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Giuseppe Forte,1 Giovanna Troisi,2 Francesca Favieri,1 Vilfredo De Pascalis,2 Viviana Langher,1 Maria Casagrande1 1Department of Dynamic and Clinical Psychology and Health Studies, Sapienza University of Rome, Roma, 00185, Italy; 2Department of Psychology, Sapienza University of Rome, Roma, 00185, ItalyCorrespondence: Giuseppe Forte; Maria Casagrande, Department of Dynamic and Clinical Psychology and Health Studies, Sapienza University of Rome, Roma, 00185, Italy, Email g.forte@uniroma1.it; maria.casagrande@uniroma1.itIntroduction: Pain is a complex experience that requires executive functions (EFs) to be processed. The autonomic outcome of the neural networks involved in the cognitive evaluation of pain is reflected by heart rate variability (HRV), an index of self-regulation abilities. Although some results suggest a relationship between HRV, EFs, and pain, studies focusing on this three-way relationship are still scarce.Objective: This study aims to investigate the relationship between pain, cognitive, and autonomic mechanisms, hypothesizing an association between resting HRV and both cognitive and motor inhibition as indices of executive functioning. This relationship was investigated after an experimental-induced pain.Methods: Seventy-six young adults were exposed to the Cold Pressure Arm Warp to induce experimental pain. HRV was collected, and cognitive tasks were administered to assess executive performance.Results: The results showed that (1) HRV indices significantly increased during pain stimulation, (2) cognitive inhibition was positively correlated with vagal indices and with pain parameters, (3) both inhibition tasks significantly predicted pain threshold while the performance on the Stroop Task predicted pain tolerance.Conclusion: Results suggest a three-way relationship. Further research would focus on the role of HRV and cognitive strategies in pain management in chronic pain conditions.Keywords: Stroop task, Go-NoGo, autonomic, pain, heart rate variability, cognition

Giuseppe Forte,* Francesca Favieri,* Renata Tambelli, Maria Casagrande Department of Dynamic and Clinical Psychology and Health, “Sapienza” University of Rome, Rome, Italy*These authors contributed equally to this workCorrespondence: Giuseppe Forte; Maria Casagrande, Department of Dynamic and Clinical Psychology and Health, “Sapienza” University of Rome, Via degli Apuli 1, 00185, Rome, Italy, Email g.forte@uniroma1.it; maria.casagrande@uniroma1.itObjective: New TV-watching patterns increased the practice of binge-watching (BW). Considering the adaptive-maladaptive continuum of BW, the relationship between BW and health outcomes is still unclear. This study aimed to analyze some features of BW related to quality of life, focusing on sleep quality.Methods: Four-hundred eighty-two young adults were classified into four groups according to their BW approach. Then, sleep quality, mood, and quality of life were assessed.Results: All the investigated variables were associated with problematic and moderate BW. No differences emerged between BW as a leisure activity and not watching TV series. Moreover, quality of life is directly affected by BW.Conclusion: Accordingly, BW should be considered a continuum of behavioral patterns from a leisure activity characterized by positive outcomes to a maladaptive behavior characterized by negative outcomes for sleep, mood, and quality of life.Graphical Abstract: Keywords: behavioral addiction, leisure activity, sleep quality, health status, psychological well-being

Estrogens and progestogens act on female reproductive tissues in opposite ways. As they counteract each other actions, the correct balance between these two classes of hormones is pivotal to avoid dangerous states. Unopposed estrogens occur when progestogen levels do not balance estrogens, primarily deriving from overproduction of estrogens via aromatase enzyme. In the endometrium, unopposed estrogens induce proliferative or invasive phenomena, which represent the first step toward different diseases. These pathologies include endometrial hyperplasia, endometrial polyps, endometriosis and adenomyosis. Endometrial hyperplasia and polyps are proliferative pathologies, while endometriosis and adenomyosis are characterized by the invasion of other tissues by endometrial cells. Current pharmacological treatments include Gonadotropin-Releasing-Hormone analogs, aromatase inhibitors and progestogens, either alone or in combination with estrogens. As these drugs usually lead to burdensome undesired effects, researchers seek to find new therapeutical molecules. Recent literature highlights the positive effects of metformin, an insulin sensitizing drug that reduces the insulin proliferative stimulus on the endometrium. d-chiro-inositol is an insulin second messenger with insulin sensitizing and mimetic properties, recently described as an aromatase down-regulator. Based on current evidence, d-chiro-inositol may be useful to treat the pathologies responsive to unopposed estrogens. [ABSTRACT FROM AUTHOR]

Soil management is a sustainable agronomic practice to produce grapes, wine, and grape pomace with a low environmental impact in viticulture, affecting soil microbial biodiversity, organic matter, and healthy roots. Grape pomace is the main by-product of winemaking and a valuable source of natural phytochemicals. This research aimed to evaluate the phenolic content and antioxidant activity of pomace deriving from the microvinification of the Primitivo wine grapes obtained by four different soil management techniques: cover crop (C), soil mechanical tillage (T), green manure (G) and farm soil management (F). The content of total phenolic compounds and anthocyanins in grapes and wines is the highest with the vineyard cover cropping system. Moreover, grape pomace derived by cover crop soil management shows a significant abundance of these molecules and a more elevated antioxidant activity than the other soil technique.

Cardiac fibrosis occurs following insults to the myocardium and is characterized by the abnormal accumulation of non-compliant extracellular matrix (ECM), which compromises cardiomyocyte contractile activity and eventually leads to heart failure. This phenomenon is driven by the activation of cardiac fibroblasts (cFbs) to myofibroblasts and results in changes in ECM biochemical, structural and mechanical properties. The lack of predictive in vitro models of heart fibrosis has so far hampered the search for innovative treatments, as most of the cellular-based in vitro reductionist models do not take into account the leading role of ECM cues in driving the progression of the pathology. Here, we devised a single-step decellularization protocol to obtain and thoroughly characterize the biochemical and micro-mechanical properties of the ECM secreted by activated cFbs differentiated from human induced pluripotent stem cells (iPSCs). We activated iPSC-derived cFbs to the myofibroblast phenotype by tuning basic fibroblast growth factor (bFGF) and transforming growth factor beta 1 (TGF-β1) signalling and confirmed that activated cells acquired key features of myofibroblast phenotype, like SMAD2/3 nuclear shuttling, the formation of aligned alpha-smooth muscle actin (α-SMA)-rich stress fibres and increased focal adhesions (FAs) assembly. Next, we used Mass Spectrometry, nanoindentation, scanning electron and confocal microscopy to unveil the characteristic composition and the visco-elastic properties of the abundant, collagen-rich ECM deposited by cardiac myofibroblasts in vitro. Finally, we demonstrated that the fibrotic ECM activates mechanosensitive pathways in iPSC-derived cardiomyocytes, impacting on their shape, sarcomere assembly, phenotype, and calcium handling properties. We thus propose human bio-inspired decellularized matrices as animal-free, isogenic cardiomyocyte culture substrates recapitulating key pathophysiological changes occurring at the cellular level during cardiac fibrosis., Competing Interests: Declaration of competing interest Luca Bersanini and Malin Becker are employees of Optics11 Life B.V., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Drug resistance is a significant challenge in oncology and is driven by various mechanisms, among which a crucial role is played by enhanced DNA repair. Thus, targeting DNA damage response (DDR) factors with specific inhibitors is emerging as a promising therapeutic strategy. An important process involved in the modulation of DNA repair pathways, and hence in drug resistance, is post-translational modification (PTM). PTMs such as methylation affect protein function and are critical in cancer biology. Methylation is catalyzed by specific enzymes called protein methyltransferases. In recent years, the SET domain-containing N-lysine methyltransferase SMYD3 has emerged as a significant oncogenic driver. It is overexpressed in several tumor types and plays a signal-dependent role in promoting gastrointestinal cancer formation and development. Recent evidence indicates that SMYD3 is involved in the maintenance of cancer genome integrity and contributes to drug resistance in response to genotoxic stress by regulating DDR mechanisms. Several potential SMYD3 interactors implicated in DNA repair, especially in the homologous recombination and non-homologous end-joining pathways, have been identified by in silico analyses and confirmed by experimental validation, showing that SMYD3 promotes DDR protein interactions and enzymatic activity, thereby sustaining cancer cell survival. Targeting SMYD3, in combination with standard or targeted therapy, shows promise in overcoming drug resistance in colorectal, gastric, pancreatic, breast, endometrial, and lung cancer models, supporting the integration of SMYD3 inhibition into cancer treatment regimens. In this review, we describe the role played by SMYD3 in drug resistance and analyze its potential as a molecular target to sensitize cancer cells to treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

T cells play a major role in immune defense against viral infections and diseases such as cancer. Accordingly, developing nanoparticle (NP) systems to effectively deliver therapeutics to T cells is of interest. However, NP-mediated delivery of drugs to T cells is challenging because of the nonphagocytic nature of T cells. To engage T cells and induce cellular internalization, NPs are typically decorated with specific receptor-targeting antibodies, often using laborious and costly procedures. Herein, we report that natural glycogen NPs (i.e., nanosugars) with different sizes (20-80 nm) and surface charges (neutral and positively charged) engage Jurkat T cells, undergo intracellular trafficking, and release encapsulated drug without the use of receptor-targeting antibodies. Specifically, glycogen-resveratrol constructs are employed to reactivate HIV-1 latently infected Jurkat T cells (J-Lat A2) and trigger proviral expression. Both neutral and positively charged glycogen NPs engage with J-Lat A2 cells. Large (84 ± 29 nm) and positively charged (23 ± 5 mV) NPs, denoted phytoglycogen-ethylenediamine (PG EDA ) NPs, readily associate with the cell membrane and are internalized (60%) in J-Lat A2 cells but remain confined in the endocytic vesicles, with moderate reactivation of latent HIV-1 (4.7 ± 0.5%). Conversely, small (21 ± 5 nm) and positively charged (10 ± 6 mV) NPs, bovine glycogen-EDA (BG EDA ) NPs, associate slowly with T cells but show nearly 100% internalization and efficient endosomal escape properties, resulting in 1.5-fold higher reactivation of latent HIV-1 in T cells. PG EDA NPs and BG EDA NPs are also internalized by primary human T cells (>90% cell association) and enable the transfection of mRNA, with BG EDA NPs showing a 2-fold higher transfection than PG EDA NPs. This work highlights the potential of BG EDA NPs for the effective intracellular delivery of small-molecule drugs and mRNA in T cells.

Importance: The number of both US citizen and noncitizen international medical graduates (IMGs) practicing in the United States has grown substantially over the last two decades, but little is known about how these groups differ in clinical specialty and practice location., Objective: To evaluate the effects of citizenship status on IMG specialty choice (primary care vs nonprimary care) and practice location (rural and health professional shortage areas [HPSAs])., Design: To analyze the retrospective, cross sectional data between 2010 and 2019, we estimated a series of multivariate logistic regressions with year fixed effects after assessing trends in new physician specialty choice and practice location., Setting: Survey of Residents Completing Training in New York, the largest publicly available annual survey of graduating residents and fellows in the US., Participants: 15,133 new physicians who accepted a job offer in our study period, including 8,177 US medical graduates (USMGs), 2,753 US citizen IMGs, 1,057 permanent resident IMGs, and 3,146 noncitizen non-permanent resident (NCNP) IMGs., Exposure: IMG and Citizenship status., Main Outcomes: Whether a new physician chose to practice primary care; whether a new primary care physician chose to work in a rural area; whether a new primary care physician chose to work in a HPSA., Results: Compared to 2010, there were 20% fewer NCNP IMGs entering primary care in 2019. Our logistic analysis found that US citizen IMGs were five times, permanent resident IMGs seven times, and NCNP IMGs nine times more likely to enter primary care compared to USMGs. Among new primary care physicians, NCNP IMGs were more likely to work in a rural area compared to USMGs while US citizen IMGs and permanent resident IMGs acted similarly to USMGs. NCNP IMGs were five times more likely to work in a HPSA while US citizen IMGs and permanent resident IMGs were less likely, compared to USMGs., Conclusion: There was a declining proportion of NCNP IMGs entering primary care; citizenship status affected IMGs' specialty and practice location choices with NCNP IMGs more likely to choose primary care and work in rural areas and HPSAs., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Background/Objectives: Pain is a multidimensional experience influenced by sensory, emotional, and cognitive factors. Traditional pain assessments often fail to capture this complexity. This study aimed to develop and validate the Pain Multidimensional Questionnaire (Pa-M-QU), a new self-report tool designed to assess pain catastrophizing, sensitivity, and coping strategies. Methods: Two independent samples of Italian-speaking participants, aged 18 and above, were recruited online. The first sample ( n = 392; mean age = 29.36) was used for exploratory factor analysis (EFA), and the second sample ( n = 123; mean age = 28.0) for confirmatory factor analysis (CFA). Pearson's correlations and convergent validity analyses were conducted. Results: From an initial pool of 59 items identified through focus group discussions, 35 items were removed based on reliability analysis. The final 24-item Pa-M-QU features a three-factor structure: catastrophizing, pain sensitivity, and coping with pain. Conclusions: The Pa-M-QU offers a rapid, non-invasive assessment that captures the multidimensional nature of pain. It is a starting point to develop tools for both clinical and research settings, aiding in evaluating pain in healthy individuals and predicting acute and chronic pain disorders. Future research should focus on refining the Pa-M-QU for broader clinical applications and exploring its potential to complement or replace traditional pain assessments, thereby advancing pain management and research.

Polycystic ovary syndrome (PCOS) is one of the most widespread endocrinopathy affecting women of reproductive age with detrimental effects on life quality and health. Among several mechanisms involved in its aetiopathogenesis, recent studies have also postulated the involvement of the vaginal and intestinal microbiota in the development of this disorder. In this study, an accurate insight into the microbial changes associated with PCOS was performed through a pooled-analysis highlighting that this syndrome is characterized by intestinal and vaginal dysbiosis with a reduction of beneficial microorganisms and a higher proportion of potential pathogens. Based on this observation, we evaluated the ability of a milk-derived protein exerting positive outcomes in the management of PCOS, that is, α-lactalbumin (α-LA), to recover PCOS-related dysbiosis. In vitro experiments revealed that this protein improved the growth performances of members of two health-promoting bacterial genera, that is, Bifidobacterium and Lactobacillus, depleted in both intestinal and vaginal microbiota of PCOS-affected women. In addition, α-LA modulated the taxonomic composition and growth performances of the microbial players of the complex intestinal and vaginal microbiota. Finally, an in vivo pilot study further corroborated these observations. The oral administration of α-LA for 30 days to women with PCOS revealed that this protein may have a role in favouring the growth of health-promoting bacteria yet limiting the proliferation of potential pathogens. Overall, our results could pave the way to the use of α-LA as a valid compound with 'prebiotic effects' to limit/restore the PCOS-related intestinal and vaginal dysbiosis., (© 2024 The Author(s). Microbial Biotechnology published by John Wiley & Sons Ltd.)

Decision-making (DM) is a complex cognitive behavior that involves gathering information and assessing options to identify choices under risky and uncertain conditions. Mild Cognitive Impairment (MCI) is a construct that includes a constellation of symptoms ranging from behavioral to cognitive impairments. This cluster of symptoms is frequently associated with poor decision-making. This study aimed to examine decision-making in pathological aging, specifically MCI. Therefore, we conducted a systematic review and meta-analysis to evaluate these relationships. According to the PRISMA 2020 Statement, nine studies were selected for the systematic review and eight for the meta-analysis. The results highlighted that MCI is associated with impaired decision-making in risky and ambiguous situations. The systematic review reported that MCI was associated with impaired decision-making in ambiguous and in risky conditions. In contrast, the meta-analysis showed significant differences in overall decision-making and particularly in ambiguous conditions. This difficulty may be due to different impairments that affect MCI. The difficulty in advantageous decision-making could be due to different brain alterations in MCI, which could lead to problems in tasks requiring feedback-based responses. These findings advance our understanding of decision-making in aging and suggest how decision-making alterations in MCI would affect the totality of executive functions and daily activities., Competing Interests: Declaration of competing interest This manuscript has not been published and is not under consideration for publication elsewhere. The paper has been seen and approved by all authors. All the authors contributed to the development and draft of the manuscript. We have no conflict of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

The subject of polycystic ovary syndrome (PCOS) has been extensively covered in the literature; however, there is a paucity of data regarding eumenorrheic women with hyperandrogenism and/or hyperandrogenemia without ultrasound evidence of PCO morphology (EuHyperA), and even less data on the comparison between PCOS and EuHyperA subjects. It has previously been shown that around half of PCOS women exhibit a hyper-response of serum 17-hydroxy-progesterone (17-OHP) to the stimulation by GnRH-agonists, also indicated as functional ovarian hyperandrogenism (FOH). Often, this stimulation test is preceded by suppression of the adrenal steroidogenesis with oral dexamethasone (Dex). FOH has been associated with an increase of the P450c17 activity in the ovaries driven by elevated insulin levels. Interestingly, treatment of women with PCOS with Dex suppression and GnRH-agonist stimulation (buserelin) highlighted the possible existence of two clusters of patients: hyper-responders (HR) and normal responders (NR). In this retrospective study, we included 15 hyper-responders (HR) EuHyperA, 34 normal responders (NR) EuHyperA, 62 HR-PCOS and 45 NR-PCOS. The demographic characteristics, glucose-metabolism indices, and the hormonal response to Dex or buserelin were analyzed, with both intra-group and inter-group comparisons performed. The rate of FOH was significantly greater in PCOS than EuHyperA women. Compared to HR-PCOS, HR-EuHyperA had [i.] significantly greater age at observation; [ii.] lower cortisol, 17-OHP, Δ4-androstenedione (Δ4-ASD), total testosterone (TT), LH, and buserelin-stimulated whole curve of dehydroepiandrosterone sulfate (DHEAS), 17-OHP, Δ4-ASD and TT. Compared to NR-PCOS, NR-EuHyperA had [i.] significantly greater FSH, and buserelin-stimulated whole curve of DHEAS; [ii.] significantly lower post-HD Dex Δ4-ASD, TT, buserelin-stimulated whole curve of 17-OHP, Δ4-ASD and TT. Compared to NR-PCOS, HR-PCOS had [i.] significantly greater body mass index (BMI), homeostasis model assessment for insulin resistance (HOMA-IR), cortisol, DHEAS, Δ4-ASD, TT, FT, FAI, E2, and insulin AUC 0-120min (area under the curve) at oral glucose tolerance test (OGTT); [ii] higher levels of post-LD and post-HD Dex 17-OHP, Δ4-ASD, TT, post-HD Dex DHEAS (with greater levels indicating weaker adrenal suppression), whole curve of DHEAS, 17-OHP, Δ4-ASD, TT and LH; [iii] significantly lower sex-hormone binding globulin (SHBG). Even if most of the parameters evaluated were statistically similar in the two sets of comparisons, interesting differences were observed. Women with PCOS exhibit higher androgen levels at baseline, after adrenal suppression and at the buserelin test, further to a higher ovarian volume. Of note, the percentage of women with HOMA-IR≥2.5 and serum insulin levels were greater in PCOS group compared to EuHyperA women. Moreover, within women with PCOS, the HR subgroup has higher insulin levels compared to the NR subgroup, when OGTT is performed. The alteration of the glucose-insulin balance and elevation of circulating androgens were more pronounced in PCOS, thus indicating that [i.] metabolic alterations might be crucial in the onset of PCOS itself and, [ii] EuHyperA might represent a milder form of PCOS., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Vittorio Unfer reports a relationship with Lo.Li. pharma that includes: employment. M.R., G.F and V.U. are employees of Lo.Li Pharma s.r.l. All other authors have no conflicts of interest to declare. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.]., (© 2024 The Author(s).)

Background: The minor G-allele of FOXO3 rs2802292 is associated with human longevity. The aim of this study was to test the protective effect of the variant against the association with type 2 Diabetes and NAFLD. Methods: rs2802292 was genotyped in a large population of middle-aged subjects (n = 650) from a small city in Southern Italy. All participants were interviewed to collect information about lifestyle and dietary habits; clinical characteristics were recorded, and blood samples were collected from all subjects. The association between rs2802292 and NAFLD or diabetes was tested using a logistic model and mediation analysis adjusted for covariates. Results: Overall, the results indicated a statistical association between diabetes and rs2802292, especially for the TT genotype (OR = 2.14, 1.01 to 4.53 95% C.I., p = 0.05) or in any case for those who possess the G-allele (OR = 0.45, 0.25 to 0.81 95% C.I., p = 0.008). Furthermore, we found a mediation effect of rs2802292 on diabetes (as mediator) and NAFLD. There is no direct relationship between rs2802292 and NAFLD, but the effect is direct (β = 0.10, -0.003 to 0.12 95% C.I., p = 0.04) on diabetes, but only in TT genotypes. Conclusions: The data on our cohort indicate that the longevity-associated FOXO3 variant may have protective effects against diabetes and NAFLD.