Miracle-dz/UniFAR-FTUs huggingface dataset:
Sex-Related Differences in Regional Blood–Brain Barrier Integrity in Non-Demented Elderly Subjects

The role of the blood–brain barrier (BBB) breakdown has been recognized as being important in Alzheimer’s disease pathogenesis. We aimed to evaluate whether regional BBB integrity differed according to sex and whether differences in BBB integrity changed as a consequence of aging or cognitive decline, using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI). In total, 75 participants with normal cognition (NC) or mild cognitive impairment (MCI) underwent cognitive assessments and MRI examination including DCE-MRI. Regional Ktrans was calculated in cortical regions and the Patlak permeability model was used to calculate BBB permeability (Ktrans, min−1). Females had a lower median Ktrans in the cingulate and occipital cortices. In the “older old” group, sex differences in Ktrans were only observed in the occipital cortex. In the MCI group, sex differences in Ktrans were only observed in the occipital cortex. Age was the only predictor of cognitive assessment scores in the male MCI group; however, educational years and Ktrans in the occipital cortex could predict cognitive scores in the female MCI group. Our study revealed that females may have better BBB integrity in cingulate and occipital cortices. We also found that sex-related differences in BBB integrity are attenuated with aging or cognitive decline.
Attitude and Behaviors towards SARS-CoV-2 Vaccination among Healthcare Workers: A Cross-Sectional Study from Poland

Healthcare workers are particularly exposed to biological risk during their daily occupational activities. Nowadays, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become one of the most widespread infectious agents. In the current study, we performed a survey on the attitude and behavior of Polish healthcare workers (HCW), which comprise physicians (MD) and administrative healthcare assistants (HA) towards the Coronavirus Disease 2019 (COVID-19) vaccination. Our study involved 2300 subjects (42.17% female; 10.96% MD; 5.87% HA). The evaluation was conducted using a Google Forms survey based on original questions and the Depression, Anxiety and Stress Scale—21 Items questionnaire. HCW significantly more often demonstrated their willingness to get vaccinated against the SARS-CoV-2 as compared to the control group (82.95% vs. 54.31%, respectively). The main concern, as regards all groups, was the development of long-term side effects after getting COVID-19 vaccine. The study revealed that depression significantly affects the willingness to get vaccinated. The readiness was significantly strengthened by positive medical history of recommended vaccinations, fear of catching COVID-19, as well as fear of passing on the disease to the relatives. Overall, the percentage of HCW, who want to be vaccinated against COVID-19 remains unsatisfactory. Further works exploring this subject are needed to take a step closer to achieving the herd immunity in the era of the COVID-19 pandemic.
Energy Transfer in Supramolecular Artificial Antennae Units of Synthetic Zinc Chlorins and Co-aggregated Energy Traps. A Time-Resolved Fluorescence Study†,‡

Using time-resolved fluorescence, we explored the energy transfer process(es) in supramolecular zinc chlorin aggregates co-aggregated with various kinds of energy traps. The energy transfer times from the antenna aggregate to the trap are in the picosecond time range (7−9 ps) under reducing conditions (addition of dithionite to avoid oxidative quenching) and were resolved in all cases. Under nonreducing conditions substantial fluorescence quenching occurred in the antenna aggregates. We tentatively suggest that a small amount of chlorin cations acts as a quencher. We find that in the aggregates the excitation is delocalized over at least 10−15 pigments, on the basis of the corresponding strong increase of the pure radiative rate vs a monomeric chlorin. In bacteriochlorophyll-based aggregates the transfer to the energy trap is biexponential (27 and 91 ps), which is reminiscent of native isolated chlorosomes from green sulfur bacteria. For the zinc chlorin-based light-harvesting units the overall efficiency.
Longitudinal Event-Level Sexual Risk and Substance Use among Gay, Bisexual, and Other Men Who Have Sex with Men

(1) Background: Condomless anal sex and substance use are associated with STI risk among gay, bisexual, and other men who have sex with men (gbMSM). Our first study objective was to describe event-level sexual risk and substance use trends among gbMSM. Our second study objective was to describe substances associated with event-level sexual risk. (2) Methods: Data come from the Momentum Health Study in Vancouver, British Columbia and participants were recruited from 2012–2015, with follow-up until 2018. Stratified by self-reported HIV status, we used generalized estimating equations to assess trends of sexual event-level substance use and assessed interactions between substance use and time period on event-level higher risk sex defined as condomless anal sex with an HIV serodifferent or unknown status partner. (3) Results: Event-level higher risk anal sex increased across the study period among HIV-negative/unknown (baseline prevalence: 13% vs. study end prevalence: 29%) and HIV-positive gbMSM (baseline prevalence: 16% vs. study end prevalence: 38%). Among HIV-negative/unknown gbMSM, event-level erectile drug use increased, while alcohol use decreased over the study period. Overall, interactions between substance use and time on higher risk anal sex were not statistically significant, regardless of serostatus. However, we found a number of time-specific significant interactions for erectile drugs, poppers, Gamma-hydroxybutyrate (GHB), crystal methamphetamine and ecstasy/MDMA use among HIV-negative/unknown gbMSM. (4) Conclusion: Significant differences in substance use trends and associated risks exist and are varied among gbMSM by serostatus. These findings provide a more comprehensive understanding of the effects of event-level substance use on sexual risk through longitudinal follow-up of nearly six years.
Taking Particle Tracking into Practice by Novel Software and Screening Approach: Case-Study of Oral Lipid Nanocarriers

The success on the design of new oral nanocarriers greatly depends on the identification of the best physicochemical properties that would allow their diffusion across the mucus layer that protects the intestinal epithelium. In this context, particle tracking (PT) has arisen in the pharmaceutical field as an excellent tool to evaluate the diffusion of individual particles across the intestinal mucus. In PT, the trajectories of individual particles are characterized by the mean square displacement (MSD), which is used to calculate the coefficient of diffusion (D) and the anomalous diffusion parameter (α) as MSD=4Dτα. Unfortunately, there is no stablished criteria to evaluate the goodness-of-fit of the experimental data to the mathematical model. This work shows that the commonly used R2 parameter may lead to an overestimation of the diffusion capacity of oral nanocarriers. We propose a screening approach based on a combination of R2 with further statistical parameters. We have analyzed the effect of this approach to study the intestinal mucodiffusion of lipid oral nanocarriers, compared to the conventional screening approach. Last, we have developed software able to perform the whole PT analysis in a time-saving, user-friendly, and rational fashion.
SARS-CoV-2 Infection and Inflammatory Response in a Twin Pregnancy

There is growing literature about the SARS-CoV-2 pathogenetic effects exerted during pregnancy and whether vertical transmission or premature birth is possible. It is not well known whether changes in the immune system of pregnant women may lead to a marked susceptibility to infectious processes and the risk of adverse maternal and neonatal complications such as preterm birth, spontaneous abortion, hospitalization in an intensive care unit, transmission to the fetus or newborns, and fetal mortality are poorly understood. Along with this ongoing debate, it is not well defined whether, during pregnancy, the role of host susceptibility in producing a specific inflammatory response to SARS-CoV-2 may represent distinctive markers of risk of vertical transmission. Furthermore, SARS-CoV-2 impact on the vaginal microbiome has not yet been described, despite mounting evidence on its possible effect on the gastrointestinal microbiome and its influence on infectious diseases and preterm labor. This report describes the impact of SARS-CoV-2 on a twin pregnancy diagnosed with infection at the third trimester of gestation including tissue infections, inflammatory response, antibody production, cytokine concentration, and vaginal microbiome composition. We identified a pattern of cytokines including IL1-Ra, IL-9 G-CSF, IL-12, and IL-8 differently expressed, already associated with previously infected patients. We detected a similar concentration of almost all the cytokines tested in both twins, suggesting that the SARS-CoV-2-induced cytokine storm is not substantially impaired during the placental passage. The analysis of the vaginal microbiome did not show relevant signs of dysbiosis, similar to other healthy pregnant women and twin healthy pregnancies. The aim of this report was to analyze the immunological response against SARS-CoV-2 infection and virus tissue tropism in a twin pregnancy.
Phenol-Rich Food Acceptability: The Influence of Variations in Sweetness Optima and Sensory-Liking Patterns

The consumption of phenol-rich foods is limited by their prominent bitterness and astringency. This issue has been addressed by adding sweet tastes, which suppress bitterness, but this is not a complete solution since individuals also differ in their preference for sweetness. In this study, we aimed at identifying groups of consumers differing in sweetness optima and sensory-liking patterns. To this end, increasing concentrations of sucrose were added to a chocolate pudding base. This allowed us to (1) investigate if individual differences in sensory responses are associated with different sweet liking optima in a product context, (2) define the psychological and oro-sensory profile of sweet liker phenotypes derived using a product context, and (3) assess if individuals differing in sweet liking optima differ also in consumption and liking of phenol-rich foods and beverages as a function of their sensory properties (e.g., sweeter vs. more bitter and astringent products). Individuals (1208; 58.4% women, 18–69 years) were characterised for demographics, responsiveness to 6-n-propylthiouracil (PROP), personality traits and attitudes toward foods. Three clusters were identified based on correlations between sensory responses (sweetness, bitterness and astringency) and liking of the samples: liking was positively related to sweetness and negatively to bitterness and astringency in High and Moderate Sweet Likers, and the opposite in Inverted U-Shaped. Differences between clusters were found in age, gender and personality. Furthermore, the Inverted-U Shaped cluster was found to have overall healthier food behaviours and preferences, with higher liking and consumption of phenol-rich vegetables and beverages without added sugar. These findings point out the importance of identifying the individual sensory-liking patterns in order to develop more effective strategies to promote the acceptability of healthy phenol-rich foods.
QT Interval Prolongation in Patients with Systemic Sclerosis—Are the Holter ECG Recordings a Better Option for QT Interval Evaluation?

Background and Objectives: Cardiac involvement in systemic sclerosis has important consequences on patient survival. Myocardial fibrosis and microcirculation involvement can generate arrhythmic complications, which can be associated with a higher death risk. QT interval prolongation is considered as a risk factor for ectopic ventricular events and can be evaluated using standard short ECG recordings or 24-h Holter ECG recordings. Materials and Methods: 39 patients with systemic sclerosis were submitted to a standard ECG recording at admission and 24-h Holter ECG monitoring. Results: QT interval values resulted from Holter ECG monitoring are higher than the values generated by the short-term ECG recordings. Holter ECG monitoring permits the detection of ventricular ectopy in patients with no events on standard ECG. Conclusions: In patients with systemic sclerosis, 24-h Holter ECG recordings can realize a more precise evaluation of the extent of QTc interval prolongation and ventricular ectopic events associated with myocardial involvement.
Dietary Fucose Affects Macrophage Polarization and Reproductive Performance in Mice

Intestinal mucus protects epithelial and immune cells from the gut resident microorganisms, and provides growth-promoting factors as mucus-derived O-glycans for beneficial bacteria. A lack of intestinal protective mucus results in changes in the commensal microflora composition, mucosal immune system reprogramming, and inflammation. Previous work has shown that fucose, the terminal glycan chain component of the intestinal glycoprotein Mucin2, and fucoidan polysaccharides have an anti-inflammatory effect in some mouse models of colitis. This study evaluates the effect of fucose on reproductive performance in heterozygous mutant Muc2 female mice. We found that even though Muc2+/− females are physiologically indistinguishable from C57Bl/6 mice, they have a significantly reduced reproductive performance upon dietary fucose supplementation. Metagenomic analysis reveals that the otherwise healthy wild-type siblings of Muc2−/− animals have reduced numbers of some of the intestinal commensal bacterial species, compared to C57BL/6 mice. We propose that the changes in beneficial microflora affect the immune status in Muc2+/− mice, which causes implantation impairment. In accordance with this hypothesis, we find that macrophage polarization during pregnancy is impaired in Muc2+/− females upon addition of fucose. Metabolic profiling of peritoneal macrophages from Muc2+/− females reveals their predisposition towards anaerobic glycolysis in favor of oxidative phosphorylation, compared to C57BL/6-derived cells. In vitro experiments on phagocytosis activity and mitochondrial respiration suggest that fucose affects oxidative phosphorylation in a genotype-specific manner, which might interfere with implantation depending on the initial status of macrophages. This hypothesis is further confirmed in BALB/c female mice, where fucose caused pregnancy loss and opposed implantation-associated M2 macrophage polarization. Taken together, these data suggest that intestinal microflora affects host immunity and pregnancy outcome. At the same time, dietary fucose might act as a differential regulator of macrophage polarization during implantation, depending on the immune status of the host.
Adjustment of Whey:Casein Ratio from 20:80 to 60:40 in Milk Formulation Affects Food Intake and Brainstem and Hypothalamic Neuronal Activation and Gene Expression in Laboratory Mice

Adjustment of protein content in milk formulations modifies protein and energy levels, ensures amino acid intake and affects satiety. The shift from the natural whey:casein ratio of ~20:80 in animal milk is oftentimes done to reflect the 60:40 ratio of human milk. Studies show that 20:80 versus 60:40 whey:casein milks differently affect glucose metabolism and hormone release; these data parallel animal model findings. It is unknown whether the adjustment from the 20:80 to 60:40 ratio affects appetite and brain processes related to food intake. In this set of studies, we focused on the impact of the 20:80 vs. 60:40 whey:casein content in milk on food intake and feeding-related brain processes in the adult organism. By utilising laboratory mice, we found that the 20:80 whey:casein milk formulation was consumed less avidly and was less preferred than the 60:40 formulation in short-term choice and no-choice feeding paradigms. The relative PCR analyses in the hypothalamus and brain stem revealed that the 20:80 whey:casein milk intake upregulated genes involved in early termination of feeding and in an interplay between reward and satiety, such as melanocortin 3 receptor (MC3R), oxytocin (OXT), proopiomelanocortin (POMC) and glucagon-like peptide-1 receptor (GLP1R). The 20:80 versus 60:40 whey:casein formulation intake differently affected brain neuronal activation (assessed through c-Fos, an immediate-early gene product) in the nucleus of the solitary tract, area postrema, ventromedial hypothalamic nucleus and supraoptic nucleus. We conclude that the shift from the 20:80 to 60:40 whey:casein ratio in milk affects short-term feeding and relevant brain processes.
Emerging Trends for Radio-Immunotherapy in Rectal Cancer

Simple Summary Despite recent advances in understanding the molecular biology of tumors, obstacles still exist in the treatment of patients affected by rectal cancer. Recent evidence shows that ionizing radiation may have profound immunostimulatory effects, hinting at the possibility of exploiting radiotherapy to boost anti-tumor immunity. A bulk of work in pre-clinical tumor models have highlighted the potential benefit of this approach. Following these results, a few clinical trials are now evaluating the combination of radiotherapy and immune checkpoint inhibition. Remarkably, encouraging safety and toxicity profiles from these studies indicate that radio-immunotherapy combinations could represent a valid opportunity for rectal cancer patients. Yet, the biological and clinical impact of a radio-immunotherapy combination in rectal cancer remains unclear and further studies need to be performed to optimize the effect of these combinations. Abstract Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.
Mitochondrial Dysfunction Plays a Relevant Role in Pathophysiology of Peritoneal Membrane Damage Induced by Peritoneal Dialysis

Preservation of the peritoneal membrane is an essential determinant of the long-term outcome of peritoneal dialysis (PD). Epithelial-to-mesenchymal transition (EMT) plays a central role in the pathogenesis of PD-related peritoneal membrane injury. We hypothesized that mitochondria may be implicated in the mechanisms that initiate and sustain peritoneal membrane damage in this setting. Hence, we carried out ex vivo studies of effluent-derived human mesothelial cells, which disclosed a significant increase in mitochondrial reactive oxygen species (mtROS) production and a loss of mitochondrial membrane potential in mesothelial cells with a fibroblast phenotype, compared to those preserving an epithelial morphology. In addition, in vitro studies of omentum-derived mesothelial cells identified mtROS as mediators of the EMT process as mitoTEMPO, a selective mtROS scavenger, reduced fibronectin protein expression induced by TGF-ß1. Moreover, we quantified mitochondrial DNA (mtDNA) levels in the supernatant of effluent PD solutions, disclosing a direct correlation with small solute transport characteristics (as estimated from the ratio dialysate/plasma of creatinine at 240 min), and an inverse correlation with peritoneal ultrafiltration. These results suggest that mitochondria are involved in the EMT that human peritoneal mesothelial cells suffer in the course of PD therapy. The level of mtDNA in the effluent dialysate of PD patients could perform as a biomarker of PD-induced damage to the peritoneal membrane.
D-α-Tocopherol-Based Micelles for Successful Encapsulation of Retinoic Acid

All-trans-retinoic acid (ATRA) represents the first-choice treatment for several skin diseases, including epithelial skin cancer and acne. However, ATRA’s cutaneous side effects, like redness and peeling, and its high instability limit its efficacy. To address these drawbacks and to improve ATRA solubilization, we prepared ATRA-loaded micelles (ATRA-TPGSs), by its encapsulation in D-α-tocopheryl-polyethylene-glycol-succinate (TPGS). First, to explore the feasibility of the project, a solubility study based on the equilibrium method was performed; then, six ATRA-TPGS formulations were prepared by the solvent-casting method using different TPGS amounts. ATRA-TPGSs showed small sizes (11–20 nm), low polydispersity, slightly negative zeta potential, and proved good encapsulation efficiency, confirmed by a chemometric-assisted Fourier transform infrared spectroscopy (FTIR) investigation. ATRA-TPGS stability was also investigated to choose the most stable formulation. Using Carbopol® 980 as gelling agent, ATRA-TPGS-loaded gels were obtained and analyzed for their rheological profiles. Ex vivo release studies from ATRA-TPGSs were performed by Franz cells, demonstrating a permeation after 24 h of 22 ± 4 µ cm−2. ATRA-TPGSs showed enhanced cytotoxic effects on melanoma cells, suggesting that these formulations may represent a valid alternative to improve patient compliance and to achieve more efficacious therapeutic outcomes.
Hydrogen Sulfide as a Potential Therapy for Heart Failure—Past, Present, and Future

Hydrogen sulfide (H2S) is an endogenous, gaseous signaling molecule that plays a critical role in cardiac and vascular biology. H2S regulates vascular tone and oxidant defenses and exerts cytoprotective effects in the heart and circulation. Recent studies indicate that H2S modulates various components of metabolic syndrome, including obesity and glucose metabolism. This review will discuss studies exhibiting H2S -derived cardioprotective signaling in heart failure with reduced ejection fraction (HFrEF). We will also discuss the role of H2S in metabolic syndrome and heart failure with preserved ejection fraction (HFpEF).