bluuebunny/crossref_metadata_2025 huggingface dataset:
Aerosolized miR-138-5p and miR-200c targets PD-L1 for lung cancer prevention
Authors: Zhang Qi , Pan Jing , Xiong Donghai , Zheng Junjun , McPherson Kristi N. , Lee Sangbeom , Huang Mofei , Xu Yitian , Chen Shu-hsia , Wang Yian , Hildebrandt Ruiz Lea , You Ming
Published: July 2023

The development of chemopreventive strategies with the ability to prevent the progression of lung lesions to malignant cancers would reduce the mortality and morbidity resulting from this deadly disease. Delivery of microRNA (miRNA) by inhalation is a novel method for lung cancer prevention. In this study, we investigated the combined efficacy of aerosolized miR-138-5p and miR-200c miRNA mimics in lung cancer prevention. Combination of the two miRNAs inhibited Benzo(a)pyrene (B((a))P)-induced lung adenomas and N-nitroso-tris-chloroethylurea (NTCU)-induced lung squamous cell carcinomas with no detectable side effects. Using single-cell RNA sequencing (scRNA-seq) and imaging mass cytometry (IMC), we found that both miRNAs inhibited programmed cell death ligand 1 (PD-L1) expression. Our flow cytometry results showed that aerosolized delivery of combined miRNAs increased CD4+ and CD8+ T cells and reduced the expression of programmed cell death protein 1 (PD-1) and T-regulatory cells. Our results demonstrated that the delivery of aerosolized microRNAs targeting PD-L1 can be highly effective in preventing lung cancer development and progression in mice.
End-binding protein 1 regulates the metabolic fate of CD4+ T lymphoblasts and Jurkat T cells and the organization of the mitochondrial network
Authors: Gómez-Morón Álvaro , Requena Silvia , Pertusa Clara , Lozano-Prieto Marta , Calzada-Fraile Diego , Scagnetti Camila , Sánchez-García Inés , Calero-García Ana Adela , Izquierdo Manuel , Martín-Cófreces Noa B.
Published: July 2023

The organization of the mitochondrial network is relevant for the metabolic fate of T cells and their ability to respond to TCR stimulation. This arrangement depends on cytoskeleton dynamics in response to TCR and CD28 activation, which allows the polarization of the mitochondria through their change in shape, and their movement along the microtubules towards the immune synapse. This work focus on the role of End-binding protein 1 (EB1), a protein that regulates tubulin polymerization and has been previously identified as a regulator of intracellular transport of CD3-enriched vesicles. EB1-interferred cells showed defective intracellular organization and metabolic strength in activated T cells, pointing to a relevant connection of the cytoskeleton and metabolism in response to TCR stimulation, which leads to increased AICD. By unifying the organization of the tubulin cytoskeleton and mitochondria during CD4+ T cell activation, this work highlights the importance of this connection for critical cell asymmetry together with metabolic functions such as glycolysis, mitochondria respiration, and cell viability.
Mechanisms of airway epithelial injury and abnormal repair in asthma and COPD
Authors: Raby Katie Louise , Michaeloudes Charalambos , Tonkin James , Chung Kian Fan , Bhavsar Pankaj Kumar
Published: July 2023

The airway epithelium comprises of different cell types and acts as a physical barrier preventing pathogens, including inhaled particles and microbes, from entering the lungs. Goblet cells and submucosal glands produce mucus that traps pathogens, which are expelled from the respiratory tract by ciliated cells. Basal cells act as progenitor cells, differentiating into different epithelial cell types, to maintain homeostasis following injury. Adherens and tight junctions between cells maintain the epithelial barrier function and regulate the movement of molecules across it. In this review we discuss how abnormal epithelial structure and function, caused by chronic injury and abnormal repair, drives airway disease and specifically asthma and chronic obstructive pulmonary disease (COPD). In both diseases, inhaled allergens, pollutants and microbes disrupt junctional complexes and promote cell death, impairing the barrier function and leading to increased penetration of pathogens and a constant airway immune response. In asthma, the inflammatory response precipitates the epithelial injury and drives abnormal basal cell differentiation. This leads to reduced ciliated cells, goblet cell hyperplasia and increased epithelial mesenchymal transition, which contribute to impaired mucociliary clearance and airway remodelling. In COPD, chronic oxidative stress and inflammation trigger premature epithelial cell senescence, which contributes to loss of epithelial integrity and airway inflammation and remodelling. Increased numbers of basal cells showing deregulated differentiation, contributes to ciliary dysfunction and mucous hyperproduction in COPD airways. Defective antioxidant, antiviral and damage repair mechanisms, possibly due to genetic or epigenetic factors, may confer susceptibility to airway epithelial dysfunction in these diseases. The current evidence suggests that a constant cycle of injury and abnormal repair of the epithelium drives chronic airway inflammation and remodelling in asthma and COPD. Mechanistic understanding of injury susceptibility and damage response may lead to improved therapies for these diseases.
Secretory pathways and multiple functions of nonstructural protein 1 in flavivirus infection
Authors: Zhang Senzhao , He Yu , Wu Zhen , Wang Mingshu , Jia Renyong , Zhu Dekang , Liu Mafeng , Zhao Xinxin , Yang Qiao , Wu Ying , Zhang Shaqiu , Huang Juan , Ou Xumin , Gao Qun , Sun Di , Zhang Ling , Yu Yanling , Chen Shun , Cheng Anchun
Published: July 2023

The genus Flavivirus contains a wide variety of viruses that cause severe disease in humans, including dengue virus, yellow fever virus, Zika virus, West Nile virus, Japanese encephalitis virus and tick-borne encephalitis virus. Nonstructural protein 1 (NS1) is a glycoprotein that encodes a 352-amino-acid polypeptide and has a molecular weight of 46–55 kDa depending on its glycosylation status. NS1 is highly conserved among multiple flaviviruses and occurs in distinct forms, including a dimeric form within the endoplasmic reticulum, a cell-associated form on the plasma membrane, or a secreted hexameric form (sNS1) trafficked to the extracellular matrix. Intracellular dimeric NS1 interacts with other NSs to participate in viral replication and virion maturation, while extracellular sNS1 plays a critical role in immune evasion, flavivirus pathogenesis and interactions with natural vectors. In this review, we provide an overview of recent research progress on flavivirus NS1, including research on the structural details, the secretory pathways in mammalian and mosquito cells and the multiple functions in viral replication, immune evasion, pathogenesis and interaction with natural hosts, drawing together the previous data to determine the properties of this protein.
The methylation profile of IL4, IL5, IL10, IFNG and FOXP3 associated with environmental exposures differed between Polish infants with the food allergy and/or atopic dermatitis and without the disease
Authors: Gorzkiewicz Marta , Łoś-Rycharska Ewa , Gawryjołek Julia , Gołębiewski Marcin , Krogulska Aneta , Grzybowski Tomasz
Published: July 2023

Objectives

Epigenetic dynamics has been indicated to play a role in allergy development. The environmental stimuli have been shown to influence the methylation processes. This study investigated the differences in CpGs methylation rate of immune-attached genes between healthy and allergic infants. The research was aimed at finding evidence for the impact of environmental factors on methylation-based regulation of immunological processes in early childhood.

Methods

The analysis of methylation level of CpGs in the IL4, IL5, IL10, IFNG and FOXP3 genes was performed using high resolution melt real time PCR technology. DNA was isolated from whole blood of Polish healthy and allergic infants, with food allergy and/or atopic dermatitis, aged under six months.

Results

The significantly lower methylation level of FOXP3 among allergic infants compared to healthy ones was reported. Additional differences in methylation rates were found, when combining with environmental factors. In different studied groups, negative correlations between age and the IL10 and FOXP3 methylation were detected, and positive - in the case of IL4. Among infants with different allergy symptoms, the decrease in methylation level of IFNG, IL10, IL4 and FOXP3 associated with passive smoke exposure was observed. Complications during pregnancy were linked to different pattern of the IFNG, IL5, IL4 and IL10 methylation depending on allergy status. The IFNG and IL5 methylation rates were higher among exclusively breastfed infants with atopic dermatitis compared to the non-breastfed. A decrease in the IFNG methylation was noted among allergic patients fed exclusively with milk formula. In different study groups, a negative correlation between IFNG, IL5 methylation and maternal BMI or IL5 methylation and weight was noted. Some positive correlations between methylation rate of IL10 and child’s weight were found. A higher methylation of IL4 was positively correlated with the number of family members with allergy.

Conclusion

The FOXP3 methylation in allergic infants was lower than in the healthy ones. The methylation profile of IL4, IL5, IL10, IFNG and FOXP3 associated with environmental exposures differed between the studied groups. The results offer insights into epigenetic regulation of immunological response in early childhood.
IGF2BP family of RNA-binding proteins regulate innate and adaptive immune responses in cancer cells and tumor microenvironment
Authors: Elcheva Irina A. , Gowda Chethana P. , Bogush Daniel , Gornostaeva Svetlana , Fakhardo Anna , Sheth Neil , Kokolus Kathleen M. , Sharma Arati , Dovat Sinisa , Uzun Yasin , Schell Todd D. , Spiegelman Vladimir S.
Published: July 2023

Insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1, IGF2BP2, and IGF2BP3) are a family of RNA-binding proteins that play an essential role in the development and disease by regulating mRNA stability and translation of critical regulators of cell division and metabolism. Genetic and chemical inhibition of these proteins slows down cancer cell proliferation, decreases invasiveness, and prolongs life span in a variety of animal models. The role of RNA-binding proteins in the induction of tissues’ immunogenicity is increasingly recognized, but, the impact of the IGF2BPs family of proteins on the induction of innate and adaptive immune responses in cancer is not fully understood. Here we report that downregulation of IGF2BP1, 2, and 3 expression facilitates the expression of interferon beta-stimulated genes. IGF2BP1 has a greater effect on interferon beta and gamma signaling compared to IGF2BP2 and IGF2BP3 paralogs. We demonstrate that knockdown or knockout of IGF2BP1, 2, and 3 significantly potentiates inhibition of cell growth induced by IFNβ and IFNγ. Mouse melanoma cells with Igf2bp knockouts demonstrate increased expression of MHC I (H-2) and induce intracellular Ifn-γ expression in syngeneic T-lymphocytes in vitro. Increased immunogenicity, associated with Igf2bp1 inhibition, “inflames” mouse melanoma tumors microenvironment in SM1/C57BL/6 and SW1/C3H mouse models measured by a two-fold increase of NK cells and tumor-associated myeloid cells. Finally, we demonstrate that the efficiency of anti-PD1 immunotherapy in the mouse melanoma model is significantly more efficient in tumors that lack Igf2bp1 expression. Our retrospective data analysis of immunotherapies in human melanoma patients indicates that high levels of IGF2BP1 and IGF2BP3 are associated with resistance to immunotherapies and poor prognosis. In summary, our study provides evidence of the role of IGF2BP proteins in regulating tumor immunogenicity and establishes those RBPs as immunotherapeutic targets in cancer.
Sediment sink-source transitions in the middle and lower reaches of the Yangtze River estuary
Authors: Yang Yunping , Zheng Jinhai , Zhang Mingjin , Zhu Lingling
Published: July 2023

Human activities have severely altered the Yangtze River (Changjiang) Estuary’s pattern, beach-trough shape, and delta in recent decades. Existing research has studied the sediment “source–sink” relationship between the Yangtze River mainstream and estuary using gauged suspended sediment data. This method overestimated the decline in the suspended sediment concentration in the estuary, as riverbed scouring or deposition have not filtered out amounts related to sand mining or waterway dredging. This study took the Yangtze River Basin as the research subject and used spot observed runoff, sediment, and riverbed topography data gathered between 1980 and 2020 to analyze the sediment trapping effect of the Three Gorges Reservoir (TGR) and study the “source-sink” relationship of suspended sediment transport in the middle-lower reaches of the Yangtze River. The Yangtze Estuary Delta is dominated by scouring, which shows an increasing trend. During the operation of the TGR (2003–2020), the suspended sediment load entering the Yangtze Estuary from the Yangtze River mainstream decreased by 68% compared to the amount prior to operation commencing (1960–2002). However, studies have found that there are still large amounts of bottom sand with riverbed load movement characteristics after the operation of the Three Gorges Project and that riverbed souring of the downstream dam has increased the degree of deposition recharge. The amount of sediment in the Yangtze Estuary decreased between 2003 and 2018 compared with the period 1981 to 2002, with an annual decrease of 16.9%. The cumulative deposition of the Yichang–Datong and Datong–Xuliujing reaches from 1981–2002 was 3.13×108 m3 and 1.60×108 m3, respectively, and cumulative scouring from 2002–2018 was 28.52×108 m3 and 16.01×108 m3. This study concluded that even if the suspended sediment load entering the estuary decreased significantly after the operation of the TGR, the riverbed in the middle-lower reaches of the Yangtze River has gradually transformed from the “sink” of sediment deposition to the “source” of sediment supply.
Application of novel AI-based algorithms to biobank data: uncovering of new features and linear relationships
Authors: Sherlock Lee , Martin Brendan R. , Behsangar Sinah , Mok K. H.
Published: July 2023

We independently analyzed two large public domain datasets that contain 1H-NMR spectral data from lung cancer and sex studies. The biobanks were sourced from the Karlsruhe Metabolomics and Nutrition (KarMeN) study and Bayesian Automated Metabolite Analyzer for NMR data (BATMAN) study. Our approach of applying novel artificial intelligence (AI)-based algorithms to NMR is an attempt to globalize metabolomics and demonstrate its clinical applications. The intention of this study was to analyze the resulting spectra in the biobanks via AI application to demonstrate its clinical applications. This technique enables metabolite mapping in areas of localized enrichment as a measure of true activity while also allowing for the accurate categorization of phenotypes.
Characterization of sound pressure levels and sound sources in the intensive care unit: a 1 week observational study
Authors: Naef Aileen C. , Knobel Samuel E. J. , Ruettgers Nicole , Rossier Marilyne , Jeitziner Marie-Madlen , Zante Bjoern , Müri René M. , Schefold Joerg C. , Nef Tobias , Gerber Stephan M.
Published: July 2023

Background

Exposure to elevated sound pressure levels within the intensive care unit is known to negatively affect patient and staff health. In the past, interventions to address this problem have been unsuccessful as there is no conclusive evidence on the severity of each sound source and their role on the overall sound pressure levels. Therefore, the goal of the study was to perform a continuous 1 week recording to characterize the sound pressure levels and identify negative sound sources in this setting.

Methods

In this prospective, systematic, and quantitative observational study, the sound pressure levels and sound sources were continuously recorded in a mixed medical–surgical intensive care unit over 1 week. Measurements were conducted using four sound level meters and a human observer present in the room noting all sound sources arising from two beds.

Results

The mean 8 h sound pressure level was significantly higher during the day (52.01 ± 1.75 dBA) and evening (50.92 ± 1.66 dBA) shifts than during the night shift (47.57 ± 2.23; F(2, 19) = 11.80, p < 0.001). No significant difference was found in the maximum and minimum mean 8 h sound pressure levels between the work shifts. However, there was a significant difference between the two beds in the based on location during the day (F(3, 28) = 3.91, p = 0.0189) and evening (F(3, 24) = 5.66, p = 0.00445) shifts. Cleaning of the patient area, admission and discharge activities, and renal interventions (e.g., dialysis) contributed the most to the overall sound pressure levels, with staff talking occurring most frequently.

Conclusion

Our study was able to identify that continuous maintenance of the patient area, patient admission and discharge, and renal interventions were responsible for the greatest contribution to the sound pressure levels. Moreover, while staff talking was not found to significantly contribute to the sound pressure levels, it was found to be the most frequently occurring activity which may indirectly influence patient wellbeing. Overall, identifying these sound sources can have a meaningful impact on patients and staff by identifying targets for future interventions, thus leading to a healthier environment.
The emergence of multi-drug resistant and virulence gene carrying Escherichia coli strains in the dairy environment: a rising threat to the environment, animal, and public health
Authors: Shoaib Muhammad , He Zhoulin , Geng Xiang , Tang Minjia , Hao Ruochen , Wang Shengyi , Shang Ruofeng , Wang Xuehong , Zhang Hongjuan , Pu Wanxia
Published: July 2023

Escherichia coli is a common inhabitant of the intestinal microbiota and is responsible for udder infection in dairy cattle and gastro-urinary tract infections in humans. We isolated E. coli strains from a dairy farm environment in Xinjiang, China, and investigated their epidemiological characteristics, phenotypic and genotypic resistance to antimicrobials, virulence-associated genes, and phylogenetic relationship. A total of 209 samples were collected from different sources (feces, slurry, water, milk, soil) and cultured on differential and selective agar media (MAC and EMB). The presumptive identification was done by the VITEK2 system and confirmed by 16S rRNA gene amplification by PCR. Antimicrobial susceptibility testing was done by micro-dilution assay, and genomic characterization was done by simple and multiplex polymerase chain reaction (PCR). A total of 338 E. coli strains were identified from 141/209 (67.5%) of the samples. Most of the E. coli strains were resistant to sulfamethoxazole/trimethoprim (62.43%), followed by cefotaxime (44.08%), ampicillin (33.73%), ciprofloxacin (31.36%), tetracycline (28.99%), and a lesser extent to florfenicol (7.99%), gentamicin (4.44%), amikacin (1.77%), and fosfomycin (1.18%). All of the strains were susceptible to meropenem, tigecycline, and colistin sulfate. Among the resistant strains, 44.4% were identified as multi-drug resistant (MDR) showing resistance to at least one antibiotic from ≥3 classes of antibiotics. Eighteen out of 20 antibiotic-resistance genes (ARGs) were detected with sul2 (67.3%), blaTEM (56.3%), gyrA (73.6%), tet(B) (70.4%), aph(3)-I (85.7%), floR (44.4%), and fosA3 (100%, 1/1) being the predominant genes among different classes of antibiotics. Among the virulence-associated genes (VAGs), ompA was the most prevalent (86.69%) followed by ibeB (85.0%), traT (84.91%), ompT (73.96%), fyuA (23.1%), iroN (23.1%), and irp2 gene (21.9%). Most of the E. coli strains were classified under phylogenetic group B1 (75.45%), followed by A (18.34%), C (2.96%), D (1.18%), E (1.18%), and F (0.30%). The present study identified MDR E. coli strains carrying widely distributed ARGs and VAGs from the dairy environment. The findings suggested that the dairy farm environment may serve as a source of mastitis-causing pathogens in animals and horizontal transfer of antibiotic resistance and virulence genes carrying bacterial strains to humans via contaminated milk and meat, surface water and agricultural crops.
In vivo and in vitro immune responses against Francisella tularensis vaccines are comparable among Fischer 344 rat substrains
Authors: De Pascalis Roberto , Bhargava Varunika , Espich Scott , Wu Terry H. , Gelhaus H. Carl , Elkins Karen L.
Published: July 2023

Identifying suitable animal models and standardizing preclinical methods are important for the generation, characterization, and development of new vaccines, including those against Francisella tularensis. Non-human primates represent an important animal model to evaluate tularemia vaccine efficacy, and the use of correlates of vaccine-induced protection may facilitate bridging immune responses from non-human primates to people. However, among small animals, Fischer 344 rats represent a valuable resource for initial studies to evaluate immune responses, to identify correlates of protection, and to screen novel vaccines. In this study, we performed a comparative analysis of three Fischer rat substrains to determine potential differences in immune responses, to evaluate methods used to quantify potential correlates of protection, and to evaluate protection after vaccination. To this end, we took advantage of data previously generated using one of the rat substrains by evaluating two live vaccines, LVS and F. tularensis SchuS4-ΔclpB (ΔclpB). We compared immune responses after primary vaccination, adaptive immune responses upon re-stimulation of leukocytes in vitro, and sensitivity to aerosol challenge. Despite some detectable differences, the results highlight the similarity of immune responses to tularemia vaccines and challenge outcomes between the three substrains, indicating that all offer acceptable and comparable approaches as animal models to study Francisella infection and immunity.
Molecular dissection studies of TAC1, a transcription activator of Candida drug resistance genes of the human pathogenic fungus Candida albicans
Authors: Jain Tushar , Mishra Pankaj , Kumar Sushil , Panda Gautam , Banerjee Dibyendu
Published: July 2023

The up-regulation of ABC transporters Cdr1p and Cdr2p that efflux antifungal azole drugs are a leading cause of Multi-Drug Resistance (MDR) in the white fungus Candida albicans. C. albicans was reported to infect patients following the recent Covid-19 pandemic after they were given steroids for recovery. Previously, the TAC1 gene was identified as the transcriptional activator of Candida drug resistance genes (CDR1 and CDR2) and has no known human homologs. This makes it a good target for the development of novel antifungals. We, therefore, carried out the molecular dissection study of TAC1 to understand the functional regulation of the ABC transporter genes (CDR1 and CDR2) under its control. The N-terminal DNA Binding Domain (DBD) of Tac1p interacts with the Drug Responsive Element (DRE) present in the upstream promoter region of CDR1 and CDR2 genes of C. albicans. The interaction between DBD and DRE recruits Tac1p to the promoter of CDR genes. The C-terminal Acidic Activation Domain (AAD) of Tac1p interacts with the TATA box Binding Protein (TBP) and thus recruits TBP to the TATA box of CDR1 and CDR2 genes. Taking a cue from a previous study involving a TAC1 deletion strain that suggested that Tac1p acts as a xenobiotic receptor, in this study, we identified that the Middle Homology Region (MHR) of Tac1p acts as a probable xenobiotic binding domain (XBD) which plays an important role in Candida drug resistance. In addition, we studied the role of Tac1p in the regulation of some lipid profiling genes and stress response genes since they also contain the DRE consensus sequence and found that some of them can respond to xenobiotic stimuli.
Production and characterization of monoclonal antibodies for the detection of the hepatitis C core antigen
Authors: Vidal-Alcántara Erick Joan , Mas Vicente , Yélamos María Belén , Gómez Julián , Amigot-Sánchez Rafael , Resino Salvador , Martinez Isidoro
Published: July 2023

Background: Despite highly effective treatments to cure hepatitis C, almost 80% of chronically HCV-infected people are not treated, as they are unaware of their infection. Diagnostic rates and linkage to care must be substantially improved to reverse this situation. The HCV core antigen (HCVcAg) is a highly conserved protein that can be detected in the blood of HCV-infected patients and indicates active infection.

Aim: To produce murine monoclonal antibodies against HCVcAg suitable for rapid and inexpensive tests to detect HCV infection.

Methods: BALB/c mice were sequentially inoculated with purified recombinant HCVcAg from Gt1a, Gt3a, Gt4a, and Gt1b genotypes. Hybridomas producing the desired monoclonal antibodies were selected, and the reactivity of antibodies against HCVcAg from various genotypes was tested by Western blotting and dot blotting. The binding kinetics of the antibodies to purified HCVcAg was analyzed by surface plasmon resonance (SPR), and their ability to detect HCVcAg was tested by double antibody sandwich ELISA (DAS-ELISA).

Results: Four specific monoclonal antibodies (1C, 2C, 4C, and 8C) were obtained. 1C, 2C, and 4C recognized HCVcAg of all genotypes tested (Gt1a, Gt1b, Gt2a, Gt3a, and Gt4a), while 8C did not recognize the Gt2a and Gt3a genotypes. Based on SPR data, the antibody-HCVcAg complexes formed are stable, with 2C having the strongest binding properties. DAS-ELISA with different antibody combinations easily detected HCVcAg in culture supernatants from HCV-infected cells.

Conclusion: Specific and cross-reactive anti-HCVcAg monoclonal antibodies with strong binding properties were obtained that may be useful for detecting HCVcAg in HCV-infected samples.
Plant-derived extracts and metabolic modulation in leukemia: a promising approach to overcome treatment resistance
Authors: Arévalo Cindy Mayerli , Cruz-Rodriguez Nataly , Quijano Sandra , Fiorentino Susana
Published: July 2023

Leukemic cells acquire complex and often multifactorial mechanisms of resistance to treatment, including various metabolic alterations. Although the use of metabolic modulators has been proposed for several decades, their use in clinical practice has not been established. Natural products, the so-called botanical drugs, are capable of regulating tumor metabolism, particularly in hematopoietic tumors, which could partly explain the biological activity attributed to them for a long time. This review addresses the most recent findings relating to metabolic reprogramming—Mainly in the glycolytic pathway and mitochondrial activity—Of leukemic cells and its role in the generation of resistance to conventional treatments, the modulation of the tumor microenvironment, and the evasion of immune response. In turn, it describes how the modulation of metabolism by plant-derived extracts can counteract resistance to chemotherapy in this tumor model and contribute to the activation of the antitumor immune system.
Distinct topographic organization and network activity patterns of corticocollicular neurons within layer 5 auditory cortex
Authors: Schmitt Tatjana T. X. , Andrea Kira M. A. , Wadle Simon L. , Hirtz Jan J.
Published: July 2023

The auditory cortex (AC) modulates the activity of upstream pathways in the auditory brainstem via descending (corticofugal) projections. This feedback system plays an important role in the plasticity of the auditory system by shaping response properties of neurons in many subcortical nuclei. The majority of layer (L) 5 corticofugal neurons project to the inferior colliculus (IC). This corticocollicular (CC) pathway is involved in processing of complex sounds, auditory-related learning, and defense behavior. Partly due to their location in deep cortical layers, CC neuron population activity patterns within neuronal AC ensembles remain poorly understood. We employed two-photon imaging to record the activity of hundreds of L5 neurons in anesthetized as well as awake animals. CC neurons are broader tuned than other L5 pyramidal neurons and display weaker topographic order in core AC subfields. Network activity analyses revealed stronger clusters of CC neurons compared to non-CC neurons, which respond more reliable and integrate information over larger distances. However, results obtained from secondary auditory cortex (A2) differed considerably. Here CC neurons displayed similar or higher topography, depending on the subset of neurons analyzed. Furthermore, specifically in A2, CC activity clusters formed in response to complex sounds were spatially more restricted compared to other L5 neurons. Our findings indicate distinct network mechanism of CC neurons in analyzing sound properties with pronounced subfield differences, demonstrating that the topography of sound-evoked responses within AC is neuron-type dependent.
Aberrant age-related alterations in spontaneous cortical activity in participants with cerebral palsy
Authors: Bergwell Hannah , Trevarrow Michael P. , Heinrichs-Graham Elizabeth , Reelfs Anna , Ott Lauren R. , Penhale Samantha H. , Wilson Tony W. , Kurz Max J.
Published: July 2023

Introduction

Cerebral Palsy (CP) is the most common neurodevelopmental motor disability, resulting in life-long sensory, perception and motor impairments. Moreover, these impairments appear to drastically worsen as the population with CP transitions from adolescents to adulthood, although the underlying neurophysiological mechanisms remain poorly understood.

Methods

We began to address this knowledge gap by utilizing magnetoencephalographic (MEG) brain imaging to study how the amplitude of spontaneous cortical activity (i.e., resting state) is altered during this transition period in a cohort of 38 individuals with spastic diplegic CP (Age range = 9.80–47.50 years, 20 females) and 67 neurotypical controls (NT) (Age range = 9.08–49.40 years, Females = 27). MEG data from a five-minute eyes closed resting-state paradigm were source imaged, and the power within the delta (2–4 Hz), theta (5–7 Hz), alpha (8–12 Hz), beta (15–29 Hz), and gamma (30–59 Hz) frequency bands were computed.

Results

For both groups, the delta and theta spontaneous power decreased in the bilateral temporoparietal and superior parietal regions with age, while alpha, beta, and gamma band spontaneous power increased in temporoparietal, frontoparietal and premotor regions with age. We also found a significant group x age interaction, such that participants with CP demonstrated significantly less age-related increases in the spontaneous beta activity in the bilateral sensorimotor cortices compared to NT controls.

Discussion

Overall, these results demonstrate that the spontaneous neural activity in individuals with CP has an altered trajectory when transitioning from adolescents to adulthood. We suggest that these differences in spontaneous cortical activity may play a critical role in the aberrant motor actions seen in this patient group, and may provide a neurophysiological marker for assessing the effectiveness of current treatment strategies that are directed at improving the mobility and sensorimotor impairments seen in individuals with CP.
Single subanesthetic dose of ketamine produces delayed impact on brain [18F]FDG PET imaging and metabolic connectivity in rats
Authors: Chaib Sarah , Bouillot Caroline , Bouvard Sandrine , Vidal Benjamin , Zimmer Luc , Levigoureux Elise
Published: July 2023

Introduction

Ketamine, a glutamate NMDA receptor antagonist, is suggested to act very rapidly and durably on the depressive symptoms including treatment-resistant patients but its mechanisms of action remain unclear. There is a requirement for non-invasive biomarkers, such as imaging techniques, which hold promise in monitoring and elucidating its therapeutic impact.

Methods

We explored the glucose metabolism with [18F]FDG positron emission tomography (PET) in ten male rats in a longitudinal study designed to compare imaging patterns immediately after acute subanaesthetic ketamine injection (i.p. 10 mg/kg) with its sustained effects, 5 days later. Changes in [18F]FDG uptake following ketamine administration were estimated using a voxel-based analysis with SPM12 software, and a region of interest (ROI) analysis. A metabolic connectivity analysis was also conducted to estimate the immediate and delayed effects of ketamine on the inter-individual metabolic covariance between the ROIs.

Results

No significant difference was observed in brain glucose metabolism immediately following acute subanaesthetic ketamine injection. However, a significant decrease of glucose uptake appeared 5 days later, reflecting a sustained and delayed effect of ketamine in the frontal and the cingulate cortex. An increase in the raphe, caudate and cerebellum was also measured. Moreover, metabolic connectivity analyses revealed a significant decrease between the hippocampus and the thalamus at day 5 compared to the baseline.

Discussion

This study showed that the differences in metabolic profiles appeared belatedly, 5 days after ketamine administration, particularly in the cortical regions. Finally, this methodology will help to characterize the effects of future molecules for the treatment of treatment resistant depression.
Development of CRISPR Cas9, spin-off technologies and their application in model construction and potential therapeutic methods of Parkinson’s disease
Authors: Qu Jiangbo , Liu Na , Gao Lu , Hu Jia , Sun Miao , Yu Dongyi
Published: July 2023

Parkinson’s disease (PD) is one of the most common degenerative diseases. It is most typically characterized by neuronal death following the accumulation of Lewis inclusions in dopaminergic neurons in the substantia nigra region, with clinical symptoms such as motor retardation, autonomic dysfunction, and dystonia spasms. The exact molecular mechanism of its pathogenesis has not been revealed up to now. And there is a lack of effective treatments for PD, which places a burden on patients, families, and society. CRISPR Cas9 is a powerful technology to modify target genomic sequence with rapid development. More and more scientists utilized this technique to perform research associated neurodegenerative disease including PD. However, the complexity involved makes it urgent to organize and summarize the existing findings to facilitate a clearer understanding. In this review, we described the development of CRISPR Cas9 technology and the latest spin-off gene editing systems. Then we focused on the application of CRISPR Cas9 technology in PD research, summarizing the construction of the novel PD-related medical models including cellular models, small animal models, large mammal models. We also discussed new directions and target molecules related to the use of CRISPR Cas9 for PD treatment from the above models. Finally, we proposed the view about the directions for the development and optimization of the CRISPR Cas9 technology system, and its application to PD and gene therapy in the future. All these results provided a valuable reference and enhanced in understanding for studying PD.
The PANoptosis-related signature indicates the prognosis and tumor immune infiltration features of gliomas
Authors: Song Jingjing , Xu Zekun , Fan Qingchen , Sun Yanfei , Lin Xiaoying
Published: July 2023

Background

Gliomas are the most common primary tumors of the central nervous system, with high heterogeneity and highly variable survival rates. Accurate classification and prognostic assessment are key to the selection of treatment strategies. One hallmark of the tumor is resistance to cell death. PANoptosis, a novel mode of programmed cell death, has been frequently reported to be involved in the innate immunity associated with pathogen infection and played an important role in cancers. However, the intrinsic association of PANoptosis with glioma requires deeper investigation.

Methods

The genetics and expression of the 17 reported PANoptosome-related genes were analyzed in glioma. Based on these genes, patients were divided into two subtypes by consensus clustering analysis. After obtaining the differentially expressed genes between clusters, a prognostic model called PANopotic score was constructed after univariate Cox regression, LASSO regression, and multivariate Cox regression. The expression of the 5 genes included in the PANopotic score was also examined by qPCR in our cohort. The prognostic differences, clinical features, TME infiltration status, and immune characteristics between PANoptotic clusters and score groups were compared, some of which even extended to pan-cancer levels.

Results

Gene mutations, CNVs and altered gene expression of PANoptosome-related genes exist in gliomas. Two PANoptotic clusters were significantly different in prognosis, clinical features, immune characteristics, and mutation landscapes. The 5 genes included in the PANopotic score had significantly altered expression in glioma samples in our cohort. The high PANoptotic score group was inclined to show an unfavorable prognosis, lower tumor purity, worse molecular genetic signature, and distinct immune characteristics related to immunotherapy. The PANoptotic score was considered as an independent prognostic factor for glioma and showed superior prognostic assessment efficacy over several reported models. PANopotic score was included in the nomogram constructed for the potential clinical prognostic application. The associations of PANoptotic score with prognostic assessment and tumor immune characteristics were also reflected at the pan-cancer level.

Conclusion

Molecular subtypes of glioma based on PANoptosome-related genes were proposed and PANoptotic score was constructed with different clinical characteristics of anti-tumor immunity. The potential intrinsic association between PANoptosis and glioma subtypes, prognosis, and immunotherapy was revealed.
Do agronomic approaches aligned to regenerative agriculture improve the micronutrient concentrations of edible portions of crops? A scoping review of evidence
Authors: Manzeke-Kangara Muneta Grace , Joy Edward J. M. , Lark R. Murray , Redfern Sally , Eilander Ans , Broadley Martin R.
Published: July 2023

Regenerative Agriculture (RA) is used to describe nature-based agronomic approaches that aim to build soil health and crop resilience, minimize negative environmental outcomes, and improve farmer livelihoods. A benefit that is increasingly attributed to crops grown under RA practices is improved nutritional content. However, we do not know the extent to which RA influences crop nutritional quality and under what management approaches and context, can such effects be realized. A scoping review of recent literature (Web of Science, 2000–2021) was carried out to assess the evidence that RA approaches improve crop micronutrient quality. Papers included combinations of agronomic approaches that could be defined as Regenerative: “Organic Inputs” including composts and manures, cover crops, crop rotations, crop residues and biochars; “Reduced Tillage”, “Intercropping”, “Biostimulants” e.g. arbuscular mycorrhizal fungi; plant growth promoting bacteria, and “Irrigation”, typically deficit-irrigation and alternate wetting and drying. The crop types reviewed were predetermined covering common sources of food and included: Tomato (Solanum lycopersicum L.), Wheat (Triticum aestivum L.), Rice (Oryza sativa L.), Maize (Zea mays L.), Pulses (Fabaceae), Alliums (Allium spp.), and “other” crop types (30 types). This scoping review supports a potential role for RA approaches in increasing the concentrations of micronutrients in the edible portions of several crop types under specific practices, although this was context specific. For example, rice grown under increased organic inputs showed significant increases in grain zinc (Zn) concentration in 15 out of 16 studies. The vitamin C concentration of tomato fruit increased in ~50% of studies when plants were grown under increased organic inputs, and in 76% of studies when plants were grown under deficit irrigation. Overall, the magnitude and reproducibility of the effects of RA practices on most crop nutritional profiles were difficult to assess due to the diversity of RA approaches, geographical conditions, and the limited number of studies for most crops in each of these categories. Future research with appropriate designs, improved on-farm surveillance and nutritional diagnostics are needed for better understanding the potential role of RA in improving the quality of food, human nutrition, and health.
Glucose variability in 6–12-month-old healthy infants
Authors: Hauschild Michael , Monnard Cathriona , Eldridge Alison L. , Antoniou Maria Christina , Bouthors Thérèse , Hansen Erik , Dwyer Andrew A. , Rytz Andreas , Darimont Christian
Published: July 2023

Background

Metabolic programming of glucose homeostasis in the first 1,000 days of life may impact lifelong metabolic and cardiovascular health. Continuous glucose monitoring (CGM) devices may help measure the impact of dietary intake on glucose rhythms and metabolism in infants during the complementary feeding period.

Objectives

Demonstrate the feasibility of CGM to measure and quantify glucose variability in response to infant feeding and to evaluate associations between macronutrient meal composition and glucose variability.

Methods

The “FreeStyle Libre Pro®” device interstitial glucose meter was applied to the anterior thigh of 10 healthy 6–12-month-old infants. Parents recorded food intake, time of feeding, and used daily dairies to record sleep time and duration. Descriptive statistics were employed for food intake, sleep and key glycemic parameters over three full days. Mixed linear models were used to assess glycemic changes.

Results

Mid-day, afternoon, and evening feeds contained >30 g carbohydrate and induced higher 2-h iAUC (3.42, 3.41, and 3.50 mmol/L*h respectively) compared to early and mid-morning feedings with ≤25 g carbohydrates (iAUC 2.72 and 2.81 mmol/L*h, p < 0.05). Early morning and evening milk feedings contained approximately 9 g of fat and induced a longer time to reach maximal glucose value (Tmax; 75 and 68 min, respectively) compared to lower fat feedings (2.9–5.9 g; Tmax range: 34–60 min; p < 0.05). Incremental glucose value at time of food intake (C0) increased significantly from 0.24 ± 0.39 mM in early morning to 1.07 ± 0.57 mM in the evening (p < 0.05). Over the day, 70% of glucose values remained within the normal range (3.5–5.5 mmol/L), 10% were between 5.5–10 mmol/L, and 20% were < 3.5 mmol/L.

Conclusion

Our data support the feasibility of using CGM to measure glucose in 6–12-month-old infants. The observation of possible diurnal glucose variability and typical glucose values may have implications for future studies investigating metabolic adaptation to nutritional intake in early life.
The effects of hesperidin supplementation on cardiovascular risk factors in adults: a systematic review and dose–response meta-analysis
Authors: Khorasanian Atie Sadat , Fateh Sahand Tehrani , Gholami Fatemeh , Rasaei Niloufar , Gerami Hadis , Khayyatzadeh Sayyed Saeid , Shiraseb Farideh , Asbaghi Omid
Published: July 2023

Hesperidin is a naturally occurring bioactive compound that may have an impact on cardiovascular disease risks, but the evidence is not conclusive. To investigate further, this study aimed to explore the effects of hesperidin supplementation on cardiovascular risk factors in adults. A comprehensive search was conducted up to August 2022 using relevant keywords in databases such as Scopus, PubMed, Embase, Cochrane Library, and ISI Web of Science for all randomized controlled trials (RCTs). The results showed that hesperidin supplementation had a significant effect on reducing serum triglyceride (TG), total cholesterol (TC), low-density cholesterol (LDL), tumor necrosis factor-alpha (TNF-α), and systolic blood pressure (SBP), whereas weight was increased. However, no significant effect was observed on high-density cholesterol (HDL), waist circumference (WC), fasting blood glucose (FBG), insulin, homeostatic model assessment for insulin resistance (HOMA-IR), C-reactive protein (CRP), interleukin-6 (IL-6), body mass index (BMI), and diastolic blood pressure (DBP). The study also found that an effective dosage of hesperidin supplementation was around 1,000 mg/d, and a more effective duration of supplementation was more than eight weeks to decrease insulin levels. Furthermore, the duration of intervention of more than six weeks was effective in decreasing FBG levels.
Electron stream effect in 0.35 Tesla magnetic resonance image guided radiotherapy for breast cancer
Authors: Lee Hsin-Hua , Wang Chun-Yen , Chen Shan-Tzu , Lu Tzu-Ying , Chiang Cheng-Han , Huang Ming-Yii , Huang Chih-Jen
Published: July 2023

Purpose

This research aimed to analyze electron stream effect (ESE) during magnetic resonance image guided radiotherapy (MRgRT) for breast cancer patients on a MR-Linac (0.35 Tesla, 6MV), with a focus on the prevention of redundant radiation exposure.

Materials and methods

RANDO phantom was used with and without the breast attachment in order to represent the patients after breast conserving surgery (BCS) and those received modified radical mastectomy (MRM). The prescription dose is 40.05 Gy in fifteen fractions for whole breast irradiation (WBI) or 20 Gy single shot for partial breast irradiation (PBI). Thirteen different portals of intensity-modulated radiation therapy were created. And then we evaluated dose distribution in five areas (on the skin of the tip of the nose, the chin, the neck, the abdomen and the thyroid.) outside of the irradiated field with and without 0.35 Tesla. In addition, we added a piece of bolus with the thickness of 1cm on the skin in order to compare the ESE difference with and without a bolus. Lastly, we loaded two patients’ images for PBI comparison.

Results

We found that 0.35 Tesla caused redundant doses to the skin of the chin and the neck as high as 9.79% and 5.59% of the prescription dose in the BCS RANDO model, respectively. For RANDO phantom without the breast accessory (simulating MRM), the maximal dose increase were 8.71% and 4.67% of the prescription dose to the skin of the chin and the neck, respectively. Furthermore, the bolus we added efficiently decrease the unnecessary dose caused by ESE up to 59.8%.

Conclusion

We report the first physical investigation on successful avoidance of superfluous doses on a 0.35T MR-Linac for breast cancer patients. Future studies of MRgRT on the individual body shape and its association with ESE influence is warranted.