Thyreophoran vertebrae from the Callovian (Middle Jurassic) of the Vaches Noires cliffs (Normandy,France), with remarks on the dinosaur assemblage from the Vaches Noires

Two associated incomplete thyreophoran dorsal vertebrae from the Callovian Marnes de Dives Formation of the Vaches Noires cliffs, on the Normandy coast, are referred to an indeterminate stegosaur that appears to be different from Lexovisaurus, previously reported from the Callovian of western France. These vertebrae are the first evidence of thyreophorans from the Vaches Noires and complement the dinosaur assemblage from this locality, which hitherto consisted of several theropod taxa and an indeterminate sauropod. The dinosaur record from the Vaches Noires is heavily dominated by theropods and this imbalance is difficult to explain. A possible explanation may be that the dinosaur sample from the Vaches Noires is too small to be statistically significant and representative of the original faunal assemblage from which it is derived.     

Early tetrapodomorph biogeography: Controlling for fossil record bias in macroevolutionary analyses

The fossil record provides direct empirical data for understanding macroevolutionary patterns and processes. Inherent biases in the fossil record are well known to confound analyses of this data. Sampling bias proxies have been used as covariates in regression models to test for such biases. Proxies, such as formation count, are associated with paleobiodiversity, but are insufficient for explaining species dispersal owing to a lack of geographic context. Here, we develop a sampling bias proxy that incorporates geographic information and test it with a case study on early tetrapodomorph biogeography. We use recently-developed Bayesian phylogeographic models and a new supertree of early tetrapodomorphs to estimate dispersal rates and ancestral habitat locations. We find strong evidence that geographic sampling bias explains supposed radiations in dispersal rate (potential adaptive radiations). Our study highlights the necessity of accounting for geographic sampling bias in macroevolutionary and phylogenetic analyses and provides an approach to test for its effect.     

Inner structural organization of the mandibular corpus in the late Early Pleistocene human specimens Tighenif 1 and Tighenif 2

The present study investigates the inner structural organization of the two mandible specimens Tighenif 1 and Tighenif 2 from the late early Pleistocene site of Tighenif, Algeria. Using (micro)tomographic scans, we built a new protocol to investigate the cortical bone topography at the post-canine level. We selected two cross-sectional slices placed between the P3/P4 and M1/M2 on the right and left sides and assessed the cortical bone thickness topography (CBT) on each slice. Our analyses demonstrate that the mandibles from Tighenif exhibit higher CBT and a different topographic distribution pattern at the molar level than in modern humans, resulting in a proportionally more robust inner structure, while a similar signal is observed between the fossil and extant specimens at the premolar level. Further studies need to be done in order to determine if this feature is related to functional constraints during mastication or paramasticatory activities; or if it is related to any independent evolutionary process.     

Upregulation of the p53-p21 pathway by G2019S LRRK2 contributes to the cellular senescence and accumulation of α-synuclein

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (LB) in neurons. α-Synuclein (αSyn) is a major component of LB and promote the PD pathogenesis via its accumulation by the impaired proteasomal or autophagic clearance. Numerous studies have revealed that the reduction of proteasome activity and autophagy is accelerated by cellular senescence. Leucine-rich repeat kinase 2 (LRRK2) contributes to PD progression and its most prevalent mutation, G2019S LRRK2, increases its activity. Our previous report has shown that the G2019S LRRK2 mutant promoted p53-induced p21 expression and neuronal cytotoxicity. The p53-p21 pathway plays a role in cellular senescence. We hypothesized that the loss of dopaminergic neurons by the stimulated p53-p21 pathway via the G2019S LRRK2 mutation might be associated with cellular senescence, thereby promoting the accumulation of αSyn. We confirmed that the ectopic expression of the phosphomimetic p53 mutant, p21, or G2019 in differentiated SH-SY5Y cells increased the following: 1) the expression of β-galactosidase, a marker of cellular senescence, and the activity of senescence-associated β-galactosidase, 2) endogenous αSyn protein level, but not its mRNA level, and 3) αSyn fibril accumulation in dSH-SY5Y via low proteasome and cathepsin D activities. Elevated oligomeric αSyn and the increase in β-galactosidase with induced p21 were observed in brain lysates of G2019S transgenic mice. Our results suggest that cellular senescence is promoted via the p53-p21 pathway due to the G2019S LRRK2 mutation. Eventually, decreased protein degradation by G2019S-mediated senescence could accelerate αSyn aggregate formation.     

Effects of low-level combined static and weak low-frequency alternating magnetic fields on cytokine production and tumor development in mice

We investigated the effects of weak combined magnetic fields (MFs) produced by superimposing a constant MF (in the range 30 - 150 µT) and an alternating MF (100 or 200 nT) on cytokine production in healthy Balb/C male mice exposed 2 h daily for 14 days. The alternating magnetic field was a sum of several frequencies (ranging from 2.5 - 17.5 Hz). The frequencies of the alternating magnetic field were calculated formally based on the cyclotron resonance of ions of free amino acids (glutamic and aspartic acids, arginine, lysine, histidine, and tyrosine). The selection of different intensity and frequency combinations of constant and alternating magnetic fields was performed to find the optimal characteristics for cytokine production stimulation in immune cells. MF with a constant component of 60 μT and an alternating component of 100 nT, which was a sum of six frequencies (from 5 to 7 Hz), was found to stimulate the production of tumor necrosis factor-α, interferon-gamma, interleukin-2, and interleukin-3 in healthy mouse cells and induce cytokine accumulation in blood plasma. Then, we studied the effect of this MF on tumor-bearing mice with solid tumors induced by Ehrlich ascite carcinoma cells by observing tumor development processes, including tumor size, mouse survival rate, and average lifespan. Tumor-bearing mice exposed to a combined constant magnetic field of 60 μT and an alternating magnetic field of 100 nT containing six frequencies showed a strong suppression of tumor growth with an increase in survival rate and enhancement of average lifespan.     

Naturally occurring biflavonoids with amyloid β aggregation inhibitory activity for development of anti-Alzheimer agents

Amyloid β (Aβ) aggregation plays an essential role in promoting the progression of Alzheimer’s disease (AD). Therefore, the inhibition of Aβ aggregation is a potential therapeutic approach for AD. Herein, twenty-seven biflavonoids with different inter-flavonyl linkages and methoxy substitution patterns were isolated from several plants, and their Aβ₄₀ aggregation inhibitory activity was evaluated by the thioflavin-T fluorescence assay. Amentoflavone (1) and its monomethoxy derivatives (2, 3, and 5) exhibited the most potent inhibitory activity, with IC₅₀ values of approximately 5 μM. It was clarified that increasing the number of methoxy substituents on the biflavonoid structures attenuated the inhibitory activity. Moreover, the linkage and the methoxy substitution pattern had a marked influence on the inhibitory activity. Our investigation strongly supports that biflavonoids can be considered a new type of anti-Alzheimer agents that may be successfully developed for AD patients.     

Synthesis and biological evaluation of 9-fluorenone derivatives for SPECT imaging of α7-nicotinic acetylcholine receptor

The α7-nicotinic acetylcholine receptor (α7-nAChR) subtype, is found to have a connection with the pathogenesis of a variety of psychiatric and neurological disorders. Herein, we report the development of radioiodinated 9-fluorenone derivatives as single-photon emission computed tomography (SPECT) imaging tracers for α7-nAChRs. Among the derivatives, the best member of the series 10 (Ki = 2.23 nM) were radiolabeled with ¹²⁵I for in vitro and in vivo studies. The radiotracer [¹²⁵I]10 exhibited robust brain uptake and specifically labeled α7-nAChRs with a peak uptake value of 9.49 ± 0.87%ID/g in brain. Blocking studies demonstrated that the tracer was highly specific toward α7-nAChR. Furthermore, ex vivo autoradiography and micro-SPECT/CT dynamic imaging in mice confirmed the excellent imaging properties. In addition, molecular docking was also performed to rationalize the potency of the chosen compounds towards α7-nAChRs. To conclude, compound 10 could serve as a promising radiotracer for the α7-nAChRs.     

Development of a novel inducer for EBV lytic therapy

Epstein-Barr virus (EBV) is a human herpesvirus that infects over 90% of the world's population that persists as a latent infection in various lymphoid and epithelial malignancies. The total number of EBV associated malignancies is estimated to exceed 200,000 new cancers per year. Current chemotherapeutic treatments of EBV-positive cancers include broad-spectrum cytotoxic drugs that ignore the EBV positive status of tumors and have limited safety and selectivity. In an effort to develop new and more efficacious molecules for inducing EBV reactivation, we have developed high-throughput screening assays to identify a class of small molecules (referred to as the C60 series) that efficiently activate the EBV lytic cycle in multiple latency types, including lymphoblastoid and nasopharyngeal carcinoma cell lines. In this paper we report our preliminary structure activity relationship studies and demonstrate reactivation of EBV in the SNU719 gastric carcinoma mouse model and the AGS-Akata gastric carcinoma mouse model.