bluuebunny/crossref_metadata_2025 huggingface dataset:
Artificial intelligence in critical illness and its impact on patient care: a comprehensive review
Authors: Saqib Muhammad , Iftikhar Muhammad , Neha Fnu , Karishma Fnu , Mumtaz Hassan
Published: April 2023

Artificial intelligence (AI) has great potential to improve the field of critical care and enhance patient outcomes. This paper provides an overview of current and future applications of AI in critical illness and its impact on patient care, including its use in perceiving disease, predicting changes in pathological processes, and assisting in clinical decision-making. To achieve this, it is important to ensure that the reasoning behind AI-generated recommendations is comprehensible and transparent and that AI systems are designed to be reliable and robust in the care of critically ill patients. These challenges must be addressed through research and the development of quality control measures to ensure that AI is used in a safe and effective manner. In conclusion, this paper highlights the numerous opportunities and potential applications of AI in critical care and provides guidance for future research and development in this field. By enabling the perception of disease, predicting changes in pathological processes, and assisting in the resolution of clinical decisions, AI has the potential to revolutionize patient care for critically ill patients and improve the efficiency of health systems.
Stability and Antibiofilm Efficiency of Slightly Acidic Electrolyzed Water Against Mixed-Species of Listeria monocytogenes and Staphylococcus aureus
Authors: Yan Pianpian , Chelliah Ramachandran , Jo Kyoung-hee , Selvakumar Vijayalakshmi , Chen Xiuqin , Jo Hyeon-yeong , Oh Deog Hwan
Published: April 2023

In the natural environment, most microorganisms live in mixed-species biofilms, in which the metabolism and growth of organisms are different from that in single-species biofilms. Adhesive bacteria and their biofilms on the surface of food processing equipment are the sources of cross-contamination, leading to the risk for humans. Slightly acidic electrolyzed water (SAEW) has been proposed as a novel sanitizer in the food and agriculture industry. In this study, we investigated the changes in the physical properties of SAEW under different conditions and the disinfection abilities of SAEW against spore-forming and non-spore-forming pathogens. Furthermore, we examined the disinfection abilities of SAEW after 12 months of shelf life on a mixed-species biofilm of Listeria monocytogenes Scott A and Staphylococcus aureus. The results showed that SAEW at 30 and 50 ppm achieved all-kill of the spore-forming pathogen Bacillus cereus within 30 s. Changes in the ACC and pH of the produced SAEW were generally affected by the storage conditions. Both spore-forming and non-spore-forming pathogens were not detected under treatment with 50 ppm SAEW for 5 min under HDPE-closed conditions throughout the whole storage period. Moreover, 25 mg/L SAEW can inactivate L. monocytogenes Scott A and S. aureus biofilm cells in ~2.45 and 2.57 log CFU/mL in biofilms within 5-min treatment. However, the decline of the two bacteria in the mixed-species biofilm was 1.95 and 1.43 log CFU/mL, respectively. The changes in the cell membrane permeability of the mixed-species biofilm under treatment with SAEW were observed by using atomic force microscopy and confocal laser scanning microscopy. L. monocytogenes Scott A was more sensitive to SAEW in the mixed-species biofilm cells. These findings exhibited strong antibiofilm activities of SAEW in impairing biofilm cell membranes, decreasing cell density, and eliminating biofilm, which suggest that SAEW is an excellent antibacterial agent in the food processing industries.
Complete genome analysis of sugarcane root associated endophytic diazotroph Pseudomonas aeruginosa DJ06 revealing versatile molecular mechanism involved in sugarcane development
Authors: Guo Dao-Jun , Singh Pratiksha , Yang Bin , Singh Rajesh Kumar , Verma Krishan K. , Sharma Anjney , Khan Qaisar , Qin Ying , Chen Ting-Su , Song Xiu-Peng , Zhang Bao-Qing , Li Dong-Ping , Li Yang-Rui
Published: April 2023

Sugarcane is an important sugar and bioenergy source and a significant component of the economy in various countries in arid and semiarid. It requires more synthetic fertilizers and fungicides during growth and development. However, the excess use of synthetic fertilizers and fungicides causes environmental pollution and affects cane quality and productivity. Plant growth-promoting bacteria (PGPB) indirectly or directly promote plant growth in various ways. In this study, 22 PGPB strains were isolated from the roots of the sugarcane variety GT42. After screening of plant growth-promoting (PGP) traits, it was found that the DJ06 strain had the most potent PGP activity, which was identified as Pseudomonas aeruginosa by 16S rRNA gene sequencing. Scanning electron microscopy (SEM) and green fluorescent protein (GFP) labeling technology confirmed that the DJ06 strain successfully colonized sugarcane tissues. The complete genome sequencing of the DJ06 strain was performed using Nanopore and Illumina sequencing platforms. The results showed that the DJ06 strain genome size was 64,90,034 bp with a G+C content of 66.34%, including 5,912 protein-coding genes (CDSs) and 12 rRNA genes. A series of genes related to plant growth promotion was observed, such as nitrogen fixation, ammonia assimilation, siderophore, 1-aminocyclopropane-1-carboxylic acid (ACC), deaminase, indole-3-acetic acid (IAA) production, auxin biosynthesis, phosphate metabolism, hydrolase, biocontrol, and tolerance to abiotic stresses. In addition, the effect of the DJ06 strain was also evaluated by inoculation in two sugarcane varieties GT11 and B8. The length of the plant was increased significantly by 32.43 and 12.66% and fresh weight by 89.87 and 135.71% in sugarcane GT11 and B8 at 60 days after inoculation. The photosynthetic leaf gas exchange also increased significantly compared with the control plants. The content of indole-3-acetic acid (IAA) was enhanced and gibberellins (GA) and abscisic acid (ABA) were reduced in response to inoculation of the DJ06 strain as compared with control in two sugarcane varieties. The enzymatic activities of oxidative, nitrogen metabolism, and hydrolases were also changed dramatically in both sugarcane varieties with inoculation of the DJ06 strain. These findings provide better insights into the interactive action mechanisms of the P. aeruginosa DJ06 strain and sugarcane plant development.
Photo-responsive polymeric micelles for the light-triggered release of curcumin targeting antimicrobial activity
Authors: Trigo-Gutierrez Jeffersson Krishan , Calori Italo Rodrigo , de Oliveira Bárbara Geovana , Pavarina Ana Claudia , Gonçalves Renato Sonchini , Caetano Wilker , Tedesco Antonio Claudio , Mima Ewerton Garcia de Oliveira
Published: April 2023

Nanocarriers have been successfully used to solubilize, deliver, and increase the bioavailability of curcumin (CUR), but slow CUR release rates hinder its use as a topical photosensitizer in antimicrobial photodynamic therapy. A photo-responsive polymer (PRP) was designed for the light-triggered release of CUR with an effective light activation-dependent antimicrobial response. The characterization of the PRP was compared with non-responsive micelles comprising Pluronics™ P123 and F127. According to the findings, the PRP formed photo-responsive micelles in the nanometric scale (< 100 nm) with a lower critical micelle concentration (3.74 × 10−4 M−1, 5.8 × 10−4 M−1, and 7.2 × 10−6 M−1 for PRP, F127, P123, respectively, at 25°C) and higher entrapment efficiency of CUR (88.7, 77.2, and 72.3% for PRP, F127, and P123 micelles, respectively) than the pluronics evaluated. The PRP provided enhanced protection of CUR compared to P123 micelles, as demonstrated in fluorescence quenching studies. The light-triggered release of CUR from PRP occurred with UV light irradiation (at 355 nm and 25 mW cm−2) and a cumulative release of 88.34% of CUR within 1 h compared to 80% from pluronics after 36 h. In vitro studies showed that CUR-loaded PRP was non-toxic to mammal cell, showed inactivation of the pathogenic microorganisms Candida albicans, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus, and decreased biofilm biomass when associated with blue light (455  nm, 33.84 J/cm2). The findings show that the CUR-loaded PRP micelle is a viable option for antimicrobial activity.
Vector competence evaluation of mosquitoes for Tahyna virus PJ01 strain, a new Orthobunyavirus in China
Authors: Cai Tong , Liu Ran , Jiang Yuting , Jia Nan , Jian Xianyi , Cheng Xiaolan , Song Fenglin , Guo Xiaoxia , Zhao Tongyan
Published: April 2023

Introduction

Tahyna virus (TAHV), an arbovirus of the genus Orthobunyavirus, is a cause of human diseases and less studied worldwide. In this study, a new strain of TAHV was isolated from Aedes sp. mosquitoes collected in Panjin city, Liaoning province. However, the competent vector of TAHV in China is still unknown.

Methods

The genome of newly isolated TAHV was sequenced and phylogenetic analysis is performed. Aedes albopictus and Culex pipiens pallens were orally infected with artificial virus blood meals (1:1 of virus suspension and mouse blood), the virus was detected in the midgut, ovary, salivary gland and saliva of the mosquitoes. Then, the transmission and dissemination rates, vertical transmission and horizontal transmission of the virus by the mosquitoes were assessed.

Results

Phylogenetic analysis revealed that the virus shared high similarity with TAHV and was named the TAHV PJ01 strain. After oral infection with virus blood meals, Ae. albopictus showed positive for the virus in all tested tissues with an extrinsic incubation period of 2 days and a fluctuating increasement of transmission and dissemination rates. Whereas no virus was detected in the saliva of Cx. pipiens pallens. Suckling mice bitten by infectious Ae. albopictus developed obvious neurological symptoms, including inactivity, hind-leg paralysis and difficulty turning over, when the virus titer reached 1.70×105 PFU/mL in the brain. Moreover, TAHV was detected in the eggs, larvae and adults of F1 offspring of Ae. albopictus.

Discussion

Ae. albopictus is an efficient vector to transmit TAHV but Cx. pipiens pallens is not. Ae. albopictus is also a reservoir host that transmits the virus vertically, which further increases the risk of outbreaks. This study has important epidemiological implications for the surveillance of pathogenic viruses in China and guiding comprehensive vector control strategies to counteract potential outbreaks in future.
Bacterial extracellular vesicles and associated functional proteins in fermented dairy products with Lacticaseibacillus paracasei
Authors: Pérez Martínez Gaspar , Giner-Pérez Lola , Castillo-Romero Keshia F.
Published: April 2023

Cells of all kingdoms produce extracellular vesicles (EVs); hence, they are present in most environments and body fluids. Lacticaseibacillus paracasei produces EVs that have attached biologically active proteins (P40 and P75). In this study, EV and functional proteins were found in five different commercial dairy-fermented products carrying L. paracasei. Strains present in those products were isolated, and with one exception, all produced small EVs (24–47 d.nm) carrying P40 and P75. In order to winnow bacterial EV from milk EV, products were subjected to centrifugal fractionation at 15,000 × g (15 K), 33,000 × g (33 K), and 100,000 × g (100 K). P75 was present in all supernatants and pellets, but P40 was only found in two products bound to the 15 and 33 K pellets, and 16S rDNA of L. paracasei could be amplified from all 100 K EVs, indicating the presence of L. paracaseiEV. To investigate the interactions of bacterial EV and proteins with milk EV, L. paracasei BL23 EV was added to three commercial UHT milk products. Small-size vesicles (50–60 d.nm) similar to L. paracasei BL23 EV were found in samples from 100 K centrifugations, but intriguingly, P40 and P75 were bound to EV in 15 and 33 K pellets, containing bovine milk EV of larger size (200–300 d.nm). Sequencing 16S rDNA bands amplified from EV evidenced the presence of bacterial EVs of diverse origins in milk and fermented products. Furthermore, L. paracasei 16S rDNA could be amplified with species-specific primers from all samples, showing the presence of L. paracasei EV in all EV fractions (15, 33, and 100 K), suggesting that these bacterial EVs possibly aggregate and are co-isolated with EV from milk. P40 and P75 proteins would be interacting with specific populations of milk EV (15 and 33 K) because they were detected bound to them in fermented products and milk, and this possibly forced the sedimentation of part of L. paracasei EV at lower centrifugal forces. This study has solved technically complex problems and essential questions which will facilitate new research focusing on the molecular behavior of probiotics during fermentation and the mechanisms of action mediating the health benefits of fermented products.
Biomechanical and biochemical assessment of YB-1 expression in A375 melanoma cell line: Exploratory study
Authors: Cykowska Anna , Hofmann Ulf Krister , Tiwari Aadhya , Kosnopfel Corinna , Riester Rosa , Danalache Marina
Published: April 2023

Malignant melanoma is the most lethal form of skin cancer. Y-box binding protein 1 (YB-1) plays a prominent role in mediating metastatic behavior by promoting epithelial-to-mesenchymal transition (EMT). Migratory melanoma cells exhibit two major migration modes: elongated mesenchymal or rounded amoeboid. Using A375 melanoma cell line and the YB-1 knock-out model, we aimed to elucidate biochemical and biomechanical changes in migration signaling pathways in the context of melanoma metastases. We subjected A375 YB-1 knock-out and parental cells to atomic force microscopy (stiffness determination), immunolabelling, and proteome analysis. We found that YB-1 expressing cells were significantly stiffer compared to the corresponding YB-1 knock-out cell line. Our study demonstrated that the constitutive expression of YB-1 in A375 melanoma cell line appears to be closely related to known biomarkers of epithelial-to-mesenchymal transition, nestin, and vimentin, resulting in a stiffer phenotype, as well as a wide array of proteins involved in RNA, ribosomes, and spliceosomes. YB-1 knock-out resulted in nestin depletion and significantly lower vimentin expression, as well as global upregulation of proteins related to the cytoskeleton and migration. YB-1 knock-out cells demonstrated both morphological features and biochemical drivers of mesenchymal/ameboid migration. Melanoma is a highly plastic, adaptable, and aggressive tumor entity, capable of exhibiting characteristics of different migratory modes.
Novel rRNA transcriptional activity of NhaR revealed by its growth recovery for the bipA-deleted Escherichia coli at low temperature
Authors: Choi Eunsil , Huh Ahhyun , Hwang Jihwan
Published: April 2023

The BipA protein is a universally conserved GTPase in bacterial species and is structurally similar to translational GTPases. Despite its wide distribution, BipA is dispensable for growth under optimal growth conditions but is required under stress conditions. In particular, bipA-deleted cells (ESC19) have been shown to display a variety of phenotypic changes in ribosome assembly, capsule production, lipopolysaccharide (LPS) synthesis, biofilm formation, and motility at low temperature, suggesting its global regulatory roles in cold adaptation. Here, through genomic library screening, we found a suppressor clone containing nhaR, which encodes a Na+-responsive LysR-type transcriptional regulator and whose gene product partially restored the growth of strain ESC19 at 20°C. The suppressed cells showed slightly reduced capsule production and improved biofilm-forming ability at 20°C, whereas the defects in the LPS core and swimming motility were not restored but aggravated by overexpression of nhaR. Notably, the overexpression partially alleviated the defects in 50S ribosomal subunit assembly and rRNA processing of ESC19 cells by enhancing the overall transcription of rRNA. Electrophoretic mobility shift assay revealed the association of NhaR with the promoter of seven rrn operons, suggesting that NhaR directly regulates rRNA transcription in ESC19 at 20°C. The suppressive effects of NhaR on ribosomes, capsules, and LPS were dependent on its DNA-binding activity, implying that NhaR might be a transcriptional factor involved in regulating these genes at 20°C. Furthermore, we found that BipA may be involved in adaptation to salt stress, designating BipA as a global stress-responsive regulator, as the deletion of bipA led to growth defects at 37°C and high Na+ concentrations without ribosomal defects.
Projections of the insular cortex to orbitofrontal and medial prefrontal cortex: A tracing study in the rat
Authors: Mathiasen Mathias L. , Aggleton John P. , Witter Menno P.
Published: April 2023

The dense fiber pathways that connect the insular cortex with frontal cortices are thought to provide these frontal areas with interoceptive information, crucial for their involvement in executive functions. Using anterograde neuroanatomical tracing, we mapped the detailed organization of the projections from the rat insular cortex to its targets in orbitofrontal (OFC) and medial prefrontal (mPFC) cortex. In OFC, main insular projections distribute to lateral and medial parts, avoiding ventral parts. Whereas projections from the primary gustatory cortex densely innervate dorsolateral OFC, likely corresponding to what in primates is known as the secondary gustatory cortex, these projections avoid mPFC. Instead, mPFC is targeted almost exclusively by projections from agranular fields of the insular cortex. Finally, “parietal” domains of the insular cortex project specifically to the dorsolateral OFC, and strongly innervate ventral portions of mPFC, i.e., the dorsal peduncular cortex.
Automatic vessel plate number recognition for surface unmanned vehicles with marine applications
Authors: Zhang Renran , Zhang Lei , Su Yumin , Yu Qingze , Bai Gaoyi
Published: April 2023

In the practical application scenarios of USVs, it is necessary to identify a vessel in order to accomplish tasks. Considering the sensors equipped on the USV, visible images provide the fastest and most efficient way of determining the hull number. The current studies divide the task of recognizing vessel plate number into two independent subtasks: text localization in the image and its recognition. Then, researchers are focusing on improving the accuracy of localization and recognition separately. However, these methods cannot be directly applied to USVs due to the difference between these two application scenarios. In addition, as the two independent models are serial, there will be inevitable propagation of error between them, as well as an increase in time costs, resulting in a less satisfactory performance. In view of the above, we proposed a method based on object detection model for recognizing vessel plate number in complicated sea environments applied to USVs. The accuracy and stability of model have been promoted by recursive gated convolution structure, decoupled head, reconstructing loss function, and redesigning the sizes of anchor boxes. To facilitate this research, a vessel plate number dataset is established in this paper. Furthermore, we conducted a experiment utilizing a USV platform in the South China Sea. Compared with the original YOLOv5, the mAP (mean Average Precision) value of proposed method is increased by 6.23%. The method is employed on the “Tian Xing” USV platform and the experiment results indicates both the ship and vessel plate number can be recognized in real-time. In both the civilian and military sectors, this has a great deal of significance.
Hedgehog-GLI mediated control of renal formation and malformation
Authors: Greenberg Dina , D’Cruz Robert , Lacanlale Jon L. , Rowan Christopher J. , Rosenblum Norman D.
Published: April 2023

CAKUT is the leading cause of end-stage kidney disease in children and comprises a broad spectrum of phenotypic abnormalities in kidney and ureter development. Molecular mechanisms underlying the pathogenesis of CAKUT have been elucidated in genetic models, predominantly in the mouse, a paradigm for human renal development. Hedgehog (Hh) signaling is critical to normal embryogenesis, including kidney development. Hh signaling mediates the physiological development of the ureter and stroma and has adverse pathophysiological effects on the metanephric mesenchyme, ureteric, and nephrogenic lineages. Further, disruption of Hh signaling is causative of numerous human developmental disorders associated with renal malformation; Pallister-Hall Syndrome (PHS) is characterized by a diverse spectrum of malformations including CAKUT and caused by truncating variants in the middle-third of the Hh signaling effector GLI3. Here, we outline the roles of Hh signaling in regulating murine kidney development, and review human variants in Hh signaling genes in patients with renal malformation.
Asymmetry measures for quantification of mechanisms contributing to dynamic stability during stepping-in-place gait
Authors: Peterka Robert J. , Gruber-Fox Apollonia , Heeke Paige K.
Published: April 2023

The goal of this study is to introduce and to motivate the use of new quantitative methods to improve our understanding of mechanisms that contribute to the control of dynamic balance during gait. Dynamic balance refers to the ability to maintain a continuous, oscillating center-of-mass (CoM) motion of the body during gait even though the CoM frequently moves outside of the base of support. We focus on dynamic balance control in the frontal plane or medial–lateral (ML) direction because it is known that active, neurally-mediated control mechanisms are necessary to maintain ML stability. Mechanisms that regulate foot placement on each step and that generate corrective ankle torque during the stance phase of gait are both known to contribute to the generation of corrective actions that contribute to ML stability. Less appreciated is the potential role played by adjustments in step timing when the duration of the stance and/or swing phases of gait can be shortened or lengthened to allow torque due to gravity to act on the body CoM over a shorter or longer time to generate corrective actions. We introduce and define four asymmetry measures that provide normalized indications of the contribution of these different mechanisms to gait stability. These measures are ‘step width asymmetry’, ‘ankle torque asymmetry’, ‘stance duration asymmetry’, and ‘swing duration asymmetry’. Asymmetry values are calculated by comparing corresponding biomechanical or temporal gait parameters from adjacent steps. A time of occurrence is assigned to each asymmetry value. An indication that a mechanism is contributing to ML control is obtained by comparing asymmetry values to the ML body motion (CoM angular position and velocity) at the time points associated with the asymmetry measures. Example results are demonstrated with measures obtained during a stepping-in-place (SiP) gait performed on a stance surface that either remained fixed and level or was pseudorandomly tilted to disturb balance in the ML direction. We also demonstrate that the variability of asymmetry measures obtained from 40 individuals during unperturbed, self-paced SiP were highly correlated with corresponding coefficient of variation measures that have previously been shown to be associated with poor balance and fall risk.
The α2δ-1-NMDA receptor complex and its potential as a therapeutic target for ischemic stroke
Authors: Wu Tao , Chen Shao-Rui , Pan Hui-Lin , Luo Yi
Published: April 2023

N-methyl-D-aspartate receptors (NMDARs) play a critical role in excitotoxicity caused by ischemic stroke, but NMDAR antagonists have failed to be translated into clinical practice for treating stroke patients. Recent studies suggest that targeting the specific protein–protein interactions that regulate NMDARs may be an effective strategy to reduce excitotoxicity associated with brain ischemia. α2δ-1 (encoded by the Cacna2d1 gene), previously known as a subunit of voltage-gated calcium channels, is a binding protein of gabapentinoids used clinically for treating chronic neuropathic pain and epilepsy. Recent studies indicate that α2δ-1 is an interacting protein of NMDARs and can promote synaptic trafficking and hyperactivity of NMDARs in neuropathic pain conditions. In this review, we highlight the newly identified roles of α2δ-1-mediated NMDAR activity in the gabapentinoid effects and NMDAR excitotoxicity during brain ischemia as well as targeting α2δ-1-bound NMDARs as a potential treatment for ischemic stroke.
Risks of suicide in migraine, non-migraine headache, back, and neck pain: a systematic review and meta-analysis
Authors: Giakas Alec , Mangold Kiersten , Androulakis Anthony , Hyduke Noah , Galynker Igor , Thiam Melinda , Cai Guoshuai , Androulakis X. Michelle
Published: April 2023

Objective

To conduct a systematic review and meta-analysis on suicidal ideation, attempts, and death in patients with head, neck, and back pain.

Method

Search was performed using PubMed, Embase, and Web of Science from the date of the first available article through September 31, 2021. A random effects model was used to estimate the pooled odds ratios (ORs) and 95% confidence intervals (95% CI) for the association between suicidal ideation and/or attempt and head, back/neck pain conditions. Articles describing non-migraine headache disorders and death by suicide were also reviewed but not included in the meta-analysis due to an insufficient number of studies.

Results

A total of 20 studies met criteria for systemic review. A total of 186,123 migraine patients and 135,790 of neck/back pain patients from 11 studies were included in the meta-analysis. The meta-analysis showed that the estimated risk of combined suicidal ideation and attempt in migraine [OR 2.49; 95% CI: 2.15–2.89] is greater than that in back/neck pain pain [OR 2.00; 95% CI: 1.63–2.45] compared to non-pain control groups. Risk of suicide ideation/planning is 2 folds higher [OR: 2.03; 95% CI: 1.92–2.16] and risk of suicide attempt is more than 3 folds higher [OR: 3.47; 95% CI: 2.68–4.49] in migraine as compared to healthy controls.

Conclusion

There is an elevated risk of suicidal ideation and attempt in both migraine and neck/back pain patients in comparison to healthy controls, and this risk is particularly higher among migraine patients. This study underscores the critical need for suicide prevention in migraine patients.
Cox regression and survival analysis from the tauro-urso-deoxycholic trial in amyotrophic lateral sclerosis
Authors: Reggiardo Giorgio , Lo Giudice Maria , Lalli Stefania , Rinaldi Gilberto , Albanese Alberto
Published: April 2023

Recent phase II pilot clinical trials suggested that tauro-urso-deoxycholic acid (TUDCA) might slow functional decline and increase survival in patients with amyotrophic lateral sclerosis (ALS). We performed a multivariate analysis of the original TUDCA cohort to better define the treatment effect and allow comparability with other trials. Linear regression slope analysis showed statistical differences in the decline rate, favoring the active treatment arm (p-value < 0.01; −0.262 for the TUDCA group and −0.388 for the placebo group). Mean survival time, estimated by the Kaplan–Meier analysis, showed a 1-month difference, favoring active treatment (log-rank test p-value = 0.092). Cox regression analysis demonstrated that placebo treatment was associated with a higher risk of death (p-value = 0.055). These data further support the disease-modifying effect of TUDCA monotherapy and raise the question of what could be the additional effect of combining TUDCA with sodium phenylbutyrate.
Microstructural and functional impairment of the basal ganglia in Wilson’s disease: a multimodal neuroimaging study
Authors: Su Dongning , Zhang Zhijin , Zhang Zhe , Gan Yawen , Zhang Yingkui , Liu Xinyao , Bi Jingfeng , Ma Lingyan , Zhao Huiqing , Wang Xuemei , Wang Zhan , Ma Huizi , Sifat Shairy , Zhou Junhong , Li Wei , Wu Tao , Jing Jing , Feng Tao
Published: April 2023

Objectives

Magnetic susceptibility changes in brain MRI of Wilson’s disease (WD) patients have been described in subcortical nuclei especially the basal ganglia. The objectives of this study were to investigate its relationship with other microstructural and functional alterations of the subcortical nuclei and the diagnostic utility of these MRI-related metrics.

Methods

A total of 22 WD patients and 20 healthy controls (HCs) underwent 3.0T multimodal MRI scanning. Susceptibility, volume, diffusion microstructural indices and whole-brain functional connectivity of the putamen (PU), globus pallidus (GP), caudate nucleus (CN), and thalamus (TH) were analyzed. Receiver operating curve (ROC) was applied to evaluate the diagnostic value of the imaging data. Correlation analysis was performed to explore the connection between susceptibility change and microstructure and functional impairment of WD and screen for neuroimaging biomarkers of disease severity.

Results

Wilson’s disease patients demonstrated increased susceptibility in the PU, GP, and TH, and widespread atrophy and microstructural impairments in the PU, GP, CN, and TH. Functional connectivity decreased within the basal ganglia and increased between the PU and cortex. The ROC model showed higher diagnostic value of isotropic volume fraction (ISOVF, in the neurite orientation dispersion and density imaging model) compared with susceptibility. Severity of neurological symptoms was correlated with volume and ISOVF. Susceptibility was positively correlated with ISOVF in GP.

Conclusion

Microstructural impairment of the basal ganglia is related to excessive metal accumulation in WD. Brain atrophy and microstructural impairments are useful neuroimaging biomarkers for the neurological impairment of WD.
Efficient strategies based on behavioral and electrophysiological methods for epilepsy-related gene screening in the Drosophila model
Authors: Liu Chu-Qiao , Qu Xiao-Chong , He Ming-Feng , Liang De-Hai , Xie Shi-Ming , Zhang Xi-Xing , Lin Yong-Miao , Zhang Wen-Jun , Wu Ka-Chun , Qiao Jing-Da
Published: April 2023

Introduction

With the advent of trio-based whole-exome sequencing, the identification of epilepsy candidate genes has become easier, resulting in a large number of potential genes that need to be validated in a whole-organism context. However, conducting animal experiments systematically and efficiently remains a challenge due to their laborious and time-consuming nature. This study aims to develop optimized strategies for validating epilepsy candidate genes using theDrosophilamodel.

Methods

This study incorporate behavior, morphology, and electrophysiology for genetic manipulation and phenotypic examination. We utilized the Gal4/UAS system in combination with RNAi techniques to generate loss-of-function models. We performed a range of behavioral tests, including two previously unreported seizure phenotypes, to evaluate the seizure behavior of mutant and wild-type flies. We used Gal4/UAS-mGFP flies to observe the morphological alterations in the brain under a confocal microscope. We also implemented patch-clamp recordings, including a novel electrophysiological method for studying synapse function and improved methods for recording action potential currents and spontaneous EPSCs on targeted neurons.

Results

We applied different techniques or methods mentioned above to investigate four epilepsy-associated genes, namelyTango14,Klp3A,Cac, andSbf, based on their genotype-phenotype correlation. Our findings showcase the feasibility and efficiency of our screening system for confirming epilepsy candidate genes in the Drosophila model.

Discussion

This efficient screening system holds the potential to significantly accelerate and optimize the process of identifying epilepsy candidate genes, particularly in conjunction with trio-based whole-exome sequencing.
Quercetin activates vitamin D receptor and ameliorates breast cancer induced hepatic inflammation and fibrosis
Authors: Sannappa Gowda Nirmala G. , Shiragannavar Varsha D. , Puttahanumantharayappa Lakshana D. , Shivakumar Ashwini Tumkur , Dallavalasa Siva , Basavaraju Chaithanya G. , Bhat Smitha S. , Prasad Shashanka K. , Vamadevaiah Ravishankar M. , Madhunapantula SubbaRao V. , Santhekadur Prasanna K.
Published: April 2023

Aims

To explore the hepatoprotective role of quercetin and its novel molecular mechanism of action on breast cancer associated hepatic inflammation and fibrosis via Vitamin D receptor (VDR).

Main methods

We used Ehrlich Ascites Carcinoma (mouse mammary carcinoma) model for our in-vivo experiments and human breast cancer cell lines for in-vitro assays. We inoculated 1.5 × 106 Ehrlich ascites carcinoma cells into female Swiss albino mice. Quercetin (50 mg/kg) was administered intraperitoneally for 15 days. Liver enzymes activity was determined using a spectrophotometric assay. The hallmarks of inflammation and fibrosis were determined using Immunohistochemistry. The effect of quercetin on tumor formation was elucidated using human breast cancer cell lines and chick chorioallantoic membrane assay. Docking study was performed to explore the binding mode of quercetin with VDR.

Key findings

In EAC tumor-bearing mice, cell numbers, tumor volume, body weight and liver weight were dramatically increased, while they significantly decreased in mice treated with quercetin. Additionally, the peritoneal neo-angiogenesis was also significantly suppressed in the quercetin-treated mice, compared to the control. In addition, quercetin treated EAC tumor bearing mice had lower levels of liver enzymes, decreased hepatic inflammation and fibrosis compared with EAC tumor bearing mice. Docking study confirmed VDR-quercetin interaction. Furthermore, in-vitro assays and chick chorioallantoic membrane assay revealed the Vitamin D mimicking effect of quercetin.

Significance

Dietary flavonoid, quercetin could act as a promising therapeutic drug to suppress the breast cancer induced tumor angiogenesis, hepatic inflammation, and fibrosis possibly via activation of VDR.
A novel 25-ferroptosis-related gene signature for the prognosis of gliomas
Authors: Peng Xiaojiang , Liu Chun , Li Jing , Bao Zeqing , Huang Tao , Zeng Lingfeng , He Qixiong , Xue Daojin
Published: April 2023

Background

Ferroptosis is closely associated with cancer and is of great importance in the immune evasion of cancer. However, the relationship between ferroptosis and glioma is unclear.

Methods

We downloaded the expression profiles and clinical data of glioma from the GlioVis database and obtained the expression profiles of ferroptosis genes. A ferroptosis-related gene signature was developed for the prognosis of gliomas.

Results

We screened out prognostic ferroptosis genes, named ferroptosis-related genes, by the Cox regression method. Based on these genes, we used unsupervised clustering to obtain two different clusters; the principal component analysis algorithm was applied to determine the gene score of each patient, and then all the patients were classified into two subgroups. Results showed that there exist obvious differences in survival between different clusters and different gene score subgroups. The prognostic model constructed by the 25 ferroptosis-related genes was then evaluated to predict the clinicopathological features of immune activity in gliomas.

Conclusion

The ferroptosis-related genes play an important role in the malignant process of gliomas, potentially contributing to the development of prognostic stratification and treatment strategies.
High VISTA expression is linked to a potent epithelial-mesenchymal transition and is positively correlated with PD1 in breast cancer
Authors: Rezouki Ibtissam , Zohair Basma , Ssi Saadia Ait , Karkouri Mehdi , Razzouki Ibtissam , Elkarroumi Mohamed , Badou Abdallah
Published: April 2023

Breast cancer is the most common type of tumor in women worldwide. Immune checkpoint inhibitors, particularly anti-PDL1, have shown promise as a therapeutic approach for managing this disease. However, this type of immunotherapy still fails to work for some patients, leading researchers to explore alternative immune checkpoint targets. The Ig suppressor of T cell activation domain V (VISTA) has emerged as a novel immune checkpoint that delivers inhibitory signals to T cells and has demonstrated encouraging results in various cancers. Our study investigated the association of VISTA expression with clinicopathological parameters in breast cancer patients, its involvement in the Epithelial-Mesenchymal-Transition (EMT) process, and its correlation with PD1 expression. Transcriptomic analysis revealed that VISTA was associated with lobular and metaplastic histological type, tumor size, lymph node status, ER and PR negative status, and the TNBC molecular subtype. Furthermore, VISTA expression was strongly associated with an immunosuppressive tumor microenvironment. Immunohistochemistry analysis corroborated the transcriptomic results, indicating that VISTA was expressed in most immune cells (94%) and was significantly expressed in breast cancer tumor cells compared to matched adjacent tissues. Our study also showed for the first time that VISTA overexpression in breast cancer cells could be associated with the EMT process. Additionally, we identified a positive correlation between VISTA and PD-1 expression. Together, these results highlight the immunosuppressive effect of VISTA in breast cancer patients and suggest that bi-specific targeting of VISTA and PD-1 in combination therapy could be beneficial for these patients.
Machine learning-based construction of a ferroptosis and necroptosis associated lncRNA signature for predicting prognosis and immunotherapy response in hepatocellular cancer
Authors: Zhao Lei , You Zhixuan , Bai Zhixun , Xie Jian
Published: April 2023

Introduction

Liver hepatocellular carcinoma (LIHC), one of the most common malignancies worldwide, occurs with high incidence and mortality. Ferroptosis and necroptosis are critically associated with LIHC prognosis. Some long non-coding RNAs (lncRNAs) have been found to induce ferroptosis and necroptosis in hepatocellular carcinoma cells.

Methods

Cox regression analysis was used to construct a risk model for LIHC based on differentially expressed ferroptosis and necroptosis related lncRNAs (F-NLRs), and their expression in SMMC7721, HepG2 and WRL68 cells was detected by qPCR.

Results

Five F-NLRs were associated with LIHC prognosis, including KDM4A-AS1, ZFPM2-AS1, AC099850.3, MKLN1-AS, and BACE1-AS. Kaplan-Meier survival analysis indicated that patients with LIHC in the high-risk group were associated with poor prognosis. The combined F-NLR signature model demonstrated a prognostic AUC value of 0.789 and was more accurate than standard clinical variables for predicting LIHC prognosis. T cell functions and immunotherapy responses differed significantly between patients in the low- and high-risk groups. Additionally, immune checkpoints and m6A-related genes were differentially expressed between patients in the two risk groups. Furthermore, proteins encoded by the five F-NLRs were overexpressed in four liver cancer cell lines compared to that in human liver cell line WRL68. Pan-cancer examination revealed that expression levels of the five F-NLRs differed between most common tumor types and normal tissues.

Conclusion

F-NLRs identified in this study provide a predictive signature representing ferroptosis and necroptosis in LIHC, which correlated well with patient prognosis, clinicopathological characteristics, and immunotherapy responses. The study findings help to elucidate the mechanisms of F-NLRs in LIHC and provide further guidance for the selection and development of immunotherapeutic agents for LIHC.
Deflux® Endoscopic Treatment of Vesicoureteral Reflux (VUR) in Japan
Authors:   The Japanese Deflux Injection Therapy Study Group
Published: April 2023

Introduction

The aim of this study is to present the results of a multi-institutional outcome analysis conducted to determine the extent of endoscopic Deflux® injection for treating primary vesicoureteral reflux in Japan.

Methods

A 22-question survey was distributed to 174 certified pediatric urologists (Ninteii in Japanese) and councilors of the Japanese Society of Pediatric Urology working at 140 centers to determine the usage and clinical efficacy of Deflux® for treating primary vesicoureteral reflux in Japan.

Results

Forty-three of 140 (30.7%) centers participated, which exceeded participation rates of 27.9 and 18.0% for similar surveys conducted in America in 2006 and 2014, respectively. Deflux® was administered at 43 centers using subureteral transurethral injection (n = 19; 44.2%), hydrodistention implantation (n = 5; 11.6%), or double hydrodistention implantation (n = 19; 44.2%) and was the first-line treatment for primary vesicoureteral reflux at 39 (90.7%) centers. Overall, 1,563 ureters were treated in 1,076 patients. The male:female ratio was 527:549; mean follow-up was 5.1 years (range: 3.2–8 years); mean age at diagnosis of primary vesicoureteral reflux was 4.2 years, and mean age at first Deflux® treatment was 6.2 years. Overall cure rates were 65.3% after one Deflux® treatment, 75.3% after two, and 77.3% after three.

Conclusion

To the best of our knowledge, this is the first multi-institutional outcome analysis of Deflux® usage for primary vesicoureteral reflux in Japan.
Metformin acts as a dual glucose regulator in mouse brain
Authors: Jin Bo-Yeong , Kim Hyun-Ju , Oh Mi-Jeong , Ha Na-Hee , Jeong Yong Taek , Choi Sang-Hyun , Lee Jun-Seok , Kim Nam Hoon , Kim Dong-Hoon
Published: April 2023

Aims: Metformin improves glucose regulation through various mechanisms in the periphery. Our previous study revealed that oral intake of metformin activates several brain regions, including the hypothalamus, and directly activates hypothalamic S6 kinase in mice. In this study, we aimed to identify the direct effects of metformin on glucose regulation in the brain.

Materials and methods: We investigated the role of metformin in peripheral glucose regulation by directly administering metformin intracerebroventricularly in mice. The effect of centrally administered metformin (central metformin) on peripheral glucose regulation was evaluated by oral or intraperitoneal glucose, insulin, and pyruvate tolerance tests. Hepatic gluconeogenesis and gastric emptying were assessed to elucidate the underlying mechanisms. Liver-specific and systemic sympathetic denervation were performed.

Results: Central metformin improved the glycemic response to oral glucose load in mice compared to that in the control group, and worsened the response to intraperitoneal glucose load, indicating its dual role in peripheral glucose regulation. It lowered the ability of insulin to decrease serum glucose levels and worsened the glycemic response to pyruvate load relative to the control group. Furthermore, it increased the expression of hepatic G6pc and decreased the phosphorylation of STAT3, suggesting that central metformin increased hepatic glucose production. The effect was mediated by sympathetic nervous system activation. In contrast, it induced a significant delay in gastric emptying in mice, suggesting its potent role in suppressing intestinal glucose absorption.

Conclusion: Central metformin improves glucose tolerance by delaying gastric emptying through the brain-gut axis, but at the same time worsens it by increasing hepatic glucose production via the brain-liver axis. However, with its ordinary intake, central metformin may effectively enhance its glucose-lowering effect through the brain-gut axis, which could surpass its effect on glucose regulation via the brain-liver axis.
Combination therapy for high-volume versus low-volume metastatic hormone-sensitive prostate cancer: A systematic review and network meta-analysis
Authors: Jian Tengteng , Zhan Yang , Yu Ying , Yu Kai , Hu Rui , Wang Jixue , Lu Ji
Published: April 2023

Purpose: To conduct a systematic review and network meta-analysis (NMA) to compare the efficacy of currently available combination therapies in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

Methods: Qualified publications were searched in the PubMed, Embase, and Cochrane CENTRAL databases. Overall survival (OS) and radiographic progression-free survival (rPFS) were indirectly compared and assessed using NMA and the surface under the cumulative ranking curve, respectively. Adverse events (AEs) were also compared.

Results: Eighteen publications from 12 trials were analyzed in the NMA. In the overall population, triplet therapy was ranked first for OS (hazard ratio [HR]: 0.57, 95% credible interval [CrI]: 0.48–0.67) and rPFS (HR: 0.33, 95% CrI:0.26–0.41) compared with androgen deprivation therapy (ADT) with or without standard non-steroidal antiandrogen. In high-volume mHSPC, triplet therapy was also ranked first in OS (HR, 0.57; 95% CrI:0.44–0.75) and rPFS(HR, 0.29; 95% CrI: 0.23–0.37). Specifically, abiraterone triplet therapy was ranked first in OS (HR, 0.52; 95% CrI:0.38–0.72) and rPFS (HR, 0.28; 95% CrI:0.21–0.38) among all therapies. ADT plus rezvilutamide was ranked first among doublet therapies (OS: HR, 0.58; 95% CrI:0.44–0.77; rPFS: HR, 0.44; 95% CrI:0.33–0.58). In low-volume mHSPC, doublet and triplet therapies were ranked first in OS (HR:0.68, 95% CrI:0.58–0.80) and rPFS (HR:0.37, 95% CrI:0.25–0.55), respectively. ADT plus apalutamide was ranked first in OS among all therapies (HR:0.53, 95% CrI:0.35–0.79), whereas enzalutamide triplet therapy was ranked first in rPFS (HR:0.27, 95% CrI:0.15–0.51). ADT plus rezvilutamide showed a relatively lower incidence of AE among all therapies (OR:1.00, 95% CrI:0.31–3.15), and a lower risk of specific AEs among doublet therapies, particularly regarding seizure (OR, 0.29; 95% CrI:0.01–8.18) and fatigue (OR, 0.96; 95% CrI:0.63–1.46). Docetaxel-based doublet or triplet therapies significantly increased the risk of any AEs or grade ≥3 AEs.

Conclusion: Triplet therapy was the best treatment option for the overall population. In high-volume mHSPC, triplet therapy and ADT plus rezvilutamide had the greatest potential to benefit patients. Patients with low-volume mHSPC were most likely to benefit from ADT plus androgen receptor-targeted agents. Triplet therapy was associated with a higher risk of AEs than the other therapies.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022375347, identifier PROSPERO:CRD42022375347.
Bulbospinal nociceptive ON and OFF cells related neural circuits and transmitters
Authors: Peng Bingxue , Jiao Yingfu , Zhang Yunchun , Li Shian , Chen Sihan , Xu Saihong , Gao Po , Fan Yinghui , Yu Weifeng
Published: April 2023

The rostral ventromedial medulla (RVM) is a bulbospinal nuclei in the descending pain modulation system, and directly affects spinal nociceptive transmission through pronociceptive ON cells and antinociceptive OFF cells in this area. The functional status of ON and OFF neurons play a pivotal role in pain chronification. As distinct pain modulative information converges in the RVM and affects ON and OFF cell excitability, neural circuits and transmitters correlated to RVM need to be defined for an in-depth understanding of central-mediated pain sensitivity. In this review, neural circuits including the role of the periaqueductal gray, locus coeruleus, parabrachial complex, hypothalamus, amygdala input to the RVM, and RVM output to the spinal dorsal horn are discussed. Meanwhile, the role of neurotransmitters is concluded, including serotonin, opioids, amino acids, cannabinoids, TRPV1, substance P and cholecystokinin, and their dynamic impact on both ON and OFF cell activities in modulating pain transmission. Via clarifying potential specific receptors of ON and OFF cells, more targeted therapies can be raised to generate pain relief for patients who suffer from chronic pain.