bluuebunny/crossref_metadata_2025 huggingface dataset:
Multigene testing panels reveal pathogenic variants in sporadic breast cancer patients in northern China
Authors: Liu Yinfeng , Zheng Jie , Xu Yue , Lv Ji , Wu Zizheng , Feng Kai , Liu Jiani , Yan Weitao , Wei Liguang , Zhao Jiangman , Jiang Lisha , Han Meng
Published: November 2023

Background: Breast cancer, the most prevalent malignancy in women worldwide, presents diverse onset patterns and genetic backgrounds. This study aims to examine the genetic landscape and clinical implications of rare mutations in Chinese breast cancer patients.

Methods: Clinical data from 253 patients, including sporadic and familial cases, were analyzed. Comprehensive genomic profiling was performed, categorizing identified rare variants according to the American College of Medical Genetics (ACMG) guidelines. In silico protein modeling was used to analyze potentially pathogenic variants’ impact on protein structure and function.

Results: We detected 421 rare variants across patients. The most frequently mutated genes were ALK (22.2%), BARD1 (15.6%), and BRCA2 (15.0%). ACMG classification identified 7% of patients harboring Pathogenic/Likely Pathogenic (P/LP) variants, with one case displaying a pathogenic BRCA1 mutation linked to triple-negative breast cancer (TNBC). Also identified were two pathogenic MUTYH variants, previously associated with colon cancer but increasingly implicated in breast cancer. Variants of uncertain significance (VUS) were identified in 112 patients, with PTEN c.C804A showing the highest frequency. The role of these variants in sporadic breast cancer oncogenesis was suggested. In-depth exploration of previously unreported variants led to the identification of three potential pathogenic variants: ATM c.C8573T, MSH3 c.A2723T, and CDKN1C c.C221T. Their predicted impact on protein structure and stability suggests a functional role in cancer development.

Conclusion: This study reveals a comprehensive overview of the genetic variants landscape in Chinese breast cancer patients, highlighting the prevalence and potential implications of rare variants. We emphasize the value of comprehensive genomic profiling in breast cancer management and the necessity of continuous research into understanding the functional impacts of these variants.
“When a bad thing happens…you are better only when you are home:” alienation and mental health challenges experienced by Congolese and Somali migrants in Johannesburg, South Africa
Authors: Walker Rebecca , Lakika Dostin , Makandwa Tackson , Boeyink Clayton
Published: November 2023

This article explores the link between migration and alienation and its impact on the mental health and wellbeing of Congolese and Somali asylum seekers and refugees—two of the largest populations of displaced migrants in South Africa. Drawing on ethnographic research in Johannesburg, we highlight the various ways alienation is both imposed upon and experienced by migrants and argue that systemicdisintegration, or acts of alienation, can be seen as deliberate and active policies and practices that are instrumental in excluding asylum seekers and refugees from everyday life. The experiences of marginalization and othering narrated by Congolese and Somali migrants highlight ways in which alienation anddisintegration from critical social connections including family, community, and familiar contexts fundamentally impact wellbeing and mental health as well as strategies of care-seeking, and other forms of relational resilience. While conceptualizations and metrics of integration may in some ways capture the fallout of disintegration, such as access to livelihoods, housing, education, and healthcare, we suggest that this does not adequately assess the profound damage by acts of alienation on crucial relationships. The alienated psyche of innumerable migrants in South Africa results in the feeling that “when a bad thing happens…you are better only when you are home.” This pain, or feelings of alienation, we argue, are a crucial aspect to our understanding of alienation and in turn, highlight the importance of alienation as an apt analytical tool through which experiences of asylum-seeking in South Africa can be understood.
Regulatory T cells inhibit autoantigen-specific CD4+ T cell responses in lupus-prone NZB/W F1 mice
Authors: Rosenberger Stefan , Undeutsch Reinmar , Akbarzadeh Reza , Ohmes Justus , Enghard Philipp , Riemekasten Gabriela , Humrich Jens Y.
Published: November 2023

Introduction

Progressive loss of regulatory T cell (Treg)-mediated control over autoreactive effector T cells contributes to the development of systemic lupus erythematosus (SLE). Accordingly, we hypothesized that Treg may also have the capacity to suppress the activation of autoreactive CD4+ T cells that are considered to drive autoimmunity.

Methods

To investigate whether Treg are involved in the control of autoreactive CD4+ T cells, we depleted CD25+ Treg cells either in vivo or in vitro, or combined both approaches before antigen-specific stimulation with the SLE-associated autoantigen SmD1(83-119) in the NZB/W F1 mouse model either after immunization against SmD1(83-119) or during spontaneous disease development. Frequencies of autoantigen-specific CD4+ T cells were determined by flow cytometry using the activation marker CD154.

Results

Both in vitro and in vivo depletion of CD25+ Treg, respectively, increased the frequencies of detectable autoantigen-specific CD4+ T cells by approximately 50%. Notably, the combined in vivo and in vitro depletion of CD25+ Treg led almost to a doubling in their frequencies. Frequencies of autoantigen-specific CD4+ T cells were found to be lower in immunized haploidentical non-autoimmune strains and increased frequencies were detectable in unmanipulated NZB/W F1 mice with active disease. In vitro re-addition of CD25+ Treg after Treg depletion restored suppression of autoantigen-specific CD4+ T cell activation.

Discussion

These results suggest that the activation and expansion of autoantigen-specific CD4+ T cells are partly controlled by Treg in murine lupus. Depletion of Treg therefore can be a useful approach to increase the detectability of autoantigen-specific CD4+ T cells allowing their detailed characterization including lineage determination and epitope mapping and their sufficient ex vivo isolation for cell culture.
Optimized peptide nanofibrils as efficient transduction enhancers for in vitro and ex vivo gene transfer
Authors: Rauch-Wirth Lena , Renner Alexander , Kaygisiz Kübra , Weil Tatjana , Zimmermann Laura , Rodriguez-Alfonso Armando A. , Schütz Desiree , Wiese Sebastian , Ständker Ludger , Weil Tanja , Schmiedel Dominik , Münch Jan
Published: November 2023

Chimeric antigen receptor (CAR)-T cell therapy is a groundbreaking immunotherapy for cancer. However, the intricate and costly manufacturing process remains a hurdle. Improving the transduction rate is a potential avenue to cut down costs and boost therapeutic efficiency. Peptide nanofibrils (PNFs) serve as one such class of transduction enhancers. PNFs bind to negatively charged virions, facilitating their active engagement by cellular protrusions, which enhances virion attachment to cells, leading to increased cellular entry and gene transfer rates. While first-generation PNFs had issues with aggregate formation and potential immunogenicity, our study utilized in silico screening to identify short, endogenous, and non-immunogenic peptides capable of enhancing transduction. This led to the discovery of an 8-mer peptide, RM-8, which forms PNFs that effectively boost T cell transduction rates by various retroviral vectors. A subsequent structure-activity relationship (SAR) analysis refined RM-8, resulting in the D4 derivative. D4 peptide is stable and assembles into smaller PNFs, avoiding large aggregate formation, and demonstrates superior transduction rates in primary T and NK cells. In essence, D4 PNFs present an economical and straightforward nanotechnological tool, ideal for refining ex vivo gene transfer in CAR-T cell production and potentially other advanced therapeutic applications.
Crystalline silica-induced proinflammatory eicosanoid storm in novel alveolar macrophage model quelled by docosahexaenoic acid supplementation
Authors: Favor Olivia K. , Rajasinghe Lichchavi D. , Wierenga Kathryn A. , Maddipati Krishna R. , Lee Kin Sing Stephen , Olive Andrew J. , Pestka James J.
Published: November 2023

Introduction

Phagocytosis of inhaled crystalline silica (cSiO2) particles by tissue-resident alveolar macrophages (AMs) initiates generation of proinflammatory eicosanoids derived from the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (ARA) that contribute to chronic inflammatory disease in the lung. While supplementation with the ω-3 PUFA docosahexaenoic acid (DHA) may influence injurious cSiO2-triggered oxylipin responses, in vitro investigation of this hypothesis in physiologically relevant AMs is challenging due to their short-lived nature and low recovery numbers from mouse lungs. To overcome these challenges, we employed fetal liver-derived alveolar-like macrophages (FLAMs), a self-renewing surrogate that is phenotypically representative of primary lung AMs, to discern how DHA influences cSiO2-induced eicosanoids.

Methods

We first compared how delivery of 25 µM DHA as ethanolic suspensions or as bovine serum albumin (BSA) complexes to C57BL/6 FLAMs impacts phospholipid fatty acid content. We subsequently treated FLAMs with 25 µM ethanolic DHA or ethanol vehicle (VEH) for 24 h, with or without LPS priming for 2 h, and with or without cSiO2 for 1.5 or 4 h and then measured oxylipin production by LC-MS lipidomics targeting for 156 oxylipins. Results were further related to concurrent proinflammatory cytokine production and cell death induction.

Results

DHA delivery as ethanolic suspensions or BSA complexes were similarly effective at increasing ω-3 PUFA content of phospholipids while decreasing the ω-6 PUFA arachidonic acid (ARA) and the ω-9 monounsaturated fatty acid oleic acid. cSiO2 time-dependently elicited myriad ARA-derived eicosanoids consisting of prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acids in unprimed and LPS-primed FLAMs. This cSiO2-induced eicosanoid storm was dramatically suppressed in DHA-supplemented FLAMs which instead produced potentially pro-resolving DHA-derived docosanoids. cSiO2 elicited marked IL-1α, IL-1β, and TNF-α release after 1.5 and 4 h of cSiO2 exposure in LPS-primed FLAMs which was significantly inhibited by DHA. DHA did not affect cSiO2-triggered death induction in unprimed FLAMs but modestly enhanced it in LPS-primed FLAMs.

Discussion

FLAMs are amenable to lipidome modulation by DHA which suppresses cSiO2-triggered production of ARA-derived eicosanoids and proinflammatory cytokines. FLAMs are a potential in vitro alternative to primary AMs for investigating interventions against early toxicant-triggered inflammation in the lung.
Serum protein biomarkers for HCC risk prediction in HIV/HBV co-infected people: a clinical proteomic study using mass spectrometry
Authors: Ke Hengning , Yuan Rui , Liu Huan , Luo Mingqi , Hu Hui , Zhang Ejuan , Zhuang Ke , Yang Yong , Yang Rongrong
Published: November 2023

Background

HBV coinfection is frequent in people living with HIV (PLWH) and is the leading cause of hepatocellular carcinoma (HCC). While risk prediction methods for HCC in patients with HBV monoinfection have been proposed, suitable biomarkers for early diagnosis of HCC in PLWH remain uncommon.

Methods

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to examine serum protein alterations in HCC and non-HCC patients with HIV and HBV co-infection. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO) enrichment analysis were performed on the differentially expressed proteins (DEPs). The risk prediction model was created using five-cross-validation and LASSO regression to filter core DEPs.

Results

A total of 124 DEPs were discovered, with 95 proteins up-regulated and 29 proteins down-regulated. Extracellular matrix organization and membrane component were the DEPs that were most abundant in the categories of biological processes (BP) and cellular components (CC). Proteoglycans in cancer were one of the top three DEPs primarily enriched in the KEGG pathway, and 60.0% of DEPs were linked to various neoplasms in terms of DO enrichment. Eleven proteins, including GAPR1, PLTP, CLASP2, IGHV1-69D, IGLV5-45, A2M, VNN1, KLK11, ANPEP, DPP4 and HYI, were chosen as the core DEPs, and a nomogram was created to predict HCC risk.

Conclusion

In HIV/HBV patients with HCC, several differential proteins can be detected in plasma by mass spectrometry, which can be used as screening markers for early diagnosis and risk prediction of HCC. Monitoring protease expression differences can help in the diagnosis and prognosis of HCC.
Crosstalk: keratinocytes and immune cells in psoriasis
Authors: Kamata Masahiro , Tada Yayoi
Published: November 2023

In the past, psoriasis was considered a skin disease caused only by keratinocyte disorders. However, the efficacy of immunosuppressive drugs and biologics used to treat psoriasis proves that psoriasis is an immune-mediated disease. Indeed, a variety of immune cells are involved in the pathogenesis of psoriasis, including dendritic cells, Th17 cells, and resident memory T cells. Furthermore, keratinocytes play a role in the development of psoriasis as immune cells by secreting antibacterial peptides, chemokines, tumor necrosis factor-α, interleukin (IL)-36, and IL-23. These immune cells and skin cells interact and drive the aberrant differentiation and proliferation of keratinocytes. This crosstalk between keratinocytes and immune cells critical in the pathogenesis of psoriasis forms an inflammatory loop, resulting in the persistence or exacerbation of psoriasis plaques.
Osteofluorosis in free ranging California sea lions (Zalophus californianus)
Authors: Martinez Margaret E. , Rivard Michelle , Sykes Chelsea , Isbell Jaclyn , Grimes Sarah W. , Poppenga Robert , Duignan Pádraig J.
Published: November 2023

We report the first case series of osteofluorosis in free ranging marine mammals and documentation of baseline bone fluoride concentrations in this population; however, the exact source is not known. A stranded subadult male California sea lion, one subadult male carcass, and one partial carcass, presumably adult male, demonstrated osseous (bony) proliferations on various appendicular and axial bones. The most severe lesions were from the index case with symmetrical segmental circumferential periosteal new bone proliferation on the diaphysis of both femurs and humeri. This case, and the second case, also had significant segmental periosteal new bone proliferation on the mandibles as well as increased tooth wear with dull enamel. Total fluoride concentrations in various bones of the cases ranged from 3,700 to 9,700 ppm dw, with a mean of 5,431 ppm dw, approximately twice the concentration in adult cattle with osteofluorosis. Ribs from four control California sea lions of various ages and both sexes had an average total fluoride of 1,575 ppm dw, which is three times as high as the bone fluoride concentration of normal adult cattle, but four times lower than the mean rib fluoride concentrations in the cases. This is the first report of osteofluorosis in free ranging marine mammals and documentation of baseline bone fluoride concentrations in this population. The exact source of the excessive fluoride levels is not known as male California sea lions have a large range and varied diet.
Evaluation of sustainable development of the Bohai Sea Rim based on integrated land–sea management: a multi-system coupling and coordination study at coastal, provincial, and city level
Authors: Yan Jinling , Xue Yongjie , Wu Huilan , Li Dahai , Mohsin Muhammad
Published: November 2023

Based on the Integrated Land–Sea Management, this study established a theoretical framework for the sustainability of coastal regions by combining sustainable development with coupling coordination theory. The improved coupling coordination model was used to analyze the sustainable development of the Bohai Rim and its coastal provinces and cities from 2006 to 2020. Our implications were as follows: (1) The theoretical framework showed an S-shaped spiral trend, and the empirical results on the Bohai Rim were consistent with the trajectory conclusions. (2) The economic subsystem played a crucial role in the system’s evolution toward sustainable development. (3) The region and city models demonstrated consistent coupling and coordination development degrees. However, the consistency was not completely synchronous. Conscious eco-environmental governance activities can promote benign interactions among systems and improve this relationship. (4) The sustainable development of coastal cities is different from that of the provinces in which they are located. It merely demonstrates their relative status among all coastal cities and does not fully represent the wider region in which they are located. The findings suggest that adaptive policies, whether economic, social or environmental, can promote sustainable development. Economic stimulus policies can promote a transition of sustainable development; in the economic downturn, the adaptive environmental policy is realized by adjusting the relationship between subsystems to promote the coordination of regional systems, preparing for the next sustainable system transition. The established theoretical model and improvised mathematical method can be extended to study various coastal regions
Exploring contaminants as a disruptor of temperature-dependent sex determination in sea turtle hatchlings
Authors: Barraza Arthur D. , Young Larissa , Smith Caitlin E. , Booth David T. , Hof Christine A. Madden , Finlayson Kimberly A. , Leusch Frederic D. L. , van de Merwe Jason P.
Published: November 2023

Sea turtle nesting beaches are experiencing increased sand temperatures as climate change progresses. In one major green turtle (Chelonia mydas) nesting beach in the northern Great Barrier Reef, over 99 percent of hatchlings are female. The effects of contaminants on sea turtle hatchling sex determination are not often explored. Liver samples were collected from green turtle hatchlings that were sacrificed for histological sex determination in a parallel study on the effects of sand cooling on sex ratios, and analysed for trace elements via acid digestion and organic contaminants via in vitro cytotoxicity bioassays. Chromium, antimony, barium, and cadmium have previously been demonstrated to be estrogenic, and concentrations of these elements were used to calculate three estrogenic indexes for each clutch: predicted relative estrogenic potency (PEEQA), the sum of percent trace elements above the median of all samples (TEOM), and the sum of percent estrogenic elements above the median of all samples (EstroEOM). Excluding an outlier clutch, cadmium, antimony, and EstroEOM had significant positive relationships with sex ratio deviation. Mean clutch cobalt, lead, antimony and barium, also had a significant positive relationship with clutch sex ratio. There was no relationship between in vitro cytotoxicity of liver extracts and sex ratio, however, 9% of hatchlings had organic contaminants high enough to suggest potential cellular damage. Contaminant effects on sex determination are likely to be caused by a mixture of contaminant interactions as well as temperature. Many trace elements detected in this study have also been linked to negative health effects on hatchlings in previous studies. Considering the risks of feminization due to climate change and potential contaminant effects on hatchling health and sex determination, future studies exploring contaminant effects on sea turtle hatchling sex determination are recommended.
Classification of seabed landforms on continental and island shelves
Authors: Linklater Michelle , Morris Bradley D. , Hanslow David J.
Published: November 2023

The increasing availability and quality of high-resolution bathymetry data has led to a growing need for automated classification approaches to extract seabed features and better understand our ever-changing and complex seascapes. Here we present a new set of GIS tools designed to classify seabed landforms on continental and island shelf settings. The classification approach utilises bathymetry data and its derivatives of slope, ruggedness and bathymetric position index to delineate key components of the seabed surface. The user is guided through a series of steps to break down the seabed surface into components termed ‘surface elements’ (e.g. smooth, rugose, slope areas), which are subsequently grouped into prominent seabed features termed ‘seabed landforms’ (e.g. reefs, channels, scarps). Manual review and editing are incorporated into the workflow, striking a balance between automation and expert manual interpretation. We present the toolset using examples from the statewide marine lidar dataset from New South Wales, Australia, and explore tool settings using bathymetric data representing different data sources (multibeam and marine lidar), environmental seascapes, data resolutions (2, 5, 10 and 20 m cell size) and data preparation treatments (with and without data smoothing). The GIS toolset presented offers an effective and flexible method to extract key features from high-resolution shelf bathymetry data. Such mapping provides fundamental baseline data for vast applications within marine planning, research and management.
Research on underwater acoustic field prediction method based on physics-informed neural network
Authors: Du Libin , Wang Zhengkai , Lv Zhichao , Wang Lei , Han Dongyue
Published: November 2023

In the field of underwater acoustic field prediction, numerical simulation methods and machine learning techniques are two commonly used methods. However, the numerical simulation method requires grid division. The machine learning method can only sometimes analyze the physical significance of the model. To address these problems, this paper proposes an underwater acoustic field prediction method based on a physics-informed neural network (UAFP-PINN). Firstly, a loss function incorporating physical constraints is introduced, incorporating the Helmholtz equation that describes the characteristics of the underwater acoustic field. This loss function is a foundation for establishing the underwater acoustic field prediction model using a physics-informed neural network. The model takes the coordinate information of the acoustic field point as input and employs a fully connected deep neural network to output the predicted values of the coordinates. The predicted value is refined using the loss function with physical information, ensuring the trained model possesses clear physical significance. Finally, the proposed prediction model is analyzed and validated in two dimensions: the two-dimensional acoustic field and the three-dimensional acoustic field. The results show that the mean square error between the prediction and simulation values of the two-dimensional model is only 0.01. The proposed model can effectively predict the distribution of the two-dimensional underwater sound field, and the model can also predict the sound field in the three-dimensional space.
Development and validation of an online dynamic prognostic nomogram for incidental gallbladder adenocarcinoma patients without distant metastasis after surgery: a population-based study
Authors: Chen Jie , Han Yehong
Published: November 2023

Background

Gallbladder cancer is the most common malignant tumor of the biliary system, most of which is adenocarcinoma. Our study explored developing and validating a nomogram to predict overall and cancer-specific survival probabilities internally and externally for incidental gallbladder adenocarcinoma patients without distant metastasis after surgery.

Methods

Patients screened and filtered in the Surveillance, Epidemiology, and End Results (SEER) database, whose years of diagnosis between 2010 and 2015 were collected as a derivation cohort, while those between 2016 and 2019 were a temporal validation cohort. Overall survival (OS) and cancer-specific survival (CSS) were chosen as the primary and secondary endpoints of the retrospective study cohort. Potential clinical variables were selected for a Cox regression model analysis by performing both-direction stepwise selection to confirm the final variables. The performance of final nomograms was evaluated by Harrell’s C statistic and Brier score, with a graphical receptor operating characteristic (ROC) curve and calibration curve.

Results

Seven variables of age, race, tumor size, histologic grade, T stage, regional lymph nodes removed, and positive regional lymph nodes were finally determined for the OS nomogram; sex had also been added to the CSS nomogram. Novel dynamic nomograms were established to predict the prognosis of incidental gallbladder adenocarcinoma patients without distant metastasis after surgery. The ROC curve demonstrated good accuracy in predicting 1-, 3-, and 5-year OS and CSS in both derivation and validation cohorts. Correspondingly, the calibration curve presented perfect reliability between the death or cancer-specific death probability and observed death or cancer-specific death proportion in both derivation and validation cohorts.

Conclusion

Our study established novel dynamic nomograms based on seven and eight clinical variables separately to predict OS and CSS of incidental gallbladder adenocarcinoma patients without distant metastasis after surgery, which might assist doctors in advising and guiding therapeutic strategies for postoperative gallbladder adenocarcinoma patients in the future.
Novel STAT3 variant causing infantile-onset autoimmune disease
Authors: Pan Miao , Kurtz Justin
Published: November 2023

Signal transducer and activator of transcription 3 (STAT3) is a member of the STAT protein family implicated in the development of infantile-onset multisystem autoimmune disease. STAT3-related autoimmune disease is characterized by multiorgan autoimmunity, lymphoproliferative disease, and recurrent infections. The presentation is variable, with some patients also developing neonatal diabetes mellitus and interstitial lung disease. Gain-of-function variants in the Src homology 2 domain, leading to autophosphorylation and activation of STAT3, have been previously reported in patients with disease. Here, we report a patient with a novel missense variant, p.Glu616Ala, in STAT3 presenting with infantile-onset multisystem autoimmune disease.
Non-invasive prenatal testing: a revolutionary journey in prenatal testing
Authors: Abedalthagafi Malak , Bawazeer Shahad , Fawaz Romy I. , Heritage A. Merrihew , Alajaji Nouf M. , Faqeih Eissa
Published: November 2023

Non-invasive prenatal testing (NIPT) is a pioneering technique that has consistently advanced the field of prenatal testing to detect genetic abnormalities and conditions with the aim of decreasing the incidence and prevalence of inherited conditions. NIPT remains a method of choice for common autosomal aneuploidies, mostly trisomy 21, and several monogenic disorders. The advancements in gene sequencing techniques have expanded the panel of conditions where NIPT could be offered. However, basic research on the impact of several genetic conditions lags behind the methods of detection of these sequence aberrations, and the impact of the expansion of NIPT should be carefully considered based on its utility. With interest from commercial diagnostics and a lack of regulatory oversight, there remains a need for careful validation of the predictive values of different tests offered. NIPT comes with many challenges, including ethical and economic issues. The scientific evidence, technical feasibility, and clinical benefit of NIPT need to be carefully investigated before new tests and developments are translated into clinical practice. Moreover, the implementation of panel expansion of NIPT should accompany expert genetic counseling pre- and post-testing.
The transcriptional regulator EarA and intergenic terminator sequences modulate archaellation in Pyrococcus furiosus
Authors: Stöckl Richard , Nißl Laura , Reichelt Robert , Rachel Reinhard , Grohmann Dina , Grünberger Felix
Published: November 2023

The regulation of archaellation, the formation of archaeal-specific cell appendages called archaella, is crucial for the motility, adhesion, and survival of archaeal organisms. Although the heavily archaellated and highly motile Pyrococcus furiosus is a key model organism for understanding the production and function of archaella in Euryarchaea, the transcriptional regulation of archaellum assembly is so far unknown. Here we show that the transcription factor EarA is the master regulator of the archaellum (arl) operon transcription, which is further modulated by intergenic transcription termination signals. EarA deletion or overexpression strains demonstrate that EarA is essential for archaellation in P. furiosus and governs the degree of archaellation. Providing a single-molecule update on the transcriptional landscape of the arl operon in P. furiosus, we identify sequence motifs for EarA binding upstream of the arl operon and intergenic terminator sequences as critical elements for fine-tuning the expression of the multicistronic arl cluster. Furthermore, transcriptome re-analysis across different Thermococcales species demonstrated a heterogeneous production of major archaellins, suggesting a more diverse composition of archaella than previously recognized. Overall, our study provides novel insights into the transcriptional regulation of archaellation and highlights the essential role of EarA in Pyrococcus furiosus. These findings advance our understanding of the mechanisms governing archaellation and have implications for the functional diversity of archaella.
Immunological responses and gut microbial shifts in Phthorimaea absoluta exposed to Metarhizium anisopliae isolates under different temperature regimes
Authors: Maingi Felix Muendo , Akutse Komivi Senyo , Ajene Inusa Jacob , Omolo Kevin Mbogo , Khamis Fathiya Mbarak
Published: November 2023

The invasive tomato leaf miner, Phthorimaea absoluta, is conventionally controlled through chemical insecticides. However, the rise of insecticide resistance has necessitated sustainable and eco-friendly alternatives. Entomopathogenic fungi (EPF) have shown potential due to their ability to overcome resistance and have minimal impact on non-target organisms. Despite this potential, the precise physiological mechanisms by which EPF acts on insect pests remain poorly understood. To attain a comprehensive understanding of the complex physiological processes that drive the successful control of P. absoluta adults through EPF, we investigated the impacts of different Metarhizium anisopliae isolates (ICIPE 665, ICIPE 20, ICIPE 18) on the pest’s survival, cellular immune responses, and gut microbiota under varying temperatures. The study unveiled that ICIPE 18 caused the highest mortality rate among P. absoluta moths, while ICIPE 20 exhibited the highest significant reduction in total hemocyte counts after 10 days at 25°C. Moreover, both isolates elicited notable shifts in P. absoluta’s gut microbiota. Our findings revealed that ICIPE 18 and ICIPE 20 compromised the pest’s defense and physiological functions, demonstrating their potential as biocontrol agents against P. absoluta in tomato production systems.
Alkaloid diversity expansion of a talent fungus Penicillium raistrichii through OSMAC-based cultivation
Authors: Zhong Meijia , Kang Huihui , Liu Weizhong , Ma Liying , Liu Desheng
Published: November 2023

Introduction

Alkaloidal natural products are attractive for their broad spectrum of pharmaceutical bioactivities. In the present work, the highly productive saline soil derived fungus, Penicillium raistrichii, was subjected to the strategy of OSMAC (one strain many compounds) with changes of cultivation status. Then, the work-flow led to the expansion of the alkaloid chemical diversity and subsequently induced the accumulation of four undescribed alkaloids, named raistrimides A–D (1–4), including three β-carbolines (1–3), one 2-quinolinone (4), and one new natural product, 2-quinolinone (5), along with five known alkaloid chemicals (6–10).

Methods

A set of NMR techniques including 1H, 13C, HSQC and HMBC, along with other spectroscopic data of UV-Vis, IR and HRESIMS, were introduced to assign the plain structures of compounds 1–10. The absolute configuration of 1–3 were elucidated by means of X-ray crystallography or spectroscopic analyses on optical rotation values and experimental electronic circular dichroism (ECD) data. In addition, it was the first report on the confirmation of structures of 6, 7 and 9 by X-ray crystallography data. The micro-broth dilution method was applied to evaluate antimicrobial effect of all compounds towards Staphylococcus aureus, Escherichia coli, and Candida albicans.

Results and discussion

The results indicated compounds 1, 3 and 4 to be bioactive, which may be potential for further development of anti-antimicrobial agents. The finding in this work implied that OSMAC strategy was a powerful and effective tool for promotion of new chemical entities from P. raistrichii.
Multi-omics analysis reveals genes and metabolites involved in Bifidobacterium pseudocatenulatum biofilm formation
Authors: Zhang Ting , Liu Zongmin , Wang Hongchao , Zhang Hao , Li Haitao , Lu Wenwei , Zhu Jinlin
Published: November 2023

Bacterial biofilm is an emerging form of life that involves cell populations living embedded in a self-produced matrix of extracellular polymeric substances (EPS). Currently, little is known about the molecular mechanisms of Bifidobacterium biofilm formation. We used the Bifidobacterium biofilm fermentation system to preparation of biofilms on wheat fibers, and multi-omics analysis of both B. pseudocatenulatum biofilms and planktonic cells were performed to identify genes and metabolites involved in biofilm formation. The average diameter of wheat fibers was around 50 μm, while the diameter of particle in wheat fibers culture of B. pseudocatenulatum was over 260 μm at 22 h with 78.96% biofilm formation rate (BR), and the field emission scanning electron microscopy (FESEM) results showed that biofilm cells on the surface of wheat fibers secreted EPS. Transcriptomic analysis indicated that genes associated with stress response (groS, mntH, nth, pdtaR, pstA, pstC, radA, rbpA, whiB, ybjG), quorum sensing (dppC, livM, luxS, sapF), polysaccharide metabolic process (rfbX, galE, zwf, opcA, glgC, glgP, gtfA) may be involved in biofilm formation. In addition, 17 weighted gene co-expression network analysis (WGCNA) modules were identified and two of them positively correlated to BR. Metabolomic analysis indicated that amino acids and amides; organic acids, alcohols and esters; and sugar (trehalose-6-phosphate, uridine diphosphategalactose, uridine diphosphate-N-acetylglucosamine) were main metabolites during biofilm formation. These results indicate that stress response, quorum sensing (QS), and EPS production are essential during B. pseudocatenulatum biofilm formation.
Predicting progression of white matter hyperintensity using coronary artery calcium score based on coronary CT angiography—feasibility and accuracy
Authors: Jin Hui , Hou Jie , Qin Xue , Du Xingyue , Zheng Guangying , Meng Yu , Shu Zhenyu , Wei Yuguo , Gong Xiangyang
Published: November 2023

Objective

Coronary artery disease (CAD) usually coexists with subclinical cerebrovascular diseases given the systematic nature of atherosclerosis. In this study, our objective was to predict the progression of white matter hyperintensity (WMH) and find its risk factors in CAD patients using the coronary artery calcium (CAC) score. We also investigated the relationship between the CAC score and the WMH volume in different brain regions.

Methods

We evaluated 137 CAD patients with WMH who underwent coronary computed tomography angiography (CCTA) and two magnetic resonance imaging (MRI) scans from March 2018 to February 2023. Patients were categorized into progressive (n = 66) and nonprogressive groups (n = 71) by the change in WMH volume from the first to the second MRI. We collected demographic, clinical, and imaging data for analysis. Independent risk factors for WMH progression were identified using logistic regression. Three models predicting WMH progression were developed and assessed. Finally, patients were divided into groups based on their total CAC score (0 to <100, 100 to 400, and > 400) to compare their WMH changes in nine brain regions.

Results

Alcohol abuse, maximum pericoronary fat attenuation index (pFAI), CT-fractional flow reserve (CT-FFR), and CAC risk grade independently predicted WMH progression (p < 0.05). The logistic regression model with all four variables performed best (training: AUC = 0.878, 95% CI: 0.790, 0.938; validation: AUC = 0.845, 95% CI: 0.734, 0.953). An increased CAC risk grade came with significantly higher WMH volume in the total brain, corpus callosum, and frontal, parietal and occipital lobes (p < 0.05).

Conclusion

This study demonstrated the application of the CCTA-derived CAC score to predict WMH progression in elderly people (≥60 years) with CAD.
Differential metabolic alterations in IDH1 mutant vs. wildtype glioma cells promote epileptogenesis through distinctive mechanisms
Authors: McAfee Darrian , Moyer Mitchell , Queen Jaden , Mortazavi Armin , Boddeti Ujwal , Bachani Muzna , Zaghloul Kareem , Ksendzovsky Alexander
Published: November 2023

Glioma-related epilepsy (GRE) is a hallmark clinical presentation of gliomas with significant impacts on patient quality of life. The current standard of care for seizure management is comprised of anti-seizure medications (ASMs) and surgical resection. Seizures in glioma patients are often drug-resistant and can often recur after surgery despite total tumor resection. Therefore, current research is focused on the pro-epileptic pathological changes occurring in tumor cells and the peritumoral environment. One important contribution to seizures in GRE patients is metabolic reprogramming in tumor and surrounding cells. This is most evident by the significantly heightened seizure rate in patients with isocitrate dehydrogenase mutated (IDHmut) tumors compared to patients with IDH wildtype (IDHwt) gliomas. To gain further insight into glioma metabolism in epileptogenesis, this review compares the metabolic changes inherent to IDHmut vs. IDHwt tumors and describes the pro-epileptic effects these changes have on both the tumor cells and the peritumoral environment. Understanding alterations in glioma metabolism can help to uncover novel therapeutic interventions for seizure management in GRE patients.
Case report: Cerebral amyloid angiopathy-related inflammation in a patient with granulomatosis with polyangiitis
Authors: Seifert Rebecca M. , Rauch Michael , Klingebiel Randolf , Boese Lennart-Maximilian , Greeve Isabell , Rudwaleit Martin , Schäbitz Wolf-Rüdiger
Published: November 2023

Background

Cerebral amyloid angiopathy-related inflammation (CAA-ri) defines a subacute autoimmune encephalopathy, which is presumably caused by increased CSF concentrations of anti-Aβ autoantibodies. This autoinflammatory reaction is temporally and regionally associated with microglial activation, inflammation and radiological presence of vasogenic edema. Clinical characteristics include progressive demential development as well as headache and epileptic seizures. In the absence of histopathologic confirmation, the criteria defined by Auriel et al. allow diagnosis of probable resp. possible CAA-ri. CAA-ri shows responsiveness to immunosuppressive therapies and a possible coexistence with other autoinflammatory diseases.

Methods

We present a case report and literature review on the diagnosis of CAA-ri in a patient with known granulomatosis with polyangiitis (GPA).

Results

Initially, the presented patient showed neuropsychiatric abnormalities and latent arm paresis. Due to slight increase in CSF cell count, an initial antiviral therapy was started. MR tomography showed a pronounced frontotemporal edema as well as cerebral microhemorrhages, leading to the diagnosis of CAA-ri. Subsequent high-dose steroid treatment followed by six intravenous cyclophosphamide pulses resulted in decreased CSF cell count and regression of cerebral MRI findings.

Conclusion

The symptoms observed in the patient are consistent with previous case reports on CAA-ri. Due to previously known GPA, we considered a cerebral manifestation of this disease as a differential diagnosis. However, absence of pachymeningitis as well as granulomatous infiltrations on imaging made cerebral GPA less likely. An increased risk for Aβ-associated pathologies in systemic rheumatic diseases is discussed variously.
Human behavior in free search online shopping scenarios can be predicted from EEG activation using Hjorth parameters
Authors: Horr Ninja Katja , Mousavi Bijan , Han Keren , Li Ao , Tang Ruihong
Published: November 2023

The present work investigates whether and how decisions in real-world online shopping scenarios can be predicted based on brain activation. Potential customers were asked to search through product pages on e-commerce platforms and decide, which products to buy, while their EEG signal was recorded. Machine learning algorithms were then trained to distinguish between EEG activation when viewing products that are later bought or put into the shopping card as opposed to products that are later discarded. We find that Hjorth parameters extracted from the raw EEG can be used to predict purchase choices to a high level of accuracy. Above-chance predictions based on Hjorth parameters are achieved via different standard machine learning methods with random forest models showing the best performance of above 80% prediction accuracy in both 2-class (bought or put into card vs. not bought) and 3-class (bought vs. put into card vs. not bought) classification. While conventional EEG signal analysis commonly employs frequency domain features such as alpha or theta power and phase, Hjorth parameters use time domain signals, which can be calculated rapidly with little computational cost. Given the presented evidence that Hjorth parameters are suitable for the prediction of complex behaviors, their potential and remaining challenges for implementation in real-time applications are discussed.
Gut-brain axis: gut dysbiosis and psychiatric disorders in Alzheimer’s and Parkinson’s disease
Authors: Denman Charlotte R. , Park Sang Myun , Jo Junghyun
Published: November 2023

Gut dysbiosis and psychiatric symptoms are common early manifestations of Alzheimer’s disease (AD) and Parkinson’s disease (PD). These diseases, characterised by progressive neuron loss and pathological protein accumulation, impose debilitating effects on patients. Recently, these pathological proteins have been linked with gut dysbiosis and psychiatric disorders. The gut-brain axis links the enteric and central nervous systems, acting as a bidirectional communication pathway to influence brain function and behavior. The relationship triad between gut dysbiosis, psychiatric disorders, and neurodegeneration has been investigated in pairs; however, evidence suggests that they are all interrelated and a deeper understanding is required to unravel the nuances of neurodegenerative diseases. Therefore, this review aims to summarise the current literature on the roles of gut dysbiosis and psychiatric disorders in pathological protein-related neurodegenerative diseases. We discussed how changes in the gut environment can influence the development of psychiatric symptoms and the progression of neurodegeneration and how these features overlap in AD and PD. Moreover, research on the interplay between gut dysbiosis, psychiatric disorders, and neurodegeneration remains in its early phase. In this review, we highlighted potential therapeutic approaches aimed at mitigating gastrointestinal problems and psychiatric disorders to alter the rate of neurodegeneration. Further research to assess the molecular mechanisms underlying AD and PD pathogenesis remains crucial for developing more effective treatments and achieving earlier diagnoses. Moreover, exploring non-invasive, early preventive measures and interventions is a relatively unexplored but important avenue of research in neurodegenerative diseases.
Transsynaptic entrainment of cerebellar nuclear cells by alternating currents in a frequency dependent manner
Authors: Kang Qi , Lang Eric J. , Sahin Mesut
Published: November 2023

Transcranial alternating current stimulation (tACS) is a non-invasive neuromodulation technique that is being tested clinically for treatment of a variety of neural disorders. Animal studies investigating the underlying mechanisms of tACS are scarce, and nearly absent in the cerebellum. In the present study, we applied 10–400 Hz alternating currents (AC) to the cerebellar cortex in ketamine/xylazine anesthetized rats. The spiking activity of cerebellar nuclear (CN) cells was transsynaptically entrained to the frequency of AC stimulation in an intensity and frequency-dependent manner. Interestingly, there was a tuning curve for modulation where the frequencies in the midrange (100 and 150 Hz) were more effective, although the stimulation frequency for maximum modulation differed for each CN cell with slight dependence on the stimulation amplitude. CN spikes were entrained with latencies of a few milliseconds with respect to the AC stimulation cycle. These short latencies and that the transsynaptic modulation of the CN cells can occur at such high frequencies strongly suggests that PC simple spike synchrony at millisecond time scales is the underlying mechanism for CN cell entrainment. These results show that subthreshold AC stimulation can induce such PC spike synchrony without resorting to supra-threshold pulse stimulation for precise timing. Transsynaptic entrainment of deep CN cells via cortical stimulation could help keep stimulation currents within safety limits in tACS applications, allowing development of tACS as an alternative treatment to deep cerebellar stimulation. Our results also provide a possible explanation for human trials of cerebellar stimulation where the functional impacts of tACS were frequency dependent.