Visual Cortex Engagement in Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a family of inherited disorders caused by the progressive degeneration of retinal photoreceptors. There is no cure for RP, but recent research advances have provided promising results from many clinical trials. All these therapeutic strategies are focused on preserving existing photoreceptors or substituting light-responsive elements. Vision recovery, however, strongly relies on the anatomical and functional integrity of the visual system beyond photoreceptors. Although the retinal structure and optic pathway are substantially preserved at least in early stages of RP, studies describing the visual cortex status are missing. Using a well-established mouse model of RP, we analyzed the response of visual cortical circuits to the progressive degeneration of photoreceptors. We demonstrated that the visual cortex goes through a transient and previously undescribed alteration in the local excitation/inhibition balance, with a net shift towards increased intracortical inhibition leading to improved filtering and decoding of corrupted visual inputs. These results suggest a compensatory action of the visual cortex that increases the range of residual visual sensitivity in RP.     

Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients.     

Local Therapies and Modulation of Tumor Surrounding Stroma in Malignant Pleural Mesothelioma: A Translational Approach

Malignant Pleural Mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural mesothelium, mainly associated with asbestos exposure and still lacking effective therapies. Modern targeted biological strategies that have revolutionized the therapy of other solid tumors have not had success so far in the MPM. Combination immunotherapy might achieve better results over chemotherapy alone, but there is still a need for more effective therapeutic approaches. Based on the peculiar disease features of MPM, several strategies for local therapeutic delivery have been developed over the past years. The common rationale of these approaches is: (i) to reduce the risk of drug inactivation before reaching the target tumor cells; (ii) to increase the concentration of active drugs in the tumor micro-environment and their bioavailability; (iii) to reduce toxic effects on normal, non-transformed cells, because of much lower drug doses than those used for systemic chemotherapy. The complex interactions between drugs and the local immune-inflammatory micro-environment modulate the subsequent clinical response. In this perspective, the main interest is currently addressed to the development of local drug delivery platforms, both cell therapy and engineered nanotools. We here propose a review aimed at deep investigation of the biologic effects of the current local therapies for MPM, including cell therapies, and the mechanisms of interaction with the tumor micro-environment.     

The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

After 26 years of discovery of the determinant survival motor neuron 1 and the modifier survival motor neuron 2 genes (SMN1 and SMN2, respectively), three SMN-dependent specific therapies are already approved by FDA and EMA and, as a consequence, worldwide SMA patients are currently under clinical investigation and treatment. Bi-allelic pathogenic variants (mostly deletions) in SMN1 should be detected in SMA patients to confirm the disease. Determination of SMN2 copy number has been historically employed to correlate with the phenotype, predict disease evolution, stratify patients for clinical trials and to define those eligible for treatment. In view that discordant genotype-phenotype correlations are present in SMA, besides technical issues with detection of SMN2 copy number, we have hypothesized that copy number determination is only the tip of the iceberg and that more deepen studies of variants, sequencing and structures of the SMN2 genes are necessary for a better understanding of the disease as well as to investigate possible influences in treatment responses. Here, we highlight the importance of a comprehensive approach of SMN1 and SMN2 genetics with the perspective to apply for better prediction of SMA in positive neonatal screening cases and early diagnosis to start treatments.     

Influence of space allowance and housing conditions on the welfare, immune response and production performance of dairy ewes

The experiment used 45 Comisana ewes, divided into 3 groups of 15. The aim was to determine the effects of two different stocking densities and two different housing conditions on welfare, and on production performance of dairy ewes. The stocking densities tested were: high stocking density (1 x 5 m2/ewe, HD group) and low stocking density (3 m2/ewe, LD group); the two housing conditions tested were: ewes housed indoors (LD group, 3 m2/ewe) and ewes allowed to use an outdoor area (LDP group, 3 m2/ewe divided into 1 x 5 m2/ewe indoors and 1 x 5 m2/ewe outdoors). At the beginning of the experiment, and then every 2 months, the cell-mediated immune status of sheep was evaluated. One month after the beginning of the experiment, and 20 d later, the ewes were injected with chicken egg albumin (OVA) to assess their humoural immune responses. Starting from the beginning of the experiment and then monthly, behavioural activities of ewes were monitored using 15-min scans. After lamb weaning, milk yield from individual ewes was measured and milk composition analysed weekly. Housing conditions (low density reared ewes indoors v. low density reared ewes with free access to an outdoor area) affected cell-mediated response, which was higher in LDP than in LD ewes. Concentrations of anti-OVA IgG were mainly influenced by space allowance, with higher antibody titres in LD than in HD ewes throughout the experiment. Both housing conditions and space allowance affected sheep behavioural activities: a greater proportion of LDP ewes displayed standing and drinking behaviours than LD ewes, and a greater proportion of LD ewes was observed walking than HD ewes. Ewes allowed access to the outdoor area had a higher protein content and lower somatic cell count in their milk, whereas reduced space allowance led to a reduction in milk yield and an increase in somatic cell count of milk. Results indicate that both increased space allowance and availability of outdoor area can improve the welfare and production performance of the lactating ewe.     

Effect of Gamma Radiation and Oregano Essential Oil on Murein and ATP Concentration of Staphylococcus aureus

ABSTRACT:  The study was carried out to evaluate the effects of gamma-irradiation alone or in combination with oregano essential oil on murein composition of  Staphylococcus aureus  and on the intracellular and extracellular concentration of ATP. The bacterial strain was treated with 3 irradiation doses: 1.2 kGy to induce cell damage, 2.9 kGy to obtain a viable but nonculturable state, and 3.5 kGy to cause cell death. Oregano essential oil was used at 0.010% and 0.013% (w/v), which is the minimum inhibitory concentration (MIC). All treatments had a significant effect ( P  ≤ 0.05) on the murein composition, although some muropeptides did not seem to be affected by the treatment. Each treatment influenced differently the relative percentage and number of muropeptides. There was a significant ( P  ≤ 0.05) correlation between the reduction of intracellular ATP and increase in extracellular ATP following treatment of the cells with oregano oil. The reduction of intracellular ATP was even more important when essential oil was combined with irradiation. Also, irradiation alone of  S. aureus  induced a significant decrease ( P  ≤ 0.05) of the internal ATP and a significant increase ( P  ≤ 0.05) of the external ATP. However, no significant difference ( P  > 0.05) was observed in ATP concentrations between different radiation doses. Transmission electron microscopic observation revealed that oregano oil and irradiation have an effect on cell wall structure.     

The Effect of Colour Contrast on Consumers' Attentive Behaviours and Perception of Fresh Produce

The market for fruits and vegetables has received considerable interest in recent years, with much of its growth attributed to consumer interest in nutrition and health. Quality has been indicated to be the most important factor in produce sales, and appearance is of noted significance with regard to perceived quality. The broad objectives of this research were to identify the impact of simultaneous colour contrast (i.e. the produce viewed through a mesh bag) on (a) attentive behaviours as measured by eye tracking and (b) perceived quality, visual appeal and purchase intention as measured with a Likert scale. To accomplish these objectives, six different types of produce (red apples, oranges, lemons, green apples, purple onions and white onions) were photographed with four differently coloured mesh treatments: the same (as the produce), complementary, complementary‐analogous and analogous. Visual stimuli were then presented during the eye tracking study and in a subsequent questionnaire. Colour contrast was found to have a significant effect on both resultant eye tracking variables [number of visual fixations (p < 0.001) and time spent (p < 0.001)]. Produce shown with mesh of the same, or an analogous colour, induced significantly more visual fixations and more time than those depicted with complementary or complementary‐analogous treatments. Subsequent to the eye tracking study, subjects were shown the stimuli and asked to rate the expected quality, visual appeal and their purchase intention for the 24 photographs (6 types of produce × 4 colour contrasts) by using a Likert scale. Pairwise comparisons suggested that produce packaged in the same or analogous mesh were perceived by subjects to be of higher quality, more visually appealing and evoked a higher level of purchase intention than those packaged in complementary or complementary‐analogous mesh (α = 0.05). Copyright © 2012 John Wiley & Sons, Ltd.     

The surface modification of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) copolymers to improve the attachment of urothelial cells

Biocompatible and biodegradable poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) [P(HB-co-HHx)] substrates were modified to improve the attachment of porcine urothelial cell culture. The pristine copolymer exhibits excellent mechanical properties to replace the bladder tissue, but its surface lacks chemical functionalities to interact with cells. Thus, wet chemical treatments based on NaOH and ethylenediamine in aqueous [ED(aq)] and isopropanol [ED(isoOH)] media to functionalize the P(HB-co-HHx) films surfaces were compared. Among these treatments, short ED(aq) treatment was able to decrease the hydrophobicity, rendering a surface with amino groups and without a significant alteration of the mechanical properties. Furthermore, to enhance the interaction with urothelial cells, laminin derived YIGSR sequence was covalently bound to these amino functionalized substrates. The focal attachment was clearly improved with this last treatment, comparing with those results found with the unmodified and first-step functionalized P(HB-co-HHx).