Edited by Paul E. FraserIndividuals who are infected with HIV-1 accumulate damage to cells and tissues (e.g. neurons) that are not directly infected by the virus. These include changes known as HIV-associated neurodegenerative disorder (HAND), leading to the loss of neuronal functions, including synaptic long-term potentiation (LTP). Several mechanisms have been proposed for HAND, including direct effects of viral proteins such as the Tat protein. Searching for the mechanisms involved, we found here that HIV-1 Tat inhibits E2F transcription factor 3 (E2F3), CAMP-responsive element-binding protein (CREB), and brain-derived neurotropic factor (BDNF) by up-regulating the microRNA miR-34a. These changes rendered murine neurons dysfunctional by promoting neurite retraction, and we also demonstrate that E2F3 is a specific target of miR-34a. Interestingly, bioinformatics analysis revealed the presence of an E2F3-binding site within the CREB promoter, which we validated with ChIP and transient transfection assays. Of note, luciferase reporter assays revealed that E2F3 up-regulates CREB expression and that Tat interferes with this up-regulation. Further, we show that miR-34a inhibition or E2F3 overexpression neutralizes Tat's effects and restores normal distribution of the synaptic protein synaptophysin, confirming that Tat alters these factors, leading to neurite retraction inhibition. Our results suggest that E2F3 is a key player in neuronal functions and may represent a good target for preventing the development of HAND.

Involvement of the human immunodeficiency virus type 1 (HIV-1) trans-activator of transcription (Tat) protein in neuronal deregulation and in the development of HIV-1 associated neurocognitive disorders (HAND) has been amply explored; however the mechanisms involved remain unclear. In search for the mechanisms, we demonstrated that Tat deregulates neuronal functions through a pathway that involved p73 and p53 pathway. We showed that Tat uses microRNA-196a (miR-196a) to deregulate the p73 pathway. Further, we found that the Abelson murine leukemia (c-Abl) phosphorylates p73 on tyrosine residue 99 (Tyr-99) in Tat-treated cells. Interestingly, Tat lost its ability to promote accumulation and phosphorylation of p73 in the presence of miR-196a mimic. Interestingly, accumulation of p73 did not lead to neuronal cell death by apoptosis as obtained by cell viability assay. Western blot analysis using antibodies directed against serine residues 807 and 811 of retinoblastoma (Rb) protein was also used to validate our data regarding lack of cell death. Hyperphosphorylation of RB (S807/811) is an indication of cell neuronal viability. These results highlight the key role played by p73 and microRNA in Tat-treated neurons leading to their deregulation and it deciphers mechanistically one of the pathways used by Tat to cause neuronal dysfunction that contributes to the development of HAND.

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<p>An experiment was carried out to determine if organic fertilizer and deficit irrigation combination could replace the traditional management of processing tomato crop (mineral fertilizer and irrigation of 100% crop evapotranspiration, ETc), without affecting yield and quality of production. The study was conducted from June 2022 to September 2022 at the experimental farm of the University of Padova, adopting a split-plot experimental design. The experiment was conducted under a plastic tunnel greenhouse where only the roof was covered to avoid the rainfall influence and at the same time to permit air circulation. Four fertilizer treatments, control (no fertilization), mineral fertilizer, unseived compost, and sieved compost (< 2mm) were applied in factorial combination with two irrigation treatments, 100% ETc and 75% ETc. Data on the vegetative, physiological, yield, and quality parameters were collected. The maximum plant height (75.3 cm) and stem diameter (17.0 mm) were recorded on plants fertilized with unseived compost; both of these parameters did not show significant differences in response to the irrigation level. For physiological parameters, significant differences were found among irrigation treatments. During the daytime, the 25% reduction of optimal irrigation water volume determined a reduction of 4.6% for stomal conductance (0.372 mol m<sup>-2 </sup>s<sup>-1</sup> at 100% ETc) and of 14.2% for transpiration (4.56 mmol m<sup>-2 </sup>s<sup>-1</sup> at 100% ETc). Regarding fluorescence, the highest value (0.769) was recorded for 75% ETc and mineral fertilization, while the lowest (0.733) was for 100% ETc and mineral fertilization. The number of ripe fruits per plant was significantly higher in the treatments with compost (60 fruits plant<sup>-1</sup>) than in the unfertilized control (39 fruits plant<sup>-1</sup>). The yield was neither influenced by fertilization nor by irrigation level showing an average value of 2 kg plant<sup>-1</sup>. Similarly, the qualitative analysis of the tomato fruits showed significantly higher soluble solid content (+5.8%) and pH (+1.4%) at 100% ETc than 75% ETc which showed an average value of 4.11 ˚Brix and 4.20, respectively. The fruits' dry matter content was not significantly influenced by the studied treatments. The results were derived from one year experiment, and they have to be confirmed in future experiments. However, they indicate that compost, whether sieved or not can be a valuable solution for the processing tomato fertilization and that deficit irrigation can be a valuable solution to reduce agricultural water use with only a few effects on plant production and quality parameters.</p>