bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Genetic Variants of Uncertain Significance for the ALPL Gene in Patients With Adult Hypophosphatasia
Authors: Sanabria-de la Torre Raquel , Martínez-Heredia Luis , González-Salvatierra Sheila , Andújar-Vera Francisco , Iglesias-Baena Iván , Villa-Suárez Juan Miguel , Contreras-Bolívar Victoria , Corbacho-Soto Mario , Martínez-Navajas Gonzalo , Real Pedro J. , García-Fontana Cristina , Muñoz-Torres Manuel , García-Fontana Beatriz
Published: April 2022

Hypophosphatasia (HPP) a rare disease caused by mutations in the ALPL gene encoding for the tissue-nonspecific alkaline phosphatase protein (TNSALP), has been identified as a potentially under-diagnosed condition worldwide which may have higher prevalence than currently established. This is largely due to the overlapping of its symptomatology with that of other more frequent pathologies. Although HPP is usually associated with deficient bone mineralization, the high genetic variability of ALPL results in high clinical heterogeneity, which makes it difficult to establish a specific HPP symptomatology. In the present study, three variants of ALPL gene with uncertain significance and no previously described (p.Del Glu23_Lys24, p.Pro292Leu and p.His379Asn) were identified in heterozygosis in patients diagnosed with HPP. These variants were characterized at phenotypic, functional and structural levels. All genetic variants showed significantly lower in vitro ALP activity than the wild-type (WT) genotype (p-value <0.001). Structurally, p.His379Asn variant resulted in the loss of two Zn2+ binding sites in the protein dimer which may greatly affect ALP activity. In summary, we identified three novel ALPL gene mutations associated with adult HPP. The correct identification and characterization of new variants and the subsequent study of their phenotype will allow the establishment of genotype-phenotype relationships that facilitate the management of the disease as well as making it possible to individualize treatment for each specific patient. This would allow the therapeutic approach to HPP to be personalized according to the unique genetic characteristics and clinical manifestations of each patient.
Optimal Regulation Strategy of Electric Vehicle Charging and Discharging Based on Dynamic Regional Dispatching Price
Authors: Yu Shaohua , Du Zhaobin , Chen Lidan
Published: April 2022

With the continuous and rapid growth of electric vehicle (EV) ownership, a large number of disorderly charging loads accessed to the regional grid may lead to problems such as widening of the peak-to-valley load difference and deterioration of power quality. This study proposes an optimal EV charging and discharging regulation strategy based on dynamic regional dispatching price to give full play to the EV vehicle-to-grid (V2G) regulation potential and reasonably regulate EV charging and discharging behavior to ensure safe, high-quality, and economic operation of the grid. First, the EV travel chain model is constructed according to the travel behavior pattern of EV users to obtain the spatial and temporal distribution characteristics of EV charging and discharging loads. Second, considering the difference in regional grid operation states, a dynamic update strategy of regional dispatching price integrating power grid spatial and temporal information is proposed. Furthermore, considering the characteristics of EV mobile energy storage and user demand, an EV V2G optimal regulation model that takes into account the interests of distribution system operators, EV aggregators, and EV users is established to effectively guide the regulation of EV charging and discharging behavior. Finally, the simulation results show that the proposed strategy can effectively reduce the load deviation of each regional grid, operation cost of EV aggregators, and charging cost of EV users and significantly improve the safety and economy of the power system.
Can Depopulation Stop Deforestation? The Impact of Demographic Movement on Forest Cover Changes in the Settlements of the South Banat District (Serbia)
Authors: Gatarić Dragica , Đerčan Bojan , Živković Milka Bubalo , Ostojić Miloš , Manojlović Sanja , Sibinović Mikica , Lukić Tamara , Jeftić Marija , Lutovac Miloš , Lutovac Milena
Published: April 2022

The key problem of rural settlements in the South Banat district lasted into the 21st century through the spread of depopulated areas. Considering that settlements give a cultural landscape its basic features, that they are the main bearers of functional organization, and the hotspots of geo-spatial transformation, based on quantitative-qualitative indicators this paper analyzes the spatial-demographic determinants of the development of 94 settlements, and the impact of depopulation on the changes in the surrounding forest cover. The time span included in the analytical-statistical research of the demographic components and forest dislocation lasted from 1990 to 2018. Geo-spatial data for forest areas were taken from the Corine Land Cover database. The data obtained were then turned into visual representations, or maps, using the GIS ArcMap 10.8. software. The results indicated that total depopulation has been an ongoing, 30-years process in this area on the one hand, while the forest cover in the depopulated settlements located on the outskirts of the Deliblato sands (a special nature reserve) has decreased, and the forest cover in the depopulated settlements in the zone of the Vršac mountains has increased, on the other. These analyses are useful for obtaining more detailed insight into the state of forested areas in this part of Serbia, which is the least afforested one.
Comparing Elevational Patterns of Taxonomic, Phylogenetic, and Functional Diversity of Woody Plants Reveal the Asymmetry of Community Assembly Mechanisms on a Mountain in the Hengduan Mountains Region
Authors: Zhao Fu , Yang Tao , Luo Caifang , Rao Wenge , Yang Gengchen , Li Guo , Shen Zehao
Published: April 2022

The contributions and interaction of biotic and abiotic processes in community assembly are crucial for understanding the elevational patterns of biodiversity. The combined analyses of taxonomic, phylogenetic, and functional diversity are necessary to resolve this issue. By investigating vegetation in 24 transects sampled on Hongla Snow Mountain, in the central Hengduan Mountain Ranges in Southwest China, we delineated the elevational vegetation spectrum on the eastern and western slopes, analyzed the elevational variation in taxonomic, phylogenetic, and functional diversity of woody plant species, and compared the community structure of phylogeny and function in the low-elevational shrublands, mid-elevational forests, and alpine shrubs and meadows. The species richness, phylogenetic diversity, and functional diversity of woody plants showed nonstandard hump-shaped patterns with two peaks along the elevational gradient. The community structure of phylogeny and function (including tree height, leaf area, specific leaf area, leaf thickness, bark thickness, and wood density) clustered in the low-elevation shrub communities, being random and over-dispersed in mid-elevational forests. The phylogenic structure was over-dispersed in alpine communities, whereas the functional structure was clustered. Elevational patterns in taxonomic, phylogenetic, and functional diversity, together with the mean and variation in woody plant functional traits, suggested drought stress and freeze stress as environmental filters dominating the assembly of low and high elevation non-forest communities, and a conspicuous effect of biotic facilitation was also suggested for alpine habitats. By contrast, interspecific competition dominated the community assembly of forests at mid-elevations. The difference in biodiversity indices between the west and east slopes reflected the effects of the Indian Monsoon on the geomorphic patterns of ecosystem structure. These results increased our understanding of biodiversity patterns and underlying mechanisms in the Hengduan Mountains of Southwest China and highlighted the priorities for biodiversity conservation in this region.
Schizophrenia Risk Mediated by microRNA Target Genes Overlapped by Genome-Wide Rare Copy Number Variation in 22q11.2 Deletion Syndrome
Authors: Ying Shengjie , Heung Tracy , Zhang Zhaolei , Yuen Ryan K. C. , Bassett Anne S.
Published: April 2022

The 22q11.2 deletion is associated with >20-fold increased risk for schizophrenia. The presence of gene DGCR8 in the 22q11.2 deletion region has suggested microRNA (miRNA) dysregulation as possibly contributing to this risk. We therefore investigated the role of miRNA target genes in the context of previously identified genome-wide risk for schizophrenia conveyed by additional copy number variation (CNV) in 22q11.2 deletion syndrome (22q11.2DS). Using a cohort of individuals with 22q11.2DS and documented additional rare CNVs overlapping protein coding genes, we compared those with schizophrenia (n = 100) to those with no psychotic illness (n = 118), assessing for rare CNVs that overlapped experimentally supported miRNA target genes. We further characterized the contributing miRNA target genes using gene set enrichment analyses and identified the miRNAs most implicated. Consistent with our hypothesis, we found a significantly higher proportion of individuals in the schizophrenia than in the non-psychotic group to have an additional rare CNV that overlapped one or more miRNA target genes (odds ratio = 2.12, p = 0.0138). Gene set analyses identified an enrichment of FMRP targets and genes involved in nervous system development and postsynaptic density amongst these miRNA target genes in the schizophrenia group. The miRNAs most implicated included miR-17-5p, miR-34a-5p and miR-124-3p. These results provide initial correlational evidence in support of a possible role for miRNA perturbation involving genes affected by rare genome-wide CNVs in the elevated risk for schizophrenia in 22q11.2DS, consistent with the multi-hit and multi-layered genetic mechanisms implicated in this and other forms of schizophrenia.
Hepatic Models in Precision Medicine: An African Perspective on Pharmacovigilance
Authors: Hurrell Tracey , Naidoo Jerolen , Scholefield Janine
Published: April 2022

Pharmaceuticals are indispensable to healthcare as the burgeoning global population is challenged by diseases. The African continent harbors unparalleled genetic diversity, yet remains largely underrepresented in pharmaceutical research and development, which has serious implications for pharmaceuticals approved for use within the African population. Adverse drug reactions (ADRs) are often underpinned by unique variations in genes encoding the enzymes responsible for their uptake, metabolism, and clearance. As an example, individuals of African descent (14–34%) harbor an exclusive genetic variant in the gene encoding a liver metabolizing enzyme (CYP2D6) which reduces the efficacy of the breast cancer chemotherapeutic Tamoxifen. However, CYP2D6 genotyping is not required prior to dispensing Tamoxifen in sub-Saharan Africa. Pharmacogenomics is fundamental to precision medicine and the absence of its implementation suggests that Africa has, to date, been largely excluded from the global narrative around stratified healthcare. Models which could address this need, include primary human hepatocytes, immortalized hepatic cell lines, and induced pluripotent stem cell (iPSC) derived hepatocyte-like cells. Of these, iPSCs, are promising as a functional in vitro model for the empirical evaluation of drug metabolism. The scale with which pharmaceutically relevant African genetic variants can be stratified, the expediency with which these platforms can be established, and their subsequent sustainability suggest that they will have an important role to play in the democratization of stratified healthcare in Africa. Here we discuss the requirement for African hepatic models, and their implications for the future of pharmacovigilance on the African continent.
Application of hiPSC as a Drug Tester Via Mimicking a Personalized Mini Heart
Authors: Wei Li , Xia Shutao , Li Yifei , Qi Yan , Wang Yue , Zhang Donghui , Hua Yimin , Luo Shuhua
Published: April 2022

Human induced pluripotent stem cells (hIPSC) have been used to produce almost all types of human cells currently, which makes them into several potential applications with replicated patient-specific genotype. Furthermore, hIPSC derived cardiomyocytes assembled engineering heart tissue can be established to achieve multiple functional evaluations by tissue engineering technology. This short review summarized the current advanced applications based on the hIPSC derived heart tissue in molecular mechanisms elucidating and high throughput drug screening.
The Role of IL-17 During Infections in the Female Reproductive Tract
Authors: Bagri Puja , Anipindi Varun C. , Kaushic Charu
Published: April 2022

Interleukin-17 (IL-17A) is a cytokine involved in a complex array of both protective and detrimental processes. Although early biological studies focused on the pro-inflammatory function of IL-17 in the context of autoimmune and inflammatory disorders, it has become increasingly evident that the roles of IL-17 are far more nuanced. Recent work has demonstrated that the functions of IL-17 are highly context- and tissue-dependent, and there is a fine balance between the pathogenic and protective functions of IL-17. This is especially evident in mucosal tissues such as the female reproductive tract, where IL-17 has been shown to play an important role in the immune response generated during fungal, bacterial and viral infections associated with protection, but also with inflammation. In this review, we discuss the evolving landscape of IL-17 biology within the context of the vaginal mucosa, focusing on key findings that highlight the importance of this cytokine in genital mucosal immunity.
Bibliometric Analysis of γδ T Cells as Immune Regulators in Cancer Prognosis
Authors: Liu Bing , He Xu , Wang Yong , Huang Jian-wen , Zheng You-bing , Li Yong , Lu Li-gong
Published: April 2022

γδ T cells are one of only three immune cell types that express antigen receptors that undergo somatic recombination, and they contribute to immune responses to infection, cellular transformation, and tissue damage. As a “bridge” between the innate and adaptive immune systems, γδ T cells have been noted to be involved in various immune responses during cancer progression. The purpose of our study was to review current published information on γδ T cells and investigate their functions in different types of malignancy using bibliometric and bioinformatic methods. Our results indicated that studies on γδ T cells and cancer progression increased from 2014, and the number had peaked by 2021. We discovered that there is international cooperation in the performance of studies among 26 countries, where China was identified as the most productive with the highest citations. Using keyword co-occurrence analysis, we found that among all the cancer types investigated, gastric and breast cancers were most closely related to γδ T cells. Furthermore, interleukin (IL)-17 and IL-2 were the most common cytokines linked to γδ T cells and our investigation of their potential involvement in the prognosis of gastric and breast cancers, identified their different roles in various malignancies. Thus, we concluded that γδ T cells might influence the progression of different cancers in diverse ways.
Trans-Generational Symbiont Transmission Reduced at High Temperatures in a West Nile Virus Vector Mosquito Culex quinquefasciatus
Authors: Tokash-Peters Amanda G. , Jabon Jaimy D. , Fung Megan E. , Peters Jessica A. , Lopez Sergio G. , Woodhams Douglas C.
Published: April 2022

The influence of environmental factors on the efficacy of the endosymbiont Wolbachia used in mosquito and pathogen control are poorly characterized and may be critical for disease control. We studied the vector mosquito Culex pipiens quinquefasciatus (Say) to determine the effect of temperature on the composition of the relative abundance of Wolbachia spp. and the microbiome, as well as key immune genes of interest in the Toll and IMD pathways. 16S barcode sequencing was used to determine the microbiome composition and qPCR was used to determine the relative abundance of Wolbachia spp. based on the highly utilized marker Wolbachia surface protein (wsp) gene. We found no effect of temperature within a single generation on the relative abundance of Wolbachia or immune gene expression, nor on the alpha or beta diversity of the microbiome. However, there was a significant difference in the abundance of Wolbachia between generations at high temperatures (≥ 28°C), but not at lower temperatures (≤ 23°C). These results support the idea that Wolbachia are reduced at higher temperatures between generations, which has an influence on the establishment of pathogens including West Nile Virus (WNV). Modulation of the Toll or IMD mosquito immune pathways was not indicated. Wolbachia endosymbiosis and trans-generation transmission appears especially sensitive to high temperatures, which may have implications for Wolbachia-based vector control strategies under climate change scenarios.
Refractive Lens Exchange Surgery in Early-Onset High Myopia Patients With Partial Cataract
Authors: Zhang Xi-Fang , Li Xiao-Xia , Xin Chen , Kline Brad , Kang Meng-Tian , Li Meng , Qiao Li-Ya , Wang Ning-Li
Published: April 2022

Purpose

By reporting clinical characteristics and retinal image quality before and after refractive lens replacement surgery in early-onset high myopia (eoHM) patients presenting with partial cataract, we emphasized the need for an objective way to grade the severity of partial cataracts.

Methods

This retrospective, consecutive case series included six Chinese patients (nine eyes). Analysis of previous medical records, visual acuity, optometry, retinal image quality, and axial length (AXL) before surgery and after surgery was performed.

Results

Five females and one male (nine eyes) with a mean (± SD) age of 11.6 ± 7.9 years (range: 4–25 years) were included in this study. The preoperative spherical power ranged from −7.5 to −42 D. The mean follow-up time was 36 months (range: 24–48 months). Phacoemulsification was followed by in-the-bag implantation of intraocular lens. For patients who were under 6 years old, posterior capsulotomy + anterior vitrectomy were performed simultaneously. All surgeries were uneventful and no postoperative complications occurred during the entire follow-up period. All patients’ uncorrected visual acuity improved by ≥2 lines postoperatively(Snellen acuity). LogMAR best-corrected visual acuity was improved at 24-month (P= 0.042) and endpoint (P= 0.046) follow-ups. Modulation transfer function cutoff frequency (MTFcutoff) and objective scatter index (OSI) was significantly improved at 12-month (P= 0.025,P= 0.038), 24-month (P= 0.005,P= 0.007) and endpoint (P= 0.005,P= 0.008) follow-ups. Postoperative AXL remained stable during 2–4 year follow-ups (P> 0.05).

Conclusion

Refractive lens replacement surgery is safe and effective for improving functional vision in eoHM patients presenting with partial cataract. Retinal image quality could provide a useful and objective way to facilitate partial cataract severity evaluation and surgery decision making.
A 2-Gene Signature Related to Interferon-Gamma Predicts Prognosis and Responsiveness to Immune Checkpoint Blockade of Glioma
Authors: Li Yongzhe , Ji Hang , Gao Xin
Published: April 2022

Background

Gliomas represent the most common and aggressive brain malignancy. Interferon-gamma (IFNG) is a potent inducer of immune response, developing IFNG-related gene signature may promote the diagnosis and treatment of this disease.

Methods

Bulk tumor and single-cell mRNA-seq datasets of glioma ranging from WHO grade II to IV with corresponding demographics were included. Multiple bioinformatics and machine learning algorithms were performed to develop an IFNG-related prognostic signature and evaluate immune checkpoint blockade (ICB) therapy response.

Results

IFNGR1 and IFNGR2 were used as concise IFNG-related gene signature based on which the IFNGR score well-characterized the IFNG response in the glioma microenvironment. Increased IFNGR score was associated with clinicopathological parameters relating to tumor malignancy and prevailing molecular pathological markers. Notably, K-M and Cox regression analysis found that the IFNGR score was an effective prognostic biomarker, and was associated with tumor relapse for a subset of patients. Notably, IFNGR1 and IFNGR2 were preferentially expressed by the Mono/Macro cells in the glioma microenvironment and were significantly correlated with M2 macrophage. Thus, the IFNGR score-high group had increased expression of immune checkpoints and had the potential to predict ICB responsiveness.

Conclusion

In conclusion, we have developed a concise IFNG-related gene signature of clinical significance, which may improve the current diagnosis and treatment of glioma.
Pitfalls of Echocardiographic Image Perception: How to Overcome Them?
Authors: Leitman Marina , Tyomkin Vladimir , Beeri Ronen
Published: April 2022

In recent years, the significant development of echocardiography systems has led to a sharp improvement in echocardiographic images' quality. In parallel with this, computerized technologies are also going far forward, which today make it possible to ensure a high level of transmission, storage, and display of echocardiography studies. Despite this, many cardiologists are not familiar with modern computerized technologies' new possibilities and continue to use the old standards. That is why many echocardiography laboratories with the best echocardiography systems work following the old minimalist approach. In this paper, we will look at some of the most common mistakes that result from the improper transmission, storage, and demonstration of echocardiography studies, and describe possible ways to overcome these problems.
Lipidomic Profiling in Synovial Tissue
Authors: Coras Roxana , Murillo-Saich Jessica D. , Singh Abha G. , Kavanaugh Arthur , Guma Monica
Published: April 2022

The analysis of synovial tissue offers the potential for the comprehensive characterization of cell types involved in arthritis pathogenesis. The studies performed to date in synovial tissue have made it possible to define synovial pathotypes, which relate to disease severity and response to treatment. Lipidomics is the branch of metabolomics that allows the quantification and identification of lipids in different biological samples. Studies in animal models of arthritis and in serum/plasma from patients with arthritis suggest the involvement of different types of lipids (glycerophospholipids, glycerolipids, sphingolipids, oxylipins, fatty acids) in the pathogenesis of arthritis. We reviewed studies that quantified lipids in different types of tissues and their relationship with inflammation. We propose that combining lipidomics with currently used “omics” techniques can improve the information obtained from the analysis of synovial tissue, for a better understanding of pathogenesis and the development of new therapeutic strategies.
Gene Expression Profile of Mycobacterium leprae Contribution in the Pathology of Leprosy Neuropathy
Authors: Souza Beatriz Junqueira de , Mendes Mayara Abud , Sperandio da Silva Gilberto Marcelo , Sammarco-Rosa Patrícia , Moraes Milton Ozorio de , Jardim Marcia Rodrigues , Sarno Euzenir Nunes , Pinheiro Roberto Olmo , Mietto Bruno Siqueira
Published: April 2022

Peripheral neuropathy is the main cause of physical disability in leprosy patients. Importantly, the extension and pattern of peripheral damage has been linked to how the host cell will respond against Mycobacterium leprae (M. leprae) infection, in particular, how the pathogen will establish infection in Schwann cells. Interestingly, viable and dead M. leprae have been linked to neuropathology of leprosy by distinct mechanisms. While viable M. leprae promotes transcriptional modifications that allow the bacteria to survive through the use of the host cell's internal machinery and the subvert of host metabolites, components of the dead bacteria are associated with the generation of a harmful nerve microenvironment. Therefore, understanding the pathognomonic characteristics mediated by viable and dead M. leprae are essential for elucidating leprosy disease and its associated reactional episodes. Moreover, the impact of the viable and dead bacteria in Schwann cells is largely unknown and their gene signature profiling has, as yet, been poorly explored. In this study, we analyzed the early differences in the expression profile of genes involved in peripheral neuropathy, dedifferentiation and plasticity, neural regeneration, and inflammation in human Schwann cells challenged with viable and dead M. leprae. We substantiated our findings by analyzing this genetic profiling in human nerve biopsies of leprosy and non-leprosy patients, with accompanied histopathological analysis. We observed that viable and dead bacteria distinctly modulate Schwann cell genes, with emphasis to viable bacilli upregulating transcripts related to glial cell plasticity, dedifferentiation and anti-inflammatory profile, while dead bacteria affected genes involved in neuropathy and pro-inflammatory response. In addition, dead bacteria also upregulated genes associated with nerve support, which expression profile was similar to those obtained from leprosy nerve biopsies. These findings suggest that early exposure to viable and dead bacteria may provoke Schwann cells to behave differentially, with far-reaching implications for the ongoing neuropathy seen in leprosy patients, where a mixture of active and non-active bacteria are found in the nerve microenvironment.
Aging of Pelvic Floor in Animal Models: A Sistematic Review of Literature on the Role of the Extracellular Matrix in the Development of Pelvic Floor Prolapse
Authors: Gardella Barbara , Scatigno Annachiara Licia , Belli Giacomo , Gritti Andrea , Visoná Silvia Damiana , Dominoni Mattia
Published: April 2022

Pelvic organ prolapse (POP) affects many women and contributes significantly to a decrease in their quality of life causing urinary and/or fecal incontinence, sexual dysfunction and dyspareunia. To better understand POP pathophysiology, prevention and treatment, many researchers resorted to evaluating animal models. Regarding this example and because POP affects principally older women, our aim was to provide an overview of literature on the possible biomechanical changes that occur in the vaginas of animal models and their supportive structures as a consequence of aging. Papers published online from 2000 until May 2021 were considered and particular attention was given to articles reporting the effects of aging on the microscopic structure of the vagina and pelvic ligaments in animal models. Most research has been conducted on rodents because their vagina structure is well characterized and similar to those of humans; furthermore, they are cost effective. The main findings concern protein structures of the connective tissue, known as elastin and collagen. We have noticed a significant discordance regarding the quantitative changes in elastin and collagen related to aging, especially because it is difficult to detect them in animal specimens. However, it seems to be clear that aging affects the qualitative properties of elastin and collagen leading to aberrant forms which may affect the elasticity and the resilience of tissues leading to pelvic floor disease. The analysis of histological changes of pelvic floor tissues related to aging underlines how these topics appear to be not fully understood so far and that more research is necessary.
The Role of Quantitative and Semi-quantitative [18F]FDG-PET/CT Indices for Evaluating Disease Activity and Management of Patients With Dermatomyositis and Polymyositis
Authors: Yildiz Halil , D'abadie Philippe , Gheysens Olivier
Published: April 2022

Idiopathic inflammatory myopathies (IIM) are considered systemic diseases involving different organs and some subtypes are associated with increased cancer risk. In this review, we provide a comprehensive summary of the current use and potential applications of (semi-)quantitative [18F]FDG-PET/CT indices in patients with IIM focusing on dermatomyositis and polymyositis. Visual interpretation and (semi-)quantitative [18F]FDG-PET indices have a good overall performance to detect muscle activity but objective, robust and standardized interpretation criteria are currently lacking. [18F]FDG-PET/CT is a suitable modality to screen for malignancy in patients with myositis and may be a promising tool to detect inflammatory lung activity and to early identify patients with rapidly progressive lung disease. The latter remains to be determined in large, prospective comparative trials.
The TbD1 Locus Mediates a Hypoxia-Induced Copper Response in Mycobacterium bovis
Authors: Ma Ruoyao , Farrell Damien , Gonzalez Gabriel , Browne John A. , Nakajima Chie , Suzuki Yasuhiko , Gordon Stephen V.
Published: April 2022

The Mycobacterium tuberculosis complex (MTBC) contains the causative agents of tuberculosis (TB) in mammals. The archetypal members of the MTBC, Mycobacterium tuberculosis and Mycobacterium bovis, cause human tuberculosis and bovine tuberculosis, respectively. Although M. tuberculosis and M. bovis share over 99.9% genome identity, they show distinct host adaptation for humans and animals; hence, while the molecular basis of host adaptation is encoded in their genomes, the mechanistic basis of host tropism is still unclear. Exploration of the in vitro phenotypic consequences of known genetic difference between M. bovis and M. tuberculosis offers one route to explore genotype–phenotype links that may play a role in host adaptation. The TbD1 (“Mycobacterium tuberculosis deletion 1 region”) locus encompasses the mmpS6 and mmpL6 genes. TbD1 is absent in M. tuberculosis “modern” lineages (Lineages 2, 3, and 4) but present in “ancestral” M. tuberculosis (Lineages 1 and 7), Mycobacterium africanum lineages (Lineages 5 and 6), newly identified M. tuberculosis lineages (Lineages 8 and 9), and animal adapted strains, such as M. bovis. The function of TbD1 has previously been investigated in M. tuberculosis, where conflicting data has emerged on the role of TbD1 in sensitivity to oxidative stress, while the underlying mechanistic basis of such a phenotype is unclear. In this study, we aimed to shed further light on the role of the TbD1 locus by exploring its function in M. bovis. Toward this, we constructed an M. bovis TbD1 knockout (ΔTbD1) strain and conducted comparative transcriptomics to define global gene expression profiles of M. bovis wild-type (WT) and the ΔTbD1 strains under in vitro culture conditions (rolling and standing cultures). This analysis revealed differential induction of a hypoxia-driven copper response in WT and ΔTbD1 strains. In vitro phenotypic assays demonstrated that the deletion of TbD1 sensitized M. bovis to H2O2 and hypoxia-specific copper toxicity. Our study provides new information on the function of the TbD1 locus in M. bovis and its role in stress responses in the MTBC.
Cas1 and Fen1 Display Equivalent Functions During Archaeal DNA Repair
Authors: Wörtz Julia , Smith Victoria , Fallmann Jörg , König Sabine , Thuraisingam Tharani , Walther Paul , Urlaub Henning , Stadler Peter F. , Allers Thorsten , Hille Frank , Marchfelder Anita
Published: April 2022

CRISPR-Cas constitutes an adaptive prokaryotic defence system against invasive nucleic acids like viruses and plasmids. Beyond their role in immunity, CRISPR-Cas systems have been shown to closely interact with components of cellular DNA repair pathways, either by regulating their expression or via direct protein-protein contact and enzymatic activity. The integrase Cas1 is usually involved in the adaptation phase of CRISPR-Cas immunity but an additional role in cellular DNA repair pathways has been proposed previously. Here, we analysed the capacity of an archaeal Cas1 from Haloferax volcanii to act upon DNA damage induced by oxidative stress and found that a deletion of the cas1 gene led to reduced survival rates following stress induction. In addition, our results indicate that Cas1 is directly involved in DNA repair as the enzymatically active site of the protein is crucial for growth under oxidative conditions. Based on biochemical assays, we propose a mechanism by which Cas1 plays a similar function to DNA repair protein Fen1 by cleaving branched intermediate structures. The present study broadens our understanding of the functional link between CRISPR-Cas immunity and DNA repair by demonstrating that Cas1 and Fen1 display equivalent roles during archaeal DNA damage repair.
How Do MinC-D Copolymers Act on Z-Ring Localization Regulation? A New Model of Bacillus subtilis Min System
Authors: Wang Na , Zhang Tingting , Du Shuheng , Zhou Yao , Chen Yaodong
Published: April 2022

Division site selection in rod-shaped bacteria is strictly regulated spatially by the Min system. Although many sophisticated studies, including in vitro recombination, have tried to explain these regulations, the precise mechanisms are still unclear. A previous model suggested that the concentration gradient of MinC, an FtsZ inhibitor, regulates the position of the Z-ring in the cell. In Escherichia coli, the oscillation of MinCDE proteins leads to a gradient of Min proteins with the average concentration being lowest in the middle and highest near the poles. In contrast to the Min system of E. coli, the Min system of Bacillus subtilis lacks MinE and exhibits a stable concentration distribution, which is regulated by the binding of DivIVA to the negative curvature membrane. The Min proteins first accumulate at the poles of the cell and relocalize near the division site when the membrane invagination begins. It is inconsistent with the previous model of high concentrations of MinC inhibiting Z-ring formation. Our preliminary data here using electron microscopy and light scattering technology reported that B. subtilis MinC (BsMinC) and MinD (BsMinD) also assembled into large straight copolymers in the presence of ATP, similar to the Min proteins of E. coli. Their assembly is fast and dominated by MinD concentration. When BsMinD is 5 μM, a clear light scattering signal can be observed even at 0.3 μM BsMinC. Here, we propose a new model based on the MinC-D copolymers. In our hypothesis, it is not the concentration gradient of MinC, but the MinC-D copolymer assembled in the region of high concentration MinD that plays a key role in the regulation of Z-ring positioning. In B. subtilis, the regions with high MinD concentration are initially at both ends of the cell and then appear at midcell when cell division began. MinC-D copolymer will polymerize and form a complex with MinJ and DivIVA. These complexes capture FtsZ protofilaments to prevent their diffusion away from the midcell and narrow the Z-ring in the middle of the cell.
In vitro Effects of Bacterial Exposure on Secretion of Zonulin Family Peptides and Their Detection in Human Tissue Samples
Authors: Jian Ching , Kanerva Sonja , Qadri Sami , Yki-Järvinen Hannele , Salonen Anne
Published: April 2022

Commercially available ELISAs for zonulin (pre-haptoglobin 2), a protein with tight junction regulatory activity in the epithelia, were recently shown to recognize other proteins that are structurally and functionally related to zonulin, termed zonulin family peptides (ZFPs). With little or no information about the identity and property of ZFPs, various commercial zonulin ELISA kits are widely utilized in research as a marker of intestinal permeability. Bacterial exposure is a known trigger for the secretion of zonulin, but it remains unclear whether distinct bacteria differ in their capability to stimulate zonulin secretion. We hypothesized that ZFPs are similar to zonulin regarding response to bacterial exposure and aimed to compare the effects of non-pathogenic, Gram-negative bacteria (Escherichia coli RY13 and E. coli K12 DH5α) and probiotic, Gram-positive bacteria (Lactobacillus rhamnosus GG and Bifidobacterium bifidum) on ZFP secretion in an in vitro model. Additionally, utilizing samples from human clinical trials, we correlated circulating levels of ZFPs to the gut bacteria and determined the presence of ZFPs in various human tissues. Unexpectedly, we found that the ZFPs quantified by the widely used IDK® Zonulin ELISA kits are specifically triggered by the exposure to live Lactobacillus rhamnosus GG in HT-29 cells, associated with absolute abundances of intestinal Lactobacillus and Bifidobacterium in adults, and are copious in the small intestine but undetectable in the liver or adipose tissue. These characteristics appear to be different from zonulin and highlight the need for further characterization of ZFPs recognized by commercially available and widely used “zonulin” ELISAs.
Age-Related Cancer-Associated Microbiota Potentially Promotes Oral Squamous Cell Cancer Tumorigenesis by Distinct Mechanisms
Authors: Zhang Zhen , Feng Qiang , Li Meihui , Li Zhihui , Xu Qin , Pan Xinhua , Chen Wantao
Published: April 2022

The oral squamous cell cancer (OSCC) incidence in young patients has increased since the end of the last century; however, the underlying mechanism is still unclear. Oral microbiota dysbiosis was proven to be a tumorigenesis factor, and we propose that there is a distinct bacterial composition in young patients that facilitates the progression of OSCC. Twenty elderly (>60 years old) and 20 young (<50 years old) subjects were included in this study. OSCC tissue was collected during surgery, sent for 16S rDNA sequencing and analyzed by the QIIME 2 pipeline. The results showed that Ralstonia, Prevotella, and Ochrobactrum were significantly enriched in younger OSCC tissue microbiota, while Pedobacter was more abundant in elderly OSCC tissues. Fusobacterium had high relative abundance in both cohorts. At the phylum level, Proteobacteria was the dominant taxon in all samples. The functional study showed that there were significant differences in the taxa abundance from metabolic and signaling pathways. The results indicated that the microbiota of younger OSCC tissues differed from that of elderly OSCC tissues by both taxon composition and function, which partially explains the distinct roles of bacteria during tumorigenesis in these two cohorts. These findings provide insights into different mechanisms of the microbiota-cancer relationship with regard to aging.
The C-Terminal Transmembrane Domain of Cowpea Mild Mottle Virus TGBp2 Is Critical for Plasmodesmata Localization and for Its Interaction With TGBp1 and TGBp3
Authors: Jiang Chong , Shan Shiqi , Huang Yue , Mao Chenyang , Zhang Hehong , Li Yanjun , Chen Jianping , Wei Zhongyan , Sun Zongtao
Published: April 2022

The movement of some plant RNA viruses is mediated by triple gene block (TGB) proteins, which cooperate to transfer the viral genome from cell to cell through plasmodesmata. Here, we investigated the function of the TGB proteins of cowpea mild mottle virus (CPMMV; genus Carlavirus, family Betaflexiviridae), which causes severe damage to soybean production. Subcellular localization experiments demonstrated that TGBp1 and TGBp3 were localized to the endoplasmic reticulum (ER), plasmodesmata (PD) and nucleus in Nicotiana benthamiana leaves. TGBp2 was unusually localized to PD. In protein interaction assays TGBp2 significantly enhanced the interaction between TGBp3 and TGBp1. Interaction assays using deletion mutants showed that the C-terminal transmembrane (TM) domain of TGBp2 is critical for its localization to PD and for its interaction with TGBp1 and TGBp3.
Novel Antiviral Activity of Ethyl 3-Hydroxyhexanoate Against Coxsackievirus B Infection
Authors: Olasunkanmi Oluwatayo Israel , Mageto James , Avala Ntsigouaye Juval , Yi Ming , Fei Yanru , Chen Yang , Chen Sijia , Xu Weizhen , Lin Lexun , Zhao Wenran , Wang Yan , Zhong Zhao-Hua
Published: April 2022

Coxsackievirus group B (CVB) is a member of the genus Enterovirus in the family Picornaviridae. CVB infection has been implicated as a major etiologic agent of viral myocarditis, dilated cardiomyopathy, meningitis, and pancreatitis among children and young adults. Until date, no antiviral agent has been licensed for the treatment of Coxsackievirus infection. In an effort to identify antiviral agents against diseases caused by the CVB, we found that ethyl 3-hydroxyhexanoate (EHX), a volatile compound present in fruits and food additives, is a potent antiviral compound. In this study, we demonstrated that EHX treatment significantly inhibits CVB replication both in vivo and in vitro. Furthermore, EHX possesses antiviral activity at 50% effective concentration (EC50) of 1.2 μM and 50% cytotoxicity (CC50) of 25.6 μM, yielding a selective index (SI) value as high as 20.8. Insights into the mechanism of antiviral activity of EHX showed that it acts at the step of viral RNA replication. Since EHX has received approval as food additives, treatment of CVB-related infections with EHX might be a safe therapeutic option and may be a promising strategy for the development of semi-synthetic antiviral drugs for viral diseases.
Recent Advances Regarding the Physiological Functions and Biosynthesis of D-Allulose
Authors: Chen Zhou , Gao Xiao-Dong , Li Zijie
Published: April 2022

D-Allulose, a generally regarded as safe (GRAS) sugar, is rare in nature. It is among the most promising sweeteners for future use due to its low caloric content, sucrose-like taste, and unique functions. D-Allulose has many physiological effects, such as antiobesity, antihyperglycemia, antidiabetes, anti-inflammatory, antioxidant, and neuroprotective effects. Therefore, D-allulose has important application value in the food, pharmaceutical, and healthcare industries. However, the high cost of D-allulose production limits its large-scale application. Currently, biotransformation is very attractive for D-allulose synthesis, with the two main methods of biosynthesis being the Izumoring strategy and the DHAP-dependent aldolase strategy. This article reviews recent advances regarding the physiological functions and biosynthesis of D-allulose. In addition, future perspectives on the production of D-allulose are presented.
Multisystem Inflammatory Syndrome and Autoimmune Diseases Following COVID-19: Molecular Mechanisms and Therapeutic Opportunities
Authors: Hosseini Parastoo , Fallahi Mohammad Sadegh , Erabi Gisou , Pakdin Majid , Zarezadeh Seyed Mahdi , Faridzadeh Arezoo , Entezari Sarina , Ansari Arina , Poudineh Mohadeseh , Deravi Niloofar
Published: April 2022

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), has led to huge concern worldwide. Some SARS-CoV-2 infected patients may experience post–COVID-19 complications such as multisystem inflammatory syndrome, defined by symptoms including fever and elevated inflammatory markers (such as elevation of C reactive protein (CRP), erythrocyte sedimentation rate, fibrinogen, procalcitonin test, D-dimer, ferritin, lactate dehydrogenase or IL-6, presence of neutrophilia, lymphopenia, decreased albumin, and multiple organ dysfunction). Post–COVID-19 complications may also manifest as autoimmune diseases such as Guillain-Barré syndrome and systemic lupus erythematosus. Signaling disorders, increased inflammatory cytokines secretion, corticosteroid use to treat COVID-19 patients, or impaired immune responses are suggested causes of autoimmune diseases in these patients. In this review, we discuss the molecular and pathophysiological mechanisms and therapeutic opportunities for multisystem inflammatory syndrome and autoimmune diseases following SARS-CoV-2 infection with the aim to provide a clear view for health care providers and researchers.
Computational Site Saturation Mutagenesis of Canonical and Non-Canonical Amino Acids to Probe Protein-Peptide Interactions
Authors: Holden Jeffrey K. , Pavlovicz Ryan , Gobbi Alberto , Song Yifan , Cunningham Christian N.
Published: April 2022

Technologies for discovering peptides as potential therapeutics have rapidly advanced in recent years with significant interest from both academic and pharmaceutical labs. These advancements in turn drive the need for new computational tools to design peptides for purposes of advancing lead molecules into the clinic. Here we report the development and application of a new automated tool, AutoRotLib, for parameterizing a diverse set of non-canonical amino acids (NCAAs), N-methyl, or peptoid residues for use with the computational design program Rosetta. In addition, we developed a protocol for designing thioether-cyclized macrocycles within Rosetta, due to their common application in mRNA display using the RaPID platform. To evaluate the utility of these new computational tools, we screened a library of canonical and NCAAs on both a linear peptide and a thioether macrocycle, allowing us to quickly identify mutations that affect peptide binding and subsequently measure our results against previously published data. We anticipate in silico screening of peptides against a diverse chemical space will be a fundamental component for peptide design and optimization, as more amino acids can be explored in a single in silico screen than an in vitro screen. As such, these tools will enable maturation of peptide affinity for protein targets of interest and optimization of peptide pharmacokinetics for therapeutic applications.
Physical Predictors of Favorable Postoperative Outcomes in Patients Undergoing Laminectomy or Laminotomy for Central Lumbar Spinal Stenosis: Secondary Analysis of a Randomized Controlled Trial
Authors: Marchand Andrée-Anne , Houle Mariève , O'Shaughnessy Julie , Châtillon Claude-Édouard , Descarreaux Martin
Published: April 2022

Study Design

Secondary analysis of a randomized controlled trial.

Objective

To identify preoperative physical variables associated with favorable postoperative outcome in individuals undergoing laminectomy or laminotomy for degenerative central lumbar spinal stenosis.

Summary of Background Data

Clinical or condition specific variables have most commonly been studied as predictors of postoperative outcome in lumbar spinal stenosis. If associated to favorable postoperative outcome, modifiable physical variables would inform prehabilitation interventions for patients with degenerative central lumbar spinal stenosis.

Methods

Patients awaiting surgery for central lumbar spinal stenosis were recruited to participate in a randomized controlled trial. Following baseline data collection of demographics, clinical portrait and physical testing, participants were randomized to either 6-week active prehabilitation program or hospital standard care. Complete baseline and postoperative data were obtained from 58 participants which were included in the present analysis. Favorable postoperative outcome was determined based on two outcome measures. Favorable outcome was defined as a decrease of ≥30% on the Numerical Rating Scale for leg pain intensity and a decrease of ≥30% on the Oswestry Disability Index for low back disability. Baseline physical variables were used to conduct binary logistic regression.

Results

Sixty percent of participants were determined as having a favorable postoperative outcome. None of the included physical variables were found to be predictors of a favorable postoperative outcome based on leg pain intensity and low back pain-associated disability [trunk flexors muscle strength (OR = 0.73; 95%CI (0.02–27.12)] lumbar extensors muscle endurance [OR= 1.09; 95%CI (0.95–1.24)] total ambulation time [OR = 1.00 95%CI (0.99–1.01)] lumbar active range of motion in extension [OR = 1.08; 95%CI (0.95–1.23)] and knee extensors muscle strength [OR=1.02; 95%CI (0.98–1.06)].

Conclusion

Results show that none of the investigated variables, all related to low back and lower limbs physical capacity, were predictors of postoperative recovery. Further testing in larger cohort is needed to assess the full potential of physical outcome measures as predictors of postoperative recovery.