Harnessing IGF-1 and IL-2 as biomarkers for calcineurin activity to tailor optimal FK506 dosage in α-synucleinopathies.

Introduction: Rise in Calcium (Ca2+) and hyperactive Ca2+-dependent phosphatase calcineurin represent two key determinants of a-synuclein (a-syn) pathobiology implicated in Parkinson's Disease (PD) and other neurodegenerative diseases. Calcineurin activity can be inhibited with FK506, a Food and Drug Administration (FDA)-approved compound. Our previous work demonstrated a protective effect of low doses of FK506 against a-syn pathology in various models of a-syn related pathobiology. Methods: Control and a-syn-expressing mice (12-18 months old) were injected with vehicle or two single doses of FK506 administered 4 days apart. Cerebral cortex and serum from these mice were collected and assayed using a meso scale discovery quickplex SQ 120 for cytokines and Enzyme-linked immunosorbent assay for IGF-1. Results: In this study we present evidence that reducing calcineurin activity with FK506 in a-syn transgenic mice increased insulin growth factor (IGF-1), while simultaneously decreasing IL-2 levels in both cerebral cortex and serum. Discussion: The highly conserved Ca2+/calcineurin signaling pathway is known to be affected in a-syn-dependent human disease. FK506, an already approved drug for other uses, exhibits high brain penetrance and a proven safety profile. IL-2 and IGF-1 are produced throughout life and can be measured using standard clinical methods. Our findings provide two potential biomarkers that could guide a clinical trial of FK506 in PD patients, without posing significant logistical or regulatory challenges.

Octopamine metabolically reprograms astrocytes to confer neuroprotection against α-synuclein.

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-Ca2+-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.

Herpesviruses assimilate kinesin to produce motorized viral particles.

Neurotropic alphaherpesviruses initiate infection in exposed mucosal tissues and, unlike most viruses, spread rapidly to sensory and autonomic nerves where life-long latency is established1. Recurrent infections arise sporadically from the peripheral nervous system throughout the life of the host, and invasion of the central nervous system may occur, with severe outcomes2. These viruses directly recruit cellular motors for transport along microtubules in nerve axons, but how the motors are manipulated to deliver the virus to neuronal nuclei is not understood. Here, using herpes simplex virus type I and pseudorabies virus as model alphaherpesviruses, we show that a cellular kinesin motor is captured by virions in epithelial cells, carried between cells, and subsequently used in neurons to traffic to nuclei. Viruses assembled in the absence of kinesin are not neuroinvasive. The findings explain a critical component of the alphaherpesvirus neuroinvasive mechanism and demonstrate that these viruses assimilate a cellular protein as an essential proviral structural component. This principle of viral assimilation may prove relevant to other virus families and offers new strategies to combat infection.

A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6.

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.

Comparison of 66 chemical element contents in normal and benign hyperplastic 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.

Associations between age and 50 trace element contents and relationships in intact thyroid of males.

BACKGROUND: 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. AIM: To examine the variation with age of the mass fraction of 50 trace elements in intact (normal) male thyroid. METHOD: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSION: Age-related changes in intra-thyroidal trace element contents and disturbances in trace element relationships are involved in goitre- and carcinogenesis.

FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome.

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.

Allele-specific interaction between glutathione peroxidase 1 and manganese superoxide dismutase affects the levels of Bcl-2, Sirt3 and E-cadherin.

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 role of Ca2+ signaling in Parkinson's disease.

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.

Selenium levels in human breast carcinoma tissue are associated with a common polymorphism in the gene for SELENOP (Selenoprotein P).

Selenium supplementation of the diets of rodents has consistently been shown to suppress mammary carcinogenesis and some, albeit not all, human epidemiological studies have indicated an inverse association between selenium and breast cancer risk. In order to better understand the role selenium plays in breast cancer, 30 samples of tumor tissue were obtained from women with breast cancer and analyzed for selenium concentration, the levels of several selenium-containing proteins and the levels of the MnSOD anti-oxidant protein. Polymorphisms within the genes for these same proteins were determined from DNA isolated from the tissue samples. There was a wide range of selenium in these tissues, ranging from 24 to 854ng/gm. The selenium levels in the tissues were correlated to the genotype of the SELENOP selenium carrier protein, but not to other proteins whose levels have been reported to be responsive to selenium availability, including GPX1, SELENOF and SBP1. There was an association between a polymorphism in the gene for MnSOD and the levels of the encoded protein. These studies were the first to examine the relationship between selenium levels, genotypes and protein levels in human tissues. Furthermore, the obtained data provide evidence for the need to obtain data about the effects of selenium in breast cancer by examining samples from that particular tissue type.

NOS1-derived nitric oxide promotes NF-κB transcriptional activity through inhibition of suppressor of cytokine signaling-1.

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.

Differences between chemical element contents in hyperplastic and nonhyperplastic prostate glands investigated by neutron activation analysis.

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 ± SΕΜ) 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.

INAA application in the assessment of chemical element mass fractions in adult and geriatric prostate glands.

The variation with age of the mass fraction of 37 chemical elements in intact nonhyperplastic prostate of 65 healthy 21-87 year old males was investigated by instrumental neutron activation analysis with high resolution spectrometry of short- and long-lived radionuclides. Mean values (M±SΕΜ) for mass fractions (mg kg(-1), dry mass basis) of the chemical elements studied were: Ag-0.055±0.007, Br-33.2±3.3, Ca-2150±118, Cl-13014±703, Co-0.038±0.003, Cr-0.47±0.05, Fe-99.3±6.1, Hg-0.044±0.006, K-11896±356, Mg-1149±68, Mn-1.41±0.07, Na-10886±339, Rb-12.3±0.6, Sb-0.049±0.005, Sc-0.021±0.003, Se-0.65±0.03, and Zn-795±71. The mass fraction of other chemical elements measured in this study were lower than the corresponding detection limits (mg kg(-1), dry mass basis): As<0.1, Au<0.01, Ba<100, Cd<2, Ce<0.1, Cs<0.05, Eu<0.001, Gd<0.02, Hf<0.2, La<0.5, Lu<0.003, Nd<0.1, Sm<0.01, Sr<3, Ta<0.01, Tb<0.03, Th<0.05, U<0.07, Yb<0.03, and Zr<0.3. This work revealed that there is a significant trend for increase with age in mass fractions of Co (p<0.0085), Fe (p<0.037), Hg (p<0.035), Sc (p<0.015), and Zn (p<0.0014) and for a decrease in the mass fraction of Mn (p<0.018) in prostates, obtained from young adult up to about 60 years, with age. In the nonhyperplastic prostates of males in the sixth to ninth decades, the magnitude of mass fractions of all chemical element were maintained at near constant levels. Our finding of correlation between the prostatic chemical element mass fractions indicates that there is a great variation of chemical element relationships with age.

The Ca, Cl, Mg, Na, and P mass fractions in human bone affected by Ewing's sarcoma.

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.

Relations of the Al, B, Ba, Br, Ca, Cl, Cu, Fe, K, Li, Mg, Mn, Na, P, S, Si, Sr, and Zn mass fractions to morphometric parameters in pediatric and nonhyperplastic young adult prostate glands.

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.

Relations of bromine, iron, rubidium, strontium, and zinc content to morphometric parameters in pediatric and nonhyperplastic young adult prostate glands.

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.

Age-related histological and zinc content changes in adult nonhyperplastic prostate glands.

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.

NAA-SLR and ICP-AES application in the assessment of mass fraction of 19 chemical elements in pediatric and young adult prostate glands.

The effect of age on the mass fraction of 19 chemical elements in the intact prostate of 50 apparently healthy 0-30-year-old males was investigated by neutron activation analysis with high-resolution spectrometry of short-lived radionuclides and inductively coupled plasma atomic emission spectrometry. Mean values (M ± standard error of the mean) for mass fraction (in milligrams per kilogram, on dry weight basis) of chemical elements were as follows: Al, 77 ± 17; B, 1.31 ± 0.29; Ba, 4.0 ± 1.2; Br, 37.7 ± 4.3; Ca, 1,536 ± 189; Cl, 13,414 ± 949; Cu, 12.3 ± 2.1; Fe, 132 ± 11; K, 11,547 ± 468; Li, 0.064 ± 0.009; Mg, 922 ± 89; Mn, 1.88 ± 0.16; Na, 9,834 ± 411; P, 6,741 ± 335; S, 8,034 ± 251; Si, 199 ± 34; Sr, 1.40 ± 0.19; and Zn, 277 ± 33. The upper limit of mean mass fraction of V was ≤0.24. This work revealed that there is significant tendency for the mass fractions of Ca, K, Mg, and Zn in the prostate tissue of healthy individuals to increase with age from the time of birth up to 30 years. It means that Ca, K, Mg, and Zn mass fractions in prostate tissue are the androgen-dependent parameters. Our finding of a positive correlation between the prostatic Zn and Ca, K, Mg, P, and S mass fractions indicates that there is a special relationship of Zn with some main electrolytes (Ca, K, and Mg) and with P- and S-containing compounds in the prostate. It was shown also that high levels of Al, B, Ba, Br, Cl, Li, Na, and Sr mass fraction in prostate tissue do not indicate a direct involvement of these elements in the reproductive function of the prostate.

The effect of age on Br, Ca, Cl, K, Mg, Mn, and Na mass fraction in pediatric and young adult prostate glands investigated by neutron activation analysis.

The effect of age on chemical element mass fractions in intact prostate of 50 apparently healthy 0-30 year old males was investigated by neutron activation analysis with high resolution spectrometry of short-lived radionuclides. Mean values (M ± SΕΜ) for mass fraction (mgkg(-1), dry mass basis) of chemical elements before the time of puberty and in the period of puberty and post-puberty were: Br 46.0 ± 6.7, Ca 1151 ± 140, Cl 14572 ± 700, K 10147 ± 700, Mg 771 ± 131, Mn 2.13 ± 0.25, Na 9880 ± 659 and Br 29.0 ± 4.6, Ca 2049 ± 364, Cl 11518 ± 1121, K 13029 ± 542, Mg 1186 ± 134, Mn 1.74 ± 0.16, Na 9887 ± 716, respectively. A tendency of age-related increase in Ca, K, and Mg mass fraction and of age-related decrease in Br mass fraction was observed in period of life from 0 to 30 years. This new data indicates that of the elements studied, only the Ca, K, and Mg mass fraction in prostate tissue is an androgen-dependent parameter.

The herpesvirus VP1/2 protein is an effector of dynein-mediated capsid transport and neuroinvasion.

Microtubule 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.