bluuebunny/crossref_metadata_2025 huggingface dataset:
The Clinical Features and Predictive Factors of Nocturnal Enuresis in Adult Women
Authors: Song Qi-Xiang , Li Jiayi , Gu Yiyuan , Xu Lei , Abrams Paul , Xue Wei
Published: January 2022

Objective

Our current knowledge on nocturnal enuresis (NE) in adults is scarce due to its uncommon nature. The present study was designed to investigate symptom characteristics and risk factors of NE in adult women to improve the current clinical understanding and management of this rare disease.

Methods

Over a 3-year period, we enrolled 70 adult women who complained of bedwetting, with a frequency of at least once per week and a symptom duration of 3 months or longer. Patients were excluded if they had known pregnancy, current urinary tract infection, untreated malignancies, anatomical abnormalities, and irregular sleep cycle. The International Consultation on Incontinence Modular Questionnaire—female lower urinary tract symptoms and bladder diary were employed to appraise lower urinary tract symptoms and voiding behavior. Urodynamics was performed to assess the bladder function. A linear regression analysis was applied to determine potential risk factors for NE frequency.

Results

Among the recruited subjects, comorbidities and lower urinary tract symptoms were frequently reported. On bladder diary, patients commonly presented with nocturnal polyuria (NP), reduced nocturnal voided volumes (RNVVs), or both. Urodynamics revealed multiple dysfunctions, namely, detrusor overactivity (DO), urodynamic stress incontinence (USI), reduced compliance, bladder outlet obstruction, detrusor underactivity (DU), and simultaneous DO and DU. Patients with more frequent NE (≥4/week) demonstrated markedly increased body mass index, more comorbid conditions, worse incontinence symptoms, NP or NP plus RNVVs, reduced compliance, and poorer voiding possibly owing to DU. Whereas, RNVVs alone and worse overactive bladder-related parameters were associated with milder NE. Multivariate analysis indicated that frequency/urgency quality of life, incontinence symptom, NP + RNVVs, poor flow, increased bladder sensation, USI, and simultaneous detrusor overactivity plus DU were independent risk factors for NE severity.

Conclusion

NE in adult women may have both urological and non-urological pathophysiology. Imbalanced circadian urine production, jeopardized continence mechanisms, overactive bladder, and DU-induced poor voiding are major factors that contribute to the pathogenesis of NE in adult women. Focused treatments on restoring these functions should be individually considered.
Effects of Elobixibat on Constipation and Lipid Metabolism in Patients With Moderate to End-Stage Chronic Kidney Disease
Authors: Matsuyama Momoko , Hirai Keiji , Nonaka Hiroaki , Ueda Moeka , Morino Junki , Kaneko Shohei , Minato Saori , Mutsuyoshi Yuko , Yanai Katsunori , Ishii Hiroki , Kitano Taisuke , Aomatsu Akinori , Miyazawa Haruhisa , Ito Kiyonori , Ueda Yuichiro , Ookawara Susumu , Morishita Yoshiyuki
Published: January 2022

Objective:

The aim of this study was to investigate the effects of elobixibat on constipation and lipid metabolism; and determine the factors associated with the effect of elobixibat on constipation in patients with moderate to end-stage chronic kidney disease (CKD).

Methods:

Stool frequency and serum lipid parameters were retrospectively analyzed before and after 4 weeks of elobixibat administration in 42 patients (CKD stage G3, 6; stage G4, 9; stage G5, 9; stage G5D, 18). Relationships between the change in stool frequency after initiation of elobixibat and various clinical parameters were analyzed by using linear regression analysis.

Results:

Elobixibat increased stool frequency from 0.5 ± 0.4 per day to 1.1 ± 0.6 per day (p < 0.001) regardless of whether patients were undergoing dialysis, on concomitant laxatives, or were administered elobixibat before or after breakfast. Elobixibat reduced low-density lipoprotein cholesterol concentration (from 90.9 ± 37.2 mg/dL to 77.5 ± 34.8 mg/dL, p < 0.05) and increased high-density lipoprotein cholesterol concentration (from 44.9 ± 14.3 mg/dL to 57.0 ± 25.8 mg/dL, p < 0.05), but did not change triglyceride concentration. Adverse effects were observed in two patients (nausea and diarrhea). Only phosphate concentration was correlated with the change in stool frequency after initiation of elobixibat (standard coefficient = 0.321, p = 0.043).

Conclusions:

Elobixibat improved constipation and lipid metabolism in patients with moderate to end-stage CKD, without serious adverse events.
The Human Microbiome in Chronic Kidney Disease: A Double-Edged Sword
Authors: Wehedy Eman , Shatat Ibrahim F. , Al Khodor Souhaila
Published: January 2022

Chronic kidney disease (CKD) is an increasing global health burden. Current treatments for CKD include therapeutics to target factors that contribute to CKD progression, including renin–angiotensin–aldosterone system inhibitors, and drugs to control blood pressure and proteinuria control. Recently, associations between chronic disease processes and the human microbiota and its metabolites have been demonstrated. Dysbiosis—a change in the microbial diversity—has been observed in patients with CKD. The relationship between CKD and dysbiosis is bidirectional; gut-derived metabolites and toxins affect the progression of CKD, and the uremic milieu affects the microbiota. The accumulation of microbial metabolites and toxins is linked to the loss of kidney functions and increased mortality risk, yet renoprotective metabolites such as short-chain fatty acids and bile acids help restore kidney functions and increase the survival rate in CKD patients. Specific dietary interventions to alter the gut microbiome could improve clinical outcomes in patients with CKD. Low-protein and high-fiber diets increase the abundance of bacteria that produce short-chain fatty acids and anti-inflammatory bacteria. Fluctuations in the urinary microbiome are linked to increased susceptibility to infection and antibiotic resistance. In this review, we describe the potential role of the gut, urinary and blood microbiome in CKD pathophysiology and assess the feasibility of modulating the gut microbiota as a therapeutic tool for treating CKD.
Prognosis of Patients With Colorectal Cancer and Apical Lymph Node Metastasis at the Inferior Mesenteric Artery: A Systematic Review and Meta-Analysis
Authors: Zhou Senjun , Shen Yi , Huang Chen , Li Gang
Published: January 2022

Background

This review was designed to compile the evidence on the prognosis of patients with colorectal cancer and apical lymph node (APN) metastasis and the long-term benefit of inferior mesenteric artery lymph node (IMA-LN) resection.

Methods

We searched the PubMed Central, Cochrane library, EMBASE, and MEDLINE databases from inception until May 2021 for relevant publications. We assess the quality of the studies using the Newcastle Ottawa scale. We conducted a random-effects model meta-analysis and report pooled hazard ratios (HRs) with 95% confidence intervals (CIs).

Results

We analyzed data from 13 studies conducted in Japan, China, and Korea with 6,193 participants. Most studies were retrospective in nature and of low quality. We found that patients with APN metastasis had shorter OSs (pooled HR, 2.41; 95% CI, 1.92–3.02) and PFSs (pooled HR, 2.42; 95% CI, 1.90–3.09) than the patients without the metastasis. We identified significant heterogeneity without publication bias for both outcomes. Moreover, our sensitivity analysis revealed robust estimates were robust for the individual effects.

Conclusion

Our findings suggest that patients with colorectal cancer and APN metastases have significantly worse OS and DFS than those without the metastasis. However, inclusion of low-quality retrospective studies with high heterogeneity limits the generalizability of study findings.
Effect of Clinical Typing on Serum Urate Targets of Benzbromarone in Chinese Gout Patients: A Prospective Cohort Study
Authors: Xue Xiaomei , Yuan Xuan , Han Lin , Li Xinde , Merriman Tony R. , Cui Lingling , Liu Zhen , Sun Wenyan , Wang Can , Yan Fei , He Yuwei , Ji Aichang , Lu Jie , Li Changgui
Published: January 2022

Introduction

Achieving a goal of serum urate levels in patients with gout is an important way to prevent gout and its complications while it remains difficult with a low targeting rate worldwidely. Currently, hyperuricemia classification has not been widely applied to the management of gout owing to insufficient clinical evidences. This study aimed to evaluate the effectiveness of achieving target urate based on hyperuricemia classification in Chinese patients with gout.

Methods

In this prospective study, patients with gout receiving urate lowering therapy with benzbromarone were assigned to two groups, a renal underexcretion and an unclassified type. The primary endpoint was the proportion of patients achieving the serum urate target (<360 μmol/L) during the 12-week study. The frequency of acute gout attacks as well as physical and chemical indicators were secondary endpoints.

Results

Target serum urate level was achieved in 60.5% of underexcretors compared with 39.0% of patients of the unclassified type at week 12 (P = 0.002). Blood glucose and cholesterol levels were lower in the underexcretor group compared with the unclassified type group at the end of the trial, without significant different frequencies in gout flare during the study. In subgroup analysis, stratified by body mass index and estimated glomerular filtration rate, the proportion of patients with serum urate <360 μmol/L was greater in the underexcretion compared with the unclassified type group.

Conclusions

The increased achievement of target serum urate in the underexcretion group supports the use of a clinical hyperuricemia typing treatment strategy for gout.
Effects of Prone Positioning on Respiratory Mechanics and Oxygenation in Critically Ill Patients With COVID-19 Requiring Venovenous Extracorporeal Membrane Oxygenation
Authors: Laghlam Driss , Charpentier Julien , Hamou Zakaria Ait , Nguyen Lee S. , Pene Frédéric , Cariou Alain , Mira Jean-Paul , Jozwiak Mathieu
Published: January 2022

Background:

The effect of prone positioning (PP) on respiratory mechanics remains uncertain in patients with severe acute respiratory distress syndrome (ARDS) requiring venovenous extracorporeal membrane oxygenation (VV-ECMO).

Methods:

We prospectively analyzed the effects of PP on respiratory mechanics from continuous data with over a thousand time points during 16-h PP sessions in patients with COVID-19 and ARDS under VV-ECMO conditions. The evolution of respiratory mechanical and oxygenation parameters during the PP sessions was evaluated by dividing each PP session into four time quartiles: first quartile: 0–4 h, second quartile: 4–8 h, third quartile: 8–12 h, and fourth quartile: 12–16 h.

Results:

Overall, 38 PP sessions were performed in 10 patients, with 3 [2–5] PP sessions per patient. Seven (70%) patients were responders to at least one PP session. PP significantly increased the PaO2/FiO2 ratio by 14 ± 21% and compliance by 8 ± 15%, and significantly decreased the oxygenation index by 13 ± 18% and driving pressure by 8 ± 12%. The effects of PP on respiratory mechanics but not on oxygenation persisted after supine repositioning. PP-induced changes in different respiratory mechanical parameters and oxygenation started as early as the first-time quartile, without any difference in PP-induced changes among the different time quartiles. PP-induced changes in driving pressure (−14 ± 14 vs. −6 ± 10%, p = 0.04) and mechanical power (−11 ± 13 vs. −0.1 ± 12%, p = 0.02) were significantly higher in responders (increase in PaO2/FiO2 ratio > 20%) than in non-responder patients.

Conclusions:

In patients with COVID-19 and severe ARDS, PP under VV-ECMO conditions improved the respiratory mechanical and oxygenation parameters, and the effects of PP on respiratory mechanics persisted after supine repositioning.
Screening for Stereopsis Using an Eye-Tracking Glasses-Free Display in Adults: A Pilot Study
Authors: Liu Fang , Zhao Jing , Han Tian , Shen Yang , Li Meng , Liu Jingrong , Yang Dong , Fang Yong , Yan Li , Zhou Xingtao
Published: January 2022

Purpose:

To explore the feasibility and repeatability of a novel glasses-free display combined with random-dot stimulus and eye-tracking technology for screening stereopsis in adults.

Methods:

A total of 74 patients aged 18–44 years were recruited in this study (male: female, 32:42), including 33 patients with high myopia [≤ -6.0 diopters (D)] and 41 patients with moderate-to-low myopia (>-6.0 D). Stereopsis was measured using glasses-free, polarized, and Titmus stereotests. All patients completed a visual fatigue questionnaire after the polarized stereotest and glasses-free test. Kendall's W and Cohen's Kappa tests were used to evaluate repeatability and consistency of the glasses-free stereotest.

Results:

The stereotest results using the glasses-free monitor showed strong repeatability in the three consecutive tests (W = 0.968, P < 0.01) and good consistency with the polarized stereotest and Titmus test results (vs. polarization: Kappa = 0.910, P < 0.001; vs. Titmus: Kappa = 0.493, P < 0.001). Stereopsis levels of the high myopia group were significantly poorer than those of the moderate-to-low myopia group in three stereotest monitors (all P < 0.05). There was no significant difference in visual fatigue level between the polarized and the glasses-free display test (P = 0.72). Compared with the polarized test, 56.76% of patients preferred the glasses-free display and found it more comfortable, 20.27% reported both tests to be acceptable.

Conclusions:

In our adult patients, the new eye-tracking glasses-free display system feasibly screened stereopsis with good repeatability, consistency, and patient acceptance.
Current Advances in Mechanisms and Treatment of Dry Eye Disease: Toward Anti-inflammatory and Immunomodulatory Therapy and Traditional Chinese Medicine
Authors: Ling Jiawei , Chan Ben Chung-Lap , Tsang Miranda Sin-Man , Gao Xun , Leung Ping Chung , Lam Christopher Wai-Kei , Hu Jiang-Miao , Wong Chun Kwok
Published: January 2022

Dry eye is currently one of the most common ocular surface disease. It can lead to ocular discomfort and even cause visual impairment, which greatly affects the work and quality of life of patients. With the increasing incidence of dry eye disease (DED) in recent years, the disease is receiving more and more attention, and has become one of the hot research fields in ophthalmology research. Recently, with the in-depth research on the etiology, pathogenesis and treatment of DED, it has been shown that defects in immune regulation is one of the main pathological mechanisms of DED. Since the non-specific and specific immune response of the ocular surface are jointly regulated, a variety of immune cells and inflammatory factors are involved in the development of DED. The conventional treatment of DED is the application of artificial tears for lubricating the ocular surface. However, for moderate-to-severe DED, treatment with anti-inflammatory drugs is necessary. In this review, the immunomodulatory mechanisms of DED and the latest research progress of its related treatments including Chinese medicine will be discussed.
The Future of Precision Prevention for Advanced Melanoma
Authors: Lee Katie J. , Betz-Stablein Brigid , Stark Mitchell S. , Janda Monika , McInerney-Leo Aideen M. , Caffery Liam J. , Gillespie Nicole , Yanes Tatiane , Soyer H. Peter
Published: January 2022

Precision prevention of advanced melanoma is fast becoming a realistic prospect, with personalized, holistic risk stratification allowing patients to be directed to an appropriate level of surveillance, ranging from skin self-examinations to regular total body photography with sequential digital dermoscopic imaging. This approach aims to address both underdiagnosis (a missed or delayed melanoma diagnosis) and overdiagnosis (the diagnosis and treatment of indolent lesions that would not have caused a problem). Holistic risk stratification considers several types of melanoma risk factors: clinical phenotype, comprehensive imaging-based phenotype, familial and polygenic risks. Artificial intelligence computer-aided diagnostics combines these risk factors to produce a personalized risk score, and can also assist in assessing the digital and molecular markers of individual lesions. However, to ensure uptake and efficient use of AI systems, researchers will need to carefully consider how best to incorporate privacy and standardization requirements, and above all address consumer trust concerns.
Key Factors Governing Microbial Community in Extremely Acidic Mine Drainage (pH <3)
Authors: Huang Ye , Li Xiu-Tong , Jiang Zhen , Liang Zong-Lin , Wang Pei , Liu Zheng-Hua , Li Liang-Zhi , Yin Hua-Qun , Jia Yan , Huang Zhong-Sheng , Liu Shuang-Jiang , Jiang Cheng-Ying
Published: January 2022

The microbial community of acid mine drainage (AMD) fascinates researchers by their adaption and roles in shaping the environment. Molecular surveys have recently helped to enhance the understanding of the distribution, adaption strategy, and ecological function of microbial communities in extreme AMD environments. However, the interactions between the environment and microbial community of extremely acidic AMD (pH <3) from different mining areas kept unanswered questions. Here, we measured physicochemical parameters and profiled the microbial community of AMD collected from four mining areas with different mineral types to provide a better understanding of biogeochemical processes within the extremely acidic water environment. The prominent physicochemical differences across the four mining areas were in SO42−, metal ions, and temperature, and distinct microbial diversity and community assemblages were also discovered in these areas. Mg2+ and SO42− were the predominant factors determining the microbial structure and prevalence of dominant taxa in AMD. Leptospirillum, Ferroplasma, and Acidithiobacillus were abundant but showed different occurrence patterns in AMD from different mining areas. More diverse communities and functional redundancy were identified in AMD of polymetallic mining areas compared with AMD of copper mining areas. Functional prediction revealed iron, sulfur, nitrogen, and carbon metabolisms driven by microorganisms were significantly correlated with Mg2+ and SO42−, Ca2+, temperature, and Fe2+, which distinguish microbial communities of copper mine AMD from that of polymetallic mine AMD. In summary, microbial diversity, composition, and metabolic potential were mainly shaped by Mg2+ and SO42− concentrations of AMD, suggesting that the substrate concentrations may contribute to the distinct microbiological profiles of AMD from different mining areas. These findings highlight the microbial community structure in extremely acidic AMD forming by types of minerals and the interactions of physicochemical parameters and microbiology, providing more clues of the microbial ecological function and adaptation mechanisms in the extremely acidic environment.
Nε-Lysine Acetylation of the Histone-Like Protein HBsu Regulates the Process of Sporulation and Affects the Resistance Properties of Bacillus subtilis Spores
Authors: Luu Jackson , Mott Connor M. , Schreiber Olivia R. , Giovinco Holly M. , Betchen Melanie , Carabetta Valerie J.
Published: January 2022

Bacillus subtilis produces dormant, highly resistant endospores in response to extreme environmental stresses or starvation. These spores are capable of persisting in harsh environments for many years, even decades, without essential nutrients. Part of the reason that these spores can survive such extreme conditions is because their chromosomal DNA is well protected from environmental insults. The α/β-type small acid-soluble proteins (SASPs) coat the spore chromosome, which leads to condensation and protection from such insults. The histone-like protein HBsu has been implicated in the packaging of the spore chromosome and is believed to be important in modulating SASP-mediated alterations to the DNA, including supercoiling and stiffness. Previously, we demonstrated that HBsu is acetylated at seven lysine residues, and one physiological function of acetylation is to regulate chromosomal compaction. Here, we investigate if the process of sporulation or the resistance properties of mature spores are influenced by the acetylation state of HBsu. Using our collection of point mutations that mimic the acetylated and unacetylated forms of HBsu, we first determined if acetylation affects the process of sporulation, by determining the overall sporulation frequencies. We found that specific mutations led to decreases in sporulation frequency, suggesting that acetylation of HBsu at some sites, but not all, is required to regulate the process of sporulation. Next, we determined if the spores produced from the mutant strains were more susceptible to heat, ultraviolet (UV) radiation and formaldehyde exposure. We again found that altering acetylation at specific sites led to less resistance to these stresses, suggesting that proper HBsu acetylation is important for chromosomal packaging and protection in the mature spore. Interestingly, the specific acetylation patterns were different for the sporulation process and resistance properties of spores, which is consistent with the notion that a histone-like code exists in bacteria. We propose that specific acetylation patterns of HBsu are required to ensure proper chromosomal arrangement, packaging, and protection during the process of sporulation.
Metabolomic Profiling Reveals New Insight of Fowl Adenovirus Serotype 4 Infection
Authors: Ma Haiying , Niu Yujuan
Published: January 2022

Highly pathogenic fowl adenovirus serotype 4 (FAdV-4) is the causative agent of hydropericardium syndrome (HPS), which is characterized by pericardial effusion and hepatitis, and is one of the foremost causes of economic losses to the poultry industry over the last 30 years. However, the metabolic changes in cells in response to FAdV-4 infection remain unclear. In order to understand the metabolic interactions between the host cell and virus, we utilized ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry to analyze the metabolic profiles with hepatocellular carcinoma cell line (LMH) infected with FAdV-4. The results showed that FAdV-4 could restore metabolic networks in LMH cells and tricarboxylic acid cycle, glycolysis, and metabolism of purines, pyrimidines, alanine, aspartate, glutamate, and amino sugar and nucleotide sugar moieties. Moreover, FAdV-4 production was significantly reduced in LMH cells cultured in glucose or glutamine-deficient medium. These observations highlighted the importance of host cell metabolism in virus replication. Therefore, similarities and disparities in FAdV-4-regulation of the metabolism of host cells could help improve targeted drug and reduce infection.
Development of Loop-Mediated Isothermal Amplification Assay Targeting lytA and psaA Genes for Rapid and Visual Diagnosis of Streptococcus pneumoniae Pneumonia in Children
Authors: Du Shuheng , Yan Chao , Du Bing , Zhao Hanqing , Xue Guanhua , Zheng Ping , Feng Yanling , Cui Jinghua , Gan Lin , Feng Junxia , Fan Zheng , Xu Ziying , Fu Tongtong , Fu Hanyu , Zhang Qun , Li Nannan , Zhang Rui , Liu Shiyu , Li Xiaoran , Cui Xiaohu , Zhou Yao , Zhang Qi , Chen Yaodong , Yuan Jing
Published: January 2022

Streptococcus pneumoniae (S. pneumoniae) is a common major human pathogen associated with community-acquired pneumonia, septicemia, meningitis, and otitis media. It is difficult to isolate and identify S. pneumoniae form clinical samples. To evaluate a novel, rapid, sensitive, and specific loop-mediated isothermal amplification (LAMP) assay to detect S. pneumoniae pneumonia in children, we designed specific LAMP primers targeting lytA and psaA genes. We optimized the reaction time and reaction system, and evaluated its sensitivity and specificity of detection using real-time turbidity monitoring and visual observation. We also analyzed the molecular characteristics of the isolates obtained from the positive samples. The primer sets LytA-1 and PsaA-2 amplified the genes in the shortest times, and 63°C was confirmed as the optimum reaction temperature. The detection sensitivity of each reaction was 10 and 100 copies/μL with primer sets LytA-1 and PsaA-2, respectively. This LAMP assay showed no cross-reactivity with other 27 pathogens. To describe the availability of this method, we collected 748 clinical samples from children with pneumonia. Among them, 135 were confirmed to be S. pneumoniae positive by LAMP. The sensitivity was 100% (95% CI 96.4–100%), specificity 99.0% (95% CI 97.8–99.6%). Including them, 50 were co-infected with Mycoplasma pneumoniae. This LAMP assay detected S. pneumoniae in 1 h and the results can be identified with visual naked eyes. Thus, it will be a powerful tool for S. pneumoniae early diagnosis and effective antibiotic therapy.
Prophage Gene Rv2650c Enhances Intracellular Survival of Mycobacterium smegmatis
Authors: Fan Xiangyu , Liu Zichen , Wan Zhibin , Zou Hanlu , Ji Mengzhi , Sun Kaili , Gao Rongfeng , Li Zhongfang , Li Wu
Published: January 2022

Background

Induced by the pathogen Mycobacterium tuberculosis, tuberculosis remains one of the most dangerous infectious diseases in the world. As a special virus, prophage is domesticated by its host and are major contributors to virulence factors for bacterial pathogenicity. The function of prophages and their genes in M. tuberculosis is still unknown.

Methods

Rv2650c is a prophage gene in M. tuberculosis genome. We constructed recombinant Mycobacterium smegmatis (M. smegmatis) to observe bacteria morphology and analyze the resistance to various adverse environments. Recombinant and control strains were used to infect macrophages, respectively. Furthermore, we performed ELISA experiments of infected macrophages.

Results

Rv2650c affected the spread of colonies of M. smegmatis and enhanced the resistance of M. smegmatis to macrophages and various stress agents such as acid, oxidative stress, and surfactant. ELISA experiments revealed that the Rv2650c can inhibit the expression of inflammatory factors TNF-α, IL-10, IL-1β, and IL-6.

Conclusion

This study demonstrates that the prophage gene Rv2650c can inhibit the spread of colonies and the expression of inflammatory factors and promote intracellular survival of M. smegmatis. These results build the foundation for the discovery of virulence factors of M. tuberculosis, and provide novel insights into the function of the prophage in Mycobacterium.
Exosomes Secreted by Nucleus Pulposus Stem Cells Derived From Degenerative Intervertebral Disc Exacerbate Annulus Fibrosus Cell Degradation via Let-7b-5p
Authors: Zhuang Yin , Song Sheng , Xiao Dan , Liu Xueguang , Han Xiaofei , Du Shihao , Li Yuan , He Yanming , Zhang Shujun
Published: January 2022

The pathogenesis of intervertebral disc degeneration (IDD) is complex and remains unclear. Nucleus pulposus stem cells (NPSCs) and annulus fibrosus cells (AFCs) play a critical role in the maintenance of intervertebral disc structure and function. Exosome-mediated miRNAs regulate cell proliferation, differentiation, apoptosis, and degradation. However, it is not clear whether the degenerative intervertebral disc-derived nucleus pulposus stem cells (D-NPSCs) can regulate the function of AFCs by delivering exosomes. Here, we show that exosomes secreted by nucleus pulposus stem cells derived from degenerative intervertebral disc (D-DPSC-exo) can exacerbate AFC degeneration via inhibiting cell proliferation, migration, matrix synthesis, and promoting apoptosis. Specifically, let-7b-5p was highly expressed in D-DPSC-exo. Transfection of let-7b-5p mimic was found to promote apoptosis and inhibit proliferation migration and matrix synthesis of AFCs. In addition, transfection with let-7b-5p inhibitor caused the effect of D-DPSC-exo on AFCs to be reversed. Furthermore, we found that D-DPSC-exo and let-7b-5p inhibited IGF1R expression and blocked the activation of the PI3K–Akt pathway. Results suggested that NPSC-exo exacerbated cell degeneration of AFCs via let-7b-5p, accompanied by inhibition of IGF1R expression, and PI3K–Akt pathway activation. Therefore, insights from this work may provide a clue for targeted molecular therapy of intervertebral disc degeneration.
TanP: A Multifunctional Anionic Peptide From Tityus stigmurus Scorpion Venom
Authors: Melo Menilla Maria Alves de , Oliveira Verônica da Silva , Queiroz Neto Moacir Fernandes de , Paiva Weslley de Souza , Torres-Rêgo Manoela , Silva Sérgio Ruschi Bergamachi , Pontes Daniel de Lima , Rocha Hugo Alexandre Oliveira , Souza Miguel Ângelo Fonseca de , Silva-Júnior Arnóbio Antônio da , Fernandes-Pedrosa Matheus de Freitas
Published: January 2022

Anionic peptides of scorpions are molecules rich in aspartic and/or glutamic acid residues and correspond to a class of peptides without disulfide bonds that are still little explored. TanP is a linear anionic peptide (50 amino acid residues and net charge −20) present in the venom gland of the scorpion, Tityus stigmurus, with chelating properties for Cu2+ ion and immunomodulatory properties. The therapeutic application of chelating molecules is related to cases of acute or chronic intoxication by metals, neurodegenerative diseases, hematological diseases, healing of skin wounds, cardiovascular diseases, and cancer. In this approach, the chelating activity of TanP was evaluated in relation to new metal ions (Fe2+ and Zn2+) of biological importance, as well as its antioxidant, hemostatic, immunomodulatory, and healing potential, aiming to expand the biological and biotechnological potential of this peptide. TanP (25 µM) was able to form stable complexes with Fe2+ in a ratio of 1:5 (TanP: Fe2+). Theoretical results suggest that TanP can work as a sensor to identify and quantify Fe2+ ions. The fluorescence intensity of TanP (1.12 µM) decreased significantly after the addition of Fe2+, obtaining the highest ratio 1: 7.4 (TanP: Fe2+) that led to the lowest fluorescence intensity. For Zn2+, no relevant spectral change was noted. TanP (50 µM) showed a maximum of 3% of hemolytic activity, demonstrating biocompatibility, as well as exhibiting a 1,1-diphenyl-2-picrylhydrazyl radical–scavenging activity of above 70% at all the concentrations tested (1–25 μM), and 89.7% iron-chelating activity at 25 μM and 96% hydroxyl radical–scavenging activity at 73.6 μM. In addition, TanP (12.5 and 25 µM) revealed an anticoagulant effect, prolonging the clotting time in prothrombin time and activated partial thromboplastin time assays, with no fibrinogenolytic activity. TanP (12.5 and 25 µM) induced the release of TNF-α by murine macrophages, in the absence of lipopolysaccharides, with a concentration-dependent increase and also stimulated the migration of 3T3 cells in the in vitro healing assay. Thus, TanP revealed a multifunctional potential, being useful as a prototype for the development of new therapeutic and biotechnological agents.
Molecular Dynamics of Lysozyme Amyloid Polymorphs Studied by Incoherent Neutron Scattering
Authors: Matsuo Tatsuhito , De Francesco Alessio , Peters Judith
Published: January 2022

Lysozyme amyloidosis is a hereditary disease, which is characterized by the deposition of lysozyme amyloid fibrils in various internal organs. It is known that lysozyme fibrils show polymorphism and that polymorphs formed at near-neutral pH have the ability to promote more monomer binding than those formed at acidic pH, indicating that only specific polymorphs become dominant species in a given environment. This is likely due to the polymorph-specific configurational diffusion. Understanding the possible differences in dynamical behavior between the polymorphs is thus crucial to deepen our knowledge of amyloid polymorphism and eventually elucidate the molecular mechanism of lysozyme amyloidosis. In this study, molecular dynamics at sub-nanosecond timescale of two kinds of polymorphic fibrils of hen egg white lysozyme, which has long been used as a model of human lysozyme, formed at pH 2.7 (LP27) and pH 6.0 (LP60) was investigated using elastic incoherent neutron scattering (EINS) and quasi-elastic neutron scattering (QENS). Analysis of the EINS data showed that whereas the mean square displacement of atomic motions is similar for both LP27 and LP60, LP60 contains a larger fraction of atoms moving with larger amplitudes than LP27, indicating that the dynamical difference between the two polymorphs lies not in the averaged amplitude, but in the distribution of the amplitudes. Furthermore, analysis of the QENS data showed that the jump diffusion coefficient of atoms is larger for LP60, suggesting that the atoms of LP60 undergo faster diffusive motions than those of LP27. This study thus characterizes the dynamics of the two lysozyme polymorphs and reveals that the molecular dynamics of LP60 is enhanced compared with that of LP27. The higher molecular flexibility of the polymorph would permit to adjust its conformation more quickly than its counterpart, facilitating monomer binding.
Colonic Leucine-Rich Repeat Kinase 2 Expression Is Increased and Associated With Disease Severity in Patients With Parkinson’s Disease
Authors: Liao Peng-Hsiang , Chiang Han-Lin , Shun Chia-Tung , Hang Jen-Fan , Chiu Han-Mo , Wu Ming-Shiang , Lin Chin-Hsien
Published: January 2022

Background

Mutations in leucine-rich repeat kinase 2 (LRRK2) comprise a common genetic risk factor for Parkinson’s disease (PD) and inflammatory bowel disease (IBD). We investigated the expression of LRRK2 in colonic biopsies obtained from a cohort of PD patients and healthy controls.

Methods

A cohort of 51 PD patients and 40 age- and gender-matched controls who have colonic biopsied samples were recruited. Among these participants, 26 individuals (12 PD patients and 14 controls) had a series of colon biopsies. For the patients with PD, the first biopsies were taken before the PD diagnosis. The colonic expression of LRRK2 was assayed by immunohistochemical staining.

Results

The fraction of LRRK2-positive cells among the total cell count in biopsied colonic tissues was significantly higher in PD patients than controls (0.81% ± 0.53% vs. 0.45% ± 0.39%; P = 0.02). Colonic LRRK2 immunoreactivity was higher in those with LRRK2 genetic variants compared to those with wild type LRRK2 (2.44% ± 1.15% vs. 0.21 ± 0.13%, P < 0.01). Age had no effect on LRRK2 expression (P = 0.96). LRRK2 expression correlated with disease severity in regards to motor symptoms measured by the UPDRS part III scores (r = 6335, P < 0.001) and cognitive dysfunction measured by the mini-mental status examination scores (r = -0.5774, P < 0.001). PD patients in the prodromal phase had a steeper increase in colonic LRRK2 expression compared to controls during the serial colon biopsy assessment (P < 0.01).

Conclusion

Colonic LRRK2 expression was increased in PD patients compared to controls, and the expression level correlated with disease severity.
The Signaling and Pharmacology of the Dopamine D1 Receptor
Authors: Jones-Tabah Jace , Mohammad Hanan , Paulus Emma G. , Clarke Paul B. S. , Hébert Terence E.
Published: January 2022

The dopamine D1 receptor (D1R) is a Gαs/olf-coupled GPCR that is expressed in the midbrain and forebrain, regulating motor behavior, reward, motivational states, and cognitive processes. Although the D1R was initially identified as a promising drug target almost 40 years ago, the development of clinically useful ligands has until recently been hampered by a lack of suitable candidate molecules. The emergence of new non-catechol D1R agonists, biased agonists, and allosteric modulators has renewed clinical interest in drugs targeting this receptor, specifically for the treatment of motor impairment in Parkinson's Disease, and cognitive impairment in neuropsychiatric disorders. To develop better therapeutics, advances in ligand chemistry must be matched by an expanded understanding of D1R signaling across cell populations in the brain, and in disease states. Depending on the brain region, the D1R couples primarily to either Gαs or Gαolf through which it activates a cAMP/PKA-dependent signaling cascade that can regulate neuronal excitability, stimulate gene expression, and facilitate synaptic plasticity. However, like many GPCRs, the D1R can signal through multiple downstream pathways, and specific signaling signatures may differ between cell types or be altered in disease. To guide development of improved D1R ligands, it is important to understand how signaling unfolds in specific target cells, and how this signaling affects circuit function and behavior. In this review, we provide a summary of D1R-directed signaling in various neuronal populations and describe how specific pathways have been linked to physiological and behavioral outcomes. In addition, we address the current state of D1R drug development, including the pharmacology of newly developed non-catecholamine ligands, and discuss the potential utility of D1R-agonists in Parkinson's Disease and cognitive impairment.
Quantifying the Kinetics of Signaling and Arrestin Recruitment by Nervous System G-Protein Coupled Receptors
Authors: Hoare Sam R. J. , Tewson Paul H. , Sachdev Shivani , Connor Mark , Hughes Thomas E. , Quinn Anne Marie
Published: January 2022

Neurons integrate inputs over different time and space scales. Fast excitatory synapses at boutons (ms and μm), and slow modulation over entire dendritic arbors (seconds and mm) are all ultimately combined to produce behavior. Understanding the timing of signaling events mediated by G-protein-coupled receptors is necessary to elucidate the mechanism of action of therapeutics targeting the nervous system. Measuring signaling kinetics in live cells has been transformed by the adoption of fluorescent biosensors and dyes that convert biological signals into optical signals that are conveniently recorded by microscopic imaging or by fluorescence plate readers. Quantifying the timing of signaling has now become routine with the application of equations in familiar curve fitting software to estimate the rates of signaling from the waveform. Here we describe examples of the application of these methods, including (1) Kinetic analysis of opioid signaling dynamics and partial agonism measured using cAMP and arrestin biosensors; (2) Quantifying the signaling activity of illicit synthetic cannabinoid receptor agonists measured using a fluorescent membrane potential dye; (3) Demonstration of multiplicity of arrestin functions from analysis of biosensor waveforms and quantification of the rates of these processes. These examples show how temporal analysis provides additional dimensions to enhance the understanding of GPCR signaling and therapeutic mechanisms in the nervous system.
The Broad Clinical Spectrum of Epilepsies Associated With Protocadherin 19 Gene Mutation
Authors: Dell'Isola Giovanni Battista , Vinti Valerio , Fattorusso Antonella , Tascini Giorgia , Mencaroni Elisabetta , Di Cara Giuseppe , Striano Pasquale , Verrotti Alberto
Published: January 2022

Protocadherin 19 (PCDH19) gene is one of the most common genes involved in epilepsy syndromes. According to literature data PCDH19 is among the 6 genes most involved in genetic epilepsies. PCDH19 is located on chromosome Xq22.1 and is involved in neuronal connections and signal transduction. The most frequent clinical expression of PCDH19 mutation is epilepsy and mental retardation limited to female (EFMR) characterized by epileptic and non-epileptic symptoms affecting mainly females. However, the phenotypic spectrum of these mutations is considerably variable from genetic epilepsy with febrile seizure plus to epileptic encephalopathies. The peculiar exclusive involvement of females seems to be caused by a cellular interference in heterozygosity, however, affected mosaic-males have been reported. Seizure types range from focal seizure to generalized tonic-clonic, tonic, atonic, absences, and myoclonic jerks. Treatment of PCDH19-related epilepsy is limited by drug resistance and by the absence of specific treatment indications. However, seizures become less severe with adolescence and some patients may even become seizure-free. Non-epileptic symptoms represent the main disabilities of adult patients with PCDH19 mutation. This review aims to analyze the highly variable phenotypic expression of PCDH19 gene mutation associated with epilepsy.
Organ on a Chip: A Novel in vitro Biomimetic Strategy in Amyotrophic Lateral Sclerosis (ALS) Modeling
Authors: Arjmand Babak , Kokabi Hamidpour Shayesteh , Rabbani Zahra , Tayanloo-Beik Akram , Rahim Fakher , Aghayan Hamid Reza , Larijani Bagher
Published: January 2022

Amyotrophic lateral sclerosis is a pernicious neurodegenerative disorder that is associated with the progressive degeneration of motor neurons, the disruption of impulse transmission from motor neurons to muscle cells, and the development of mobility impairments. Clinically, muscle paralysis can spread to other parts of the body. Hence it may have adverse effects on swallowing, speaking, and even breathing, which serves as major problems facing these patients. According to the available evidence, no definite treatment has been found for amyotrophic lateral sclerosis (ALS) that results in a significant outcome, although some pharmacological and non-pharmacological treatments are currently applied that are accompanied by some positive effects. In other words, available therapies are only used to relieve symptoms without any significant treatment effects that highlight the importance of seeking more novel therapies. Unfortunately, the process of discovering new drugs with high therapeutic potential for ALS treatment is fraught with challenges. The lack of a broad view of the disease process from early to late-stage and insufficiency of preclinical studies for providing validated results prior to conducting clinical trials are other reasons for the ALS drug discovery failure. However, increasing the combined application of different fields of regenerative medicine, especially tissue engineering and stem cell therapy can be considered as a step forward to develop more novel technologies. For instance, organ on a chip is one of these technologies that can provide a platform to promote a comprehensive understanding of neuromuscular junction biology and screen candidate drugs for ALS in combination with pluripotent stem cells (PSCs). The structure of this technology is based on the use of essential components such as iPSC- derived motor neurons and iPSC-derived skeletal muscle cells on a single miniaturized chip for ALS modeling. Accordingly, an organ on a chip not only can mimic ALS complexities but also can be considered as a more cost-effective and time-saving disease modeling platform in comparison with others. Hence, it can be concluded that lab on a chip can make a major contribution as a biomimetic micro-physiological system in the treatment of neurodegenerative disorders such as ALS.
Multi-Sensor Wearable Health Device Framework for Real-Time Monitoring of Elderly Patients Using a Mobile Application and High-Resolution Parameter Estimation
Authors: Pinheiro Gabriel P. M. , Miranda Ricardo K. , Praciano Bruno J. G. , Santos Giovanni A. , Mendonça Fábio L. L. , Javidi Elnaz , da Costa João Paulo Javidi , de Sousa Rafael T.
Published: January 2022

Automatized scalable healthcare support solutions allow real-time 24/7 health monitoring of patients, prioritizing medical treatment according to health conditions, reducing medical appointments in clinics and hospitals, and enabling easy exchange of information among healthcare professionals. With recent health safety guidelines due to the COVID-19 pandemic, protecting the elderly has become imperative. However, state-of-the-art health wearable device platforms present limitations in hardware, parameter estimation algorithms, and software architecture. This paper proposes a complete framework for health systems composed of multi-sensor wearable health devices (MWHD), high-resolution parameter estimation, and real-time monitoring applications. The framework is appropriate for real-time monitoring of elderly patients' health without physical contact with healthcare professionals, maintaining safety standards. The hardware includes sensors for monitoring steps, pulse oximetry, heart rate (HR), and temperature using low-power wireless communication. In terms of parameter estimation, the embedded circuit uses high-resolution signal processing algorithms that result in an improved measure of the HR. The proposed high-resolution signal processing-based approach outperforms state-of-the-art HR estimation measurements using the photoplethysmography (PPG) sensor.
The Neural Correlates of Semantic and Grammatical Encoding During Sentence Production in a Second Language: Evidence From an fMRI Study Using Structural Priming
Authors: Nakagawa Eri , Koike Takahiko , Sumiya Motofumi , Shimada Koji , Makita Kai , Yoshida Haruyo , Yokokawa Hirokazu , Sadato Norihiro
Published: January 2022

Japanese English learners have difficulty speaking Double Object (DO; give B A) than Prepositional Object (PO; give A to B) structures which neural underpinning is unknown. In speaking, syntactic and phonological processing follow semantic encoding, conversion of non-verbal mental representation into a structure suitable for expression. To test whether DO difficulty lies in linguistic or prelinguistic process, we conducted functional magnetic resonance imaging. Thirty participants described cartoons using DO or PO, or simply named them. Greater reaction times and error rates indicated DO difficulty. DO compared with PO showed parieto-frontal activation including left inferior frontal gyrus, reflecting linguistic process. Psychological priming in PO produced immediately after DO and vice versa compared to after control, indicated shared process between PO and DO. Cross-structural neural repetition suppression was observed in occipito-parietal regions, overlapping the linguistic system in pre-SMA. Thus DO and PO share prelinguistic process, whereas linguistic process imposes overload in DO.
Projections and the Potential Societal Impact of the Future of Neurotechnologies
Authors: Gaudry Kate S. , Ayaz Hasan , Bedows Avery , Celnik Pablo , Eagleman David , Grover Pulkit , Illes Judy , Rao Rajesh P. N. , Robinson Jacob T. , Thyagarajan Krishnan ,   The Working Group on Brain-Interfacing Devices in 2040
Published: January 2022

Traditionally, recording from and stimulating the brain with high spatial and temporal resolution required invasive means. However, recently, the technical capabilities of less invasive and non-invasive neuro-interfacing technology have been dramatically improving, and laboratories and funders aim to further improve these capabilities. These technologies can facilitate functions such as multi-person communication, mood regulation and memory recall. We consider a potential future where the less invasive technology is in high demand. Will this demand match that the current-day demand for a smartphone? Here, we draw upon existing research to project which particular neuroethics issues may arise in this potential future and what preparatory steps may be taken to address these issues.