bluuebunny/crossref_metadata_2025 huggingface dataset:
An innovative gene expression modulating strategy by converting nucleic acids into HNC therapeutics using carrier-free nanoparticles
Authors: Liu Heyuan , Huang Yinong , Li Zongfang , Han Suxia , Liu Tianya , Zhao Qian
Published: January 2024

Background

Cell fate and microenvironmental changes resulting from aberrant expression of specific proteins in tumors are one of the major causes of inadequate anti-tumor immune response and poor prognosis in head and neck cancer (HNC). Eukaryotic initiation factor 3C (eIF3c) has emerged as a promising therapeutic target for HNC due to its ability to regulate protein expression levels in tumor cells, but its drug development is difficult to achieve by targeting traditional protein-protein interactions. siRNA has emerged as a highly promising modality for drug development targeting eIF3c, while its application is hindered by challenges pertaining to inadequate stability and insufficient concentration specifically within tumor sites.

Method

We employed a method to convert flexible siRNAs into stable and biologically active infinite Auric-sulfhydryl coordination supramolecular siRNAs (IacsRNAs). Through coordinated self-assembly, we successfully transformed eIF3C siRNAs into the carrier-free HNC nanotherapeutic agent Iacs-eif3c-RNA. The efficacy of this agent was evaluated in vivo using HNC xenograft models, demonstrating promising antitumor effects.

Results

Iacs-eif3c-RNA demonstrated the ability to overcome the pharmacological obstacle associated with targeting eIF3C, resulting in a significant reduction in eIF3C expression within tumor tissues, as well as effective tumor cell proliferating suppression and apoptosis promotion. In comparison to monotherapy utilizing the chemotherapeutic agent cisplatin, Iacs-eif3c-RNA exhibited superior anti-tumor efficacy and favorable biosafety.

Conclusion

The utilization of Iacs-eif3c-RNA as a carrier-free nanotherapeutic agent presents a promising and innovative approach for addressing HNC treating challenges. Moreover, this strategy demonstrates potential for the translation of therapeutic siRNAs into clinical drugs, extending its applicability to the treatment of other cancers and various diseases.
Observations of biennial reproduction in Caribbean reef sharks ‘Carcharhinus perezi’
Authors: Campbell Beckah A. , Shipley Oliver N. , Jones Taeler R. , Gallagher Austin J. , Sulikowski James A.
Published: January 2024

Effective management and conservation of threatened species biodiversity requires knowledge of reproductive biology, such as cyclicity, mode, and age at maturity. We combined reproductive endocrinology and in-situ ultrasonography to examine reproductive characteristics of female Caribbean reef sharks Carcharhinus perezi, a widely distributed, threatened marine predator which remains largely understudied throughout its range. Unique to this study was the opportunity to conduct longitudinal assessments of two individuals, recaptured across multiple seasons during sampling in The Bahamas. Within-individual, paired hormone analyses and in-situ ultrasounds of female sharks that were confirmed as either pregnant, non-pregnant, or reproductively active, suggest a biennial reproductive cycle for Carcharhinus perezi. This unique opportunity to assess the reproductive biology of the same individuals over time underscore the importance of repeated sampling for elucidating population reproductive cyclicity of highly mobile sharks in the wild.
Blue carbon in sediment from Sanggou Bay: composition, burial flux and its response to human activities
Authors: Yang Shu , Yang Qian , Song Xianli , Zhou Wei , Liu Jihua , Qi Xiandong , Chen Junfeng , Huang Jun , Li Bin , Sun Yao
Published: January 2024

Marine primary production and terrestrial input are the main sources of buried carbon in sediments of marginal seas. Only marine-source carbon buried in sediments, fixed and stored by marine ecosystems, belongs to “blue carbon” and reflects marine ecosystems’ carbon sink function. The pattern of buried blue carbon in sediments, its flux, and its relationship with environmental changes remain unclear. The study aimed to investigate the composition of blue carbon in the sediments of Sanggou Bay, a special type of marginal sea. The analysis of sediment carbon sources was conducted through the C/N ratio and microscopic examination. The study also examined the long-term changes in the blue carbon burial fluxes. Results showed Blue carbon, which is sea-sourced carbon, accounted for about 23% of the total carbon content and its concentration ranged from 0.17% to 0.51%, with an average of about 0.25% ± 0.10%. The content of organic blue carbon in this sea area ranges from 0.09% to 0.26%, with an average of around 0.18% ± 0.04%. It constitutes approximately 72% of the buried blue carbon in the sediment, making it the primary component of buried blue carbon. Meanwhile, the content of inorganic blue carbon ranges from 0.01% to 0.32%. Over the past 70 years, the burial fluxes of sedimentary blue carbon, organic blue carbon and inorganic blue carbon in the Sanggou Bay are about 0.54 ± 0.22 mmol/(cm2a), 0.38 ± 0.07 mmol/(cm2a) and 0.17 ± 0.22 mmol/(cm2a), respectively; their long-term changes have been significantly affected by human aquaculture activities. Large-scale raft-rack aquaculture activities have caused a reduction in water flow velocity and an increase in the deposition of particulate organic matter, which in turn has led to the burial of organic blue carbon in the sediment. Additionally, the competition between aquaculture products and small calcareous organisms, such as mussels, foraminifera, may have inhibited the growth of small calcareous organisms. We suggest this has resulted in reduced burial fluxes of inorganic blue carbon and a decrease in its proportion among total blue carbon in the sea area. Our findings imply that aquaculture activities in Sanggou Bay had a negative impact on the burial of blue carbon in the sediments.
Profiling of plasma extracellular vesicles identifies proteins that strongly associate with patient’s global assessment of disease activity in rheumatoid arthritis
Authors: Arntz Onno J. , Thurlings Rogier M. , Blaney Davidson Esmeralda N. , Jansen Pascal W. T. C. , Vermeulen Michiel , Koenders Marije I. , van der Kraan Peter M. , van de Loo Fons A. J.
Published: January 2024

Background

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial inflammation and cartilage/bone damage. Intercellular messengers such as IL-1 and TNF play a crucial role in the pathophysiology of RA but have limited diagnostic and prognostic values. Therefore, we assessed whether the protein content of the recently discovered extracellular vesicles (EVs), which have gained attention in the pathogenesis of RA, correlates with disease activity parameters in RA patients.

Methods

We identified and quantified proteins in plasma-derived EVs (pEVs), isolated by size exclusion chromatography from 17 RA patients by mass spectrophotometry (MS). Quantified protein levels were correlated with laboratory and clinical parameters and the patient’s own global assessment of their disease activity (PGA-VAS). In a second MS run, the pEV proteins of nine other RA patients were quantified and compared to those from nine healthy controls (HC).

Results

No differences were observed in the concentration, size, and protein content of pEVs from RA patients. Proteomics revealed >95% overlapping proteins in RA-pEVs, compared to HC-pEVs (data are available via ProteomeXchange with identifier PXD046058). Remarkably, in both runs, the level of far more RA-pEV proteins correlated positively to PGA-VAS than to either clinical or laboratory parameters. Interestingly, all observed PGA-VAS positively correlated RA-pEV proteins were associated with the actin-cytoskeleton linker proteins, ezrin, and moesin.

Conclusion

Our observation suggests that PGA-VAS (loss of vitality) may have a different underlying pathological mechanism in RA, possibly related to enhanced muscle actin-cytoskeleton activity. Furthermore, our study contributes to the growing awareness and evidence that pEVs contain valuable biomarkers for diseases, with added value for RA patients.
Resurgence of influenza A after SARS-CoV-2 omicron wave and comparative analysis of hospitalized children with COVID-19 and influenza A virus infection
Authors: Lin Fen , Chen Man-Tong , Zhang Lin , Wu Min , Xie He , Guan Ze-Xiang , Yang Zhe , Cai Zhong-Xian , Wen Jin-Zhou , Yang Li-Ye
Published: January 2024

Context

The highly infectious Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused large-scale transmission from Dec 2022 to Feb 2023 in China. After this event, a remarkable surge of influenza A (Flu A) occurred from March to May 2023, especially in pediatric patients.

Objectives

This study aimed to investigate the differences between pediatric patients infected with COVID-19 Omicron and Flu A virus.

Methods

A total of 1,063 hospitalized children who admitted into two tertiary general hospital of Guangdong province of China were included. Medical records were compared retrospectively in these patients during the pandemic periods of SARS-CoV-2 omicron and Flu A.

Results

A total of 592 Patients with Flu A were mostly preschool and school-aged (>3y, 76.0%), they showed higher ratio of high fever (≥39°C), cough, rhinorrhea, and vomiting than patients with SARS-CoV-2 omicron. Most of the 471 Omicron patients were young children (0–3y, 74.5%) and had more poor appetite and dyspnea symptom. Benign acute children myositis (BACM) was only observed in patients with Flu A, and a significant male predominance. Multisystem inflammatory syndrome in children (MIS-C) was only found in patients with SARS-CoV-2 Omicron. Compared to the SARS-CoV-2 Omicron group, for both age groups (0–3 years and > 3 years), the Flu A group showed significantly reduced lymphocyte (Lym) counts (P < 0.001), and elevated levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatinine kinase-MB (CK-MB) in laboratory indexes (all P < 0.001). Additionally, it was found that more children hospitalized with COVID-19 had increased C-reactive protein (CRP) levels compared to those with Flu A.

Conclusion

Influenza A infections have notably surged in children, coinciding with the relaxation of COVID-19 related social restrictions. During the epidemic periods of Omicron and Flu A virus infection, different clinical and laboratory characteristics were observed in hospitalized children.
Chlormethine gel in combination with other therapies for treatment of mycosis fungoides: a review with patient cases
Authors: Ardigò Marco , Nikbakht Neda , Teoli Miriam , Gleason Laura , Crisan Liliana , Querfeld Christiane
Published: January 2024

Topical chlormethine gel has been approved as monotherapy for treatment of adult patients with mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma. In clinical practice, chlormethine gel is often combined with other skin-directed or systemic therapies to optimize response and target recalcitrant lesions. Positive outcomes with combination regimens using chlormethine gel and topical corticosteroids, phototherapy, retinoids, methotrexate, or interferon-α have been reported in literature. However, there are no treatment guidelines on the use of combination regimens with chlormethine gel. To provide real-world evidence and guidance on the use of chlormethine gel combination regimens, several cases of patients treated with chlormethine gel combined with phototherapy (n = 5), retinoids (n = 16), or mogamulizumab (n = 3) are presented. These different combination regimens showed promising results. Most patients had a complete or partial response following treatment and the combinations were well-tolerated over extended treatment periods. Patients receiving chlormethine gel with retinoids had long-term periods of remission, even after treatment discontinuation. Durations of response of up to 3 years were observed in these patients. This long-term disease control may be the result of disease-modifying effects of chlormethine. Previous studies have shown targeted reductions in malignant T-cell clones in patients treated with chlormethine gel as well as improved post-treatment responses. Further research is needed to determine the effectiveness and safety of combination treatment regimens with chlormethine gel and to assess the impact chlormethine gel has on disease control.
Sinus metastasis of lung adenocarcinoma: a case report
Authors: Xu Mingyuan , Sun Qi , Lv Xin , Chen Fangjun , Su Shu , Wang Lifeng
Published: January 2024

Metastatic carcinoma of the paranasal sinuses in lung cancer is an extremely uncommon condition. We report here a 57-year-old female patient with epidermal growth factor receptor (EGFR)-positive stage IV non-small cell lung cancer (NSCLC) with multiple bone metastases. After resistance to second- and third-generation EGFR-tyrosine kinase inhibitors (TKIs), the patient presented with headache accompanied by progressively enlarging lesions of the nasal cavity on CT scan. Further endoscopic sinus neoplasmectomy confirmed sinus metastasis of lung adenocarcinoma. Although subsequent chemotherapy and immunotherapy were both administered, the disease continued to progress, and the patient passed away 21 months after diagnosis. Combined with real-time dynamic next-generation sequencing (NGS) during the different generations of EGFR-TKI treatments and dynamic tumour microenvironment analysis, we discussed the clinical manifestations of sinus metastasis and the molecular biology and tumour immune microenvironment changes after resistance to the second-and third- generation of EGFR-TKI therapy.
Investigation of Campylobacter concisus gastric epithelial pathogenicity using AGS cells
Authors: Luk Christopher Yau Man , Lee Seul A. , Naidovski Nicholas , Liu Fang , Tay Alfred Chin Yen , Wang Liang , Riordan Stephen , Zhang Li
Published: January 2024

Campylobacter concisus is an oral bacterium. Recent studies suggest that C. concisus may be involved in human gastric diseases. The mechanisms, however, by which C. concisus causes human gastric diseases have not been investigated. Here we examined the gastric epithelial pathogenicity of C. concisus using a cell culture model. Six C. concisus strains and the human gastric epithelial cell line AGS cells were used. IL-8 produced by AGS cells after incubation with C. concisus was measured using enzyme-linked immunosorbent assay (ELISA), and AGS cell apoptosis was determined by caspase 3/7 activities. The effects of C. concisus on actin arrangement in AGS cells was determined using fluorescence staining. The effects of C. concisus on global gene expression in AGS cells was determined by transcriptomic analysis and quantitative real-time PCR (qRT-PCR). The role of the upregulated CYP1A1 gene in gastric cancer survival was assessed using the Kaplan-Meier method. C. concisus induced production of IL-8 by AGS cells with strain variation. Significantly increased caspase 3/7 activities were observed in AGS cells incubated with C. concisus strains when compared to AGS cells without bacteria. C. concisus induced actin re-arrangement in AGS cells. C. concisus upregulated 30 genes in AGS cells and the upregulation of CYP1A1 gene was confirmed by qRT-PCR. The Kaplan-Meier analysis showed that upregulation of CYP1A1 gene is associated with worse survival in gastric cancer patients. Our findings suggest that C. concisus may play a role in gastric inflammation and the progression of gastric cancer. Further investigation in clinical studies is warranted.
Identification of taxonomic changes in the fecal bacteriome associated with colorectal polyps and cancer: potential biomarkers for early diagnosis
Authors: Grion Beatriz Alessandra Rudi , Fonseca Paula Luize Camargos , Kato Rodrigo Bentes , García Glen Jasper Yupanqui , Vaz Aline Bruna Martins , Jiménez Beatriz Nafría , Dambolenea Ainhoa Lapitz , Garcia-Etxebarria Koldo , Brenig Bertram , Azevedo Vasco , Bujanda Luis , Banales Jesus M. , Góes-Neto Aristóteles
Published: January 2024

Colorectal cancer (CRC) commonly arises in individuals with premalignant colon lesions known as polyps, with both conditions being influenced by gut microbiota. Host-related factors and inherent characteristics of polyps and tumors may contribute to microbiome variability, potentially acting as confounding factors in the discovery of taxonomic biomarkers for both conditions. In this study we employed shotgun metagenomics to analyze the taxonomic diversity of bacteria present in fecal samples of 90 clinical subjects (comprising 30 CRC patients, 30 with polyps and 30 controls). Our findings revealed a decrease in taxonomic richness among individuals with polyps and CRC, with significant dissimilarities observed among the study groups. We identified significant alterations in the abundance of specific taxa associated with polyps (Streptococcaceae, Lachnoclostridium, and Ralstonia) and CRC (Lactobacillales, Clostridiaceae, Desulfovibrio, SFB, Ruminococcus, and Faecalibacterium). Clostridiaceae exhibited significantly lower abundance in the early stages of CRC. Additionally, our study revealed a positive co-occurrence among underrepresented genera in CRC, while demonstrating a negative co-occurrence between Faecalibacterium and Desulfovibrio, suggesting potential antagonistic relationships. Moreover, we observed variations in taxonomic richness and/or abundance within the polyp and CRC bacteriome linked to polyp size, tumor stage, dyslipidemia, diabetes with metformin use, sex, age, and family history of CRC. These findings provide potential new biomarkers to enhance early CRC diagnosis while also demonstrating how intrinsic host factors contribute to establishing a heterogeneous microbiome in patients with CRC and polyps.
Key enzymes involved in the utilization of fatty acids by Saccharomyces cerevisiae: a review
Authors: Wang Zhaoyun , Su Chunli , Zhang Yisang , Shangguan Sifan , Wang Ruiming , Su Jing
Published: January 2024

Saccharomyces cerevisiae is a eukaryotic organism with a clear genetic background and mature gene operating system; in addition, it exhibits environmental tolerance. Therefore, S. cerevisiae is one of the most commonly used organisms for the synthesis of biological chemicals. The investigation of fatty acid catabolism in S. cerevisiae is crucial for the synthesis and accumulation of fatty acids and their derivatives, with β-oxidation being the predominant pathway responsible for fatty acid metabolism in this organism, occurring primarily within peroxisomes. The latest research has revealed distinct variations in β-oxidation among different fatty acids, primarily attributed to substrate preferences and disparities in the metabolic regulation of key enzymes involved in the S. cerevisiae fatty acid metabolic pathway. The synthesis of lipids, on the other hand, represents another crucial metabolic pathway for fatty acids. The present paper provides a comprehensive review of recent research on the key factors influencing the efficiency of fatty acid utilization, encompassing β-oxidation and lipid synthesis pathways. Additionally, we discuss various approaches for modifying β-oxidation to enhance the synthesis of fatty acids and their derivatives in S. cerevisiae, aiming to offer theoretical support and serve as a valuable reference for future studies.
Genomic profiles of four novel cyanobacteria MAGs from Lake Vanda, Antarctica: insights into photosynthesis, cold tolerance, and the circadian clock
Authors: Lumian Jessica , Grettenberger Christen , Jungblut Anne D. , Mackey Tyler J. , Hawes Ian , Alatorre-Acevedo Eduardo , Sumner Dawn Y.
Published: January 2024

Cyanobacteria in polar environments face environmental challenges, including cold temperatures and extreme light seasonality with small diurnal variation, which has implications for polar circadian clocks. However, polar cyanobacteria remain underrepresented in available genomic data, and there are limited opportunities to study their genetic adaptations to these challenges. This paper presents four new Antarctic cyanobacteria metagenome-assembled genomes (MAGs) from microbial mats in Lake Vanda in the McMurdo Dry Valleys in Antarctica. The four MAGs were classified as Leptolyngbya sp. BulkMat.35, Pseudanabaenaceae cyanobacterium MP8IB2.15, Microcoleus sp. MP8IB2.171, and Leptolyngbyaceae cyanobacterium MP9P1.79. The MAGs contain 2.76 Mbp – 6.07 Mbp, and the bin completion ranges from 74.2–92.57%. Furthermore, the four cyanobacteria MAGs have average nucleotide identities (ANIs) under 90% with each other and under 77% with six existing polar cyanobacteria MAGs and genomes. This suggests that they are novel cyanobacteria and demonstrates that polar cyanobacteria genomes are underrepresented in reference databases and there is continued need for genome sequencing of polar cyanobacteria. Analyses of the four novel and six existing polar cyanobacteria MAGs and genomes demonstrate they have genes coding for various cold tolerance mechanisms and most standard circadian rhythm genes with the Leptolyngbya sp. BulkMat.35 and Leptolyngbyaceae cyanobacterium MP9P1.79 contained kaiB3, a divergent homolog of kaiB.
Fecal and oral microbiome analysis of snakes from China reveals a novel natural emerging disease reservoir
Authors: Hu Xiaoliang , Yang Lu , Zhang Yue , Yang Manman , Li Jiayi , Fan Yuping , Guo Peng , Tian Zhige
Published: January 2024

Introduction

The gastrointestinal tract and oral cavity of animal species harbor complex microbial communities, the composition of which is indicative of the behavior, co-evolution, diet, and immune system of the host.

Methods

This study investigated the microbial composition in snakes from varying altitudinal ranges by assessing the fecal and oral bacterial communities in Protobothrops mucrosquamatus, Elaphe dione, and Gloydius angusticeps from Sichuan Province, China, using metagenomic sequencing.

Results and discussion

It was revealed that Bacteroidetes, Proteobacteria, Firmicutes, and Fusobacteria were the core microbial phyla in fecal samples across all three species, while Proteobacteria, Bacteroidetes, Actinobacteria, and Firmicutes were the core microbial phyla in oral samples across all three species. Notably, the dominance of Armatimonadetes was documented for the first time in the feces of all three species. Comparative analysis of the microbiomes of the three species indicated distinct microbiological profiles between snakes living at low- and high-altitude regions. Furthermore, 12 to 17 and 22 to 31 bacterial pathogens were detected in the oral and fecal samples, respectively, suggesting that snakes may serve as a novel reservoir for emerging diseases. Overall, this study provides a comparative analysis of the fecal and oral microbiomes in three snake species. Future investigations are anticipated to further elucidate the influence of age, genetics, behavior, diet, environment, ecology, and evolution on the gut and oral microbial communities of snakes.
Leveraging machine learning for taxonomic classification of emerging astroviruses
Authors: Alipour Fatemeh , Holmes Connor , Lu Yang Young , Hill Kathleen A. , Kari Lila
Published: January 2024

Astroviruses are a family of genetically diverse viruses associated with disease in humans and birds with significant health effects and economic burdens. Astrovirus taxonomic classification includes two genera, Avastrovirus and Mamastrovirus. However, with next-generation sequencing, broader interspecies transmission has been observed necessitating a reexamination of the current host-based taxonomic classification approach. In this study, a novel taxonomic classification method is presented for emergent and as yet unclassified astroviruses, based on whole genome sequence k-mer composition in addition to host information. An optional component responsible for identifying recombinant sequences was added to the method’s pipeline, to counteract the impact of genetic recombination on viral classification. The proposed three-pronged classification method consists of a supervised machine learning method, an unsupervised machine learning method, and the consideration of host species. Using this three-pronged approach, we propose genus labels for 191 as yet unclassified astrovirus genomes. Genus labels are also suggested for an additional eight as yet unclassified astrovirus genomes for which incompatibility was observed with the host species, suggesting cross-species infection. Lastly, our machine learning-based approach augmented by a principal component analysis (PCA) analysis provides evidence supporting the hypothesis of the existence of human astrovirus (HAstV) subgenus of the genus Mamastrovirus, and a goose astrovirus (GoAstV) subgenus of the genus Avastrovirus. Overall, this multipronged machine learning approach provides a fast, reliable, and scalable prediction method of taxonomic labels, able to keep pace with emerging viruses and the exponential increase in the output of modern genome sequencing technologies.
Enduring sex-dependent implications of pubertal stress on the gut-brain axis and mental health
Authors: Dworsky-Fried Michaela , Tchida Jessica A. , Krnel Rebecca , Ismail Nafissa
Published: January 2024

The gut-brain axis (GBA) is a network responsible for the bidirectional communication between the central nervous system and the gastrointestinal tract. This multifaceted system is comprised of a complex microbiota, which may be altered by both intrinsic and extrinsic factors. During critical periods of development, these intrinsic and extrinsic factors can cause long-lasting sex-dependent changes in the GBA, which can affect brain structure and function. However, there is limited understanding of how the GBA is altered by stress and how it may be linked to the onset of mental illness during puberty. This article reviews current literature on the relationships between the GBA, the effects of stress during puberty, and the implications for mental health.
Time-delay signature suppression in delayed-feedback semiconductor lasers as a paradigm for feedback control in complex physiological networks
Authors: Hong Yanhua , Zhong Zhuqiang , Shore K. Alan
Published: January 2024

Physiological networks, as observed in the human organism, involve multi-component systems with feedback loops that contribute to self-regulation. Physiological phenomena accompanied by time-delay effects may lead to oscillatory and even chaotic dynamics in their behaviors. Analogous dynamics are found in semiconductor lasers subjected to delayed optical feedback, where the dynamics typically include a time-delay signature. In many applications of semiconductor lasers, the suppression of the time-delay signature is essential, and hence several approaches have been adopted for that purpose. In this paper, experimental results are presented wherein photonic filters utilized in order to suppress time-delay signatures in semiconductor lasers subjected to delayed optical feedback effects. Two types of semiconductor lasers are used: discrete-mode semiconductor lasers and vertical-cavity surface-emitting lasers (VCSELs). It is shown that with the use of photonic filters, a complete suppression of the time-delay signature may be affected in discrete-mode semiconductor lasers, but a remnant of the signature persists in VCSELs. These results contribute to the broader understanding of time-delay effects in complex systems. The exploration of photonic filters as a means to suppress time-delay signatures opens avenues for potential applications in diverse fields, extending the interdisciplinary nature of this study.
Bi-sinusoidal light stimulation reveals an enhanced response power and reduced phase coherence at the visual cortex in migraine
Authors: van den Hoek Thomas C. , Perenboom Matthijs J. L. , Terwindt Gisela M. , Tolner Else A. , van de Ruit Mark
Published: January 2024

Introduction

Migraine is associated with enhanced visual sensitivity during and outside attacks. Processing of visual information is a highly non-linear process involving complex interactions across (sub)cortical networks. In this exploratory study, we combined electroencephalography with bi-sinusoidal light stimulation to assess non-linear features of visual processing in participants with migraine.

Methods

Twenty participants with migraine (10 with aura, 10 without aura) and ten non-headache controls were measured (outside attacks). Participants received bi-sinusoidal 13 + 23 Hz red light visual stimulation. Electroencephalography spectral power and multi-spectral phase coherence were compared between groups at the driving stimulation frequencies together with multiples and combinations of these frequencies (harmonic and intermodulation frequencies) caused by non-linearities.

Results

Only at the driving frequency of 13 Hz higher spectral power was found in migraine with aura participants compared with those with migraine without aura and controls. Differences in phase coherence were present for 2nd, 4th, and 5th-order non-linearities in those with migraine (migraine with and without aura) compared with controls. Bi-sinusoidal light stimulation revealed evident non-linearities in the brain’s electroencephalography response up to the 5th order with reduced phase coherence for higher order interactions in interictal participants with migraine.

Discussion

Insight into interictal non-linear visual processing may help understand brain dynamics underlying migraine attack susceptibility. Future research is needed to determine the clinical value of the results.
Mental states in caregivers toward people with Alzheimer’s disease at different stages
Authors: Li Bei , Jin Haiqiang , Yan Guiying , Zhang Chen , Chen Siwei , Wang Yue , Wang Ting , Wan Qiaoqin , Wei Zhimin , Sun Yongan
Published: January 2024

Introduction

Caring for people with Alzheimer’s disease (AD) is burdensome, especially when family members act as caregivers. This multicenter survey first aimed to investigate caregivers’ mental states as well as its influencing factors in caring for people with different severities of AD in China.

Methods

People with AD and their caregivers from 30 provincial regions in mainland China were enrolled from October 2020 to December 2020 to be surveyed for caregivers’ mental states and living conditions, as well as caregivers’ attitudes toward treatment and caring. Logistic regression was used to explore the factors that influence the positive and negative states of caregivers who care for people with different stages of AD.

Results

A total of 1,966 valid questionnaires were analyzed (mild AD: 795, moderate AD: 521, severe AD: 650). A total of 73.6% of caregivers maintained normal states (mild group: 71.9%, moderate group: 73.9%, severe group: 75.2%; X2 = 2.023, p = 0.364), and the proportions of caregivers with positive and negative states were 26.3% (mild group: 38.4%, moderate group: 24.6%, severe group: 13.1%; X2 = 119.000, p < 0.001) and 36.5% (mild group: 25.2%, moderate group: 36.9%, severe group: 50.2%; X2 = 96.417, p < 0.001), respectively. The major factors that both influenced caregivers’ positive and negative states were the severity of AD, perceived efficacy of treatment, safety issues after AD dementia diagnosis and perceived social support (p < 0.005), while neuropsychiatric symptoms causing stress in caregivers (p < 0.001) only affected the negative states of caregivers. The results of further analysis according to disease severity showed that safety issues after AD dementia diagnosis (p < 0.005) only made significant differences in the mild-to-moderate group.

Conclusion

To reduce negative states and promote positive states among caregivers, flexible and sensitive caregiving support could be built on caregivers’ demands in caring for people with different stages of AD. The support of emotion, social functioning and nursing skills is one of the significant ways for health workers to enhance caregivers’ competency.
Hippocampal ΔFosB expression is associated with cognitive impairment in a subgroup of patients with childhood epilepsies
Authors: Fu Chia-Hsuan , You Jason C. , Mohila Carrie , Rissman Robert A. , Yoshor Daniel , Viaene Angela N. , Chin Jeannie
Published: January 2024

Epilepsy is a chronic neurological disorder characterized by recurrent seizures, and is often comorbid with other neurological and neurodegenerative diseases, such as Alzheimer's disease (AD). Patients with recurrent seizures often present with cognitive impairment. However, it is unclear how seizures, even when infrequent, produce long-lasting deficits in cognition. One mechanism may be seizure-induced expression of ΔFosB, a long-lived transcription factor that persistently regulates expression of plasticity-related genes and drives cognitive dysfunction. We previously found that, compared with cognitively-intact subjects, the activity-dependent expression of ΔFosB in the hippocampal dentate gyrus (DG) was increased in individuals with mild cognitive impairment (MCI) and in individuals with AD. In MCI patients, higher ΔFosB expression corresponded to lower Mini-Mental State Examination scores. Surgically resected DG tissue from patients with temporal lobe epilepsy also showed robust ΔFosB expression; however, it is unclear whether ΔFosB expression also corresponds to cognitive dysfunction in non-AD-related epilepsy. To test whether DG ΔFosB expression is indicative of cognitive impairment in epilepsies with different etiologies, we assessed ΔFosB expression in surgically-resected hippocampal tissue from 33 patients with childhood epilepsies who had undergone Wechsler Intelligence Scale for Children (WISC) testing prior to surgery. We found that ΔFosB expression is inversely correlated with Full-Scale Intelligence Quotient (FSIQ) in patients with mild to severe intellectual disability (FSIQ < 85). Our data indicate that ΔFosB expression corresponds to cognitive impairment in epilepsies with different etiologies, supporting the hypothesis that ΔFosB may epigenetically regulate gene expression and impair cognition across a wide range of epilepsy syndromes.
Gunshot-related nerve injuries of the upper extremities: clinical, electromyographic, and ultrasound features in 22 patients
Authors: Shields Lisa B. E. , Iyer Vasudeva G. , Zhang Yi Ping , Shields Christopher B.
Published: January 2024

Objectives

Gunshot wounds of the upper extremities may cause permanent neurovascular injuries, leading to significant morbidity, chronic pain, functional loss, and disability. While there are many reports on the incidence and intraoperative findings in gunshot-related nerve injuries (GSNI) sustained during wars, there is a paucity of details pertaining to GSNI of the upper extremities in civilians. The goal of this paper is to provide the clinical, electrodiagnostic (EDX), and ultrasound (US) findings in 22 patients with GSNI of the upper extremities.

Methods

This is a retrospective study of patients referred for EDX studies to evaluate the presence of nerve injury after sustaining GSWs to the upper extremities. All patients underwent EDX studies, and 16 patients had US evaluations. Numerous metrics were documented including presenting symptoms, neurological abnormalities, EDX findings, and US features.

Results

The forearm was the most frequent location of injury (8 [36%] patients). The ulnar nerve was the most common injured nerve (10 [45%] patients), followed by the brachial plexus (7 [32%] patients). All patients complained of muscle weakness; the most frequently affected muscles were the first dorsal interosseous (FDI) (14 [64%] patients) and abductor pollicis brevis (APB) (11 [50%] patients). Muscle atrophy was noted in 19 (86%) patients, 15 of whom had atrophy of the FDI. Axonotmesis was the type of nerve injury in all patients based on EDX studies. Of the 16 patients who underwent US studies, a neuroma in continuity was noted in 4 (25%) patients and neurotmesis in 1 (6.2%) patient. Eleven (69%) patients had enlarged and/or hypoechoic nerves.

Conclusions

Axonotmesis of the ulnar nerve was the most common finding among patients sustaining gunshot injuries to the upper extremities. EDX and US studies provide valuable insight into the underlying pathophysiology and guidance for management of patients with GSNI of the upper extremities.
Elevation of inositol pyrophosphate IP7 in the mammalian spinal cord of amyotrophic lateral sclerosis
Authors: Ito Masatoshi , Fujii Natsuko , Kohara Saori , Tanaka Masayuki , Takao Masaki , Mihara Ban , Saito Yuko , Mizuma Atsushi , Nakayama Taira , Netsu Shizuka , Suzuki Naoto , Kakita Akiyoshi , Nagata Eiichiro
Published: January 2024

Background

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive impairment of spinal motor neurons. Continuous research endeavor is underway to fully understand the molecular mechanisms associating with this disorder. Although several studies have implied the involvement of inositol pyrophosphate IP7 in ALS, there is no direct experimental evidence proving this notion. In this study, we analyzed inositol pyrophosphate IP7 and its precursor IP6 in the mouse and human ALS biological samples to directly assess whether IP7 level and/or its metabolism are altered in ALS disease state.

Methods

We used a liquid chromatography-mass spectrometry (LC-MS) protocol originally-designed for mammalian IP6 and IP7 analysis. We measured the abundance of these molecules in the central nervous system (CNS) of ALS mouse model SOD1(G93A) transgenic (TG) mice as well as postmortem spinal cord of ALS patients. Cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) from ALS patients were also analyzed to assess if IP7 status in these biofluids is associated with ALS disease state.

Results

SOD1(G93A) TG mice showed significant increase of IP7 level in the spinal cord compared with control mice at the late stage of disease progression, while its level in cerebrum and cerebellum remains constant. We also observed significantly elevated IP7 level and its product-to-precursor ratio (IP7/IP6) in the postmortem spinal cord of ALS patients, suggesting enhanced enzymatic activity of IP7-synthesizing kinases in the human ALS spinal cord. In contrast, human CSF did not contain detectable level of IP6 and IP7, and neither the IP7 level nor the IP7/IP6 ratio in human PBMCs differentiated ALS patients from age-matched healthy individuals.

Conclusion

By directly analyzing IP7 in the CNS of ALS mice and humans, the findings of this study provide direct evidence that IP7 level and/or the enzymatic activity of IP7-generating kinases IP6Ks are elevated in ALS spinal cord. On the other hand, this study also showed that IP7 is not suitable for biofluid-based ALS diagnosis. Further investigation is required to elucidate a role of IP7 in ALS pathology and utilize IP7 metabolism on the diagnostic application of ALS.
Targeting TRP channels: recent advances in structure, ligand binding, and molecular mechanisms
Authors: Huang Jian , Korsunsky Aron , Yazdani Mahdieh , Chen Jianhan
Published: January 2024

Transient receptor potential (TRP) channels are a large and diverse family of transmembrane ion channels that are widely expressed, have important physiological roles, and are associated with many human diseases. These proteins are actively pursued as promising drug targets, benefitting greatly from advances in structural and mechanistic studies of TRP channels. At the same time, the complex, polymodal activation and regulation of TRP channels have presented formidable challenges. In this short review, we summarize recent progresses toward understanding the structural basis of TRP channel function, as well as potential ligand binding sites that could be targeted for therapeutics. A particular focus is on the current understanding of the molecular mechanisms of TRP channel activation and regulation, where many fundamental questions remain unanswered. We believe that a deeper understanding of the functional mechanisms of TRP channels will be critical and likely transformative toward developing successful therapeutic strategies targeting these exciting proteins. This endeavor will require concerted efforts from computation, structural biology, medicinal chemistry, electrophysiology, pharmacology, drug safety and clinical studies.
Effect of milk fat globules on growth and metabolism in rats fed an unbalanced diet
Authors: Argov-Argaman Nurit , Altman Hodaya , Janssen Jerome Nicolas , Daeem Seman , Raz Chen , Mesilati-Stahy Ronit , Penn Svetlana , Monsonego-Ornan Efrat
Published: January 2024

We assessed the effects of supplementing milk fat globules (MFG) on the growth and development of the skeleton in rats fed a Western unbalanced diet (UBD). The UBD is high in sugar and fat, low in protein, fiber, and micronutrients, and negatively impacts health. The MFG—a complex lipid-protein assembly secreted into milk—has a unique structure and composition, which differs significantly from isolated and processed dietary ingredients. Rats consuming the UBD exhibited growth retardation and disrupted bone structural and mechanical parameters; these were improved by supplementation with small MFG. The addition of small MFG increased the efficiency of protein utilization for growth, and improved trabecular and cortical bone parameters. Furthermore, consumption of UBD led to a decreased concentration of saturated fatty acids and increased levels of polyunsaturated fatty acids (PUFA), particularly omega-6 PUFA, in the serum, liver, and adipose tissue. The addition of small MFG restored PUFA concentration and the ratio of omega-6 to omega-3 PUFA in bone marrow and adipose tissue. Finally, large but not small MFG supplementation affected the cecal microbiome in rats. Overall, our results suggest that natural structure MFG supplementation can improve metabolism and bone development in rats fed an UBD, with the effects depending on MFG size. Moreover, the benefits of small MFG to bone development and metabolism were not mediated by the microbiome, as the detrimental effects of an UBD on the microbiome were not mitigated by MFG supplementation.
Capacity and kinetics of zearalenone adsorption by Geotrichum candidum LG-8 and its dried fragments in solution
Authors: Jiao Fengping , Cui Xianping , Shi Shujin , Jiang Guozheng , Dong Mingsheng , Meng Ling
Published: January 2024

The application of LG-8 and its dry fragments as zearalenone (ZEN) adsorbents was investigated. The study showed that Geotrichum candidum LG-8 and its fragments dried at 55°C or through lyophilization are able to adsorb around 80% of ZEN. However, besides in water and 55°C-drying conditions, SEM indicated that higher 90% of ZEN binding tended to occur when cell walls of fragments were intact with less adhesion among themselves. Notably, ZEN/LG-8 fragments complexes were quite stable, as only 1.262% and 1.969% of ZEN were released after successive pH treatments for 4 h and 5 min. The kinetic data signified that adsorption of ZEN onto LG-8 fragments followed well the pseudo-first-order kinetic model. Isotherm calculations showed Langmuir model was favourable and monolayer adsorption of ZEN occurred at functional binding sites on fragments surface. Therefore, we conclude that it can be an alternative biosorbent to treat water contained with ZEN, since LG-8 is low-cost biomass and its fragments have a considerable high biosorption capacity avoiding impacting final product quality and immunodeficient patients.
A comparative analysis of radical cystectomy with perioperative chemotherapy, chemoradiation therapy, or systemic therapy in patients with clinically advanced node-positive bladder cancer (cN2/N3)
Authors: Garg Harshit , Bhandari Mukund , Dursun Furkan , Liss Michael A. , Kaushik Dharam , Svatek Robert S. , Mansour Ahmed M.
Published: January 2024

Introduction

The management of non-metastatic clinically advanced lymph nodal (cN2/N3) bladder cancer (Stage IIIB) could involve radical cystectomy, chemoradiation, or systemic therapy alone. However, a definitive comparison between these approaches is lacking. This study aims to compare the outcomes of patients undergoing radical cystectomy with pelvic lymph node dissection (RC-PLND), chemoradiation therapy (CRT) or systemic therapy (including immunotherapy) (ST) only in patients with stage IIIB bladder cancer.

Materials and methods

A retrospective analysis of the National Cancer Database for patients with stage IIIB urothelial bladder cancer was done from 2004-2019. Patients were classified as Group A: Those who received RC-PLND with perioperative chemotherapy, Group B: Those who received CRT, and Group C: Those who received only ST alone. The primary outcome was overall survival (OS). Inverse probability weighting (IPW)-adjusted Kaplan Meier curves were utilized to compare overall survival (OS) and cox multivariate regression analysis was used to identify predictors for OS.

Results

Overall, 2,575 patients were identified. They were classified into Group A (n=1,278), Group B (n=317) and Group C (n=980). Compared to Group B, patients in Group A were younger (SMD=19.6%), had lower comorbidities (SMD=18.2%), had higher income (SMD=31.5%), had private insurance (SMD= 26.7%), were treated at academic centres (SMD=29.3%) and had higher percentage of N2 disease (SMD=31.1%). Using IPW-adjusted survival analysis, compared to Group C, the median OS was significantly higher in Group A (20.7 vs 14.2 months, p<0.001) and Group B (19.7 vs 14.2 months, p<0.001) but similar between Group A and Group B (20.9 vs 19.7 months, p=0.74). Both surgery (HR=0.72 (0.65-0.80), p<0.001) and CRT (0.70 (0.59-0.82), p<0.001) appeared to be independent predictors for OS on cox-regression analysis. The major limitations include bias due to retrospective analysis and non-assessment of cancer-specific survival.

Conclusion

In stage IIIB bladder cancer with advanced lymph nodal disease, both RC and CRT offer equivalent survival benefits and are superior to systemic therapy alone.
Peroxisome proliferator-activated receptorα/γ agonist pioglitazone for rescuing relapsed or refractory neoplasias by unlocking phenotypic plasticity
Authors: Harrer Dennis Christoph , Lüke Florian , Pukrop Tobias , Ghibelli Lina , Gerner Christopher , Reichle Albrecht , Heudobler Daniel
Published: January 2024

A series of seven clinical trials on relapsed or refractory (r/r) metastatic neoplasias followed the question: Are networks of ligand-receptor cross-talks that support tumor-specific cancer hallmarks, druggable with tumor tissue editing approaches therapeutically exploiting tumor plasticity? Differential recombinations of pioglitazone, a dual peroxisome-proliferator activated receptorα/γ (PPARα/γ) agonist, with transcriptional modulators, i.e., all-trans retinoic acid, interferon-α, or dexamethasone plus metronomic low-dose chemotherapy (MCT) or epigenetic modeling with azacitidine plus/minus cyclooxygenase-2 inhibition initiated tumor-specific reprogramming of cancer hallmarks, as exemplified by inflammation control in r/r melanoma, renal clear cell carcinoma (RCCC), Hodgkin’s lymphoma (HL) and multisystem Langerhans cell histiocytosis (mLCH) or differentiation induction in non-promyelocytic acute myeloid leukemia (non-PML AML). Pioglitazone, integrated in differentially designed editing schedules, facilitated induction of tumor cell death as indicated by complete remission (CR) in r/r non-PML AML, continuous CR in r/r RCCC, mLCH, and in HL by addition of everolimus, or long-term disease control in melanoma by efficaciously controlling metastasis, post-therapy cancer repopulation and acquired cell-resistance and genetic/molecular-genetic tumor cell heterogeneity (M-CRAC). PPARα/γ agonists provided tumor-type agnostic biomodulatory efficacy across different histologic neoplasias. Tissue editing techniques disclose that wide-ranging functions of PPARα/γ agonists may be on-topic focused for differentially unlocking tumor phenotypes. Low-dose MCT facilitates targeted reprogramming of cancer hallmarks with transcriptional modulators, induction of tumor cell death, M-CRAC control and editing of non-oncogene addiction. Thus, pioglitazone, integrated in tumor tissue editing protocols, is an important biomodulatory drug for addressing urgent therapeutic problems, such as M-CRAC in relapsed or refractory tumor disease.