Psychic Life-Biological Molecule Bidirectional Relationship: Pathways, Mechanisms, and Consequences for Medical and Psychological Sciences-A Narrative Review.

Today, it is possible to investigate the biological paths and mechanisms that link mental life to biological life. Emotions, feelings, desires, and cognitions influence biological systems. In recent decades, psychoneuroendocrinoimmunology research has highlighted the routes linking the psyche-brain-immune systems. Recently, epigenetics research has shown the molecular mechanisms by which stress and mental states modulate the information contained in the genome. This research shapes a new paradigm considering the human being as a whole, integrating biology and psychology. This will allow us to progress towards personalized precision medicine, deeply changing medical and psychological sciences and clinical practice. In this paper, we recognize leading research on both bidirectional relations between the psyche-brain-immunity and molecular consequences of psychological and mental states.

Effect of Ergodic and Non-Ergodic Fluctuations on a Charge Diffusing in a Stochastic Magnetic Field.

In this paper, we study the basic problem of a charged particle in a stochastic magnetic field. We consider dichotomous fluctuations of the magnetic field where the sojourn time in one of the two states are distributed according to a given waiting-time distribution either with Poisson or non-Poisson statistics, including as well the case of distributions with diverging mean time between changes of the field, corresponding to an ergodicity breaking condition. We provide analytical and numerical results for all cases evaluating the average and the second moment of the position and velocity of the particle. We show that the field fluctuations induce diffusion of the charge with either normal or anomalous properties, depending on the statistics of the fluctuations, with distinct regimes from those observed, e.g., in standard Continuous-Time Random Walk models.

Tau oligomers accumulation sensitizes prostate cancer cells to docetaxel treatment.

PURPOSE: Human tau is a highly dynamic, multifunctional protein expressed in different isoforms and conformers, known to modulate microtubule turnover. Tau oligomers are considered pathologic forms of the protein able to initiate specific protein accumulation diseases, called tauopathies. In our study, we investigated the potential association between autophagy and tau oligomers accumulation and its role in the response of prostate cancer cells to docetaxel. METHODS: We evaluated in vitro the expression of tau oligomers in prostate cancer cell lines, PC3 and DU145, in presence of autophagy inhibitors and investigated the role of tau oligomers accumulation in resistance to docetaxel treatment. RESULTS: Tau protein was basally expressed in prostate cancer lines as several monomeric and oligomeric forms. The pharmacologic inhibition of autophagy induced in cancer cells the accumulation of tau protein, with a prevalent expression of oligomeric forms. Immunofluorescence analysis of untreated cells revealed that tau was visible mainly in dividing cells where it was localized on the mitotic spindle. Inhibition of autophagy determined an evident upregulation of tau signal in dividing cells and the presence of aberrant monoastral mitotic spindles. The accumulation of tau oligomers was associated with DNA DSB and increased cytotoxic effect by docetaxel. CONCLUSIONS: Our data indicate that autophagy could exert a promoting role in cancer growth and during chemotherapy facilitating degradation of tau protein and thus blocking the antimitotic effect of accumulated tau oligomers. Thus, therapeutic strategies aimed at stimulating tau oligomers formation, such as autophagy inhibition, could be an effective adjuvant in cancer therapy.

Caputo Fractional Derivative and Quantum-Like Coherence.

We study two forms of anomalous diffusion, one equivalent to replacing the ordinary time derivative of the standard diffusion equation with the Caputo fractional derivative, and the other equivalent to replacing the time independent diffusion coefficient of the standard diffusion equation with a monotonic time dependence. We discuss the joint use of these prescriptions, with a phenomenological method and a theoretical projection method, leading to two apparently different diffusion equations. We prove that the two diffusion equations are equivalent and design a time series that corresponds to the anomalous diffusion equation proposed. We discuss these results in the framework of the growing interest in fractional derivatives and the emergence of cognition in nature. We conclude that the Caputo fractional derivative is a signature of the connection between cognition and self-organization, a form of cognition emergence different from the other source of anomalous diffusion, which is closely related to quantum coherence. We propose a criterion to detect the action of self-organization even in the presence of significant quantum coherence. We argue that statistical analysis of data using diffusion entropy should help the analysis of physiological processes hosting both forms of deviation from ordinary scaling.

Effect of decreasing population growth-rate on deforestation and population sustainability.

We consider the effect of non-constant parameters on the human-forest interaction logistic model coupled with human technological growth introduced in [1]. In recent years in fact, a decrease in human population growth rate has emerged which can be measured to about 1.7% drop per year since 1960 value, which coincides with latest UN projections for next decades up to year 2100 [2]. We therefore consider here the effect of decreasing human population growth-rate on the aforementioned model and we evaluate its effect on the probability of survival of human civilization without going through a catastrophic population collapse. We find that for realistic values of the human population carrying capacity of the earth (measured by the parameter ß) this decrease would not affect previous results, leading to a low probability of avoiding a catastrophic collapse. For larger more optimistic values of ß instead, a decrease in growth-rate would tilt the probability in favor of a positive outcome, i.e. from 10-20% up to even 95% likelihood of avoiding collapse.

Deforestation and world population sustainability: a quantitative analysis.

In this paper we afford a quantitative analysis of the sustainability of current world population growth in relation to the parallel deforestation process adopting a statistical point of view. We consider a simplified model based on a stochastic growth process driven by a continuous time random walk, which depicts the technological evolution of human kind, in conjunction with a deterministic generalised logistic model for humans-forest interaction and we evaluate the probability of avoiding the self-destruction of our civilisation. Based on the current resource consumption rates and best estimate of technological rate growth our study shows that we have very low probability, less than 10% in most optimistic estimate, to survive without facing a catastrophic collapse.

Psychoneuroendocrinoimmunology-based meditation (PNEIMED) training reduces salivary cortisol under basal and stressful conditions in healthy university students: Results of a randomized controlled study.

BACKGROUND: Meditation represents an effective and safe practice to lower distress and promote well-being. PsychoNeuroEndocrinoImmunology-based Meditation (PNEIMED) is a validated method that can reduce stress-related symptoms and salivary cortisol secretion. To date, few randomised controlled trials (RCTs) have assessed cortisol levels through salivary samples, collected both in the morning phase and during acute mental stress elicitation, in healthy young subjects following brief meditation training. AIM: The present study aims to investigate, in healthy young undergraduate students, the effects of a brief PNEIMED training course on HPA axis by measuring salivary cortisol levels. METHODS: Forty students attending the Faculty of Psychology, without comorbidities and previous experience of meditation, were enrolled in the study. Twenty subjects were randomly assigned to 30 h of PNEIMED training (intervention group, IG), and twenty subjects were randomly assigned to 30 h of academic lessons (control group, CG). Salivary cortisol measures included basal morning (t0 = baseline time, collected 30 min after waking) and under stress-eliciting task values. Cortisol measurement under the stress-eliciting task was provided through the Subtraction Stress Task (SST) at scheduled time intervals (t1 = 5 min pre-SST, t2 = 10 min post-SST, t3 = 30 min = post-SST). Salivary cortisol was measured among all subjects (IG + CG) at the beginning (pre-test) and at the end (post-test, four days later) of the study. RESULTS: ANOVA between-group analysis of basal diurnal salivary cortisol showed a significant hormone deflection in the IG at the end of the PNEIMED course (post-test) when compared to the CG (IG post-test 5.64 ± 4.2 vs CG post-test 9.44 ± 4.9; F1,38 = 6.838; p = 0.013). RM-ANOVA within-group analysis for the IG also showed that time and condition effects were statistically significant, with Ftime = 5.438; p = 0.002 and Fcondition = 10.478; p = 0.004, respectively. The IG group presented a significant reduction in basal morning cortisol at the end of the PNEIMED course (post-test) compared to the salivary concentration at baseline (pre-test) (IG pre-test 9.42 ± 6.0 vs IG post-test 5.64 ± 4.2; F1,38 8,354; p = 0.009). RM-ANOVA for the control group showed only the main effect of time (F1,38 = 40.348; p < 0.001). Regarding cortisol measures under the SST-stress eliciting task, ANOVA between-groups analysis showed higher cortisol levels in the IG than in the CG before the PNEIMED course, with significant differences between groups at time t2 and time t3. After the PNEIMED course, the cortisol levels in the IG had decreased, although the differences between groups were not significant. Interestingly, ANOVA within-groups analysis showed that in the IG, the cortisol levels post-test (after the PNEIMED course) were lower than at pre-test (before the PNEIMED course), showing a significant difference of cortisol salivary concentration between conditions at t3 (F = 5.326; p = 0.032). In the control group, the post-hoc analyses for pairwise comparisons between conditions (pre-test vs post-test) did not show significant differences. CONCLUSION: Although the low number of subjects enrolled in the study does not allow for definitive conclusions to be drawn, the present findings confirmed the capability of the PNEIMED method to lower stress hormone secretion both at baseline and under acute mental stimulation in a group of young naïve practitioners and make a contribution to the existing literature by increasing the number of published RCTs about the topic.

Body mass index represents a good predictor of vitamin D status in women independently from age.

BACKGROUND & AIMS: Vitamin D is a pleiotropic hormone targeting several tissues and is involved in basic homeostatic processes, including bone mineralization, immune response and muscle strength. Although hypovitaminosis D is common in Europe and North America, representing a risk factor for several chronic diseases, the contribution of factors other than sun exposure is largely underestimated. METHODS: In our study, we retrospectively collected data from medical records of women with age between 19 and 80 screened in Central Italy (42°N) for increased risk of metabolic syndrome. Vitamin D status was evaluated by serum 25-hydroxyvitamin D (25(OH)D) measurement and the association among vitamin D status and anthropometric and clinic variables was tested by multivariate logistic analysis. RESULTS: More than 80% of women presented serum 25(OH)D concentration lower than 30 ng/mL (75 nM), with the majority of values falling between 10 and 20 ng/mL. 25(OH)D concentration was dependent on season, with the highest 25(OH)D mean value measured in September and the lowest mean value in March. Among different clinical characteristics, body mass index (BMI) demonstrated the highest significant inverse correlation with serum 25(OH)D values, independently from season and age. Serum 25(OH)D values demonstrated a seasonal-directed sinusoidal trend and they raised during spring/summer in a similar manner in both obese and non-obese women. However, the obese group had lower mean values of vitamin D respect to overweight and to normal weight groups in both winter and summer, reaching frequently the status of vitamin D deficiency (<10 ng/mL). CONCLUSIONS: In conclusion, at our latitude, seasonal UV irradiance availability determines an obligate sinusoidal trend in vitamin D status. However, body mass is able to reduce proportionally circulating vitamin D over calendar months determining vitamin D deficiency. These results suggest taking in particular account BMI in clinical management of vitamin D status in overweight and obese women.

Non-Poisson renewal events and memory.

We study two different forms of fluctuation-dissipation processes generating anomalous relaxations to equilibrium of an initial out-of-equilibrium condition, the former being based on a stationary although very slow correlation function and the latter characterized by the occurrence of crucial events, namely, non-Poisson renewal events, incompatible with the stationary condition. Both forms of regression to equilibrium have the same nonexponential Mittag-Leffler structure. We analyze the single trajectories of the two processes by recording the time distances between two consecutive origin recrossings and establishing the corresponding waiting time probability density function (PDF), ψ(t). In the former case, with no crucial events, ψ(t) is an exponential, and in the latter case, with crucial events, ψ(t) is an inverse power law PDF with a diverging first moment. We discuss the consequences that this result is expected to have for the correct interpretation of some anomalous relaxation processes.

Ergodicity breaking and localization.

We study the joint action of the non-Poisson renewal events (NPR) yielding Continuous-time random walk (CTRW) with index α<1 and two different generators of Hurst coefficient H≠0.5, one generating fractional Brownian motion (FBM) and another scaled Brownian motion (SBM). We discuss the ergodicity breaking emerging from these joint actions and we find that in both cases the adoption of time averages leads to localization. In the case of the joint action of NPR and SBM, localization occurs when SBM would produce subdiffusion. The joint action of NPR and FBM, on the contrary, may lead to localization when FBM is a source of superdiffusion. The joint action of NPR and FBM is equivalent to extending the CTRW to the case where the jumps of the runner are correlated and we argue that the the memory-induced localization requires a refinement of the theoretical perspective about determinism and randomness.

Nonergodic complexity management.

Linear response theory, the backbone of nonequilibrium statistical physics, has recently been extended to explain how and why nonergodic renewal processes are insensitive to simple perturbations, such as in habituation. It was established that a permanent correlation results between an external stimulus and the response of a complex system generating nonergodic renewal processes, when the stimulus is a similar nonergodic process. This is the principle of complexity management, whose proof relies on ensemble distribution functions. Herein we extend the proof to the nonergodic case using time averages and a single time series, hence making it usable in real life situations where ensemble averages cannot be performed because of the very nature of the complex systems being studied.

Serum 25(OH)D seasonality in urologic patients from central Italy.

Hypovitaminosis D is increasingly recognized as a cofactor in several diseases. In addition to bone homeostasis, vitamin D status influences immune system, muscle activity and cell differentiation in different tissues. Vitamin D is produced in the skin upon exposure to UVB rays, and sufficient levels of serum 25(OH)D are dependent mostly on adequate sun exposure, and then on specific physiologic variables, including skin type, age and Body Mass Index (BMI). In contrast with common belief, epidemiologic data are demonstrating that hypovitaminosis D must be a clinical concern not only in northern Countries. In our study, we investigated vitamin D status in a male population enrolled in a urology clinic of central Italy. In addition, we evaluated the correlation between vitamin D status and UVB irradiance measured in our region. The two principal pathologies in the 95 enrolled patients (mean age 66years) were benign prostate hypertrophy and prostate carcinoma. >50% of patients had serum 25(OH)D values in the deficient range (<20ng/mL), and only 16% of cases had serum vitamin D concentration higher than 30ng/mL (optimal range). The seasonal stratification of vitamin D concentrations revealed an evident trend with the minimum mean value recorded in April and a maximum mean value obtained in September. UVB irradiance measured by pyranometer in our region (Abruzzo, central Italy) revealed a large difference during the year, with winter months characterized by an UV irradiance about tenfold lower than summer months. Then we applied a mathematical model in order to evaluate the expected vitamin D production according to the standard erythemal dose measured in the different seasons. In winter months, the low available UVB radiation and the small exposed skin area resulted not sufficient to obtain the recommended serum doses of vitamin D. Although in summer months UVB irradiance was largely in excess to produce vitamin D in the skin, serum vitamin D resulted sufficient in September only in those patients who declared an outdoor time of at least 3h per day in the previous summer. In conclusion, hypovitaminosis D is largely represented in elderly persons in our region. Seasonal fluctuation in serum 25(OH)D was explained by a reduced availability of UVB in winter and by insufficient solar exposure in summer. The relatively high outdoor time that emerged to be correlated with sufficient serum 25(OH)D in autumn warrants further studies to individuate potential risk co-variables for hypovitaminosis D in elderly men.

Leptin contributes to long-term stabilization of HIF-1α in cancer cells subjected to oxygen limiting conditions.

Leptin, a cytokine produced by the adipose tissue in response to food intake, is a key player in the regulation of energy balance and body weight control. Physiological action of leptin in modulating the metabolic adaptation of different peripheral tissues supports the hypothesis that it could also exert a direct effect on cancer cells. In vitro, treatment with leptin up-regulated HIF-1α and stimulated adhesion and invasion of prostate cancer cells cultured in hypoxia. Leptin action was effective in both low and high glycolytic cancer cell lines, and determined the up-regulation of lactate exporter MCT4 and its associated protein CD147. HIF-1α stabilization was oligomycin-independent and was associated with an important modulation of mitochondrial homeostasis. In fact, leptin treatment produced mitochondrial biogenesis, stabilization of mitochondrial membrane potential and increased uncoupled respiration through the up-regulation of UCP2. Furthermore, leptin counteracted the downmodulation of SIRT1 induced by hypoxia, and persistent high levels of SIRT1 were directly involved in HIF-1α stabilization. Leptin can sustain cancer progression in hypoxic environment and when mitochondrial respiration is impaired. Leptin signaling axis, including the new proposed intermediate SIRT1, could represent a new diagnostic and therapeutic target in prostate cancer.

A non-linear mathematical model for a three species ecosystem: Hippos in Lake Edward.

In this work we study a non-linear mathematical model based on three different interacting species. We apply our model to Lake Edward ecosystem consisting in hippos, tilapia fishes and human inhabitants. In this case, we estimate the values of the key parameters using actual data and show the reliability of the proposed model as a predictive tool. We also show, via numerical calculations and parameter values that the ecosystem associated to the lake is very far from reaching a stable equilibrium. Through our analysis we provide the conditions for a possible coexistence among the three species.

Tumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression.

BACKGROUND: Cancer cell adopts peculiar metabolic strategies aimed to sustain the continuous proliferation in an environment characterized by relevant fluctuations in oxygen and nutrient levels. Monocarboxylate transporters MCT1 and MCT4 can drive such adaptation permitting the transport across plasma membrane of different monocarboxylic acids involved in energy metabolism. METHODS: Role of MCTs in tumor-stroma metabolic relationship was investigated in vitro and in vivo using transformed prostate epithelial cells, carcinoma cell lines and normal fibroblasts. Moreover prostate tissues from carcinoma and benign hypertrophy cases were analyzed for individuating clinical-pathological implications of MCT1 and MCT4 expression. RESULTS: Transformed prostate epithelial (TPE) and prostate cancer (PCa) cells express both MCT1 and MCT4 and demonstrated variable dependence on aerobic glycolysis for maintaining their proliferative rate. In glucose-restriction the presence of L-lactate determined, after 24 h of treatment, in PCa cells the up-regulation of MCT1 and of cytochrome c oxidase subunit I (COX1), and reduced the activation of AMP-activated protein kinase respect to untreated cells. The blockade of MCT1 function, performed by si RNA silencing, determined an appreciable antiproliferative effect when L-lactate was utilized as energetic fuel. Accordingly L-lactate released by high glycolytic human diploid fibroblasts WI-38 sustained survival and growth of TPE and PCa cells in low glucose culture medium. In parallel, the treatment with conditioned medium from PCa cells was sufficient to induce glycolytic metabolism in WI-38 cells, with upregulation of HIF-1a and MCT4. Co-injection of PCa cells with high glycolytic WI-38 fibroblasts determined an impressive increase in tumor growth rate in a xenograft model that was abrogated by MCT1 silencing in PCa cells. The possible interplay based on L-lactate shuttle between tumor and stroma was confirmed also in human PCa tissue where we observed a positive correlation between stromal MCT4 and tumor MCT1 expression. CONCLUSIONS: Our data demonstrated that PCa progression may benefit of MCT1 expression in tumor cells and of MCT4 in tumor-associated stromal cells. Therefore, MCTs may result promising therapeutic targets in different phases of neoplastic transformation according to a strategy aimed to contrast the energy metabolic adaptation of PCa cells to stressful environments.

Renewal and memory origin of anomalous diffusion: a discussion of their joint action.

The adoption of the formalism of fractional calculus is an elegant way to simulate either subdiffusion or superdiffusion from within a renewal perspective where the occurrence of an event at a given time t does not have any memory of the events occurring at earlier times. We illustrate a physical model to assign infinite memory to renewal anomalous diffusion and we find (i) a condition where the simultaneous action of a renewal and a memory source of subdiffusion generates localization and (ii) a condition where they make subdiffusion weaker and superdiffusion emerge. We argue that our approach may provide important contributions to the current search to distinguish the renewal from the memory source of subdiffusion.

Linear response at criticality.

We study a set of cooperatively interacting units at criticality, and we prove with analytical and numerical arguments that they generate the same renewal non-Poisson intermittency as that produced by blinking quantum dots, thereby giving a stronger support to the results of earlier investigation. By analyzing how this out-of-equilibrium system responds to harmonic perturbations, we find that the response can be described only using a new form of linear response theory that accounts for aging and the nonergodic behavior of the underlying process. We connect the undamped response of the system at criticality to the decaying response predicted by the recently established nonergodic fluctuation-dissipation theorem for dichotomous processes using information about the second moment of the fluctuations. We demonstrate that over a wide range of perturbation frequencies the response of the cooperative system is greatest when at criticality.

Increased expression of a set of genes enriched in oxygen binding function discloses a predisposition of breast cancer bone metastases to generate metastasis spread in multiple organs.

Bone is the preferential site of distant metastasis in breast carcinoma (BrCa). Patients with metastasis restricted to bone (BO) usually show a longer overall survival compared to patients who rapidly develop multiple metastases also involving liver and lung. Hence, molecular predisposition to generate bone and visceral metastases (BV) represents a clear indication of poor clinical outcome. We performed microarray analysis with two different chip platforms, Affymetrix and Agilent, on bone metastasis samples from BO and BV patients. The unsupervised hierarchical clustering of the resulting transcriptomes correlated with the clinical progression, segregating the BO from the BV profiles. Matching the twofold significantly regulated genes from Affymetrix and Agilent chips resulted in a 15-gene signature with 13 upregulated and two downregulated genes in BV versus BO bone metastasis samples. In order to validate the resulting signature, we isolated different MDA-MB-231 clonal subpopulations that metastasize only in the bone (MDA-BO) or in bone and visceral tissues (MDA-BV). Six of the signature genes were also significantly upregulated in MDA-BV compared to MDA-BO clones. A group of upregulated genes, including Hemoglobin B (HBB), were involved in oxygen metabolism, and in vitro functional analysis of HBB revealed that its expression in the MDA subpopulations was associated with a reduced production of hydrogen peroxide. Expression of HBB was detected in primary BrCa tissue but not in normal breast epithelial cells. Metastatic lymph nodes were frequently more positive for HBB compared to the corresponding primary tumors, whereas BO metastases had a lower expression than BV metastases, suggesting a positive correlation between HBB and ability of bone metastasis to rapidly spread to other organs. We propose that HBB, along with other genes involved in oxygen metabolism, confers a more aggressive metastatic phenotype in BrCa cells disseminated to bone.

A mathematical model for the Andean Tiwanaku civilization collapse: climate variations.

We propose a mathematical nonlinear model for the Tiwanaku civilization collapse based on the assumption, supported by archeological data, that a drought caused a lack of the main resource, water. We evaluate the parameter of our model using archaeological data. According to our numerical simulation the population core should have decreased from 45,000 to 2000 inhabitants due to lake surface contraction.

Identification of potent c-Src inhibitors strongly affecting the proliferation of human neuroblastoma cells.

Neuroblastoma (NB) represents the most common extracranial paediatric solid tumor for which no specific FDA-approved treatment is currently available. The tyrosine kinase c-Src has been reported to play an important role in the differentiation, cell-adhesion and survival of NB cells. Starting from dual Src/Abl inhibitors previously found active in NB cell lines (1-3), small modification of the original structures almost abolished the Abl activity with a contemporary improvement of affinity and specificity for c-Src. Among the synthesized compounds, the most potent c-Src inhibitor (10a) showed a very interesting antiproliferative activity in SH-SY5Y cells with an IC(50) of 80 nM and a favourable ADME profile. A 3D SAR analysis was also attempted and may guide the design of more potent c-Src inhibitors as potential agents for NB treatment.