90Y-Labeled Anti-ROBO1 Monoclonal Antibody Exhibits Antitumor Activity against Small Cell Lung Cancer Xenografts

IntroductionROBO1 is a membrane protein that contributes to tumor metastasis and angiogenesis. We previously reported that ⁹⁰Y-labeled anti-ROBO1 monoclonal antibody (⁹⁰Y-anti-ROBO1 IgG) showed an antitumor effect against ROBO1-positive tumors. In this study, we performed a biodistribution study and radioimmunotherapy (RIT) against ROBO1-positive small cell lung cancer (SCLC) models.MethodsFor the biodistribution study, ¹¹¹In-labeled anti-ROBO1 monoclonal antibody (¹¹¹In-anti-ROBO1 IgG) was injected into ROBO1-positive SCLC xenograft mice via the tail vein. To evaluate antitumor effects, an RIT study was performed, and SCLC xenograft mice were treated with ⁹⁰Y-anti-ROBO1 IgG. Tumor volume and body weight were periodically measured throughout the experiments. The tumors and organs of mice were then collected, and a pathological analysis was carried out.ResultsAs a result of the biodistribution study, we observed tumor uptake of ¹¹¹In-anti-ROBO1 IgG. The liver, kidney, spleen, and lung showed comparably high accumulation of ¹¹¹In-labeled anti-ROBO1. In the RIT study, ⁹⁰Y-anti-ROBO1 IgG significantly reduced tumor volume compared with baseline. Pathological analyses of tumors revealed coagulation necrosis and fatal degeneration of tumor cells, significant reduction in the number of Ki-67-positive cells, and an increase in the number of apoptotic cells. A transient reduction of hematopoietic cells was observed in the spleen, sternum, and femur.ConclusionsThese results suggest that RIT with ⁹⁰Y-anti-ROBO1 IgG is a promising treatment for ROBO1-positive SCLC.     

Evidence for Anaerobic CH 4 Oxidation in Freshwater Peatlands

This study involved in vitro assays of peat soil to investigate the occurrence, importance and potential mechanism(s) of anaerobic methane oxidation (AOM) in several northern peatlands ranging from ombrotrophic bog to minerotrophic fen. Although strong evidence suggests that AOM is linked to sulfate reduction in marine sediments, very little is known about AOM in freshwater systems such as northern peatlands, which have large methane (CH ₄ ) production and are a significant source of atmospheric CH ₄ . Our results showed a mean net AOM rate of 17 ± 2.6 nmol kg ^{? 1} s ^{? 1} with a maximum rate of 176 nmol kg ^{? 1} s ^{? 1} for a minerotrophic fen in central New York. AOM was demonstrated with three independent methods to verify our results: (a) additions of methanogenic inhibitors, (b) stable isotope enrichment ( ¹³ C-CH ₄ ), and (c) natural abundance stable isotope analysis ( ¹³ C-CH ₄ ). These experiments confirmed that AOM occurs simultaneously with methanogenesis, consumes a significant portion of gross CH ₄ production, and significantly fractionates C isotopes (～ ?127‰). Experiments using a variety of potential electron acceptors demonstrated that Fe(III) and SO₄ ^{2 ?} are not quantitatively important, while the role of NO ₃ ^? is uncertain and deserves more attention. The exact mechanism(s) for AOM in peat soils remains unclear; however the AOM rates reported in this study are similar to those reported for CH ₄ production and aerobic CH ₄ oxidation in northern peatlands, suggesting that AOM may be an important control on CH ₄ fluxes in northern peatland ecosystems.     

MOLECULAR AND PHARMACOLOGICAL CHARACTERISATION OF THE MSH-R ALLELES IN SWISS CATTLE BREEDS

ABSTRACT

The coat colour in mammals is determined by the relative amounts of eumelanin (black/brown) and phaeomelanin (red/yellow), produced in melanocytes, which are controlled by melanocyte stimulating hormone receptor (MSH-R). Melanocyte stimulating hormone receptor is activated by α-melanocyte-stimulating hormone (α-MSH). Stimulated MSH-R activates adenylyl cyclase (AC), thereby increasing the amount of cyclic AMP in the cell, which activates the enzyme tyrosinase resulting in eumelanin synthesis. In this study the complete coding sequences of five alleles of the MSH-R gene found in Holstein, Red Holstein, Simmental, and Brown Swiss cattle were cloned into a mammalian expression vector and transfected into human embryonic kidney (HEK) 293 cells. The expressed receptors were analyzed for their ability to increase intracellular cAMP in response to stimulation by α-MSH. The recessive red allele (e) found in Red Holstein and Simmental and the dominant black allele (E^D) found in Holstein were unresponsive to a wide range of α-MSH concentrations. Two alleles from Brown Swiss (E^d1, E^d2) and one allele found in the Simmental breed (e^f) responded to stimulation by α-MSH in a dose-dependent manner. When compared to E^d1 and E^d2, the cells transfected with the e^f MSH-R allele, however, reached the corresponding intracellular cAMP concentrations at a 10-fold higher concentration of α-MSH. In conjunction with the mode of inheritance of coat colour, the results indicate that the e MSH-R allele is a non-functional receptor, E^D is constitutively activated receptor, and E^d1 and E^d2 are hormonally activated receptors. The delay in e^f MSH-R response may explain the similarity between the e and e^f phenotypes.     

Dosimetric investigation of a new high dose rate 192Ir brachytherapy source,IRAsource, by Monte Carlo method

PurposeThe purpose of the present study was to perform an independent calculation of dosimetric parameters associated with a new ¹⁹²Ir brachytherapy source model, IRAsource.Materials and methodsThe parameters of air kerma strength (AKS), dose rate constant (DRC), geometry function (GF), radial dose function (RDF), as well as two-dimensional (2D) anisotropy function (AF) of IRAsource ¹⁹²Ir source model were calculated in this study. The MC n-particle extended (MCNPX) code was also employed for simulating high dose rate (HDR), IRAsource and ¹⁹²Ir source; and formalism was used for calculating dosimetry parameters based on task group number 43 updated report (TG-43 U1).ResultsThe results of this study were consistent with the ones reported about the IRAsource source by Sarabiasl et al. The AKS per 1 mCi activity and the DRC values were also equal to 3.65 cGycm² h^–1 mCi^–1 and 1.094 cGyh^–1U^–1; respectively. The comparison of the results of the DRC and the RDF reported by Sarabiasl et al. also validated the ¹⁹²Ir IRAsource simulation in this study. Moreover, the AFs of IRAsource source model were in a good agreement with those of Sarabiasl et al. at different distances, which could be attributed to identical geometries.ConclusionIn line with those reported by Sarabiasl et al., the results of this study confirmed the IRAsource ¹⁹²Ir source for clinical uses. The calculated dosimetric parameters of the IRAsource source could be utilized in clinical practices as input data sets or for validation of treatment planning system calculations.     

Synthesis and Characterization of C8 Analogs of c-di-GMP

We have synthesized five analogs of c-di-GMP with different substituents at the guanine C8 position, to study their effects on the metal-dependent polymorphism we had previously demonstrated for the parent compound. Of these, only the K⁺ salt of c-di-Br-GMP, 2, forms higher order complexes, predominantly two different syn octamolecular ones. Its Na⁺ salt, as well as both the K⁺ and Na⁺ salts of c-di-thio-GMP, 3, c-di-methylthio-GMP, 4, c-di-phenyl-GMP, 5, and c-di-acetylphenyl-GMP, 6, all form primarily a syn bimolecular structure.     

Synthesis,characterization and nucleic acid binding studies of mononuclear copper(II) complexes derived from azo containing O,O donor ligands

Abstract

Azo linked salicyldehyde and a new 2-hydroxy acetophenone based ligands (HL¹ and HL²) with their copper(II) complexes [Cu(L¹)₂] (1) and [Cu(L²)₂] (2) were synthesized and characterized by spectroscopic methods such as ¹H, 13C NMR, UV–Vis spectroscopy and elemental analyses. Calculation based on Density Functional Theory (DFT), have been performed to obtain optimized structures. Binding studies of these copper (II) complexes with calf thymus DNA (ct-DNA) and torula yeast RNA (t-RNA) were analyzed by absorption spectra, emission spectra and Viscosity studies and Molecular Docking techniques. The absorption spectral study indicated that the copper(II) complexes of 1 and 2 had intrinsic binding constants with DNA or RNA in the range of 7.6?±?0.2?×?10³?M^?1 or 6.5?±?0.3?×?10³M^?1 and 5.7?±?0.4?×?10⁴ M^?1 or 1.8?±?0.5?×?10³ M^?1 respectively. The synthesized compounds and nucleic acids were simulated by molecular docking to explore more details mode of interaction of the complexes and their orientations in the active site of the receptor.     

Chalcones isolated from Angelica keiskei inhibit cysteine proteases of SARS-CoV

Two viral proteases of severe acute respiratory syndrome coronavirus (SARS-CoV), a chymotrypsin-like protease (3CL^pro) and a papain-like protease (PL^pro) are attractive targets for the development of anti-SARS drugs. In this study, nine alkylated chalcones (1–9) and four coumarins (10–13) were isolated from Angelica keiskei, and the inhibitory activities of these constituents against SARS-CoV proteases (3CL^pro and PL^pro) were determined (cell-free/based). Of the isolated alkylated chalcones, chalcone 6, containing the perhydroxyl group, exhibited the most potent 3CL^pro and PL^pro inhibitory activity with IC₅₀ values of 11.4 and 1.2?µM. Our detailed protein-inhibitor mechanistic analysis of these species indicated that the chalcones exhibited competitive inhibition characteristics to the SARS-CoV 3CL^pro, whereas noncompetitive inhibition was observed with the SARS-CoV PL^pro.     

In vitro and ex vivo biofilms of dermatophytes: a new panorama for the study of antifungal drugs

Abstract

This study describes an ex vivo model that creates an environment for dermatophyte biofilm growth, with features that resemble those of in vivo conditions, designing a new panorama for the study of antifungal susceptibility. Regarding planktonic susceptibility, MIC ranges were 0.125-1?µg ml^?1 for griseofulvin and 0.000097-0.25?µg ml^?1 for itraconazole and terbinafine. sMIC50 ranges were 2->512?µg ml^?1 for griseofulvin and 0.25->64?µg ml^?1 for itraconazole and terbinafine. CLSM images demonstrated a reduction in the amount of cells within the biofilm, but hyphae and conidia were still observed and biofilm biomass was maintained. SEM analysis demonstrated a retraction in the biofilm matrix, but fungal structures and water channels were preserved. These results show that ex vivo biofilms are more tolerant to antifungal drugs than in vitro biofilms, suggesting that environmental and nutritional conditions created by this ex vivo model favor biofilm growth and robustness, and hence drug tolerance.     

Syndromes paranéoplasiques : intérêt de la tomographie par émission de positons (TEP) au 18F-fluoro-déoxyglucose (FDG)

BackgroundWe evaluated the performance of ¹⁸F-fluorodeoxyglucose (¹⁸FDG) positon emission tomography (PET) in the diagnosis of underlying malignancy in cases of suspected paraneoplastic syndrome (PS).Methods¹⁸FDG-PET was performed in 31 patients, clinically suspected to have PS. The PS were 34, among which 12 neurological diseases, eight endocrine, seven rheumatological, one dermatological and six vascular. We compared computed tomography (CT), iodine-enhanced most of the time, and ¹⁸FDG-PET reports to clinicians definitive conclusion at the end of the work-up and a follow-up period of, at least, two months.ResultsWe obtained a histological diagnosis of cancer for ten patients, but could only identify the primary site of malignancy for nine of them. ¹⁸FDG-PET showed six primary sites among which three were not seen on CT. CT disclosed four primary sites, among which one was not seen on ¹⁸FDG-PET. In one case, ¹⁸FDG-PET disclosed regional lymph node metastases whereas these were not identified by CT. Eleven non-neoplasic causes were evidenced, among which ¹⁸FDG-PET played a major role in three cases. Ten causes were still undetermined at the end of the study.ConclusionWhole-body ¹⁸FDG-PET study plays an important role in the identification of underlying malignancy in clinically suspected paraneoplastic syndromes; either by identifying the primary tumor or by directing biopsy of metastases. Furthermore, it can identify non-neoplasic causes.     

Age-dependent effect of ouabain on renal Na+,K+-ATPase

AimsThis study examines the effect of chronic ouabain-treatment on renal Na⁺ handling in 12-week and 52-week old rats.Main methodsWistar Kyoto rats aged 5 weeks or 45 weeks were treated with ouabain or vehicle during 7 weeks. Blood pressure was measured in conscious animals throughout the study. After 7 weeks of treatment urinary electrolyte concentration, Na⁺,K⁺-ATPase activity and α₁-subunit expression were determined in 12-week and 52-week old rats.Key findingsIn 12-week and 52-week old rats ouabain produced a significant increase in systolic blood pressure. Although no differences were observed in Na⁺ excretion in these animals, 12-week old ouabain-treated rats had lower Na⁺,K⁺-ATPase activity in proximal tubules. However, 12-week old ouabain-treated rats had decreased fractional excretion of Na⁺. In proximal tubules of 52-week old rats Na⁺,K⁺-ATPase activity did not differ between vehicle and ouabain-treated groups.SignificanceOur results show that in Wistar Kyoto rats renal response to ouabain treatment may be age-dependent and that the hypertensive effect of ouabain is independent of the effect on renal Na⁺,K⁺-ATPase.     

Structure-activity study of phosphoramido acid esters as acetylcholinesterasf inhibitors

Phosphoramido acid esters (CH₃)₂NP(O)X(p-OC₆H₄-CH₃) (containing P-Cl (1), P-O (2), P-F (3), P-CN (5), and P-N (4,6) bonds, X for 2, 4 and 6 is OCH₃, (C₂H₅)₂N and morpholin) have been synthesized to investigate the structure-activity study of AChE enzyme inhibition, through the parameters logP, δ³¹P and IC₅₀. After their characterization by ³¹P, ³¹P{¹H}, ¹³C, ¹H NMR, IR and mass spectroscopy, the parameters logP and δ³¹P (³¹P chemical shift in NMR) were used to evaluated the lipophilicity and electronical properties. The ability of compounds to inhibit human AChE was predicted by PASS software (version 1.193), and experimentally evaluated by a modified Ellman's assay.     

Évaluation fonctionnelle par TEP 18F-FDopa des paragangliomes et phéochromocytomes non métastatiques : impact de la localisation lésionnelle et du statut génétique

ObjectiveParaganglioma (PGL) and pheochromocytoma (PCC) are neuroendocrine tumors most often benign associated with hereditary syndromes in about 30% of cases. This study aims to define the impact of tumor location and patient genotype on the clinical value of ¹⁸F-FDopa PET by assessing in detail the false negative occurrences.Patients and methodsA retrospective study was conducted on a cohort of 53 cases with non-metastatic sporadic or inherited PGL/PCC (SDHx or VHL related syndromes), investigated with ¹⁸F-FDopa PET.ResultsOverall detection sensitivity of ¹⁸F-FDopa PET was 88%. Seventy-three lesions were found using this technique, including 49 head-and-neck PGL (HNP), two thoracic PGL (1 sympathetic and 1 parasympathetic), eight extra-adrenal retroperitoneal PGL and 15 PCC. The 10 missed lesions were seven extra-adrenal abdominal PGL (2 SDHB, 2 SDHD), two HNP (1 sporadic, 1 SDHD) and one PCC (1 SDHD).Conclusion¹⁸F-FDopa PET is a sensitive technique for the evaluation of non-metastatic head and neck and adrenal PGLs. Exploration of extra-adrenal retroperitoneal PGL associated with SDHB or SDHD syndrome is the main limitation of this technique, encouraging the use of alternative functional imaging modalities like FDG-PET. Negativity of ¹⁸F-FDopa PET in the initial assessment of a PGL should prompt to search for a SDHx mutation.     

Dose-response relationship of elements with blood lipids and the potential interaction: A cross-sectional study from four areas with different pollution levels in China

BackgroundA growing number of researches indicated the association between plasma trace elements and blood lipids. However, the potential interaction and dose-response relationship were less frequently reported.MethodsIn this study, a total of 3548 participants were recruited from four counties in Hunan Province, South China. Demographic characteristics were collected by face-to-face interviews and inductively coupled plasma mass spectrometry (ICPMS) was used to determine the levels of 23 trace elements in plasma. We applied a fully adjusted generalized linear regression model (GLM) and a multivariate restricted cubic spline (RCS) to estimate the correlation, dose-response relationship and possible interaction between 23 trace elements and four blood lipid markers.ResultsThe results indicated positive dose-response relationships of plasma ⁶⁶zinc with triglycerides (TG) and low density lipoprotein cholesterol (LDL-C), plasma ⁷⁸selenium with LDL-C and total cholesterol (TCH), and plasma ⁵⁹cobalt with high-density lipoprotein cholesterol (HDL-C). There was a negative dose-response relationship between ⁵⁹cobalt and LDL-C. Further analysis found that ⁶⁶zinc and ⁵⁹cobalt had an antagonistic effect on the risk of increased LDL-C level.ConclusionsThis study added new evidence for the potential adverse effects of ⁶⁶Zn and ⁷⁸Se on blood lipids, and provided new insight into the threshold value setting for metals as well as the intervention strategy for dyslipidemia.     

Impact of 68Ga-PSMA PET/CT in the treatment of prostate cancer: Initial experience in Spain

AimTo evaluate whether positron-emission tomography/computed tomography with ⁶⁸Ga-PSMA (⁶⁸Ga-PSMA PET/CT) influences the therapeutic management of patients with primary or recurrent prostate cancer (PCa).BackgroundAlthough ⁶⁸Ga-PSMA PET/CT is one of the best options for staging or restaging patients with PCa, its availability is still very limited in Spain. The present study reports the results of the first group of patients in Spain who underwent ⁶⁸Ga-PSMA PET/CT imaging.Materials and methodsAll patients (n = 27) with a histological diagnosis of PCa who underwent ⁶⁸Ga-PSMA PET/CT prior to the definitive treatment decision at the only centre with this technology in Spain during 2017–2018 were included. Two nuclear medicine physicians and a radiologist reviewed the imaging studies. The clinical impact was assessed from a theoretical perspective, based on the treatment that would have been applied if no data from the ⁶⁸Ga-PSMA PET/CT were available.ResultsMost patients (n = 26; 96%) had persistent disease or biochemical recurrence after radical prostatectomy, radiotherapy, or combined treatment. One patient underwent ⁶⁸Ga-PSMA PET/CT imaging to stage high-risk PCa. Overall, ⁶⁸Ga-PSMA PET/CT was positive in 19 patients (70.4%). In 68.75% of these patients, none of the other imaging tests—MRI, CT, or bone scans—performed prior to the ⁶⁸Ga-PSMA PET/CT were able to detect the presence of cancerous lesions. Overall, the findings of the ⁶⁸Ga-PSMA PET/CT led to a modification of the therapeutic approach in 62.96% of the patients in the study.Conclusions⁶⁸Ga-PSMA PET/CT alters the therapeutic approach in a substantial proportion of patients with PCa.     

Étude clinique de phase I avec bénéfice individuel direct de radioimmunothérapie du myélome multiple utilisant l’anticorps anti-CD138 marqué à l’iode 131 (131I-B-B4)

PurposeThe objective of this study was to evaluate the toxicity, the absorbed dose to critical organs and tumour of B-B4 monoclonal antibody labeled with Iodine 131 in patients with multiple myeloma (MM) enrolled in a phase I study.Patients and methodFour patients with MM were enrolled and received for dosimetric study an injection of 20 mg/m² of B-B4 coupled with 370 MBq of Iodine 131. During the treatment phase, after viewing the target, three patients received a fixed dose of 20 mg/m² of ¹³¹I-B-B4 with an initial activity of 555 MBq/m², corresponding to level 1.ResultsImmunoscintigraphy showed an early and intensive uptake of the axial skeleton confirming the targeting of the disease by the antibody. Grade 3/4 haematological toxicity was observed in two patients with a trend to tally with the estimated average dose received by the bone marrow, calculated in the dosimetric study (blood method and imaging method). No other toxicity was observed. No complete or partial response was observed.ConclusionThe dose of 555 MBq/m² of ¹³¹I-B-B4 has shown encouraging results in terms of dosimetry and toxicity of RIT in MM. Other developments are possible with the use of humanized monoclonal antibody and the labeling with an alpha particle emitter.     

Densities and dispersion of breeding Eurasian Hobbies Falco subbuteo in southeast England

Capsule Breeding Hobbies are more numerous in parts of southeast England than previously recognized, and in suitable habitat their breeding dispersion shows a regular pattern.

Aims To establish the density and breeding dispersion pattern of a population of Hobbies in southeast England.

Methods Surveys to locate every pair of Hobbies present were conducted in six study areas of between 48.0 and 201.2 km² in three counties in southeast England during 2005–10.

Results Each study area held between 7 and 21 pairs. Densities were higher than in previous studies conducted in Britain, at between 9.0 and 15.0 pairs per 100 km². Mean densities per unit area of non-developed habitat were also consistently higher than expected, at between 10.1 and 17.3 pairs per 100 km². The mean nearest known neighbour distances fell within the range 1.8–2.8 km. In all six study areas, pairs were regularly spaced. The majority (68.0%) of nesting and territorial pairs occupied sites in woodland.

Conclusions Breeding Hobbies are considerably more numerous in parts of southeast England than previously recognized, and numbers appear to be continuing to increase. Accurate population estimates for Hobbies require species-specific fieldwork.     

流式细胞仪分选人外周血T淋巴细胞的方法建立与评价

目的:利用流式细胞仪同时分离外人周血单个核细胞中T淋巴细胞并检测其分离纯度及存活率。方法:本文采用流式细胞仪同时分选人外周血CD4~+、CD8~+T淋巴细胞为例,推而广之,采用人外周血淋巴细胞分离液梯度离心法制备外周血单个核细胞,采用流式细胞仪同时分选CD4~+、CD8~+T淋巴细胞,分离细胞再通过流式细胞仪回测其分离纯度并通过台盼蓝染色检测分离细胞的存活率。结果:采用此方法能有效人外周血细胞CD4~+、CD8~+T淋巴细胞,分选前CD4~+淋巴细胞纯度为(50.5±11.5)%、CD8~+T淋巴细胞纯度为纯度为(15.4±7.1)%;分选后CD4~+T淋巴细胞纯度为(94.3±1.3)%、CD8~+T淋巴细胞纯度为(93.6±1.6)%;分选后CD4~+T淋巴细胞存活率为(95.3±1.8)%,CD8~+T淋巴细胞存活率为(94.8±1.5)%,细胞的形态完整。结论:采用人外周血淋巴细胞分离液梯度离心法制备外周血单个核细胞后利用流式细胞仪分选的方法能够高效、快速的分离人外周血CD4~+、CD8~+T淋巴细胞,且存活率高,为进一步研究其功能提供了保证。采用不同的荧光抗体标记其他淋巴细胞亚群,也能高效、快速的分离出细胞。     

Simplified patient-specific renal dosimetry in 177Lu therapy: a proof of concept

PurposeThe aim of this proof-of-concept study is to propose a simplified personalized kidney dosimetry procedure in ¹⁷⁷Lu peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors and metastatic prostate cancer. It relies on a single quantitative SPECT/CT acquisition and multiple radiometric measurements executed with a collimated external probe, properly directed on kidneys.MethodsWe conducted a phantom study involving external count-rate measurements in an abdominal phantom setup filled with activity concentrations of ^99mTc, reproducing patient-relevant organ effective half-lives occurring in ¹⁷⁷Lu PRRT. GATE Monte Carlo (MC) simulations of the experiment, using ^99mTc and ¹⁷⁷Lu as sources, were performed. Furthermore, we tested this method via MC on a clinical case of ¹⁷⁷Lu-DOTATATE PRRT with SPECT/CT images at three time points (2, 20 and 70 hrs), comparing a simplified kidney dosimetry, employing a single SPECT/CT and probe measurements at three time points, with the complete MC dosimetry.ResultsThe experimentally estimated kidney half-life with background subtraction applied was compatible within 3% with the expected value. The MC simulations of the phantom study, both with ^99mTc and ¹⁷⁷Lu, confirmed a similar level of accuracy. Concerning the clinical case, the simplified dosimetric method led to a kidney dose estimation compatible with the complete MC dosimetry within 6%, 12% and 2%, using respectively the SPECT/CT at 2, 20 and 70 hrs.ConclusionsThe proposed simplified procedure provided a satisfactory accuracy and would reduce the imaging required to derive the kidney absorbed dose to a unique quantitative SPECT/CT, with consequent benefits in terms of clinic workflows and patient comfort.     

Biosynthesis of Resorcylic Acid Lactone (5S)-5-Hydroxylasiodiplodin in Lasiodiplodia theobromae

An administration study of ²H-labeled precursors showed that the 9-hydroxydecanoyl unit, the acyl intermediate of lasiodiplodin (1), was also the intermediate of (5S)-5-hydroxylasiodiplodin (2) in Lasiodiplodia theobromae. The incorporation of [O-methyl-²H₃]-lasiodiplodin (6) into 2 indicated that hydroxylation at C-5 occurred after cyclization.     

Divergent effects of peripheral and global neuropeptide Y deletion

Objectives:Neuropeptide Y (NPY) is involved in the coordination of bone mass and adiposity. However, multiple NPY sources exist and their individual contribution to the skeleton and adiposity not known. The objectives of our study were to evaluate the effects of peripheral mesenchymal derived NPY to the skeleton and adiposity and to compare them to the global NPY^KO model.Methods:To study the role of mesenchymal-derived NPY, we crossed conditional NPY (NPY^fl/fl) mice with Prx1cre to generate PrxNPY^KO mice. The bone phenotype was assessed using micro-CT. The skeletal phenotype of PrxNPY^KO mice was subsequently compared to global NPY^KO model. We evaluated body weight, adiposity and functionally assessed the feeding response of NPY neurons to determine whether central NPY signaling was altered by Prx1cre.Results:We identified the increase in cortical parameters in PrxNPY^KO mice with no changes to cancellous bone. This was the opposite phenotype to global NPY^KO mice generated from the same conditional allele. Male NPY^KO mice have increased adiposity, while PrxNPY^KO mice showed no difference, demonstrating that local mesenchymal-derived NPY does not influence adiposity.Conclusion:NPY mediates both positive and negative effects on bone mass via separate regulatory pathways. Deletion of mesenchymal-derived NPY had a positive effect on bone mass.