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Molecular Brain Jun 2024Chronic perturbations of neuronal activity can evoke homeostatic and new setpoints for neurotransmission. Using chemogenetics to probe the relationship between neuronal...
Chronic perturbations of neuronal activity can evoke homeostatic and new setpoints for neurotransmission. Using chemogenetics to probe the relationship between neuronal cell types and behavior, we recently found reversible decreases in dopamine (DA) transmission, basal behavior, and amphetamine (AMPH) response following repeated stimulation of DA neurons in adult mice. It is unclear, however, whether altering DA neuronal activity via chemogenetics early in development leads to behavioral phenotypes that are reversible, as alterations of neuronal activity during developmentally sensitive periods might be expected to induce persistent effects on behavior. To examine the impact of developmental perturbation of DA neuron activity on basal and AMPH behavior, we expressed excitatory hM3D(Gq) in postnatal DA neurons in TH-Cre and WT mice. Basal and CNO- or AMPH-induced locomotion and stereotypy was evaluated in a longitudinal design, with clozapine N-oxide (CNO, 1.0 mg/kg) administered across adolescence (postnatal days 15-47). Repeated CNO administration did not impact basal behavior and only minimally reduced AMPH-induced hyperlocomotor response in adolescent TH-Cre mice relative to WT littermate controls. Following repeated CNO administration, however, AMPH-induced stereotypic behavior robustly decreased in adolescent TH-Cre mice relative to controls. A two-month CNO washout period rescued the diminished AMPH-induced stereotypic behavior. Our findings indicate that the homeostatic compensations that take place in response to chronic hM3D(Gq) stimulation during adolescence are temporary and are dependent on ongoing chemogenetic stimulation.
Topics: Animals; Amphetamine; Dopaminergic Neurons; Stereotyped Behavior; Clozapine; Locomotion; Mice; Male; Motor Activity; Mice, Transgenic; Tyrosine 3-Monooxygenase; Behavior, Animal; Integrases
PubMed: 38858755
DOI: 10.1186/s13041-024-01110-9 -
ACS Nano Jun 2024Ferritin, a spherical protein shell assembled from 24 subunits, functions as an efficient iron storage and release system through its channels. Understanding how various...
Ferritin, a spherical protein shell assembled from 24 subunits, functions as an efficient iron storage and release system through its channels. Understanding how various chemicals affect the structural behavior of ferritin is crucial for unravelling the origins of iron-related diseases in living organisms including humans. In particular, the influence of chemicals on ferritin's dynamics and iron release is barely explored at the single-protein level. Here, by employing optical nanotweezers using double-nanohole (DNH) structures, we examined the effect of ascorbic acid (reducing reagent) and pH on individual ferritin's conformational dynamics. The dynamics of ferritin increased as the concentration of ascorbic acid approached saturation. At pH 2.0, ferritin exhibited significant structural fluctuations and eventually underwent a stepwise disassembly into fragments. This work demonstrated the disassembly pathway and kinetics of a single ferritin molecule in solution. We identified four critical fragments during its disassembly pathway, which are 22-mer, 12-mer, tetramer, and dimer subunits. Moreover, we present single-molecule evidence of the cooperative disassembly of ferritin. Interrogating ferritin's structural change in response to different chemicals holds importance for understanding their roles in iron metabolism, hence facilitating further development of medical treatments for its associated diseases.
Topics: Ferritins; Kinetics; Optical Tweezers; Ascorbic Acid; Hydrogen-Ion Concentration; Protein Conformation; Iron; Humans
PubMed: 38850556
DOI: 10.1021/acsnano.4c01221 -
Cancer Control : Journal of the Moffitt... 2024Our objective is to develop a predictive model utilizing the ferritin and transferrin ratio (FTR) and clinical factors to forecast overall survival (OS) in breast cancer...
BACKGROUND
Our objective is to develop a predictive model utilizing the ferritin and transferrin ratio (FTR) and clinical factors to forecast overall survival (OS) in breast cancer (BC) patients.
METHODS
We conducted a retrospective analysis of clinical data from 2858 BC patients diagnosed between 2013 and 2021. Subsequently, the cohort of 2858 BC patients underwent random assignment into distinct subsets: a training cohort comprising 2002 patients and a validation cohort comprising 856 patients, maintaining a proportional ratio of 7:3. Employing multivariable Cox regression analysis within the training cohort, we derived a prognostic nomogram. The predictive performance was assessed using calibration curves, C-index, and decision curve analysis.
RESULTS
The final prognostic model included the TNM stage, subtype, hemoglobin levels, and the ferritin-transferrin ratio. The nomogram achieved a C-index of .794 (95% CI: .777-.810). The nomogram demonstrated superior predictive accuracy for OS at 3, 5, and 7 years for BC, with area under the time-dependent curves of .812, .782, and .773, respectively. These values notably outperformed those of the conventional TNM stage. Decision curve analysis reaffirmed the greater net benefit of our nomogram compared to the TNM stage. These findings were subsequently validated in the independent validation cohort.
CONCLUSION
The FTR-based prognostic model may predict a patient's OS better than the TNM stage in a clinical setting. The nomogram can provide an early, affordable, and reliable tool for survival prediction, as well as aid clinicians in treatment option-making and prognosis evaluation. However, further multi-center prospective trials are required to confirm the reliability of the existing nomogram.
Topics: Humans; Nomograms; Breast Neoplasms; Female; Ferritins; Transferrin; Middle Aged; Retrospective Studies; Prognosis; Adult; Aged; Neoplasm Staging
PubMed: 38850515
DOI: 10.1177/10732748241261553 -
JAMA Network Open Jun 2024The prevalence of iron deficiency varies widely according to how it is defined.
IMPORTANCE
The prevalence of iron deficiency varies widely according to how it is defined.
OBJECTIVE
To compare the prevalence of iron deficiency among women using 3 different definitions.
DESIGN, SETTING, AND PARTICIPANTS
The cross-sectional Hemochromatosis and Iron Overload Screening Study (HEIRS; 2000-2006) evaluated the prevalence, determinants, and outcomes of hemochromatosis and other iron-related disorders. Multiethnic, primary care-based screening (2001-2003) was performed at 5 field centers (4 in the US and 1 in Canada). Volunteer women aged 25 years and older were recruited at primary care venues associated with the field centers. Data were analyzed from June to December 2023.
MAIN OUTCOMES AND MEASURES
Measures included transferrin saturation, serum ferritin level, and self-reported age, pregnancy, and race and ethnicity. Three iron deficiency definitions were studied: (1) combined transferrin saturation less than 10% and serum ferritin less than 15 ng/mL (HEIRS), (2) serum ferritin less than 15 ng/mL (World Health Organization [WHO]), and (3) serum ferritin less than 25 ng/mL (a threshold for iron-deficient erythropoiesis [IDE]).
RESULTS
Among 62 685 women (mean [SD] age, 49.58 [14.27] years), 1957 women (3.12%) had iron deficiency according to the HEIRS definition, 4659 women (7.43%) had iron deficiency according to the WHO definition, and 9611 women (15.33%) had iron deficiency according to the IDE definition. Among 40 381 women aged 25 to 54 years, 1801 women (4.46%) had iron deficiency according to HEIRS, 4267 women (10.57%) had iron deficiency according to WHO, and 8573 women (21.23%) had iron deficiency according to IDE. Prevalence rates of iron deficiency among 2039 women aged 25 to 44 years who reported pregnancy were 5.44% (111 women) according to HEIRS, 18.05% (368 women) according to WHO, and 36.10% (736 women) according to IDE. Iron deficiency prevalence by the 3 respective definitions increased significantly in each racial and ethnic group and was significantly higher among Black and Hispanic participants than Asian and White participants. The relative iron deficiency prevalence among the 62 685 women increased 2.4-fold (95% CI, 2.3-2.5; P < .001) using the WHO definition and increased 4.9-fold (95% CI, 4.7-5.2; P < .001) using the IDE definition.
CONCLUSIONS AND RELEVANCE
Three definitions of iron deficiency were associated with significantly different prevalence of iron deficiency in women, regardless of self-reported age, pregnancy, or race and ethnicity. Using higher serum ferritin thresholds to define iron deficiency could lead to diagnosis and treatment of more women with iron deficiency and greater reduction of related morbidity.
Topics: Humans; Female; Prevalence; Canada; Adult; Cross-Sectional Studies; Middle Aged; United States; Anemia, Iron-Deficiency; Ferritins; Transferrin; Pregnancy; Iron Deficiencies; Aged
PubMed: 38848068
DOI: 10.1001/jamanetworkopen.2024.13967 -
Archives of Dermatological Research Jun 2024Telogen effluvium is characterized by excessive hair shedding usually following a stressful event. Ferritin has been used in clinical practice as a biomarker of...
Telogen effluvium is characterized by excessive hair shedding usually following a stressful event. Ferritin has been used in clinical practice as a biomarker of nonanemic iron deficiency in cases of telogen effluvium. During the years of the COVID19 pandemic, telogen effluvium was reported as a part of post covid manifestations. As ferritin was also a biomarker for inflammation in cases with covid infection, this study was designed to evaluate the value of ferritin in cases with postcovid telogen effluvium one hundred patients recovering from covid 19 for 4-12 weeks were included in the study, detailed drug and laboratory history was obtained and serum ferritin level was measured. the mean serum level of ferritin among telogen effluvium patients was significantly lower than controls (68.52 ± 126 and 137 ± 137.597 ug/L respectively). Patients with telogen effluvium used significantly more azithromycin and ivermectin and significantly less vitamin C, D, lactoferrin and zinc than the controls Although serum ferritin is lower among telogen effluvium patients, it was still higher than the cutoff value for diagnosing nonanemic iron deficiency, we suggest that it will not be a good biomarkers in these cases. Our secondary outcomes showed that dietary supplements used during active infection such as vitamin C, D, lactoferrin and zinc might have a preventive value on postcovid hair loss, while azithromycin and ivermectin could have a negative long term effect on telogen effluvium.
Topics: Humans; Ferritins; COVID-19; Biomarkers; Female; Adult; Male; Case-Control Studies; Dietary Supplements; Middle Aged; SARS-CoV-2; Azithromycin; Ivermectin; Alopecia; Hair; Young Adult
PubMed: 38844670
DOI: 10.1007/s00403-024-03004-1 -
Ecotoxicology and Environmental Safety Jul 2024The contamination of water by arsenic (As) has emerged as a significant environmental concern due to its well-documented toxicity. Environmentally relevant...
The contamination of water by arsenic (As) has emerged as a significant environmental concern due to its well-documented toxicity. Environmentally relevant concentrations of As have been reported to pose a considerable threat to fish. However, previous studies mainly focused on the impacts of As at environmentally relevant concentrations on adult fish, and limited information is available regarding its impacts on fish at early life stage. In this study, zebrafish embryos were employed to evaluate the environmental risks following exposure to different concentrations (0, 25, 50, 75 and 150 μg/L) of pentavalent arsenate (AsV) for 120 hours post fertilization. Our findings indicated that concentrations ≤ 150 μg/L AsV did not exert significant effects on survival or aberration; however, it conspicuously inhibited heart rate of zebrafish larvae. Furthermore, exposure to AsV significantly disrupted mRNA transcription of genes associated with cardiac development, and elongated the distance between the sinus venosus and bulbus arteriosus at 75 μg/L and 150 μg/L treatments. Additionally, AsV exposure enhanced superoxide dismutase (SOD) activity at 50, 75 and 150 μg/L treatments, and increased mRNA transcriptional levels of Cu/ZnSOD and MnSOD at 75 and 150 μg/L treatments. Concurrently, AsV suppressed metallothionein1 (MT1) and MT2 mRNA transcriptions while elevating heat shock protein70 mRNA transcription levels in zebrafish larvae resulting in elevated malondialdehyde (MDA) levels. These findings provide novel insights into the toxic effects exerted by low concentrations of AsV on fish at early life stage, thereby contributing to an exploration into the environmental risks associated with environmentally relevant concentrations.
Topics: Animals; Zebrafish; Arsenates; Water Pollutants, Chemical; Oxidative Stress; Embryo, Nonmammalian; Heart; Superoxide Dismutase; Metallothionein; Larva; Heart Rate; Dose-Response Relationship, Drug
PubMed: 38843745
DOI: 10.1016/j.ecoenv.2024.116529 -
Frontiers in Plant Science 2024
PubMed: 38841279
DOI: 10.3389/fpls.2024.1430708 -
BMC Genomics Jun 2024Broussonetia papyrifera is an economically significant tree with high utilization value, yet its cultivation is often constrained by soil contamination with heavy metals...
BACKGROUND
Broussonetia papyrifera is an economically significant tree with high utilization value, yet its cultivation is often constrained by soil contamination with heavy metals (HMs). Effective scientific cultivation management, which enhances the yield and quality of B. papyrifera, necessitates an understanding of its regulatory mechanisms in response to HM stress.
RESULTS
Twelve Metallothionein (MT) genes were identified in B. papyrifera. Their open reading frames ranged from 186 to 372 bp, encoding proteins of 61 to 123 amino acids with molecular weights between 15,473.77 and 29,546.96 Da, and theoretical isoelectric points from 5.24 to 5.32. Phylogenetic analysis classified these BpMTs into three subclasses: MT1, MT2, and MT3, with MT2 containing seven members and MT3 only one. The expression of most BpMT genes was inducible by Cd, Mn, Cu, Zn, and abscisic acid (ABA) treatments, particularly BpMT2e, BpMT2d, BpMT2c, and BpMT1c, which showed significant responses and warrant further study. Yeast cells expressing these BpMT genes exhibited enhanced tolerance to Cd, Mn, Cu, and Zn stresses compared to control cells. Yeasts harboring BpMT1c, BpMT2e, and BpMT2d demonstrated higher accumulation of Cd, Cu, Mn, and Zn, suggesting a chelation and binding capacity of BpMTs towards HMs. Site-directed mutagenesis of cysteine (Cys) residues indicated that mutations in the C domain of type 1 BpMT led to increased sensitivity to HMs and reduced HM accumulation in yeast cells; While in type 2 BpMTs, the contribution of N and C domain to HMs' chelation possibly corelated to the quantity of Cys residues.
CONCLUSION
The BpMT genes are crucial in responding to diverse HM stresses and are involved in ABA signaling. The Cys-rich domains of BpMTs are pivotal for HM tolerance and chelation. This study offers new insights into the structure-function relationships and metal-binding capabilities of type-1 and - 2 plant MTs, enhancing our understanding of their roles in plant adaptation to HM stresses.
Topics: Metallothionein; Metals, Heavy; Phylogeny; Broussonetia; Gene Expression Regulation, Plant; Plant Proteins; Stress, Physiological; Amino Acid Sequence; Protein Binding
PubMed: 38840042
DOI: 10.1186/s12864-024-10477-x -
Open Heart Jun 2024Iron deficiency (ID) has been reported in patients with congenital heart disease. There is, however, a scarcity of data on its prevalence in patients with a Fontan...
BACKGROUND
Iron deficiency (ID) has been reported in patients with congenital heart disease. There is, however, a scarcity of data on its prevalence in patients with a Fontan circulation. The aim of this study is to investigate the prevalence of ID in Fontan patients and to investigate the association between ID and exercise capacity in this population.
METHODS AND RESULTS
Blood count and haematological parameters were determined in plasma of 61 Fontan patients (51% female, mean age 29±9 years). ID was defined as transferrin saturation (TSAT) ≤19.8%. The prevalence of ID was 36% (22/61 patients). Especially among women, the diagnosis of ID was highly prevalent (52%) despite normal haemoglobin levels (153.7±18.4 g/L). Mean ferritin levels were 98±80 µg/L and mean TSAT levels were 22%±12%. Cardiopulmonary exercise testing was performed in 46 patients (75%). Patients with ID had a lower peak oxygen uptake (V̇Opeak) (1397±477 vs 1692±530 mL/min; p=0.039), although this relationship was confounded by sex. The presence of ID increased the likelihood of not achieving a respiratory exchange ratio (RER) ≥1.1 by 5-fold (p=0.035).
CONCLUSION
ID is highly prevalent among patients with a Fontan circulation. V̇Opeak is lower in patients with ID. Fontan patients with ID are less likely to achieve an RER≥1.1 during cardiopulmonary exercise testing.
Topics: Humans; Female; Male; Fontan Procedure; Heart Defects, Congenital; Exercise Tolerance; Adult; Prevalence; Exercise Test; Young Adult; Biomarkers; Anemia, Iron-Deficiency; Oxygen Consumption; Iron; Iron Deficiencies; Adolescent; Ferritins
PubMed: 38839367
DOI: 10.1136/openhrt-2024-002693 -
Frontiers in Immunology 2024Swine influenza viruses (SIVs) pose significant economic losses to the pig industry and are a burden on global public health systems. The increasing complexity of the...
INTRODUCTION
Swine influenza viruses (SIVs) pose significant economic losses to the pig industry and are a burden on global public health systems. The increasing complexity of the distribution and evolution of different serotypes of influenza strains in swine herds escalates the potential for the emergence of novel pandemic viruses, so it is essential to develop new vaccines based on swine influenza.
METHODS
Here, we constructed a self-assembling ferritin nanoparticle vaccine based on the hemagglutinin (HA) extracellular domain of swine influenza A (H1N1) virus using insect baculovirus expression vector system (IBEVS), and after two immunizations, the immunogenicities and protective efficacies of the HA-Ferritin nanoparticle vaccine against the swine influenza virus H1N1 strain in mice and piglets were evaluated.
RESULTS
Our results demonstrated that HA-Ferritin nanoparticle vaccine induced more efficient immunity than traditional swine influenza vaccines. Vaccination with the HA-Ferritin nanoparticle vaccine elicited robust hemagglutinin inhibition titers and antigen-specific IgG antibodies and increased cytokine levels in serum. MF59 adjuvant can significantly promote the humoral immunity of HA-Ferritin nanoparticle vaccine. Furthermore, challenge tests showed that HA-Ferritin nanoparticle vaccine conferred full protection against lethal challenge with H1N1 virus and significantly decreased the severity of virus-associated lung lesions after challenge in both BALB/c mice and piglets.
CONCLUSION
Taken together, these results indicate that the hemagglutinin extracellular-based ferritin nanoparticle vaccine may be a promising vaccine candidate against SIVs infection.
Topics: Animals; Influenza A Virus, H1N1 Subtype; Ferritins; Influenza Vaccines; Swine; Mice; Orthomyxoviridae Infections; Nanoparticles; Hemagglutinin Glycoproteins, Influenza Virus; Antibodies, Viral; Mice, Inbred BALB C; Swine Diseases; Female; Nanovaccines
PubMed: 38835763
DOI: 10.3389/fimmu.2024.1361323