and decreased PONV related complications and Quality of Recovery−40 scores (P < 0.05). TEAS lowered the 24 h PONV risk by 20% (OR, 0.80, 95% CI, 0.65 −0.98; P = 0.032), and lowered hazard ratio by 17% (HR, 0.83, 95% CI, 0.70–0.99; P = 0.035). Both TEAS and palonosetron were the independent PONV risk protective factors for 24 h PONV incidence and cumulative PONV incidence. The combination of TEAS and palonosetron was the most effective strategy to reduce the PONV incidence (P < 0.001).

Conclusions and Relevance

TEAS attenuated the PONV incidence and severity in high-risk surgical patients and may be applied clinically as a complement therapy to prevent PONV.

Clinical Trial Registration

https://clinicaltrials.gov/ct2/show/NCT04043247, identifier: NCT04043247.
Association Between Extracellular Superoxide Dismutase Activity and 1-Year All-Cause Mortality in Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study
Authors: Li Haiqing , Hong Wei , Zeng Zixiong , Gong Shan , Wu Fan , Wang Zihui , Tian Heshen , Cheng Juan , Sun Ruiting , Gao Mi , Liang Chunxiao , Cao Weitao , Hu Guoping , Li Yuqun , Wei Liping , Zhou Yumin , Ran Pixin
Published: March 2022

Background and Objectives

Accumulating evidence suggests that oxidative stress is involved in the development of chronic obstructive pulmonary disease (COPD) and its progression. Activity of extracellular superoxide dismutase (ecSOD), the only extracellular enzyme eliminating superoxide radicals, has been reported to decline in acute exacerbations of COPD (AECOPD). However, the association between serum ecSOD activity and 1-year all-cause mortality in AECOPD patients remains unclear. The objective of our study was to explore the usefulness of ecSOD activity on admission in AECOPD as an objective predictor for 1-year all-cause mortality.

Methods

We measured serum ecSOD activity in AECOPD patients on admission in a prospective cohort study. We also recorded their laboratory and clinical data. Multivariate Cox regression was used to analyze the association between ecSOD activity and the risk of 1-year all-cause mortality. Restricted cubic spline curves were used to visualize the relationship between ecSOD activity and the hazard ratio of 1-year all-cause mortality.

Results

A total of 367 patients were followed up for 1 year, and 29 patients died during a 1-year follow-up period. Compared with survivors, the non-survivors were older (79.52 ± 8.39 vs. 74.38 ± 9.34 years old, p = 0.004) and had increased levels of tobacco consumption (47.07 ± 41.67 vs. 33.83 ± 31.79 pack-years, p = 0.037). Having an ecSOD activity ≤ 98.8 U/ml was an independent risk factor of 1-year all-cause mortality after adjustment for baseline differences, clinical variables and comorbidities [hazard ratio = 5.51, 95% confidence interval (CI): 2.35–12.95, p < 0.001].

Conclusion

Lower serum ecSOD activity was a strong and independent predictor of 1-year all-cause mortality in AECOPD patients.
The Pocket-Creation Method Facilitates Endoscopic Submucosal Dissection of Gastric Neoplasms Along the Lesser Curvature at the Gastric Angle
Authors: Kitamura Masafumi , Miura Yoshimasa , Shinozaki Satoshi , Lefor Alan Kawarai , Yamamoto Hironori
Published: March 2022

Background

Endoscopic submucosal dissection (ESD) of superficial gastric lesions located along the lesser curvature at the gastric angle is a challenging situation due to paradoxical movement and a protruding angle. The pocket-creation method (PCM) can overcome this difficulty by stabilizing the tip of the endoscope in the pocket and minimizing insufflation of the stomach, which enables horizontal and straight dissection. This study aims to clarify whether the PCM improves the technical outcomes of ESD of superficial gastric neoplasms along the lesser curvature at the angle.

Methods

From October 2006 to June 2021, 158 gastric lesions along the lesser curvature at the angle were resected with needle-type knives. We retrospectively reviewed the records and divided them into the PCM group (n = 61) and the conventional method (CM) group (n = 97). The primary outcome measurement was dissection speed (in mm2/min).

Results

The two groups were not significantly different for baseline characteristics such as macroscopic type and size except for the proportion of adenomas. The proportion of expert endoscopists was not significantly different between the two groups (P = 0.141). The dissection speed was significantly faster in the PCM group than in the CM group (P = 0.001). There were no holes in the resected specimens in the PCM group, while five lesions in the CM group (5%) had a hole (P = 0.182). There were no significant differences in the incidence of adverse events.

Conclusions

This is the first study to show that the PCM outperforms the CM for ESD of lesions located along the lesser curvature at the gastric angle. The PCM facilitated ESD of these lesions by significantly increasing dissection speed when a needle-type knife is used with no increase in adverse events.
Nitrogen Regulates the Distribution of Antibiotic Resistance Genes in the Soil–Vegetable System
Authors: Wang Tingting , Sun Silu , Xu Yanxing , Waigi Michael Gatheru , Odinga Emmanuel Stephen , Vasilyeva Galina K. , Gao Yanzheng , Hu Xiaojie
Published: March 2022

The increasing antibiotic resistance genes (ARGs) in fertilizer-amended soils can potentially enter food chains through their transfer in a soil–vegetable system, thus, posing threats to human health. As nitrogen is an essential nutrient in agricultural production, the effect of nitrogen (in the forms NH4+-N and NO3−-N) on the distribution of ARGs (blaTEM-1, sul1, cmlA, str, and tetO) and a mobile genetic element (MGE; tnpA-4) in a soil–Chinese cabbage system was investigated. Not all the tested genes could transfer from soil to vegetable. For transferable ones (blaTEM-1, sul1, and tnpA-4), nitrogen application influenced their abundances in soil and vegetable but did not impact their distribution patterns (i.e., preference to either leaf or root tissues). For ARGs in soil, effects of nitrogen on their abundances varied over time, and the positive effect of NH4+-N was more significant than that of NO3−-N. The ARG accumulation to vegetables was affected by nitrogen application, and the nitrogen form was no longer a key influencing factor. In most cases, ARGs were found to prefer being enriched in roots, and nitrogen application may slightly affect their migration from root to leaf. The calculated estimated human intake values indicated that both children and adults could intake 106–107 copies of ARGs per day from Chinese cabbage consumption, and nitrogen application affected ARG intake to varying degrees. These results provided a new understanding of ARG distribution in vegetables under the agronomic measures such as nitrogen application, which may offer knowledge for healthy vegetable cultivation in future.
Computational Repurposing of Drugs and Natural Products Against SARS-CoV-2 Main Protease (Mpro) as Potential COVID-19 Therapies
Authors: Piplani Sakshi , Singh Puneet , Petrovsky Nikolai , Winkler David A.
Published: March 2022

We urgently need to identify drugs to treat patients suffering from COVID-19 infection. Drugs rarely act at single molecular targets. Off-target effects are responsible for undesirable side effects and beneficial synergy between targets for specific illnesses. They have provided blockbuster drugs, e.g., Viagra for erectile dysfunction and Minoxidil for male pattern baldness. Existing drugs, those in clinical trials, and approved natural products constitute a rich resource of therapeutic agents that can be quickly repurposed, as they have already been assessed for safety in man. A key question is how to screen such compounds rapidly and efficiently for activity against new pandemic pathogens such as SARS-CoV-2. Here, we show how a fast and robust computational process can be used to screen large libraries of drugs and natural compounds to identify those that may inhibit the main protease of SARS-CoV-2. We show that the shortlist of 84 candidates with the strongest predicted binding affinities is highly enriched (≥25%) in compounds experimentally validated in vivo or in vitro to have activity in SARS-CoV-2. The top candidates also include drugs and natural products not previously identified as having COVID-19 activity, thereby providing leads for experimental validation. This predictive in silico screening pipeline will be valuable for repurposing existing drugs and discovering new drug candidates against other medically important pathogens relevant to future pandemics.
Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability
Authors: Ren Ling , Hu Lidan , Zhang Ying , Liu Jian , Xu Wanyue , Wu Wei , Xu Jingjie , Chen Xiangjun , Yao Ke , Yu Yibo
Published: March 2022

Cataract, opacity of the eye lens, is the leading cause of visual impairment worldwide. The crucial pathogenic factors that cause cataract are misfolding and aggregation of crystallin protein. βB1‐crystallin, which is the most abundant water‐soluble protein in mammalian lens, is essential for lens transparency. A previous study identified the missense mutation βB1‐S93R being responsible for congenital cataract. However, the exact pathogenic mechanism causing cataract remains unclear. The S93 residue, which is located at the first Greek‐key motif of βB1‐crystallin, is highly conserved, and its substitution to Arginine severely impaired hydrogen bonds and structural conformation, which were evaluated via Molecular Dynamic Simulation. The βB1‐S93R was also found to be prone to aggregation in both human cell lines and Escherichia coli. Then, we isolated the βB1‐S93R variant from inclusion bodies by protein renaturation. The βB1-S93R mutation exposed more hydrophobic residues, and the looser structural mutation was prone to aggregation. Furthermore, the S93R mutation reduced the structural stability of βB1-crystallin when incubated at physiological temperature and made it more sensitive to environmental stress, such as UV irradiation or oxidative stress. We also constructed a βB1-S93R cellular model and discovered that βB1-S93R was more sensitive to environmental stress, causing not only aggregate formation but also cellular apoptosis and impaired cellular viability. All of the results indicated that lower solubility and structural stability, sensitivity to environmental stress, vulnerability to aggregation, and impaired cellular viability of βB1-S93R might be involved in cataract development.
Interventions in Nicotinamide Adenine Dinucleotide Metabolism, the Intestinal Microbiota and Microcin Peptide Antimicrobials
Authors: Baquero Fernando , del Campo Rosa , Martínez José-Luis
Published: March 2022

A proper NADH/NAD + balance allows for the flow of metabolic and catabolic activities determining cellular growth. In Escherichia coli, more than 80 NAD + dependent enzymes are involved in all major metabolic pathways, including the post-transcriptional build-up of thiazole and oxazole rings from small linear peptides, which is a critical step for the antibiotic activity of some microcins. In recent years, NAD metabolism boosting drugs have been explored, mostly precursors of NAD + synthesis in human cells, with beneficial effects on the aging process and in preventing oncological and neurological diseases. These compounds also enhance NAD + metabolism in the human microbiota, which contributes to these beneficial effects. On the other hand, inhibition of NAD + metabolism has been proposed as a therapeutic approach to reduce the growth and propagation of tumor cells and mitigating inflammatory bowel diseases; in this case, the activity of the microbiota might mitigate therapeutic efficacy. Antibiotics, which reduce the effect of microbiota, should synergize with NAD + metabolism inhibitors, but these drugs might increase the proportion of antibiotic persistent populations. Conversely, antibiotics might have a stronger killing effect on bacteria with active NAD + production and reduce the cooperation of NAD + producing bacteria with tumoral cells. The use of NADH/NAD + modulators should take into consideration the use of antibiotics and the population structure of the microbiota.
Functional Brain Connectivity and Inhibitory Control in Older Adults: A Preliminary Study
Authors: Brewster Brandon M. , Pasqualini Marcia Smith , Martin Laura E.
Published: March 2022

According to the inhibition deficit hypothesis, the ability to inhibit unwanted or irrelevant thoughts and behaviors decreases with age, which can have a significant impact on cognitive and emotional processing. However, studies examining inhibition and age have shown mixed results, with some studies finding a decrease in inhibitory control as individuals age, while others have found no relationship. The goal of this proof-of-concept study was to examine the underlying neural mechanisms that may explain why some older adults are better than others at inhibitory control by investigating the relationship between resting-state functional connectivity (rsFC) of the salience network, a network critical for detecting and focusing attention toward relevant stimuli while ignoring irrelevant information in the environment, and a behavioral measure of inhibitory control (Stroop Task interference score) in a sample of 65 healthy older individuals (ages 65+). Results revealed no direct effect of age on Stroop performance; however, there was an indirect effect of age on Stroop performance through rsFC. These results suggest that rsFC of the salience network may be an important factor to consider when it comes to understanding individual differences in inhibitory control behavior among older adults.
Prevalence and Predictors of Cerebral Microangiopathy Determined by Pulsatility Index in an Asymptomatic Population From the ILERVAS Project
Authors: Purroy Francisco , Sánchez Enric , Lecube Albert , Arqué Gloria , Vicente-Pascual Mikel , Mauri-Capdevila Gerard , Torreguitart Núria , Hernández Marta , Barbé Ferrán , Fernández Elvira , Pamplona Reinald , Farràs Cristina , Mauricio Dídac , Bermúdez-López Marcelino ,   the ILERVAS project
Published: March 2022

Background: Little is known about the prevalence of cerebral microangiopathy (CM), which is related to cognitive impairment, in an asymptomatic population. Pulsatility index (PI) is an easily measurable parameter of cerebral vascular resistance in transcranial duplex of the middle cerebral artery (MCA) study. We aimed to determine the prevalence of CM measured by PI of MCA in low to moderate vascular risk subjects.

Methods: We included 3,721 subjects between 45 and 70 years without previous history of vascular disease or diabetes mellitus and with at least one other vascular risk factor from the cross-sectional study ILERVAS (Lleida, Spain). Patients underwent transcranial duplex to determine MCA-PI. Possible CM was defined by MCA-PI >1.1. Carotid and femoral arteries ultrasound registration was done to determine the presence, the number, and the area of atheromatous plaques. Body mass index (BMI), pulse pressure (PP) and laboratory data were also recorded.

Results: 439 (11.8%) subjects were excluded due to the low quality of transcranial duplex images. Median age was 57 [IQR 52, 62] years. Possible CM was found in 424 (12.9%) subjects. CM patients had higher prevalence of plaques than non-CM (77.4 vs. 66.4%, p < 0.001). PI showed a positive linear correlation with the number of territories with plaques (r = 0.130, p < 0.001), and the total plaque area (r = 0.082, p < 0.001). The predictors of possible CM were the age, male gender, and PP.

Conclusions: In low-to-moderate vascular risk asymptomatic population, the proportion of abnormal brain microvascular bed determined by MCA-PI is not negligible. The planned 10-year follow-up will describe the clinical relevance of these findings.
Metals, Nanoparticles, Particulate Matter, and Cognitive Decline
Authors: Calderón-Garcidueñas Lilian , Chávez-Franco Diana A. , Luévano-Castro Samuel C. , Macías-Escobedo Edgar , Hernández-Castillo Ariatna , Carlos-Hernández Esperanza , Franco-Ortíz Agustina , Castro-Romero Sandra P. , Cortés-Flores Mónica , Crespo-Cortés Celia Nohemí , Torres-Jardón Ricardo , Stommel Elijah W. , Rajkumar Ravi Philip , Mukherjee Partha S. ,   Research Universidad del Valle de México UVM Group
Published: March 2022

Exposure to metals is ubiquitous and emission sources include gasoline, diesel, smoke from wildfires, contaminated soil, water and food, medical implants, waste recycling facilities, subway exposures, and occupational environments. PM2.5 exposure is associated with impaired cognitive performance, neurobehavioral alterations, incidence of dementia, and Alzheimer's disease (AD) risk. Heavy-duty diesel vehicles are major emitters of metal-rich PM2.5 and nanoparticles in Metropolitan Mexico City (MMC). Cognitive impairment was investigated in 336 clinically healthy, middle-class, Mexican volunteers, age 29.2 ± 13.3 years with 13.7 ± 2.4 years of education using the Montreal Cognitive Assessment (MoCA). MoCA scores varied with age and residency in three Mexican cities with cognition deficits impacting ~74% of the young middle-class population (MoCA ≤ 25). MMC residents ≥31 years (x¯46.2 ± 11.8 y) had MoCA x¯20.4 ± 3.4 vs. low pollution controls 25.2 ± 2.4 (p < 0.0001). Formal education years positively impacted MoCA total scores across all participants (p < 0.0001). Residency in PM2.5 polluted cities impacts multi-domain cognitive performance. Identifying and making every effort to lower key pollutants impacting neural risk trajectories and monitoring cognitive longitudinal performance are urgent. PM2.5 emission control should be prioritized, metal emissions targeted, and neuroprevention interventions implemented early.
Serial Backward Locomotor Treadmill Training Improves Bidirectional Walking Performance in Chronic Stroke
Authors: Awosika Oluwole O. , Chan Dorothy , Rizik Bridget A. , Sucharew Heidi J. , Boyne Pierce , Bhattacharya Amit , Dunning Kari , Kissela Brett M.
Published: March 2022

Background and Research Question

Walking impairment remains a major limitation to functional independence after stroke. Yet, comprehensive and effective strategies to improve walking function after stroke are presently limited. Backward Locomotor Treadmill Training (BLTT) is a promising training approach for improving walking function; however, little is known about its mechanism of effect or the relationship between backward walking training and resulting overground forward walking performance. This study aims to determine the effects of serial BLTT on spatial aspects of backward and forward walking in chronic post-stroke individuals with residual walking impairment.

Methods

Thirty-nine adults (>6 months post-stroke) underwent 6 days of BLTT (3 × /week) over 2 weeks. Outcome measures included PRE-POST changes in backward and forward walking speeds, paretic and non-paretic step lengths, and single-support center of pressure distances. To determine the association between BLTT and overground walking, correlation analyses comparing training-related changes in these variables were performed.

Results

We report an overall improvement in BLTT and overground walking speeds, bilateral step lengths, and single-support center of pressure distances over six training sessions. Further, there were weak positive associations between PRE-POST changes in BLTT speed, BLTT paretic step length, and overground forward walking speed.

Conclusion and Significance

Our findings suggest that individuals with chronic post-stroke walking impairment experience improvements in spatial walking measures during BLTT and overground. Therefore, BLTT may be a potential adjunctive training approach for post-stroke walking rehabilitation.
Effect of Seasonal Variation on Relapse Rate in Patients With Relapsing-Remitting Multiple Sclerosis in Saudi Arabia
Authors: Makkawi Seraj , Aljabri Ammar , Bin Lajdam Ghassan , Albakistani Ammar , Aljohani Abdulrahman , Labban Suhail , Felemban Razaz
Published: March 2022

Multiple sclerosis (MS) is becoming a global subject of study in which some demographic variations are thought to be correlated with its activity. Relapsing-remitting multiple sclerosis (RRMS) is the most common demyelinating disorder, characterized by periods of exacerbating attacks, followed by partial or complete remission. Several factors might play a role in disease progression and relapse frequency, such as vitamin D, ultraviolet B radiation, estrogen levels, smoking, obesity, and unhealthy lifestyles. In this study, we identified the relationship between seasonal variation and relapse rate and correlated the latter with sex, age, and vitamin D levels in patients with RRMS in Jeddah, Saudi Arabia. We retrospectively collected data from 182 RRMS patients between 2016 and 2021. A total of 219 relapses were documented in 106 patients (58.2 %). The relapse per patient ratio showed a sinusoidal pattern, peaking in January at a rate of 0.49 and troughed in June at a rate of 0.18. There was no difference in relapse rates between men and women (p =0.280). There was a significant negative correlation between vitamin D levels and relapse rate (r = −0.312, p =0.024). Therefore, the relapse rate was higher during the winter and was correlated with low vitamin D levels. However, relapses are likely multifactorial, and more population-based studies are needed to understand the role of environmental variables in MS exacerbation. A better understanding of this relationship will allow for improved treatment and possibly better prevention of relapse.
Daily-Life Physical Activity of Healthy Young Adults Associates With Function and Structure of the Hippocampus
Authors: Seoane Sara , Ezama Laura , Janssen Niels
Published: March 2022

Previous research on Physical Activity (PA) has been highly valuable in elucidating how PA affects the structure and function of the hippocampus in elderly populations that take part in structured interventions. However, how PA affects the hippocampus in younger populations that perform PA during daily-life activities remains poorly understood. In addition, this research has not examined the impact of PA on the internal structure of the hippocampus. Here, we performed a cross-sectional exploration of the way structural and functional aspects of the hippocampus are associated with habitual PA performed during work, leisure time, and sports in the daily lives of healthy young adults (n = 30; 14 female; mean age = 23.9 y.o.; SD = 7.8 y.o.). We assessed PA in these three different contexts through a validated questionnaire. The results show that PA performed during work time correlated with higher subicular volumes. In addition, we found that PA changed functional connectivity (FC) between a location in the middle/posterior hippocampus and regions of the default mode network, and between a location in the anterior hippocampus and regions of the somatomotor network. No statistical effects of PA performed during leisure time and sports were found. The results generalize the impact of PA on younger populations and show how PA performed in daily-life situations correlates with the precise internal structure and functional connectivity of the hippocampus.
Gender Differences in the Psychosocial Determinants Underlying the Onset and Maintenance of Alcohol Use Disorder
Authors: Maxwell Andrea M. , Harrison Katherine , Rawls Eric , Zilverstand Anna
Published: March 2022

A large number of different mechanisms have been linked to Alcohol Use Disorder (AUD), including psychosocial, neurocognitive, affective, and neurobiological factors. Gender has been shown to impact the presentation and progression of AUD; yet, little work has been done to parse the different mechanisms underlying AUD within the lens of gender differences. A review of the literature on adolescence revealed that psychosocial factors, in particular lack of family social support and interactions with peers, drive the onset of alcohol use more strongly in girls relative to boys. However, research done on gender differences in disease progression in adults remains limited. Our gender-specific analysis of the mechanisms underlying AUD in adults revealed that lack of social support was causally linked to negative affect, mental health symptoms, and AUD symptom severity in women, but not men. These novel results suggest that psychosocial factors may play a gender-specific role not only in the onset of use in adolescence, but also in the maintenance of addiction in adults. If confirmed, this suggests the need for investigating gender-specific recovery trajectories. In this perspective piece, we review the literature regarding gender differences in the onset and maintenance of AUD and present original data that support unique risk factors in women.
Azepine-Indole Alkaloids From Psychotria nemorosa Modulate 5-HT2A Receptors and Prevent in vivo Protein Toxicity in Transgenic Caenorhabditis elegans
Authors: Kirchweger Benjamin , Klein-Junior Luiz C. , Pretsch Dagmar , Chen Ya , Cretton Sylvian , Gasper André L. , Heyden Yvan Vander , Christen Philippe , Kirchmair Johannes , Henriques Amélia T. , Rollinger Judith M.
Published: March 2022

Nemorosine A (1) and fargesine (2), the main azepine-indole alkaloids of Psychotria nemorosa, were explored for their pharmacological profile on neurodegenerative disorders (NDs) applying a combined in silico–in vitro–in vivo approach. By using 1 and 2 as queries for similarity-based searches of the ChEMBL database, structurally related compounds were identified to modulate the 5-HT2A receptor; in vitro experiments confirmed an agonistic effect for 1 and 2 (24 and 36% at 10 μM, respectively), which might be linked to cognition-enhancing properties. This and the previously reported target profile of 1 and 2, which also includes BuChE and MAO-A inhibition, prompted the evaluation of these compounds in several Caenorhabditis elegans models linked to 5-HT modulation and proteotoxicity. On C. elegans transgenic strain CL4659, which expresses amyloid beta (Aβ) in muscle cells leading to a phenotypic paralysis, 1 and 2 reduced Aβ proteotoxicity by reducing the percentage of paralyzed worms to 51%. Treatment of the NL5901 strain, in which α-synuclein is yellow fluorescent protein (YFP)-tagged, with 1 and 2 (10 μM) significantly reduced the α-synuclein expression. Both alkaloids were further able to significantly extend the time of metallothionein induction, which is associated with reduced neurodegeneration of aged brain tissue. These results add to the multitarget profiles of 1 and 2 and corroborate their potential in the treatment of NDs.
Roles of Long Non-coding RNAs in the Development of Aging-Related Neurodegenerative Diseases
Authors: Ni Yu-Qing , Xu Hui , Liu You-Shuo
Published: March 2022

Aging-related neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are gradually becoming the primary burden of society and cause significant health-care concerns. Aging is a critical independent risk factor for neurodegenerative diseases. The pathological alterations of neurodegenerative diseases are tightly associated with mitochondrial dysfunction, inflammation, and oxidative stress, which in turn stimulates the further progression of neurodegenerative diseases. Given the potential research value, lncRNAs have attracted considerable attention. LncRNAs play complex and dynamic roles in multiple signal transduction axis of neurodegeneration. Emerging evidence indicates that lncRNAs exert crucial regulatory effects in the initiation and development of aging-related neurodegenerative diseases. This review compiles the underlying pathological mechanisms of aging and related neurodegenerative diseases. Besides, we discuss the roles of lncRNAs in aging. In addition, the crosstalk and network of lncRNAs in neurodegenerative diseases are also explored.
Five Hours Total Sleep Deprivation Does Not Affect CA1 Dendritic Length or Spine Density
Authors: Brodin Alvin T. S. , Gabulya Sarolta , Wellfelt Katrin , Karlsson Tobias E.
Published: March 2022

Sleep is essential for long term memory function. However, the neuroanatomical consequences of sleep loss are disputed. Sleep deprivation has been reported to cause both decreases and increases of dendritic spine density. Here we use Thy1-GFP expressing transgenic mice to investigate the effects of acute sleep deprivation on the dendritic architecture of hippocampal CA1 pyramidal neurons. We found that 5 h of sleep deprivation had no effect on either dendritic length or dendritic spine density. Our work suggests that no major neuroanatomical changes result from a single episode of sleep deprivation.
Where Is It Like to Be an Octopus?
Authors: Carls-Diamante Sidney
Published: March 2022

The cognitive capacities and behavioural repertoire of octopuses have led to speculation that these animals may possess consciousness. However, the nervous system of octopuses is radically different from those typically associated with conscious experience: rather than being centralised and profoundly integrated, the octopus nervous system is distributed into components with considerable functional autonomy from each other. Of particular note is the arm nervous system: when severed, octopus arms still exhibit behaviours that are nearly identical to those exhibited when the animal is intact. Given these factors, there is reason to speculate that if octopuses do possess consciousness, it may be of a form highly dissimilar to familiar models. In particular, it may be that the octopus arm is capable of supporting an idiosyncratic field of consciousness. As such, in addition to the likelihood that there is something it is like to be an octopus, there may also be something it is like to be an octopus arm. This manuscript explores this possibility.
Dietary Fiber as a Counterbalance to Age-Related Microglial Cell Dysfunction
Authors: Vailati-Riboni Mario , Rund Laurie , Caetano-Silva Maria Elisa , Hutchinson Noah T. , Wang Selena S. , Soto-Díaz Katiria , Woods Jeffrey A. , Steelman Andrew J. , Johnson Rodney W.
Published: March 2022

With increasing age, microglia shift toward a pro-inflammatory phenotype that may predispose individuals to neurodegenerative disease. Because fiber fermentation in the colon produces bioactive short-chain fatty acids (SCFAs; e.g., acetate, butyrate, and propionate) that signal through the gut-brain axis, increasing dietary fiber may prevent or reverse age-related dysregulation of microglia. Adult (3–4 months old) and aged (23–24 months old) male and female mice were given ad libitum access to a modified AIN-93M diet with 1% cellulose or the same diet with 2.5 or 5.0% inulin for 8 weeks. Several adult and aged male mice fed 0 or 5% inulin were randomly selected for whole brain single-cell RNA sequencing (scRNA-seq) and differential gene expression analysis to classify brain microglia according to gene expression profile; and identify additional genetic markers of aging as possible targets for dietary interventions. Microglia were isolated from remaining mice and expression of selected aging-, inflammatory-, and sensome-related genes was assessed by Fluidigm as was the ex vivo secretion of tumor necrosis factor-alpha (TNF-α). SCFAs were measured in samples collected from the cecum. Microglia from adult and aged mice segregated into distinct phenotypes according to their gene expression profile. In aged mice, a considerably greater proportion of the population of microglia was identified being “activated” and a considerably smaller proportion was identified being “quiescent.” These findings using whole brain scRNA-seq were largely corroborated using highly purified microglia and Fluidigm analysis to assess a selected panel of genes. Aged mice compared to adults had lower levels of SCFA’s in cecum. Dietary inulin increased SCFAs in cecum and mostly restored microglial cell gene expression and TNF-α secretion to that seen in adults. Sex differences were observed with females having lower levels of SCFAs in cecum and increased neuroinflammation. Overall, these data support the use of fiber supplementation as a strategy to counterbalance the age-related microglial dysregulation.