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Octopamine is a well-established invertebrate neurotransmitter involved in fight or flight responses. In mammals, its function was replaced by epinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of α-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Physiological levels of neuron-derived octopamine act on astrocytes via a trace amine-associated receptor 1–Orai1–Ca 2+ –calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the monocarboxylase transporter 2–calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by α-synuclein halt lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a unique function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to α-synucleinopathies.

Octopamine is a well-established invertebrate neurotransmitter involved in fight-or-flight responses. In mammals, its function was replaced by norepinephrine. Nevertheless, it is present at trace amounts and can modulate the release of monoamine neurotransmitters by a yet unidentified mechanism. Here, through a multidisciplinary approach utilizing in vitro and in vivo models of α-synucleinopathy, we uncovered an unprecedented role for octopamine in driving the conversion from toxic to neuroprotective astrocytes in the cerebral cortex by fostering aerobic glycolysis. Physiological levels of neuron-derived octopamine act on astrocytes via a TAAR1-Orai1-Ca2+-calcineurin-mediated signaling pathway to stimulate lactate secretion. Lactate uptake in neurons via the MCT2-calcineurin-dependent pathway increases ATP and prevents neurodegeneration. Pathological increases of octopamine caused by α-synuclein halts lactate production in astrocytes and short-circuits the metabolic communication to neurons. Our work provides a novel function of octopamine as a modulator of astrocyte metabolism and subsequent neuroprotection with implications to α-synucleinopathies.

Introduction: In our previous studies it was concluded that the zinc (Zn) level in in human expressed prostatic fluid (EPF) is a first candidate with the role of offering a new, simple, fast, reliable, and non-invasive diagnostic tool for prostate cancer (PCa) screening. However it was unclear how other non-prostatic diseases inherent of the old persons, including heart diseases, atherosclerosis, diabetes, asymptomatic cancer of different localization and some others, impact on a chemical element composition of expressed prostatic fluid. Thus, the purpose of this study was to evaluate whether significant changes in the levels of Zn in EPF exist in patients with bladder cancer (BC). Methods: Prostatic fluid levels of Zn were prospectively evaluated in 17 patients with BC and 51 healthy male inhabitants (control group). Measurements were performed using 109Cd radionuclide-induced energy dispersive X-ray fluorescent microanalysis developed by us. Results: Mean value  standard deviation of mean (MSD) for concentration of Zn in the EPF of healthy males and patients with BC was 573202 mg/L and 625±108 mg/L, respectively. Using both parametric Student’s t-test and non-parametric Wilcoxon-Mann-Whitney U-test it was shown that the Zn concentration in the EPF of patients with BC did not differ from that in healthy subjects. Conclusion: Such serious illness as BC did not impact on the Zn concentration in the EPF., {"references":["aitt HE. Global trends and prostate cancer: A review of incidence, detection, and mortality as influenced by race, ethnicity, and geographic location. Am J Mens Health. 2018;12(6):1807-23 doi: 10.1177/1557988318798279.","Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1) 7-30. doi: 10.3322/caac.21387.","Qi D, Wu C, Liu F, Gu K, Shi Z, Liu X, et al. Trends of prostate cancer incidence and mortality in Shanghai, China from 1973 to 2009. 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The effect of age on Br, Fe, Rb, Sr, and Zn concentrations as well as on Zn/Br, Zn/Fe, Zn/Rb, and Zn/Sr content ratios in human prostatic fluid was investigated by 109Cd radionuclide-induced energy dispersive X-ray fluorescent microanalysis. Specimens of expressed prostatic fluid were obtained from 51 men (mean age 51 years, range 18-82 years) with apparently normal prostates using standard rectal massage procedure. Mean values (M ± SΕΜ) for concentration of trace elements (mg·L-1) in human prostate fluid were: Br 3.62±0.58, Fe 9.04±1.21, Rb 1.10±0.08, Sr 1.19±0.14, and Zn 573±28. Mean values for ratios of trace elements in human prostate fluid were: Zn/Br 523±103, Zn/Fe 105±16, Zn/Rb 661±63, and Zn/Sr 719±95. An age-related increase in Zn content and decrease in Br and Fe concentration was found. Moreover, the strongly pronounced increase in Zn/Br and Zn/Fe ratios was also observed.

Significance Ykt6 is a conserved SNARE that plays critical roles along multiple vesicular pathways. To achieve its function, Ykt6 cycles between the cytosol and membrane-bound compartments through reversible lipidation. The mechanism that regulates these transitions is unknown. Ykt6 function is disrupted by α-synuclein, a protein critically implicated in synucleinopathies such as Parkinson’s Disease. Through a multidisciplinary approach, we report that phosphorylation regulated by Ca2+ signaling drives a conformational change that allows Ykt6 to switch from a closed cytosolic to an open membrane-bound form. Phosphorylation is also a critical determinant for Ykt6 protein interactions with functional consequences in the secretory and autophagy pathways under normal and α-synuclein conditions. This work provides a mechanistic insight into Ykt6 regulation with therapeutic implications for synucleinopathies., Ykt6 is a soluble N-ethylmaleimide sensitive factor activating protein receptor (SNARE) critically involved in diverse vesicular fusion pathways. While most SNAREs rely on transmembrane domains for their activity, Ykt6 dynamically cycles between the cytosol and membrane-bound compartments where it is active. The mechanism that regulates these transitions and allows Ykt6 to achieve specificity toward vesicular pathways is unknown. Using a Parkinson’s disease (PD) model, we found that Ykt6 is phosphorylated at an evolutionarily conserved site which is regulated by Ca2+ signaling. Through a multidisciplinary approach, we show that phosphorylation triggers a conformational change that allows Ykt6 to switch from a closed cytosolic to an open membrane-bound form. In the phosphorylated open form, the spectrum of protein interactions changes, leading to defects in both the secretory and autophagy pathways, enhancing toxicity in PD models. Our studies reveal a mechanism by which Ykt6 conformation and activity are regulated with potential implications for PD.

Membrane fusion, an essential process in all eukaryotes, is driven by SNARE proteins. Ykt6 is an essential SNARE that plays critical roles throughout the secretory, endocytic, and autophagy pathways. Ykt6 activity is thought to be regulated by a conformational change from a closed cytosolic form to an open membrane-bound form, yet the mechanism that regulates this transition is unknown. Through genetic, pharmacologic, and structural modeling approaches in mammalian cells, we found that phosphorylation regulates Ykt6 conversion from a closed to an open state. The phosphorylation site we identified is highly conserved in evolution and is regulated by the Ca2+-dependent phosphatase, calcineurin. We found that phosphorylation is a key determinant for intracellular localization of Ykt6 and its function in macroautophagy. Our studies reveal a novel mechanism by which Ykt6 conformation and activity is regulated by Ca2+ signaling with implications in Parkinson’s Disease in which Ykt6 has been shown to play a role.

Across all kingdoms in the tree of life, calcium (Ca2+) is an essential element used by cells to respond and adapt to constantly changing environments. In multicellular organisms, it plays fundamental roles during fertilization, development and adulthood. The inability of cells to regulate Ca2+ can lead to pathological conditions that ultimately culminate in cell death. One such pathological condition is manifested in Parkinson's disease, the second most common neurological disorder in humans, which is characterized by the aggregation of the protein, α-synuclein. This Review discusses current evidence that implicates Ca2+ in the pathogenesis of Parkinson's disease. Understanding the mechanisms by which Ca2+ signaling contributes to the progression of this disease will be crucial for the development of effective therapies to combat this devastating neurological condition.

Background and objective: the prostate gland is subject to various disorders and of them chronic prostatitis (CP) is a complex disease. Various studies indicate some discrepancies regarding zinc (Zn) levels in prostatic fluid of normal and inflamed glands. The present study evaluated by systematic analysis the published data for Zn levels analyzed in expressed prostatic fluid (EPF) of normal and inflamed glands. Methods: The present systematic analysis included 25 studies, all of which were published in the years from 1961 to 2018 and selected by searching the databases Scopus, PubMed, MEDLINE, ELSEVIER-EMBASE, Cochrane Library, and the Web of Science. The articles were analyzed and “Median of Means” and “Range of Means” were used to examine heterogeneity of Zn concentrations in two groups of subjects – apparently healthy men “N” and patients with prostatitis “P”. Moreover, using the ratios of prostatic fluid Zn in “P” group to prostatic fluid Zn in “N” group (ZnP/ZnN) obtained (or calculated by us) in the reviewed studies, “Median of Means” and “Range of Means” for these ratios were found. The objective analysis was performed on data from the 25 studies, with total 285 subjects in “P” group and more than 900 subjects in “N” group. Results: The range of means of Zn concentration reported in the literature for normal EPF varies widely from 47.1 mg/L to 825 mg/L with median of means 501 mg/L. The range of means of Zn concentration for EPF of untreated prostatitis varies also widely from 56 mg/L to 491 mg/L, with median of means 268 mg/L. Thus, the obtained median of means for Zn concentration in normal human prostatic fluid is about two times higher than median of mean values of the element content in EPF of inflamed prostate. In other words, the analysis of 25 studies with discordant data regarding prostatic fluid concentration of Zn demonstrated that there is a significantly diminished concentration of Zn in EPF of patients with prostatitis compared to controls. Conclusion: There is a significant relationship between lowered Zn concentrations in prostatic fluid and prostatitis, but because of small sample size and high data heterogeneity, we recommend other primary studies.

A prevalence of thyroid dysfunction is higher in the elderly as compared to the younger population. An excess or deficiency of trace element contents in thyroid play important role in goitro-and carcinogenesis of gland. The variation with age of the mass fraction of six trace elements (Br, Cu, Fe, Rb, Sr, and Zn) in intact (normal) thyroid of 33 females (mean age 54.5 years, range 3.5-87) was investigated by109 Cd radionuclide-induced energy dispersive X-ray fluorescent analysis.

Objectives: The aim of this study was to evaluate the changes in the prostatic levels of trace elements in the malignant human prostate. Methods: Contents of 43 trace elements in normal (N, n = 37), benign hypertrophic (BPH, n = 32) and cancerous (PCa, n = 60) prostate were investigated. Measurements were performed using instrumental neutron activation analysis and inductively coupled plasma mass spectrometry. Results: The mass fractions of all trace elements with the exception of La, Nb, and Yb show significant variations in cancerous prostate when compared with normal and BPH prostate. The contents of Co, Hg, Rb, Sc, Se, and Zn were significantly lower and those of Ag, Al, Au, B, Be, Bi, Br, Ce, Cr, Cs, Dy, Er, Gd, Ho, Li, Mn, Mo, Nd, Ni, Pb, Pr, Sb, Sm, Sn, Tb, Th, Ti, Tl, Tm, U, Y, Yb, and Zr were significantly higher in PCa than in BPH tissues. When trace elements of cancerous prostate were compared with those in normal prostatic parenchyma, contents of Cd, Rb, Sc, Se, and Zn were significantly lower and Ag, Al, Au, B, Be, Bi, Br, Ce, Cr, Dy, Er, Fe, Gd, Hg, Ho, Li, Mn, Nd, Ni, Pr, Sb, Sm, Sn, Tb, Th, Tl, Y, and Zr were significantly higher. Conclusion: The Ag, Al, B, Br, Li, Mn, Ni, and Zn mass fraction in a needle-biopsy core can be used as the informative indicators for distinguishing malignant from benign prostate. Sensitivity, specificity, and accuracy of these tests were in range 72% - 100%, 66% - 100%, and 74% - 98%, respectively.

To clarify the role of trace elements in the etiology and the pathogenesis of the osteomyelitis, a nondestructive neutron activation analysis with high resolution spectrometry of long-lived radionuclides were performed. The silver (Ag), cobalt (Co), chromium (Cr), iron (Fe), mercury (Hg), rubidium (Rb), antimony (Sb), selenium (Se), and zinc (Zn) mass fraction were estimated in normal bone samples from 27 patients with intact bone (12 females and 15 males, aged from 16 to 49 years), who had died from various non bone related causes, mainly unexpected from trauma, and in samples, obtained from open biopsies or after operation of 10 patients with osteomyelitis (3 females and 7 males, 9 to 21 years old). The reliability of difference in the results between intact bone and bone affected by osteomyelitis was evaluated by Student’s t-test. In the bone affected by osteomyelitis the mass fractions of Co, Cr, Fe, Se, and Zn are significantly higher than in normal bone tissues. In the inflamed bone tissue many correlations between trace elements found in the control group are no longer evident. In bone affected by osteomyelitis the trace element homeostasis is significantly disturbed.

The effect of age on Ca, Cl, K, Mg, Mn, Na, P, and Sr contents in intact roots of permanent teeth of 38 apparently healthy women aged 15–55 years was investigated by neutron activation analysis. It was found that mass fractions of Ca, Cl, K, Mg, and P are at a maximum in the age range 25–35 years and above 35 years there is a monotonic decrease. A statistically significant age-dependent decrease was shown only for Mg and P. The Sr content significantly increases with age. The mass fractions of Mn and Na remain stable for the ages 15–55 years.

The Ca, Cl, Mg, Na, and P content and Ca/P, Ca/Mg, Ca/Na, Cl/Ca, and Cl/Na ratios in tissue of intact bone, chondroma and chondrosarcoma were investigated by neutron activation analysis. It was shown that higher mass fraction of Cl and Na and also Cl/Na mass fraction ratio as well as lower Ca/Cl and Ca/Na mass fraction ratios are typical of the chondrosarcoma tissue compared to chondroma. Finally, it was proposed to use the estimation of such parameters as the Cl mass fraction and the Ca/Cl and Ca/Na mass fraction ratios as an additional test for differential diagnosis between chondroma and chondrosarcoma.

NOS1−/− mice show reduced inflammatory responses and tissue damage in experimental sepsis models. Baig et al show that NOS1-derived NO production in macrophages leads to proteolysis of SOCS1 to alleviate its repression of NFkB transcriptional activity in response to TLR4-mediated responses., The NF-κB pathway is central to the regulation of inflammation. Here, we demonstrate that the low-output nitric oxide (NO) synthase 1 (NOS1 or nNOS) plays a critical role in the inflammatory response by promoting the activity of NF-κB. Specifically, NOS1-derived NO production in macrophages leads to proteolysis of suppressor of cytokine signaling 1 (SOCS1), alleviating its repression of NF-κB transcriptional activity. As a result, NOS1−/− mice demonstrate reduced cytokine production, lung injury, and mortality when subjected to two different models of sepsis. Isolated NOS1−/− macrophages demonstrate similar defects in proinflammatory transcription on challenge with Gram-negative bacterial LPS. Consistently, we found that activated NOS1−/− macrophages contain increased SOCS1 protein and decreased levels of p65 protein compared with wild-type cells. NOS1-dependent S-nitrosation of SOCS1 impairs its binding to p65 and targets SOCS1 for proteolysis. Treatment of NOS1−/− cells with exogenous NO rescues both SOCS1 degradation and stabilization of p65 protein. Point mutation analysis demonstrated that both Cys147 and Cys179 on SOCS1 are required for its NO-dependent degradation. These findings demonstrate a fundamental role for NOS1-derived NO in regulating TLR4-mediated inflammatory gene transcription, as well as the intensity and duration of the resulting host immune response.

The Ca, Cl, Mg, Na, and P content and Ca/P, Ca/Mg, Ca/Na, Cl/Ca, and Cl/Na ratios in samples of intact bone, benign and malignant giant cell tumor (GCT) of bone were investigated by neutron activation analysis with high resolution spectrometry of short-lived radionuclides. It was found that in GCT tissue the mass fractions of Cl and Na are higher and the mass fraction of Ca and P are lower than in normal bone tissues. Moreover, it was shown that higher Cl/Na mass fraction ratios as well as lower Ca/Cl, Ca/Mg, and Ca/Na mass fraction ratios are typical of the GCT tissue compared to intact bone. Finally, we propose to use the estimation of such parameters as the Cl mass fraction and the Ca/Cl mass fraction ratio as an additional test for differential diagnosis between benign and malignant GCT.

Objectives: To clarify the role of trace elements in the etiology and the pathogenesis of the osteogenic sarcoma (osteosarcoma), a non-destructive neutron activation analysis with high resolution spectrometry of long-lived radionuclides was performed. Methods: The silver (Ag), cobalt (Co), chromium (Cr), iron (Fe), mercury (Hg), rubidium (Rb), antimony (Sb), selenium (Se), and zinc (Zn) mass fraction, Rb/Co, Rb/Fe, Rb/Se, and Rb/Zn mass fraction ratios as well as Co × Zn, Fe × Zn, Sb × Zn, Se × Zn, Co × Se, and Fe × Se mass fraction multiplications were estimated in normal bone samples from 27 patients with intact bone (12 females and 15 males, aged from 16 to 49 years), who had died from various non bone related causes, mainly unexpected from trauma, and in tumor samples, obtained from open biopsies or after operation of 27 patients with osteosarcoma (9 females and 18 males, 6 to 71 years old). The reliability of difference in the results between intact bone and osteosarcoma tissues was evaluated by Student’s t-test. Results: In the osteosarcoma tissue the mass fractions of Co, Cr, Fe, Sb, Se, and Zn are significantly higher while the mass fraction of Rb is lower than in normal bone tissues. Moreover, we found significantly lower values of Rb/Co, Rb/Fe, Rb/Se, and Rb/Zn mass fraction ratios as well as significant higher mean values of Co × Zn, Fe × Zn, Sb × Zn, Se × Zn, Co × Se, and Fe × Se mass fractions multiplications in the osteosarcoma tissue compared to intact bone. In the osteosarcoma tissue many correlations between trace elements found in the control group were no longer evident. Conclusion: In osteosarcoma transformed bone tissues the trace element homeostasis is significantly disturbed.

Significance Calcineurin is an essential Ca2+-dependent phosphatase in all eukaryotes. Whether calcineurin can be endogenously regulated by factors other than Ca2+ and calmodulin is not known. Using a model of Parkinson's Disease (PD) as a surrogate for high pathophysiological calcineurin activity and employing a shotgun proteomic approach, we show that the isomerase FKBP12 physiological regulates calcineurin activity by facilitating dephosphorylation of proteins involved in vesicle recycling. Using a rodent model of PD, partial inhibition of the functional interaction between FKBP12 and calcineurin blocks the phosphatase activity toward critical vesicle recycling proteins at nigral presynaptic terminals conferring strong neuroprotection. Our work reassigns to FKBP12 a novel mechanism that supports toxicity in a PD model by modulating calcineurin's phosphatase activity with therapeutic implications., Calcineurin is an essential Ca2+-dependent phosphatase. Increased calcineurin activity is associated with α-synuclein (α-syn) toxicity, a protein implicated in Parkinson’s Disease (PD) and other neurodegenerative diseases. Calcineurin can be inhibited with Tacrolimus through the recruitment and inhibition of the 12-kDa cis-trans proline isomerase FK506-binding protein (FKBP12). Whether calcineurin/FKBP12 represents a native physiologically relevant assembly that occurs in the absence of pharmacological perturbation has remained elusive. We leveraged α-syn as a model to interrogate whether FKBP12 plays a role in regulating calcineurin activity in the absence of Tacrolimus. We show that FKBP12 profoundly affects the calcineurin-dependent phosphoproteome, promoting the dephosphorylation of a subset of proteins that contributes to α-syn toxicity. Using a rat model of PD, partial elimination of the functional interaction between FKBP12 and calcineurin, with low doses of the Food and Drug Administration (FDA)-approved compound Tacrolimus, blocks calcineurin’s activity toward those proteins and protects against the toxic hallmarks of α-syn pathology. Thus, FKBP12 can endogenously regulate calcineurin activity with therapeutic implications for the treatment of PD.

It is unclear why a prevalence of thyroid dysfunction is higher in the elderly as compared to the younger population. An excess or deficiency of trace element contents in thyroid may play important role in goitre- and carcinogenesis of gland. To examine the variation with age of the mass fraction of 50 trace elements in intact (normal) male thyroid. Samples of thyroid parenchyma obtained from 72 healthy males (mean age 37.8 years, range 2–80 years) was investigated. Measurements were performed using a combination of non-destructive and destructive methods: instrumental neutron activation analysis and inductively coupled plasma mass spectrometry, respectively. Tissue samples were divided into two portions. One was used for morphological study while the other was intended for trace element analysis. There is a statistically significant increase in Cd and Se mass fraction, as well as a decrease in Al, Be, Dy, Ga, Gd, Li, Mn, U, and Y mass fraction in the normal thyroid of male during a lifespan. Moreover, a disturbance of intra-thyroidal chemical element relationships (correlations) with increasing age was found. Our findings suggest that, at least, a goitrogenic and carcinogenic effect of Cd overload and Mn deficiency in the thyroid of old males may be assumed. Many trace elements in human thyroid behave themselves as antagonists or synergists. Therefore, an age-related disturbance in correlations between Mn and other trace element mass fractions in thyroid parenchyma may also contribute to harmful effects on the gland. Age-related changes in intra-thyroidal trace element contents and disturbances in trace element relationships are involved in goitre- and carcinogenesis.

In order to clarify the differences between Ag, Br, Ca, Co, Cr, Fe, Hg, K, Mg, Mn, Na, Rb, Sb, Sc, Se, and Zn contents in hyperplastic (patients with benign prostate hyperplasia (BPH), n = 32) and nonhyperplastic (control group of healthy male inhabitants, n = 32) prostates, an instrumental neutron activation analysis was performed. Mean values (M ± SEΜ) for mass fraction (mg/kg, dry mass basis) of chemical elements in glands of patients with BPH were the following: Ag, 0.0346 ± 0.0060; Br, 30.4 ± 3.6; Ca, 2030 ± 165; Co, 0.0716 ± 0.0097; Cr, 1.073 ± 0.119; Fe, 130.0 ± 7.9; Hg, 0.232 ± 0.030; K, 14,470 ± 740; Mg, 1200 ± 80; Mn, 1.19 ± 0.09; Na, 11,610 ± 870; Rb, 14.7 ± 0.8; Sb, 0.163 ± 0.025; Sc, 0.0257 ± 0.0040; Se, 1.243 ± 0.079; and Zn, 1235 ± 92. It was observed that in BPH tissue, the mass fraction of Co (p < 0.015), Cr (p < 0.0002), Hg (p < 0.000007), K (p < 0.001), Rb (p < 0.048), Sb (p < 0.0001), and Se (p < 0.000001) were significantly higher than in controls. In the sixth to eighth decades, the mass fractions of almost all chemical elements in hyperplastic prostates did not depend from age. Our finding of correlation between pairs of prostatic chemical element mass fractions indicates that there is a great disturbance of prostatic chemical element relationships with a benign hyperplastic transformation. The results apparently confirm the disturbed homeostasis of Zn and Se and some other chemical elements in the etiology of BPH.

Objectives: The aim of the current study was to evaluate quantitatively the effect of age and gender on calcium, phosphorus, and calcium-phosphorus ratio in the roots of permanent teeth. Methods: Calcium (Ca) and phosphorus (P) mass fractions as well as Ca/P mass fraction ratio were estimated in intact tooth root(s) samples from apparently healthy humans, 38 women and 46 men, aged from 16 to 55 years. For Ca and P mass fractions measurements, instrumental neutron activation analysis with high resolution spectrometry of short-lived radionuclides was used. Results: Mean values (mean ± standard error of mean, on dry mass basis) for the investigated parameters in two age groups (16-35 and 36-55 years) of females were: Ca 300 ± 12 g/kg, P 163 ± 7 g/kg, Ca/P ratio 1.85 ± 0.07 and Ca 277 ± 8 g/kg, P 145 ± 4 g/kg, Ca/P ratio 1.94 ± 0.06, respectively. The investigated parameters in the same age groups of males were: Ca 266 ± 13 g/kg, P 143 ± 7 g/kg, Ca/P ratio 1.88 ± 0.04 and Ca 278 ± 10 g/kg, P 152 ± 6 g/kg, Ca/P ratio 1.84 ± 0.04, respectively. The mean values for Ca, P and Ca/P ratio in the tooth root(s) were within a very wide range of reference data for dentin and close to their median. Conclusions: A tendency for reduced Ca and P mass fraction in roots of female teeth after 35 years of age as well as for raised Ca mass fraction in female tooth root(s) up to 35 years of age as compared to male was observed.

The variation with age of the mass fraction of 54 trace elements (Ag, Al, As, Au, B, Be, Bi, Br, Cd, Ce, Co, Cr, Cs, Dy, Er, Eu, Fe, Ga, Gd, Hf, Hg, Ho, Ir, La, Li, Lu, Mn, Mo, Nb, Nd, Ni, Pb, Pd, Pr, Pt, Rb, Re, Sb, Sc, Se, Sm, Sn, Ta, Tb, Te, Th, Ti, Tl, Tm, U, Y, Yb, Zn, and Zr) in intact nonhyperplastic prostate of 65 healthy 21–87 year old males was investigated by instrumental neutron activation analysis with high resolution spectrometry of long-lived radionuclides and inductively coupled plasma mass spectrometry. This work revealed that there is a significant tendency for an increase in Bi, Cd, Co, Fe, Hg, Sc, Sn, Th, U, and Zn (p

The Ca, Cl, Mg, Na, and P contents and Ca/P, Ca/Mg, Ca/Na, Cl/Ca, and Cl/Na ratios in samples of intact bone, inflamed bone, and Ewing's sarcoma tissue were investigated by neutron activation analysis with high-resolution spectrometry of short-lived radionuclides. In Ewing's sarcoma tissue, the mass fractions of Cl and Na are higher and the mass fractions of Ca and Mg are lower than those of both normal and inflamed bone tissues. It was shown that the levels of Ca and Cl mass fractions and also levels of the Ca/Cl and Cl/Na ratios can be used as an additional test for differential diagnosis between inflamed (or normal) bone and Ewing's sarcoma.

The variation with age of the 18 trace element mass fractions and some histological characteristics of intact prostate glands of 50 subjects aged 0-30 years was investigated by instrumental neutron activation analysis, inductively coupled plasma atomic emission spectrometry, and a quantitative morphometric analysis. Mean values ± standard error of the mean (M ± SΕΜ) for the mass fractions (in milligrams per kilogram wet tissue) of these trace elements in pre-puberty were: Al 28.5 ± 9.0, B 0.40 ± 0.11, Ba 1.48 ± 0.44, Br 10.5 ± 1.5, Ca 241 ± 30, Cl 3,203 ± 278, Cu 3.51 ± 0.89, Fe 33.7 ± 4.1, K 2,364 ± 145, Li 0.020 ± 0.004, Mg 153 ± 23, Mn 0.46 ± 0.06, Na 2,286 ± 130, P 1,391 ± 100, S 1,698 ± 132, Si 62 ± 11, Sr 0.38 ± 0.08, and Zn 27.6 ± 2.3. During puberty and postpuberty, when there is a significant increase in circulating androgens, the mean values were: Al 7.2 ± 1.4, B 0.21 ± 0.05, Ba 0.25 ± 0.06, Br 5.8 ± 1.0, Ca 433 ± 81, Cl 2,314 ± 201, Cu 1.77 ± 0.13, Fe 20.9 ± 1.6, K 2,585 ± 118, Li 0.0088 ± 0.0014, Mg 232 ± 27, Mn 0.34 ± 0.04, Na 1,875 ± 107, P 1,403 ± 98, S 1,673 ± 73, Si 22.2 ± 3.1, Sr 0.22 ± 0.03, and Zn 93.3 ± 8.9. Mean values (M ± SΕΜ) of percent volumes (%) of the stroma, epithelium and lumen in the prostate before puberty were 73.4 ± 2.6, 20.4 ± 1.7, and 4.45 ± 0.94, respectively, versus 46.5 ± 2.5, 38.5 ± 1.9, and 14.9 ± 1.2 during puberty and postpuberty. This work's results confirm that the Zn mass fraction in prostate tissue is an androgen-dependent parameter. For the first time it has been demonstrated that the glandular lumen is a main pool of Ca, Mg, and Zn accumulation and that the stroma is a main pool of Al, B, Ba, Br, Cl, Cu, Fe, Mn, Na, and Si accumulation in the normal human prostate, for the age range 0-30 years. It was concluded that the Ca, Mg, and Zn binds tightly within the prostatic fluid, because the volume of glandular lumen reflects the volume of prostatic fluid.

The variation with age of the Br, Fe, Rb, Sr, and Zn mass fractions and some histological characteristics of intact prostate glands of 50 subjects aged 0-30 years was investigated by an energy-dispersive X-ray fluorescence and a quantitative morphometric analysis. Mean values ± standard error of the mean (M ± SΕΜ) for the mass fractions (in milligrams per kilogram wet-mass basis) of these trace elements in pre-puberty were: Br-10.5 ± 1.3, Fe-28.6 ± 4.1, Rb-3.05 ± 0.27, Sr-0.42 ± 0.08, and Zn-32.9 ± 3.2. During puberty and postpuberty, when there is a significant increase in circulating androgens, the mean values were: Br-5.60 ± 0.57, Fe-19.3 ± 1.6, Rb-3.50 ± 0.28, Sr-0.24 ± 0.03, and Zn-113 ± 10. Mean values (M ± SΕΜ) of percent volumes (%) of the stroma, epithelium, and lumen in the prostate before puberty were 73.4 ± 2.6, 20.4 ± 1.7, and 4.45 ± 0.94, respectively, versus 46.5 ± 2.5, 38.5 ± 1.9, and 14.9 ± 1.2 during puberty and postpuberty. A significant positive correlation between the prostatic Zn and percent volume of both glandular epithelium (r = 0.573, p ≤ 0.001) and glandular lumen (r = 0.725, p ≤ 0.001) was found. For the first time, it has been demonstrated that the glandular lumen is a main pool of Zn accumulation, and that the stroma is a main pool of Br and Fe accumulation in the normal human prostate, for the age range 14 to 30 years. It was concluded that the Zn binds tightly within the prostatic fluid because the volume of glandular lumen reflects the volume of prostatic fluid.

To clarify age-related histological and Zn content changes in nonhyperplastic adult prostate glands, a quantitative morphometric and energy-dispersive X-ray fluorescence analyses were performed. The prostates were obtained from autopsies of 63 subjects aged 21-70 years who died mainly from trauma. It was found that histologically normal prostate tissue undergoes substantial changes throughout aging. These changes are reflected in an increase of the percent volume of the glandular lumen for the third to fifth decades, reaching a maximum for the decade 41-50 years. Over the same period, the percent volume of the stroma remains steady, but the percent volume of epithelium decreases, approximately, linearly with age. The percent volume of glandular lumen (reflects the volume of prostatic fluid) in the prostate gland of men aged 41 to 50 years is 1.5-fold higher than that in men aged 21 to 30 years, but the epithelium/lumen (prostatic fluid) ratio is approximately twofold lower. This suggests that accumulation of the prostatic fluid develops from 30 to 50 years of age. This accumulation of the prostatic fluid results in an increase of the Zn mass fraction in the prostate. In turn, when the intraprostatic Zn level exceeds a certain level by the end of the fifth decade, it begins to work as a trigger for different factors, all of which increase the proliferation of stromal cells. Deductions from these results allow possible partial explanations of both relevant prostatic aging mechanisms and the effects of dietary interventions using supplementary Zn.

The effect of age on trace element contents in intact prostate of 50 apparently healthy 0–30 year old males was investigated by neutron activation analysis with high resolution spectrometry of long-lived radionuclides. Mean values (M ± SEΜ) for mass fraction (milligram per kilogram, on dry-weight basis) of trace elements were: Ag 0.0708 ± 0.0096, Co 0.0348 ± 0.0040, Cr 0.466 ± 0.069, Fe 100 ± 10, Hg 0.0258 ± 0.0025, Rb 12.6 ± 0.8, Sb 0.0576 ± 0.0066, Sc 0.0125 ± 0.0016, Se 0.478 ± 0.031, and Zn 273 ± 31, respectively. A strongly pronounced tendency of age-related increase in Se and Zn mass fraction and of age-related decrease in Co, Cr, Fe, and Sc mass fraction was observed in period of life from 0 to 30 years.

SummaryMicrotubule transport of herpesvirus capsids from the cell periphery to the nucleus is imperative for viral replication and, in the case of many alphaherpesviruses, transmission into the nervous system. Using the neuroinvasive herpesvirus, pseudorabies virus (PRV), we show that the viral protein 1/2 (VP1/2) tegument protein associates with the dynein/dynactin microtubule motor complex and promotes retrograde microtubule transport of PRV capsids. Functional activation of VP1/2 requires binding to the capsid protein pUL25 or removal of the capsid-binding domain. A proline-rich sequence within VP1/2 is required for the efficient interaction with the dynein/dynactin microtubule motor complex as well as for PRV virulence and retrograde axon transport in vivo. Additionally, in the absence of infection, functionally active VP1/2 is sufficient to move large surrogate cargoes via the dynein/dynactin microtubule motor complex. Thus, VP1/2 tethers PRV capsids to dynein/dynactin to enhance microtubule transport, neuroinvasion, and pathogenesis.

Manganese superoxide dismutase (MnSOD) is a mitochondrial-resident enzyme that reduces superoxide to hydrogen peroxide (H2O2), which can be further reduced to water by glutathione peroxidase (GPX1). Data from human studies have indicated that common polymorphisms in both of these proteins are associated with the risk of several cancers, including breast cancer. Moreover, polymorphisms in MnSOD and GPX1 were shown to interact to increase the risk of breast cancer. To gain an understanding of the molecular mechanisms behind these observations, we engineered human MCF-7 breast cancer cells to exclusively express GPX1 and/or MnSOD alleles and investigated the consequences on the expression of several proteins associated with cancer aetiology. Little or no effect was observed on the ectopic expression of these genes on the phosphorylation of Akt, although allele-specific effects and interactions were observed for the impact on the levels of Bcl-2, E-cadherin and Sirt3. The patterns observed were not consistent with the steady-state levels of H2O2 determined in the transfected cells. These results indicate plausible contributing factors to the effects of allelic variations on cancer risk observed in human epidemiological studies.

The questions about the androgen control and the involvement of trace elements in prostatic reproductive function still remain unanswered. One valuable way to elucidate the situation is to compare the values for the prostatic mass fractions of trace elements in pre-and post-pubertal boys. The effect of age on the mass fraction of 54 trace elements in intact prostate of 50 apparently healthy 0-30 years old males was investigated by neutron activation analysis and inductively coupled plasma mass spectrometry. Mean values (M ± SEΜ) for mass fraction (milligram per kilogram, on dry-weight basis) of trace elements were: Ag 0.062 ± 0.008, Al 80 ± 18, Au 0.0092 ± 0.0024, B 5.9 ± 3.5, Be 0.0034 ± 0.0009, Bi 0.018 ± 0.010, Br 26 ± 3, Cd 0.26 ± 0.05, Ce 0.049 ± 0.012, Co 0.035 ± 0.004, Cr 0.49 ± 0.07, Cs 0.036 ± 0.005, Dy 0.0072 ± 0.0018, Er 0.0040 ± 0.0011, Fe 100 ± 10, Gd 0.0065 ± 0.0018, Hg 0.031 ± 0.004, Ho 0.0013 ± 0.0004, La 0.034 ± 0.007, Li 0.064 ± 0.009, Mn 1.69 ± 0.15, Mo 0.54 ± 0.13, Nb 0.013 ± 0.004, Nd 0.025 ± 0.006, Ni 4.1 ± 0.6, Pb 1.3 ± 0.2, Pr 0.0058 ± 0.0015, Rb 14.5 ± 0.8, Sb 0.051 ± 0.006, Sc 0.013 ± 0.002, Se 0.54 ± 0.03, Sm 0.0055 ± 0.0015, Sn 0.22 ± 0.05, Tb 0.0012 ± 0.0004, Th 0.0076 ± 0.0020, Ti 2.8 ± 0.5, Tl 0.0032 ± 0.0009, Tm 0.00064 ± 0.00017, U 0.0025 ± 0.0004, Y 0.036 ± 0.010, Yb 0.0037 ± 0.0012, Zn 281 ± 32, and Zr 0.16 ± 0.04. The upper limit of mean mass fraction of As, Eu, Ga, Hf, Ir, Lu, Pd, Pt, Re, and Ta were: As ≤ 0.069, Eu ≤ 0.0012, Ga ≤ 0.071, Hf ≤ 0.049, Ir ≤ 0.00054, Lu ≤ 0.00063, Pd ≤ 0.014, Pt ≤ 0.0029, Re ≤ 0.0048, and Ta ≤ 0.010. This work revealed that there is a significant tendency for the mass fractions of Cd, Se and Zn in the prostate tissue of healthy individuals to increase with age from the time of birth up to 30 years. It was also shown that high levels of Al, Au, B, Br, Cr, Ga, Li, and Ni mass fraction in prostate tissue do not indicate a direct involvement of these elements in the reproductive function of prostate.

Objective: The aim of this study was to clarify the differences between the prostatic levels of chemical elements in patients with benign prostatic hyperplasia (BPH) and healthy male. Methods: We evaluated the prostatic level of 66 chemical elements in 43 patients with BPH and 37 healthy males. Measurements were performed using five instrumental analytical methods. Results: In the hyperplastic prostates, we have observed a significant increase in the mean level of Bi, Cr, Hg, K, Sb, and Se accompanied a significant decrease in the mean level of Al, Ce, Cs, Dy, Er, Gd, Ho, La, Mo, Nd, Pb, Pr, Sm, Sn, Tb, Tm, U, and Y. No differences were found in the mean prostatic level of other chemical elements including Ag, Al, Au, B, Ba, Be, Br, Ca, Cd, Co, Cu, Fe, Li, Mg, Mn, Na, Nb, Ni, P, Rb, S, Sc, Si, Th, Ti, Tl, Yb, Zn, and Zr between BPH patients and healthy males. Conclusions: The finding of chemical element contents and correlation between pairs of chemical element mass fractions indicates that there is a great disturbance of prostatic chemical element metabolism in BPH gland. Trace elements Bi, Cr, Hg, K, Sb, and Se may be regarded as the possible tissue biomarkers of hyperplastic transformation of prostate gland. Obtained data did not confirm a critical role of Cd and Pb accumulation in the pathogenesis of BPH. A potential age-related Zn, Fe, and Se deficiency in the prostate tissue has not been found as being involved in the etiology of BPH. Keywords: Benign prostate hyperplasia, Prostatic chemical element contents, Trace element supplementations, Energy dispersive X-ray fluorescence analysis, Neutron activation analysis, Inductively coupled plasma atomic emission and mass spectrometry

A facility and method for 109Cd radionuclide-induced energy-dispersive X-ray fluorescent (EDXRF) were developed to determine the Fe, Zn, Br, Rb, and Sr concentrations in the specimens of human prostatic fluid. Specimens of expressed prostatic fluid were obtained from 51 men (mean age 51 years, range 18–82 years) with apparently normal prostates using standard rectal massage procedure. Mean values (M ± SEΜ) for concentration of trace elements (mg L−1) in human prostate fluid were: Fe 9.04 ± 1.21, Zn 573 ± 35, Br 3.58 ± 0.59, Rb 1.10 ± 0.08, and Sr ≤ 0.76. It was shown that the results of trace element analysis in the micro-samples (20 μL) are sufficiently representative for assessment of the Fe, Zn, Br, and Rb concentration in the prostate fluid. The facility for 109Cd radionuclide-induced EDXRF is comparatively compact and can be located in close proximity to the site of carrying out the massage procedure. The means of Zn and Rb concentration obtained for prostate fluid agree well with median of reported means. For the first time, the Fe and Br concentrations, as well as the upper limit of the Sr concentration, were determined in the human prostate fluid.