cAMP/PKA signaling and RIM1alpha mediate presynaptic LTP in the lateral amygdala

NMDA receptor-dependent long-term potentiation (LTP) of glutamatergic synaptic transmission in sensory pathways from auditory thalamus or cortex to the lateral amygdala (LA) underlies the acquisition of auditory fear conditioning. Whereas the mechanisms of postsynaptic LTP at thalamo–LA synapses are well understood, much less is known about the sequence of events mediating presynaptic NMDA receptor-dependent LTP at cortico–LA synapses. Here, we show that presynaptic cortico–LA LTP can be entirely accounted for by a persistent increase in the vesicular release probability. At the molecular level, we found that signaling via the cAMP/PKA pathway is necessary and sufficient for LTP induction. Moreover, by using mice lacking the active-zone protein and PKA target RIM1α (RIM1α^−/−), we demonstrate that RIM1α is required for both chemically and synaptically induced presynaptic LTP. Further analysis of cortico–LA synaptic transmission in RIM1α^−/− mice revealed a deficit in Ca²⁺-release coupling leading to a lower baseline release probability. Our results reveal the molecular mechanisms underlying the induction of presynaptic LTP at cortico–LA synapses and indicate that RIM1α-dependent LTP may involve changes in Ca²⁺-release coupling.     

A systematic review of vaccine-induced thrombotic thrombocytopenia in individuals who received COVID-19 adenoviral-vector-based vaccines

Journal of Thrombosis and Thrombolysis - Reports of thrombotic response after receiving COVID-19 Adenoviral-Vector Based Vaccines raise concerns about vaccine-induced thrombotic thrombocytopenia...     

APOBECs and Herpesviruses

The apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family of DNA cytosine deaminases provides a broad and overlapping defense against viral infections. Successful viral pathogens, by definition, have evolved strategies to escape restriction by the APOBEC enzymes of their hosts. HIV-1 and related retroviruses are thought to be the predominant natural substrates of APOBEC enzymes due to obligate single-stranded (ss)DNA replication intermediates, abundant evidence for cDNA strand C-to-U editing (genomic strand G-to-A hypermutation), and a potent APOBEC degradation mechanism. In contrast, much lower mutation rates are observed in double-stranded DNA herpesviruses and the evidence for APOBEC mutation has been less compelling. However, recent work has revealed that Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and herpes simplex virus-1 (HSV-1) are potential substrates for cellular APOBEC enzymes. To prevent APOBEC-mediated restriction these viruses have repurposed their ribonucleotide reductase (RNR) large subunits to directly bind, inhibit, and relocalize at least two distinct APOBEC enzymes—APOBEC3B and APOBEC3A. The importance of this interaction is evidenced by genetic inactivation of the EBV RNR (BORF2), which results in lower viral infectivity and higher levels of C/G-to-T/A hypermutation. This RNR-mediated mechanism therefore likely functions to protect lytic phase viral DNA replication intermediates from APOBEC-catalyzed DNA C-to-U deamination. The RNR-APOBEC interaction defines a new pathogen-host conflict that the virus must win in real-time for transmission and pathogenesis. However, partial losses over evolutionary time may also benefit the virus by providing mutational fuel for adaptation.     

Effect of Cu,Ni and Pb doping on the photo-electrochemical activity of ZnO thin films

In the present study, the effects of metallic doping on the photoelectron\chemical properties of zinc oxide thin films have been studied. All films have been deposited using the spray pyrolysis technique at a constant doping level of 3 wt% whereby Cu, Ni, and Pb were used as dopants. The structure of all films was studied by X-ray diffraction which showed the grain size of all doped films to be 50 nm. The energy band gap of all films was estimated using optical transmission spectroscopy. The Ni, Cu, and Pb-doped ZnO photoelectrodes were applied for the photoelectrochemical (PEC) H₂ generation from H₂O. Pb doping leads to the highest photocurrent of the ZnO photoelectrodes. The current density–potential characteristics were measured under white light and monochromatic illumination. The stability of the electrode was quantified as a function of the number of H₂ production runs and exposure time. Finally, the incident photon-to-current conversion efficiency, IPCE, and applied bias photon-to-current efficiency, ABPE, were calculated. The optimum IPCE at 390 nm was ∼30% whereas the ABPE was 0.636 at 0.5 V.

In the present study, the effects of metallic doping on the photoelectron\chemical properties of zinc oxide thin films have been studied.     

Familial focal segmental glomerulosclerosis and retinitis pigmentosa: a new association

The association of retinitis pigmentosa with renal disease is rare and occurs mainly in two conditions: medullary cystic disease and Bardet-Biedl syndrome; here we describe a case of retinitis pigmentosa with familial focal segmental glomerulosclerosis, which to the best of our knowledge has never been reported previously.     

Biocompatibility of calcined mesoporous silica particles with cellular bioenergetics in murine tissues

A novel in vitro system was developed to investigate the effects of two forms of calcined mesoporous silica particles (MCM41-cal and SBA15-cal) on cellular respiration of mouse tissues. O(2) consumption by lung, liver, kidney, spleen, and pancreatic tissues was unaffected by exposure to 200 μg/mL MCM41-cal or SBA15-cal for several hours. Normal tissue histology was confirmed by light microscopy. Intracellular accumulation of the particles in the studied tissues was evident by electron microscopy. The results show reasonable in vitro biocompatibility of the mesoporous silicas with murine tissue bioenergetics.     

Cleavage of growth differentiation factor 15 (GDF15) by membrane type 1-matrix metalloproteinase abrogates GDF15-mediated suppression of tumor cell growth

Growth differentiation factor 15 (GDF15), a transforming growth factor (TGF)-β superfamily member, has been cloned from a placenta cDNA library as a gene product that has promoted activation of pro-matrix metalloproteinase (MMP)2 mediated by membrane type (MT)1-MMP. Expression of MT1-MMP in HEK293T cells caused cleavage of the GDF15 mature form at N²⁵²–M²⁵³ to produce a 6-kDa C -terminal fragment. Treatment of MCF7 cells with GDF15 induced activation of p53 and enhanced expression of p21, which was abrogated by MT1-MMP expression. GDF15 mRNA synthesis was also shown to be induced by treatment of cells with GDF15. Treatment of MCF7 cells with GDF15 caused suppression of cell proliferation. However, proliferation of MCF7 cells transfected with the MT1-MMP gene was not affected by GDF15 treatment, but was suppressed in the presence of the MMP inhibitor BB94. HT1080 cells transfected with the GDF15 gene, which endogenously express MT1-MMP, synthesize a high-level GDF15 precursor form and a low-level mature form, and treatment of cells with BB94 enhanced production of the GDF15 mature form. Consistent with GDF15 production, HT1080 cells transfected with the GDF15 gene proliferated almost equally with control cells, and addition of BB94 effectively suppressed growth of HT1080 cells transfected with the GDF15 gene concomitant with the accumulation of the GDF15 mature form, but not control cells. These results suggest that MT1-MMP contributes to tumor cell proliferation through the cleavage of GDF15, which down-regulates cell proliferation by inducing activation of p53 and p21 synthesis. ( Cancer Sci 2007; 98: 1330–1335)     

Synthesis and antimicrobial activity of acyclo C-nucleosides: 3-(alditol-1-yl)-7-oxo-5-phenyl-1,2,4-triazolo[4,3-a]pyrimidines

Condensation of 2-hydrazino-4-oxo-6-phenylpyrimidine (1) with aldopentoses 2a-d or aldohexoses 2e-g gave the corresponding aldehydo-sugar (4-oxo-6-phenylpyrimidin-2-yl)hydrazones 3a-g which were acetylated to the corresponding poly-O-acetyl-aldehydo-sugar (3-acetyl-4-oxo-6-phenylpyrimidin-2-yl)hydrazones 4a-g. The latter compounds underwent oxidative cyclization with bromine in acetic acid and in the presence of sodium acetate to the corresponding 8-acetyl-3- (poly-O-acetyl-alditol-1-yl)-7-oxo-5-phenyl-1,2,4-triazolo[4,3-a]pyrimid ines 6a-g. Compounds 6a-g were also obtained by consecutive one-pot oxidative cyclization/acetylation in which the parent hydrazones 3a-g were treated with bromine/acetic acid/sodium acetate followed by acetic anhydride. Deacetylation of 6a-g with ammonium hydroxide in methanol gave the title compounds 7a-g. The antibacterial and antifungal activities of compounds 3c, 3f, 7c and 7f are reported.