Regional Brain Atrophy and Functional Connectivity Changes Related to Fatigue in Multiple Sclerosis

Fatigue is one of the most frequent symptoms in multiple sclerosis (MS), and recent studies have described a relationship between the sensorimotor cortex and its afferent and efferent pathways as a substrate of fatigue. The objectives of this study were to assess the neural correlates of fatigue in MS through gray matter (GM) and white matter (WM) atrophy, and resting state functional connectivity (rs-FC) of the sensorimotor network (SMN). Eighteen healthy controls (HCs) and 60 relapsing-remitting patients were assessed with the Fatigue Severity Scale (FSS). Patients were classified as fatigued (F) or nonfatigued (NF). We investigated GM and WM atrophy using voxel-based morphometry, and rs-FC changes with a seed-based method and independent component analysis (ICA). F patients showed extended GM and WM atrophy focused on areas related to the SMN. High FSS scores were associated with reductions of WM in the supplementary motor area. Seed analysis of GM atrophy in the SMN showed that HCs presented increased rs-FC between the primary motor and somatosensory cortices while patients with high FSS scores were associated with decreased rs-FC between the supplementary motor area and associative somatosensory cortex. ICA results showed that NF patients presented higher rs-FC in the primary motor cortex compared to HCs and in the premotor cortex compared to F patients. Atrophy reduced functional connectivity in SMN pathways and MS patients consequently experienced high levels of fatigue. On the contrary, NF patients experienced high synchronization in this network that could be interpreted as a compensatory mechanism to reduce fatigue sensation.     

Anti-inflammatory effect of l-cysteine (a semi-essential amino acid) on 5-FU-induced oral mucositis in hamsters

Oral mucositis is an inflammation of the oral mucosa mainly resulting from the cytotoxic effect of 5-fluorouracil (5-FU). The literature shows anti-inflammatory action of l-cysteine (l-cys) involving hydrogen sulfide (H₂S). In view of these properties, we investigate the effect of l-cys in oral mucositis induced by 5-FU in hamsters. The animals were divided into the following groups: saline 0.9%, mechanical trauma, 5-FU 60–40 mg/kg, l-cys 10/40 mg and NaHS 27 µg/kg. 5-FU was administered on days 1st to 2nd; 4th day excoriations were made on the mucosa; 5th–6th received l-cys and NaHS. For data analysis, histological analyses, mast cell count, inflammatory and antioxidants markers, and immunohistochemistry (cyclooxygenase-2(COX-2)/inducible nitric oxide synthase (iNOs)/H₂S) were performed. Results showed that l-cys decreased levels of inflammatory markers, mast cells, levels of COX-2, iNOS and increased levels of antioxidants markers and H₂S when compared to the group 5-FU (p < 0.005). It is suggested that l-cys increases the H₂S production with anti-inflammatory action in the 5-FU lesion.

     

Structural heterozygosity in Scilla hyacinthoides L. and Scilla amoena L. (Liliaceae). Karyological analysis

Abstract

A karyological analysis carried out in Scilla hyacinthoides L. and Scilla amoena L. on material collected in the Botanical Garden of Cagliari (Sardinia), has shown the presence of heterozygous karyotypes in the two species. The chromosome number of S. hyacinthoides was found to be 2n = 20, while the chromosome number of S. amoena was 2n = 12, in accordance with the data found in the literature. Both the observed karyotypes show clear structural alterations, especially evident in one pair of clearly heteromorphic chromosomes. The analysis of the karyotypes seem to exclude a hybrid origin of the material examined and it is probable that such karyotypes may be the result of various structural re-arrangements, still evolving and aiming at a cytogenetic stabilization of the genus Scilla.     

Genetic variation in eggplant for Nitrogen Use Efficiency under contrasting NO3‐ supply

Eggplant (Solanum melongena L.) yield is highly sensitive to N fertilization, the excessive use of which is responsible for environmental and human health damage. Lowering N input together with the selection of improved Nitrogen‐Use‐Efficiency (NUE) genotypes, more able to uptake, utilize, and remobilize N available in soils, can be challenging to maintain high crop yields in a sustainable agriculture. The aim of this study was to explore the natural variation among eggplant accessions from different origins, in response to Low (LN) and High (HN) Nitrate (NO₃^‐) supply, to identify NUE‐contrasting genotypes and their NUE‐related traits, in hydroponic and greenhouse pot experiments. Two eggplants, AM222 and AM22, were identified as N‐use efficient and inefficient, respectively, in hydroponic, and these results were confirmed in a pot experiment, when crop yield was also evaluated. Overall, our results indicated the key role of N‐utilization component (NUtE) to confer high NUE. The remobilization of N from leaves to fruits may be a strategy to enhance NUtE, suggesting glutamate synthase as a key enzyme. Further, omics technologies will be used for focusing on C‐N metabolism interacting networks. The availability of RILs from two other selected NUE‐contrasting genotypes will allow us to detect major genes/quantitative trait loci related to NUE.     

Plant natural fragments,an innovative approach for drug discovery

Plant natural products (PNP) (e.g., secondary vegetal metabolites and their derivatives) have been a productive source of active ingredients for the pharmaceutical industry. The High Throughput Screening of Plant Natural Products (PNP-HTS) with extracts or isolated compounds has shown to be time consuming, expensive, and not as successful as expected. Recently building upon the innovative fragment-based drug discovery (FBDD) a disruptive approach was developed based on PNP. The fragment approach involves elaboration and/or isolation of weakly binding small molecules with molecular weights between 150 and 250 Da. This method is fundamentally different from HTS in almost every aspect (i.e., size of the compound library, screening methods, and optimization steps from hit to lead). Due to their nature, vegetal natural fragments have unique three-dimensional (3D) properties, high Fsp³, low aromaticity, and large chemo-diversities which represent potential opportunities for developing novel drugs. Preliminary results using vegetal natural fragments appear to be a promising and emerging field which offers valuable prospects for developing new drugs.

     

Inhibition of bromodomain and extra‐terminal proteins increases sensitivity to venetoclax in chronic lymphocytic leukaemia

The development of drugs able to target BTK, PI3k‐delta and BCL2 has dramatically improved chronic lymphocytic leukaemia (CLL) therapies. However, drug resistance to these therapies has already been reported due to non‐recurrent changes in oncogenic pathways and genes expression signatures. In this study, we investigated the cooperative role of the BCL2 inhibitor venetoclax and the BRD4 inhibitor JQ1. In particular, we found that JQ1 shows additional activity with venetoclax, in CLL cell lines and in ex vivo isolated primary CD19⁺ lymphocytes, arguing in favour of combination strategies. Lastly, JQ1 is also effective in venetoclax‐resistant CLL cell lines. Together, our findings indicated that the BET inhibitor JQ1 could be a promising therapy in CLL, both as first‐line therapy in combination with venetoclax and as second‐line therapy, after the emergence of venetoclax‐resistant clones.