Showing papers by "University of Modena and Reggio Emilia published in 2002"

A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening

Abstract: High-throughput and virtual screening are widely used to discover novel leads for drug design. On examination, many screening hits appear non-drug-like: they act noncompetitively, show little relationship between structure and activity, and have poor selectivity. Attempts to develop these peculiar molecules into viable leads are often futile, and much time can be wasted on the characterization of these “phony” hits. Despite their common occurrence, the mechanism of action of these promiscuous molecules remains unknown. To investigate this problem, 45 diverse screening hits were studied. Fifteen of these were previously reported as inhibitors of various receptors, including β-lactamase, malarial protease, dihydrofolate reductase, HIV Tar RNA, thymidylate synthase, kinesin, insulin receptor, tyrosine kinases, farnesyltransferase, gyrase, prions, triosephosphate isomerase, nitric oxide synthase, phosphoinositide 3-kinase, and integrase; 30 were from an in-house screening library of a major pharmaceutical co...

Muscle-derived hematopoietic stem cells are hematopoietic in origin

Abstract: It has recently been shown that mononuclear cells from murine skeletal muscle contain the potential to repopulate all major peripheral blood lineages in lethally irradiated mice, but the origin of this activity is unknown. We have fractionated muscle cells on the basis of hematopoietic markers to show that the active population exclusively expresses the hematopoietic stem cell antigens Sca-1 and CD45. Muscle cells obtained from 6- to 8-week-old C57BL/6-CD45.1 mice and enriched for cells expressing Sca-1 and CD45 were able to generate hematopoietic but not myogenic colonies in vitro and repopulated multiple hematopoietic lineages of lethally irradiated C57BL/6-CD45.2 mice. These data show that muscle-derived hematopoietic stem cells are likely derived from the hematopoietic system and are a result not of transdifferentiation of myogenic stem cells but instead of the presence of substantial numbers of hematopoietic stem cells in the muscle. Although CD45-negative cells were highly myogenic in vitro and in vivo, CD45-positive muscle-derived cells displayed only very limited myogenic activity and only in vivo.

Nature of DNA Damage in Ejaculated Human Spermatozoa and the Possible Involvement of Apoptosis

Abstract: Numerous studies have shown the presence of DNA strand breaks in human ejaculated spermatozoa. The nature of this nuclear anomaly and its relationship to patient etiology is however poorly understood. The aim of this study was to investigate the relationship between nuclear DNA damage, assessed using the TUNEL assay and a number of key apoptotic markers, including Fas, Bcl-x, and p53, in ejaculated human spermatozoa from men with normal and abnormal semen parameters. We also determined the nature of the DNA damage by examining the percentage of ejaculated spermatozoa exhibiting DNA damage using the comet assay and by challenging sperm chromatin to attack by micrococcal nuclease S7 and DNase I. We show that TUNEL positivity and apoptotic markers do not always exist in unison; however, semen samples that had a low sperm concentration and poor morphology were more likely to show high levels of TUNEL positivity and Fas and p53 expression. In addition, the DNA damage in ejaculated human sperm is represented by both single- and double-stranded DNA breaks, and access to the DNA is restricted by the compacted nature of ejaculated spermatozoa. This DNA protection is poorer in men with abnormal semen parameters. We propose that the presence of DNA damage is not directly linked to an apoptotic process occurring in spermatozoa and arises due to problems in the nuclear remodeling process. Subsequently, the presence of apoptotic proteins in ejaculated spermatozoa may be linked to defects in cytoplasmic remodeling during the later stages of spermatogenesis.

Identification of the nicotinic receptor subtypes expressed on dopaminergic terminals in the rat striatum.

Abstract: Neuronal nicotinic acetylcholine receptors (nAChRs) expressed on mesostriatal dopaminergic neurons are thought to mediate several behavioral effects of nicotine, including locomotion, habit learning, and reinforcement. Using immunoprecipitation and ligand-binding techniques, we have shown that both alpha6beta2* and alpha4(nonalpha6)beta2* nAChRs are expressed in the caudate-putamen and that only alpha6* nAChRs can bind alpha-conotoxin MII and methyllycaconitine with affinities of 1.3 and 40 nm, respectively. Further studies performed on 6-hydroxydopamine-lesioned striatum led to the identification of nAChR subtypes selectively expressed on dopaminergic terminals [alpha4alpha5beta2, alpha4alpha6beta2(beta3), and alpha6beta2(beta3)], nondopaminergic neuronal structures (alpha2alpha4beta2), or both structures (alpha4beta2). The identification of the nAChRs expressed on striatal dopaminergic terminals opens up the possibility of developing selective nAChR ligands active on dopaminergic systems and associated diseases, such as Parkinson's disease.

Increased Expression of the Chemokine Receptor CXCR3 and Its Ligand CXCL10 in Peripheral Airways of Smokers with Chronic Obstructive Pulmonary Disease

Abstract: CXCR3 is a chemokine receptor preferentially expressed on lymphocytes, particularly on type-1 T-lymphocytes. Smokers who develop chronic obstructive pulmonary disease (COPD) have a chronic bronchopulmonary inflammation that is characterized by an increased infiltration of T-lymphocytes, particularly CD8(+), in the airways and lung parenchyma. To investigate the expression of CXCR3 and its ligand interferon-induced protein 10/CXCL10 in COPD, we counted the number of CXCR3(+) cells and analyzed the expression of CXCL10 in the peripheral airways of 19 patients undergoing lung resection for localized pulmonary lesions. We examined lung specimens from seven smokers with fixed airflow limitation (COPD), five smokers with normal lung function, and seven nonsmoking subjects with normal lung function. The number of CXCR3(+) cells was immunohistochemically quantified in the epithelium, in the submucosa, and in the adventitia of peripheral airways. The number of CXCR3(+) cells in the epithelium and submucosa was increased in smokers with COPD as compared with nonsmoking subjects, but not as compared with smokers with normal lung function. Immunoreactivity for the CXCR3-ligand CXCL10 was present in the bronchiolar epithelium of smokers with COPD but not in the bronchiolar epithelium of smoking and nonsmoking control subjects. Most CXCR3(+) cells coexpressed CD8 and produced interferon gamma. These findings suggest that the CXCR3/CXCL10 axis may be involved in the T cell recruitment that occurs in peripheral airways of smokers with COPD and that these T cells may have a type-1 profile.

Distribution and Pharmacology of α6-Containing Nicotinic Acetylcholine Receptors Analyzed with Mutant Mice

Abstract: The alpha6 subunit of the nicotinic acetylcholine receptor (nAChR) is expressed at very high levels in dopaminergic (DA) neurons. However, because of the lack of pharmacological tools selective for alpha6-containing nAChRs, the role of this subunit in the etiology of nicotine addiction remains unknown. To provide new tools to investigate this issue, we generated an alpha6 nAChR knock-out mouse. Homozygous null mutants (alpha6-/-) did not exhibit any gross neurological or behavioral deficits. A careful anatomic and molecular examination of alpha6-/- mouse brains demonstrated the absence of developmental alterations in these animals, especially in the visual and dopaminergic pathways, where the alpha6 subunit is normally expressed at the highest levels. On the other hand, receptor autoradiography revealed a decrease in [3H]nicotine, [3H]epibatidine, and [3H]cytisine high-affinity binding in the terminal fields of retinal ganglion cells of alpha6-/- animals, whereas high-affinity [125I]alpha-conotoxinMII (alphaCtxMII) binding completely disappeared in the brain. Moreover, inhibition of [3H]epibatidine binding on striatal membranes, using unlabeled alphaCtxMII or cytisine, revealed the absence of alphaCtxMII-sensitive and cytisine-resistant [3H]epibatidine binding sites in alpha6-/- mice, although the total amount of binding was unchanged. Because alphaCtxMII, a toxin formerly thought to be specific for alpha3beta2-containing nAChRs, is known to partially inhibit nicotine-induced dopamine release, these results support the conclusion that alpha6 rather than alpha3 is the partner of beta2 in the nicotinic modulation of DA neurons. They further show that alpha6-/- mice might be useful tools to understand the mechanisms of nicotine addiction, although some developmental compensation might occur in these mice.

Risk of Non-Hodgkin Lymphoma in Celiac Disease

Abstract: ContextCeliac disease is one of the most common lifelong disorders. Non-Hodgkin lymphoma is a possible complication of celiac disease and may lead to a large portion of lymphoma cases.ObjectiveTo quantify the risk for developing non-Hodgkin lymphoma of any primary site associated with celiac disease.Design and SettingMulticenter, case-control study conducted between January 1996 and December 1999 throughout Italy.PatientsCases were older than 20 years (median, 57; range, 20-92 years) with non-Hodgkin lymphoma of any primary site and histological type and were recruited at the time of the diagnosis. Controls were healthy adults (2739 men and 2981 women) from the general population.Main Outcome MeasurePositive test result for class A serum antiendomysial antibody.ResultsCeliac disease was diagnosed in 6 (0.92%) of 653 patients with lymphoma. Of the 6 cases, 3 were of B-cell and 3 were of T-cell origin. Four of 6 cases had lymphoma primarily located in the gut. In the control group, 24 (0.42%) had celiac disease. The odds ratio (adjusted for age and sex) for non-Hodgkin lymphoma of any primary site associated with celiac disease was 3.1 (95% confidence interval [CI], 1.3-7.6), 16.9 (95% CI, 7.4-38.7) for gut lymphoma, and 19.2 (95% CI, 7.9-46.6) for T-cell lymphoma, respectively. The risk for non-Hodgkin lymphoma for the overall population, which was adjusted for age and sex, was 0.63% (95% CI, − 0.12% to 1.37%).ConclusionCeliac disease is associated with an increased risk for non-Hodgkin lymphoma, especially of T-cell type and primarily localized in the gut. However, the association does not represent a great enough risk to justify early mass screening for celiac disease.

Hyper Inverse Wishart Distribution for Non-decomposable Graphs and its Application to Bayesian Inference for Gaussian Graphical Models

Abstract: While conjugate Bayesian inference in decomposable Gaussian graphical models is largely solved, the non-decomposable case still poses difficulties concerned with the specification of suitable priors and the evaluation of normalizing constants. In this paper we derive the DY-conjugate prior (Diaconis & Ylvisaker, 1979) for non-decomposable models and show that it can be regarded as a generalization to an arbitrary graph G of the hyper inverse Wishart distribution (Dawid & Lauritzen, 1993). In particular, if G is an incomplete prime graph it constitutes a non-trivial generalization of the inverse Wishart distribution. Inference based on marginal likelihood requires the evaluation of a normalizing constant and we propose an importance sampling algorithm for its computation. Examples of structural learning involving non-decomposable models are given. In order to deal efficiently with the set of all positive definite matrices with non-decomposable zero-pattern we introduce the operation of triangular completion of an incomplete triangular matrix. Such a device turns out to be extremely useful both in the proof of theoretical results and in the implementation of the Monte Carlo procedure.

Accuracy of an eight-point tactile-electrode impedance method in the assessment of total body water.

Abstract: Objective: To establish the accuracy of an eight-polar tactile-electrode impedance method in the assessment of total body water (TBW). Design: Transversal study. Setting: University department. Subjects: Fifty healthy subjects (25 men and 25 women) with a mean (s.d.) age of 40 (12) y. Methods: TBW measured by deuterium oxide dilution; resistance (R) of arms, trunk and legs measured at frequencies of 5, 50, 250 and 500 kHz with an eight-polar tactile-electrode impedance-meter (InBody 3.0, Biospace, Seoul, Korea). Results: An algorithm for the prediction of TBW from the whole-body resistance index at 500 kHz (height 2/R500 where R is the sum of the segmental resistances of arms, trunk and legs) was developed in a randomly chosen subsample of 35 subjects. This algorithm had an adjusted coefficient of determination (r2adj) of 0.81 (P<0.0001) and a root mean square error (RMSE) of 3.6 l (9%). Cross-validation of the predictive algorithm in the remaining 15 subjects gave an r2adj of 0.87 (P<0.0001) and an RMSE of 3.0 l (8%). The precision of eight-polar BIA, determined by measuring R three times a day for five consecutive days in a fasting subject, was ≤2.8% for all segments and frequencies. Conclusion: Eight-polar BIA is a precise method that offers accurate estimates of TBW in healthy subjects. This promising method should undergo further studies of precision and its accuracy in assessing extracellular water and appendicular body composition should be determined. Sponsorship: Modena and Reggio Emilia University.

Characterisation of gastric ghrelin cells in man and other mammals: studies in adult and fetal tissues

Abstract: Ghrelin is a new gastric peptide involved in food intake control and growth hormone release. We aimed to assess its cell localisation in man during adult and fetal life and to clarify present interspecies inconsistencies of gastric endocrine cell types. A specific serum generated against amino acids 13–28 of ghrelin was tested on fetal and adult gastric mucosa and compared with ghrelin in situ hybridisation. Immunogold electron microscopy was performed on normal human, rat and dog adult stomach. Ghrelin cells were detected in developing gut, pancreas and lung from gestational week 10 and in adult human, rat and dog gastric mucosa. By immunogold electron microscopy, gastric ghrelin cells showed distinctive morphology and hormone reactivity in respect to histamine enterochromaffin-like, somatostatin D, glucagon A or serotonin enterochromaffin cells. Ghrelin cells were characterised by round, compact, electron-dense secretory granules of P/D1 type in man (mean diameter 147±30 nm), A-like type in the rat (183±37 nm) and X type in the dog (273±49 nm). It is concluded that, ghrelin is produced by well-defined cell types, which in the past had been labelled differently in various mammals mostly because of the different size of their secretory granule. In man ghrelin cells develop during early fetal life.

EuroCOIN: a real time coincident indicator for the Euro area business cycle

Abstract: This Paper is the result of the Bank of Italy-CEPR project to construct a monthly coincident indicator of the business cycle of the euro area. The index is estimated on the basis of a harmonized data set of monthly statistics of the euro area (951 series) which we constructed from a variety of sources. We use the information of this large panel to obtain an indicator which has three characteristics: (i) it provides real time information on monthly coincident activity since it is updated as new information become available in a non-synchronous way; (ii) it is cleaned from noise originated from measurement error and idiosyncratic national and sectoral dynamics; (iii) it is cleaned from seasonal and short-run dynamics through a filter that requires very little revision at the end of the sample. Unlike other methods used in the literature, the procedure takes into consideration the cross-country as well as the within-country correlation structure and exploits all information on dynamic cross-correlations. As a by product of our analysis, we provide a characterization of the commonality and dynamic relations of the series in the data set with respect to the coincident indicator and a dating of the euro area cycle.

Cramped synchronized general movements in preterm Infants as an early marker for cerebral palsy

Abstract: Objective To ascertain whether specific abnormalities (ie, cramped synchronized general movements [GMs]) can predict cerebral palsy and the severity of later motor impairment in preterm infants affected by brain lesions. Design Traditional neurological examination was performed, and GMs were serially videotaped and blindly observed for 84 preterm infants with ultrasound abnormalities from birth until 56 to 60 weeks' postmenstrual age. The developmental course of GM abnormalities was compared with brain ultrasound findings alone and with findings from neurological examination, in relation to the patient's outcome at age 2 to 3 years. Results Infants with consistent or predominant (33 cases) cramped synchronized GMs developed cerebral palsy. The earlier cramped synchronized GMs were observed, the worse was the neurological outcome. Transient cramped synchronized character GMs (8 cases) were followed by mild cerebral palsy (fidgety movements were absent) or normal development (fidgety movements were present). Consistently normal GMs (13 cases) and poor repertoire GMs (30 cases) either lead to normal outcomes (84%) or cerebral palsy with mild motor impairment (16%). Observation of GMs was 100% sensitive, and the specificity of the cramped synchronized GMs was 92.5% to 100% throughout the age range, which is much higher than the specificity of neurological examination. Conclusions Consistent and predominant cramped synchronized GMs specifically predict cerebral palsy. The earlier this characteristic appears, the worse is the later impairment.

Mica Crystal Chemistry and the Influence of Pressure, Temperature, and Solid Solution on Atomistic Models

Abstract: The 2:1 mica layer is composed of two opposing tetrahedral (T) sheets with an octahedral (M) sheet between to form a “TMT” layer (Fig. 1a⇓). The mica structure has a general formula of A M2–3 T4 O10 X2 [in natural micas: A = interlayer cations, usually K, Na, Ca, Ba, and rarely Rb, Cs, NH4, H3O, and Sr; M = octahedral cations, generally Mg, Fe2+, Al, and Fe3+, but other cations such as Li, Ti, V, Cr, Mn, Co, Ni, Cu, and Zn can occur also in mica species; T = tetrahedral cations, generally Si, Al and Fe3+ and rarely B and Be; X = (OH), F, Cl, O, S]. Vacant positions (symbol:□) are also common in the mica structure (Rieder et al. 1998). In the tetrahedral sheet, individual TO4 tetrahedra are linked with neighboring TO4 by sharing three corners each (i.e., the basal oxygen atoms) to form an infinite two-dimensional “hexagonal” mesh pattern (Fig. 1b⇓). The fourth oxygen atom (i.e., the apical oxygen atom) forms a corner of the octahedral coordination unit around the M cations. Thus, each octahedral anion atom-coordination unit is comprised of four apical oxygen atoms (two from the upper and two from the lower tetrahedral sheet) and by two (OH) or F, Cl, O and S anions [the X anions, usually indicated as the OH or O(4) site]. The OH site is at the same level as the apical oxygen but not shared with tetrahedra. In the octahedral sheet, individual octahedra are linked laterally by sharing octahedral edges (Fig. 1c⇓). The smallest structural unit contains three octahedral sites. Structures with all three sites occupied are known as trioctahedral, whereas, if only two octahedra are occupied [usually M(2)] …

Revising the past (while thinking in the future perfect tense)

Abstract: Accounting for organizational history is essential to any change process. We argue, however, that the intentional revision of that history also can be important. We treat history as malleable, because events and actions from the past are susceptible to reinterpretation as organizations try to align with the way they see themselves in the present and want to see themselves in the future. Because change is a prospective, future‐oriented process, whereas sensemaking is a retrospective, past‐oriented process, making sense of the future requires an ability to envision the future as having already occurred, i.e. to think in the future perfect tense. We offer an initial conceptual exploration of organizational change from a revisionist history perspective that turns on future perfect thinking, a view that enlarges our conceptualization of the ways in which history affects organizational adaptation and change.

Control of cytochrome C redox potential: axial ligation and protein environment effects.

Abstract: Axial iron ligation and protein encapsulation of the heme cofactor have been investigated as effectors of the reduction potential (E degrees ') of cytochrome c through direct electrochemistry experiments. Our approach was that of partitioning the E degrees ' changes resulting from binding of imidazole, 2-methyl-imidazole, ammonia, and azide to both cytochrome c and microperoxidase-11 (MP11), into the enthalpic and entropic contributions. N-Acetylmethionine binding to MP11 was also investigated. These ligands replace Met80 and a water molecule axially coordinated to the heme iron in cytochrome c and MP11, respectively. This factorization was achieved through variable temperature E degrees ' measurements. In this way, we have found that (i) the decrease in E degrees ' of cytochrome c due to Met80 substitution by a nitrogen-donor ligand is almost totally enthalpic in origin, as a result of the stronger electron donor properties of the exogenous ligand which selectively stabilize the ferric state; (ii) on the contrary, the binding of the same ligands and N-acetylmethionine to MP11 results in an enthalpic stabilization of the reduced state, whereas the entropic effect invariably decreases E degrees ' (the former effect prevails for the methionine ligand and the latter for the nitrogenous ligands). A comparison of the reduction thermodynamics of cytochrome c and the MP11 adducts offers insight on the effect of changing axial heme ligation and heme insertion into the folded polypeptide chain. Principally, we have found that the overall E degrees ' increase of approximately 400 mV, comparing MP11 and native cytochrome c, consists of two opposite enthalpic and entropic terms of approximately +680 and -280 mV, respectively. The enthalpic term includes contributions from both axial methionine binding (+300 mV) and protein encapsulation of the heme (+380 mV), whereas the entropic term is almost entirely manifest at the stage of axial ligand binding. Both terms are dominated by the effects of water exclusion from the heme environment.

Magnetic anisotropy of the antiferromagnetic ring [Cr8F8Piv16].

Abstract: A new tetragonal (P4212) crystalline form of [Cr8F8Piv16] (HPiv=pivalic acid, trimethyl acetic acid) is reported. The ring-shaped molecules, which are aligned in a parallel fashion in the unit cell, form almost perfectly planar, regular octagons. The interaction between the CrIII ions is antiferromagnetic (J=12 cm−1) which results in a S=0 spin ground state. The low-lying spin excited states were investigated by cantilever torque magnetometry (CTM) and high-frequency EPR (HFEPR). The compound shows hard-axis anisotropy. The axial zero-field splitting (ZFS) parameters of the first two spin excited states (S=1 and S=2, respectively) are D1=1.59(3) cm−1 or 1.63 cm−1 (from CTM and HFEPR, respectively) and D2=0.37 cm−1 (from HFEPR). The dipolar contributions to the ZFS of the S=1 and S=2 spin states were calculated with the point dipolar approximation. These contributions proved to be less than the combined single-ion contributions. Angular overlap model calculations that used parameters obtained from the electronic absorption spectrum, showed that the unique axis of the single-ion ZFS is at an angle of 19.3(1)° with respect to the ring axis. The excellent agreement between the experimental and the theoretical results show the validity of the used methods for the analysis of the magnetic anisotropy in antiferromagnetic CrIII rings.

Mitochondrial DNA depletion: Mutations in thymidine kinase gene with myopathy and SMA

Abstract: Background: The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an autosomal recessive disorder of early childhood characterized by decreased mtDNA copy number in affected tissues. Recently, MDS has been linked to mutations in two genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 ( TK2 ) and deoxy-guanosine kinase ( dGK ). Mutations in TK2 have been associated with the myopathic form of MDS, and mutations in dGK with the hepatoencephalopathic form. Objectives: To further characterize the frequency and clinical spectrum of these mutations, the authors screened 20 patients with myopathic MDS. Results: No patient had dGK gene mutations, but four patients from two families had TK2 mutations. Two siblings were compound heterozygous for a previously reported H90N mutation and a novel T77M mutation. The other siblings harbored a homozygous I22M mutation, and one of them had evidence of lower motor neuron disease. The pathogenicity of these mutations was confirmed by reduced TK2 activity in muscle (28% to 37% of controls). Conclusions: These results show that the clinical expression of TK2 mutations is not limited to myopathy and that the myopathic form of MDS is genetically heterogeneous.

The Italian multi-centre project on evaluation of MRI and other imaging modalities in early detection of breast cancer in subjects at high genetic risk.

Abstract: This report presents the preliminary results of the first phase (21 months) of a multi-centre, non-randomised, prospective study, aimed at evaluating the effectiveness of contrast-enhanced magnetic resonance imaging (MRI), X-ray mammography (XM) and ultrasound (US) in early diagnosis of breast cancer (BC) in subjects at high genetic risk. This Italian national trial (coordinated by the Istituto Superiore di Sanita, Rome) so far recruited 105 women (mean age 46.0 years; median age 51.0; age range 25-77 years), who were either proven BRCA1 or BRCA2 mutation carriers or had a 1 in 2 probability of being carriers (40/105 with a previous personal history of BC). Eight cases of breast carcinomas were detected in the trial (mean age 55.3 years, median age 52.5; age range 35-70 years; five with previous personal history of BC). All trial-detected BC cases (8/8) were identified by MRI, while XM and US correctly classified only one. MRI had one false positive case, XM and US none. Seven "MRI-only" detected cancers (4 invasive, 3 in situ) occurred in both pre- (n = 2) and post-menopausal (n = 5) women. With respect to the current XM screening programmes addressed to women in the age range 50-69 years, the global incidence of BC in the trial (7.6%) was over ten-fold higher. The cost per "MRI-only" detected cancer in this particular category of subjects at high genetic risk was substantially lower than that of an XM-detected cancer in the general women population. These preliminary results confirmed that MRI is a very useful tool to screen subjects at high genetic risk for breast carcinoma, not only in pre-, but also in post-menopausal age, with a low probability of false positive cases.

Genes and translocations involved in POF.

Abstract: Changes at a single autosomal locus and many X-linked loci have been implicated in women with gonadal dysgenesis [premature ovarian failure (POF) with deficits in ovarian follicles]. For the chromosome 3 locus, a forkhead transcription factor gene (FOXL2) has been identified, in which lesions result in decreased follicles by haploinsufficiency. In contrast, sporadic X; autosomal translocations are distributed at many points on the X, but concentrate in a critical region on Xq. The association of the breakpoints with genes involved in ovarian function is thus far weak (in four analyzed cases) and has not been related to pathology in other POF patients. While many more translocations can be analyzed in detail as the human genome sequence is refined, it remains possible that translocations like X monosomy (Turner syndrome) lead to POF not by interrupting specific genes important in ovarian development, but by causing aberrations in pairing or X-inactivation during folliculogenesis. It is noted that the critical region has unusual features, neighboring the X-inactivation center and including an 18 Mb region of very low recombination. These suggest that chromosome dynamics in the region may be sensitive to structural changes, and when modified by translocations might provoke apoptosis at meiotic checkpoints. Choices among models for the etiology of POF should be feasible based on studies of ovarian follicle development and attrition in mouse models. Studies would prominently include gene expression profiling of developmental-specific pathways in nascent ovaries with controlled levels of Foxl2 and interacting proteins, or with defined changes in the X chromosome.

Emx2 regulates the proliferation of stem cells of the adult mammalian central nervous system.

Abstract: The appropriate control of proliferation of neural precursors has fundamental implications for the development of the central nervous system and for cell homeostasis/replacement within specific brain regions throughout adulthood. The role of genetic determinants in this process is largely unknown. We report the expression of the homeobox transcription factor Emx2 within the periventricular region of the adult telencephalon. This neurogenetic area displays a large number of multipotent stem cells. Adult neural stem cells isolated from this region do express Emx2 and down-regulate it significantly upon differentiation into neurons and glia. Abolishing or, increasing Emx2 expression in adult neural stem cells greatly enhances or reduces their rate of proliferation, respectively. We determined that altering the expression of Emx2 affects neither the cell cycle length of adult neural stem cells nor their ability to generate neurons and glia. Rather, when Emx2 expression is abolished, the frequency of symmetric divisions that generate two stem cells increases, whereas it decreases when Emx2 expression is enhanced.

Holey fiber analysis through the finite-element method

Abstract: A holey fiber (HF), having very complex hole geometry, is studied by means of a numerical simulator for modal analysis based on the finite-element method (FEM). Polarization and dispersion properties as well as the full vector field distribution of the fundamental mode are investigated. The obtained numerical results show a good agreement with experimental ones reported in literature.

Physiology of iron transport and the hemochromatosis gene

Abstract: Iron is essential for fundamental cell functions but is also a catalyst for chemical reactions involving free radical formation, potentially leading to oxidative stress and cell damage. Cellular ir...

The long history of Cannabis and its cultivation by the Romans in central Italy, shown by pollen records from Lago Albano and Lago di Nemi

Abstract: The cores from the Albano and Nemi lakes, near Rome, were studied within the European Union funded PALICLAS project and provided high resolution records of the Late-glacial and Holocene. Pollen evidence of increasing human influence on vegetation was recorded in the Holocene parts of both diagrams, and the Cannabis (hemp) curve was one of the major signs. In this paper we present unambiguous pollen evidence from the Cannabaceae records for the cultivation of hemp in central Italy by the Romans. The oldest records of Cannabis and Humulus (hop) date from to the Late-glacial. Hop pollen values rise during the mid Holocene, while hemp pollen becomes more abundant from ca. 3000 cal B.P. onwards. The highest earliest hemp peak (21%) is dated to the 1st century A.D. This ‘Cannabis phase’, with the abrupt rise of hemp pollen soon after the rise of cultivated trees (Castanea, Juglans and Olea) is associated with the increase in cereals and ruderal plants. This unambiguous proof of cultivation by Romans around 2000 B.P. occurs as well as a long lasting pre-Roman presence of hemp in the area, which is natural and possibly also anthropogenic. Subsequent clear episodes of cultivation in the medieval period were found.

Selective COX-2 inhibitors and dual acting anti-inflammatory drugs: critical remarks.

Abstract: Non steroidal anti-inflammatory drugs (NSAIDs) are still the most commonly used remedies for rheumatic diseases. But NSAIDs produce serious adverse effects, the most important being gastric injury up to gastric ulceration and renal damage. Several strategies have been adopted in order to avoid these shortcomings, especially gastrointestinal toxicity. So, non steroidal anti-inflammatory drugs have been associated with gastroprotective agents that counteract the damaging effects of prostaglandin synthesis suppression: however, a combination therapy introduces problems of pharmacokinetics, toxicity, and patient s compliance. Also incorporation of a nitric oxide (NO)-generating moiety into the molecule of several NSAIDs was shown to greatly attenuate their ulcerogenic activity: however, several findings suggest a possible involvement of NO in the pathogenesis of arthritis and subsequent tissue destruction. A most promising approach seemed to be the preparation of novel NSAIDs, specific for the inducible isoform of cyclooxygenase (COX-2): they appear to be devoid of gastrointestinal toxicity, in that they spare mucosal prostaglandin synthesis. However, a number of recent studies raised serious questions about the two central tenets that support this approach, namely that the prostaglandins that mediate inflammation and pain are produced solely via COX-2 and that the prostaglandins that are important in gastrointestinal and renal function are produced solely via COX-1. So, increasing evidence shows that COX-2 (not only COX-1) also plays a physiological role in several body functions and that, conversely, COX-1 (not only COX-2) may also be induced at sites of inflammation. Moreover, COX-2 selective NSAIDs have lost the cardiovascular protective effects of non-selective NSAIDs, effects which are mediated through COX-1 inhibition (in addition, COX-2 has a role in sustaining vascular prostacyclin production). The products generated by the 5-lipoxygenase pathway (leukotrienes) are particularly important in inflammation: indeed, leukotrienes increase microvascular permeability and are potent chemotactic agents; moreover, inhibition of 5-lipoxygenase indirectly reduces the expression of TNF-alpha (a cytokine that plays a key role in inflammation). This explains the efforts to obtain drugs able to inhibit both 5-lipoxygenase and cyclooxygenases: the so-called dual acting anti-inflammatory drugs. Such compounds retain the activity of classical NSAIDs, while avoiding their main drawbacks, in that curtailed production of gastroprotective prostaglandins is associated with a concurrent curtailed production of the gastro-damaging and bronchoconstrictive leukotrienes. Moreover, thanks to their mechanism of action, dual acting anti-inflammatory drugs could not merely alleviate symptoms of rheumatic diseases, but might also satisfy, at least in part, the criteria of curative drugs. Indeed, leukotrienes are pro-inflammatory, increase microvascular permeability, are potent chemotactic agents and attract eosinophils, neutrophils and monocytes into the synovium. Finally, recent data strongly suggest that dual inhibitors may have specific protective activity also in neurodegeneration.