Brain Intraventricular Injection of Amyloid-β in Zebrafish Embryo Impairs Cognition and Increases Tau Phosphorylation,Effects Reversed by Lithium

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with no effective treatment and commonly diagnosed only on late stages. Amyloid-β (Aβ) accumulation and exacerbated tau phosphorylation are molecular hallmarks of AD implicated in cognitive deficits and synaptic and neuronal loss. The Aβ and tau connection is beginning to be elucidated and attributed to interaction with different components of common signaling pathways. Recent evidences suggest that non-fibrillary Aβ forms bind to membrane receptors and modulate GSK-3β activity, which in turn phosphorylates the microtubule-associated tau protein leading to axonal disruption and toxic accumulation. Available AD animal models, ranging from rodent to invertebrates, significantly contributed to our current knowledge, but complementary platforms for mechanistic and candidate drug screenings remain critical for the identification of early stage biomarkers and potential disease-modifying therapies. Here we show that Aβ1–42 injection in the hindbrain ventricle of 24 hpf zebrafish embryos results in specific cognitive deficits and increased tau phosphorylation in GSK-3β target residues at 5dpf larvae. These effects are reversed by lithium incubation and not accompanied by apoptotic markers. We believe this may represent a straightforward platform useful to identification of cellular and molecular mechanisms of early stage AD-like symptoms and the effects of neuroactive molecules in pharmacological screenings.     

Reproductive parameters of Bering-Chukchi-Beaufort Seas bowhead whales

Data from Bering-Chukchi-Beaufort Seas bowhead whales (Balaena mysticetus), harvested during 1973–2021 by aboriginal subsistence hunters, were used to estimate reproductive parameters: length at sexual maturity (LSM), age at sexual maturity (ASM), pregnancy rate (PR), and calving interval. Sexual maturity (N = 187 females) was determined from the presence/absence of corpora in the ovaries, or a fetus. Using sampling bias-corrected logistic regression, LSM was estimated at 13.5 m, 95% CI [13.0, 13.8]. There was a downward trend in LSM over time, statistically significant with one method but marginal with another. A growth model translated this estimate to an ASM estimate of 23.5 years, 95% CI [20.4, 26.7]. Pregnancy rate was determined from mature females (N = 125), and from a subset limited to certain autumn-caught whales (n = 37) to reduce bias. The PR was estimated at 0.46 globally, 95% CI [0.36, 0.55] and 0.38 for the autumn sample, 95% CI [0.20, 0.51]. Both estimated PRs are consistent with a 3-year calving interval, because the larger estimate includes two cohorts of pregnant whales harvested in spring, and bowhead whale gestation is longer than 12 months. These analyses represent the most conclusive empirical estimates of ASM, LSM, and PR for this bowhead whale stock from the largest available data sets to date.     

Environmental stresses inhibit splicing in the aquatic fungus Blastocladiella emersonii

Background  

Exposure of cells to environmental stress conditions can lead to the interruption of several intracellular processes, in particular those performed by macromolecular complexes such as the spliceosome.     

Binding of oxindole-Schiff base copper(II) complexes to DNA and its modulation by the ligand

Previous studies on copper(II) complexes with oxindole-Schiff base ligands have shown their potential antitumor activity towards different cells, inducing apoptosis through a preferential attack to DNA and/or mitochondria. Herein, we better characterize the interactions between some of these copper(II) complexes and DNA. Investigations on its binding ability to DNA were carried out by fluorescence measurements in competitive experiments with ethidium bromide, using plasmidial or calf-thymus DNA. These results indicated an efficient binding process similar to that observed with copper(II)-phenanthroline species, [Cu(o-phen)₂]²⁺, with binding constants in the range 3 to 9 × 10² M^− 1. DNA cleavage experiments in the presence and absence of distamycin, a recognized binder of DNA, indicated that this binding probably occurs at major or minor groove, leading to double-strand DNA cleavage, and being modulated by the imine ligand. Corroborating these data, discrete changes in EPR spectra of the studied complexes were observed in the presence of DNA, while more remarkable changes were observed in the presence of nucleotides (AMP, GMP, CMP or UMP). Additional evidence for preferential coordination of the copper centers to the bases guanine or cytosine was obtained from titrations of these complexes with each nucleotide, monitored by absorption spectral changes. Therefore, the obtained data point out to their action as groove binders to DNA bases, rather than as intercalators or covalent cross-linkers. Further investigations by SDS PAGE using ³²P-ATP or ³²P-oligonucleotides attested that no hydrolysis of phosphate linkage in DNA or RNA occurs, in the presence of such complexes, confirming their main oxidative mechanism of action.     

A 35-Year Trend Analysis for Back Pain in Austria: The Role of Obesity

Background

The prevalence of back pain is constantly increasing and a public health problem of high priority. In Austria there is a lack of empirical evidence for the development of back pain and its related factors. The present study aims to investigate trends in the prevalence of back pain across different subpopulations (sex, age, obesity).

Methods

A secondary data analysis based on five nationally representative cross-sectional health surveys (1973–2007) was carried out. Face-to-face interviews were conducted in private homes in Austria. Subjects aged 20 years and older were included in the study sample (n = 178,818). Obesity was defined as BMI≥30 kg/m² and adjusted for self-report bias. Back pain was measured as the self-reported presence of the disorder.

Results

The age-standardized prevalence of back pain was 32.9% in 2007; it was higher among women than men (p<0.001), higher in older than younger subjects (p<0.001) and higher in obese than non-obese individuals (p<0.001). During the investigation period the absolute change in the prevalence of back pain was +19.4%. Among all subpopulations the prevalence steadily increased. Obese men showed the highest increase of and the greatest risk for back pain.

Conclusion

These results help to understand the development of back pain in Austria and can be used to plan controlled promotion programs. Further monitoring is recommended in order to control risk groups and plan target group-specific prevention strategies. In Austria particular emphasis should be on obese individuals. We recommend conducting prospective studies to confirm our results and investigate causal relationships.     

Active synovial matrix metalloproteinase-2 is associated with radiographic erosions in patients with early synovitis

Serum and synovial tissue expression of the matrix metalloproteinase (MMP)-2 and -9 and their molecular regulators, MMP-14 and TIMP-2 was examined in 28 patients with inflammatory early synovitis and 4 healthy volunteers and correlated with the presence of erosions in the patients. Immunohistological staining of MMP-2, MMP-14 and TIMP-2 localized to corresponding areas in the synovial lining layer and was almost absent in normal synovium. Patients with radiographic erosions had significantly higher levels of active MMP-2 than patients with no erosions, suggesting that activated MMP-2 levels in synovial tissue may be a marker for a more aggressive synovial lesion.     

SorCS2 Controls Functional Expression of Amino Acid Transporter EAAT3 and Protects Neurons from Oxidative Stress and Epilepsy-Induced Pathology

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Effects of Plectin Depletion on Keratin Network Dynamics and Organization

The keratin intermediate filament cytoskeleton protects epithelial cells against various types of stress and is involved in fundamental cellular processes such as signaling, differentiation and organelle trafficking. These functions rely on the cell type-specific arrangement and plasticity of the keratin system. It has been suggested that these properties are regulated by a complex cycle of assembly and disassembly. The exact mechanisms responsible for the underlying molecular processes, however, have not been clarified. Accumulating evidence implicates the cytolinker plectin in various aspects of the keratin cycle, i.e., by acting as a stabilizing anchor at hemidesmosomal adhesion sites and the nucleus, by affecting keratin bundling and branching and by linkage of keratins to actin filament and microtubule dynamics. In the present study we tested these hypotheses. To this end, plectin was downregulated by shRNA in vulvar carcinoma-derived A431 cells. As expected, integrin β4- and BPAG-1-positive hemidesmosomal structures were strongly reduced and cytosolic actin stress fibers were increased. In addition, integrins α3 and β1 were reduced. The experiments furthermore showed that loss of plectin led to a reduction in keratin filament branch length but did not alter overall mechanical properties as assessed by indentation analyses using atomic force microscopy and by displacement analyses of cytoplasmic superparamagnetic beads using magnetic tweezers. An increase in keratin movement was observed in plectin-depleted cells as was the case in control cells lacking hemidesmosome-like structures. Yet, keratin turnover was not significantly affected. We conclude that plectin alone is not needed for keratin assembly and disassembly and that other mechanisms exist to guarantee proper keratin cycling under steady state conditions in cultured single cells.     

Inflammation and metabolic dysfunction: links to cardiovascular diseases

Abdominal obesity is a major risk factor for cardiovascular disease, and recent studies highlight a key role of adipose tissue dysfunction, inflammation, and aberrant adipokine release in this process. An increased demand for lipid storage results in both hyperplasia and hypertrophy, finally leading to chronic inflammation, hypoxia, and a phenotypic change of the cellular components of adipose tissue, collectively leading to a substantially altered secretory output of adipose tissue. In this review we have assessed the adipo-vascular axis, and an overview of adipokines associated with cardiovascular disease is provided. This resulted in a first list of more than 30 adipokines. A deeper analysis only considered adipokines that have been reported to impact on inflammation and NF-κB activation in the vasculature. Out of these, the most prominent link to cardiovascular disease was found for leptin, TNF-α, adipocyte fatty acid-binding protein, interleukins, and several novel adipokines such as lipocalin-2 and pigment epithelium-derived factor. Future work will need to address the potential role of these molecules as biomarkers and/or drug targets.