bluuebunny/crossref_metadata_2025 huggingface dataset:
Atherosclerosis treatment with nanoagent: potential targets, stimulus signals and drug delivery mechanisms
Authors: Luo Ting , Zhang Zhen , Xu Junbo , Liu Hanxiong , Cai Lin , Huang Gang , Wang Chunbin , Chen Yingzhong , Xia Long , Ding Xunshi , Wang Jin , Li Xin
Published: June 2023

Cardiovascular disease (CVDs) is the first killer of human health, and it caused up at least 31% of global deaths. Atherosclerosis is one of the main reasons caused CVDs. Oral drug therapy with statins and other lipid-regulating drugs is the conventional treatment strategies for atherosclerosis. However, conventional therapeutic strategies are constrained by low drug utilization and non-target organ injury problems. Micro-nano materials, including particles, liposomes, micelles and bubbles, have been developed as the revolutionized tools for CVDs detection and drug delivery, specifically atherosclerotic targeting treatment. Furthermore, the micro-nano materials also could be designed to intelligently and responsive targeting drug delivering, and then become a promising tool to achieve atherosclerosis precision treatment. This work reviewed the advances in atherosclerosis nanotherapy, including the materials carriers, target sites, responsive model and treatment results. These nanoagents precisely delivery the therapeutic agents to the target atherosclerosis sites, and intelligent and precise release of drugs, which could minimize the potential adverse effects and be more effective in atherosclerosis lesion.
Genetic risk factors for postoperative atrial fibrillation—a nationwide genome-wide association study (GWAS)
Authors: Christensen Mathias A. , Bonde Alexander , Sillesen Martin
Published: June 2023

Background

Atrial fibrillation (AF) is a major cause of morbidity with a high prevalence among the elderly and has an established genetic disposition. Surgery is a well-known risk factor for AF; however, it is currently not recognized how much common genetic variants influence the postoperative risk. The purpose of this study was to identify Single Nucleotide Polymorphisms associated with postoperative AF.

Methods

The UK Biobank was utilized to conduct a Genome-Wide Association Study (GWAS) to identify variants associated with AF after surgery. An initial discovery GWAS was performed in patients that had undergone surgery with subsequent replication in a unique non-surgical cohort. In the surgical cohort, cases were defined as newly diagnosed AF within 30 days after surgery. The threshold for significance was set at 5 × 10−8.

Results

After quality control, 144,196 surgical patients with 254,068 SNPs were left for analysis. Two variants (rs17042171 (p = 4.86 × 10−15) and rs17042081 (p = 7.12 × 10−15)) near the PITX2-gene reached statistical significance. These variants were replicated in the non-surgical cohort (1.39 × 10−101 and 1.27 × 10−93, respectively). Several other loci were significantly associated with AF in the non-surgical cohort.

Conclusion

In this GWAS-analysis of a large national biobank, we identified 2 variants that were significantly associated with postoperative AF. These variants were subsequently replicated in a unique non-surgical cohort. These findings bring new insight in the genetics of postoperative AF and may help identify at-risk patients and guide management.
Mechanisms by which statins protect endothelial cells from radiation-induced injury in the carotid artery
Authors: Ait-Aissa Karima , Leng Linette N. , Lindsey Nathanial R. , Guo Xutong , Juhr Denise , Koval Olha M. , Grumbach Isabella M.
Published: June 2023

Background

The incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. However, the mechanisms by which statins protect the vasculature from irradiation injury remain poorly understood.

Objectives

Identify the mechanisms by which the hydrophilic and lipophilic statins pravastatin and atorvastatin preserve endothelial function after irradiation.

Methods

Cultured human coronary and umbilical vein endothelial cells irradiated with 4 Gy and mice subjected to 12 Gy head-and-neck irradiation were pretreated with statins and tested for endothelial dysfunction, nitric oxide production, oxidative stress, and various mitochondrial phenotypes at 24 and 240 h after irradiation.

Results

Both pravastatin (hydrophilic) and atorvastatin (lipophilic) were sufficient to prevent the loss of endothelium-dependent relaxation of arteries after head-and-neck irradiation, preserve the production of nitric oxide by endothelial cells, and suppress the cytosolic reactive oxidative stress associated with irradiation. However, only pravastatin inhibited irradiation-induced production of mitochondrial superoxide; damage to the mitochondrial DNA; loss of electron transport chain activity; and expression of inflammatory markers.

Conclusions

Our findings reveal some mechanistic underpinnings of the vasoprotective effects of statins after irradiation. Whereas both pravastatin and atorvastatin can shield from endothelial dysfunction after irradiation, pravastatin additionally suppresses mitochondrial injury and inflammatory responses involving mitochondria. Clinical follow-up studies will be necessary to determine whether hydrophilic statins are more effective than their lipophilic counterparts in reducing the risk of cardiovascular disease in patients undergoing radiation therapy.
Clustering features and seismogenesis of the 2014 M6.6 Jinggu earthquake in Yunnan Province, China
Authors: Zheng Jianchang
Published: June 2023

Seismic activities can be seen as the composition of background and clustering earthquakes. It is important to identify seismicity clusters from background events. Based on the Nearest Neighbour Distance algorithm proposed by Zaliapin, we use the Gaussian mixture model (GMM) to fit its spatiotemporal distribution and use the probability corresponding to clustering seismicity in the GMM model as the clustering ratio. After testing with synthetic catalogues under the ETAS (epidemic-type aftershock sequence) model, We believe the method can discriminate cluster events from randomly occurring background seismicity in a more physical background. We investigate the seismicity and its clustering features before the M6.6 Jinggu earthquake in Yunnan Province, China on 7 October 2014. Our results show the following: 1) The seismogenic process of this strong earthquake has three stages, which are already described by the IPE model (the model is similiar to dilatancy diffusion model, growth of cracks is also involved but diffusion of water in and out of the focal region is not required); 2) The main shock might have been caused by the breaking of a local locked barrier in the hypocentre, and the meta-instability stage was sustained for about 1 year on the fault. From this study, we conclude that the evolution of seismicity clustering features can reflect changes in stress in the crust, and it is closely connected to the seismogenic process of a strong earthquake.
Signalling cognition: the gut microbiota and hypothalamic-pituitary-adrenal axis
Authors: Rusch Jody A. , Layden Brian T. , Dugas Lara R.
Published: June 2023

Cognitive function in humans depends on the complex and interplay between multiple body systems, including the hypothalamic-pituitary-adrenal (HPA) axis. The gut microbiota, which vastly outnumbers human cells and has a genetic potential that exceeds that of the human genome, plays a crucial role in this interplay. The microbiota-gut-brain (MGB) axis is a bidirectional signalling pathway that operates through neural, endocrine, immune, and metabolic pathways. One of the major neuroendocrine systems responding to stress is the HPA axis which produces glucocorticoids such as cortisol in humans and corticosterone in rodents. Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory, and studies have shown that microbes modulate the HPA axis throughout life. Stress can significantly impact the MGB axis via the HPA axis and other pathways. Animal research has advanced our understanding of these mechanisms and pathways, leading to a paradigm shift in conceptual thinking about the influence of the microbiota on human health and disease. Preclinical and human trials are currently underway to determine how these animal models translate to humans. In this review article, we summarize the current knowledge of the relationship between the gut microbiota, HPA axis, and cognition, and provide an overview of the main findings and conclusions in this broad field.
Machine learning-assisted analysis of epithelial mesenchymal transition pathway for prognostic stratification and immune infiltration assessment in ovarian cancer
Authors: Li Qian , Xiao Xiyun , Feng Jing , Yan Ruixue , Xi Jie
Published: June 2023

Background

Ovarian cancer is the most lethal gynaecological malignancy, and serous ovarian cancer (SOC) is one of the more important pathological subtypes. Previous studies have reported a significant association of epithelial tomesenchymal transition (EMT) with invasive metastasis and immune modulation of SOC, however, there is a lack of prognostic and immune infiltration biomarkers reported for SOC based on EMT.

Methods

Gene expression data for ovarian cancer and corresponding patient clinical data were collected from the TCGA database and the GEO database, and cell type annotation and spatial expression analysis were performed on single cell sequencing data from the GEO database. To understand the cell type distribution of EMT-related genes in SOC single-cell data and the enrichment relationships of biological pathways and tumour functions. In addition, GO functional annotation analysis and KEGG pathway enrichment analysis were performed on mRNAs predominantly expressed with EMT to predict the biological function of EMT in ovarian cancer. The major differential genes of EMT were screened to construct a prognostic risk prediction model for SOC patients. Data from 173 SOC patient samples obtained from the GSE53963 database were used to validate the prognostic risk prediction model for ovarian cancer. Here we also analysed the direct association between SOC immune infiltration and immune cell modulation and EMT risk score. and calculate drug sensitivity scores in the GDSC database.In addition, we assessed the specific relationship between GAS1 gene and SOC cell lines.

Results

Single cell transcriptome analysis in the GEO database annotated the major cell types of SOC samples, including: T cell, Myeloid, Epithelial cell, Fibroblast, Endothelial cell, and Bcell. cellchat revealed several cell type interactions that were shown to be associated with EMT-mediated SOC invasion and metastasis. A prognostic stratification model for SOC was constructed based on EMT-related differential genes, and the Kapan-Meier test showed that this biomarker had significant prognostic stratification value for several independent SOC databases. The EMT risk score has good stratification and identification properties for drug sensitivity in the GDSC database.

Conclusions

This study constructed a prognostic stratification biomarker based on EMT-related risk genes for immune infiltration mechanisms and drug sensitivity analysis studies in SOC. This lays the foundation for in-depth clinical studies on the role of EMT in immune regulation and related pathway alterations in SOC. It is also hoped to provide effective potential solutions for early diagnosis and clinical treatment of ovarian cancer.
Empirical prediction of blast-induced vibration on adjacent tunnels
Authors: Li Wenxin , Wang Xiao , Chen Lianjun , Wang Chunguang , Liu Jinxiao
Published: June 2023

The blast-induced vibration during excavation by the drilling and blasting method has an important impact on the surrounding buildings/structures and auxiliary equipment. In particular, with the development of tunnel engineering, the impact of blasting vibration on tunnel construction has attracted extensive attention. Based on literature data statistics, this paper first explored the performance of several commonly used empirical equations in predicting the propagation and attenuation characteristics of blasting vibration on adjacent tunnels. Secondly, the relationships between the empirical parameters of the blasting vibration prediction equation and the geological strength index (GSI) of tunnel surrounding rock were discussed, and two new blasting vibration prediction equations based on site rock GSI were established to approximately predict blast-induced vibration on adjacent tunnels. Finally, the application feasibility of the established prediction equation in practical engineering was discussed based on field test data. The research results show that under the condition of multiple groups of data, the prediction performance of various prediction models does not differ significantly. With the increase of the GSI of the surrounding rock mass of the adjacent tunnel, the site coefficients β and k of the blasting vibration prediction equation in predicting PPV (peak particle velocity, resultant velocity) both show a decreasing trend as a whole. The site coefficient k is generally within 3,000. Two new empirical prediction equations of blasting vibration propagation and attenuation on adjacent tunnels under different site conditions were established: Eq. (14) for PPV and Eq. (15) for PPVi (max) (maximum value of the three component velocities; i = x, y, z represent peak component particle velocity). The verification analysis of five sites shows that these two equations have a certain practical application value. Compared with other empirical equations, these two equations do not need regression fitting blasting vibration data, they only used the GSI of the site rock mass, and they are more easy to use in the field when there is a lack of monitoring data.
Function of TRP channels in monocytes/macrophages
Authors: Wu Jiangbo , Li Zhuo , Deng Ya , Lu Xianmin , Luo Chen , Mu Xingyi , Zhang Ting , Liu Qi , Tang Siqi , Li Jiajing , An Qimin , Fan Dongdong , Xiang Yiwei , Wu Xianli , Hu Yanxia , Du Qian , Xu Jingyu , Xie Rui
Published: June 2023

The transient receptor potential channel (TRP channel) family is a kind of non- specific cation channel widely distributed in various tissues and organs of the human body, including the respiratory system, cardiovascular system, immune system, etc. It has been reported that various TRP channels are expressed in mammalian macrophages. TRP channels may be involved in various signaling pathways in the development of various systemic diseases through changes in intracellular concentrations of cations such as calcium and magnesium. These TRP channels may also intermingle with macrophage activation signals to jointly regulate the occurrence and development of diseases. Here, we summarize recent findings on the expression and function of TRP channels in macrophages and discuss their role as modulators of macrophage activation and function. As research on TRP channels in health and disease progresses, it is anticipated that positive or negative modulators of TRP channels for treating specific diseases may be promising therapeutic options for the prevention and/or treatment of disease.
Phytoplankton pigment in situ measurements uncertainty evaluation: an HPLC interlaboratory comparison with a European-scale dataset
Authors: Canuti Elisabetta
Published: June 2023

Phytoplankton pigment data play a crucial role in ecological studies, enabling the identification of algal groups and estimation of primary production rates. Accurate measurements of chlorophyll a (TChl a) and other marine pigments are essential for the development of bio-optical algorithms and the validation of satellite data products. High-performance liquid chromatography (HPLC) is the gold standard method for quantifying multiple pigments in a single water sample. This study aims to investigate the uncertainties associated with phytoplankton pigment quantification by comparing duplicate sample analyses conducted by two laboratories, the Joint Research Centre of the European Commission (J) and the DHI Group, Denmark (D). The analyses were performed using the same HPLC method. The dataset comprised 957 natural samples collected between 2012 and 2017 from various European seas, representing different trophic conditions with TChl a concentrations ranging from 0.083 to 27.35 mg/m3. The study compared the results of the two independent analyses for TChl a and primary phytoplankton pigments, including chlorophyll b, chlorophyll c, carotens, fucoxanthin, 19′-butanoyloxyfucoxanthin, diadinoxanthin, diatoxanthin, 19′-hexanoyloxyfucoxanthin, peridin, and zeaxanthin. The percent difference between the two analyses was calculated to assess the uncertainties associated with pigment quantification. The mean percent difference observed between the two independent analyses of TChl a was 10.8%. For the primary phytoplankton pigments, the associated mean percent difference was 16.9%. These results meet the requirements of 15% and 25% uncertainties, respectively, which are applicable for the validation of satellite data products. The comparative analysis between the two laboratories demonstrates that the uncertainties associated with phytoplankton pigment quantification are within acceptable ranges for the validation of satellite data products. Moreover, the study investigates the propagation of uncertainties in diagnostic pigment values to phytoplankton indexes, which are derived using pigment-based algorithms to characterize phytoplankton populations according to functional types.
Activation mechanism and activity of globupain, a thermostable C11 protease from the Arctic Mid-Ocean Ridge hydrothermal system
Authors: Røyseth Victoria , Hurysz Brianna M. , Kaczorowska Anna-Karina , Dorawa Sebastian , Fedøy Anita-Elin , Arsın Hasan , Serafim Mateus Sá M. , Myers Samuel A. , Werbowy Olesia , Kaczorowski Tadeusz , Stokke Runar , O’Donoghue Anthony J. , Steen Ida Helene
Published: June 2023

Deep-sea hydrothermal vents offer unique habitats for heat tolerant enzymes with potential new enzymatic properties. Here, we present the novel C11 protease globupain, which was prospected from a metagenome-assembled genome of uncultivated Archaeoglobales sampled from the Soria Moria hydrothermal vent system located on the Arctic Mid-Ocean Ridge. Sequence comparisons against the MEROPS-MPRO database showed that globupain has the highest sequence identity to C11-like proteases present in human gut and intestinal bacteria. Successful recombinant expression in Escherichia coli of the wild-type zymogen and 13 mutant substitution variants allowed assessment of residues involved in maturation and activity of the enzyme. For activation, globupain required the addition of DTT and Ca2+. When activated, the 52kDa proenzyme was processed at K137 and K144 into a 12kDa light- and 32kDa heavy chain heterodimer. A structurally conserved H132/C185 catalytic dyad was responsible for the proteolytic activity, and the enzyme demonstrated the ability to activate in-trans. Globupain exhibited caseinolytic activity and showed a strong preference for arginine in the P1 position, with Boc-QAR-aminomethylcoumarin (AMC) as the best substrate out of a total of 17 fluorogenic AMC substrates tested. Globupain was thermostable (Tm activated enzyme = 94.51°C ± 0.09°C) with optimal activity at 75°C and pH 7.1. Characterization of globupain has expanded our knowledge of the catalytic properties and activation mechanisms of temperature tolerant marine C11 proteases. The unique combination of features such as elevated thermostability, activity at relatively low pH values, and ability to operate under high reducing conditions makes globupain a potential intriguing candidate for use in diverse industrial and biotechnology sectors.
Restless leg syndrome in multiple sclerosis: a case–control study
Authors: Aljarallah Salman , Alkhawajah Nuha , Aldosari Omar , Alhuqbani Mohammed , Alqifari Faisal , Alkhuwaitir Bassam , Aldawood Abdullah , Alshenawy Omar , BaHammam Ahmed S.
Published: June 2023

Objectives

This study assessed the prevalence of restless leg syndrome (RLS) among patients with multiple sclerosis (pwMS) and the association between RLS and MS disease duration, sleep disturbance, and daytime fatigue.

Methods

In this cross-sectional study, we interviewed 123 patients via phone calls using preset questionnaires containing the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria, Pittsburgh Sleep Quality Index (PSQI), and Fatigue Severity Scale (FSS) diagnostic criteria validated in both Arabic and English. The prevalence of RLS in MS was compared to a group of healthy controls.

Results

The prevalence of RLS in pwMS, defined by meeting all four requirements included in the IRLSSG diagnostic criteria, was 30.3% compared to 8.3% in the control group. About 27.3% had mild RLS, 36.4% presented with moderate, and the remaining had severe or very severe symptoms. Patients with MS who experience RLS had a 2.8 times higher risk of fatigue compared to pwMS without RLS. pwMS with RLS had worse sleep quality, with a mean difference of 0.64 in the global PSQI score. Sleep disturbance and latency had the most significant impact on sleep quality.

Conclusion

The prevalence of RLS among MS patients was significantly higher compared to the control group. We recommend educating neurologists and general physicians to increase their awareness of the increasing prevalence of RLS and its association with fatigue and sleep disturbance in patients with MS.
Increased neurocardiological interplay after mindfulness meditation: a brain oscillation-based approach
Authors: Gao Junling , Sun Rui , Leung Hang Kin , Roberts Adam , Wu Bonnie Wai Yan , Tsang Eric W. , Tang Andrew C. W. , Sik Hin Hung
Published: June 2023

Background

Brain oscillations facilitate interaction within the brain network and between the brain and heart activities, and the alpha wave, as a prominent brain oscillation, plays a major role in these coherent activities. We hypothesize that mindfully breathing can make the brain and heart activities more coherent in terms of increased connectivity between the electroencephalogram (EEG) and electrocardiogram (ECG) signals.

Methods

Eleven participants (28–52 years) attended 8 weeks of Mindfulness Based Stress Reduction (MBSR) training. EEG and ECG data of two states of mindful breathing and rest, both eye-closed, were recorded before and after the training. EEGLAB was used to analyze the alpha band (8–12 Hz) power, alpha peak frequency (APF), peak power and coherence. FMRIB toolbox was used to extract the ECG data. Heart coherence (HC) and heartbeat evoked potential (HEP) were calculated for further correlation analysis.

Results

After 8 weeks of MBSR training, the correlation between APF and HC increased significantly in the middle frontal region and bilateral temporal regions. The correlation between alpha coherence and heart coherence had similar changes, while alpha peak power did not reflect such changes. In contrast, spectrum analysis alone did not show difference before and after MBSR training.

Conclusion

The brain works in rhythmic oscillation, and this rhythmic connection becomes more coherent with cardiac activity after 8 weeks of MBSR training. Individual APF is relatively stable and its interplay with cardiac activity may be a more sensitive index than power spectrum by monitoring the brain-heart connection. This preliminary study has important implications for the neuroscientific measurement of meditative practice.
Neurochronometry of choice-induced preference changes: when do preferences actually change?
Authors: Davydova Alina , Sheronova Julia , Kosonogov Vladimir , Shestakova Anna , Klucharev Vasily
Published: June 2023

According to cognitive dissonance theory, a discrepancy between preferences and actions may lead to the revaluation of preferences, increasing preference for the chosen options and decreasing for the rejected options. This phenomenon is known as the spreading of alternatives (SoA), which results in a choice-induced preference change (CIPC). Previous neuroimaging studies have identified several brain regions that play a role in cognitive dissonance. However, the neurochronometry of the cognitive mechanisms underlying CIPC is a topic of debate. In other words, does it occur during the difficult choice, immediately after the choice, or when people encounter the options again? Furthermore, it remains unclear what is the exact time point, relative to the onset of facing options, either within the choice or after it, when the attitudes start to be revised. We argue that applying online protocols of transcranial magnetic stimulation (TMS), during or immediately after the choice process, could be the most efficient way to better understand the temporal dynamics of the SoA effect. TMS allows for achieving high temporal and spatial resolution, modulating the activity of areas of interest, and examining the causal relationships. Besides, unlike the offline TMS, the online instrument allows tracking of the neurochronometry of attitude change, by varying stimulation onsets and durations with respect to the option stimuli. Based on scrupulous analysis of previous findings, employing online TMS studies of conflict monitoring, cognitive control, and CIPC neuroimaging results, we conclude that the use of online TMS is critical to examine the neurochronometry of CIPC.
Knockout of angiotensin converting enzyme-2 receptor leads to morphological aberrations in rodent olfactory centers and dysfunctions associated with sense of smell
Authors: Mahajan Sarang , Sen Deepshikha , Sunil Anantu , Srikanth Priyadharshini , Marathe Shruti D. , Shaw Karishma , Sahare Mahesh , Galande Sanjeev , Abraham Nixon M.
Published: June 2023

Neuronal morphological characterization and behavioral phenotyping in mouse models help dissecting neural mechanisms of brain disorders. Olfactory dysfunctions and other cognitive problems were widely reported in asymptomatic carriers and symptomatic patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). This led us to generate the knockout mouse model for Angiotensin Converting Enzyme-2 (ACE2) receptor, one of the molecular factors mediating SARS-CoV-2 entry to the central nervous system, using CRISPR-Cas9 based genome editing tools. ACE2 receptors and Transmembrane Serine Protease-2 (TMPRSS2) are widely expressed in the supporting (sustentacular) cells of human and rodent olfactory epithelium, however, not in the olfactory sensory neurons (OSNs). Hence, acute inflammation induced changes due to viral infection in the olfactory epithelium may explain transient changes in olfactory detectabilities. As ACE2 receptors are expressed in different olfactory centers and higher brain areas, we studied the morphological changes in the olfactory epithelium (OE) and olfactory bulb (OB) of ACE2 KO mice in comparison with wild type animals. Our results showed reduced thickness of OSN layer in the OE, and a decrease in cross-sectional area of glomeruli in the OB. Aberrations in the olfactory circuits were revealed by lowered immunoreactivity toward microtubule associated protein 2 (MAP2) in the glomerular layer of ACE2 KO mice. Further, to understand if these morphological alterations lead to compromised sensory and cognitive abilities, we performed an array of behavioral assays probing their olfactory subsystems’ performances. ACE2 KO mice exhibited slower learning of odor discriminations at the threshold levels and novel odor identification impairments. Further, ACE2 KO mice failed to memorize the pheromonal locations while trained on a multimodal task implying the aberrations of neural circuits involved in higher cognitive functions. Our results thus provide the morphological basis for the sensory and cognitive disabilities caused by the deletion of ACE2 receptors and offer a potential experimental approach to study the neural circuit mechanisms of cognitive impairments observed in long COVID.
Botulinum toxin A decreases neural activity in pain-related brain regions in individuals with chronic ocular pain and photophobia
Authors: Reyes Nicholas , Huang Jaxon J. , Choudhury Anjalee , Pondelis Nicholas , Locatelli Elyana V. , Felix Elizabeth R. , Pattany Pradip M. , Galor Anat , Moulton Eric A.
Published: June 2023

Introduction

To examine the effect of botulinum toxin A (BoNT-A) on neural mechanisms underlying pain and photophobia using functional magnetic resonance imaging (fMRI) in individuals with chronic ocular pain.

Methods

Twelve subjects with chronic ocular pain and light sensitivity were recruited from the Miami Veterans Affairs eye clinic. Inclusion criteria were: (1) chronic ocular pain; (2) presence of ocular pain over 1 week recall; and (3) presence of photophobia. All individuals underwent an ocular surface examination to capture tear parameters before and 4–6 weeks after BoNT-A injections. Using an event-related fMRI design, subjects were presented with light stimuli during two fMRI scans, once before and 4–6 weeks after BoNT-A injection. Light evoked unpleasantness ratings were reported by subjects after each scan. Whole brain blood oxygen level dependent (BOLD) responses to light stimuli were analyzed.

Results

At baseline, all subjects reported unpleasantness with light stimulation (average: 70.8 ± 32.0). Four to six weeks after BoNT-A injection, unpleasantness scores decreased (48.1 ± 33.6), but the change was not significant. On an individual level, 50% of subjects had decreased unpleasantness ratings in response to light stimulation compared to baseline (“responders,” n = 6), while 50% had equivalent (n = 3) or increased (n = 3) unpleasantness (“non-responders”). At baseline, several differences were noted between responders and non-responders; responders had higher baseline unpleasantness ratings to light, higher symptoms of depression, and more frequent use of antidepressants and anxiolytics, compared to non-responders. Group analysis at baseline displayed light-evoked BOLD responses in bilateral primary somatosensory (S1), bilateral secondary somatosensory (S2), bilateral anterior insula, paracingulate gyrus, midcingulate cortex (MCC), bilateral frontal pole, bilateral cerebellar hemispheric lobule VI, vermis, bilateral cerebellar crus I and II, and visual cortices. BoNT-A injections significantly decreased light evoked BOLD responses in bilateral S1, S2 cortices, cerebellar hemispheric lobule VI, cerebellar crus I, and left cerebellar crus II. BoNT-A responders displayed activation of the spinal trigeminal nucleus at baseline where non-responders did not.

Discussion

BoNT-A injections modulate light-evoked activation of pain-related brain systems and photophobia symptoms in some individuals with chronic ocular pain. These effects are associated with decreased activation in areas responsible for processing the sensory-discriminative, affective, dimensions, and motor responses to pain.
Sex-specific responses in glucose-insulin homeostasis and lipoprotein-lipid components after high-dose supplementation with marine n-3 PUFAs in abdominal obesity: a randomized double-blind crossover study
Authors: Laupsa-Borge Johnny , Grytten Elise , Bohov Pavol , Bjørndal Bodil , Strand Elin , Skorve Jon , Nordrehaug Jan Erik , Berge Rolf K. , Rostrup Espen , Mellgren Gunnar , Dankel Simon N. , Nygård Ottar K.
Published: June 2023

Background

Clinical studies on effects of marine-derived omega-3 (n-3) polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the plant-derived omega-6 (n-6) PUFA linoleic acid (LA) on lipoprotein-lipid components and glucose-insulin homeostasis have shown conflicting results, which may partly be explained by differential responses in females and males. However, we have lacked data on sexual dimorphism in the response of cardiometabolic risk markers following increased consumption of n-3 or n-6 PUFAs.

Objective

To explore sex-specific responses after n-3 (EPA + DHA) or n-6 (LA) PUFA supplementation on circulating lipoprotein subfractions, standard lipids, apolipoproteins, fatty acids in red blood cell membranes, and markers of glycemic control/insulin sensitivity among people with abdominal obesity.

Methods

This was a randomized double-blind crossover study with two 7-week intervention periods separated by a 9-week washout phase. Females (n = 16) were supplemented with 3 g/d of EPA + DHA (fish oil) or 15 g/d of LA (safflower oil), while males (n = 23) received a dose of 4 g/d of EPA + DHA or 20 g/d of LA. In fasting blood samples, we measured lipoprotein particle subclasses, standard lipids, apolipoproteins, fatty acid profiles, and markers of glycemic control/insulin sensitivity.

Results

The between-sex difference in relative change scores was significant after n-3 for total high-density lipoproteins (females/males: −11%*/−3.3%, p = 0.036; *: significant within-sex change), high-density lipoprotein particle size (+2.1%*/−0.1%, p = 0.045), and arachidonic acid (−8.3%*/−12%*, p = 0.012), and after n-6 for total (+37%*/+2.1%, p = 0.041) and small very-low-density lipoproteins (+97%*/+14%, p = 0.021), and lipoprotein (a) (−16%*/+0.1%, p = 0.028). Circulating markers of glucose-insulin homeostasis differed significantly after n-3 for glucose (females/males: −2.1%/+3.9%*, p = 0.029), insulin (−31%*/+16%, p < 0.001), insulin C-peptide (−12%*/+13%*, p = 0.001), homeostasis model assessment of insulin resistance index 2 (−12%*/+14%*, p = 0.001) and insulin sensitivity index 2 (+14%*/−12%*, p = 0.001), and quantitative insulin sensitivity check index (+4.9%*/−3.4%*, p < 0.001).

Conclusion

We found sex-specific responses after high-dose n-3 (but not n-6) supplementation in circulating markers of glycemic control/insulin sensitivity, which improved in females but worsened in males. This may partly be related to the sex differences we observed in several components of the lipoprotein-lipid profile following the n-3 intervention.

Clinical trial registration

https://clinicaltrials.gov/, identifier [NCT02647333].
Deep eutectic solvent-ultrasound assisted extraction as a green approach for enhanced extraction of naringenin from Searsia tripartita and retained their bioactivities
Authors: El Maaiden Ezzouhra , El Kahia Houda , Nasser Boubker , Moustaid Khadija , Qarah Nagib , Boukcim Hassan , Hirich Abdelaziz , Kouisni Lamfeddal , El Kharrassi Youssef
Published: June 2023

Background

Naringenin (NA) is a natural flavonoid used in the formulation of a wide range of pharmaceutical, fragrance, and cosmetic products. In this research, NA was extracted from Searsia tripartita using an environmentally friendly, high efficiency extraction method: an ultrasound-assisted extraction with deep eutectic solvents (UAE-DES).

Methods

Six natural deep eutectic solvent systems were tested. Choline chloride was used as the hydrogen bond acceptor (HBA), and formic acid, ethylene glycol, lactic acid, urea, glycerol, and citric acid were used as hydrogen bond donors (HBD).

Results

Based on the results of single-factor experiments, response surface methodology using a Box-Behnken design was applied to determine the optimal conditions for UAE-DES. According to the results, the optimal NA extraction parameters were as follows: DES-1 consisted of choline chloride (HBA) and formic acid (HBD) in a mole ratio of 2:1, an extraction time of 10 min, an extraction temperature of 50°C, an ultrasonic amplitude of 75 W, and a solid-liquid ratio of 1/60 g/mL. Extracted NA was shown to inhibit the activity of different enzymes in vitro, including α-amylase, acetylcholinesterase, butyrylcholinesterase, tyrosinase, elastase, collagenase, and hyaluronidase.

Conclusion

Thus, the UAE-DES technique produced high-efficiency NA extraction while retaining bioactivity, implying broad application potential, and making it worthy of consideration as a high-throughput green extraction method.
Preoperative immunological plasma markers TRAIL, CSF1 and TIE2 predict survival after resection for biliary tract cancer
Authors: Jansson Hannes , Cornillet Martin , Sun Dan , Filipovic Iva , Sturesson Christian , O’Rourke Colm J. , Andersen Jesper B. , Björkström Niklas K. , Sparrelid Ernesto
Published: June 2023

Introduction

Systemic inflammatory markers have been validated as prognostic factors for patients with biliary tract cancer (BTC). The aim of this study was to evaluate specific immunologic prognostic markers and immune responses by analyzing preoperative plasma samples from a large prospectively collected biobank.

Methods

Expression of 92 proteins representing adaptive and innate immune responses was investigated in plasma from 102 patients undergoing resection for BTC 2009-2017 (perihilar cholangiocarcinoma n=46, intrahepatic cholangiocarcinoma n=27, gallbladder cancer n=29), by means of a high-throughput multiplexed immunoassay. Association with overall survival was analyzed by Cox regression, with internal validation and calibration. Tumor tissue bulk and single-cell gene expression of identified markers and receptors/ligands was analyzed in external cohorts.

Results

Three preoperative plasma markers were independently associated with survival: TRAIL, TIE2 and CSF1, with hazard ratios (95% confidence intervals) 0.30 (0.16-0.56), 2.78 (1.20-6.48) and 4.02 (1.40-11.59) respectively. The discrimination of a preoperative prognostic model with the three plasma markers was assessed with concordance-index 0.70, while the concordance-index of a postoperative model with histopathological staging was 0.66. Accounting for subgroup differences, prognostic factors were assessed for each type of BTC. TRAIL and CSF1 were prognostic factors in intrahepatic cholangiocarcinoma. In independent cohorts, TRAIL-receptor expression was higher in tumor tissue and seen in malignant cells, with TRAIL and CSF1 expressed by intra- and peritumoral immune cells. Intratumoral TRAIL-activity was decreased compared to peritumoral immune cells, while CSF1-activity was increased. The highest CSF1 activity was seen in intratumoral macrophages, while the highest TRAIL-activity was seen in peritumoral T-cells.

Discussion

In conclusion, three preoperative immunological plasma markers were prognostic for survival after surgery for BTC, providing good discrimination, even compared to postoperative pathology. TRAIL and CSF1, prognostic factors in intrahepatic cholangiocarcinoma, showed marked differences in expression and activity between intra- and peritumoral immune cells.
Genomic landscape of clinically advanced KRAS wild-type pancreatic ductal adenocarcinoma
Authors: Ashok Kumar Prashanth , Serinelli Serenella , Zaccarini Daniel J. , Huang Richard , Danziger Natalie , Janovitz Tyler , Basnet Alina , Sivapiragasam Abirami , Graziano Stephen , Ross Jeffrey S.
Published: June 2023

Introduction

KRAS mutation is a common occurrence in Pancreatic Ductal Adenocarcinoma (PDA) and is a driver mutation for disease development and progression. KRAS wild-type PDA may constitute a distinct molecular and clinical subtype. We used the Foundation one data to analyze the difference in Genomic Alterations (GAs) that occur in KRAS mutated and wild-type PDA.

Methods

Comprehensive genomic profiling (CGP) data, tumor mutational burden (TMB), microsatellite instability (MSI) and PD-L1 by Immunohistochemistry (IHC) were analyzed.

Results and discussion

Our cohort had 9444 cases of advanced PDA. 8723 (92.37%) patients had KRAS mutation. 721 (7.63%) patients were KRAS wild-type. Among potentially targetable mutations, GAs more common in KRAS wild-type included ERBB2 (mutated vs wild-type: 1.7% vs 6.8%, p <0.0001), BRAF (mutated vs wild-type: 0.5% vs 17.9%, p <0.0001), PIK3CA (mutated vs wild-type: 2.3% vs 6.5%, p <0.001), FGFR2 (mutated vs wild-type: 0.1% vs 4.4%, p <0.0001), ATM (mutated vs wild-type: 3.6% vs 6.8%, p <0.0001). On analyzing untargetable GAs, the KRAS mutated group had a significantly higher percentage of TP53 (mutated vs wild-type: 80.2% vs 47.6%, p <0.0001), CDKN2A (mutated vs wild-type: 56.2% vs 34.4%, p <0.0001), CDKN2B (mutated vs wild-type: 28.9% vs 23%, p =0.007), SMAD4 (mutated vs wild-type: 26.8% vs 15.7%, p <0.0001) and MTAP (mutated vs wild-type: 21.7% vs 18%, p =0.02). ARID1A (mutated vs wild-type: 7.7% vs 13.6%, p <0.0001 and RB1(mutated vs wild-type: 2% vs 4%, p =0.01) were more prevalent in the wild-type subgroup. Mean TMB was higher in the KRAS wild-type subgroup (mutated vs wild-type: 2.3 vs 3.6, p <0.0001). High TMB, defined as TMB > 10 mut/mB (mutated vs wild-type: 1% vs 6.3%, p <0.0001) and very-high TMB, defined as TMB >20 mut/mB (mutated vs wild-type: 0.5% vs 2.4%, p <0.0001) favored the wild-type. PD-L1 high expression was similar between the 2 groups (mutated vs wild-type: 5.7% vs 6%,). GA associated with immune checkpoint inhibitors (ICPIs) response including PBRM1 (mutated vs wild-type: 0.7% vs 3.2%, p <0.0001) and MDM2 (mutated vs wild-type: 1.3% vs 4.4%, p <0.0001) were more likely to be seen in KRAS wild-type PDA.
Whole-tumor histogram analysis of apparent diffusion coefficients for predicting lymphovascular space invasion in stage IB-IIA cervical cancer
Authors: Cheng Jin-mei , Luo Wei-xiao , Tan Bang-guo , Pan Jian , Zhou Hai-ying , Chen Tian-wu
Published: June 2023

Objectives

To investigate the value of apparent diffusion coefficient (ADC) histogram analysis based on whole tumor volume for the preoperative prediction of lymphovascular space invasion (LVSI) in patients with stage IB-IIA cervical cancer.

Methods

Fifty consecutive patients with stage IB-IIA cervical cancer were stratified into LVSI-positive (n = 24) and LVSI-negative (n = 26) groups according to the postoperative pathology. All patients underwent pelvic 3.0T diffusion-weighted imaging with b-values of 50 and 800 s/mm2 preoperatively. Whole-tumor ADC histogram analysis was performed. Differences in the clinical characteristics, conventional magnetic resonance imaging (MRI) features, and ADC histogram parameters between the two groups were analyzed. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of ADC histogram parameters in predicting LVSI.

Results

ADCmax, ADCrange, ADC90, ADC95, and ADC99 were significantly lower in the LVSI-positive group than in the LVSI-negative group (all P-values < 0.05), whereas no significant differences were reported for the remaining ADC parameters, clinical characteristics, and conventional MRI features between the groups (all P-values > 0.05). For predicting LVSI in stage IB-IIA cervical cancer, a cutoff ADCmax of 1.75×10−3 mm2/s achieved the largest area under ROC curve (Az) of 0.750, followed by a cutoff ADCrange of 1.36×10−3 mm2/s and ADC99 of 1.75×10−3 mm2/s (Az = 0.748 and 0.729, respectively), and the cutoff ADC90 and ADC95 achieved an Az of <0.70.

Conclusion

Whole-tumor ADC histogram analysis has potential value for preoperative prediction of LVSI in patients with stage IB-IIA cervical cancer. ADCmax, ADCrange, and ADC99 are promising prediction parameters.
Optimizing the xWORM assay for monitoring hookworm larvae motility
Authors: Lennox-Bulow Danica , Becker Luke , Loukas Alex , Seymour Jamie , Smout Michael
Published: June 2023

Parasitic worms (helminths) infect almost all taxa across the animal kingdom, and pose significant challenges to public health and economies, particularly in developing countries. To address this problem, researchers have developed various tools to measure the motility and viability of helminths. However, the conditions used in anthelmintic screening assays are often not optimized, and can vary considerably between research teams. These unoptimized conditions may impact novel drug screens, as little is known about the effects of different conditions on the health of the target parasites. To improve future research, this study determined the effects of key assay parameters including, media type, media concentration, in-well parasite density, and assay duration on the infective third-stage larva (L3) of two types of hookworms, namely Nippostrongylus brasiliensis in rodents, and Necator americanus in humans. Conditions were screened over several days using the xCELLigence worm real-time motility assay (xWORM); a real-time impedance-based helminth motility assay using the xCELLigence system with 96-well microplates. While results varied depending on the species and media used, the study found that 500–1,000 L3/200-µL and a media concentration of 3.13–25% generally produced good to excellent assay conditions. The findings of this study can guide the future selection of xWORM assay parameters for novel drug trials involving these parasite species and serve as a suggested model for optimizing trial conditions for alternative parasite targets and assays.
Observed to expected lung area to head circumference ratio (O/E LHR) in fetuses with congenital anomalies of the kidney and urinary tract (CAKUT): assessment and evaluation as predictive factor for acute postnatal outcome—a single center study
Authors: Sourouni M. , Haisch L. , Oelmeier K. , Möllers M. , Willy D. , Sondern K. , Köster H. , Steinhard J. , Sandkötter J. , Klockenbusch W. , Schmitz R. , Potratz J.
Published: June 2023

Introduction

To assess the observed to expected lung area to head circumference ratio (O/E LHR) in fetuses with congenital anomalies of the kidney and urinary tract (CAKUT) and to explore its value as a potential predictive factor for postnatal outcome.

Methods

A retrospective single-center study was conducted on pregnancies complicated by CAKUT between 2007 and 2018. The lung-to-head ratio (LHR) was calculated for each fetus by two independent observers. Correlations between O/E LHR and various perinatal outcome factors were assessed with Spearman's rank correlation. Furthermore, nominal logistic regression was performed to assess O/E LHR as predictive factor for respiratory distress in newborn.

Results

Of 64 pregnancies complicated by CAKUT, 23 were terminated. In the 41 cases of continuation of pregnancy, newborn presenting respiratory distress with need for respiratory support in the delivery room showed earlier gestational age at onset of amniotic fluid abnormalities and at birth. Although median O/E LHR and median single deepest pocket (SDP) of amniotic fluid were significantly smaller in newborn that did develop respiratory distress with need of respiratory support in the delivery room, neither O/E LHR nor SDP were accurate predictors for the development of respiratory distress.

Conclusions

Our data show that O/E LHR alone cannot serve as a predictive marker for fetal outcome in pregnancies complicated by CAKUT, though it might still be a helpful parameter together with detailed renal ultrasound evaluation, onset of amniotic fluid abnormality and SDP, particularly in its extreme values.