Miracle-dz/UniFAR-FTUs huggingface dataset:
COVID Feel Good—An Easy Self-Help Virtual Reality Protocol to Overcome the Psychological Burden of Coronavirus

Background Living in the time of the COVID-19 means experiencing not only a global health emergency but also extreme psychological stress with potential emotional side effects such as sadness, grief, irritability, and mood swings. Crucially, lockdown and confinement measures isolate people who become the first and the only ones in charge of their own mental health: people are left alone facing a novel and potentially lethal situation, and, at the same time, they need to develop adaptive strategies to face it, at home. In this view, easy-to-use, inexpensive, and scientifically validated self-help solutions aiming to reduce the psychological burden of coronavirus are extremely necessary. Aims This pragmatic trial aims to provide the evidence that a weekly self-help virtual reality (VR) protocol can help overcome the psychological burden of the Coronavirus by relieving anxiety, improving well-being, and reinforcing social connectedness. The protocol will be based on the “Secret Garden” 360 VR video online (www.covidfeelgood.com) which simulates a natural environment aiming to promote relaxation and self-reflection. Three hundred sixty–degree or spherical videos allow the user to control the viewing direction. In this way, the user can explore the content from any angle like a panorama and experience presence and immersion. The “Secret Garden” video is combined with daily exercises that are designed to be experienced with another person (not necessarily physically together), to facilitate a process of critical examination and eventual revision of core assumptions and beliefs related to personal identity, relationships, and goals. Methods This is a multicentric, pragmatic pilot randomized controlled trial involving individuals who experienced the COVID-19 pandemic and underwent a lockdown and quarantine procedures. The trial is approved by the Ethics Committee of the Istituto Auxologico Italiano. Each research group in all the countries joining the pragmatic trial, aims at enrolling at least 30 individuals in the experimental group experiencing the self-help protocol, and 30 in the control group, over a period of 3 months to verify the feasibility of the intervention. Conclusion The goal of this protocol is for VR to become the “surgical mask” of mental health treatment. Although surgical masks do not provide the wearer with a reliable level of protection against the coronavirus compared with FFP2 or FFP3 masks, surgical masks are very effective in protecting others from the wearer’s respiratory emissions. The goal of the VR protocol is the same: not necessarily to solve complex mental health problems but rather to improve well-being and preserve social connectedness through the beneficial social effects generated by positive emotions.
Nature and dimensions of the cytokine storm and its attenuation by convalescent plasma in severe COVID-19

In a randomized control trial on convalescent plasma therapy (CPT) in severe COVID-19, we characterized the nature, in terms of abundance of forty eight cytokines, and dimensions, in terms of their interrelationships, of the hyper-immune activation-associated cytokine storm in patients suffering from acute respiratory distress syndrome. We found plasma MCP3 level to be a key correlate for mitigation of hypoxia, irrespective of therapeutic regimen. We also identified an anti-inflammatory role of CPT independent of its neutralizing antibody content, and a linear regression analysis revealed that neutralizing antibodies as well as the anti-inflammatory effect of CPT both contribute to marked immediate reductions in hypoxia, as compared to patients on standard therapy.
Intercellular Adhesion Molecule-1 as Target for CAR-T-Cell Therapy of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) comprises lethal malignancies with limited treatment options. Chimeric antigen receptor T (CAR-T) cell therapy is an effective immunotherapeutic strategy that has demonstrated unprecedented efficacy in the treatment of hematological malignancies but has shown limited success in the management of some solid tumors. Many malignant tumors are related to increased expression of intercellular adhesion molecule-1 (ICAM1), providing a rationale for ICAM1-specific immunotherapies for the treatment of cancer. Here, we validated the expression of ICAM1 in TNBC tissues. Subsequently, we generated a phage-displayed single-chain variable fragment (scFv) library using splenocytes from ICAM1-immunized mice and selected a novel ICAM1-specific scFv, mG2-scFv. Using mG2-scFv as the extracellular antigen binding domain, we constructed ICAM1-specific CAR-T cells and demonstrated the robust and specific killing of TNBC cell lines in vitro. Most importantly, in the TNBC mouse model, ICAM1-specific CAR-T cells significantly reduced the growth of the TNBC tumor, resulting in long-term remission and improved survival. Together, these results indicated that ICAM1-specific CAR-T cells have high therapeutic potential against ICAM1-positive TNBC tumors.
Selflessness, Depression, and Neuroticism: An Interactionist Perspective on the Effects of Self-Transcendence, Perspective-Taking, and Materialism

Dominant theories of depression position self-concept as a central determinant of psychological functioning, but the relationship between the structure of self-concept and depression has not been extensively explored. The present study investigates the relationship between the structure of the self and psychopathological outcomes (depressive symptoms and neuroticism) with two methodological approaches. Using an established framework that draws insight from Buddhist psychology, the structure of the self is conceptualized in terms of selflessness and self-centeredness. Specifically, selflessness is construed as a multidimensional concept characterized by interdependence, outsider phenomenology, and impermanence. The three dimensions of the self were assessed at age 26 with inventories of self-transcendence, perspective-taking, and materialism, respectively (N = 814). First, a variable-centered approach was used to investigate potential interactions between the dimensions of selflessness. Self-transcendence negatively predicted depressive symptoms and neuroticism, whereas perspective-taking and materialism were positively associated with the outcomes. Self-transcendence moderated the relationship between perspective-taking and depressive symptoms. Perspective-taking was not statistically related to depressive symptoms for participants who exhibited higher levels of self-transcendence. The results clarify ambiguous associations between perspective-taking and depression found in previous research. Second, person-centered analyses were used to identify five profiles of self-structure: (1) Selfless, (2) Selfless Materialist, (3) Interdependent Insider, (4) Self-centered Non-materialist, and (5) Self-centered. As hypothesized, the Selfless cluster was associated with low levels of depressive symptoms and neuroticism, whereas the Self-centered cluster was associated with high levels. The profiles demonstrate the manifestation of several combinations of features of the self, which contributes to overall understanding of selflessness by complicating the traditional dichotomy between selflessness and self-centeredness.
Heat Shock Alters Mesenchymal Stem Cell Identity and Induces Premature Senescence

Heat stress can have a serious impact on the health of both humans and animals. A major question is how heat stress affects normal development and differentiation at both the cellular and the organism levels. Here we use an in vitro experimental system to address how heat shock treatment influences the properties of bovine mesenchymal stem cells (MSCs)—multipotent progenitor cells—which are found in most tissues. Because cattle are sensitive to harsh external temperatures, studying the effects of heat shock on MSCs provides a unique platform to address cellular stress in a physiologically relevant model organism. Following isolation and characterization of MSCs from the cow’s umbilical cord, heat shock was induced either as a pulse (1 h) or continuously (3 days), and consequent effects on MSCs were characterized. Heat shock induced extensive phenotypic changes in MSCs and dramatically curtailed their capacity to proliferate and differentiate. These changes were associated with a partial arrest in the G1/S or G2/M checkpoints. Furthermore, MSCs lost their ability to resolve the inflammatory response of RAW macrophages in coculture. A possible explanation for this loss of function is the accumulation of reactive oxygen species and malfunction of the mitochondria in the treated cells. Heat shock treatments resulted in stress-induced premature senescence, affecting the MSCs’ ability to proliferate properly for many cell passages to follow. Exposure to elevated external temperatures leads to mitochondrial damage and oxidative stress, which in turn conveys critical changes in the proliferation, differentiation, and immunomodulatory phenotype of heat-stressed MSCs. A better understanding of the effect of heat shock on humans and animals may result in important health and economic benefits.
Low-Zone IL-2 Signaling: Fusion Proteins Containing Linked CD25 and IL-2 Domains Sustain Tolerogenic Vaccination in vivo and Promote Dominance of FOXP3+ Tregs in vitro

Low-zone IL-2 signaling is key to understanding how CD4+ CD25high FOXP3+ regulatory T cells (Tregs) exhibit dominance and overgrow conventional effector T cells (Tcons) that typically express lower levels of the IL-2 receptor alpha chain (i.e., CD25). Thus, modalities such as low-dose IL-2 or IL-2/anti-IL-2 antibody complexes have been advanced in the clinic to selectively expand Treg populations as a treatment for chronic inflammatory autoimmune diseases. However, more effective reagents that efficiently lock IL-2 signaling into a low signaling mode are needed to validate and exploit the low-zone IL-2 signaling niche of Tregs. This study focuses on CD25-IL2 and IL2-CD25 fusion proteins (FPs) that were approximately 32 and 320-fold less potent than IL-2. These FPs exhibited transient binding to transmembrane CD25 on human embryonic kidney (HEK) cells, had partially occluded IL-2 binding sites, and formed higher order multimeric conformers that limited the availability of bioactive IL-2. These FPs exhibited broad bell-shaped concentration ranges that favored dominant Treg outgrowth during continuous culture and were used to derive essentially pure long-term Treg monocultures (∼98% Treg purity). FP-induced Tregs had canonical Treg suppressive activity in that these Tregs suppressed antigen-specific proliferative responses of naïve CD4+ T cells. The in vivo administration of CD25-IL2/Alum elicited robust increases in circulating Tregs and selectively augmented CD25 expression on Tregs but not on Tcons. A single injection of a Myelin Oligodendrocyte Glycoprotein (MOG35-55)-specific tolerogenic vaccine elicited high levels of circulating MOG-specific Tregs in vivo that waned after 2–3 weeks, whereas boosting with CD25-IL2/Alum maintained MOG-specific CD25high Tregs throughout the 30-day observation period. However, these FPs did not antagonize free monomeric IL-2 and lacked therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE). In conclusion, these data reveal that CD25-IL2 FPs can be used to select essentially pure long-term lines of FOXP3+ CD25high Tregs. This study also shows that CD25-IL2 FPs can be administered in vivo in synergy with tolerogenic vaccination to maintain high circulating levels of antigen-specific Tregs. Because tolerogenic vaccination and Treg-based adoptive immunotherapy are limited by gradual waning of Tregs, these FPs have potential utility in sustaining tolerogenic Treg responses in vivo.
Qualitative Transcriptional Signature for the Pathological Diagnosis of Pancreatic Cancer

It is currently difficult for pathologists to diagnose pancreatic cancer (PC) using biopsy specimens because samples may have been from an incorrect site or contain an insufficient amount of tissue. Thus, there is a need to develop a platform-independent molecular classifier that accurately distinguishes benign pancreatic lesions from PC. Here, we developed a robust qualitative messenger RNA signature based on within-sample relative expression orderings (REOs) of genes to discriminate both PC tissues and cancer-adjacent normal tissues from non-PC pancreatitis and healthy pancreatic tissues. A signature comprising 12 gene pairs and 17 genes was built in the training datasets and validated in microarray and RNA-sequencing datasets from biopsy samples and surgically resected samples. Analysis of 1,007 PC tissues and 257 non-tumor samples from nine databases indicated that the geometric mean of sensitivity and specificity was 96.7%, and the area under receiver operating characteristic curve was 0.978 (95% confidence interval, 0.947–0.994). For 20 specimens obtained from endoscopic biopsy, the signature had a diagnostic accuracy of 100%. The REO-based signature described here can aid in the molecular diagnosis of PC and may facilitate objective differentiation between benign and malignant pancreatic lesions.
Effects of Thujaplicins on the Promoter Activities of the Human SIRT1 and Telomere Maintenance Factor Encoding Genes

Resveratrol (Rsv) has been shown to extend the lifespan of diverse range of species to activate sirtuin (SIRT) family proteins, which belong to the class III NAD+ dependent histone de-acetylases (HDACs). The protein deacetylating enzyme SIRT1 has been implicated in the regulation of cellular senescence and aging processes in mammalian cells. However, higher concentrations of this natural compound cause cell death. Therefore, novel compounds that have reduced cellular toxicity will be required for anti-aging therapy, especially for dermatological treatments. In this study, the Luciferase (Luc) expression vector pGL4-SIRT1 containing 396-bp of the 5’-upstream region of the human SIRT1 gene was transfected into HeLa S3 cells and Luc assay was performed. The results showed that treatments with the natural compound, α-, β- and γ-thujaplicins increase the SIRT1 promoter activity more than that with Rsv. Moreover, we carried out multiple transfection of Luc reporter vectors containing 5’-upstream regions of various human telomere maintenance factor encoding genes, and observed that β−thujaplicin (hinokitiol) activates TERT, RTEL, TRF1, DKC1, RAP1 (TERF2IP) and TPP1(ACD) promoters. These results suggest that that the β−thujaplicin could be used as anti-aging drugs to delay cellular senescence through activating SIRT1 transcription along with strengthening stability of telomeres.
Higher Body-Mass Index and Lower Gray Matter Volumes in First Episode of Psychosis

Background Neurostructural alterations are often reported in first episode of psychosis (FEP), but there is heterogeneity in the direction and location of findings between individual studies. The reasons for this heterogeneity remain unknown. Obesity is disproportionately frequent already early in the course of psychosis and is associated with smaller brain volumes. Thus, we hypothesized that obesity may contribute to brain changes in FEP. Method We analyzed MRI scans from 120 participants with FEP and 114 healthy participants. In primary analyses, we performed voxel-based morphometry (VBM) with small volume corrections to regions associated with FEP or obesity in previous meta-analyses. In secondary analyses, we performed whole-brain VBM analyses. Results In primary analyses, we found that when controlling for BMI, FEP had lower GM volume than healthy participants in a) left fronto-temporal region (pTFCE = 0.008) and b) left postcentral gyrus (pTFCE = 0.043). When controlling for FEP, BMI was associated with lower GM volume in left cerebellum (pTFCE < 0.001). In secondary analyses, we found that when controlling for BMI, FEP had lower GM volume than healthy participants in the a) cerebellum (pTFCE = 0.004), b) left frontal (pTFCE = 0.024), and c) right temporal cortex (pTFCE = 0.031). When controlling for FEP, BMI was associated with lower GM volume in cerebellum (pTFCE = 0.004). Levels of C-reactive protein, HDL and LDL-cholesterol correlated with obesity related neurostructural alterations. Conclusions This study suggests that higher BMI, which is frequent in FEP, may contribute to cerebellar alterations in schizophrenia. As previous studies showed that obesity-related brain alterations may be reversible, our ﬁndings raise the possibility that improving the screening for and treatment of obesity and associated metabolic changes could preserve brain structure in FEP.
Mediation of Mucosal Immunoglobulins in Buccal Cavity of Teleost in Antibacterial Immunity

The buccal mucosa (BM) of vertebrates is a critical mucosal barrier constantly exposed to rich and diverse pathogens from air, water, and food. While mammals are known to contain a mucosal associated lymphoid tissue (MALT) in the buccal cavity which induces B-cells and immunoglobulins (Igs) responses against bacterial pathogens, however, very little is known about the evolutionary roles of buccal MALT in immune defense. Here we developed a bath infection model that rainbow trout experimentally exposed to Flavobacterium columnare (F. columnare), which is well known as a mucosal pathogen. Using this model, we provided the first evidence for the process of bacterial invasion in the fish BM. Moreover, strong pathogen-specific IgT responses and accumulation of IgT+ B-cells were induced in the buccal mucus and BM of infected trout with F. columnare. In contrast, specific IgM responses were for the most part detected in the fish serum. More specifically, we showed that the local proliferation of IgT+ B-cells and production of pathogen-specific IgT within the BM upon bacterial infection. Overall, our findings represent the first demonstration that IgT is the main Ig isotype specialized for buccal immune responses against bacterial infection in a non-tetrapod species.
Stability and stabilisation of switched time-varying delay systems: a multiple discontinuous Lyapunov function approach

In this paper, stability and stabilisation of switched time-varying delay systems are investigated. By developing, a multiple discontinuous Lyapunov function approach and using the mode-dependent average dwell time (MDADT) switching signal, sufficient conditions are first proposed to guarantee the exponential stability of the switched system with stable and unstable subsystems where the time-varying delay is considered in the states. Relaxed stability conditions are also obtained by using a form of the Bessel–Legendre inequality. Then stabilisation of the proposed system is presented by designing a sliding mode controller. Sufficient conditions and sufficient relaxed conditions of a reduced-order sliding mode dynamics are derived, and desired sliding surfaces in the form of linear matrix inequalities (LMIs) are also given. The obtained conditions are checked by using the combined genetic algorithm and convex programming techniques. Moreover, some numerical and practical examples are given to illustrate the effectiveness of the obtained theoretical results.
Not All Words Are Equally Acquired: Transitional Probabilities and Instructions Affect the Electrophysiological Correlates of Statistical Learning

Statistical learning (SL), the process of extracting regularities from the environment, is a fundamental skill of our cognitive system to structure the world regularly and predictably. SL has been studied using mainly behavioral tasks under implicit conditions and with triplets presenting the same level of difficulty, i.e., a mean transitional probability (TP) of 1.00. Yet, the neural mechanisms underlying SL under other learning conditions remain largely unknown. Here, we investigated the neurofunctional correlates of SL using triplets (i.e., three-syllable nonsense words) with a mean TP of 1.00 (easy “words”) and 0.50 (hard “words”) in an SL task performed under incidental (implicit) and intentional (explicit) conditions, to determine whether the same core mechanisms were recruited to assist learning. Event-related potentials (ERPs) were recorded while participants listened firstly to a continuous auditory stream made of the concatenation of four easy and four hard “words” under implicit instructions, and subsequently to another auditory stream made of the concatenation of four easy and four hard “words” drawn from another artificial language under explicit instructions. The stream in each of the SL tasks was presented in two consecutive blocks of ~3.5-min each (~7-min in total) to further examine how ERP components might change over time. Behavioral measures of SL were collected after the familiarization phase of each SL task by asking participants to perform a two-alternative forced-choice (2-AFC) task. Results from the 2-AFC tasks revealed a moderate but reliable level of SL, with no differences between conditions. ERPs were, nevertheless, sensitive to the effect of TPs, showing larger amplitudes of N400 for easy “words,” as well as to the effect of instructions, with a reduced N250 for “words” presented under explicit conditions. Also, significant differences in the N100 were found as a result of the interaction between TPs, instructions, and the amount of exposure to the auditory stream. Taken together, our findings suggest that triplets’ predictability impacts the emergence of “words” representations in the brain both for statistical regularities extracted under incidental and intentional instructions, although the prior knowledge of the “words” seems to favor the recruitment of different SL mechanisms.
Association of Clinical Phenotypes in Haploinsufficiency A20 (HA20) With Disrupted Domains of A20

Background: Haploinsufficiency A20 (HA20) is a newly described monogenic disease characterized by a wide spectrum of manifestations and caused by heterozygous mutations in TNFAIP3 which encodes A20 protein. TNFAIP3 mutation leads to disruption of the A20 ovarian tumor (OTU) domain and/or the zinc finger (ZnF) domain. This study aims at exploring the association between the various manifestations of HA20 and different domains disruption of A20. Methods: We reviewed the HA20 cases in previous literature and summarized the clinical features, TNFAIP3 mutation loci and the disrupted domains caused by different sites and patterns of mutations. Patients were classified into three groups according to the A20 domains disruption. Results: A total of 89 patients from 39 families with a genetic diagnosis of HA20 were included. Overall, the age at onset of HA20 was early (median:5.92, IQR:1-10). Patients in the ZnF group showed the earliest onset (median:2.5, IQR:0.6-5), followed by patients in the OTU+ZnF group (median:6, IQR:1-10) and patients in the OTU group (median:10, IQR:8-14). The main manifestations of HA20 patients were recurrent oral ulcers (70%), recurrent fever (42%), gastrointestinal ulcers (40%), skin lesion (38%), genital ulcers (36%), and musculoskeletal disorders (34%). The percentage of patients with musculoskeletal disorders was significantly different among the three groups (p = 0.005). Patients in the OTU+ZnF group and ZnF group were more likely to develop musculoskeletal disorders than patients in the OTU group (p = 0.002 and p = 0.035, respectively). Besides, forty-three percent of HA20 patients were initially diagnosed as Behcet's disease (BD). Compared to the ZnF group, the OTU+ZnF group and OTU group had a higher percentage of patients initially diagnosed as BD (p = 0.006 and p < 0.001, respectively). Conclusion: HA20 is characterized by early-onset and the most common symptoms of HA20 are recurrent oral ulcers, fever and gastrointestinal ulcers. The onset of HA20 in patients with the ZnF domain disruption is earlier than patients with the OTU domain disruption. Compared to the OTU domain, the ZnF domain may be more closely related to musculoskeletal disorders.