bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of HPV-16 E6 and E7 oncoproteins alters Chlamydia trachomatis developmental cycle and induces increased levels of immune regulatory molecules
Authors: Olivera Carolina , Mosmann Jessica P. , Anna Ailen N. , Bettucci Ferrero Gloria N. , Paira Daniela A. , Ferreyra Fernando N. , Martinez María S. , Motrich Rubén D. , Cuffini Cecilia G. , Saka Héctor Alex , Rivero Virginia E.
Published: September 2023

Introduction

Infection with Human Papillomavirus (HPV) is a recognized risk factor for Chlamydia trachomatis (CT) infection and vice versa. Coinfection of HPV and CT in women is a very common and usually asymptomatic finding that has been linked to increased risk of cervical cancer. It has been demonstrated that CT facilitates the entry of multiple high risk HPV genotypes, leading to damage of the mucosal barrier and interfering with immune responses and viral clearance, which ultimately favours viral persistence and malignant transformation. Although the facilitating effects elicited by CT infection on viral persistence have been reported, little is known about the consequences of HPV infection on CT development.

Methods

Herein, we took advantage of a genetically modified human cervical cell line co-expressing HPV-16 major oncogenic proteins E6 and E7, as an experimental model allowing to investigate the possible effects that HPV infection would have on CT development.

Results and discussion

Our results show that CT infection of HPV-16 E6E7 expressing cells induced an upregulation of the expression of E6E7 oncoproteins and host cell inhibitory molecules PD-L1, HVEM and CD160. Additionally, smaller chlamydial inclusions and reduced infectious progeny generation was observed in E6E7 cells. Ultrastructural analysis showed that expression of E6 and E7 did not alter total bacterial counts within inclusions but resulted in increased numbers of reticulate bodies (RB) and decreased production of infectious elementary bodies (EB). Our results indicate that during CT and HPV coinfection, E6 and E7 oncoproteins impair RB to EB transition and infectious progeny generation. On the other hand, higher expression of immune inhibitory molecules and HPV-16 E6E7 are cooperatively enhanced in CT-infected cells, which would favour both oncogenesis and immunosuppression. Our findings pose important implications for clinical management of patients with HPV and CT coinfection, suggesting that screening for the mutual infection could represent an opportunity to intervene and prevent severe reproductive health outcomes, such as cervical cancer and infertility.
Occurrence conditions of the reverse rotation of rockfall and its influence on the restitution coefficient
Authors: Ji Zhong-Min , Wang Ting-Hui , Wu Fa-Quan , Wang Dong-Po , Li Zhen-Hua
Published: September 2023

When rockfall occurs along dense rock slopes, the rotation direction of rockfall is not always downhill. Specifically, the rockfall may obtain a reverse rotation speed (RRS) after impact under certain conditions, the effect of which on the restitution coefficient (RC) cannot be ignored. According to the statistical results of the reverse rotation (RR) phenomena of blocks obtained from previous experiments, the occurrence of RR is correlated to the block shape, incident angle, and contact attitude. In this study, considering a typically shaped cubic block, the critical condition for the RR is preliminarily deduced. Based on the results, the influence of the RRS on the RC for four typically shaped blocks is examined using a customized device. Results show that the tangential RC (Rt) values of each block are not sensitive to the change in the RRS, the distribution is relatively concentrated and the values are high. Moreover, the normal RC (Rn) values are not sensitive to the RRS, and the distribution is relatively discrete. The RRS influences Rn; however, it is difficult to directly establish the relationship between them. To this end, considering the contact attitude and shape of the block, an integral variable, the impact coefficient (Ic), is proposed to determine the influence of RRS on Rn. Moreover, the impact-bounce behaviours of the block are categorized and analysed. For the block rebound following a single impact, Ic and Rn are positively and negatively correlated when the mass centre of the block (MC) is in front and behind the contact point (CP), respectively. For the block rebound following two successive impacts, with the increase in Ic, the Rn increases. These conclusions help clarify the mechanism of the influence of the RRS on RC and provide vital information and ideas for the development and optimization of a program to accurately predict rockfall trajectories.
Late Miocene landform construction in east-southern Tibet: seismic evidence and a synthetic review
Authors: Xiang Bo , Xu Xiao , Yu Jiahao , Guo Xiaoyu , Wu You , Li Chunsen , Wu Jiajie , Tong Xiaofei , Luo Xucong
Published: September 2023

The north-south striking landform perpendicular to the dominant collision zone between the Indian and Eurasian plates was constructed in east-southern Tibet (EST) during the Late Miocene. The building processes remain ambiguous, partly owing to the lack of recognition of crustal-scale architecture. Here we deployed an east-west-oriented 120 km-long short-period dense array across the northwestern corner of EST. Results from P-wave receiver functions show a mid-crustal ductile detachment atop the crystalline basement of the eastern Lhasa terrane that has displaced the overlying crust including the upper part of the Yardong-Gulu Rift (YGR) eastward for about 100 km and an offset Moho geometry left behind beneath the Nyainqentanghla Range. Combined previous studies on the vertical heterogeneity in crustal strength beneath the YGR, a synthetic view implies a decoupled crustal architecture of EST to respond the dynamic interactions between the eastward extrusion of the Tibetan Plateau and the northward penetration of the Indian plate that constitutes the Eastern Himalayan Syntaxis. The integrated processes eventually brought active landform construction in the plateau’s interior and partly contributing to the contemporaneous intensification of monsoon in SE Asia.
The impact of pedagogical and ICT training in teachers’ approaches to online teaching and use of digital tools
Authors: Haarala-Muhonen Anne , Myyry Liisa , Pyörälä Eeva , Kallunki Veera , Anttila Henrika , Katajavuori Nina , Kinnunen Päivi , Tuononen Tarja
Published: September 2023

This study examines the relationship between teachers’ pedagogical and ICT training, their approaches to online teaching and the use of digital tools. The participants were 265, teachers from the large multi-disciplinary university in Finland. The data was collected in May–June 2020 during the early stages of COVID-19 pandemic. The results showed that teachers used digital tools more for delivering information and less for activating students. The study revealed that pedagogical training enhanced teachers’ learning-focused approach to online teaching and diverse use of digital tools. Contrary to expectations, teachers’ ICT training was not related to the use of digital tools. Therefore, it is important to provide pedagogical training to support teachers in implementing teaching in diverse teaching-learning environments and enhance building an online teaching, in which digital tools are used to promote interaction in online environment.
Catalyst for co-construction: the role of AI-directed speech recognition technology in the self-organization of knowledge
Authors: Halonen Niina , Ståhle Pirjo , Juuti Kalle , Paavola Sami , Lonka Kirsti
Published: September 2023

The purpose of this study was to analyze knowledge co-construction as a self-organization process and the role of technology as its catalyst. Novel AI-directed speech recognition technology and the artifacts it generates were deployed to scaffold the knowledge co-construction process in two groups of pre-service teachers in a science education context. Throughout the lesson, the focus of the learning tasks was on pedagogical content knowledge and students' preconceptions. Analysis was conducted through the key characteristics of the social system's self-organization theory. The process of self-organization refers to the system's capacity to diverge from familiar structures, perspectives, and operations. Through the lenses of system theories, the active role of artifacts in co-construction was grasped and the role of technology in the self-organization of knowledge was analyzed. The pedagogical design of knowledge co-construction followed the principles of student-engaging learning. The technology used in co-construction was novel speech recognition AI software, which produced visual and editable word cloud artifacts from oral discussions on the large-format screen to edit. The data included videos and audio recordings. In this qualitative study, a content analysis and interaction analysis were used with descriptive analysis. The results showed that when technology became visible, as an active component of the system, artifacts triggered key signs of the social system's self-organization in co-construction. Exchange of information, “entropy levels,” were rapidly increased, and different viewpoints were expressed. Also, “chaos zones,” far-from-equilibrium states, were reached in both groups. Editable artifacts on the screen represented bifurcation spaces where groups' discussions were crystallized for the first time. Information was further categorized and evaluated through artifacts and this demonstrated how the groups processed communication into learning insights. Based on the results, the role played by this kind of technology was significant in the self-organization of knowledge. Materialized artifacts pushed the groups from small group conversation phases, comfort zones, toward uncertainty and confusion, which are central in self-organization. Technology in the system is seen not only as an interactor but also as an active agent that can facilitate epistemic emotions and support the group in the self-organization of knowledge.
Association of serum 25-hydroxyvitamin D with urinary incontinence in elderly men: evidence based on NHANES 2007-2014
Authors: Liu Li , Xu Mingming , Zhou Hang , Hao Xuexue , Chen Xiangyu , Liu Xiaoqiang
Published: September 2023

Background

The correlation between serum 25-hydroxyvitamin D (25(OH)D) and different sub-types of urinary incontinence in elderly men continues to be uncertain. Hence, we performed this research to evaluate whether serum 25(OH)D levels are correlated with urinary incontinence among elderly men.

Methods

The present study incorporated the male population aged 50 years and above from four cycles of the NHANES database spanning from 2007 to 2014, for the purpose of analysis. The assessment of urinary incontinence was carried out through a correlation questionnaire, while standardized liquid chromatography-tandem mass spectrometry (LC-MS/MS) was adopted to quantify serum 25(OH)D. A weighted multi-factorial logistic regression analysis was carried out to ascertain and investigate any potential correlation that may exist between serum 25(OH)D and urinary incontinence in senior males.

Results

Ultimately, a sum of 4663 elderly men were involved in our analysis. The outcomes of the univariable analysis illustrated that the group with vitamin D deficiency exhibited augmented odds of all three urinary incontinence types in comparison to the vitamin D-sufficient group. After accounting for age, race, and BMI, no appreciable variations in the outcomes were noticed. However, after accounting for all covariates, only SUI (OR = 1.677; 95% confidence interval (CI) = 1.074–2.618) and MUI (OR = 1.815; 95% confidence interval (CI) = 1.010–3.260) demonstrated statistical significance.

Conclusion

Decreased serum 25(OH)D levels were connected with stress urinary incontinence and mixed urinary incontinence in elderly men.
The causal association between polycystic ovary syndrome and susceptibility and severity of COVID-19: a bidirectional Mendelian randomization study using genetic data
Authors: Si Yu , Fei Yuye , Ma Hua , Xu Yating , Ning Li , Li Xiu , Ren Qingling
Published: September 2023

Introduction

Observational studies have reported an association between polycystic ovary syndrome (PCOS) and COVID-19, but a definitive causal relationship has not been established. This study aimed to assess this association using two-way two-sample Mendelian randomization (MR).

Methods

A summary of PCOS characteristics was compiled using the PCOS summary statistics from the Apollo University of Cambridge Repository. COVID-19 susceptibility and severity statistics, including hospitalization and extremely severe disease, were obtained from genome-wide association studies from the COVID-19 Host Genetics Initiative. The primary analysis used the inverse variance-weighted method, supplemented by the weighted median, MR-Egger, and MR-PRESSO methods.

Results

The forward MR analysis showed no significant impact of PCOS on COVID-19 susceptibility, hospitalization, or severity (OR = 0.983, 1.011, 1.014; 95% CI = 0.958–1.008, 0.958–1.068, 0.934–1.101; and p = 0.173, 0.68, 0.733; respectively). Similarly, reverse MR analysis found no evidence supporting COVID-19 phenotypes as risk or protective factors for PCOS (OR = 1.041, 0.995, 0.944; 95% CI = 0.657–1.649, 0.85–1.164, 0.843–1.058; and p = 0.864, 0.945, 0.323; respectively). Consequently, no significant association between any COVID-19 phenotype and PCOS was established.

Conclusion

This MR study suggested that PCOS is not a causal risk factor for the susceptibility and severity of COVID-19. The associations identified in previous observational studies might be attributable to the presence of comorbidities in the patients.
Analysis of sensitive factors for sidetrack drilling in water-flooded oil reservoirs: data mining based on actual field data
Authors: Wang Xiang , Rui Cheng , Liu Haicheng
Published: September 2023

Sidetracking technology is an important measure to increase production and efficiency, too many complex factors affect the development effect of sidetracking wells. At present, most of the research on sensitive factors of sidetracking wells is based on theory, numerical simulation, or application analysis of limited wells. In this study, we adopt a data-driven research paradigm to conduct data mining studies on the actual data of a large number of sidetracking wells accumulated in the oil fields. Actual data from more than 130 sidetracking wells in oil fields within 5 years is collected and cleaned. An index system including 25 indicators for the analysis of sidetracking effect and a sample set of influencing factors are established. On this basis, scatter plots between various influencing factors and sidetracking development effect parameters are drawn to achieve intuitive qualitative understanding through visualization. The correlation coefficients between each parameter are calculated by Pearson and Spearman correlation analysis methods to quantitatively characterize and analyze the linear and nonlinear correlation degrees between each indicator. A feature importance calculation method based on a decision tree is constructed to calculate and rank the importance of each influencing factor for the development effect of sidetracking wells. The results show that compared with Pearson, the Spearman correlation coefficient can more accurately reflect the complex nonlinear correlation relationship between each indicator. Four indicators such as sidetracking target point position show medium or above correlation with sidetracking development effect. Through the calculation of the feature importance of the decision tree, it can be known that the importance of remaining recoverable reserves to the development effect of sidetracking wells exceeds 10%. The importance of six indicators, such as perforation thickness, is small, all less than 3%. This research work can provide guidance for future sidetracking well design and development work.
Spatial distribution of congenital syphilis in the state of Bahia, Brazil from 2009 to 2018
Authors: Vital Caroline Luz , Reis Renato Barbosa , Soares Jorgana Fernanda de Souza , Miranda Diego Lopes Paim , Reis Mitermayer Galvão
Published: September 2023

Objective

To describe the temporal trend and spatial distribution of congenital syphilis (CS) cases in the state of Bahia, Brazil between 2009 and 2018.

Method

Mixed ecological study conducted through the analysis of data obtained from the Notifiable Diseases Information System and the Live Birth Information System. Global Moran Index I was performed in order to analyze spatial autocorrelation of CS cases in the municipalities of Bahia and the Local Spatial Association Indicator (LISA) was used to identify the formation of spatial regimes in the GeoDA software.

Results

8,786 cases of CS were registered in the period. An increasing growth in CS incidence, with a 511% increase between 2009 and 2018. Spatial autocorrelation was observed between the municipalities (I Moran = 0.452; p < 0.001) and four clusters were identified. More frequently, mothers were aged 20–29 years (50.7%); had incomplete primary education (54.9%); were Black and multiracial (93.2%); received prenatal care (82.2%); 49.0% were diagnosed with syphilis during prenatal care; 68.8% were not adequately treated, and 81.1% of their partners were not treated.

Conclusion

The results showed that CS consolidates as a serious public health problem in Bahia, with an incidence 8.4 times higher in the period than the WHO target of 0.5/1,000 live births, predominantly related to inadequate prenatal care and social vulnerability indicators: young mothers with low education levels, as well as individuals identified as Black and multiracial. Thus, programs aimed at women of childbearing age and pregnant women need to be intensified.
Altitudinal shifting of major forest tree species in Italian mountains under climate change
Authors: Noce Sergio , Cipriano Cristina , Santini Monia
Published: September 2023

Climate change has profound implications for global ecosystems, particularly in mountainous regions where species distribution and composition are highly sensitive to changing environmental conditions. Understanding the potential impacts of climate change on native forest species is crucial for effective conservation and management strategies. Despite numerous studies on climate change impacts, there remains a need to investigate the future dynamics of climate suitability for key native forest species, especially in specific mountainous sections. This study aims to address this knowledge gap by examining the potential shifts in altitudinal range and suitability for forest species in Italy's mountainous regions. By using species distribution models, through MaxEnt we show the divergent impacts among species and scenarios, with most species experiencing a contraction in their altitudinal range of suitability whereas others show the potential to extend beyond the current tree line. The Northern and North-Eastern Apennines exhibit the greatest and most widespread impacts on all species, emphasizing their vulnerability. Our findings highlight the complex and dynamic nature of climate change impacts on forest species in Italy. While most species are projected to experience a contraction in their altitudinal range, the European larch in the Alpine region and the Turkey oak in the Apennines show potential gains and could play significant roles in maintaining wooded populations. The tree line is generally expected to shift upward, impacting the European beech—a keystone species in the Italian mountain environment—negatively in the Alpine arc and Northern Apennines, while showing good future suitability above 1,500 meters in the Central and Southern Apennines. Instead, the Maritime pine emerges as a promising candidate for the future of the Southern Apennines. The projected impacts on mountain biodiversity, particularly in terms of forest population composition, suggest the need for comprehensive conservation and management strategies. The study emphasizes the importance of using high-resolution climate data and considering multiple factors and scenarios when assessing species vulnerability. The findings have implications at the local, regional, and national levels, emphasizing the need for continued efforts in producing reliable datasets and forecasts to inform targeted conservation efforts and adaptive management strategies in the face of climate change.
Homeostatic role of B-1 cells in tissue immunity
Authors: Suchanek Ondrej , Clatworthy Menna R.
Published: September 2023

To date, studies of tissue-resident immunity have mainly focused on innate immune cells and T cells, with limited data on B cells. B-1 B cells are a unique subset of B cells with innate-like properties, enriched in murine pleural and peritoneal cavities and distinct from conventional B-2 cells in their ontogeny, phenotype and function. Here we discuss how B-1 cells represent exemplar tissue-resident immune cells, summarizing the evidence for their long-term persistence & self-renewal within tissues, differential transcriptional programming shaped by organ-specific environmental cues, as well as their tissue-homeostatic functions. Finally, we review the emerging data supporting the presence and homeostatic role of B-1 cells across non-lymphoid organs (NLOs) both in mouse and human.
Eosinophilic infiltration as the initial trace of acute mixed cellular and antibody mediated rejection in a heart transplant patient with concomitant immense epitope-associated HLA-antibody production: a case report
Authors: Skougaard Marie , Bærentzen Steen , Eiskjær Hans , Koefoed-Nielsen Pernille
Published: September 2023

Acute mixed cellular and antibody-mediated rejection (MR) has an estimated prevalence of 7.8%. However, knowledge of MR immune pathogenesis in cardiac graft rejection remains sparse. We report a case of acute MR in a heart transplant patient with a mutation in the MYH7 gene encoding the protein β-myosin heavy chain, resulting in familial hypertrophic cardiomyopathy. The patient presented with substantial eosinophilic infiltration and extensive production of Human Leukocyte Antigen (HLA)-antibodies associated with shared epitopes. Eosinophilic infiltration in the endo- and myocardium was diagnosed in routine post-transplant biopsies stained with hematoxylin-eosin on day 6 after transplantation. On day 27, the patient presented with dyspnea, weight gain, increased pro-brain natriuretic peptide, and was hospitalized due to suspected acute rejection. Endomyocardial biopsies showed eosinophils in endo- and myocardium with additional lymphocytes and hyperplastic endothelium. Immunohistochemistry, including CD31/CD68 double stain confirmed endothelium-associated macrophages in capillaries and severe C4d positivity in the capillaries and endocardial endothelium. Lymphocytes were identified as primarily CD45+/CD3+ T cells with a concomitant few CD45+/CD20+ B cells. HLA-antibody analysis demonstrated a significant increase in 13 HLA-antibodies present in pre-transplant-serum, of which anti-B7 was donor-specific, and 23 strong de-novo HLA-class I antibodies of which anti-B62 was donor-specific. 72% of HLA-antibodies, including the two donor-specific antibodies, shared the same HLA antigen epitope; 43P+69A or 163L+167W. This is a case reporting both HLA-antibody and pathohistological data indicating the need for better understanding of interactions between cellular and antibody-mediated immune response mechanisms in graft rejection, and the significance of pre-transplant donor-specific antibodies during immunological pre-transplant risk assessment.
Identification of potential hub genes linked to immune and metabolic alterations in postoperative systemic inflammatory dysregulation
Authors: Cao Silu , Tang Jinxuan , Fei Miaomiao , Jing Qi , Meng Fanbing , Zhang Meixian , Liu Qidong , Zhang Hui , Li Cheng
Published: September 2023

Background

Postoperative systemic inflammatory dysregulation (PSID) is characterised by strongly interlinked immune and metabolic abnormalities. However, the hub genes responsible for the interconnections between these two systemic alterations remain to be identified.

Methods

We analysed differentially expressed genes (DEGs) of individual peripheral blood nucleated cells in patients with PSID (n = 21, CRP > 250 mg/L) and control patients (n = 25, CRP < 75 mg/L) following major abdominal surgery, along with their biological functions. Correlation analyses were conducted to explore the interconnections of immune-related DEGs (irDEGs) and metabolism-related DEGs (mrDEGs). Two methods were used to screen hub genes for irDEGs and mrDEGs: we screened for hub genes among DEGs via 12 algorithms using CytoHubba in Cytoscape, and also screened for hub immune-related and metabolic-related genes using weighted gene co-expression network analysis. The hub genes selected were involved in the interaction between changes in immunity and metabolism in PSID. Finally, we validated our results in mice with PSID to confirm the findings.

Results

We identified 512 upregulated and 254 downregulated DEGs in patients with PSID compared with controls. Gene enrichment analysis revealed that DEGs were significantly associated with immune- and metabolism-related biological processes and pathways. Correlation analyses revealed a close association between irDEGs and mrDEGs. Fourteen unique hub genes were identified via 12 screening algorithms using CytoHubba in Cytoscape and via weighted gene co-expression network analysis. Among these, CD28, CD40LG, MAPK14, and S100A12 were identified as hub genes among both immune- and metabolism-related genes; these genes play a critical role in the interaction between alterations in immunity and metabolism in PSID. The experimental results also showed that the expression of these genes was significantly altered in PSID mice.

Conclusion

This study identified hub genes associated with immune and metabolic alterations in patients with PSID and hub genes that link these alterations. These findings provide novel insights into the mechanisms underlying immune and metabolic interactions and new targets for clinical treatment can be proposed on this basis.
Socio-ecological analysis of the eutrophication in Chesapeake Bay, USA
Authors: Leyva Ollivier María Esther , Newton Alice , Kelsey Heath
Published: September 2023

This study is a social-ecological analysis of eutrophication in the Chesapeake Bay, United States of America (USA). It uses an expanded DPSIR framework (Drivers/Pressures/State/ Impacts/Responses) methodology to analyze the issue. In addition, a typology of the social actors and stakeholders in the socio-economic part of the system is identified. These stakeholders include residents, agriculturists, fishers, real estate developers, tourism operators, scientific researchers, and state and federal regulators. The framework results found that the Drivers are food security, housing, economic development, recreation pursuits, a sense of belonging, and population growth. These result in human Activities such as land and coastal change for development, coastline changes for fisheries, urban or suburban development, burning fossil fuels, and agricultural fertilization. The activities exert Pressures such as wastewater discharge, runoff from cleared land, atmospheric deposition (NOx), nutrient input, decreased tidal vegetation, and overfishing of filter feeders. These alterations change the State of the environment and its resilience by increasing the duration and areal extent of hypoxia, turbidity, and change in nutrient ratios. This also causes ecosystem changes, such as a decrease in wildlife diversity, and affects ecosystem services, such as decreasing nutrient buffering. The health of Chesapeake Bay benefits all stakeholders and wildlife, so the reduction of ecosystem services results in Impacts on society’s welfare and well-being, the economy, and environmental justice. Examples are decreased fishery yields and poorer water quality, affecting aesthetics, tourism, and ultimately human health. The governance Response to the degradation of the Chesapeake Bay and main management Measures has been the formation of the Chesapeake Bay Program, which has developed several agreements to improve water quality. The Chesapeake Bay Foundation, Chesapeake Progress, and Report Cards are accountability tools to observe and communicate the management project results or enforce state laws. The current management shows promising results, but further efforts are required to improve the water quality. Using various management options may bridge this gap to benefit all stakeholders. The main conclusion is that, although eutrophication is a complex problem, there is a scientific knowledge-base and a range of management options to restore the Chesapeake Bay.
Beyond antibiotics: phage-encoded lysins against Gram-negative pathogens
Authors: Shah Sanket , Das Ritam , Chavan Bhakti , Bajpai Urmi , Hanif Sarmad , Ahmed Syed
Published: September 2023

Antibiotics remain the frontline agents for treating deadly bacterial pathogens. However, the indiscriminate use of these valuable agents has led to an alarming rise in AMR. The antibiotic pipeline is insufficient to tackle the AMR threat, especially with respect to the WHO critical category of priority Gram-negative pathogens, which have become a serious problem as nosocomial and community infections and pose a threat globally. The AMR pandemic requires solutions that provide novel antibacterial agents that are not only effective but against which bacteria are less likely to gain resistance. In this regard, natural or engineered phage-encoded lysins (enzybiotics) armed with numerous features represent an attractive alternative to the currently available antibiotics. Several lysins have exhibited promising efficacy and safety against Gram-positive pathogens, with some in late stages of clinical development and some commercially available. However, in the case of Gram-negative bacteria, the outer membrane acts as a formidable barrier; hence, lysins are often used in combination with OMPs or engineered to overcome the outer membrane barrier. In this review, we have briefly explained AMR and the initiatives taken by different organizations globally to tackle the AMR threat at different levels. We bring forth the promising potential and challenges of lysins, focusing on the WHO critical category of priority Gram-negative bacteria and lysins under investigation for these pathogens, along with the challenges associated with developing them as therapeutics within the existing regulatory framework.
Vibrio gazogenes-dependent disruption of aflatoxin biosynthesis in Aspergillus flavus: the connection with endosomal uptake and hyphal morphogenesis
Authors: Jesmin Rubaiya , Cary Jeffrey W. , Lebar Matthew D. , Majumdar Rajtilak , Gummadidala Phani M. , Dias Travis , Chandler Savannah , Basu Paramita , Decho Alan W. , Keller Nancy P. , Chanda Anindya
Published: September 2023

Aflatoxins, a family of fungal secondary metabolites, are toxic and carcinogenic compounds that pose an enormous threat to global food safety and agricultural sustainability. Specifically agricultural products in African, Southeast Asian and hot and humid regions of American countries suffer most damage from aflatoxin producing molds due to the ideal climate conditions promoting their growth. Our recent studies suggest that Vibrio gazogenes (Vg), an estuarine bacterium non-pathogenic to plants and humans, can significantly inhibit aflatoxin biosynthesis in the producers. In this study, we investigated the mechanism underlying Vg-dependent aflatoxin inhibition using the prominent aflatoxin producer, Aspergillus flavus. We show that aflatoxin inhibition upon Vg treatment was associated with fungal uptake of Vg-prodigiosin, a red pigment, which was consistently visible inside fungal hyphae during treatment. The association of prodigiosin with aflatoxin inhibition was further evident as Serratia marcescens, another prodigiosin producer, significantly inhibited aflatoxin, while non-producers like Escherichia coli, Staphylococcus aureus, Vibrio harveyi, and Vibrio fischeri did not. Also, pure prodigiosin significantly inhibited aflatoxin biosynthesis. Endocytosis inhibitors, filipin and natamycin, reduced the Vg-prodigiosin uptake by the fungus leading to a significant increase in aflatoxin production, suggesting that uptake is endocytosis-dependent. The Vg treatment also reduced hyphal fusion (>98% inhibition) and branching, which are both endosome-dependent processes. Our results, therefore, collectively support our theory that Vg-associated aflatoxin inhibition is mediated by an endocytosis-dependent uptake of Vg-prodigiosin, which possibly leads to a disruption of normal endosomal functions.
Molecular characterization and differential effects of levofloxacin and ciprofloxacin on the potential for developing quinolone resistance among clinical Pseudomonas aeruginosa isolates
Authors: Kanafani Zeina A. , Sleiman Ahmad , Frem Jim Abi , Doumat George , Gharamti Amal , El Hafi Bassam , Doumith Michel , AlGhoribi Majed F. , Kanj Souha S. , Araj George F. , Matar Ghassan M. , Abou Fayad Antoine G.
Published: September 2023

Background

Fluoroquinolones are some of the most used antimicrobial agents for the treatment of Pseudomonas aeruginosa. This study aimed at exploring the differential activity of ciprofloxacin and levofloxacin on the selection of resistance among P. aeruginosa isolates at our medical center.

Methods

233 P. aeruginosa clinical isolates were included in this study. Antimicrobial susceptibility testing (AST) was done using disk diffusion and broth microdilution assays. Random Amplification of Polymorphic DNA (RAPD) was done to determine the genetic relatedness between the isolates. Induction of resistance against ciprofloxacin and levofloxacin was done on 19 isolates. Fitness cost assay was done on the 38 induced mutants and their parental isolates. Finally, whole genome sequencing was done on 16 induced mutants and their 8 parental isolates.

Results

AST results showed that aztreonam had the highest non-susceptibility. RAPD results identified 18 clusters. The 19 P. aeruginosa isolates that were induced against ciprofloxacin and levofloxacin yielded MICs ranging between 16 and 256 μg/mL. Levofloxacin required fewer passages in 10 isolates and the same number of passages in 9 isolates as compared to ciprofloxacin to reach their breakpoints. Fitness cost results showed that 12 and 10 induced mutants against ciprofloxacin and levofloxacin, respectively, had higher fitness cost when compared to their parental isolates. Whole genome sequencing results showed that resistance to ciprofloxacin and levofloxacin in sequenced mutants were mainly associated with alterations in gyrA, gyrB and parC genes.

Conclusion

Understanding resistance patterns and risk factors associated with infections is crucial to decrease the emerging threat of antimicrobial resistance.
A study on feature selection using multi-domain feature extraction for automated k-complex detection
Authors: Li Yabing , Dong Xinglong , Song Kun , Bai Xiangyun , Li Hongye , Karray Fakhreddine
Published: September 2023

Background

K-complex detection plays a significant role in the field of sleep research. However, manual annotation for electroencephalography (EEG) recordings by visual inspection from experts is time-consuming and subjective. Therefore, there is a necessity to implement automatic detection methods based on classical machine learning algorithms. However, due to the complexity of EEG signal, current feature extraction methods always produce low relevance to k-complex detection, which leads to a great performance loss for the detection. Hence, finding compact yet effective integrated feature vectors becomes a crucially core task in k-complex detection.

Method

In this paper, we first extract multi-domain features based on time, spectral analysis, and chaotic theory. Those features are extracted from a 0.5-s EEG segment, which is obtained using the sliding window technique. As a result, a vector containing twenty-two features is obtained to represent each segment. Next, we explore several feature selection methods and compare their performance in detecting k-complex. Based on the analysis of the selected features, we identify compact features which are fewer than twenty-two features and deemed as relevant and proceeded to the next step. Additionally, three classical classifiers are employed to evaluate the performance of the feature selection models.

Results

The results demonstrate that combining different features significantly improved the k-complex detection performance. The best performance is achieved by applying the feature selection method, which results in an accuracy of 93.03%±7.34, sensitivity of 93.81%±5.62%, and specificity 94.13±5.81, respectively, using a smaller number of the combined feature sets.

Conclusion

The proposed method in this study can serve as an efficient tool for the automatic detection of k-complex, which is useful for neurologists or doctors in the diagnosis of sleep research.
Expression of the schizophrenia associated gene FEZ1 in the early developing fetal human forebrain
Authors: Alhesain Maznah , Ronan Hannah , LeBeau Fiona E. N. , Clowry Gavin J.
Published: September 2023

Introduction

The protein fasciculation and elongation zeta-1 (FEZ1) is involved in axon outgrowth but potentially interacts with various proteins with roles ranging from intracellular transport to transcription regulation. Gene association and other studies have identified FEZ1 as being directly, or indirectly, implicated in schizophrenia susceptibility. To explore potential roles in normal early human forebrain neurodevelopment, we mapped FEZ1 expression by region and cell type.

Methods

All tissues were provided with maternal consent and ethical approval by the Human Developmental Biology Resource. RNAseq data were obtained from previously published sources. Thin paraffin sections from 8 to 21 post-conceptional weeks (PCW) samples were used for RNAScope in situ hybridization and immunohistochemistry against FEZ1 mRNA and protein, and other marker proteins.

Results

Tissue RNAseq revealed that FEZ1 is highly expressed in the human cerebral cortex between 7.5–17 PCW and single cell RNAseq at 17–18 PCW confirmed its expression in all neuroectoderm derived cells. The highest levels were found in more mature glutamatergic neurons, the lowest in GABAergic neurons and dividing progenitors. In the thalamus, single cell RNAseq similarly confirmed expression in multiple cell types. In cerebral cortex sections at 8–10 PCW, strong expression of mRNA and protein appeared confined to post-mitotic neurons, with low expression seen in progenitor zones. Protein expression was observed in some axon tracts by 16–19 PCW. However, in sub-cortical regions, FEZ1 was highly expressed in progenitor zones at early developmental stages, showing lower expression in post-mitotic cells.

Discussion

FEZ1 has different expression patterns and potentially diverse functions in discrete forebrain regions during prenatal human development.
Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer
Authors: Song Yurong , Kerr Travis D. , Sanders Chelsea , Dai Lisheng , Baxter Shaneen S. , Somerville Brandon , Baugher Ryan N. , Mellott Stephanie D. , Young Todd B. , Lawhorn Heidi E. , Plona Teri M. , Xu Bingfang , Wei Lei , Hu Qiang , Liu Song , Hutson Alan , Karim Baktiar , Burkett Sandra , Difilippantonio Simone , Pinto Ligia , Gebert Johannes , Kloor Matthias , Lipkin Steven M. , Sei Shizuko , Shoemaker Robert H.
Published: September 2023

Background

Genome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, and PMS2) play a critical role in the DNA damage response pathway for genome integrity maintenance. Germline mutations of MMR genes can lead to Lynch syndrome or constitutional mismatch repair deficiency syndrome, resulting in an increased lifetime risk of developing cancer characterized by high microsatellite instability (MSI-H) and high mutation burden. Although immunotherapy has been approved for MMR-deficient (MMRd) cancer patients, the overall response rate needs to be improved and other management options are needed.

Methods

To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization.

Results

The organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node.

Conclusions

The established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.
Minimally invasive management of combined esophageal atresia with tracheoesophageal fistula and duodenal atresia: a comprehensive case report
Authors: Jung Eunyoung
Published: September 2023

A newborn presented with a rare combination of esophageal atresia with tracheoesophageal fistula (EA/TEF) and duodenal atresia (DA), which was successfully managed using minimally invasive surgical techniques. The patient was a 1-day-old male for whom passing a feeding tube was infeasible and who had a double bubble sign on radiography. The neonate underwent a thoracoscopic ligation of the tracheoesophageal fistula (TEF) and a laparoscopic duodeno-duodenostomy on the same day, resulting in stabilized vital signs. Ten days after the initial operation, a thoracoscopic esophago-esophagostomy was successfully performed. The patient demonstrated full feeding capability and normal weight gain after the surgeries. The co-occurrence of EA/TEF and DA is a rare and complex anomaly. This case indicates that minimally invasive techniques can effectively manage this condition.
Postbiotics in the medical field under the perspective of the ISAPP definition: scientific, regulatory, and marketing considerations
Authors: Vinderola Gabriel , Druart Céline , Gosálbez Luis , Salminen Seppo , Vinot Nina , Lebeer Sarah
Published: September 2023

Diverse terms have been used in the literature to refer to the health benefits obtained from the administration of non-viable microorganisms or their cell fragments and metabolites. In an effort to provide continuity to this emerging field, the International Scientific Association of Probiotics and Prebiotics (ISAPP) convened a panel of experts to consider this category of substances and adopted the term postbiotic, which they defined as a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host.” This definition does not stipulate any specific health benefit, finished product, target population or regulatory status. In this perspective article, we focused on postbiotics developed for pharmaceutical uses, including medicinal products and medical devices. We address how this field is regulated for products based on inanimate microorganisms, marketing considerations and existing examples of postbiotics products developed as cosmetics for the skin, for vaginal health, and as orally consumed products. We focus on the European Union for regulatory aspects, but also give examples from other geographical areas.
Implementation of pharmacogenetic testing in oncology: DPYD-guided dosing to prevent fluoropyrimidine toxicity in British Columbia
Authors: Wu Angela , Anderson Helen , Hughesman Curtis , Young Sean , Lohrisch Caroline , Ross Colin J. D. , Carleton Bruce C.
Published: September 2023

Background: Fluoropyrimidine toxicity is often due to variations in the gene (DPYD) encoding dihydropyrimidine dehydrogenase (DPD). DPYD genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels.

Methods: A multiplex QPCR assay was locally developed to allow genotyping for six DPYD variants. The test was offered prospectively for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across B.C., Canada as well as retrospectively for patients suspected to have had an adverse reaction to therapy. Dose adjustments were made for variant carriers. The incidence of toxicity in the first three cycles was compared between DPYD variant allele carriers and non-variant carriers. Subsequent to an initial implementation phase, this test was made available province-wide.

Results: In 9 months, 186 patients were tested and 14 were found to be heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in DPYD variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Of note, 22% (3 patients) of the variant carriers experienced severe toxicity even after DPYD-guided dose reductions. For one of these carriers who experienced severe thrombocytopenia within the first week, DPYD testing likely prevented lethal toxicity. In DPYD variant carriers who tolerate reduced doses, a later 25% increase led to chemotherapy discontinuation. As a result, a recommendation was made to clinicians based on available literature and expert opinion specifying that variant carriers who tolerated two cycles without toxicity can have a dose escalation of only 10%.

Conclusion:DPYD-guided dose reductions were a feasible and acceptable method of preventing severe toxicity in DPYD variant carriers. Even with dose reductions, there were variant carriers who still experienced severe fluoropyrimidine toxicity, highlighting the importance of adhering to guideline-recommended dose reductions. Following the completion of the pilot phase of this study, DPYD genotyping was made available province-wide in British Columbia.
A novel grid multi-structure chaotic attractor and its application in medical image encryption
Authors: Hu Zhenhua , Lin Hairong , Wang Chunhua
Published: September 2023

Grid multi-scroll/wing chaotic systems are complex non-linear dynamic systems, which are widely used in secure communication. The grid multi-scroll/wing chaotic systems are usually realized by using the function control method, which has a complex realization method, many control parameters, and a simple unit attractor structure. In this paper, based on the Hopfield neural network, a memristive Hopfield neural network model is proposed by using the memristor synapse control method. The model can generate novel grid multi-structure chaotic attractors, which have the characteristics of a simple implementation method, few control parameters, and complex unit attractor structure. Firstly, the generation mechanism of the grid multi-structure chaotic attractors is analyzed by the equilibrium points and stability. Secondly, its basic dynamical characteristics including the Lyapunov exponent spectrum, fractal dimension, time series, power spectrum, bifurcation diagram, and Poincaré section are analyzed. Thirdly, an analog circuit of the neural network model is designed and realized by Multisim. Finally, combined with the chaos encryption principle, an image encryption scheme is designed based on the generated grid multi-structure attractors. Experimental results show that compared with the existing schemes, the proposed scheme has larger information entropy, higher key sensitivity, and a good application prospect.