-
International Journal of Molecular... Jun 2024Noise-induced hearing loss (NIHL) is a major cause of hearing impairment and is linked to dementia and mental health conditions, yet no FDA-approved drugs exist to...
Noise-induced hearing loss (NIHL) is a major cause of hearing impairment and is linked to dementia and mental health conditions, yet no FDA-approved drugs exist to prevent it. Downregulating the mitogen-activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL, but the molecular targets and the mechanism of protection are not fully understood. Here, we tested specifically the role of the kinases ERK1/2 in noise otoprotection using a newly developed, highly specific ERK1/2 inhibitor, tizaterkib, in preclinical animal models. Tizaterkib is currently being tested in phase 1 clinical trials for cancer treatment and has high oral bioavailability and low predicted systemic toxicity in mice and humans. In this study, we performed dose-response measurements of tizaterkib's efficacy against permanent NIHL in adult FVB/NJ mice, and its minimum effective dose (0.5 mg/kg/bw), therapeutic index (>50), and window of opportunity (<48 h) were determined. The drug, administered orally twice daily for 3 days, 24 h after 2 h of 100 dB or 106 dB SPL noise exposure, at a dose equivalent to what is prescribed currently for humans in clinical trials, conferred an average protection of 20-25 dB SPL in both female and male mice. The drug shielded mice from the noise-induced synaptic damage which occurs following loud noise exposure. Equally interesting, tizaterkib was shown to decrease the number of CD45- and CD68-positive immune cells in the mouse cochlea following noise exposure. This study suggests that repurposing tizaterkib and the ERK1/2 kinases' inhibition could be a promising strategy for the treatment of NIHL.
Topics: Animals; Mice; Administration, Oral; Hearing Loss, Noise-Induced; Male; Protein Kinase Inhibitors; MAP Kinase Signaling System; Female; Disease Models, Animal; Cochlea
PubMed: 38928015
DOI: 10.3390/ijms25126305 -
Biomolecules May 2024Encapsulins are self-assembling nano-compartments that naturally occur in bacteria and archaea. These nano-compartments encapsulate cargo proteins that bind to the... (Review)
Review
Encapsulins are self-assembling nano-compartments that naturally occur in bacteria and archaea. These nano-compartments encapsulate cargo proteins that bind to the shell's interior through specific recognition sequences and perform various metabolic processes. Encapsulation enables organisms to perform chemical reactions without exposing the rest of the cell to potentially harmful substances while shielding cargo molecules from degradation and other adverse effects of the surrounding environment. One particular type of cargo protein, the ferritin-like protein (FLP), is the focus of this review. Encapsulated FLPs are members of the ferritin-like protein superfamily, and they play a crucial role in converting ferrous iron (Fe) to ferric iron (Fe), which is then stored inside the encapsulin in mineralized form. As such, FLPs regulate iron homeostasis and protect organisms against oxidative stress. Recent studies have demonstrated that FLPs have tremendous potential as biosensors and bioreactors because of their ability to catalyze the oxidation of ferrous iron with high specificity and efficiency. Moreover, they have been investigated as potential targets for therapeutic intervention in cancer drug development and bacterial pathogenesis. Further research will likely lead to new insights and applications for these remarkable proteins in biomedicine and biotechnology.
Topics: Ferritins; Humans; Iron; Bacterial Proteins; Bacteria
PubMed: 38927029
DOI: 10.3390/biom14060624 -
Scientific Reports Jun 2024Occupational radiation protection should be applied to the design of treatment rooms for various radiation therapy techniques, including BNCT, where escaping particles...
Occupational radiation protection should be applied to the design of treatment rooms for various radiation therapy techniques, including BNCT, where escaping particles from the beam port of the beam shaping assembly (BSA) may reach the walls or penetrate through the entrance door. The focus of the present study is to design an alternative shielding material, other than the conventional material of lead, that can be considered as the material used in the door and be able to effectively absorb the BSA neutrons which have slowed down to the thermal energy range of eV after passing through the walls and the maze of the room. To this aim, a thermal neutron shield, composed of polymer composite and polyethylene, has been simulated using the Geant4 Monte Carlo code. The neutron flux and dose values were predicted using an artificial neural network (ANN), eliminating the need for time-consuming Monte Carlo simulations in all possible suggestions. Additionally, this technique enables simultaneous optimization of the parameters involved, which is more effective than the traditional sequential and separate optimization process. The results indicated that the optimized shielding material, chosen through ANN calculations that determined the appropriate thickness and weight percent of its compositions, can decrease the dose behind the door to lower than the allowable limit for occupational exposure. The stability of ANN was tested by considering uncertainties with the Gaussian distributions of random numbers to the testing data. The results are promising as they indicate that ANNs could be used as a reliable tool for accurately predicting the dosimetric results, providing a drastically powerful alternative approach to the time-consuming Monte Carlo simulations.
PubMed: 38926477
DOI: 10.1038/s41598-024-65207-w -
Scientific Reports Jun 2024The main objective of this study was to use deep learning, and convolutional neural networks (CNN), integrated with field geology to identify distinct lithological...
The main objective of this study was to use deep learning, and convolutional neural networks (CNN), integrated with field geology to identify distinct lithological units. The Samadia-Tunduba region of the South Eastern Desert of Egypt was mapped geologically for the first time thanks to the use of processed developed CNN algorithms using Landsat 9 OLI-2, which were further enhanced by geological fieldwork, spectral measurements of field samples, and petrographic examination. According to previously published papers, a significant difference was observed in the distribution of rocks and their boundaries, as well as the previously published geological maps that were not accurately compatible with the nature of the area. The many lithologic units in the region are refined using principal component analysis, color ratio composites, and false-color composites. These techniques demonstrated the ability to distinguish between various igneous and metamorphic rock types, especially metavolcanics, metasediments, granodiorite, and biotite monzogranite. The Key structural trends, lithological units, and wadis affecting the area under study are improved by the principal component analysis approach (PC 3, 2, 1), (PC 2, 3, 4), (PC 4, 3, 2), (PC 5, 4, 3), and (PC 6, 5, 4) in RGB, respectively. The best band ratios recorded in the area are recorded the good discrimination (6/5, 4/3, and 2/1), (4/2, 6/7, and 5/6), and (3/2, 5/6, and 4/6) for RGB. The classification map achieved an overall accuracy of 95.27%, and these results from Landsat-9 data were validated by field geology and petrographical studies. The results of this survey can make a significant difference to detailed geological studies. A detailed map of the new district has been prepared through a combination of deep learning and fieldwork.
PubMed: 38926393
DOI: 10.1038/s41598-024-62093-0 -
BMJ Quality & Safety Jun 2024To estimate and quantify the cost implications and health impacts of improving the performance of English endoscopy services to the optimum quality as defined by...
OBJECTIVE
To estimate and quantify the cost implications and health impacts of improving the performance of English endoscopy services to the optimum quality as defined by postcolonoscopy colorectal cancer (PCCRC) rates.
DESIGN
A semi-Markov state-transition model was constructed, following the logical treatment pathway of individuals who could potentially undergo a diagnostic colonoscopy. The model consisted of three identical arms, each representing a high, middle or low-performing trust's endoscopy service, defined by PCCRC rates. A cohort of 40-year-old individuals was simulated in each arm of the model. The model's time horizon was when the cohort reached 90 years of age and the total costs and quality-adjusted life-years (QALYs) were calculated for all trusts. Scenario and sensitivity analyses were also conducted.
RESULTS
A 40-year-old individual gains 0.0006 QALYs and savings of £6.75 over the model lifetime by attending a high-performing trust compared with attending a middle-performing trust and gains 0.0012 QALYs and savings of £14.64 compared with attending a low-performing trust. For the population of England aged between 40 and 86, if all low and middle-performing trusts were improved to the level of a high-performing trust, QALY gains of 14 044 and cost savings of £249 311 295 are possible. Higher quality trusts dominated lower quality trusts; any improvement in the PCCRC rate was cost-effective.
CONCLUSION
Improving the quality of endoscopy services would lead to QALY gains among the population, in addition to cost savings to the healthcare provider. If all middle and low-performing trusts were improved to the level of a high-performing trust, our results estimate that the English National Health Service would save approximately £5 million per year.
PubMed: 38925929
DOI: 10.1136/bmjqs-2023-016932 -
PLoS Neglected Tropical Diseases Jun 2024Gold miners working illegally in mines live in poor health conditions related to their strenuous work and precarious housing. Therefore, they are at higher risk for...
Gold miners working illegally in mines live in poor health conditions related to their strenuous work and precarious housing. Therefore, they are at higher risk for infectious diseases. American tegumentary leishmaniasis (ATL) appears to be of great concern to the population living in the Guiana Shield region. Our aim was to describe their demographic characteristics, the clinical features of cutaneous leishmaniasis (CL), and the frequency of Leishmania infection in people working in illegal gold mines in French Guiana. A cross-sectional study was carried out from October to December 2019 in Oiapoque city, Amapá, Brazil. Indeed, many gold miners working in French Guiana are originally from Brazil, and from Oiapoque in particular. A total of 105 participants from 31 different mining sites in French Guiana were recruited. Suspected Leishmania infection was confirmed by the following: detection of kDNA in blood or the lesion site; detection of specific antibodies; or detection of IFN-γ release after blood incubation with leishmanial antigens (IGRA-Leish). Nine active CL cases, 38 healed ATL (hATL) and 58 cases with no history of ATL (noATL), were identified. Only half of the treated hATL (50.0%; n = 14) reported having been assisted by a health care unit and the others treated themselves. PCR-kDNA for Leishmania was positive in the blood of 100% of CL cases. Curiously, blood PCR-kDNA was positive in 13% of hATL patients and in 15.5% of noATL patients. The IGRA-Leish was positive in 60.5% of hATL and in 37.9% of noATL. In addition to scars suggestive of CL, 71% of hATL had laboratory evidence of Leishmania infection. Restriction fragment polymorphism (RFLP) of the hsp70 gene identified a sympatric circulation of L. (V.) guyanensis (n = 4), L. (V.) braziliensis (n = 1), L. (L.) amazonensis (n = 2), L. (V.) shawi (n = 1) and L. (V.) naiffi/shawi (n = 1). Taking the laboratory techniques and the clinical evaluations together, 76% (n = 80) of the 105 participants had evidence of Leishmania infection. These results suggests that illegal gold miners working in French Guiana are at high risk for infection with different species of Leishmania, but their illegal condition and remoteness make it difficult for them to access health services.
Topics: Humans; French Guiana; Brazil; Adult; Male; Cross-Sectional Studies; Gold; Miners; Middle Aged; Leishmaniasis, Cutaneous; Mining; Leishmania; Female; Young Adult
PubMed: 38923969
DOI: 10.1371/journal.pntd.0012210 -
Genome Biology and Evolution Jun 2024Molecular studies of animal regeneration typically focus on conserved genes and signaling pathways that underlie morphogenesis. To date, a holistic analysis of gene...
Molecular studies of animal regeneration typically focus on conserved genes and signaling pathways that underlie morphogenesis. To date, a holistic analysis of gene expression across animals has not been attempted, as it presents a suite of problems related to differences in experimental design and gene homology. By combining orthology analyses with a novel statistical method for testing gene enrichment across large datasets, we are able to test whether tissue regeneration across animals share transcriptional regulation. We applied this method to a meta-analysis of 6 publicly available RNA-Seq datasets from diverse examples of animal regeneration. We recovered 160 conserved orthologous gene clusters, which are enriched in structural genes as opposed to those regulating morphogenesis. A breakdown of gene presence/absence provides limited support for the conservation of pathways typically implicated in regeneration, such as Wnt signaling and cell pluripotency pathways. Such pathways are only conserved if we permit large amounts of paralog switching through evolution. Overall, our analysis does not support the hypothesis that a shared set of ancestral genes underlie regeneration mechanisms in animals. After applying the same method to heat shock studies and getting similar results, we raise broader questions about the ability of comparative RNA-Seq to reveal conserved gene pathways across deep evolutionary relationships.
PubMed: 38922665
DOI: 10.1093/gbe/evae120 -
Journal of Functional Biomaterials Jun 2024With the rising demand for medical implants and the dominance of implant-associated failures including infections, extensive research has been prompted into the...
With the rising demand for medical implants and the dominance of implant-associated failures including infections, extensive research has been prompted into the development of novel biomaterials that can offer desirable characteristics. This study develops and evaluates new titanium-based alloys containing gallium additions with the aim of offering beneficial antibacterial properties while having a reduced stiffness level to minimise the effect of stress shielding when in contact with bone. The focus is on the microstructure, mechanical properties, antimicrobial activity, and cytocompatibility to inform the suitability of the designed alloys as biometals. Novel Ti-33Nb-xGa alloys (x = 3, 5 wt%) were produced via casting followed by homogenisation treatment, where all results were compared to the currently employed alloy Ti-6Al-4V. Optical microscopy, scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS) results depicted a single beta (β) phase microstructure in both Ga-containing alloys, where Ti-33Nb-5Ga was also dominated by dendritic alpha (α) phase grains in a β-phase matrix. EDS analysis indicated that the α-phase dendrites in Ti-33Nb-5Ga were enriched with titanium, while the β-phase was richer in niobium and gallium elements. Mechanical properties were measured using nanoindentation and microhardness methods, where the Young's modulus for Ti-33Nb-3Ga and Ti-33Nb-5Ga was found to be 75.4 ± 2.4 and 67.2 ± 1.6 GPa, respectively, a significant reduction of 37% and 44% with respect to Ti-6Al-4V. This reduction helps address the disproportionate Young's modulus between titanium implant components and cortical bone. Importantly, both alloys successfully achieved superior antimicrobial properties against Gram-negative and Gram-positive bacteria. Antibacterial efficacy was noted at up to 90 ± 5% for the 3 wt% alloy and 95 ± 3% for the 5 wt% alloy. These findings signify a substantial enhancement of the antimicrobial performance when compared to Ti-6Al-4V which exhibited very small rates (up to 6.3 ± 1.5%). No cytotoxicity was observed in hGF cell lines over 24 h. Cell morphology and cytoskeleton distribution appeared to depict typical morphology with a prominent nucleus, elongated fibroblastic spindle-shaped morphology, and F-actin filamentous stress fibres in a well-defined structure of parallel bundles along the cellular axis. The developed alloys in this work have shown very promising results and are suggested to be further examined towards the use of orthopaedic implant components.
PubMed: 38921540
DOI: 10.3390/jfb15060167 -
Healthcare (Basel, Switzerland) Jun 2024Evaluation of post-nephrectomy social health in living kidney donors is essential. This systematic review examines their emotional need for social relatedness... (Review)
Review
INTRODUCTION
Evaluation of post-nephrectomy social health in living kidney donors is essential. This systematic review examines their emotional need for social relatedness post-donation.
METHODS
Following the PRISMA guidelines, we systematically searched Scopus, CINAHL, and PsycINFO.
RESULTS
Among the screened records, 32 quantitative and 16 qualitative papers met the inclusion criteria. Quantitative research predominantly utilized questionnaires featuring generic items on social functioning. However, a minority delved into emotional and social dimensions, aligning with qualitative studies emphasizing the importance of social connection and perceived social support post-donation. Specifically, post-donation changes in connecting with others encompass a sense of belongingness, heightened autonomy, shifts in concern for the recipient's health, and continued care by shielding the recipient from personal health issues. Social acknowledgment and social support from both close and extended networks are reported as relevant for recovery after nephrectomy.
DISCUSSION
These findings underscore the necessity for targeted measures of emotional needs and social functioning to effectively assess post-donation adjustment. They also inform the identification of key health themes for kidney donor Patient-Reported Outcome Measures (PROMs) and Patient-Reported Experience Measures (PREMs) questions.
PubMed: 38921330
DOI: 10.3390/healthcare12121216 -
Gels (Basel, Switzerland) Jun 2024Wound healing involves a sophisticated biological process that relies on ideal conditions to advance through various stages of repair. Modern wound dressings are...
The Diels-Alder Cross-Linked Gelatin/Dextran Nanocomposite Hydrogels with Silver Nanoparticles for Wound Healing Applications: Synthesis, Characterization, and In Vitro Evaluation.
Wound healing involves a sophisticated biological process that relies on ideal conditions to advance through various stages of repair. Modern wound dressings are designed to imitate the natural surroundings around cells and offer properties such as moisture regulation, strength, and antimicrobial defense to boost healing. A recent research project unveiled a new type of gelatin (Gel)/dextran (Dex) hydrogels, linked through Diels-Alder (D-A) reactions, loaded with silver nanoparticles (Ag-NPs) for cutting-edge wound treatment. Gel and Dex were chemically modified to form the hydrogels via the D-A reaction. The hydrogels were enriched with Ag-NPs at varying levels. Thorough analyses of the hydrogels using methods like NMR, FT-IR, and SEM were carried out to assess their structure and nanoparticle integration. Rheological tests displayed that the hydrogels had favorable mechanical attributes, particularly when Ag-NPs were included. The hydrogels demonstrated controlled swelling, responsiveness to pH changes, and were non-toxic. Testing against E. coli showcased the strong antibacterial activity of the nanocomposite hydrogels in a concentration-dependent manner. This investigation showcased the promise of these bioactive nanocomposite hydrogels in promoting speedy wound healing by maintaining a moist environment, offering an antimicrobial shield, and ensuring mechanical support at the wound site.
PubMed: 38920954
DOI: 10.3390/gels10060408