bluuebunny/crossref_metadata_2025 huggingface dataset:
The Importance of Dead Seagrass (Posidonia oceanica) Matte as a Biogeochemical Sink
Authors: Apostolaki Eugenia T. , Caviglia Laura , Santinelli Veronica , Cundy Andrew B. , Tramati Cecilia D. , Mazzola Antonio , Vizzini Salvatrice
Published: March 2022

We assessed the potential of dead seagrass Posidonia oceanica matte to act as a biogeochemical sink and provide a coherent archive of environmental change in a degraded area of the Mediterranean Sea (Augusta Bay, Italy). Change in sediment properties (dry bulk density, grain size), concentration of elements (Corg, Cinorg, N, Hg) and stable isotope ratios (δ13C, δ 15N) with sediment depth were measured in dead P. oceanica matte and unvegetated (bare) sediments in the polluted area, and an adjacent P. oceanica meadow. Principal Component Analysis (PCA) revealed a clear clustering by habitat, which explained 72% of variability in our samples and was driven mainly by the accumulation of N and Hg in finer sediments of the dead matte. Assessment of the temporal trends of Corg, N and Hg concentrations in the dead matte revealed changes in the accumulation of these elements over the last 120 years, with an increase following the onset of industrial activities 65 y BP (i.e., yr. 1950) that was sustained even after seagrass loss around 35 y BP. Despite a decrease in Hg concentrations in the early 1980s following the onset of pollution abatement, overall Hg levels were 2-fold higher in the local post-industrial period, with a Hg enrichment factor of 3.5 in the dead matte. Mean stocks of Corg, N and Hg in 25 cm thick sediment deposits (4.08 ± 2.10 kg Corg m-2, 0.14 ± 0.04 kg N m-2, 0.19 ± 0.04 g Hg m-2) and accumulation in the last 120 yr (35.3 ± 19.6 g Corg m-2 y-1, 1.2 ± 0.4 g N m-2 y-1, 0.0017 ± 0.0004 g Hg m-2 y-1) were higher in the dead matte than bare sediment or adjacent P. oceanica meadow. Our results indicate that dead P. oceanica matte maintained its potential as a biogeochemical sink and, like its living counterpart, dead matte can serve as an effective archive to allow for reconstructing environmental change in coastal areas of the Mediterranean where severe perturbations have led to P. oceanica loss. Appropriate management for contaminated areas should be prioritized to prevent release of pollutants and carbon from dead mattes.
Impact of the SARS-CoV-2 Delta Variant on the Psychological States and Health-Related Quality of Life in Patients With Crohn’s Disease
Authors: Li Jiajia , Sun Yunyun , Hu Xiaolin , Zhao Tiantian , Yao Guanghuai , Xiao Weiming , Ding Yanbing , Hou Sicong , Wang Mei
Published: March 2022

Background

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic first reported in Wuhan, China, several research on the psychological impact of the pandemic on patients with Crohn’s disease (CD) have been conducted. However, with the progression of the global pandemic and the emergence of the SARS-CoV-2 B.1.617.2 (Delta) variant, follow-up studies need to be performed to monitor the alterations of psychological status and health-related quality of life (HRQoL) among CD patients.

Aims

We aimed to evaluate the impact of the SARS-CoV-2 Delta variant on the mental health and life quality among the CD population and tried to explore potent risk factors.

Methods

This observational study included 153 CD patients who responded to our pre-designed self-reported questionnaire. Demographic, clinical, and psychological information were collected and analyzed.

Results

Quite a number of CD patients were confronted with different levels of anxiety and depression, with incidence of 28.10 and 31.37% for anxiety and depression, respectively. Compared with non-pandemic circumstances, the life quality of CD patients due to the present situation was more often compromised. Isolation [odds ratio (OR): 4.71, P = 0.007] was verified as a risk factor for anxiety while use of telemedicine could help relieve anxiety (OR: 0.22, P < 0.001). Worsening of symptoms (OR: 4.92, P = 0.006), isolation (OR: 5.75, P = 0.005), and drug withdrawn (OR: 2.66, P = 0.026) were identified to be independent factors for developing depression. Likewise, use of telemedicine (OR: 0.13, P < 0.001) was negatively related to depression. Considering life quality, vaccination (OR: 3.07, P = 0.021) together with no medication (OR: 7.73, P = 0.010) was relevant to better life quality while worsening of symptoms (OR: 0.09, P = 0.034) were an independent risk factor for impaired life quality.

Conclusion

Many CD patients suffered from symptoms of anxiety and depression and impaired life quality during the COVID-19 pandemic. Those in isolation or with worsening of symptoms and drug withdrawn were more prone to experience psychological stress. Individualized management such as drug delivery and telemedicine should be promoted to maintain control of mental health and life quality during the pandemic.
How Do Family Physicians Perceive Their Role in Providing Pre-exposure Prophylaxis for HIV Prevention?–An Online Qualitative Study in Flanders, Belgium
Authors: Vanhamel Jef , Reyniers Thijs , Wouters Edwin , van Olmen Josefien , Vanbaelen Thibaut , Nöstlinger Christiana , Mieghem Heleen Van , Landeghem Ella Van , Rotsaert Anke , Laga Marie , Vuylsteke Bea
Published: March 2022

Introduction:

In Belgium, the provision of pre-exposure prophylaxis (PrEP) for HIV prevention is centralized in specialized HIV clinics. Engaging family physicians in PrEP care could help scale-up its delivery and reach underserved populations. The objective of this study was to gain insight into family physicians' self-perceived roles in providing PrEP.

Methods

We conducted 16 online group discussions with a total of 105 Flemish family physicians, between November 2020 and February 2021. A brief online questionnaire assessed their socio-demographics and experience with sexual health. We analyzed verbatim transcribed data using a grounded theory approach.

Results

Despite limited awareness and experience, participants reported a high willingness to be more actively involved in PrEP care. Four potential roles for the family physician in PrEP care were identified: acting as low-threshold entry point for advice; opportunistic case finding of PrEP candidates; initiating appropriate care for PrEP-eligible clients; and ensuring high-quality follow-up care for PrEP users. Participants framed each of these roles within their current activities and responsibilities as primary care providers. Yet, participants differed in their views on the concrete operationalization of these roles, and in the extent of their involvement in PrEP. Particular challenges were a lack of experience with antiretrovirals, perceived limited exposure to clients at high HIV risk, and a lack of expertise and resources to conduct time-intensive risk assessments and counseling related to PrEP.

Conclusion

Belgian family physicians demonstrated a keen willingness to be involved in PrEP care, but had differing views on the practical implementation into their practices. Providing tailored training on sexual health and PrEP, and investing in collaboration between primary and secondary care, could optimize the integration of PrEP in the primary care practice.
Central Nervous System Cryptococcosis in Patients With Sarcoidosis: Comparison With Non-sarcoidosis Patients and Review of Potential Pathophysiological Mechanisms
Authors: Prevel Renaud , Guillotin Vivien , Imbert Sébastien , Blanco Patrick , Delhaes Laurence , Duffau Pierre
Published: March 2022

Introduction

Cryptococcusspp. infection of the central nervous system (CINS) is a devastating opportunistic infection that was historically described in patients with acquired immunodeficiency syndrome (AIDS).Cryptococcusspp. infections are also associated with sarcoidosis; the impairment of cell-mediated immunity and long-term corticosteroid therapy being evoked to explain this association. Nevertheless, this assertion is debated and the underlying pathophysiological mechanisms are still unknown. The aims of this study were (i) to describe the clinical and biological presentation, treatments, and outcomes of CINS patients with and without sarcoidosis and (ii) to review the pathophysiological evidence underlying this clinical association.

Patients and Methods

Every patient with positive cerebrospinal fluid (CSF) cryptococcal antigen testing, India ink preparation, and/or culture from January 2015 to December 2020 at a tertiary university hospital were included, and patients with sarcoidosis were compared with non-sarcoidosis patients. Quantitative variables are presented as mean ± SD and are compared using the Mann-Whitney Wilcoxon rank-sum test. Categorical variables are expressed as the number of patients (percentage) and compared using the χ2or Fisher's tests.

Results

During the study period, 16 patients experienced CINS, of whom 5 (31%) were associated with sarcoidosis. CINS symptoms, biological, and CSF features were similar between CINS patients with and without sarcoidosis except regarding CD4 cells percentages and CD4/CD8 ratio that was higher in those with sarcoidosis (47 ± 12 vs. 22 ± 18,p= 0.02 and 2.24 ± 1.42 vs. 0.83 ± 1.10,p= 0.03, respectively). CINS patients with sarcoidosis had less often positive blood antigen testing than those without sarcoidosis (2/5 vs. 11/11,p= 0.02). CINS patients with and without sarcoidosis were treated with similar drugs, but patients with sarcoidosis had a shorter length of treatment. CD4 cell levels do not seem to explain the association between sarcoidosis and cryptococcosis.

Conclusion

Sarcoidosis was the most frequently associated condition with CINS in this study. CINS patients associated with sarcoidosis had overall similar clinical and biological presentation than CINS patients associated with other conditions but exhibited a lower rate of positive blood cryptococcal antigen testing and higher CD4/CD8 T cells ratio. Pathophysiological mechanisms underlying this association remain poorly understood but B-1 cell deficiency or lack of IgM could be a part of the explanation. Another plausible mechanism is the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in a subset of patients with sarcoidosis, which could impair macrophage phagocytic function. Further studies are strongly needed to better understand those mechanisms and to identify at-risk patients.
Changing Professional Behaviors in the Digital World Using the Medical Education e-Professionalism (MEeP) Framework—A Mixed Methods Multicentre Study
Authors: Guraya Shaista Salman , Yusoff Muhamad Saiful Bahri , Rashid-Doubell Fiza , Harkin Denis W. , Al-Amad Suhail H. , Fredericks Salim , Halabi Mouhammad Omar O. , Abdullah Natasya , Moussa Hatem , Mallah Saad Imad Yousef , Sefen Jessica Atef Nassef , AlKoheji Heba Khalid A. Rahman Mohamed Ishaq , Althawadi Manal Ebrahim Ali , Alabbasi Lana Abdulsalam , Nor Mohd Zarawi Mat , Reguig Farida , Guraya Salman Yousuf
Published: March 2022

Background:

There is increasing evidence on the exponential use of technology-based social media in medical field that has led to a proliferation of unprofessional behaviors in digital realm. Educating, training, and changing the behaviors of healthcare professionals are essential elements to restrain the rising unprofessional incidents. Therefore, this research was designed to determine the impact of an interventional workshop on the medical and dental students in improving their professional behaviors in the digital world using the newly developed medical Education e-Professionalism (MEeP) framework.

Methods

We adopted the Theory of Planned Behavior (TPB) as a benchmark reference which explores constructs intertwined with the mission-based MEeP framework; values (whistleblowing-raising concerns), behaviors (being responsible in the digital world) and identity (reflective practice in the digital world). A multicentre 3-phased mixed-method study was conducted using a pre-workshop survey, an online interventional workshop, and a post-workshop survey. SPSS and NVivo were the tools used for the data analysis.

Results

A total of 130 students registered for workshop out of which 120 completed the pre-workshop survey, 62 joined the workshop and 59 completed the workshop and post-workshop survey. From the whistleblowing – raising concern perspective, we found that attitudes and perceived behavioral control had a significant relationship. While for responsible in digital world category, attitude and perceived behavioral control had a significant bearing on the intentions. Third, for reflective practice, attitude and subjective norms significantly enhanced the intention of participants. A multi layered thematic analysis yielded four overarching themes of attitudes, subjective norms, perceived behavioral control and intentions. Most students showed positive attitudes of being reflective, self-directed, and humane. Students realized the subjective norms had made them conscientious, self-aware and conformative. While perceived behavioural control manifested as identity and Intentions were heavily reliant on self-actualization.

Conclusion

Our mixed method study found that the interventional workshop using MEeP framework significantly improved attitudes, subjective norms, perceived behavioral control, and intentions. This study provides valuable evidence of MEeP framework evaluation using the theoretical underpinning of TPB by reporting positive changes in professional values, behaviors, and identities of undergraduate medical and dental students.
Pulmonary Hypertension in a Patient With Kartagener’s Syndrome and a Novel Homozygous Nonsense Mutation in CCDC40 Gene: A Case Report
Authors: Dai Hai-Long , Wang Duolao , Guang Xue-Feng , Zhang Wei-Hua
Published: March 2022

Kartagener’s syndrome is a subgroup of primary ciliary dyskinesia (PCD), a genetically heterogeneous condition characterised by sinusitis, bronchiectasis, and situs in versus. Genetic testing has importance for their diagnosis. Here, we report a chinese patient with Kartagener’s syndrome. Transthoracic echocardiography showed severely elevated right ventricular systolic pressure. Right heart catheterisation demonstrated a pre-capillary pulmonary hypertension. Whole-exome sequencing indicated that she had a novel homozygous nonsense mutation, c.2845C > T, p.Gln949*, in exon 18 of CCDC40 and a heterozygotic mutation, c.73G > A, p.Ala25Thr, in exon 1 of DNAH11. She was diagnosed as Kartagener’s syndrome with pulmonary hypertension. Her symptoms improved significantly by treatment of antibiotics, expectorant drugs, bronchodilators, and oxygen therapy treatment. Our findings extend the mutation spectrum of CCDC40 gene related Kartagener’s syndrome, which is very important for gene diagnosis of the disease.
Perceptions of Regulatory Decision-Making for New Drugs From the Viewpoints of the Manufacturers in South Korea
Authors: Son Kyung-Bok , Park Sylvia
Published: March 2022

Regulatory decisions for new drugs approval present high uncertainty, low reversibility, the avoidance of observable errors, and high political stakes. However, research on the behavior of regulatory agencies is scarce, particularly in the context of more open decision-making processes. We aimed to evaluate the perceptions of regulatory decision-making for new drugs approval from the viewpoints of the manufacturers in South Korea. In 2019, employees in domestic (n = 5) and foreign (n = 7) manufacturers with expertise in regulatory affairs were invited to participate in a questionnaire survey and semi-structured group interview. We asked about the relevance of various criteria in regulatory decision-making, the participation of various stakeholders, and the degree of consent for new drug approval with uncertainty. The domestic and foreign manufacturers perceived that a regulatory decision made by the MFDS was solely based on technical merit within a closed decision-making system. They responded that safety, efficacy, and benefit-to-harm ratio were the most relevant criteria and the most prioritized criteria in regulatory decision-making. They also perceived that the MFDS was the sole relevant member in a regulatory decision. However, the foreign manufacturers disagreed that the regulatory agency and the advisory committee were independent of conflicts of interest, which might imply that regulatory decisions were occasionally determined by the agency given the political benefits and/or costs within a more open system. The role of an advisory committee in terms of deliberation and participatory democracy were requested to make politically legitimate regulatory decisions from the viewpoints of the manufacturers. However, their perceptions toward public involvement in regulatory decision-making is still at the early stage.
A Novel Bacteriocin Against Shigella flexneri From Lactiplantibacillus plantarum Isolated From Tilapia Intestine: Purification, Antibacterial Properties and Antibiofilm Activity
Authors: Jiang Yu-Hang , Xin Wei-Gang , Zhang Qi-Lin , Lin Lian-Bing , Deng Xian-Yu
Published: March 2022

Few bacteriocins with antibacterial activity against Shigella flexneri have been reported. Here, a novel bacteriocin (LFX01) produced by Lactiplantibacillus plantarum strain LF-8 from the intestine of tilapia was purified and extensively characterized. LFX01 possesses a molecular weight of 1049.56 Da and an amino acid sequence of I-T-G-G-P-A-V-V-H-Q-A. LFX01 significantly inhibited S. flexneri strain 14 (S. flexneri_14) growth. Moreover, it exhibited excellent stability under heat and acid-base stress, and presented sensitivity to a variety of proteases, such as proteinase K, pepsin, and trypsin. The minimum inhibitory concentration (MIC) of LFX01 against S. flexneri_14 was 12.65 μg/mL, which was smaller than that of most of the previously found bacteriocins. Furthermore, LFX01 significantly inhibited (p < 0.05) S. flexneri_14 cells and decreased their cell viability. In addition, LFX01 could significantly (p < 0.05) inhibit biofilm formation of S. flexneri_14. Scanning electron microscopy analysis presented that the cell membrane permeability of S. flexneri_14 was demolished by LFX01, leading to cytoplasmic contents leakage and cell rupture death. In summary, a novel bacteriocin of lactic acid bacteria (LAB) was found, which could effectively control S. flexneri in both planktonic and biofilm states.
Successful Intra- but Not Inter-species Recombination of msr(D) in Neisseria subflava
Authors: de Block Tessa , González Natalia , Abdellati Saïd , Laumen Jolein Gyonne Elise , Van Dijck Christophe , De Baetselier Irith , Van den Bossche Dorien , Manoharan-Basil Sheeba S. , Kenyon Chris
Published: March 2022

Resistance acquisition via natural transformation is a common process in the Neisseria genus. Transformation has played an important role in the emergence of resistance to many antimicrobials in Neisseria gonorrhoeae and Neisseria meningitidis. In a previous study, we found that currently circulating isolates of Neisseria subflava had acquired an msr(D) gene that has been found to result in macrolide resistance in other bacteria but never found in Neisseria species before. To determine if this resistance mechanism is transferable among Neisseria species, we assessed if we could transform the msr(D) gene into other commensal and pathogenic Neisseria under low dose azithromycin pressure. Intraspecies recombination in commensal N. subflava was confirmed with PCR and resulted in high-level macrolide resistance. Whole-genome sequencing of these transformed strains identified the complete uptake of the msr(D) integration fragment. Sequence analysis showed that a large fragment of DNA (5 and 12 kb) was transferred through a single horizontal gene transfer event. Furthermore, uptake of the msr(D) gene had no apparent fitness cost. Interspecies transformation of msr(D) from N. subflava to N. gonorrhoeae was, however, not successful.
Modeling and Optimization of a Molecular Biocontroller for the Regulation of Complex Metabolic Pathways
Authors: Boada Yadira , Santos-Navarro Fernando N. , Picó Jesús , Vignoni Alejandro
Published: March 2022

Achieving optimal production in microbial cell factories, robustness against changing intracellular and environmental perturbations requires the dynamic feedback regulation of the pathway of interest. Here, we consider a merging metabolic pathway motif, which appears in a wide range of metabolic engineering applications, including the production of phenylpropanoids among others. We present an approach to use a realistic model that accounts for in vivo implementation and then propose a methodology based on multiobjective optimization for the optimal tuning of the gene circuit parts composing the biomolecular controller and biosensor devices for a dynamic regulation strategy. We show how this approach can deal with the trade-offs between the performance of the regulated pathway, robustness to perturbations, and stability of the feedback loop. Using realistic models, our results suggest that the strategies for fine-tuning the trade-offs among performance, robustness, and stability in dynamic pathway regulation are complex. It is not always possible to infer them by simple inspection. This renders the use of the multiobjective optimization methodology valuable and necessary.
Comprehensive Analysis Revealed the Potential Implications of m6A Regulators in Lung Adenocarcinoma
Authors: Xie Lingling , Dai Rongyang , Wang Xudong , Xie Guangfei , Gao Zhihua , Xu Xinxin
Published: March 2022

Background: The biological significance of RNA N6-methyladenosine (m6A) decoration in tumorigenicity and progression has been highlighted in recent studies, but whether m6A modification plays a potential role in tumor microenvironment (TME) formation and immune regulation in lung adenocarcinoma (LUAD) remains unclear.

Methods: m6A modification features were evaluated by analyzing the multi-omics features of 17 m6A regulators in over 1900 LUAD samples, and at the same time, the correlation between these modification patterns and TME characteristics was analyzed. An m6A score signature–based principal component analysis (PCA) algorithm was constructed to assess the prognosis and responses of individual patients to immunotherapeutic and targeted therapies.

Results: Three different m6A modification patterns were determined in 1901 LUAD samples, which were found to be related to diverse clinical outcomes via different biological pathways. Based on the m6A score extracted from the m6A-associated signature genes, LUAD patients were separated into high- and low-m6A score groups. It was discovered that patients with high m6A scores had longer survival, lower tumor mutation loads, and low PD-L1/PDCD1/CTLA4/TAG3 expression level. In addition, LUAD patients with high m6A scores displayed lower IC50 to some targeted drugs, including nilotinib, erlotinib, imatinib, and lapatinib.

Conclusion: m6A modification was significantly associated with the TME and clinical outcomes. These findings may help gain more insights into the role of m6A decoration in the molecular mechanism of LUAD, thus facilitating the development of more effective personalized treatment strategies.
Mitochondrial Extracellular Vesicles in CNS Disorders: New Frontiers in Understanding the Neurological Disorders of the Brain
Authors: Nakamya Mary F. , Sil Susmita , Buch Shilpa , Hakami Ramin M.
Published: March 2022

Recent findings have highlighted potential diagnostic and prognostic values of extracellular vesicles (EVs) that contain mitochondrial derived components for neurological disorders. Furthermore, functional influences of vesicles carrying mitochondrial components have been reported. In particular, this includes indications of crosstalk with mitophagy to influence progression of various CNS disorders. In this mini-review, we discuss the current state of knowledge about this intriguing class of vesicles in neurological disorders of the CNS, and outline the lacunae and thus scope of further development in this fascinating field of study.
MD Simulations Revealing Special Activation Mechanism of Cannabinoid Receptor 1
Authors: Wu Yiran , Li Xuanxuan , Hua Tian , Liu Zhi-Jie , Liu Haiguang , Zhao Suwen
Published: March 2022

Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor (GPCR) that is gaining much interest for its regulating role in the central nervous system and its value as a drug target. Structures of CB1 in inactive and active states have revealed conformational change details that are not common in other GPCRs. Here, we performed molecular dynamics simulations of CB1 in different ligand binding states and with mutations to reveal its activation mechanism. The conformational change of the “twin toggle switch” residues F2003.36 and W3566.48 that correlates with ligand efficacy is identified as a key barrier step in CB1 activation. Similar conformational change of residues 3.36/6.48 is also observed in melanocortin receptor 4, showing this “twin toggle switch” residue pair is crucial for the activation of multiple GPCR members.
Recombinant Prolidase Activates EGFR-Dependent Cell Growth in an Experimental Model of Inflammation in HaCaT Keratinocytes. Implication for Wound Healing
Authors: Nizioł Magdalena , Ościłowska Ilona , Baszanowska Weronika , Pałka Jerzy , Besio Roberta , Forlino Antonella , Miltyk Wojciech
Published: March 2022

This study was conducted to investigate the proliferative capacity of recombinant human prolidase (rhPEPD) in a human model of inflammation induced by IL-1βin HaCaT keratinocytes. In this report, we provide evidence that IL-1βstimulates keratinocyte proliferation, and rhPEPD significantly augmented this process through activation of epidermal growth factor receptor (EGFR) and downstream signaling proteins as phosphorylated Akt, ERK1/2, and STAT3, which are implicated in keratinocyte migration, proliferation, and epithelialization during the wound healing process. Inhibition of PEPD-dependent EGFR signaling by gefitinib supported the finding. Moreover, during activation of EGFR in the presence of IL-1βthe epithelial-to-mesenchymal transition (EMT) occurredviadownregulation of E-cadherin and upregulation of N-cadherin. The phenomenon was accompanied by an increase in the activity of matrix metalloproteinase-9 (MMP-9), suggesting extracellular matrix (ECM) remodeling during the inflammatory process. MMP-9 activation may result from nuclear translocation of NF-κB through IKK-mediated IκBαdegradation. Interestingly, some mutated variants of PEPD (rhPEPD-G448R, rhPEPD-231delY, and rhPEPD-E412K) evoked the ability to induce EGFR-dependent HaCaT cell proliferation. To the best of our knowledge, this is the first report on the cross-talk between PEPD and IL-1βin the process of keratinocyte proliferation. The data suggest that both enzymatically active and inactive rhPEPD may activate EGFR-dependent cell growth in an experimental model of inflammation in HaCaT keratinocytes and the knowledge may be useful for further approaches for therapy of wound healing disorders.
The Association Between Alzheimer's Disease-Related Markers and Physical Activity in Cognitively Normal Older Adults
Authors: Pedrini Steve , Chatterjee Pratishtha , Nakamura Akinori , Tegg Michelle , Hone Eugene , Rainey-Smith Stephanie R. , Rowe Christopher C. , Dore Vincent , Villemagne Victor L. , Ames David , Kaneko Naoki , Gardener Sam L. , Taddei Kevin , Fernando Binosha , Martins Ian , Bharadwaj Prashant , Sohrabi Hamid R. , Masters Colin L. , Brown Belinda , Martins Ralph N.
Published: March 2022

Previous studies have indicated that physical activity may be beneficial in reducing the risk for Alzheimer's disease (AD), although the underlying mechanisms are not fully understood. The goal of this study was to evaluate the relationship between habitual physical activity levels and brain amyloid deposition and AD-related blood biomarkers (i.e., measured using a novel high-performance mass spectrometry-based assay), in apolipoprotein E (APOE) ε4 carriers and noncarriers. We evaluated 143 cognitively normal older adults, all of whom had brain amyloid deposition assessed using positron emission tomography and had their physical activity levels measured using the International Physical Activity Questionnaire (IPAQ). We observed an inverse correlation between brain amyloidosis and plasma beta-amyloid (Aβ)1−42 but found no association between brain amyloid and plasma Aβ1−40 and amyloid precursor protein (APP)669−711. Additionally, higher levels of physical activity were associated with lower plasma Aβ1−40, Aβ1−42, and APP669−711 levels in APOE ε4 noncarriers. The ratios of Aβ1−40/Aβ1−42 and APP669−711/Aβ1−42, which have been associated with higher brain amyloidosis in previous studies, differed between APOE ε4 carriers and non-carriers. Taken together, these data indicate a complex relationship between physical activity and brain amyloid deposition and potential blood-based AD biomarkers in cognitively normal older adults. In addition, the role of APOE ε4 is still unclear, and more studies are necessary to bring further clarification.
Chronic PPARγ Stimulation Shifts Amyloidosis to Higher Fibrillarity but Improves Cognition
Authors: Blume Tanja , Deussing Maximilian , Biechele Gloria , Peters Finn , Zott Benedikt , Schmidt Claudio , Franzmeier Nicolai , Wind Karin , Eckenweber Florian , Sacher Christian , Shi Yuan , Ochs Katharina , Kleinberger Gernot , Xiang Xianyuan , Focke Carola , Lindner Simon , Gildehaus Franz-Josef , Beyer Leonie , von Ungern-Sternberg Barbara , Bartenstein Peter , Baumann Karlheinz , Adelsberger Helmuth , Rominger Axel , Cumming Paul , Willem Michael , Dorostkar Mario M. , Herms Jochen , Brendel Matthias
Published: March 2022

We undertook longitudinal β-amyloid positron emission tomography (Aβ-PET) imaging as a translational tool for monitoring of chronic treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone in Aβ model mice. We thus tested the hypothesis this treatment would rescue from increases of the Aβ-PET signal while promoting spatial learning and preservation of synaptic density. Here, we investigated longitudinally for 5 months PS2APP mice (N = 23; baseline age: 8 months) and AppNL–G–F mice (N = 37; baseline age: 5 months) using Aβ-PET. Groups of mice were treated with pioglitazone or vehicle during the follow-up interval. We tested spatial memory performance and confirmed terminal PET findings by immunohistochemical and biochemistry analyses. Surprisingly, Aβ-PET and immunohistochemistry revealed a shift toward higher fibrillary composition of Aβ-plaques during upon chronic pioglitazone treatment. Nonetheless, synaptic density and spatial learning were improved in transgenic mice with pioglitazone treatment, in association with the increased plaque fibrillarity. These translational data suggest that a shift toward higher plaque fibrillarity protects cognitive function and brain integrity. Increases in the Aβ-PET signal upon immunomodulatory treatments targeting Aβ aggregation can thus be protective.
Retinal Optical Coherence Tomography Angiography Parameters Between Patients With Different Causes of Chronic Kidney Disease
Authors: Yong Meng Hsien , Ong Ming Yean , Tan Kuan Sze , Hussein Siti Husna , Mohd Zain Ayesha , Mohd Rozita , Mustafar Ruslinda , Wan Abdul Halim Wan Haslina
Published: March 2022

Background

Chronic kidney disease (CKD) is a major public health issue because of the rising number of patients with the risk of progression to end-stage renal disease. The retinal micro-vasculatures provide a unique window to assess systemic microcirculation. Optical Coherence Tomography Angiography (OCTA) parameters may provide a non-invasive method for systemic correlation. This research aims to compare the association of OCTA parameters in different causes of CKD.

Methods

This is a single-center cross-sectional study on patients with CKD at the Universiti Kebangsaan Malaysia Medical Centre over 2 years. Patients with CKD were divided into three groups: DM group (diabetic CKD), HPT group (hypertensive CKD), and AG group (autoimmune-related glomerulonephritis CKD). The OCTA parameters, namely, the foveal avascular zone (FAZ), vascular density (VD), perfusion density (PD), and macular volume (MV), were measured and recorded using OCTA. Blood and urine analyses were taken as the patient’s CKD profile. The demographic data, the OCTA parameters and the CKD profiles, were analyzed using SPSS version 23.

Results

The right eyes of 232 patients were included. The median age of the control and CKD subjects were 36 and 61 years old respectively. The proportion of the subjects under the control, diabetes mellitus (DM), HPT, and AG group were 30.6, 53.4, 5.6, and 10.4% respectively. There was no significant difference in FAZ, but there is a significant difference in the VD, PD, and MV between the control and CKD groups. There was a statistically significant difference between the three different causes of CKD in VD and PD (p < 0.001, p = 0.001, respectively). When compared with the control group for VD and PD, there were significant differences between the DM-control group (p < 0.001, p < 0.001) even when the age variable was considered, but no significant difference when comparing the HPT-control and the AG-control. There was a significant correlation between age, FBS, and HbA1c with VD and PD. There was no significant association between CKD profile and FAZ.

Conclusion

Our study showed the meaningful reduction of VD and PD in patients with diabetes and CKD. However, the use of OCTA to screen or predict CKD in patients living with diabetes mellitus, hypertension, or autoimmune nephritis was not shown to be useful.
Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders
Authors: Allen Charles N. S. , Arjona Sterling P. , Santerre Maryline , De Lucia Claudio , Koch Walter J. , Sawaya Bassel E.
Published: March 2022

A significant number of patients infected with HIV-1 suffer from HIV-associated neurocognitive disorders (HAND) such as spatial memory impairments and learning disabilities (SMI-LD). SMI-LD is also observed in patients using combination antiretroviral therapy (cART). Our lab has demonstrated that the HIV-1 protein, gp120, promotes SMI-LD by altering mitochondrial functions and energy production. We have investigated cellular processes upstream of the mitochondrial functions and discovered that gp120 causes metabolic reprogramming. Effectively, the addition of gp120 protein to neuronal cells disrupted the glycolysis pathway at the pyruvate level. Looking for the players involved, we found that gp120 promotes increased expression of polypyrimidine tract binding protein 1 (PTBP1), causing the splicing of pyruvate kinase M (PKM) into PKM1 and PKM2. We have also shown that these events lead to the accumulation of advanced glycation end products (AGEs) and prevent the cleavage of pro-brain-derived neurotrophic factor (pro-BDNF) protein into mature brain-derived neurotrophic factor (BDNF). The accumulation of proBDNF results in signaling that increases the expression of the inducible cAMP early repressor (ICER) protein which then occupies the cAMP response element (CRE)-binding sites within the BDNF promoters II and IV, thus altering normal synaptic plasticity. We reversed these events by adding Tepp-46, which stabilizes the tetrameric form of PKM2. Therefore, we concluded that gp120 reprograms cellular metabolism, causing changes linked to disrupted memory in HIV-infected patients and that preventing the disruption of the metabolism presents a potential cure against HAND progression.
Neuromodulation Enables Temperature Robustness and Coupling Between Fast and Slow Oscillator Circuits
Authors: Städele Carola , Stein Wolfgang
Published: March 2022

Acute temperature changes can disrupt neuronal activity and coordination with severe consequences for animal behavior and survival. Nonetheless, two rhythmic neuronal circuits in the crustacean stomatogastric ganglion (STG) and their coordination are maintained across a broad temperature range. However, it remains unclear how this temperature robustness is achieved. Here, we dissociate temperature effects on the rhythm generating circuits from those on upstream ganglia. We demonstrate that heat-activated factors extrinsic to the rhythm generators are essential to the slow gastric mill rhythm’s temperature robustness and contribute to the temperature response of the fast pyloric rhythm. The gastric mill rhythm crashed when its rhythm generator in the STG was heated. It was restored when upstream ganglia were heated and temperature-matched to the STG. This also increased the activity of the peptidergic modulatory projection neuron (MCN1), which innervates the gastric mill circuit. Correspondingly, MCN1’s neuropeptide transmitter stabilized the rhythm and maintained it over a broad temperature range. Extrinsic neuromodulation is thus essential for the oscillatory circuits in the STG and enables neural circuits to maintain function in temperature-compromised conditions. In contrast, integer coupling between pyloric and gastric mill rhythms was independent of whether extrinsic inputs and STG pattern generators were temperature-matched or not, demonstrating that the temperature robustness of the coupling is enabled by properties intrinsic to the rhythm generators. However, at near-crash temperature, integer coupling was maintained only in some animals while it was absent in others. This was true despite regular rhythmic activity in all animals, supporting that degenerate circuit properties result in idiosyncratic responses to environmental challenges.
P2X7 Receptor-Related Genetic Mouse Models – Tools for Translational Research in Psychiatry
Authors: Urbina-Treviño Lidia , von Mücke-Heim Iven-Alex , Deussing Jan M.
Published: March 2022

Depression is a common psychiatric disorder and the leading cause of disability worldwide. Although treatments are available, only about 60% of treated patients experience a significant improvement in disease symptoms. Numerous clinical and rodent studies have identified the purinergic P2X7 receptor (P2X7R) as one of the genetic factors potentially contributing to the disease risk. In this respect, genetically engineered mouse models targeting the P2X7R have become increasingly important in studying designated immunological features and subtypes of depressionin vivo. This review provides an overview of the P2X7R -related mouse lines currently available for translational psychiatric research and discusses their strengths, weaknesses, and potentials.
Functional Brain Connections Identify Sensorineural Hearing Loss and Predict the Outcome of Cochlear Implantation
Authors: Song Qiyuan , Qi Shouliang , Jin Chaoyang , Yang Lei , Qian Wei , Yin Yi , Zhao Houyu , Yu Hui
Published: March 2022

Identification of congenital sensorineural hearing loss (SNHL) and early intervention, especially by cochlear implantation (CI), are crucial for restoring hearing in patients. However, high accuracy diagnostics of SNHL and prognostic prediction of CI are lacking to date. To diagnose SNHL and predict the outcome of CI, we propose a method combining functional connections (FCs) measured by functional magnetic resonance imaging (fMRI) and machine learning. A total of 68 children with SNHL and 34 healthy controls (HC) of matched age and gender were recruited to construct classification models for SNHL and HC. A total of 52 children with SNHL that underwent CI were selected to establish a predictive model of the outcome measured by the category of auditory performance (CAP), and their resting-state fMRI images were acquired. After the dimensional reduction of FCs by kernel principal component analysis, three machine learning methods including the support vector machine, logistic regression, and k-nearest neighbor and their voting were used as the classifiers. A multiple logistic regression method was performed to predict the CAP of CI. The classification model of voting achieves an area under the curve of 0.84, which is higher than that of three single classifiers. The multiple logistic regression model predicts CAP after CI in SNHL with an average accuracy of 82.7%. These models may improve the identification of SNHL through fMRI images and prognosis prediction of CI in SNHL.
Gut-Derived Sterile Inflammation and Parkinson's Disease
Authors: Shannon Kathleen M.
Published: March 2022

The etiology of Parkinson's disease (PD) is unknown, but evidence is increasing that there is a prominent inflammatory component to the illness. Epidemiological, genetic, and preclinical evidence support a role for gut-derived sterile inflammation. Pro-inflammatory bacteria are over-represented in the PD gut microbiota. There is evidence for decreased gut barrier function and leak of bacterial antigen across the gut epithelium with sub-mucosal inflammation and systemic exposure to the bacterial endotoxin lipopolysaccharide. Preclinical evidence supports these clinical findings and suggests that systemic inflammation can affect the CNS through vagal pathways or the systemic circulation. We will review recent preclinical and clinical evidence to support this mechanism and suggest possible treatments directed at the gut-brain axis.
Evolving Roles of Notch Signaling in Cortical Development
Authors: Nian Fang-Shin , Hou Pei-Shan
Published: March 2022

Expansion of the neocortex is thought to pave the way toward acquisition of higher cognitive functions in mammals. The highly conserved Notch signaling pathway plays a crucial role in this process by regulating the size of the cortical progenitor pool, in part by controlling the balance between self-renewal and differentiation. In this review, we introduce the components of Notch signaling pathway as well as the different mode of molecular mechanisms, including trans- and cis-regulatory processes. We focused on the recent findings with regard to the expression pattern and levels in regulating neocortical formation in mammals and its interactions with other known signaling pathways, including Slit–Robo signaling and Shh signaling. Finally, we review the functions of Notch signaling pathway in different species as well as other developmental process, mainly somitogenesis, to discuss how modifications to the Notch signaling pathway can drive the evolution of the neocortex.
Emergence of Extreme Paw Accelerations During Cat Paw Shaking: Interactions of Spinal Central Pattern Generator, Hindlimb Mechanics and Muscle Length-Depended Feedback
Authors: Prilutsky Boris I. , Parker Jessica , Cymbalyuk Gennady S. , Klishko Alexander N.
Published: March 2022

Cat paw shaking is a spinal reflex for removing an irritating stimulus from paw by developing extremely high paw accelerations. Previous studies of paw shaking revealed a proximal-to-distal gradient of hindlimb segmental velocities/accelerations, as well as complex inter-joint coordination: passive motion-dependent interaction moments acting on distal segments are opposed by distal muscle moments. However, mechanisms of developing extreme paw accelerations during paw shaking remain unknown. We hypothesized that paw-shaking mechanics and muscle activity might correspond to a whip-like mechanism of energy generation and transfer along the hindlimb. We first demonstrated in experiments with five intact, adult, female cats that during paw shaking, energy generated by proximal muscle moments was transmitted to distal segments by joint forces. This energy transfer was mostly responsible for the segmental velocity/acceleration proximal-to-distal gradient. Distal muscle moments mostly absorbed energy of the distal segments. We then developed a neuromechanical model of hindlimb paw shaking comprised a half-center CPG, activating hip flexors and extensors, and passive viscoelastic distal muscles that produced length/velocity-depended force. Simulations reproduced whip-like mechanisms found experimentally: the proximal-to-distal velocity/acceleration gradient, energy transfer by joint forces and energy absorption by distal muscle moments, as well as atypical co-activation of ankle and hip flexors with knee extensors. Manipulating model parameters, including reversal of segmental inertia distal-to-proximal gradient, demonstrated important inertia contribution to developing the segmental velocity/acceleration proximal-to-distal gradient. We concluded that extreme paw accelerations during paw shaking result from interactions between a spinal CPG, hindlimb segmental inertia, and muscle length/velocity-depended feedback that tunes limb viscoelastic properties.
Adherence to the Vegetable-Fruit-Soy Dietary Pattern, a Reference From Mediterranean Diet, Protects Against Postmenopausal Breast Cancer Among Chinese Women
Authors: Cao Shang , Liu Linchen , Zhu Qianrang , Zhu Zheng , Zhou Jinyi , Wei Pingmin , Wu Ming
Published: March 2022

Background

The diet-center hypothesis has gained much support from the apparent protective effect of the Mediterranean diet on breast cancer. However, the evidence of the association between Mediterranean diet adherence and breast cancer molecular subtypes remains small, especially in non-Mediterranean populations.

Methods

The subjects from the Chinese Wuxi Exposure and Breast Cancer Study, a population-based case-control study, included 818 patients and 935 healthy controls. A validated food frequency questionnaire used for diet assessment and a modified version of the alternate Mediterranean Diet Score, which is called the alternate Chinese Diet Score, was developed to assess adherence to a migrated Chinese version of the Mediterranean diet, which we called the vegetable-fruit-soy dietary pattern. Soy foods, rapeseed oil, and coarse cereals replaced legumes, olive oil, and whole grains reflecting the cuisine of the region. We examined the association between the vegetable-fruit-soy diet adherence and breast cancer risk, stratified by menopause status (pre- or postmenopausal) and receptor status [estrogen-receptor (ER), progesterone-receptor (PR) status, and human epidermal growth factor 2 (HER2)] oncogene expression, followed by five specific combinations (ER+, ER–, ER+/PR+,ER–/PR–, and ER–/PR–/HER2–).

Results

The results suggest that the vegetable-fruit-soy dietary pattern was inversely associated with postmenopausal breast cancer risk [4th vs. 1st quartile, odds ratio (OR) = 0.57, 95%CI = 0.41, 0.80;Ptrend < 0.001] and that the inverse association was somewhat stronger to detect among ER- subtypes (OR = 0.63; 95%CI = 0.37, 0.94;Ptrend = 0.003) and ER–/PR–subtypes (OR = 0.64; 95%CI = 0.41, 0.93;Ptrend = 0.012). We did not observe any significant association between the vegetable-fruit-soy diet characteristics and ER+ subtype, as well as between PR+ and ER+/PR+ subtypes.

Conclusion

The favorable influence from the Mediterranean diet may also apply to Chinese women. The vegetable-fruit-soy dietary pattern may reduce the risk of postmenopausal breast cancer, particularly among ER- subtype, and ER–/PR–subtype.