Pharmacometabolomics of Response to Sertraline and to Placebo in Major Depressive Disorder – Possible Role for Methoxyindole Pathway

Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35) or placebo (n = 40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD₁₇). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, χ²(1)  = 0.75, p = 0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL.     

Increased hematopoietic toxicity following administration of interferon-å with combination dideoxynucleoside therapy (zidovudine plus DDI) administered in normal mice

Because of the urgency to develop drugs which will effectively combat HIV infection, many combination therapies which have proved effective against HIV in vitro have undergone, or are undergoing clinical trial. Unfortunately many of drugs are being used without rigorous and exhaustive preclinical evaluation to assess their potential to develope hematopoeitic toxicity. We report here the results of two in vivo studies performed to analyze the effect of combined zidovudine (AZT) plus didanosine (ddl) therapy, either with or without interferon-å (IFN-å), on murine hematopoiesis. Normal C57BL/6 female mice were administered AZT (1.0 mg/ml) plus dose-escalation ddI (0.1, 1.0 and 2.5 mg/ml) placed in their drinking water. Control mice received IFN-å (100 units/ml) alone. Mice were serially bled and sacrified over a six-week period for assessment of hematopoietic toxicity measured by peripheral blood indices and assays of hematopoietic progenitors, i.e., erythroid (BFU-E), myeloid (CFU-GM), and megakaryocyte (CFU-Meg) cultured from bone marrow and spleen. AZT plus dose-escalation ddI decreased the hematocrit and white blood cell count when administered to normal mice compared to untreated controls during the six-week examination period. Marrow derived BFU-E, CFU-GM, and CFU-Meg were all reduced, however an increase was observed from the spleen for all three progenitor cell types. Use of IFN-å, in addition to combination AZT plus ddI further decreased the hematocrit, white blood cell and platelets. Marrow derived CFU-GM and CFU-Meg were increased slightly and only marginally for BFU-E with a similar response observed from the spleen. These results demonstrate that combination AZT plus ddI when used in vivo may produce synergistic hematopoietic toxicity, and that the addition of IFN-å to this treatment regimen increases this toxicity. These data indicate caution when this therapeutic approach is suggested for patients infected with HIV. If used, these patients wil require careful monitoring for blood cel toxicity.     

Population dynamics of Corbicula fluminea (Bivalvia) in the Paraná River Delta (Argentina)

Benthic individuals and drifting planktonic juveniles of Corbicula fluminea were sampled in the Lower Delta of the Paraná River (Argentina) at monthly intervals between October 1995 and October 1996. Densities of settled clams above 1 mm, around 300–1000 ind. m-2, varied little throughout the year. Below 1 mm benthic juveniles, on the other hand, showed a single conspicuous abundance peak in October-November (up to 1722 ind. m-2), and were practically absent during the rest of the year (overall annual mean: 1070 ± 797 ind. m-2). Drifting juveniles showed one major peak in December 1995 (160 ind. m^-3), and a minor one at the end of March (24 ind. m^-3). Length-frequency analyses of the monthly field data clearly indicate a highly structured population with a single well defined reproduction period centered on October–November. Population parameters derived from the seasonally oscillating version of von Bertalanffy's growth formula were as follows: maximum shell length: 32 mm (maximum observed shell length: 33 mm); growth constant: 0.65; growth seasonality (i.e., span of summer-to-winter growth-rate difference): 0.7; winter point (i.e., time of the year when growth is minimum): 0.5 (June–July); estimated size range for one year-old individuals: 15.3–22.4 mm; for two years: 23.5–27 mm, and three years: 27.5–29.3 mm. Comparison with previous data confirm the influence of water temperature on the clam's reproduction and growth and furnish additional evidence suggesting that food availability may be as important for recruitment as thermic regimes. Contrasts between traits of the population analyzed herein with those described previously from a nearby (ca. 10 km) site more influenced by industrial pollution point at the influence of water quality on Corbicula's recruitment and growth. This revised version was published online in July 2006 with corrections to the Cover Date.     

Modulation of inflammatory response and parasitism by 15-Deoxy-Δ(12,14) prostaglandin J(2) in Trypanosoma cruzi-infected cardiomyocytes

Trypanosoma cruzi infection produces an intense inflammatory response in diverse tissues including the heart. The inflammatory reaction is critical for the control of the parasites’ proliferation and evolution of Chagas disease. 15-Deoxy-Δ^12,14 prostaglandin J₂ (15dPGJ2) can repress the inflammatory response in many experimental models. However, the precise role of peroxisome proliferator-activated receptor γ (PPARγ) ligands in T. cruzi infection or in Chagas disease is poorly understood. This work reports the first evidence that 15dPGJ2 treatment increases the number of intracellular parasites as shown by fluorescence microscopy and it is also able to inhibit the expression and activity of different inflammatory enzymes such as inducible nitric oxide synthase (NOS-2), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), as well as pro-inflammatory cytokine (TNF-α and IL-6) mRNA expression in neonatal mouse cardiomyocytes after T. cruzi infection. Transfection of cardiomyocytes with small interfering RNA (siRNA) induces silencing of PPARγ and impairs the effects of 15dPGJ2 on the modulation of pro-inflammatory enzymes. Moreover, transfection restores the ability of these cells to control the intracellular growth of T. cruzi. We also found that PPARγ-independent pathways are involved, since 15dPGJ2 also exerts its effect through extracellular signal-regulated kinases-mitogen-activated protein kinase (Erk-MAPK) and nuclear factor-κB (NF-κB). The use of specific pharmacological inhibitors confirmed these findings. Our data point out that 15dPGJ2 is a potent modulator of the inflammatory process and regulator of parasites growth through PPARγ-dependent and independent (Erk-MAPK- and NF-κB) pathways in T. cruzi infected neonatal cardiac cells.     

Modulation of Dynamin-related Protein 1 (DRP1) Function by Increased O-linked-β-N-acetylglucosamine Modification (O-GlcNAc) in Cardiac Myocytes

O-linked-N-acetyl-glucosamine glycosylation (O-GlcNAcylation) of the serine and threonine residues of cellular proteins is a dynamic process and affects phosphorylation. Prolonged O-GlcNAcylation has been linked to diabetes-related complications, including mitochondrial dysfunction. Mitochondria are dynamically remodeling organelles, that constantly fuse (fusion) and divide (fission). An imbalance of this process affects mitochondrial function. In this study, we found that dynamin-related protein 1 (DRP1) is O-GlcNAcylated in cardiomyocytes at threonine 585 and 586. O-GlcNAcylation was significantly enhanced by the chemical inhibition of N-acetyl-glucosaminidase. Increased O-GlcNAcylation decreases the phosphorylation of DRP1 at serine 637, which is known to regulate DRP1 function. In fact, increased O-GlcNAcylation augments the level of the GTP-bound active form of DRP1 and induces translocation of DRP1 from the cytoplasm to mitochondria. Mitochondrial fragmentation and decreased mitochondrial membrane potential also accompany the increased O-GlcNAcylation. In conclusion, this report shows, for the first time, that O-GlcNAcylation modulates DRP1 functionality in cardiac muscle cells.     

Modulation of Paraoxonase 2 (PON2) in Mouse Brain by the Polyphenol Quercetin: A Mechanism of Neuroprotection?

Quercetin is a common flavonoid polyphenol which has been shown to exert neuroprotective actions in vitro and in vivo. Though quercetin has antioxidant properties, it has been suggested that neuroprotection may be ascribed to its ability of inducing the cell’s own defense mechanisms. The present study investigated whether quercetin could increase the levels of paraoxonase 2 (PON2), a mitochondrial enzyme expressed in brain cells, which has been shown to have potent antioxidant properties. PON2 protein, mRNA, and lactonase activity were highest in mouse striatal astrocytes. Quercetin increased PON2 levels, possibly by activating the JNK/AP-1 pathway. The increased PON2 levels induced by quercetin resulted in decreased oxidative stress and ensuing toxicity induced by two oxidants. The neuroprotective effect of quercetin was significantly diminished in cells from PON2 knockout mice. These findings suggest that induction of PON2 by quercetin represents an important mechanism by which this polyphenol may exert its neuroprotective action.     

Patch dynamics of a native grass in relation to the spread of invasive smooth brome (Bromus inermis)

The effects of invasive species on the patch dynamics (establishment, growth, and local extinction) of native species are not well studied, owing to the need for relatively fine-scale data on the distribution of species. Within the prairie pothole region of the United States and Canada, the grass, Bromus inermis (smooth brome) has become established by invading disturbed prairies, and through repeated introductions for soil retention and animal graze. In this study, the impact of smooth brome on the patch dynamics of a dominant native grass species, Spartina pectinata (prairie cordgrass), was assessed using fine-scale (sub-meter) mapping of the distribution of cordgrass and brome in three prairie fragments from 2000 to 2006. Using GIS spatial analyses, we determined that cordgrass patch growth was two times greater in areas not invaded by smooth brome versus areas that were heavily infested with smooth brome. Among sites and time periods, there was a consistent significant negative relationship between the amount of smooth brome surrounding a patch of cordgrass and the growth of that cordgrass patch. The probability of establishment of a new patch of cordgrass averaged 1.3 times higher in areas of low brome coverage (<25%) than areas of high brome coverage (>75%). Conversely, existing cordgrass patches were 7.8 times more likely to go extinct in areas of high than low brome coverage. This is one of only a few field studies to provide evidence of the negative impact of smooth brome on native flora and hopefully will serve as justification for the development of a formal management plan to limit the distribution of this species in tallgrass prairie ecosystems.     

Isolation of 3-(2-carboxyethyl)thymine following in vitro reaction of β-propiolactone with calf thymus DNA

3-(2-Carboxyethyl)thymine (3-CET) was synthesized from β-propiolactone (BPL) and dThd5′P at pH 9.0–9.5 via the intermediate 3-(2-carboxyethyl)thymidine-5′-monophosphoric acid (3-CEdThd5′P). 3-CEdThd5′P was converted to 3-CET by hydrolysis in 1.5 N HCl at 100°C for 2 h. The structure of 3-CET was assigned on the basis of UV spectra, electron impact (EI) and isobutane chemical ionization mass spectra and the EI mass spectrum of a trimethylsilyl derivative of 3-CET. BPL was reacted in vitro with calf thymus DNA at pH 7.5. 100 A units of BPL-reacted DNA yielded, following perchloric acid hydrolysis and preparative paper chromatography, 3 A units of 3-CET. Reaction of BPL with the phosphodiester thymidylyl-(3′-5′)thymidine gave 3-(2-carboxyethyl)thymidylyl-(3′-5′)-3-(2-carboxyethyl)thymidine (～3%). Phosphotriester formation was not detected.     

Water turbidity–induced alterations in coloration and courtship behavior of male guppies (Poecilia reticulata)

acta ethologica - Water turbidity deteriorates visibility and thereby may change the physiology and behavior of aquatic animals that rely on vision. In the guppy fish (Poecilia reticulata), a key...     

Meiosis and sporulation induced in sporophytes of Ulva mutabilis (“slender”) with synchronous mitosis

Summary Sporulation preceded by meiosis was induced in young, diploid plants of Ulva mutabilis, mutant slender (Föyn). The induction was brought about either by replacement of the old culture medium (sea water plus soil extract) with new, or by the addition of a mixture of seven vitamins to old medium. The new chemical environment seems to induce a shift from presumptive mitosis to presumptive meiosis.Supported by a Danish State scholarship '63/'64 from the Danish Ministry of Education.     

Changing dynamics of the pine beauty moth (Panolis flammea) in Britain: the loss of enemy free space?

1 The pine beauty moth Panolis flammea has two main host plants in Britain: Pinus sylvestris (Scots pine), which is the ancestral food plant where the insect is never abundant enough to cause tree mortality, and Pinus contorta (lodgepole pine), an introduced host tree that has experienced periodic widespread tree mortality due to this pest.
2 We review the recent literature, published mostly after the year 2000, regarding the impact of natural enemies on the population dynamics of P. flammea in Britain.
3 The natural enemies of P. flammea are more diverse and abundant in Scots pine habitat than in lodgepole pine habitat and some of them show differential selection for P. flammea larvae in Scots pine habitat over those located in lodgepole pine habitat.
4 It is concluded that the difference in the population dynamics of this insect in the two different habitats was probably the result of the P. flammea finding enemy-free space in lodgepole pine habitat.
5 Recent evidence on the diversity and impact of natural enemies on lodgepole pine has demonstrated that they currently have a much more significant impact on this pest than they did in the 1970s and 1980s, when outbreaks were frequent.     

Exploring the dynamics of plankton diatom communities in Lake Geneva using emergent self-organizing maps (1974–2007)

Lake Geneva, situated between France and Switzerland, is a large lake of major importance for the regional economy. As a result, its ecological quality has been monitored using several parameters since 1974. Phytoplankton was one of the items monitored. Diatoms were among the most diverse algae in this compartment. In order to characterize their dynamics, diatoms were explored and clustered using an emergent self-organizing map. Eight different communities were defined on the basis of the U-matrix. Most of them displayed a clear seasonal pattern, some communities were present during the water stratification phase, and others were present during the mixing phase. These communities also displayed a clear inter-annual dynamic pattern. Some were on the decrease, some even disappearing altogether; whereas others tended to increase or to appear. These dynamic patterns were related to the re-oligotrophication of the lake; Lake Geneva was eutrophic in the 70s to mid 80s, and has been meso-eutrophic since the late 90s. A discriminant analysis showed that phosphorus was the determining parameter for diatom communities. These findings confirmed the effectiveness of diatoms for use as a trophic indicator, and their suitability for use in paleolimnological studies on Lake Geneva. Compared to multivariate analyses which only ordinate and had quite undecipherable graphs when data are numerous, e-SOM showed the advantage to cluster and ordinate data in a single analysis and to present a self-evident and intuitive visualization output.     

Single, high-dose 17β-estradiol therapy has anti-apoptotic effect and induces cerebral plasticity following transient forebrain ischemia in gerbils (Short communication)

Although much is known about the protective effect of acute estrogen therapy in cerebral ischemia, relatively little is known about the importance of apoptosis and cerebral plasticity in this mechanism. In this work 10 min global cerebral ischemia was produced by transient bilateral carotid occlusion in 4-month-old ovariectomized female gerbils. In every of our experimental group (sham for ischemia group, ischemia group and ischemia + a high, single dose 17β-estradiol pre-treatment group) apoptotic (bcl-Xl, bax) and cerebral plasticity (GAP-43, synapsin-I, nestin) hippocampal genes' expression was measured four days after surgery. Expression of the anti-apoptotic bcl-Xl (p<0.01) and the cerebral plasticity marker synapsin-I and nestin (p<0.01) increased with acute estrogen pretreatment in ischemic animals. No change, however, in bax or GAP-43 expression was detected in estrogen treated animals compared to ischemic gerbils. These results suggest that acute estrogen therapy has anti-apoptotic effect and increases cerebral plasticity, which play an important role in cytoprotection or cerebroprotection.     

Population dynamics of Stenoma catenifer Walsingham (Lepidoptera: Depressariidae) on Hass avocado orchards in México

Avocado production in Mexico represents an income of more than $3.2 billion dollars per year in foreign exchange. Unfortunately, several factors can limit the export of this fruit. One of such limiting factor is the avocado seed moth, Stenoma catenifer; however, its population dynamics is barely known. Therefore, is relevant to study the environmental factors affecting population changes, aimed to improve its management. In this study, we monitored the population fluctuations of S. catenifer males and explored its relationship with temperature and relative humidity by using pheromone-baited traps in Hass avocado orchards in the state of Colima, Mexico. From June 2018 to June 2019, a total of 6,836 males of the avocado seed moth were collected, with two population peaks. The first in June-August, during the fruiting stage, and the second in December-January, coinciding with the end of fruiting and flowering stages. Fruit infestation ranged from 0.0 to 65.0% in the orchards examined. Cluster analysis and principal coordinate analysis indicated that sampling time and relative humidity group together but differ from temperature. The effect of relative humidity and temperature on catches was analyzed by relating non-parametric bivariate distributions. The highest male catches were recorded at temperatures greater than 15.8 °C and relative humidity greater than 60% while low relative humidity did not favor moth catches. These results may be useful to predict bioecological conditions for the occurrence of populations of this pest.     

Conformational dynamics of α-1 acid glycoprotein (AGP) in cancer: A comparative study of glycosylated and unglycosylated AGP

α-1 acid glycoprotein (AGP) is one of the most abundant plasma proteins. It fulfills two important functions: immunomodulation, and binding to various drugs and receptors. These different functions are closely associated and modulated via changes in glycosylation and cancer missense mutations. From a structural point of view, glycans alter the local biophysical properties of the protein leading to a diverse ligand-binding spectrum. However, glycans can typically not be observed in the resolved X-ray crystallography structure of AGP due to their high flexibility and microheterogeneity, so limiting our understanding of AGP's conformational dynamics 70 years after its discovery. We here investigate how mutations and glycosylation interfere with AGP's conformational dynamics changing its biophysical behavior, by using molecular dynamics (MD) simulations and sequence-based dynamics predictions. The MD trajectories show that glycosylation decreases the local backbone flexibility of AGP and increases the flexibility of distant regions through allosteric effects. We observe that mutations near the glycosylation site affect glycan's conformational preferences. Thus, we conclude that mutations control glycan dynamics which modulates the protein's backbone flexibility directly affecting its accessibility. These findings may assist in the drug design targeting AGP's glycosylation and mutations in cancer.     

Influences of the lowland river Spree on phytoplankton dynamics in the flow-through Lake Müggelsee (Germany)

The influences of imports of nutrients and planktonic algae from the River Spree on the dynamics of phytoplankton were examined in the shallow, eutrophic Müggelsee, which has a retention time of only 42 days. Phytoplankton biomass and nutrient concentrations were measured in both the lake and its inflow from 1980–1990. On a long-term average, mean biomass as well as vitality of most dominant phytoplankton populations in the lake were not significantly different from those in the river. Nevertheless, during distinct periods the external rates of biomass change of single lake populations (due to dilution or enrichment) were as high as the lake internal ones. The import of inocula populations from the river probably induced the formation of the typical community structure in the lake. Growth and decay of phytoplankton populations in the river strongly influenced the load of dissolved nutrients and thus indirectly the dynamics of planktonic algae in the downstream lake. For example, intensive assimilation of phosphorus by riverine algae in spring intensified the P-shortage and supported possible P-limitation of algal growth in the lake at that time. In years with high vernal biomass of centric diatoms in the river, and thus diminished import of dissolved silicon, the growth of diatoms was suppressed and that of cyanobacteria was favoured in the lake during summer.     

Population dynamics of Triatoma vitticeps (Stål, 1859) in Itanhomi, Minas Gerais, Brazil

Taxonomic markers (head structure morphometry, isoenzymes and randon amplified polymorphism of DNA - RAPD) were used to understand the population dynamics of Triatoma vitticeps, predominant triatomine species in Itanhomi district, using samples obtained from domestic, peridomiciliary and sylvatic habitats. Morphometric analysis revealed sexual dimorphism within the three samples although specimens could not be separated according to the habitat in which they were captured. Forty-two bands were analyzed from RAPD profiles generated using four primers. A dendrogram constructed from Dice's similarity coefficient values showed that migration of the insects between the habitats has occurred, without structuring of populations. Moreover, the dendrogram obtained from the genetic distance values showed an important gene flow between the sylvatic and domestic habitats. No polymorphism was found in the electrophoretic mobility of proteins for the ten enzymes studied. Our results revealed movement of triatomines between the three habitats, suggesting that the presence of T. vitticeps in houses should not be ignored. As invasion of houses by sylvatic insects is frequent and the natural infection indices of this species are among the highest known, epidemiological vigilance studies may reveal possible changes in T. vitticeps behaviour which could present future risks to public health.     

NTCP modeling analysis of acute hematologic toxicity in whole pelvic radiation therapy for gynecologic malignancies – A dosimetric comparison of IMRT and spot-scanning proton therapy (SSPT)

PurposeThis treatment planning study was conducted to determine whether spot scanning proton beam therapy (SSPT) reduces the risk of grade ⩾3 hematologic toxicity (HT3+) compared with intensity modulated radiation therapy (IMRT) for postoperative whole pelvic radiation therapy (WPRT).Methods and materialsThe normal tissue complication probability (NTCP) of the risk of HT3+ was used as an in silico surrogate marker in this analysis. IMRT and SSPT plans were created for 13 gynecologic malignancy patients who had received hysterectomies. The IMRT plans were generated using the 7-fields step and shoot technique. The SSPT plans were generated using anterior-posterior field with single field optimization. Using the relative biological effectives (RBE) value of 1.0 for IMRT and 1.1 for SSPT, the prescribed dose was 45 Gy(RBE) in 1.8 Gy(RBE) per fractions for 95% of the planning target volume (PTV). The homogeneity index (HI) and the conformity index (CI) of the PTV were also compared.ResultsThe bone marrow (BM) and femoral head doses using SSPT were significantly lower than with IMRT. The NTCP modeling analysis showed that the risk of HT3+ using SSPT was significantly lower than with IMRT (NTCP = 0.04 ± 0.01 and 0.19 ± 0.03, p = 0.0002, respectively). There were no significant differences in the CI and HI of the PTV between IMRT and SSPT (CI = 0.97 ± 0.01 and 0.96 ± 0.02, p = 0.3177, and HI = 1.24 ± 0.11 and 1.27 ± 0.05, p = 0.8473, respectively).ConclusionThe SSPT achieves significant reductions in the dose to BM without compromising target coverage, compared with IMRT. The NTCP value for HT3+ in SSPT was significantly lower than in IMRT.