BMAA, Methylmercury, and Mechanisms of Neurodegeneration in Dolphins: A Natural Model of Toxin Exposure

Dolphins are well-regarded sentinels for toxin exposure and can bioaccumulate a cyanotoxin called β-N-methylamino-l-alanine (BMAA) that has been linked to human neurodegenerative disease. The same dolphins also possessed hallmarks of Alzheimer’s disease (AD), suggesting a possible association between toxin exposure and neuropathology. However, the mechanisms of neurodegeneration in dolphins and the impact cyanotoxins have on these processes are unknown. Here, we evaluate BMAA exposure by investigating transcription signatures using PCR for dolphin genes homologous to those implicated in AD and related dementias: APP, PSEN1, PSEN2, MAPT, GRN, TARDBP, and C9orf72. Immunohistochemistry and Sevier Münger silver staining were used to validate neuropathology. Methylmercury (MeHg), a synergistic neurotoxicant with BMAA, was also measured using PT-GC-AFS. We report that dolphins have up to a three-fold increase in gene transcription related to Aβ+ plaques, neurofibrillary tangles, neuritic plaques, and TDP-43+ intracytoplasmic inclusions. The upregulation of gene transcription in our dolphin cohort paralleled increasing BMAA concentration. In addition, dolphins with BMAA exposures equivalent to those reported in AD patients displayed up to a 14-fold increase in AD-type neuropathology. MeHg was detected (0.16–0.41 μg/g) and toxicity associated with exposure was also observed in the brain. These results demonstrate that dolphins develop neuropathology associated with AD and exposure to BMAA and MeHg may augment these processes.

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Abstract 1330: Divergent Control of the Mitochondrial Death Gene BNIP3 by Opposing Actions of the Cellular Factors Nuclear Factor kappaB and E2F-1 in Ventricular Myocytes.

Circulation ◽

10.1161/circ.116.suppl_16.ii_272-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

James Shaw ◽

Natalia Yurkova ◽

Kelly Regula ◽

Tong Zhang ◽

Floribeth Aguilar ◽

...

Keyword(s):

Gene Expression ◽

Cell Death ◽

Dna Binding ◽

Gene Transcription ◽

Ventricular Myocytes ◽

Fold Increase ◽

Genetic Ablation ◽

The Impact ◽

Chip Analysis ◽

In Cells

The hypoxia-inducible death factor Bnip3 is known to provoke mitochondrial perturbations and cell death of ventricular myocytes. The transcriptional control processes that govern Bnip3 gene expression under basal and inducible conditions remain cryptic. Sequence analysis of the Bnip3 promoter revealed the presence of distinct but overlapping DNA binding elements for the cell cycle factor E2F-1 and cellular factor NF-κB. Previously, we reported a survival role for NF-κB in ventricular myocytes. As a step toward elucidating the regulation of Bnip3 gene expression in ventricular myocytes, we tested the impact of E2F-1 and NF-κB on basal and inducible expression of Bnip3. A 2.0 fold increase in Bnip3 gene transcription was observed in cells expression wild type E2F-1 but not in cells expressing an E2F-1 mutant defective for DNA binding. Interestingly, basal Bnip3 gene transcription was increased by 2.5 fold in myocytes rendered defective for NF-κB activation with a non-phosphorylatable form of IκBα. Importantly, genetic ablation of E2F-1 inhibited basal and inducible Bnip3 transcription in NF-κB defective cells. Expression of the p65 subunit of NF-κB in NF-κB defective cells inhibited E2F-1 mediated Bnip3 transcription. Western blot analysis of cardiac cell lysate revealed that p65 NF-κB immunoprecipitated with E2F-1. ChIP analysis of the Bnip3 promoter indicated that the p65 NF-κB bound DNA under normoxic conditions. During hypoxia E2F-1 activity increased where as p65 NF-κB protein levels were decreased. ChIP analysis revealed increased binding of E2F-1 to the Bnip3 promoter during hypoxia which coincided with a 3.5 fold increase in Bnip3 gene transcription. IKKβ mediated activation of NF-κB activation abrogated hypoxia-induced E2F-1 binding to the Bnip3 promoter and Bnip3 gene transcription. To our knowledge our data provide the first direct evidence that a novel relationship exists between p65 NF-κB and E2F-1 for basal and hypoxia-inducible regulation of the Bnip3 promoter. Furthermore, our data highlight a novel survival pathway by which NF-κB averts hypoxia - induced cell death by antagonizing the E2F-1 dependent transcription of Bnip3 in ventricular myocytes.

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Advantages of Complementary Stereo Images as Viewed with the Low-Temperature Field-Emission SEM

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100131206 ◽

1992 ◽

Vol 50 (2) ◽

pp. 1314-1315

Author(s):

William P. Wergin ◽

Eric F. Erbe

Keyword(s):

Fold Increase ◽

Horizontal Displacement ◽

Three Dimensions ◽

Stereo Image ◽

Stereo Pair ◽

Sem Micrograph ◽

Left And Right ◽

The Common ◽

The Brain ◽

Pair Analysis

The eye-brain complex allows those of us with normal vision to perceive and evaluate our surroundings in three-dimensions (3-D). The principle factor that makes this possible is parallax - the horizontal displacement of objects that results from the independent views that the left and right eyes detect and simultaneously transmit to the brain for superimposition. The common SEM micrograph is a 2-D representation of a 3-D specimen. Depriving the brain of the 3-D view can lead to erroneous conclusions about the relative sizes, positions and convergence of structures within a specimen. In addition, Walter has suggested that the stereo image contains information equivalent to a two-fold increase in magnification over that found in a 2-D image. Because of these factors, stereo pair analysis should be routinely employed when studying specimens.Imaging complementary faces of a fractured specimen is a second method by which the topography of a specimen can be more accurately evaluated.

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Novel Applications of Nanotechnology in Controlling HIV and HSV Infections

Current Drug Research Reviews ◽

10.2174/2589977512999201124121931 ◽

2020 ◽

Vol 12 ◽

Author(s):

Sai Akilesh M ◽

Ashish Wadhwani

Keyword(s):

Drug Delivery ◽

Viral Infections ◽

Polymeric Nanoparticles ◽

Volume Ratio ◽

Fold Increase ◽

Multi Drug Resistance ◽

Health Crisis ◽

Pharmaceutical Properties ◽

Simplex Virus ◽

The Impact

: Infectious diseases have been prevalent since many decades and viral pathogens have caused global health crisis and economic meltdown on a devastating scale. High occurrence of newer viral infections in the recent years, in spite of the progress achieved in the field of pharmaceutical sciences defines the critical need for newer and more effective antiviral therapies and diagnostics. The incidence of multi-drug resistance and adverse effects due to the prolonged use of anti-viral therapy is also a major concern. Nanotechnology offers a cutting edge platform for the development of novel compounds and formulations for biomedical applications. The unique properties of nano-based materials can be attributed to the multi-fold increase in the surface to volume ratio at the nano-scale, tunable surface properties of charge and chemical moieties. Idealistic pharmaceutical properties such as increased bioavailability and retention times, lower toxicity profiles, sustained release formulations, lower dosage forms and most importantly, targeted drug delivery can be achieved through the approach of nanotechnology. The extensively researched nano-based materials are metal and polymeric nanoparticles, dendrimers and micelles, nano-drug delivery vesicles, liposomes and lipid based nanoparticles. In this review article, the impact of nanotechnology on the treatment of Human Immunodeficiency Virus (HIV) and Herpes Simplex Virus (HSV) viral infections during the last decade are outlined.

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A direct requirement of nuclear factor-κB for suppression of apoptosis in ventricular myocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.3.h939 ◽

2000 ◽

Vol 279 (3) ◽

pp. H939-H945 ◽

Cited By ~ 64

Author(s):

Shareef Mustapha ◽

Alla Kirshner ◽

Danielle De Moissac ◽

Lorrie A. Kirshenbaum

Keyword(s):

Dna Binding ◽

Gene Transcription ◽

Ventricular Myocytes ◽

Vital Staining ◽

Fold Increase ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Cytoplasmic Factor ◽

Tnf Α ◽

Factor Α

Nuclear factor-κB (NF-κB) is a ubiquitously expressed cellular factor regulated by the cytoplasmic factor inhibitor protein κBα (IκBα). Activation of NF-κB by cytokines, including tumor necrosis factor-α (TNF-α), requires the phosphorylation and degradation of IκBα. An anti-apoptotic role for NF-κB has recently been suggested. In the present study, we ascertained whether death-promoting signals and apoptosis mediated by TNF-α are suppressed by NF-κB in postnatal ventricular myocytes. Stimulation of myocytes with TNF-α resulted in a 12.1-fold increase ( P < 0.01) in NF-κB-dependent gene transcription and DNA binding compared with controls. This was accompanied by a corresponding increase in the NF-κB target protein A20 as determined by Western blot analysis. Vital staining revealed that TNF-α was not cytotoxic to myocytes and did not provoke apoptosis. Adenovirus-mediated delivery of a nonphosphorylatable form of IκBα to inactivate NF-κB prevented TNF-α-stimulated NF-κB-dependent gene transcription and nuclear NF-κB DNA binding. Importantly, myocytes stimulated with TNF-α and defective for NF-κB activation resulted in a 2.2-fold increase ( P < 0.001) in apoptosis. To our knowledge, the data provide the first indication that a functional NF-κB signaling pathway is crucial for suppressing death-promoting signals mediated by TNF-α in ventricular myocytes.

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Administrative Coding Methods Impact Surgical Site Infection Rates

Infection Control and Hospital Epidemiology ◽

10.1017/ice.2020.616 ◽

2020 ◽

Vol 41 (S1) ◽

pp. s111-s112

Author(s):

Mohammed Alsuhaibani ◽

Mohammed Alzunitan ◽

Kyle Jenn ◽

Daniel Diekema ◽

Michael Edmond ◽

...

Keyword(s):

Cesarean Section ◽

Surgical Procedures ◽

Hip Prosthesis ◽

Knee Prosthesis ◽

Surgical Site Infections ◽

Fold Increase ◽

Abdominal Hysterectomy ◽

Absolute Difference ◽

Coding Method ◽

The Impact

Background: Surveillance for surgical site infections (SSI) is recommended by the CDC. Currently, colon and abdominal hysterectomy SSI rates are publicly available and impact hospital reimbursement. However, the CDC NHSN allows surgical procedures to be abstracted based on International Classification of Diseases, Tenth Revision (ICD-10) or current procedural terminology (CPT) codes. We assessed the impact of using ICD and/or CPT codes on the number of cases abstracted and SSI rates. Methods: We retrieved administrative codes (ICD and/or CPT) for procedures performed at the University of Iowa Hospitals & Clinics over 1 year: October 2018–September 2019. We included 10 procedure types: colon, hysterectomy, cesarean section, breast, cardiac, craniotomy, spinal fusion, laminectomy, hip prosthesis, and knee prosthesis surgeries. We then calculated the number of procedures that would be abstracted if we used different permutations in administration codes: (1) ICD codes only, (2) CPT codes only, (3) both ICD and CPT codes, and (4) at least 1 code from either ICD or CPT. We then calculated the impact on SSI rates based on any of the 4 coding permutations. Results: In total, 9,583 surgical procedures and 180 SSIs were detected during the study period using the fourth method (ICD or CPT codes). Denominators varied according to procedure type and coding method used. The number of procedures abstracted for breast surgery had a >10-fold difference if reported based on ICD only versus ICD or CPT codes (104 vs 1,109). Hip prosthesis had the lowest variation (638 vs 767). For SSI rates, cesarean section showed almost a 3-fold increment (2.6% when using ICD only to 7.32% with both ICD & CPT), whereas abdominal hysterectomy showed nearly a 2-fold increase (1.14% when using CPT only to 2.22% with both ICD & CPT codes). However, SSI rates remained fairly similar for craniotomy (0.14% absolute difference), hip prosthesis (0.24% absolute difference), and colon (0.09% absolute difference) despite differences in the number of abstracted procedures and coding methods. Conclusions: Denominators and SSI rates vary depending on the coding method used. Variations in the number of procedures abstracted and their subsequent impact on SSI rates were not predictable. Variations in coding methods used by hospitals could impact interhospital comparisons and benchmarking, potentially leading to disparities in public reporting and hospital penalties.Funding: NoneDisclosures: None

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Combinations of Freeze-Dried Amorphous Vardenafil Hydrochloride with Saccharides as A Way to Enhance Dissolution Rate and Permeability

Pharmaceuticals ◽

10.3390/ph14050453 ◽

2021 ◽

Vol 14 (5) ◽

pp. 453

Author(s):

Gabriela Wiergowska ◽

Dominika Ludowicz ◽

Kamil Wdowiak ◽

Andrzej Miklaszewski ◽

Kornelia Lewandowska ◽

...

Keyword(s):

Physicochemical Properties ◽

Density Functional ◽

Hydroxypropyl Methylcellulose ◽

Fold Increase ◽

Crystalline Form ◽

Amorphous Form ◽

Freeze Dried ◽

Apparent Solubility ◽

Gastrointestinal Epithelium ◽

The Impact

To improve physicochemical properties of vardenafil hydrochloride (VAR), its amorphous form and combinations with excipients—hydroxypropyl methylcellulose (HPMC) and β-cyclodextrin (β-CD)—were prepared. The impact of the modification on physicochemical properties was estimated by comparing amorphous mixtures of VAR to their crystalline form. The amorphous form of VAR was obtained as a result of the freeze-drying process. Confirmation of the identity of the amorphous dispersion of VAR was obtained through the use of comprehensive analysis techniques—X-ray powder diffraction (PXRD) and differential scanning calorimetry (DSC), supported by FT-IR (Fourier-transform infrared spectroscopy) coupled with density functional theory (DFT) calculations. The amorphous mixtures of VAR increased its apparent solubility compared to the crystalline form. Moreover, a nearly 1.3-fold increase of amorphous VAR permeability through membranes simulating gastrointestinal epithelium as a consequence of the changes of apparent solubility (Papp crystalline VAR = 6.83 × 10−6 cm/s vs. Papp amorphous VAR = 8.75 × 10−6 cm/s) was observed, especially for its combinations with β-CD in the ratio of 1:5—more than 1.5-fold increase (Papp amorphous VAR = 8.75 × 10−6 cm/s vs. Papp amorphous VAR:β-CD 1:5 = 13.43 × 10−6 cm/s). The stability of the amorphous VAR was confirmed for 7 months. The HPMC and β-CD are effective modifiers of its apparent solubility and permeation through membranes simulating gastrointestinal epithelium, suggesting a possibility of a stronger pharmacological effect.

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Grill Workers Exposure to Polycyclic Aromatic Hydrocarbons: Levels and Excretion Profiles of the Urinary Biomarkers

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18010230 ◽

2020 ◽

Vol 18 (1) ◽

pp. 230

Author(s):

Marta Oliveira ◽

Sílvia Capelas ◽

Cristina Delerue-Matos ◽

Simone Morais

Keyword(s):

Polycyclic Aromatic Hydrocarbons ◽

Aromatic Hydrocarbons ◽

High Performance ◽

Principal Component ◽

Fold Increase ◽

Urinary Biomarkers ◽

Analysis Model ◽

Exposed Workers ◽

Polycyclic Aromatic ◽

The Impact

Grilling activities release large amounts of hazardous pollutants, but information on restaurant grill workers’ exposure to polycyclic aromatic hydrocarbons (PAHs) is almost inexistent. This study assessed the impact of grilling emissions on total workers’ exposure to PAHs by evaluating the concentrations of six urinary biomarkers of exposure (OHPAHs): naphthalene, acenaphthene, fluorene, phenanthrene, pyrene, and benzo(a)pyrene. Individual levels and excretion profiles of urinary OHPAHs were determined during working and nonworking periods. Urinary OHPAHs were quantified by high-performance liquid-chromatography with fluorescence detection. Levels of total OHPAHs (∑OHPAHs) were significantly increased (about nine times; p ≤ 0.001) during working comparatively with nonworking days. Urinary 1-hydroxynaphthalene + 1-hydroxyacenapthene and 2-hydroxyfluorene presented the highest increments (ca. 23- and 6-fold increase, respectively), followed by 1-hydroxyphenanthrene (ca. 2.3 times) and 1-hydroxypyrene (ca. 1.8 times). Additionally, 1-hydroxypyrene levels were higher than the benchmark, 0.5 µmol/mol creatinine, in 5% of exposed workers. Moreover, 3-hydroxybenzo(a)pyrene, biomarker of exposure to carcinogenic PAHs, was detected in 13% of exposed workers. Individual excretion profiles showed a cumulative increase in ∑OHPAHs during consecutive working days. A principal component analysis model partially discriminated workers’ exposure during working and nonworking periods showing the impact of grilling activities. Urinary OHPAHs were increased in grill workers during working days.

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Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Pharmaceutics ◽

10.3390/pharmaceutics13060892 ◽

2021 ◽

Vol 13 (6) ◽

pp. 892

Author(s):

Elisa L. J. Moya ◽

Elodie Vandenhaute ◽

Eleonora Rizzi ◽

Marie-Christine Boucau ◽

Johan Hachani ◽

...

Keyword(s):

Drug Discovery ◽

Blood Brain Barrier ◽

Early Stage ◽

Molecular Transport ◽

Brain Barrier ◽

Blood Brain ◽

Cns Drugs ◽

The Impact ◽

The Brain

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.

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The Impact of Bone on the Biology of Aging

Innovation in Aging ◽

10.1093/geroni/igaa057.2643 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 740-740

Author(s):

Gerard Karsenty

Keyword(s):

Muscle Function ◽

Male Fertility ◽

Leydig Cells ◽

Memory Loss ◽

Age Related ◽

Systematic Exploration ◽

Biology Of Aging ◽

The Impact ◽

The Brain ◽

Regulate Energy Metabolism

Abstract We hypothesized that bone may secrete hormones that regulate energy metabolism and reproduction. Testing this hypothesis revealed that the osteoblast-specific secreted protein osteocalcin is a hormone regulating glucose homeostasis and male fertility by signaling through a GPCR, Gprc6a, expressed in pancreatic β bells and Leydig cells of the testes. The systematic exploration of osteocalcin biology, revealed that it regulates an unexpectedly large spectrum of physiological functions in the brain and peripheral organs and that it has most features of an antigeromic molecule. As will be presented at the meeting, this body of work suggests that harnessing osteocalcin for therapeutic purposes may be beneficial in the treatment of age-related diseases such as depression, age-related memory loss and the decline in muscle function seen in sarcopenia.

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Crosstalk between Existential Phenomenological Psychotherapy and Neurological Sciences in Mood and Anxiety Disorders

Biomedicines ◽

10.3390/biomedicines9040340 ◽

2021 ◽

Vol 9 (4) ◽

pp. 340

Author(s):

Lehel Balogh ◽

Masaru Tanaka ◽

Nóra Török ◽

László Vécsei ◽

Shigeru Taguchi

Keyword(s):

Anxiety Disorders ◽

Biological Treatment ◽

Sense Of Self ◽

Phenomenological Approach ◽

Neurological Damage ◽

Mood And Anxiety Disorders ◽

New Interpretation ◽

And Behavior ◽

The Impact ◽

The Brain

Psychotherapy is a comprehensive biological treatment modifying complex underlying cognitive, emotional, behavioral, and regulatory responses in the brain, leading patients with mental illness to a new interpretation of the sense of self and others. Psychotherapy is an art of science integrated with psychology and/or philosophy. Neurological sciences study the neurological basis of cognition, memory, and behavior as well as the impact of neurological damage and disease on these functions, and their treatment. Both psychotherapy and neurological sciences deal with the brain; nevertheless, they continue to stay polarized. Existential phenomenological psychotherapy (EPP) has been in the forefront of meaning-centered counseling for almost a century. The phenomenological approach in psychotherapy originated in the works of Martin Heidegger, Ludwig Binswanger, Medard Boss, and Viktor Frankl, and it has been committed to accounting for the existential possibilities and limitations of one’s life. EPP provides philosophically rich interpretations and empowers counseling techniques to assist mentally suffering individuals by finding meaning and purpose to life. The approach has proven to be effective in treating mood and anxiety disorders. This narrative review article demonstrates the development of EPP, the therapeutic methodology, evidence-based accounts of its curative techniques, current understanding of mood and anxiety disorders in neurological sciences, and a possible converging path to translate and integrate meaning-centered psychotherapy and neuroscience, concluding that the EPP may potentially play a synergistic role with the currently prevailing medication-based approaches for the treatment of mood and anxiety disorders.

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