bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Different Lactic Acid Bacteria in Single or Mixed Form on the Fermentative Parameters and Nutrient Contents of Early Heading Triticale Silage for Livestock
Authors: Soundharrajan Ilavenil , Jung Jeong Sung , Muthusamy Karnan , Lee Bae Hun , Park Hyung Soo , Sivanesan Ravikumar , Choi Ki Choon
Published: November 2023

Lactic acid bacteria (LAB) are excellent anaerobic fermenters that produce highly valuable grass-based animal feed containing essential nutrients. In the present study, an ensiling process was used to improve anaerobic fermentation in triticale silage under different moisture conditions with LAB. The triticale was treated with either a single bacterium or combined LAB and then vacuum-sealed. After 180 and 360 days of storage, the silage’s fermentation characteristics, microbial changes and nutrient contents were analyzed. The pH of the silage was significantly lower than the control silage. There was a significant difference in the pH values between the silages treated with single or mixed LAB. The LAB treatment led to a substantial increase in lactic acid (LA), a decrease in butyric acid (BA), and marginal levels of acetic acid (AA). The LA content after the mixed LAB treatment was significantly higher than that after the single culture LAB treatment. After single or combined inoculant treatments, the LAB population in the silage increased, while the yeast and mold levels decreased. These findings suggest that the addition of LAB to silage during ensiling could enhance the nutritional quality and reduce unwanted microbial growth. The mixed LAB treatments produced silage with a significantly higher nutritional value than the single LAB treatments.
Derivation of Kokumi γ-Glutamyl Peptides and Volatile Aroma Compounds from Fermented Cereal Processing By-Products for Reducing Bitterness of Plant-Based Ingredients
Authors: Rodríguez Valerón Nabila , Mak Tiffany , Jahn Leonie J. , Arboleya Juan Carlos , Sörensen Pia M.
Published: November 2023

Current food production methods and consumption behaviours are unsustainable and contribute to environmental harm. One example is food waste—around 38% of food produced is wasted each year. Here, we show that two common food waste products, wheat bran and brewer’s spent grain, can successfully be upcycled via miso fermentation. During the fermentation process, kokumi γ-glutamyl peptides, known to increase mouthfulness, are produced; these include γ-ECG (oxidized), γ-EVG, γ-EV, γ-EE, γ-EF, and γ-EL. The profiles of kokumi peptides and volatile aroma compounds are correlated with koji substrate, pH, and enzymatic activity, offering straightforward parameters that can be manipulated to increase the abundance of kokumi peptides during the fermentation process. Correlation analysis demonstrates that some volatile aroma compounds, such as fatty acid ethyl esters, are correlated with kokumi peptide abundance and may be responsible for fatty, greasy, and buttery aromas. Consumer sensory analysis conveys that the bitter taste of vegetables, such as that in endives, can be dampened when miso extract containing kokumi peptides is added. This suggests that kokumi peptides, along with aroma volatile compounds, can enhance the overall flavour of plant-based products. This study opens new opportunities for cereal processing by-product upcycling via fermentation, ultimately having the potential to promote a plant-based diet.
Gauging Quince Phytonutrients and Its 4% Emulgel Effect on Amplifying Facial Skin Moisturizing Potential
Authors: Khiljee Tanzila , Akhtar Naveed , Khiljee Sonia , Khiljee Bushra , Rasheed Hafiz Majid , Ansari Siddique Akber , Alkahtani Hamad M. , Ansari Irfan Aamer
Published: November 2023

Background: The aim of this study was to evaluate the moisturizing efficacy of quince fruit, used in folk medicine. For this purpose, the phytoconstituents of Cydonia oblonga fruit extract, like phenolics and flavonoids, were determined. A stable cosmetic emulgel containing 4% Cydonia oblonga fresh fruit extract was formulated and subjected to in vivo evaluation compared with a control. Materials and Methods: Cydonia oblonga fresh fruit extract was evaluated for tyrosinase activity and phenolic and flavonoid content. A stable emulgel containing 4% Cydonia oblonga fresh fruit extract was formulated and tested in a skin irritation test. After this, in vivo tests of erythema, moisture, sebum, and skin elasticity were conducted. The in vivo evaluation was a randomized and single-blind study. Thirteen healthy female volunteers were selected for a three-month study period. Results: Cydonia oblonga fruit extract showed good phenolic and flavonoid content, which was associated with its good antioxidant and tyrosinase-inhibiting activity. Cydonia oblonga containing the emulgel showed a reduction in sebum and erythema, while the elasticity and moisture content showed increments in their levels after the three-month application of the formulation. The fruit contains chlorogenic acid and many sugars, which might account for its anti-inflammatory and sebum reduction effects; it is also capable of enhancing the skin’s hydration level and decreasing skin sagging by enhancing its elasticity. Conclusion: The emulgel loaded with Cydonia oblonga fresh fruit extract is verified regarding its folklore status as a moisturizing agent that enhances the facial skin cells’ resilience potential.
The Genetic Diversity of Horse Native Breeds in Russia
Authors: Atroshchenko Mikhail , Dementieva Natalia , Shcherbakov Yuri , Nikolaeva Olga , Azovtseva Anastasiia , Ryabova Anna , Nikitkina Elena , Makhmutova Oksana , Datsyshin Andrey , Zakharov Viktor , Zaitsev Alexander
Published: November 2023

Horses were domesticated later than other farm animals. Horse breeds have been selectively developed by humans to satisfy different needs and purposes. The factory and indigenous breeds are of particular interest, having been bred in purity for many centuries without the addition of foreign blood. Data from 31 stud farms, as well as ranches, located in fifteen regions of the Russian Federation were used in this work. DNA was sampled from 102 stallions of 11 breeds: Arabian, Akhal-Teke, Don, Orlov Trotter, Vladimir Heavy Draft, Russian Heavy Draft, Soviet Heavy Draft, Kabardin, Yakut, Tuva, and Vyatka. Data on the origin of each animal from which the material was collected were taken into account. DNA genotyping was carried out using GGP Equine 70 k ® array chips (Thermo Fisher Scientific, USA). Genetic diversity of horse breeds was estimated using Admixture 1.3. and PLINK 1.9 software. FROH inbreeding was computed via the R detectRUNS package. The minimum length for ROH was set at 1 Mb to reduce the occurrence of false positives. We conducted PCA analysis using PLINK 1.9, and used the ggplot2 library in R for visualizing the results. Indigenous equine breeds, such as Vyatka, Tuva, and Yakut, are very hardy, and well adapted to local environmental and climatic conditions. They are employed as draft power, as well as for milk and meat. Both the Akhal-Teke breed and the Arabian breed have retained a minimum effective population size over many generations. We note significant accumulations of homozygosity in these breeds. In equestrian sports, performance is a top priority. ADMIXTURE and PCA analyses showed similarities between Don equine breeds and Kabardin, as well as some Arabian breed animals. Earlier research indicated the presence of thoroughbred traits in Don stallions. The Orlov Trotter breed stands out as a separate cluster in the structural and PCA analyses. Considering the small population size of this breed, our study found high FROH in all tested animals. The general reduction in the diversity of the horse breed gene pool, due to numerous crosses for breed improvement with thoroughbreds, has lead to a decline in the differences between the top sporting breeds. Our study presents new opportunities for exploring the genetic factors that influence the formation of adaptive traits in indigenous breeds, and for finding ways to preserve genetic diversity for effective population reproduction.
Genetic Diversity and Phylogenetic Analysis of Zygophyllum loczyi in Northwest China’s Deserts Based on the Resequencing of the Genome
Authors: Wei Mengmeng , Liu Jingdian , Wang Suoming , Wang Xiyong , Liu Haisuang , Ma Qing , Wang Jiancheng , Shi Wei
Published: November 2023

In order to study the genetics of local adaptation in all main deserts of northwest China, whole genomes of 169 individuals were resequenced, which covers 20 populations of Zygophyllum loczyi (Zygophyllales: Zygophylaceae). We describe more than 15 million single nucleotide polymorphisms and numerous InDels. The expected heterozygosity and PIC values associated with local adaptation varied significantly across biogeographic regions. Variation in environmental factors contributes largely to the population genetic structure of Z. loczyi. Bayesian analysis performed with STRUCTURE defined four genetic clusters, while the results of principle component analysis were similar. Our results shows that the Qaidam Desert group appears to be diverging into two branches characterized by significant geographic separation and gene flow with two neighboring deserts. Geological data assume that it is possible that the Taklamakan Desert was the original distribution site, and Z. loczyi could have migrated later on and expanded within other desert areas. The above findings provide insights into the processes involved in biogeography, phylogeny, and differentiation within the northwest deserts of China.
Signatures of Pleistocene Marine Transgression Preserved in Lithified Coastal Dune Morphology of The Bahamas
Authors: Wilson Kat , Mohrig David
Published: November 2023

The morphology of some lithified wind-blown, carbonate dunes in The Bahamas preserves the signature of erosion from paleo-marine processes: wave-induced swash, scarping, and longshore transport. Digital elevation models were used to distinguish between two dune morphotypes—those disconnected versus connected to beach processes. Dune sinuosity and upwind slope were quantified and used to interpret which dunes remained beach-attached and subject to marine erosion and processes versus dunes that became disconnected from the shoreline via inland migration or shoreline regression. Disconnected dunes possess low slopes over stoss surfaces with sinuous planforms mimicking their crestlines. Beach-connected foredunes preserve steep, kilometers-long linear upwind faces, which are interpreted to be signatures of beach-dune morphodynamics. Foredune morphology serves as a proxy for shoreline position during past sea-level high-stands, while the basal elevations of their stoss dune toes provide an upper limit on the beach and adjacent sea level. A growing library of digital topography will allow for this tool to be used to interpret global paleo-shoreline positions through time and space.
Numerical Simulation of Rockfall Protection Embankments in Natural Soil
Authors: Vigna Stefano , Marchelli Maddalena , De Biagi Valerio , Peila Daniele
Published: November 2023

Rockfall events represent a significant hazard in mountainous regions, putting human safety and critical infrastructure at risk. Various mitigation devices are available, among which, Rockfall protection embankments (RPEs) located in natural soil are passive defense work suitable for high-energy and high-frequency events. Currently, limited research has been conducted in this area, with the Austrian standard ONR 24810 providing the sole codified design method. A parametrical analysis involving both the RPE geometry and the impact features was developed by Abaqus/Explicit FEM code, with 2270 cases overall. The research aims to identify conditions under which RPEs effectively stop falling blocks, focusing on two failure mechanisms: the block pass over the RPE after impacting the upstream side bank and the RPE structural collapse. Additionally, the interaction between RPEs and their foundations during the impact is explored. The results provide valuable insights into the dynamic behavior of these structures. In terms of design considerations, this study offers analytical equations to quantify crater depth and foundation stress induced by the impact. Furthermore, design charts are developed to assess the block passing over verification and the structural collapse verification.
Conducting Ethical Field Research on Rape in West African Settings: Case Study of 2018 Liberian Field Survey
Authors: Hanson-DeFusco Jessi , Smith Ernest Garnak , Ngafuan Richard Fotorma , Dunn William N.
Published: November 2023

Background: Rape scholarship in West Africa is growing, but studies often utilize Westernized approaches. A 2018 study using a randomized survey design assessing rape among Liberian girls incorporated modified survey design methods to improve ethical data collection relevant to the cultural and contextual contexts. This article presents the findings of a thorough review of rape scholarship and design methods. Methods: Based on a qualitative analysis of field notes by the research team, we present lessons learned and best practices identified in the planning, pilot-testing, and implementation phases of the 2018 Liberian study. Results: This study helps inform innovative design methods striving to (1) avoid using obtrusively graphic language or labels prevalent in westernized studies, (2) authentically collaborate with African experts to adapt strategies to be culturally appropriate and contextually relevant, and (3) create respectfully transparent interactions with respondents and communities. Extensive research preparation and inclusive regional expertise inform compassionate methodological techniques, yielding improved Afro-centric participant experience, low participant attrition, and quality data use in policymaking. (4) Conclusions: This article offers innovative design methods to study rape, placing context, culture, and participants at the heart. Authentic collaboration with national-level experts is vital for conducting more reliable and ethical field research in the African region.
Audiological Service Delivery and Uptake in New Zealand Regional Areas
Authors: Boseley Helen , Welch David , Reddy Ravi
Published: November 2023

Background: In New Zealand, as in many places, a significant proportion of the population lives outside the main urban centres. People living in regional areas have similar needs for audiological services as those living in urban centres; however, economic and geographical barriers can be a barrier to accessible services. The objective of this research was to explore factors that influence equitable audiological service provision and user uptake of services in regional areas of New Zealand. Methods: Fifteen participants who represented either audiological service users living in rural or non-urban areas (regional) or audiological service providers in these areas were recruited. Semi-structured interviews were conducted virtually and on average took forty minutes to complete. The interviews were transcribed and analysed using thematic analysis to identify themes and subthemes related to audiological service delivery and uptake. Results: Seven themes were identified. These are related to service provision, geographical barriers, and cultural appropriateness. Conclusions: This study provides a basis for understanding the challenges of delivering and accessing audiological services in non-urban areas in New Zealand, and in principle elsewhere. There is scope for future research to further understand policy directions needed to achieve equitable audiological service provision in regional areas.
Impact of Work Motivation on Occupational Health in Healthcare Workers
Authors: D’Alleva Antonella , Coco Angela , Pelusi Gilda , Gatti Chiara , Bussotti Pietro , Lazzari David , Bracci Massimo , Minelli Andrea , Gasperini Beatrice , Prospero Emilia
Published: November 2023

Objectives: The present cross-sectional study investigated, in a group of Italian healthcare workers (HCWs), the association between work motivation and occupational health and the impact of socio-demographic and job-related variables on this association. Methods: A total of 656 subjects (nurses, technicians, midwives and physiotherapists) completed the survey. Linear regression models were used to correlate motivation types (by Scale of Motivation At Work) with health indicators (general health, depression, professional exhaustion, satisfaction and turnover intention) and burnout’s subscales (emotional exhaustion, depersonalization and reduced professional achievement). Findings: Autonomous motivation correlated positively with general health and work satisfaction and negatively with depression, exhaustion and turnover intention. Scoring high on intrinsic/integrated regulation was associated with better health and job satisfaction and with turnover intention, depression and emotional exhaustion. Controlled motivation, demotivation and external regulation nourished burnout’s indicators, while autonomous motivation was protective. Operating in intensive care or surgical areas negatively affected general health; working as a nurse manager or midwife increased one’s depressive risk and reduced satisfaction; being older than 60 increased emotional exhaustion and turnover intention; having a master’s degree protected from exhaustion and depression. Implications: Collectively, our findings extend evidence on the role of work motivation in shaping occupational health and underline the importance for healthcare organizations of promoting actions to reinforce autonomous motivation at work.
Neurophysiology, Neuro-Immune Interactions, and Mechanobiology in Osteopathy in the Cranial Field: An Evidence-Informed Perspective for a Scientific Rationale
Authors: Barsotti Nicola , Casini Alessandro , Chiera Marco , Lunghi Christian , Fornari Mauro
Published: November 2023

(1) Background: Osteopathy in the cranial field (OCF) is a distinctive approach within osteopathy, focusing on the cranial region’s manual manipulation. Nevertheless, OCF fosters doubt in the scientific community because it refers to out-of-date models. This perspective paper critically analyzes the current knowledge in the fields of neurophysiology and mechanobiology to propose an evidence-informed rationale for OCF. (2) Methods: The reporting framework used in the current perspective article obeyed the guidelines for writing a commentary. (3) Results: The article’s main findings focus on the tactile stimulation of exocranial receptors and their implications in the management of craniofacial algic-dysfunctional syndromes implementing OCF. (4) Conclusions: By establishing an evidence-based rationale for OCF, this research aims to guide future directions in OCF and contribute to a more patient-centered and effective approach to health and wellbeing.
Effects of Exogenous 24-Epibrassinolide Leaves Spraying Application on Chlorophyll Accumulation and Gene Expression Profiles of Chlorophyll Metabolism in Celery
Authors: Chen Chen , Wang Li-Xiang , Li Meng-Yao , Tan Guo-Fei , Zhang Er-Jin , Liu Pei-Zhuo , Liu Hui , Tao Jian-Ping , Shu Sheng , Zhou Jian-Hua , Xiong Ai-Sheng
Published: November 2023

Celery is an important leaf vegetable crop in Apiaceae, of which the petiole and leaf blade are the main edible parts. The content and proportion of photosynthetic pigments, mainly chlorophyll, have an important effect on the growth and quality of celery. As a brassinosteroid (BR) plant hormone with high physiological activity, 24-epibrassinolide (24-EBL) has the physiological functions of promoting chlorophyll accumulation and delaying leaf senescence. To investigate the effects of 24-EBL treatment on chlorophyll accumulation at different growth stages of celery, celery plants (variety Ningqin NO. 1) were treated from 45~59 days after sowing (DAS), at intervals of 7 days, with two different concentrations of 24-EBL: 1.04 × 10−6 mol·L−1 and 1.67 × 10−6 mol·L−1. The content of chlorophyll and the expression levels of genes related to its metabolism were determined in celery leaf blades and petioles at three different stages (52, 59, 66 DAS). In the first stage (52 DAS), 1.04 × 10−6 mol·L−1 treatment of 24-EBL increased the expression levels of genes related to chlorophyll biosynthesis (AgHEML, AgCHLG, and AgCAO) to promote the accumulation of chlorophyll in leaf blades. During the second and third stages (59 and 66 DAS, respectively), 1.67 × 10−6 mol·L−1 24-EBL treatment induced the expression levels of genes related to chlorophyll cyclic regeneration (AgCLH) and inhibited the up-regulation of genes related to chlorophyll degradation (AgNYC, AgHCAR, and AgPPH) to promote chlorophyll (especially chlorophyll b) accumulation. These treatments regulated the ratio of chlorophyll a content to chlorophyll b content and changed the leaf color of the celery. The results show that leaf spraying with an appropriate concentration of 24-EBL can facilitate chlorophyll synthesis by promoting chlorophyll synthesis and cycling-related gene expression levels and increase chlorophyll content in the leaves of celery. This study provides a reference for exploring the specific function of 24-EBL in regulating chlorophyll content during the growth and development of celery.
COVID-19 Vaccine Mandates and Vaccine Hesitancy among Black People in Canada
Authors: Giwa Aisha , Adeagbo Morolake , Tate Shirley Anne , Tulli-Shah Mia , Salami Bukola
Published: November 2023

Objectives: COVID-19 vaccine mandates increased vaccination rates globally. Implemented as a one-size-fits-all policy, these mandates have unintended harmful consequences for many, including Black Canadians. This article reports findings on the interconnectedness of vaccine mandates and vaccine hesitancy by describing a range of responses to mandatory COVID-19 vaccination policies among Black people in Canada. Methods: Using qualitative research methods, semi-structured interviews with 36 Black people living in Canada aged 18 years and over across 6 provinces in Canada were conducted. Participants were selected across intersectional categories including migration status, income, religion, education, sex, and Black ethnicity. Thematic analysis informed the identification of key themes using Foucauldian notions of biopower and governmentality. Results: Our results show how the power relations present in the ways many Black people actualize vaccine intentions. Two main themes were identified: acceptance of the COVID-19 vaccine in the context of governmentality and resistance to vaccine mandates driven by oppression, mistrust, and religion. Conclusion: COVID-19 vaccine mandates may have reinforced mistrust of the government and decreased confidence in the COVID-19 vaccine. Policy makers need to consider non-discriminatory public health policies and monitor how these policies are implemented over time and across multiple sectors to better understand vaccine hesitancy.
Sodium-Doped 3-Amino-4-hydroxybenzoic Acid: Rediscovered Matrix for Direct MALDI Glycotyping of O-Linked Glycopeptides and Intact Mucins
Authors: Urakami Shogo , Hinou Hiroshi
Published: November 2023

3-Amino-4-hydroxybenzoic acid (AHB) was the first matrix identified by glycoprotein glycan analysis using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). However, compared to commonly used matrices, such as 2,5-dihydroxybenzoic acid (DHB), AHB is less efficient at glycan ionization and lacks the ability to ionize other molecular species, such as peptides, and thus is no longer used. In this study, we focused on the glycan-selective ionization ability of AHB and its low-noise properties in the low-molecular-weight region, as we expected that these properties could be enhanced by adding sodium to AHB. Sodium-doped AHB (AHB/Na) selectively imparts sodium adduct ions onto O-glycan fragments generated by the in-source decay (ISD) of glycopeptides and glycoproteins containing O-glycans that occurs during intense laser irradiation, enabling direct O-glycan analysis. Furthermore, we demonstrated that it is possible to investigate the internal structure of each O-glycan fragment with pseudo-MS/MS/MS using the sodium adduct ion of the O-glycan-derived ISD fragments from an intact mucin mixture.
Identification of the Major Protein Components of Human and Cow Saliva
Authors: Akula Srinivas , Welinder Charlotte , Fu Zhirong , Olsson Anna-Karin , Hellman Lars
Published: November 2023

Cows produce saliva in very large quantities to lubricate and facilitate food processing. Estimates indicate an amount of 50–150 L per day. Human saliva has previously been found to contain numerous antibacterial components, such as lysozyme, histatins, members of the S-100 family and lactoferrin, to limit pathogen colonization. Cows depend on a complex microbial community in their digestive system for food digestion. Our aim here was to analyze how this would influence the content of their saliva. We therefore sampled saliva from five humans and both nose secretions and saliva from six cows and separated the saliva on SDS-PAGE gradient gels and analyzed the major protein bands with LC-MS/MS. The cow saliva was found to be dominated by a few major proteins only, carbonic anhydrase 6, a pH-stabilizing enzyme and the short palate, lung and nasal epithelium carcinoma-associated protein 2A (SPLUNC2A), also named bovine salivary protein 30 kDa (BSP30) or BPIFA2B. This latter protein has been proposed to play a role in local antibacterial response by binding bacterial lipopolysaccharides (LPSs) and inhibiting bacterial growth but may instead, according to more recent data, primarily have surfactant activity. Numerous peptide fragments of mucin-5B were also detected in different regions of the gel in the MS analysis. Interestingly, no major band on gel was detected representing any of the antibacterial proteins, indicating that cows may produce them at very low levels that do not harm the microbial flora of their digestive system. The nose secretions of the cows primarily contained the odorant protein, a protein thought to be involved in enhancing the sense of smell of the olfactory receptors and the possibility of quickly sensing potential poisonous food components. High levels of secretory IgA were also found in one sample of cow mouth drippings, indicating a strong upregulation during an infection. The human saliva was more complex, containing secretory IgA, amylase, carbonic anhydrase 6, lysozyme, histatins and a number of other less abundant proteins, indicating a major difference to the saliva of cows that show very low levels of antibacterial components, most likely to not harm the microbial flora of the rumen.
Acute In Vivo Administration of Compound 21 Stimulates Akt and ERK1/2 Phosphorylation in Mouse Heart and Adipose Tissue
Authors: Quiroga Diego T. , Narvaéz Pardo Jorge A. , Zubiría María G. , Barrales Benjamín , Muñoz Marina C. , Giovambattista Andrés , Dominici Fernando P.
Published: November 2023

The angiotensin II type 2 (AT2) receptor has a role in promoting insulin sensitivity. However, the mechanisms underlying the AT2 receptor-induced facilitation of insulin are still not completely understood. Therefore, we investigated whether acute in vivo administration of AT2 receptor agonist compound 21 (C21) could activate insulin signaling molecules in insulin-target tissues. We report that, in male C57BL/6 mice, an acute (5 min, 0.25 mg/kg; i.v.) injection of C21 induces the phosphorylation of Akt and ERK1/2 at activating residues (Ser473 and Thr202/Tyr204, respectively) in both epididymal white adipose tissue (WAT) and heart tissue. In WAT, the extent of phosphorylation (p) of Akt and ERK1/2 induced by C21 was approximately 65% of the level detected after a bolus injection of a dose of insulin known to induce maximal activation of the insulin receptor (IR). In the heart, C21 stimulated p-Akt to a lesser extent than in WAT and stimulated p-ERK1/2 to similar levels to those attained by insulin administration. C21 did not modify p-IR levels in either tissue. We conclude that in vivo injection of the AT2 receptor agonist C21 activates Akt and ERK1/2 through a mechanism that does not involve the IR, indicating the participation of these enzymes in AT2R-mediated signaling.
Molecular Mechanisms of the Regulation of Liver Cytochrome P450 by Brain NMDA Receptors and via the Neuroendocrine Pathway—A Significance for New Psychotropic Therapies
Authors: Pukło Renata , Bromek Ewa , Haduch Anna , Basińska-Ziobroń Agnieszka , Kuban Wojciech , Daniel Władysława A.
Published: November 2023

Recent investigations have highlighted the potential utility of the selective antagonist of the NMDA receptor GluN2B subunit for addressing major depressive disorders. Our previous study showed that the systemic administration of the antagonist of the GluN2B subunit of the NMDA receptor, the compound CP-101,606, affected liver cytochrome P450 expression and activity. To discern between the central and peripheral mechanisms of enzyme regulation, our current study aimed to explore whether the intracerebral administration of CP-101,606 could impact cytochrome P450. The injection of CP-101,606 to brain lateral ventricles (6, 15, or 30 µg/brain) exerted dose-dependent effects on liver cytochrome P450 enzymes and hypothalamic or pituitary hormones. The lowest dose led to an increase in the activity, protein, and mRNA level of CYP2C11 compared to the control. The activities of CYP2A, CYP2B, CYP2C11, CYP2C6, CYP2D, and protein levels of CYP2B, CYP2C11 were enhanced compared to the highest dose. Moreover, CP-101,606 increased the CYP1A protein level coupled with elevated CYP1A1 and CYP1A2 mRNA levels, but not activity. The antagonist decreased the pituitary somatostatin level and increased the serum growth hormone concentration after the lowest dose, while independently decreasing the serum corticosterone concentration of the dose. The findings presented here unveil a novel physiological regulatory mechanism whereby the brain glutamatergic system, via the NMDA receptor, influences liver cytochrome P450. This regulatory process appears to involve the endocrine system. These results may have practical applications in predicting alterations in cytochrome P450 activity and endogenous metabolism, and potential metabolic drug–drug interactions elicited by drugs that cross the blood–brain barrier and affect NMDA receptors.
Glucocorticoid Nanoparticles Show Full Therapeutic Efficacy in a Mouse Model of Acute Lung Injury and Concomitantly Reduce Adverse Effects
Authors: Albers Gesa J. , Amouret Agathe , Ciupka Katrin , Montes-Cobos Elena , Feldmann Claus , Reichardt Holger M.
Published: November 2023

Glucocorticoids (GCs) are widely used to treat inflammatory disorders such as acute lung injury (ALI). Here, we explored inorganic–organic hybrid nanoparticles (IOH-NPs) as a new delivery vehicle for GCs in a mouse model of ALI. Betamethasone (BMZ) encapsulated into IOH-NPs (BNPs) ameliorated the massive infiltration of neutrophils into the airways with a similar efficacy as the free drug. This was accompanied by a potent inhibition of pulmonary gene expression and secretion of pro-inflammatory mediators, whereas the alveolar–capillary barrier integrity was only restored by BMZ in its traditional form. Experiments with genetically engineered mice identified myeloid cells and alveolar type II (AT II) cells as essential targets of BNPs in ALI therapy, confirming their high cell-type specificity. Consequently, adverse effects were reduced when using IOH-NPs for GC delivery. BNPs did not alter T and B cell numbers in the blood and also prevented the induction of muscle atrophy after three days of treatment. Collectively, our data suggest that IOH-NPs target GCs to myeloid and AT II cells, resulting in full therapeutic efficacy in the treatment of ALI while being associated with reduced adverse effects.
Comparative Analysis of Morphological and Functional Effects of 225Ac- and 177Lu-PSMA Radioligand Therapies (RLTs) on Salivary Glands
Authors: Feuerecker Benedikt , Gafita Andrei , Langbein Thomas , Tauber Robert , Seidl Christof , Bruchertseifer Frank , Gschwendt Jürgen E. , Weber Wolfgang A. , D’Alessandria Calogero , Morgenstern Alfred , Eiber Matthias
Published: November 2023

Most Prostate Specific Membrane Antigens (PSMAs) targeting small molecules accumulate in the salivary glands (SGs), raising concerns about SG toxicity, especially after repeated therapies or therapy with 225Ac-labeled ligands. SG toxicity is assessed clinically by the severity of patient-reported xerostomia, but this parameter can be challenging to objectively quantify. Therefore, we explored the feasibility of using SG volume as a biomarker for toxicity. In 21 patients with late-stage metastatic resistant prostate cancer (mCRPC), the PSMA volume and ligand uptake of SG were analyzed retrospectively before and after two cycles of 177Lu-PSMA (LuPSMA; cohort A) and before and after one cycle of 225Ac-PSMA-617 (AcPSMA, cohort B). Mean Volume-SG in cohort A was 59 ± 13 vs. 54 ± 16 mL (−10%, p = 0.4), and in cohort B, it was 50 ± 13 vs. 40 ± 11 mL (−20%, p = 0.007), respectively. A statistically significant decrease in the activity concentration in the SG was only observed in group B (SUVmean: 9.2 ± 2.8 vs. 5.3 ± 1.8, p < 0.0001; vs. A: SUVmean: 11.2 ± 3.3 vs. 11.1 ± 3.5, p = 0.8). SG volume and PSMA-ligand uptake are promising markers to monitor the SG toxicity after a PSMA RLT.
Elevated Serum Gastrin Is Associated with Melanoma Progression: Putative Role in Increased Migration and Invasion of Melanoma Cells
Authors: Varga Akos Janos , Nemeth Istvan Balazs , Kemeny Lajos , Varga Janos , Tiszlavicz Laszlo , Kumar Dinesh , Dodd Steven , Simpson Alec W. M. , Buknicz Tunde , Beynon Rob , Simpson Deborah , Krenacs Tibor , Dockray Graham J. , Varro Andrea
Published: November 2023

Micro-environmental factors, including stromal and immune cells, cytokines, and circulating hormones are well recognized to determine cancer progression. Melanoma cell growth was recently shown to be suppressed by cholecystokinin/gastrin (CCK) receptor antagonists, and our preliminary data suggested that melanoma patients with Helicobacter gastritis (which is associated with elevated serum gastrin) might have an increased risk of cancer progression. Therefore, in the present study, we examined how gastrin may act on melanoma cells. In 89 melanoma patients, we found a statistically significant association between circulating gastrin concentrations and melanoma thickness and metastasis, which are known risk factors of melanoma progression and prognosis. Immunocytochemistry using a validated antibody confirmed weak to moderate CCK2R expression in both primary malignant melanoma cells and the melanoma cell lines SK-MEL-2 and G361. Furthermore, among the 219 tumors in the Skin Cutaneous Melanoma TCGA Pan-Cancer dataset showing gastrin receptor (CCKBR) expression, significantly higher CCKBR mRNA levels were linked to stage III–IV than stage I–II melanomas. In both cell lines, gastrin increased intracellular calcium levels and stimulated cell migration and invasion through mechanisms inhibited by a CCK2 receptor antagonist. Proteomic studies identified increased MMP-2 and reduced TIMP-3 levels in response to gastrin that were likely to contribute to the increased migration of both cell lines. However, the effects of gastrin on tumor cell invasion were relatively weak in the presence of the extracellular matrix. Nevertheless, dermal fibroblasts/myofibroblasts, known also to express CCK2R, increased gastrin-induced cancer cell invasion. Our data suggest that in a subset of melanoma patients, an elevated serum gastrin concentration is a risk factor for melanoma tumor progression, and that gastrin may act on both melanoma and adjacent stromal cells through CCK2 receptors to promote mechanisms of tumor migration and invasion.
The Fundamental Role of Oxime and Oxime Ether Moieties in Improving the Physicochemical and Anticancer Properties of Structurally Diverse Scaffolds
Authors: Fotie Jean , Matherne Caitlyn M. , Mather Jasmine B. , Wroblewski Jordan E. , Johnson Khaitlynn , Boudreaux Lara G. , Perez Alba A.
Published: November 2023

The present review explores the critical role of oxime and oxime ether moieties in enhancing the physicochemical and anticancer properties of structurally diverse molecular frameworks. Specific examples are carefully selected to illustrate the distinct contributions of these functional groups to general strategies for molecular design, modulation of biological activities, computational modeling, and structure–activity relationship studies. An extensive literature search was conducted across three databases, including PubMed, Google Scholar, and Scifinder, enabling us to create one of the most comprehensive overviews of how oximes and oxime ethers impact antitumor activities within a wide range of structural frameworks. This search focused on various combinations of keywords or their synonyms, related to the anticancer activity of oximes and oxime ethers, structure–activity relationships, mechanism of action, as well as molecular dynamics and docking studies. Each article was evaluated based on its scientific merit and the depth of the study, resulting in 268 cited references and more than 336 illustrative chemical structures carefully selected to support this analysis. As many previous reviews focus on one subclass of this extensive family of compounds, this report represents one of the rare and fully comprehensive assessments of the anticancer potential of this group of molecules across diverse molecular scaffolds.
Ionic Conductivity of K-ion Glassy Solid Electrolytes of K2S-P2S5-KOTf System
Authors: Hona Ram Krishna , Azure Alexa D. , Guinn Mandy , Phuyal Uttam S. , Stroh Kianna , Thapa Arjun K.
Published: November 2023

Ternary glassy electrolytes containing K2S as a glass modifier and P2S5 as a network former are synthesized by introducing a new type of complex and asymmetric salt, potassium triflate (KOTf), to obtain unprecedented K+ ion conductivity at ambient temperature. The glasses are synthesized using a conventional quenching technique at a low temperature. In general, alkali ionic glassy electrolytes of ternary systems, specifically for Li+ and Na+ ion conductivity, have been studied with the addition of halide salts or oxysalts such as M2SO4, M2SiO4, M3PO4 (M = Li or Na), etc. We introduce a distinct and complex salt, potassium triflate (KOTf) with asymmetric anion, to the conventional glass modifier and former to synthesize K+-ion-conducting glassy electrolytes. Two series of glassy electrolytes with a ternary system of (0.9–x)K2S-xP2S5-0.1KOTf (x = 0.15, 0.30, 0.45, 0.60, and 0.75) and z(K2S-2P2S5)-yKOTf (y = 0.05, 0.10, 0.15, 0.20, and 0.25) on a straight line of z(K2S-2P2S5) are studied for their K+ ionic conductivities by using electrochemical impedance spectroscopy (EIS). The composition 0.3K2S-0.6P2S5-0.1KOTf is found to have the highest conductivity among the studied glassy electrolytes at ambient temperature with the value of 1.06 × 10−7 S cm−1, which is the highest of all pure K+-ion-conducting glasses reported to date. Since the glass transition temperatures of the glasses are near 100 °C, as demonstrated by DSC, temperature-dependent conductivities are studied within the range of 25 to 100 °C to determine the activation energies. A Raman spectroscopic study shows the variation in the structural units PS43−, P2S74−, and P2S64− of the network former for different glassy electrolytes. It seems that there is a role of P2S74− and P2S64− in K+-ion conductivity in the glassy electrolytes because the spectroscopic results are compatible with the composition-dependent, room-temperature conductivity trend.
Influence of Organ Culture on the Characteristics of the Human Limbal Stem Cell Niche
Authors: Polisetti Naresh , Martin Gottfried , Ulrich Eva , Glegola Mateusz , Schlötzer-Schrehardt Ursula , Schlunck Günther , Reinhard Thomas
Published: November 2023

Organ culture storage techniques for corneoscleral limbal (CSL) tissue have improved the quality of corneas for transplantation and allow for longer storage times. Cultured limbal tissue has been used for stem cell transplantation to treat limbal stem cell deficiency (LSCD) as well as for research purposes to assess homeostasis mechanisms in the limbal stem cell niche. However, the effects of organ culture storage conditions on the quality of limbal niche components are less well described. Therefore, in this study, the morphological and immunohistochemical characteristics of organ-cultured limbal tissue are investigated and compared to fresh limbal tissues by means of light and electron microscopy. Organ-cultured limbal tissues showed signs of deterioration, such as edema, less pronounced basement membranes, and loss of the most superficial layers of the epithelium. In comparison to the fresh limbal epithelium, organ-cultured limbal epithelium showed signs of ongoing proliferative activity (more Ki-67+ cells) and exhibited an altered limbal epithelial phenotype with a loss of N-cadherin and desmoglein expression as well as a lack of precise staining patterns for cytokeratin ((CK)14, CK17/19, CK15). The analyzed extracellular matrix composition was mainly intact (collagen IV, fibronectin, laminin chains) except for Tenascin-C, whose expression was increased in organ-cultured limbal tissue. Nonetheless, the expression patterns of cell–matrix adhesion proteins varied in organ-cultured limbal tissue compared to fresh limbal tissue. A decrease in the number of melanocytes (Melan-A+ cells) and Langerhans cells (HLA-DR+, CD1a+, CD18+) was observed in the organ-cultured limbal tissue. The organ culture-induced alterations of the limbal epithelial stem cell niche might hamper its use in the treatment of LSCD as well as in research studies. In contrast, reduced numbers of donor-derived Langerhans cells seem associated with better clinical outcomes. However, there is a need to consider the preferential use of fresh CSL for limbal transplants and to look at ways of improving the limbal stem cell properties of stored CSL tissue.
Dietary Potassium Supplementation Reduces Chronic Kidney Lesions Independent of Blood Pressure in Deoxycorticosterone-Acetate and High Sodium Chloride-Treated Mice
Authors: Wang Qing , Schäfer Stephan C. , Haefliger Jacques-Antoine , Maillard Marc P. , Alonso Florian
Published: November 2023

We have previously shown that an excess of deoxycorticosterone acetate and high sodium chloride intake (DOCA/salt) in one-renin gene mice induces a high urinary Na/K ratio, hypokalemia, and cardiac and renal hypertrophy in the absence of hypertension. Dietary potassium supplementation prevents DOCA/salt-induced pathological processes. In the present study, we further study whether DOCA/salt-treated mice progressively develop chronic inflammation and fibrosis in the kidney and whether dietary potassium supplementation can reduce the DOCA/salt-induced renal pathological process. Results showed that (1) long-term DOCA/salt-treated one-renin gene mice developed severe kidney injuries including tubular/vascular hypertrophy, mesangial/interstitial/perivascular fibrosis, inflammation (lymphocyte’s immigration), proteinuria, and high serum creatinine in the absence of hypertension; (2) there were over-expressed mRNAs of plasminogen activator inhibitor-1 (PAI-1), fibronectin, collagen type I and III, interferon-inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP1), transforming growth factor-β (TGF-β), tumor necrosis factor-alpha (TNF-α), osteopontin, Nuclear factor kappa B (NF-κB)/P65, and intercellular adhesion molecule (ICAM)-1; and (3) dietary potassium supplementation normalized urinary Na/K ratio, hypokalemia, proteinuria, and serum creatinine, reduced renal hypertrophy, inflammations, and fibrosis, and down-regulated mRNA expression of fibronectin, Col-I and III, TGF-β, TNF-α, osteopontin, and ICAM without changes in the blood pressure. The results provide new evidence that potassium and sodium may modulate proinflammatory and fibrotic genes, leading to chronic renal lesions independent of blood pressure.
Metformin Prevents Cocaine Sensitization: Involvement of Adenosine Monophosphate-Activated Protein Kinase Trafficking between Subcellular Compartments in the Corticostriatal Reward Circuit
Authors: Aruldas Rachel , Orenstein Laura Buczek , Spencer Sade
Published: November 2023

Repeated cocaine exposure produces an enhanced locomotor response (sensitization) paralleled by biological adaptations in the brain. Previous studies demonstrated region-specific responsivity of adenosine monophosphate-activated protein kinase (AMPK) to repeated cocaine exposure. AMPK maintains cellular energy homeostasis at the organismal and cellular levels. Here, our objective was to quantify changes in phosphorylated (active) and total AMPK in the cytosol and synaptosome of the medial prefrontal cortex, nucleus accumbens, and dorsal striatum following acute or sensitizing cocaine injections. Brain region and cellular compartment selective changes in AMPK and pAMPK were found with some differences associated with acute withdrawal versus ongoing cocaine treatment. Our additional goal was to determine the behavioral and molecular effects of pretreatment with the indirect AMPK activator metformin. Metformin potentiated the locomotor activating effects of acute cocaine but blocked the development of sensitization. Sex differences largely obscured any protein-level treatment group effects, although pAMPK in the NAc shell cytosol was surprisingly reduced by metformin in rats receiving repeated cocaine. The rationale for these studies was to inform our understanding of AMPK activation dynamics in subcellular compartments and provide additional support for repurposing metformin for treating cocaine use disorder.
Direct Current Stimulation Modulates Synaptic Facilitation via Distinct Presynaptic Calcium Channels
Authors: Vasu Sreerag Othayoth , Kaphzan Hanoch
Published: November 2023

Transcranial direct current stimulation (tDCS) is a subthreshold neurostimulation technique known for ameliorating neuropsychiatric conditions. The principal mechanism of tDCS is the differential polarization of subcellular neuronal compartments, particularly the axon terminals that are sensitive to external electrical fields. Yet, the underlying mechanism of tDCS is not fully clear. Here, we hypothesized that direct current stimulation (DCS)-induced modulation of presynaptic calcium channel conductance alters axon terminal dynamics with regard to synaptic vesicle release. To examine the involvement of calcium-channel subtypes in tDCS, we recorded spontaneous excitatory postsynaptic currents (sEPSCs) from cortical layer-V pyramidal neurons under DCS while selectively inhibiting distinct subtypes of voltage-dependent calcium channels. Blocking P/Q or N-type calcium channels occluded the effects of DCS on sEPSCs, demonstrating their critical role in the process of DCS-induced modulation of spontaneous vesicle release. However, inhibiting T-type calcium channels did not occlude DCS-induced modulation of sEPSCs, suggesting that despite being active in the subthreshold range, T-type calcium channels are not involved in the axonal effects of DCS. DCS modulates synaptic facilitation by regulating calcium channels in axon terminals, primarily via controlling P/Q and N-type calcium channels, while T-type calcium channels are not involved in this mechanism.