bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of contact aspect ratio and film to substrate elastic modulus ratio on stress vs. strain up to the point of yield during flat punch thin film indentation of an elastic-plastic film
Authors: Sinnott Aaron D. , Brazil Owen , Cross Graham L. W.
Published: October 2022

Nanoindentation is the only way to test the local mechanical properties of thin films and coatings. Current analysis treats the measurement as a perturbation of a conventional half-space indentation, typically limiting testing to films with modulus within an order of magnitude of the supporting substrate and contact dimension much smaller than the film thickness. In the layer compression test (LCT), a flat punch is aligned and indented into the film with a contact size much greater than the film thickness. This produces a novel test condition emulating uniform uniaxial strain even with significant penetration into the film beyond plastic yield. In this work, we perform a finite element analysis to assess the quality of this approximation in the confined elastic regime of deformation up to the point of yield via a parametric study of punch radius to film thickness ratio and film to substrate modulus ratio for a simple elastic-plastic material. Our simulations were performed with a low E/Y ratio of 10, which is typical of polymers, biomaterials and other amorphous systems. We find that for substrates of sufficiently high stiffness relative to the film sample, once a simple substrate stiffness correction is performed the layer compression test load vs. displacement slope estimates the film confined modulus to within a few percent with only minor variation throughout the entire pre-yield strain region for a wide range of aspect ratios. We also present experimental layer compression test findings for a supported polymer film conducted over a contact aspect ratio range of 9–22 and discuss the trends observed relative to the simulations.
Clinical outcomes and prognostic factors of bronchiectasis rheumatoid overlap syndrome: A multi-institution cohort study
Authors: Lin Horng-Chyuan , Huang Hung-Yu , Lin Chun-Yu , Fang Yueh-Fu , Lin Chiung-Hung , Huang Yu-Tung , Chang Chiung-Hsin , Wang Chun-Hua , Huang Jhen-Ling , Liao Ting-Wei , Hsieh Meng-Heng
Published: October 2022

The information regarding bronchiectasis with RA (BROS) is limited in Asia. The objective of this study was to investigate the clinical characteristics and outcomes of BROS in Taiwan. This multi-institute cohort study included patients with BROS from January 2006 to December 2017. The clinical, functional and microbiological data of these patients were retrieved from the Chang Gung Research Database. Respiratory failure and mortality were the primary outcomes. Severe exacerbation was defined as bronchiectasis- related hospitalizations or emergency department visits. A total of 343 patients with BROS were identified. One hundred and eight patients had severe exacerbation and exhibited significantly more previous exacerbations, a lower FEV1 and higher BACI score (11.1 vs. 7.5) than patients without severe exacerbation. The most prevalent species in sputum were Non-tuberculous mycobacteria (NTM) (14.8 %), Pseudomonas aeruginosa (14.2 %), and fungus (5.9%). 68.8% of BROS patients used disease modifying antirheumatic drugs (DMARD), 7.9% used biological DMARD. NTM and tuberculosis infection rates were higher in bDMARD group compared with nbDMARD group and others. Overall, the 3-year respiratory failure rate and mortality rate were 14.6 and 25.7% respectively. Patients with RA diagnosed before bronchiectasis had a significantly higher cumulative incidence of mortality in a 3-year follow-up than those with RA diagnosed after bronchiectasis. In Cox regression, age, higher RF value and systemic steroid use were independent risk factors for mortality in BROS. BROS patients with severe exacerbation had a high mortality rate in Taiwan. bDMARD is associated with a trend of increased risk of NTM and TB infections.
The add-on effect of Shufeng Jiedu capsule for treating COVID-19: A systematic review and meta-analysis
Authors: Sheng Xiaodi , Chen Chao , Jiang Guowang , Ji Zhaochen , Guo Zehui , Hu Haiyin , Wang Hui , Zhai Jingbo , Zhang Dong , Zhang Junhua , Guo Liping
Published: October 2022

Introduction

Shufeng Jiedu capsule (SFJD) is a commonly used Chinese patent medicine in China. Some studies have reported that SFJD has therapeutic effects in patients diagnosed with COVID-19. This systematic review aimed to critically evaluate the efficacy and safety of SFJD combined with western medicine (WM) for treating COVID-19.

Methods

A literature search by using WHO COVID-19 database, PubMed, Embase, Cochrane Library, the Web of Science, CKNI, Wanfang, VIP, SinoMed, and clinical trial registries was conducted, up to 1 August 2022. Randomized controlled trials (RCTs), non-RCTs, cohort studies and case series of SFJD combined with WM for COVID-19 were included. Literature screening, data extraction, and quality assessment were performed independently by two reviewers in line with the same criteria. We used the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) to assess the certainty of evidence. Meta-analyses were performed with Revman 5.3 if possible. The descriptive analysis was conducted when the studies could not be meta-analyzed.

Results

Totally 10 studies with 1,083 patients were included. Their methodological quality were moderate. The results demonstrated that compared to WM group, SFJD + WM group remarkably increased the nucleic acid negative conversion rate (RR = 1.40, 95%CI: 1.07–1.84), total effective rate (RR = 1.18, 95%CI: 1.07–1.31), cure rate (RR = 4.06, 95%CI: 2.19–7.53), and the chest CT improvement rate (RR = 1.19, 95%CI: 1.08–1.31), shorten nucleic acid negative conversion time (MD = −0.70, 95%CI: −1.14 to −0.26), reduced the clinical symptom disappearance time (fever, diarrhea, cough, fatigue, pharyngalgia, nasal congestion, and rhinorrhea), as well as improved the levels of laboratory outcomes (CRP, IL-6, Lym, and Neu). Additionally, the incidence of adverse reactions did not exhibit any statistically significant difference between SFJD + WM group and WM group.

Conclusion

SFJD combined with WM seems more effective than WM alone for the treatment of COVID-19. However, more well-designed RCTs still are warranted.

Systematic review registration

[https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42022306307].
CXCR5+CD8 T cells: Potential immunotherapy targets or drivers of immune-mediated adverse events?
Authors: Turner Christi N. , Mullins Genevieve N. , Hoyer Katrina K.
Published: October 2022

CXCR5+CD8 T cells have attracted significant interest within multiple areas of immunology, cancer, and infection. This is in part due to their apparent dual functionality. These cells perform as cytotoxic cells in a variety of infection states including LCMV, HBV, HIV and SIV. However, CXCR5+CD8 T cells also associate with B cells in peripheral organs and function to stimulate B cell proliferation, antibody/B cell receptor class-switch, and antibody production. CXCR5+CD8 T cells are similar to CXCR5+CD4 T follicular helpers in their genetic make-up, B cell interactions, and functionality despite possessing elevated programmed cell death 1 and cytotoxic proteins. Within cancer CXCR5+CD8 T cells have risen as potential prognostic markers for overall survival and are functionally cytotoxic within tumor microenvironments. In inflammatory disease and autoimmunity, CXCR5+CD8 T cells are implicated in disease progression. During viral infection and cancer, CXCR5 expression on CD8 T cells generally is indicative of progenitor memory stem-like exhausted cells, which are more responsive to immune checkpoint blockade therapy. The use of immune checkpoint inhibitors to overcome immune exhaustion in cancer, and subsequent consequence of immune adverse events, highlights the dual nature of the cellular immune response. This review will detail the functionality of CXCR5+CD8 T cells in cancer and autoimmunity with potential repercussions during immune checkpoint blockade therapy discussed.
Tools to improve the diagnosis and management of T-cell mediated adverse drug reactions
Authors: Copaescu Ana Maria , Ben-Shoshan Moshe , Trubiano Jason A.
Published: October 2022

Delayed drug T-cell immune-mediated hypersensitivity reactions have a large clinical heterogeneity varying from mild maculopapular exanthema (MPE) to severe cutaneous adverse reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and severe skin necrosis and blistering as seen in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Given the knowledge gaps related to the immunopathogenesis of these conditions, the absence of validated diagnostic tools and the significant associated morbidity and mortality, patients with SCARs often have limited drug choices. We performed a comprehensive review aiming to evaluate in vivo diagnostic tools such as delayed intradermal skin and patch testing and ex vivo/in vitro research assays such as the lymphocyte transformation test (LTT) and the enzyme-linked ImmunoSpot (ELISpot) assay. We searched through PubMed using the terms “drug allergy,” “in vivo” and “ex vivo” for original papers in the last 10 years. A detailed meticulous approach adapted to the various clinical phenotypes is recommended for the diagnostic and management of delayed drug hypersensitivity reactions. This review highlights the current diagnostic tools for the delayed drug hypersensitivity phenotypes.
A 16S rDNA sequencing-based analysis of airway microecology in patients with an acute exacerbation of chronic obstructive pulmonary disease: A cross-sectional study in Inner Mongolia, China
Authors: Zhu Shu-fen , Wu Xin-xin , Guo Yan , Li Peng-fei , Wang Jing-ran , Liu Miao , Luo Cheng-wen , Yuan Xiang-zhen , Li Shao-wei
Published: October 2022

Aim

To study the microecological characteristics of the airway and similarities and differences between healthy people and patients with the acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in Inner Mongolia, and analyze the correlation between the characteristics of the airway microecological structure and clinical indicators of AECOPD patients.

Methods

Sputum samples from 36 healthy volunteers and 34 patients with AECOPD were detected by 16S rDNA high-throughput sequencing, and the airway microecological characteristics of healthy people and AECOPD patients were revealed by an alpha diversity analysis, beta diversity analysis, and LefSe difference analysis.

Results

There were differences in the airway microecological structure between healthy people and AECOPD patients in Inner Mongolia. The airway microbiota composition of AECOPD patients showed an increase in the abundance of common pathogens and a decrease in the abundance of commensal bacteria, and the airway microbial diversity in AECOPD patients was lower than that in healthy people. Long-term use of inhaled glucocorticoid + long-acting β2 agonist mixture (ICS + LABA), procalcitonin (PCT), blood monocyte count (MONO), hemoglobin (HGB), D-dimer (D-D), and body temperature were negatively correlated with the alpha diversity of the airway micro-ecosystem.

Conclusion

The airway microecological composition of the AECOPD population in Inner Mongolia was different from that of the healthy population, and the airway microecological diversity was lower than that of the healthy population. The long-term use of ICS + LABA preparation by patients with AECOPD leads to lower alpha diversity. Alpha diversity was negatively correlated with inflammatory markers (PCT, MONO, D-dimer, body temperature) and HGB in AECOPD patients.
Waning immunity to SARS-CoV-2 following vaccination or infection
Authors: Hernandez-Suarez Carlos , Murillo-Zamora Efrèn
Published: October 2022

We use survival analysis to analyze the decay in the protection induced by eight SARS-CoV-2 vaccines using data from 33,418 fully anonymized patients from the IMSS public health system in Mexico, including only previously vaccinated, confirmed SARS-CoV-2 positive with a PCR test. We analyze the waning effect in those with complete vs. incomplete dose fitting a Weibull distribution. We compare these results with an estimate of the waning effect due to active infection. In two-dose vaccines, we found that the average protection time of a complete dose increases 2.6 times compared to that of an incomplete dose. All analyzed vaccines provided a protection that lasted longer than the protection due to active infection, except in those patients that did not fulfilled the complete dose. The average protection of a full dose is 2.2 times larger than that provided by active infection. The average protection of active infection is about the same as the average protection of an incomplete dose. All evaluated vaccines had lost most of their protective effect between 8 and 11 months of application of first shot. Our results highly correlate with NT50 and other estimates of vaccine efficacy. We found that on average, vaccination increases Age50, the age at which there is a 50% probability of severe disease if infected, in 15 years. We also found that Age50 increases with mean protection time.
Age-dependent antibody profiles to plasmodium antigens are differentially associated with two artemisinin combination therapy outcomes in high transmission setting
Authors: Andagalu Ben , Lu Pinyi , Onyango Irene , Bergmann-Leitner Elke , Wasuna Ruth , Odhiambo Geoffrey , Chebon-Bore Lorna J. , Ingasia Luicer A. , Juma Dennis W. , Opot Benjamin , Cheruiyot Agnes , Yeda Redemptah , Okudo Charles , Okoth Raphael , Chemwor Gladys , Campo Joseph , Wallqvist Anders , Akala Hoseah M. , Ochiel Daniel , Ogutu Bernhards , Chaudhury Sidhartha , Kamau Edwin
Published: October 2022

The impact of pre-existing immunity on the efficacy of artemisinin combination therapy is largely unknown. We performed in-depth profiling of serological responses in a therapeutic efficacy study [comparing artesunate-mefloquine (ASMQ) and artemether-lumefantrine (AL)] using a proteomic microarray. Responses to over 200 Plasmodium antigens were significantly associated with ASMQ treatment outcome but not AL. We used machine learning to develop predictive models of treatment outcome based on the immunoprofile data. The models predict treatment outcome for ASMQ with high (72–85%) accuracy, but could not predict treatment outcome for AL. This divergent treatment outcome suggests that humoral immunity may synergize with the longer mefloquine half-life to provide a prophylactic effect at 28–42 days post-treatment, which was further supported by simulated pharmacokinetic profiling. Our computational approach and modeling revealed the synergistic effect of pre-existing immunity in patients with drug combination that has an extended efficacy on providing long term treatment efficacy of ASMQ.
Identification of genetic elements required for Listeria monocytogenes growth under limited nutrient conditions and virulence by a screening of transposon insertion library
Authors: Narayanan Lakshmi , Ozdemir Ozan , Alugubelly Navatha , Ramachandran Reshma , Banes Michelle , Lawrence Mark , Abdelhamed Hossam
Published: October 2022

Listeria monocytogenes, the causative agent of listeriosis, displays a lifestyle ranging from saprophytes in the soil to pathogenic as a facultative intracellular parasite in host cells. In the current study, a random transposon (Tn) insertion library was constructed in L. monocytogenes strain F2365 and screened to identify genes and pathways affecting in vitro growth and fitness in minimal medium (MM) containing different single carbohydrate as the sole carbon source. About 2,000 Tn-mutants were screened for impaired growth in MM with one of the following carbon sources: glucose, fructose, mannose, mannitol, sucrose, glycerol, and glucose 6-phosphate (G6P). Impaired or abolished growth of L. monocytogenes was observed for twenty-one Tn-mutants with disruptions in genes encoding purine biosynthesis enzymes (purL, purC, purA, and purM), pyrimidine biosynthesis proteins (pyrE and pyrC), ATP synthase (atpI and atpD2), branched-chain fatty acids (BCFA) synthesis enzyme (bkdA1), a putative lipoprotein (LMOF2365_2387 described as LP2387), dUTPase family protein (dUTPase), and two hypothetical proteins. All Tn-mutants, except the atpD2 mutant, grew as efficiently as wild-type strain in a nutrient rich media. The virulence of twenty-one Tn-mutants was assessed in mice at 72 h following intravenous (IV) infection. The most attenuated mutants had Tn insertions in purA, hypothetical protein (LMOf2365_0064 described as HP64), bkdA1, dUTPase, LP2387, and atpD2, confirming the important role of these genes in pathogenesis. Six Tn-mutants were then tested for ability to replicate intracellularly in murine macrophage J774.1 cells. Significant intracellular growth defects were observed in two Tn-mutants with insertions in purA and HP64 genes, suggesting that an intact purine biosynthesis pathway is important for intracellular growth of L. monocytogens. These findings may not be fully generalized to all of L. monocytogenes strains due to their genetic diversity. In conclusion, Tn-mutagenesis identified that biosynthesis of purines, pyrimidines, ATP, and BCFA are important for L. monocytogens pathogenesis. Purine and pyrimidine auxotrophs play an important role in the pathogenicity in other bacterial pathogens, but our study also revealed new proteins essential for both growth in MM and L. monocytogenes strain F2365 virulence.
High diversity of Rickettsia spp., Anaplasma spp., and Ehrlichia spp. in ticks from Yunnan Province, Southwest China
Authors: Lu Miao , Tian Junhua , Wang Wen , Zhao Hongqing , Jiang Hai , Han Jizhou , Guo Wenping , Li Kun
Published: October 2022

Rickettsia, Anaplasma, and Ehrlichia belonging to the order Rickettsiales are causative agents of tick-borne diseases in humans. During 2021, 434 ticks including Rhipicephalus microplus and R. haemaphysaloides were collected from three sampling sites in Yunnan Province, Southwest China, and analyzed for the presence of these bacteria. Nine bacterial species were identified, including two Rickettsia spp., three Anaplasma spp., and four Ehrlichia spp., some of which are potential human pathogens. Genetic and phylogenetic analysis on 16S rRNA, gltA, groEL, ompA, ompB, and sca4 genes indicated the presence of a novel spotted fever group Rickettsia (SFGR) named “Candidatus Rickettsia shennongii” in six of the 38 R. haemaphysaloides ticks from two locations, Dehong Autonomous Prefecture and Honghe City. Another SFGR species, Candidatus Rickettsia jingxinensis was detected in ticks from all three sites, with an overall positive rate of 62.67%. Three other human pathogenic species, Anaplasma ovis (1.38%, 6/434), Ehrlichia canis (16.36%, 71/434), and E. chaffeensis (0.23%, 1/434) were detected in these ticks and characterized. Moreover, Ehrlichia sp. (4.84%, 21/434), E. minasensis (7.37%, 32/434), A. marginale (6.91%, 30/434), and Cadidatus Anaplasma boleense (1.15%, 5/434) were detected in R. microplus ticks, for which pathogenicity to humans remains to be determined. The results reveal the remarkable diversity of Rickettsiales bacteria in ticks from Yunnan Province, Southwest China. The high infection rate of some human pathogenic bacteria in ticks may indicate potential infection risk in humans, and it highlights the need for surveillance in local populations.
Pseudomonas aeruginosa reference strains PAO1 and PA14: A genomic, phenotypic, and therapeutic review
Authors: Grace Amber , Sahu Rajnish , Owen Donald R. , Dennis Vida A.
Published: October 2022

Pseudomonas aeruginosa is a ubiquitous, motile, gram-negative bacterium that has been recently identified as a multi-drug resistant pathogen in critical need of novel therapeutics. Of the approximately 5,000 strains, PAO1 and PA14 are common laboratory reference strains, modeling moderately and hyper-virulent phenotypes, respectively. PAO1 and PA14 have been instrumental in facilitating the discovery of novel drug targets, testing novel therapeutics, and supplying critical genomic information on the bacterium. While the two strains have contributed to a wide breadth of knowledge on the natural behaviors and therapeutic susceptibilities of P. aeruginosa, they have demonstrated significant deviations from observations in human infections. Many of these deviations are related to experimental inconsistencies in laboratory strain environment that complicate and, at times, terminate translation from laboratory results to clinical applications. This review aims to provide a comparative analysis of the two strains and potential methods to improve their clinical relevance.
Investigation of the growth performance, blood status, gut microbiome and metabolites of rabbit fed with low-nicotine tobacco
Authors: Jing Changliang , Wang Jiahao , Xie Yi , Zhang Jianhui , Guo Yixuan , Tian Tian , Tang Jing , Ju Fuzhu , Wang Chunkai , Liu Yanhua , Zhang Zhongfeng , Yang Xingyou , Zhang Hongbo
Published: October 2022

Tobacco contains a large amount of bioactive ingredients which can be used as source of feed. The objective of this study was to evaluate the effects of dietary addition of low-nicotine tobacco (LNT) on the growth performance, blood status, cecum microbiota and metabolite composition of meat rabbits. A total of 80 Kangda meat rabbits of similar weight were assigned randomly as four groups, and three of them were supplemented with 5%, 10%, and 20% LNT, respectively, with the other one fed with basal diet as control group. Each experiment group with 20 rabbits was raised in a single cage. The experiments lasted for 40 days with a predictive period of 7 days. The results revealed that LNT supplementation had no significant effect on the growth performance, but increased the half carcass weight compared with control group. Dietary supplemention of LNT decreased the triglycerides and cholesterol content in rabbit serum, and significantly increased the plasma concentration of lymphocytes (LYM), monocytes, eosinophils, hemoglobin HGB and red blood cells. In addition, LNT supplementation significantly changed the microbial diversity and richness, and metagenomic analysis showed that LNT supplementation significantly increased Eubacterium_siraeum_group, Alistipes, Monoglobus and Marvinbryantia at genus level. Moreover, LC–MS data analysis identified a total of 308 metabolites that markedly differed after LNT addition, with 190 significantly upregulated metabolites and 118 significantly downregulated metabolites. Furthermore, the correlation analysis showed that there was a significant correlation between the microbial difference and the rabbit growth performance. Overall, these findings provide theoretical basis and data support for the application of LNT in rabbits.
Rhizobium etli CFN42 proteomes showed isoenzymes in free-living and symbiosis with a different transcriptional regulation inferred from a transcriptional regulatory network
Authors: Taboada-Castro Hermenegildo , Gil Jeovanis , Gómez-Caudillo Leopoldo , Escorcia-Rodríguez Juan Miguel , Freyre-González Julio Augusto , Encarnación-Guevara Sergio
Published: October 2022

A comparative proteomic study at 6 h of growth in minimal medium (MM) and bacteroids at 18 days of symbiosis of Rhizobium etli CFN42 with the Phaseolus vulgaris leguminous plant was performed. A gene ontology classification of proteins in MM and bacteroid, showed 31 and 10 pathways with higher or equal than 30 and 20% of proteins with respect to genome content per pathway, respectively. These pathways were for energy and environmental compound metabolism, contributing to understand how Rhizobium is adapted to the different conditions. Metabolic maps based on orthology of the protein profiles, showed 101 and 74 functional homologous proteins in the MM and bacteroid profiles, respectively, which were grouped in 34 different isoenzymes showing a great impact in metabolism by covering 60 metabolic pathways in MM and symbiosis. Taking advantage of co-expression of transcriptional regulators (TF’s) in the profiles, by selection of genes whose matrices were clustered with matrices of TF’s, Transcriptional Regulatory networks (TRN´s) were deduced by the first time for these metabolic stages. In these clustered TF-MM and clustered TF-bacteroid networks, containing 654 and 246 proteins, including 93 and 46 TFs, respectively, showing valuable information of the TF’s and their regulated genes with high stringency. Isoenzymes were specific for adaptation to the different conditions and a different transcriptional regulation for MM and bacteroid was deduced. The parameters of the TRNs of these expected biological networks and biological networks of E. coli and B. subtilis segregate from the random theoretical networks. These are useful data to design experiments on TF gene–target relationships for bases to construct a TRN.
Predictive functional, statistical and structural analysis of CSNK2A1 and CSNK2B variants linked to neurodevelopmental diseases
Authors: Unni Prasida , Friend Jack , Weinberg Janice , Okur Volkan , Hochscherf Jennifer , Dominguez Isabel
Published: October 2022

Okur-Chung Neurodevelopmental Syndrome (OCNDS) and Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) were recently identified as rare neurodevelopmental disorders. OCNDS and POBINDS are associated with heterozygous mutations in the CSNK2A1 and CSNK2B genes which encode CK2α, a serine/threonine protein kinase, and CK2β, a regulatory protein, respectively, which together can form a tetrameric enzyme called protein kinase CK2. A challenge in OCNDS and POBINDS is to understand the genetic basis of these diseases and the effect of the various CK2⍺ and CK2β mutations. In this study we have collected all variants available to date in CSNK2A1 and CSNK2B, and identified hotspots. We have investigated CK2⍺ and CK2β missense mutations through prediction programs which consider the evolutionary conservation, functionality and structure or these two proteins, compared these results with published experimental data on CK2α and CK2β mutants, and suggested prediction programs that could help predict changes in functionality of CK2α mutants. We also investigated the potential effect of CK2α and CK2β mutations on the 3D structure of the proteins and in their binding to each other. These results indicate that there are functional and structural consequences of mutation of CK2α and CK2β, and provide a rationale for further study of OCNDS and POBINDS-associated mutations. These data contribute to understanding the genetic and functional basis of these diseases, which is needed to identify their underlying mechanisms.
Depletion of ALMS1 affects TGF-β signalling pathway and downstream processes such as cell migration and adhesion capacity
Authors: Bea-Mascato Brais , Neira-Goyanes Elena , Iglesias-Rodríguez Antía , Valverde Diana
Published: October 2022

Background:ALMS1 is a ubiquitous gene associated with Alström syndrome (ALMS). The main symptoms of ALMS affect multiple organs and tissues, generating at last, multi-organic fibrosis in the lungs, kidneys and liver. TGF-β is one of the main pathways implicated in fibrosis, controlling the cell cycle, apoptosis, cell migration, cell adhesion and epithelial-mesenchymal transition (EMT). Nevertheless, the role of ALMS1 gene in fibrosis generation and other implicated processes such as cell migration or cell adhesion via the TGF- β pathway has not been elucidated yet.

Methods: Initially, we evaluated how depletion of ALMS1 affects different processes like apoptosis, cell cycle and mitochondrial activity in HeLa cells. Then, we performed proteomic profiling with TGF-β stimuli in HeLa ALMS1 −/− cells and validated the results by examining different EMT biomarkers using qPCR. The expression of these EMT biomarkers were also studied in hTERT-BJ-5ta ALMS1 −/−. Finally, we evaluated the SMAD3 and SMAD2 phosphorylation and cell migration capacity in both models.

Results: Depletion of ALMS1 generated apoptosis resistance to thapsigargin (THAP) and C2-Ceramide (C2-C), and G2/M cell cycle arrest in HeLa cells. For mitochondrial activity, results did not show significant differences between ALMS1 +/+ and ALMS1 −/−. Proteomic results showed inhibition of downstream pathways regulated by TGF-β. The protein-coding genes (PCG) were associated with processes like focal adhesion or cell-substrate adherens junction in HeLa. SNAI1 showed an opposite pattern to what would be expected when activating the EMT in HeLa and BJ-5ta. Finally, in BJ-5ta model a reduced activation of SMAD3 but not SMAD2 were also observed. In HeLa model no alterations in the canonical TGF-β pathway were observed but both cell lines showed a reduction in migration capacity.

Conclusion:ALMS1 has a role in controlling the cell cycle and the apoptosis processes. Moreover, the depletion of ALMS1 affects the signal transduction through the TGF-β and other processes like the cell migration and adhesion capacity.
Molecular regulation after mucosal injury and regeneration in ulcerative colitis
Authors: Zheng Lie , Duan Sheng-Lei , Wen Xin-Li , Dai Yan-Cheng
Published: October 2022

Ulcerative colitis (UC) is a chronic nonspecific inflammatory disease with a complex etiology. Intestinal mucosal injury is an important pathological change in individuals with UC. Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5+) intestinal stem cells (ISCs) exhibit self-renewal and high differentiation potential and play important roles in the repair of intestinal mucosal injury. Moreover, LGR5+ ISCs are intricately regulated by both the Wnt/β-catenin and Notch signaling pathways, which jointly maintain the function of LGR5+ ISCs. Combination therapy targeting multiple signaling pathways and transplantation of LGR5+ ISCs may lead to the development of new clinical therapies for UC.
Regulation of gut microbiome by ketogenic diet in neurodegenerative diseases: A molecular crosstalk
Authors: Kaviyarasan Shobana , Chung Sia Edmund Lee , Retinasamy Thaarvena , Arulsamy Alina , Shaikh Mohd Farooq
Published: October 2022

The gut taxonomical profile is one of the contributory factors in maintaining homeostasis within the central nervous system (CNS). Of late, the efficacy of diet as a target of treatment, and how various dietary interventions may modulate gut microbiota differently have been an area of focus in research. The role of ketogenic diet (KD) in particular has been well-established in other diseases like intractable epilepsy due to its postulated effects on gut microbiome modulation, resulting in neuronal stability and prevention of epileptogenesis. Therefore, this systematic review aimed to critically evaluate the current available literature investigating the interplay between the three distinct entities: ketogenic diet, neurodegeneration, and gut microbiota, which may serve as a focus guide for future neurodegenerative diseases (ND) therapeutic research. A comprehensive literature search was performed on three databases; PubMed, Scopus, and Ovid Medline. A total of 12 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that the hopes of KD as a treatment modality for ND are being ventured into as these individuals are said to acquire gut dysbiosis, primarily through increased colonization of phyla Proteobacteria and Firmicutes. Although positive effects including restoration of healthy gut microbes such as Akkermansia Muciphilia sp., improvement in cognitive functioning and decline in neuro-inflammatory markers were noted, this systematic review also depicted conflicting results such as decrease in alpha and beta species diversity as well as diminution of healthy gut commensals such as Bifidobacteriace. In addition, positive neuromodulation were also observed, notably an increase in cerebral blood perfusion to ventromedial hippocampal region via increased expression of eNOS and clearance of amyloid-beta proteins across the blood-brain-barrier via expression of p-glycoprotein. Neuroprotective mechanisms of ketogenic diet also included downregulation of mTOR expression, to prevention acceleration of pathological diseases such as Alzheimer's. Thus due to this conflicting/contrasting results demonstrated by ketogenic diet, such as a decline in gut species richness, diminution in beneficial microbes and decline cognition unless delivered in an intermittent fasting pattern, further studies may still be required before prior recommendation of a ketogenic diet therapeutic regime in ND patients.
Assessment of Alzheimer’s disease-related biomarkers in patients with obstructive sleep apnea: A systematic review and meta-analysis
Authors: Cui Wenqi , Duan Zhenghao , Li Zijian , Feng Juan
Published: October 2022

Increasing evidence links Alzheimer’s disease (AD) to various sleep disorders, including obstructive sleep apnea (OSA). The core AD cerebrospinal fluid (CSF) biomarkers, including amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau), can reflect key elements of AD pathophysiology before the emergence of symptoms. Besides, the amyloid-β (Aβ) and tau burden can also be tested by positron emission tomography (PET) scans. Electronic databases (PubMed, Embase, Web of Science, and The Cochrane Library) were searched until August 2022 to assess the AD-related biomarkers measured by PET scans and CSF in OSA patients. The overall analysis showed significant differences in Aβ42 levels (SMD = −0.93, 95% CI:−1.57 to −0.29, P < 0.001) and total tau (t-tau) levels (SMD = 0.24, 95% CI: 0.01–0.48, P = 0.308) of CSF, and Aβ burden (SMD = 0.37, 95% CI = 0.13–0.61, P = 0.69) tested by PET scans between the OSA and controls. Furthermore, CSF Aβ42 levels showed significant differences in patients with moderate/severe OSA compared with healthy control, and levels of CSF Aβ42 showed differences in OSA patients with normal cognition as well. Besides, age and BMI have influences on heterogeneity. Our meta-analysis indicated abnormal AD-related biomarkers (CSF and PET scans) in patients with OSA, supporting the current hypothesis that OSA, especially moderate/severe OSA, may start the AD neuropathological process.

Systematic review registration

[https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021289559].
Recent progress on the role of non-coding RNA in postoperative cognitive dysfunction
Authors: Yang Yu-Shen , He Shi-Ling , Chen Wei-Can , Wang Cong-Mei , Huang Qiao-Mei , Shi Yan-Chuan , Lin Shu , He He-fan
Published: October 2022

Postoperative cognitive dysfunction (POCD), especially in elderly patients, is a serious complication characterized by impairment of cognitive and sensory modalities after surgery. The pathogenesis of POCD mainly includes neuroinflammation, neuronal apoptosis, oxidative stress, accumulation of Aβ, and tau hyperphosphorylation; however, the exact mechanism remains unclear. Non-coding RNA (ncRNA) may play an important role in POCD. Some evidence suggests that microRNA, long ncRNA, and circular RNA can regulate POCD-related processes, making them promising biomarkers in POCD diagnosis, treatment, and prognosis. This article reviews the crosstalk between ncRNAs and POCD, and systematically discusses the role of ncRNAs in the pathogenesis and diagnosis of POCD. Additionally, we explored the possible mechanisms of ncRNA-associated POCD, providing new knowledge for developing ncRNA-based treatments for POCD.
Unification of free energy minimization, spatiotemporal energy, and dimension reduction models of V1 organization: Postnatal learning on an antenatal scaffold
Authors: Wright James Joseph , Bourke Paul David
Published: October 2022

Developmental selection of neurons and synapses so as to maximize pulse synchrony has recently been used to explain antenatal cortical development. Consequences of the same selection process—an application of the Free Energy Principle—are here followed into the postnatal phase in V1, and the implications for cognitive function are considered. Structured inputs transformed via lag relay in superficial patch connections lead to the generation of circumferential synaptic connectivity superimposed upon the antenatal, radial, “like-to-like” connectivity surrounding each singularity. The spatiotemporal energy and dimension reduction models of cortical feature preferences are accounted for and unified within the expanded model, and relationships of orientation preference (OP), space frequency preference (SFP), and temporal frequency preference (TFP) are resolved. The emergent anatomy provides a basis for “active inference” that includes interpolative modification of synapses so as to anticipate future inputs, as well as learn directly from present stimuli. Neurodynamic properties are those of heteroclinic networks with coupled spatial eigenmodes.
A nomogram for predicting atrial fibrillation detected after acute ischemic stroke
Authors: Pang Ming , Li Zhuanyun , Sun Lin , Zhao Na , Hao Lina
Published: October 2022

Background

Atrial fibrillation detected after stroke (AFDAS) is associated with an increased risk of ischemic stroke (IS) recurrence and death. Early diagnosis can help identify strategies for secondary prevention and improve prognosis. However, there are no validated predictive tools to assess the population at risk for AFDAS. Therefore, this study aimed to develop and validate a predictive model for assessing the incidence of AFDAS after acute ischemic stroke (AIS).

Methods

This study was a multicenter retrospective study. We collected clinical data from 5332 patients with AIS at two hospitals between 2014.01 and 2021.12 and divided the development and validation of clinical prediction models into a training cohort (n = 3173) and a validation cohort (n = 2159). Characteristic variables were selected from the training cohort using the least absolute shrinkage and selection operator (LASSO) algorithm and multivariable logistic regression analysis. A nomogram model was developed, and its performance was evaluated regarding calibration, discrimination, and clinical utility.

Results

We found the best subset of risk factors based on clinical characteristics and laboratory variables, including age, congestive heart failure (CHF), previous AIS/transient ischemia attack (TIA), national institutes of health stroke scale (NIHSS) score, C-reactive protein (CRP), and B-type natriuretic peptide (BNP). A predictive model was developed. The model showed good calibration and discrimination, with calibration values of Hosmer-Lemeshow χ2 = 4.813, P = 0.732 and Hosmer-Lemeshow χ2 = 4.248, P = 0.834 in the training and validation cohorts, respectively. The area under the ROC curve (AUC) was 0.815, 95% CI (0.777–0.853) and 0.808, 95% CI (0.770–0.847). The inclusion of neuroimaging variables significantly improved the performance of the integrated model in both the training cohort (AUC. 0.846 (0.811–0.882) vs. 0.815 (0.777–0.853), P = 0.001) and the validation cohort (AUC: 0.841 (0.804–0.877) vs. 0.808 (0.770–0.847), P = 0.001). The decision curves showed that the integrated model added more net benefit in predicting the incidence of AFDAS.

Conclusion

Predictive models based on clinical characteristics, laboratory variables, and neuroimaging variables showed good calibration and high net clinical benefit, informing clinical decision-making in diagnosing and treating patients with AFDAS.
Cross-sectional analysis of clinical aspects in patients with long-COVID and post-COVID syndrome
Authors: Schulze Hannah , Charles James Jeyanthan , Trampe Nadine , Richter Daniel , Pakeerathan Thivya , Siems Nadine , Ayzenberg Ilya , Gold Ralf , Faissner Simon
Published: October 2022

Objective

Regarding pathogenesis, clinical manifestations, at-risk individuals, and diagnostic methods for stratifying patients for therapeutic approaches, our understanding of post-COVID syndrome is limited. Here, we set out to assess sociodemographic and clinical aspects in patients with the long-COVID and post-COVID syndrome.

Methods

We performed a cross-sectional analysis of patients presenting at our specialized university hospital outpatient clinic. We assessed patients' clinical presentation, fatigue, symptoms of depression and anxiety, and impairment of smell.

Results

A total of 101 patients were included (73.3% female), of whom 78.2% had a mild course of COVID-19. At presentation, 93.1% suffered from fatigue, 82.2% from impaired concentration, and 79.2% from impaired memory, 53.5% had impaired sleep. The most common secondary diagnosis found in our cohort was thyroid disease. Fatigue analysis showed that 81.3% of female and 58.8% of male patients had severe combined fatigue. Female gender was an independent risk factor for severe fatigue (severe cognitive fatigue OR = 8.045, p = 0.010; severe motor fatigue OR = 7.698, p = 0.013). Males suffered from more depressive symptoms, which correlated positively with the duration of symptom onset. 70.3% of patients with anamnestic smell impairment had hyposmia, and 18.9% were anosmic.

Interpretation

Most long-COVID patients suffered from severe fatigue, with the female sex as an independent risk factor. Fatigue was not associated with symptoms of depression or anxiety. Patients with long-COVID symptoms should receive an interdisciplinary diagnostic and therapeutic approach depending on the clinical presentation.
Impact of histone modifier-induced protection against autoimmune encephalomyelitis on multiple sclerosis treatment
Authors: Jayaraman Sundararajan , Jayaraman Arathi
Published: October 2022

Multiple sclerosis is a progressive demyelinating central nervous system disorder with unknown etiology. The condition has heterogeneous presentations, including relapsing-remitting multiple sclerosis and secondary and primary progressive multiple sclerosis. The genetic and epigenetic mechanisms underlying these various forms of multiple sclerosis remain elusive. Many disease-modifying therapies approved for multiple sclerosis are broad-spectrum immunomodulatory drugs that reduce relapses but do not halt the disease progression or neuroaxonal damage. Some are also associated with many severe side effects, including fatalities. Improvements in disease-modifying treatments especially for primary progressive multiple sclerosis remain an unmet need. Several experimental animal models are available to decipher the mechanisms involved in multiple sclerosis. These models help us decipher the advantages and limitations of novel disease-modifying therapies for multiple sclerosis.
Software tool for visualization of a probabilistic map of the epileptogenic zone from seizure semiologies
Authors: Pérez-García Fernando , Alim-Marvasti Ali , Romagnoli Gloria , Clarkson Matthew J. , Sparks Rachel , Duncan John S. , Ourselin Sébastien
Published: October 2022

Around one third of epilepsies are drug-resistant. For these patients, seizures may be reduced or cured by surgically removing the epileptogenic zone (EZ), which is the portion of the brain giving rise to seizures. If noninvasive data are not sufficiently lateralizing or localizing, the EZ may need to be localized by precise implantation of intracranial electroencephalography (iEEG) electrodes. The choice of iEEG targets is influenced by clinicians' experience and personal knowledge of the literature, which leads to substantial variations in implantation strategies across different epilepsy centers. The clinical diagnostic pathway for surgical planning could be supported and standardized by an objective tool to suggest EZ locations, based on the outcomes of retrospective clinical cases reported in the literature. We present an open-source software tool that presents clinicians with an intuitive and data-driven visualization to infer the location of the symptomatogenic zone, that may overlap with the EZ. The likely EZ is represented as a probabilistic map overlaid on the patient's images, given a list of seizure semiologies observed in that specific patient. We demonstrate a case study on retrospective data from a patient treated in our unit, who underwent resective epilepsy surgery and achieved 1-year seizure freedom after surgery. The resected brain structures identified as EZ location overlapped with the regions highlighted by our tool, demonstrating its potential utility.
Musicians show more integrated neural processing of contextually relevant acoustic features
Authors: Hansen Niels Chr. , Højlund Andreas , Møller Cecilie , Pearce Marcus , Vuust Peter
Published: October 2022

Little is known about expertise-related plasticity of neural mechanisms for auditory feature integration. Here, we contrast two diverging hypotheses that musical expertise is associated with more independent or more integrated predictive processing of acoustic features relevant to melody perception. Mismatch negativity (MMNm) was recorded with magnetoencephalography (MEG) from 25 musicians and 25 non-musicians, exposed to interleaved blocks of a complex, melody-like multi-feature paradigm and a simple, oddball control paradigm. In addition to single deviants differing in frequency (F), intensity (I), or perceived location (L), double and triple deviants were included reflecting all possible feature combinations (FI, IL, LF, FIL). Following previous work, early neural processing overlap was approximated in terms of MMNm additivity by comparing empirical MMNms obtained with double and triple deviants to modeled MMNms corresponding to summed constituent single-deviant MMNms. Significantly greater subadditivity was found in musicians compared to non-musicians, specifically for frequency-related deviants in complex, melody-like stimuli. Despite using identical sounds, expertise effects were absent from the simple oddball paradigm. This novel finding supports the integrated processing hypothesis whereby musicians recruit overlapping neural resources facilitating more integrative representations of contextually relevant stimuli such as frequency (perceived as pitch) during melody perception. More generally, these specialized refinements in predictive processing may enable experts to optimally capitalize upon complex, domain-relevant, acoustic cues.