HIV-1 Structural Proteins or Cell-Signaling Factors? That Is the Question!

The biological activity of structural HIV-1 proteins is not limited to ensuring a productive viral infection but also interferes with cellular homeostasis through intra- and extracellular signaling activation. This interference induces genomic instability, increases the lifespan of the infected cell by inhibiting apoptosis, and subverts cell senescence, resulting in unrestricted cell proliferation. HIV structural proteins are present in a soluble form in the lymphoid tissues and blood of infected individuals, even without active viral replication. The HIV matrix protein p17, the envelope glycoprotein gp120, the transenvelope protein gp41, and the capsid protein p24 interact with immune cells and deregulate the biological activity of the immune system. The biological activity of HIV structural proteins is also demonstrated in endothelial cells and some tumor cell lines, confirming the ability of viral proteins to promote cell proliferation and cancer progression, even in the absence of active viral replication. This review corroborates the hypothesis that HIV structural proteins, by interacting with different cell types, contribute to creating a microenvironment that is favorable to the evolution of cancerous pathologies not classically related to AIDS.

Silver and Gold Complexes with NHC-Ligands Derived from Caffeine: Catalytic and Pharmacological Activity.

N-heterocyclic carbene (NHC) silver(I) and gold(I) complexes have found different applications in various research fields, as in medicinal chemistry for their antiproliferative, anticancer, and antibacterial activity, and in chemistry as innovative and effective catalysts. The possibility of modulating the physicochemical properties, by acting on their ligands and substituents, makes them versatile tools for the development of novel metal-based compounds, mostly as anticancer compounds. As it is known, chemotherapy is commonly adopted for the clinical treatment of different cancers, even though its efficacy is hampered by several factors. Thus, the development of more effective and less toxic drugs is still an urgent need. Herein, we reported the synthesis and characterization of new silver(I) and gold(I) complexes stabilized by caffeine-derived NHC ligands, together with their biological and catalytic activities. Our data highlight the interesting properties of this series as effective catalysts in A3-coupling and hydroamination reactions and as promising anticancer, anti-inflammatory, and antioxidant agents. The ability of these complexes in regulating different pathological aspects, and often co-promoting causes, of cancer makes them ideal leads to be further structurally functionalized and investigated.

Associated effects of clinical characteristics, risk factors, and comorbidity on disease severity and mortality among patients with COVID-19 in Sulaimani City/ Kurdistan Region of Iraq.

The effects of clinical symptoms, laboratory indicators, and comorbidity status of SARS-CoV-2-infected patients on the severity of disease and the risk of death were investigated. Questionnaires and electronic medical records of 371 hospitalized COVID-19 patients were used for data collection (demographics, clinical manifestation, comorbidities, laboratory data). Association among categorical variables was determined using Kolmogorov-Smirnov test (P-value ≤0.05). Median age of study population (249 males, 122 females) was 65 years. Roc curves analysis found that age ≥64 years and age ≥67 years are significant cut-offs identifying patients with more severe disease and mortality at 30 days. CRP values at cut-off ≥80.7 and ≥95.8 significantly identify patients with more severe disease and mortality. Patients with more severe disease and risk of death were significantly identified with platelet value at the cut-off ≤160,000, hemoglobin value at the cut-off ≤11.7, D-Dimer values ≥1383 and ≥1270, and with values of neutrophil granulocytes (≥8.2 and ≤2) and lymphocytes (≤2 and ≤2.4). Detailed clinical investigation suggests granulocytes together with lymphopenia may be a potential indicator for diagnosis. Older age, several comorbidities (cancer, cardiovascular diseases, hypertension) and more laboratory abnormalities (CRP, D-Dimer, platelets, hemoglobin) were associated with development of more severity and mortality among COVID-19 patients.

Perceiving numerosity does not cause automatic shifts of spatial attention.

It is debated whether the representation of numbers is endowed with a directional-spatial component so that perceiving small-magnitude numbers triggers leftward shifts of attention and perceiving large-magnitude numbers rightward shifts. Contrary to initial findings, recent investigations have demonstrated that centrally presented small-magnitude and large-magnitude Arabic numbers do not cause leftward and rightward shifts of attention, respectively. Here we verified whether perceiving small or large non-symbolic numerosities (i.e., clouds of dots) drives attention to the left or the right side of space, respectively. In experiment 1, participants were presented with central small (1, 2) vs large-numerosity (8, 9) clouds of dots followed by an imperative target in the left or right side of space. In experiment 2, a central cloud of dots (i.e., five dots) was followed by the simultaneous presentation of two identical dot-clouds, one on the left and one on the right side of space. Lateral clouds were both lower (1, 2) or higher in numerosity (8, 9) than the central cloud. After a variable delay, one of the two lateral clouds turned red and participants had to signal the colour change through a unimanual response. We found that (a) in Experiment 1, the small vs large numerosity of the central cloud of dots did not speed up the detection of left vs right targets, respectively, (b) in Experiment 2, the detection of colour change was not faster in the left side of space when lateral clouds were smaller in numerosity than the central reference and in the right side when clouds were larger in numerosity. These findings show that perceiving non-symbolic numerosity does not cause automatic shifts of spatial attention and suggests no inherent association between the representation of numerosity and that of directional space.

Italian expert-based recommendations on the use of photo(chemo)therapy in the management of mycosis fungoides: Results of an e-Delphi consensus.

BACKGROUND: Phototherapy is a mainstay for the treatment of MF. However, there is scarce evidence for its use, mostly due to the lack of a unified schedule. AIMS: The primary aim of this study was to establish the first structured, expert-based consensus regarding the indications and technical schedules of NB-UVB and PUVA for MF. The secondary aim was to determine the consensus level for each specific item. MATERIALS & METHODS: E-delphi study. Item-specific expert consensus was defined as the number of "Totally Agree" results to ≥80% of the panelists. Cronbach alpha index ≥0.7 was used as a measure of homogeneity in the responses among questions related to the same topic. RESULTS: Overall, there was a high homogeneity among responders (0.78). On specific topics, the highest grade was observed for technical items (0.8) followed by indications for early (0.73) and advanced stages (0.7). CONCLUSIONS: Items related to the most canonical indications of phototherapy and to treatment schedules showed the highest agreements rates. There is consensus about the use of standardized treatment schedules for the induction and consolidation phases for NB-UVB and PUVA in MF.

Specific synonymous mutations tightly correlate with HIV-1 co-receptor usage and differentially affect the secondary structure of HIV-1 Env RNA.

Human immunodeficiency virus (HIV) is a pathogen that infects blood cells, using CD4 molecule and two cell receptors CCR5 and CXCR4. The other major actor is gp120/gp41 viral protein complex, which interacts with receptors. Here, the presence of synonymous mutations associated with HIV-1 tropism and the related RNA secondary-structure in HIV-1 infected patients was evaluated. The analysis includes gp120-sequences from 340 HIV-1 subtype-B infected patients, all retrieved from Los Alamos database and with phenotypic HIV tropism determination based on recombinant-virus entry-assay. Frequencies of all nucleotide substitutions were calculated. Mfold and RNAfold algorithms were used to predict RNA secondary-structure of HIV-1. Nineteen codons in V2/C2, V3 and C3 domains were found to be closely related to CCR5 and CXCR4. Additionally, in X4-sequences, gp120 gca303gcu and gua222guc synonymous mutations are positively related to the gp120 S11R and T8A/I codons in V3 protein domain. Furthermore, gua222guc increases stability of the viral RNA secondary-structure. Probably, it would not be surprising if a novel escape viral strategy therapy will be related to the gp120 synonymous mutations. Moreover, in relation to the pivotal role played by gp120 in polyvalent vaccine approaches, the impact of gp120 synonymous mutations may play an important role in HIV entry into the cell. Keywords: gp120; tropism; v3; s11r; evolution; vaccine.

Chitosan Membranes Filled with Cyclosporine A as Possible Devices for Local Administration of Drugs in the Treatment of Breast Cancer.

The aim of this work is the design, preparation and characterization of membranes based on cyclosporine A (CsA) and chitosan carboxylate (CC) to be used as an implantable subcutaneous medical device for a prolonged therapeutic effect in the treatment of breast cancer. The choice to use CsA is due to literature data that have demonstrated its possible antitumor activity on different types of neoplastic cells. To this end, CsA was bound to CC through an amidation reaction to obtain a prodrug to be dispersed in a chitosan-based polymeric membrane. The reaction intermediates and the final product were characterized by Fourier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (1H-NMR). Membranes were analyzed by differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The data obtained showed the effective formation of the amide bond between CsA and CC and the complete dispersion of CsA inside the polymeric membrane. Furthermore, preliminary tests, conducted on MDA-MB-231, a type of breast cancer cell line, have shown a high reduction in the proliferation of cancer cells. These results indicate the possibility of using the obtained membranes as an interesting strategy for the release of cyclosporin-A in breast cancer patients.

Deconstructing Reorienting of Attention: Cue Predictiveness Modulates the Inhibition of the No-target Side and the Hemispheric Distribution of the P1 Response to Invalid Targets.

Orienting of attention produces a "sensory gain" in the processing of visual targets at attended locations and an increase in the amplitude of target-related P1 and N1 ERPs. P1 marks gain reduction at unattended locations; N1 marks gain enhancement at attended ones. Lateral targets that are preceded by valid cues also evoke a larger P1 over the hemisphere contralateral to the no-target side, which reflects inhibition of this side of space [Slagter, H. A., Prinssen, S., Reteig, L. C., & Mazaheri, A. Facilitation and inhibition in attention: Functional dissociation of pre-stimulus alpha activity, P1, and N1 components. Neuroimage, 125, 25-35, 2016]. To clarify the relationships among cue predictiveness, sensory gain, and the inhibitory P1 response, we compared cue- and target-related ERPs among valid, neutral, and invalid trials with predictive (80% valid/20% invalid) or nonpredictive (50% valid/50% invalid) directional cues. Preparatory facilitation over the visual cortex contralateral to the cued side of space (lateral directing attention positivity component) was reduced during nonpredictive cueing. With predictive cues, the target-related inhibitory P1 was larger over the hemisphere contralateral to the no-target side not only in response to valid but also in response to neutral and invalid targets: This result highlights a default inhibitory hemispheric asymmetry that is independent from cued orienting of attention. With nonpredictive cues, valid targets reduced the amplitude of the inhibitory P1 over the hemisphere contralateral to the no-target side whereas invalid targets enhanced the amplitude of the same inhibitory component. Enhanced inhibition was matched with speeded reorienting to invalid targets and drop in attentional costs. These findings show that reorienting of attention is modulated by the combination of cue-related facilitatory and target-related inhibitory activity.

Spatial uncertainty improves the distribution of visual attention and the availability of sensory information for conscious report.

Picking-up and exploiting spatial and temporal regularities in the occurrence of sensory events is important for goal-directed behaviour. According to the "Predictive Coding Hypothesis" (Friston Philosophical Trans R Soc B 360(1456):815-836, 2005), these regularities are used to generate top-down predictions that are constantly compared with actual sensory events. In a previous study with the Attentional Blink (AB) paradigm, we showed that the temporal and probabilistic uncertainty of T2s that are presented outside the Attentional Blink period, i.e. at least 400 ms after T1, improves the conscious report of T2 that are presented inside the AB. The study of ERP correlated showed that this improvement was associated with a prolonged storage of pre-conscious T2 traces in extra-striate areas (Lasaponara et al. Cortex 71:15-33, 2015). Here, we tested whether variations in the probabilistic cueing of the position of a primary T1 visual target in a 4 × 4 letter array, modulate the retention of memory traces evoked by secondary letter targets (T2) that were presented in other positions of the array. Most important, in each trial, the identity of T2 was specified to participants upon disappearance of the array. We show that high probabilistic cueing facilitates T1 detection and improves the corresponding sensitivity index (d'). In contrast, retention and conscious report of secondary targets (T2) improves when the probabilistic cueing of T1 position is poor. These results suggest that uncertainty in the upcoming position of primary targets boosts the strength of memory traces evoked by secondary targets and improves the possibility that traces of secondary targets gain full access to conscious processing.

Expectancy modulates pupil size both during endogenous orienting and during re-orienting of spatial attention: A study with isoluminant stimuli.

We have recently demonstrated that when endogenous orienting of spatial attention is guided by central directional cues that reliably predict the position of lateral targets. Pupil Dilation (PDil) is higher as compared with directional cues that do not predict target position. These findings were interpreted as reflecting different levels of Locus Coeruleus-Noradrenergic activity during endogenous orienting. In contrast to this, we were not able to highlight reliable differences between PDil responses to infrequent invalid targets that are associated with predictive cues and frequent invalid targets that are associated with non-predictive ones. These null findings might have been due to the spurious influence of transitory changes in luminance at the moment of target presentation or to the short time window used for the analysis of target-related changes in PDil. Here, we re-explored cue- and target-related changes in PDil using cue and target stimuli that were kept isoluminant to their background and long lasting cue and target periods for data recording and analysis. We fully replicate our previous cue-related results and, in addition, we demonstrate that infrequent invalid targets in the predictive experimental condition evoke larger PDil as compared with frequent ones. Analyses with Linear Mixed Models highlighted that both during the cue and target period, higher levels of PDil were associated with slower reaction times. These findings confirm that PDil is a reliable marker of the expectancy components of endogenous cue-related and exogenous target-related orienting of spatial attention.

Uncoupling effects of estrogen receptor α on LKB1/AMPK interaction upon adiponectin exposure in breast cancer.

Adipose tissue is a metabolic and endocrine organ that secretes bioactive molecules called adipocytokines. Among these, adiponectin has a crucial role in obesity-associated breast cancer. The key molecule of adiponectin signaling is AMPK, which is mainly activated by liver kinase B1 (LKB1). Here, we demonstrated that estrogen receptor-α (ERα)/LKB1 interaction may negatively interfere with the LKB1 capability to phosphorylate AMPK and inhibit its downstream signaling TSC2/mTOR/p70S6k. In adiponectin-treated MCF-7 cells, AMPK signaling was not working, resulting in its downstream target acetyl-CoA carboxylase (ACC) being still active. In contrast, in MDA-MB-231 cells, AMPK and ACC phosphorylation was enhanced by adiponectin, inhibiting lipogenesis and cell growth. Upon adiponectin, ERα signaling switched the energy balance of breast cancer cells toward a lipogenic phenotype. Therefore, adiponectin played an inhibitory role on ERα-negative cell growth and progression in vitro and in vivo. In contrast, low adiponectin levels, similar to those circulating in obese patients, acted on ERα-positive cells as a growth factor, stimulating proliferation. The latter effect was blunted in vivo by high adiponectin concentration. All this may have translational relevance, addressing how the handling of adiponectin, as a therapeutic tool in breast cancer treatment, needs to be carefully considered in ERα-positive obese patients, where circulating levels of this adipocytokine are relatively low. In other words, in ERα-positive breast cancer obese patients, higher adiponectin doses should be administered with respect to ERα-negative breast cancer, also opportunely combined with antiestrogen therapy. -Mauro, L., Naimo, G. D., Gelsomino, L., Malivindi, R., Bruno, L., Pellegrino, M., Tarallo, R., Memoli, D., Weisz, A., Panno, M. L., Andò, S. Uncoupling effects of estrogen receptor α on LKB1/AMPK interaction upon adiponectin exposure in breast cancer.

The Attentional-SNARC effect 16 years later: no automatic space-number association (taking into account finger counting style, imagery vividness, and learning style in 174 participants).

The Attentional-SNARC effect (Att-SNARC) originally described by Fischer et al. (Nat Neurosci 6(6):555, 2003), consists of faster RTs to visual targets in the left side of space when these are preceded by small-magnitude Arabic cues at central fixation and by faster RTs to targets in the right side of space when these are preceded by large-magnitude cues. Verifying the consistency and reliability of this effect is important, because the effect would suggest an inherent association between the representation of space and that of number magnitude, while a number of recent studies provided no positive evidence in favour of the Att-SNARC and the inherency of this association (van Dijck et al. in Q J Exp Psychol 67(8):1500-1513, 2014; Zanolie and Pecher in Front Psychol 5:987, 2014; Fattorini et al. in Cortex 73:298-316, 2015; Pinto et al. in Cortex, DOI:10.1016/j.cortex.2017.12.015, 2018). Here, we re-analysed Att-SNARC data that we have collected in 174 participants over different studies run in our laboratory. Most important, in a subsample of 79 participants, we also verified whether the strength and reliability of the Att-SNARC is eventually linked inter-individual variations in finger counting style, imagery vividness, and verbal/visual learning style. We found no evidence for the Att-SNARC effect or for the influence of finger counting style, imagery vividness, and learning style on its direction or consistency. These results confirm no inherent link between orienting of spatial attention and representation of number magnitudes. We propose that this link is rather determined by the joint use of spatial and number magnitude or parity codes in the performance of the numerical task at hand.

Treatment of psoriasis with topical agents: Recommendations from a Tuscany Consensus.

Psoriasis is a chronic and relapsing inflammatory skin disease, clinically characterized by erythematous and scaly plaques. Treatment approach is mainly driven by disease severity, though several factors should be considered in order to identify the optimal therapeutic choice. Mild psoriasis may be treated with a wide array of topical agents including corticosteroids, vitamin D analogs, keratolytics, and calcipotriol/betamethasone propionate compound. Because guidelines may not provide practical indications regarding the therapeutic approach, the use of topical agents in psoriasis is more individually tailored. In order to homogenize the standard of care, at least in a local setting, we collected the real-life-based recommendations for the use of topical therapies from an expert panel, the Tuscany Consensus Group on Psoriasis, representing all leading centers for psoriasis established in Tuscany. With this document, this consensus group sought to define principles guiding the selection of therapeutic agents with straightforward recommendations derived from a real-life setting.

Estrogen receptor-α drives adiponectin effects on cyclin D1 expression in breast cancer cells.

Obesity is a risk factor for breast cancer, largely due to altered expression of various adipocytokines. As it concerns adiponectin, there are not univocal results regarding its role in breast cancer occurrence and progression. Here, we demonstrate that in animals injected with human estrogen receptor (ER)-α-negative MDA-MB-231 cells pretreated with adiponectin (1 and 5 µg/ml), a significant reduction (60 and 40%, respectively) in tumor volume is observed, whereas an increased tumor growth (54 and 109%, respectively) is evidenced in the animals receiving human ER-α-positive MCF-7 cells. Moreover, cyclin D1 (CD1) mRNA and protein levels are decreased in MDA-MB-231 cells, whereas they are up-regulated in ER-α-positive cells by adiponectin. These findings fit with the opposite effects of adiponectin on CD1 promoter: 0.44- and 0.34-fold decrease in MDA-MB-231 cells and 0.63- and 0.95-fold increase in MCF-7 cells, treated with 1 and 5 µg/ml, respectively. Functional studies indicate that these effects are mediated by the specific protein 1 motif located in the CD1 promoter. In the absence of ER-α, the adiponectin-mediated down-regulation of CD1 involves the recruitment of corepressors. In the presence of ER-α, the adiponectin-induced expression of CD1 requires the involvement of an activator complex. In conclusion, we propose that a possible mechanism through which adiponectin differently affects breast cancer growth is the opposite modulation of CD1 levels accordingly to ER-α expression.

To what extent is quality of life impaired in vitiligo? A multicenter study on Italian patients using the dermatology life quality index.

BACKGROUND: It is believed that vitiligo has an impact on the overall patient quality of life (QoL). OBJECTIVE: To estimate QoL in a fairly large sample of Italian vitiligo patients by using the Dermatology Life Quality Index (DLQI) questionnaire. METHODS: One hundred and sixty-one vitiligo patients referred to 9 dermatological centers were offered to participate by filling in the Italian version of the DLQI questionnaire. RESULTS: The mean total DLQI score was 4.3 (SD ±4.9; range: 0-22). In multivariate analysis, DLQI >5 was associated with female gender, stability of the disease over time and involvement of the face at disease onset. CONCLUSIONS: The impairment of QoL is overall limited in Italian vitiligo patients, especially if it is compared with results from other available studies. This could be due to cultural and ethnic characteristics of the sample.

Circulating autoantibodies and autoimmune comorbidities in vitiligo patients: a multicenter Italian study.

BACKGROUND: Autoimmune comorbidities and circulating autoantibodies have been observed in vitiligo patients, but differences in rate are present according to countries in which the studies were performed, perhaps owing to ethnic diversities or different trigger factors. OBJECTIVE: To estimate the prevalence of circulating autoantibodies and overt autoimmune diseases in a fairly large sample of Italian vitiligo patients. METHODS: 175 outpatients affected by vitiligo and referred to nine dermatological centers were included in the study. Patients were offered routine blood test, serological testing for thyroid function and search for autoantibodies. RESULTS: At least one circulating autoantibody was detected in 61 (41.8%) of 146 subjects who underwent laboratory tests. Anti-thyroperoxidase (25.6%), anti-thyroglobulin (23.4%), antinuclear antibodies (16.8%) and anti-gastric parietal cell antibodies (7.8%) were the most noticed autoantibodies. 74 (41.5%) autoimmune comorbidities, mainly autoimmune thyroiditis (37%), were reported. CONCLUSION: The prevalence of autoimmune comorbidities and circulating autoantibodies in this study was in agreement with other surveys conducted on Caucasian patients.

The Ongoing Impact of COVID-19 on Pediatric Obesity.

In the developed world, pediatric obesity (PO) has been a major health concern since the last century, and this condition may lead to detrimental life-long physical and mental comorbidities. Currently, its prevalence has increased in low- and middle-income countries and in many high-income countries. Thus, the provision of effective and tailored care for children and their families has become vital. The social consequences of the COVID-19 pandemic are known everywhere, and among these, it has been argued that the COVID-19 pandemic has had a major impact on PO. Overall, the growth of PO over the last decade has been enhanced by the pandemic. During the COVID-19 pandemic, children, adolescents and young adults gained weight as the pediatric population dealt with sedentary lifestyles and changes in food habits. In this review, we want to highlight the impact that the COVID-19 pandemic had on PO.

Transferrin-conjugated pluronic niosomes as a new drug delivery system for anticancer therapy.

An efficient tumor-targeted niosomal delivery system for the vehiculation of doxorubicin hydrochloride as an anticancer agent was designed. Niosomes were prepared from a mixture of an opportunely modified Pluronic L64 surfactant and cholesterol as a membrane additive and characterized in terms of size and related distribution function and drug entrapment efficiency. After the preparation, transferrin was conjugated to niosomes to produce transferrin (Tf) niosomes, and the cytotoxicity of the final formulation was studied. The specific uptake of Tf niosomes into cells was evaluated via incubation of MCF-7 and MDA-MB-231 cells with fluorescently rhodamine-loaded Tf niosomes for various times and concentration intervals and further investigated by fluorescence microscopy. Results showed that doxorubicin can be easily encapsulated into niosomes, which are regular and spherical in shape. Moreover, transferrin conjugate niosomes demonstrated far greater extents of cellular uptake by MCF-7 and MDA-MB-231 cells, suggesting that they were mainly taken up by transferrin receptor-mediated endocytosis. Doxorubicin-loaded niosome anticancer activity was also achieved against MCF-7 and MDA-MB-231 tumor cell lines, and a significant reduction in viability in a dose- and time-related manner was observed. Finally, our formulation could be potentially useful as a target doxorubicin delivery system in anticancer therapy.

A Scoping Review on Movement, Neurobiology and Functional Deficits in Dyslexia: Suggestions for a Three-Fold Integrated Perspective.

Developmental dyslexia is a common complex neurodevelopmental disorder. Many theories and models tried to explain its symptomatology and find ways to improve poor reading abilities. The aim of this scoping review is to summarize current findings and several approaches and theories, focusing on the interconnectedness between motion, emotion and cognition and their connection to dyslexia. Consequently, we present first a brief overview of the main theories and models regarding dyslexia and its proposed neural correlates, with a particular focus on cerebellar regions and their involvement in this disorder. After examining different types of intervention programs and remedial training, we highlight the effects of a specific structured sensorimotor intervention named Quadrato Motor Training (QMT). QMT utilizes several cognitive and motor functions known to be relevant in developmental dyslexia. We introduce its potential beneficial effects on reading skills, including working memory, coordination and attention. We sum its effects ranging from behavioral to functional, structural and neuroplastic, especially in relation to dyslexia. We report several recent studies that employed this training technique with dyslexic participants, discussing the specific features that distinguish it from other training within the specific framework of the Sphere Model of Consciousness. Finally, we advocate for a new perspective on developmental dyslexia integrating motion, emotion and cognition to fully encompass this complex disorder.