Sinorhizobium Meliloti, A Bacterium Lacking The Autoinducer-2 (AI-2) Synthase, Responds To AI-2 Supplied By Other Bacteria

Many bacterial species respond to the quorum-sensing signal autoinducer-2 (AI-2) by regulating different niche-specific genes. Here, we show that Sinorhizobium meliloti, a plant symbiont lacking the gene for the AI-2 synthase, while not capable of producing AI-2 can nonetheless respond to AI-2 produced by other species. We demonstrate that S. meliloti has a periplasmic binding protein that binds AI-2. The crystal structure of this protein (here named SmlsrB) with its ligand reveals that it binds (2R,4S)-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran (R-THMF), the identical AI-2 isomer recognized by LsrB of Salmonella typhimurium. The gene encoding SmlsrB is in an operon with orthologues of the lsr genes required for AI-2 internalization in enteric bacteria. Accordingly, S. meliloti internalizes exogenous AI-2, and mutants in this operon are defective in AI-2 internalization. S. meliloti does not gain a metabolic benefit from internalizing AI-2, suggesting that AI-2 functions as a signal in S. meliloti. Furthermore, S. meliloti can completely eliminate the AI-2 secreted by Erwinia carotovora, a plant pathogen shown to use AI-2 to regulate virulence. Our findings suggest that S. meliloti is capable of \u27eavesdropping\u27 on the AI-2 signalling of other species and interfering with AI-2-regulated behaviours such as virulence

Lepton-Flavour Violation in Ordinary and Supersymmetric Grand Unified Theories

By an explicit calculation we show that in ordinary SU(5) logarithmic divergence in the amplitude of $\mu \to e\gamma$ cancels among diagrams and remaining finite part is suppressed by at least $1/M_{GUT}^2$. In SUSY SU(5), when the effect of flavour changing wave function renormalization is taken into account such logarithmic correction disappears, provided a condition is met among SUSY breaking masses. In SUGRA-inspired SUSY GUT the remaining logarithmic effect is argued not to be taken as a prediction of the theory.Comment: 8 pages, LaTeX209 file, using axodraw.st

The PACE study: past-year prevalence of tension-type headache and its subtypes in Parma's adult general population.

The mean global prevalence of tension-type headache (TTH) in adult is 42 %. To date, there have been no Italian studies on TTH prevalence in the adult general population. Therefore, we conducted a cross-sectional study, called PACE, aimed at detecting the prevalence of primary headaches in the city of Parma's adult general population. 904 subjects representative of Parma's adult general population were interviewed face to face by a physician of our Headache Centre. Crude past-year prevalence for definite TTH was 19.4 % (95 % CI 16.8-21.9; 18.4 %, 95 % CI 14.6-22.3 in men, and 20.1 %, 95 % CI 16.6-23.6 in women), namely, 9.0 % (95 % CI 7.1-10.8) for infrequent TTH, 9.8 % (95 % CI 7.9-11.8) for frequent TTH, and 0.6 % (95 % CI 0.1-1) for chronic TTH. Crude prevalence for probable TTH was 2.3 % (95 % CI 1.3-3.3; 2 %, 95 % CI 0.6-3.4 in men, and 2.6 %, 95 % CI 1.2-3.9 in women). Our results indicate a TTH prevalence (19.4 %) at the lower limit of data ranges for Western countries, and prevalence rates for infrequent forms (9 %) do not appear different from those of frequent forms (9.8 %)

Prevalence of tension-type headache in adult general population: the PACE study and review of the literature

The mean global prevalence of tension-type headache (TTH) in adult is 42 %. To date, there have been no Italian studies on TTH prevalence in the adult general population. Therefore, we conducted a cross-sectional study, called PACE (PArma CEfalea, or "Headache in Parma"), aimed at detecting the prevalence and clinical features of primary headaches in the city of Parma's adult general population. Crude past-year prevalence for definite TTH was 19.4 % (95 % CI 16.8-21.9), namely 9.0 % (95 % CI 7.1-10.8) for infrequent TTH, 9.8 % (95 % CI 7.9-11.8) for frequent TTH, and 0.6 % (95 % CI 0.1-1) for chronic TTH. Crude prevalence for probable TTH was 2.3 % (95 % CI 1.3-3.3). Our study results indicate a TTH prevalence rate (19.4 %) at the lower limit of data ranges currently available for Western countries, and prevalence rates for infrequent forms (9 %) do not appear much different from those of frequent forms (9.8 %)

Metaflammasome components in the human brain: a role in dementia with alzheimer's pathology?

Epidemiological and genetic studies have identified metabolic disorders and inflammation as risk factors for Alzheimer's disease (AD). Evidence in obesity and type-2 diabetes suggests a role for a metabolic inflammasome (“metaflammasome”) in mediating chronic inflammation in peripheral organs implicating IKKβ (inhibitor of nuclear factor kappa-B kinase subunit beta), IRS1 (insulin receptor substrate 1), JNK (c-jun N-terminal kinase), and PKR (double-stranded RNA protein kinase). We hypothesized that these proteins are expressed in the brain in response to metabolic risk factors in AD. Neocortex from 299 participants from the MRC Cognitive Function and Ageing Studies was analysed by immunohistochemistry for the expression of the phosphorylated (active) form of IKKβ [pSer176/180], IRS1 [pS312], JNK [pThr183/Tyr185] and PKR [pT451]. The data were analyzed to investigate whether the proteins were expressed together and in relation with metabolic disorders, dementia, Alzheimer's pathology and APOE genotype. We observed a change from a positive to a negative association between the proteins and hypertension according to the dementia status. Type-2 diabetes was negatively related with the proteins among participants without dementia; whereas participants with dementia and AD pathology showed a positive association with JNK. A significant association between IKKβ and JNK in participants with dementia and AD pathology was observed, but not in those without dementia. Otherwise, weak to moderate associations were observed among the protein loads. The presence of dementia was significantly associated with JNK and negatively associated with IKKβ and IRS1. Cognitive scores showed a significant positive relationship with IKKβ and a negative with IRS1, JNK and PKR. The proteins were significantly associated with pathology in Alzheimer's participants with the relationship being inverse or not significant in participants without dementia. Expression of the proteins was not related to APOE genotype. These findings highlight a role for these proteins in AD pathophysiology but not necessarily as a complex

A niche-mimicking polymer hydrogel-based approach to identify molecular targets for tackling human pancreatic cancer stem cells.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is one of the most fatal human cancers, but effective therapies remain to be established. Cancer stem cells (CSCs) are highly resistant to anti-cancer drugs and a deeper understanding of their microenvironmental niche has been considered important to provide understanding and solutions to cancer eradication. However, as the CSC niche is composed of a wide variety of biological and physicochemical factors, the development of multidisciplinary tools that recapitulate their complex features is indispensable. Synthetic polymers have been studied as attractive biomaterials due to their tunable biofunctionalities, while hydrogelation technique further renders upon them a diversity of physical properties, making them an attractive tool for analysis of the CSC niche. METHODS: To develop innovative materials that recapitulate the CSC niche in pancreatic cancers, we performed polymer microarray analysis to identify niche-mimicking scaffolds that preferentially supported the growth of CSCs. The niche-mimicking activity of the identified polymers was further optimized by polyethylene glycol (PEG)-based hydrogelation. To reveal the biological mechanisms behind the activity of the optimized hydrogels towards CSCs, proteins binding onto the hydrogel were analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS), and the potential therapeutic targets were validated by looking at gene expression and patients' outcome in the TCGA database. RESULTS: PA531, a heteropolymer composed of 2-methoxyethyl methacrylate (MEMA) and 2-(diethylamino)ethyl methacrylate (DEAEMA) (5.5:4.5) that specifically supports the growth and maintenance of CSCs was identified by polymer microarray screening using the human PAAD cell line KLM1. The polymer PA531 was converted into five hydrogels (PA531-HG1 to HG5) and developed to give an optimized scaffold with the highest CSC niche-mimicking activities. From this polymer that recapitulated CSC binding and control, the proteins fetuin-B and angiotensinogen were identified as candidate target molecules with clinical significance due to the correlation between gene expression levels and prognosis in PAAD patients and the proteins associated with the niche-mimicking polymer. CONCLUSION: This study screened for biofunctional polymers suitable for recapitulation of the pancreatic CSC niche and one hydrogel with high niche-mimicking abilities was successfully fabricated. Two soluble factors with clinical significance were identified as potential candidates for biomarkers and therapeutic targets in pancreatic cancers. Such a biomaterial-based approach could be a new platform in drug discovery and therapy development against CSCs, via targeting of their niche

On P Systems as a Modelling Tool for Biological Systems

We introduce a variant of P systems where rules have associated a real number providing a measure for the “intrinsic reactivity”of the rule and roughly corresponding to the kinetic coefficient which, in bio-chemistry, is usually associated to each molecular reaction. The behaviour of these P systems is then defined according to a strategy which, in each step, randomly selects the next rule to be applied depending upon a certain distribution of probabilities. As an application, we present a P system model of the quorum sensing regulatory networks of the bacterium Vibrio Fischeri. In this respect, a formalisation of the network in terms of P systems is provided and some simulation results concerning the behaviour of a colony of such bacteria are reported. We also briefly describe the implementation techniques adopted by pointing out the generality of our approach which appears to be fairly independent from the particular choice of P system variant and the language used to implement it.Ministerio de Ciencia y Tecnología TIC2002-04220-C03-0

Evolution of central pattern generators for the control of a five-link bipedal walking mechanism

Central pattern generators (CPGs), with a basis is neurophysiological studies, are a type of neural network for the generation of rhythmic motion. While CPGs are being increasingly used in robot control, most applications are hand-tuned for a specific task and it is acknowledged in the field that generic methods and design principles for creating individual networks for a given task are lacking. This study presents an approach where the connectivity and oscillatory parameters of a CPG network are determined by an evolutionary algorithm with fitness evaluations in a realistic simulation with accurate physics. We apply this technique to a five-link planar walking mechanism to demonstrate its feasibility and performance. In addition, to see whether results from simulation can be acceptably transferred to real robot hardware, the best evolved CPG network is also tested on a real mechanism. Our results also confirm that the biologically inspired CPG model is well suited for legged locomotion, since a diverse manifestation of networks have been observed to succeed in fitness simulations during evolution.Comment: 11 pages, 9 figures; substantial revision of content, organization, and quantitative result

Role of the Small GTPase Rho3 in Golgi/Endosome Trafficking through Functional Interaction with Adaptin in Fission Yeast

BACKGROUND: We had previously identified the mutant allele of apm1(+) that encodes a homolog of the mammalian µ1A subunit of the clathrin-associated adaptor protein-1 (AP-1) complex, and we demonstrated the role of Apm1 in Golgi/endosome trafficking, secretion, and vacuole fusion in fission yeast. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we isolated rho3(+), which encodes a Rho-family small GTPase, an important regulator of exocystosis, as a multicopy-suppressor of the temperature-sensitive growth of the apm1-1 mutant cells. Overexpression of Rho3 suppressed the Cl(-) sensitivity and immunosuppressant sensitivity of the apm1-1 mutant cells. Overexpression of Rho3 also suppressed the fragmentation of vacuoles, and the accumulation of v-SNARE Syb1 in Golgi/endosomes and partially suppressed the defective secretion associated with apm1-deletion cells. Notably, electron microscopic observation of the rho3-deletion cells revealed the accumulation of abnormal Golgi-like structures, vacuole fragmentation, and accumulation of secretory vesicles; these phenotypes were very similar to those of the apm1-deletion cells. Furthermore, the rho3-deletion cells and apm1-deletion cells showed very similar phenotypic characteristics, including the sensitivity to the immunosuppressant FK506, the cell wall-damaging agent micafungin, Cl(-), and valproic acid. Green fluorescent protein (GFP)-Rho3 was localized at Golgi/endosomes as well as the plasma membrane and division site. Finally, Rho3 was shown to form a complex with Apm1 as well as with other subunits of the clathrin-associated AP-1 complex in a GTP- and effector domain-dependent manner. CONCLUSIONS/SIGNIFICANCE: Taken together, our findings reveal a novel role of Rho3 in the regulation of Golgi/endosome trafficking and suggest that clathrin-associated adaptor protein-1 and Rho3 co-ordinate in intracellular transport in fission yeast. To the best of our knowledge, this study provides the first evidence of a direct link between the small GTPase Rho and the clathrin-associated adaptor protein-1 in membrane trafficking