Communication

RNA-catalyzed RNA ligation is widely believed to be a key reaction for primordial biology. However, since typical chemical routes towards activating RNA substrates are incompatible with ribozyme catalysis, it remains unclear how prebiotic systems generated and sustained pools of activated building blocks needed to form increasingly larger and complex RNA. Herein, we demonstrate in situ activation of RNA substrates under reaction conditions amenable to catalysis by the hairpin ribozyme. We found that diamidophosphate (DAP) and imidazole drive the formation of 2 ',3 '-cyclic phosphate RNA mono- and oligonucleotides from monophosphorylated precursors in frozen water-ice. This long-lived activation enables iterative enzymatic assembly of long RNAs. Our results provide a plausible scenario for the generation of higher-energy substrates required to fuel ribozyme-catalyzed RNA synthesis in the absence of a highly evolved metabolism

A thrips vector of tomato spotted wilt virus responds to tomato acylsugar chemical diversity with reduced oviposition and virus inoculation.

There is increasing evidence that acylsugars deter insect pests and plant virus vectors, including the western flower thrips (WFT), Frankliniella occidentalis (Pergande), vector of tomato spotted wilt virus (TSWV). Acylsugars are sugar-polyesters composed of saturated, un-saturated, and variously branched short and long chain fatty acids (FAs) esterified to a glucose (acylglucose) or sucrose (acylsucrose) moiety. We sought to understand how acylsucrose amount and composition of associated FA profiles interacted to mediate resistance to WFT oviposition and TSWV inoculation on tomato leaves. Towards this goal, we examined WFT oviposition and TSWV inoculation behavior on tomato lines bred to exude varying amounts of acylsucrose in association with diverse FA profiles. Our data show that as acylsucrose amounts increased, WFT egg-laying (oviposition) decreased and TSWV inoculation was suppressed. Western flower thrips also responded to FA profiles that included iC4, iC11, nC12 and nC10 FA. These findings support improving acylsugar-mediated resistance against WFT by breeding tomatoes exuding greater amounts of acylsucrose associated with specific FA profiles. We show that increasing acylsucrose amount output by type IV trichomes and selecting for particular FA profiles through advanced breeding profoundly affects WFT behavior in ways that benefit management of WFT as direct pests and as TSWV vectors

Chondrosarcoma of the Pelvis: Oncologic and Functional Outcome

Purpose. Chondrosarcoma (CS) most commonly involves the pelvis. The factors that influence local and systemic control of pelvic CS and the functional outcome should be evaluated

Human HT-29 colon carcinoma cells contain mucarinic M3_3 receptors coupled to phosphoinositide metabolism

Five different musearlnie receptor subtypes ean be distinguished by the differenees in their amino aeid sequence, the eoupled signal transduetion system, pharmaeologieal binding properties and aetivation of ionie fluxes. The present study served to eharaeterize the binding profile of musearlnie receptors in human eolon eareinoma eells (HT-29) using seleetive musearlnie antagonists. The affinities of the compounds were eompared with their poteney to inhibit cholinergieally-aetivated phosphoinositide metabolism. Pirenzepine displaced [$^3$H]N-methyl-scopolamine binding and inhibited inositolphosphate (IP) release with potencies typieal of those of non-M$_1$ receptors. The M$_3$ subtype-selective antagonists sila-hexocyelium and hexahydro-sila-difenidol bad high affinity to the musearlnie reeeptors in HT-29 cells (K0 = 3.1 nM and 27 nM, respectively) and inhibited IP release at nanomolar concentrations. The M$_2$ receptor antagonists, AF-DX 116 and methoctramine, had low antimusearinic poteneies. Our results demonstrate that HT-29 human colon earcinoma cells contain an apparently pure population of M$_3$ receptors. These cells could serve as a model system for further investigations coneerning regulatory and signal transduction mechanisms associated with glandular muscarinic M$_3$ receptors

Early down-regulation of the pro-inflammatory potential of monocytes is correlated to organ dysfunction in patients after severe multiple injury: a cohort study

Introduction Severe tissue trauma results in a general inflammatory immune response (SIRS) representing an overall inflammatory reaction of the immune system. However, there is little known about the functional alterations of monocytes in the early posttraumatic phase, characterized by the battle of the individual with the initial trauma. Methods Thirteen patients with severe multiple injury; injury severity score (ISS) >16 points (17 to 57) were included. The cytokine synthesis profiles of monocytes were characterized on admission, and followed up 6, 12, 24, 48, and 72 hours after severe multiple injury using flow cytometry. Whole blood was challenged with lipopolysaccharide (LPS) and subsequently analyzed for intracellular monocyte-related TNF-alpha, IL-1 beta, IL-6, and IL-8. The degree of organ dysfunction was assessed using the multiple organ dysfunction syndrome (MODS)-score of Marshall on admission, 24 hours and 72 hours after injury. Results Our data clearly show that the capacity of circulating monocytes to produce these mediators de novo was significantly diminished very early reaching a nadir 24 hours after severe injury followed by a rapid and nearly complete recovery another 48 hours later compared with admission and controls, respectively. In contrast to the initial injury severity, there was a significant correlation detectable between the clinical signs of multiple organ dysfunction and the ex vivo cytokine response. Conclusions As our data derived from very narrow intervals of measurements, they might contribute to a more detailed understanding of the early immune alterations recognized after severe trauma. It can be concluded that indeed as previously postulated an immediate hyperactivation of circulating monocytes is rapidly followed by a substantial paralysis of cell function. Moreover, our findings clearly demonstrate that the restricted capacity of monocytes to produce proinflammatory cytokines after severe injury is not only an in vitro phenomenon but also undistinguishable associated with the onset of organ dysfunction in the clinical scenario

Syntbesis and Properries of the Selective Antimuscarinic Agent Cyclohexylphenyl(3-piperidinopropyl)silanol

Die Synthese des selektiven Antimuskarinikums Cyclohexylpheny\{3-piperidinopropyl)sila· nol (1 b) wird beschrieben. 1 b wurde - ausgehend von (3·Chlorpropyl)trimethoxysilan - durch eine vierstufige Reaktionsfolge erhalten und als Hydrochlorid 2b mit einer Gesamtausbeute von etwa 45°/o isoliert. - 1 b ist aufgrund seiner großen pharmakologischen Se· lektivität zu einer Standardsubstanz in der experimentellen Pharmakologie bei der Differenzierung von Muskarinrezeptoren geworden.The synthesis of thc selective antimuscarinic agent cyclohexylphenyl(3-piperidinopropyl)silanol (1 b) is described. Starting with (3-chloropropyl)trimethoxysilane, I b was obtained by four reaction steps and isolated as hydrochloride 2b with a total yield of about 45°/o. - Because of its high pharmacological selectivity 1 b has become a reference drug in experimental pharmacology for the differentiation of muscarinic rcceptors

The sequential trauma score - a new instrument for the sequential mortality prediction in major trauma*

<p>Abstract</p> <p>Background</p> <p>There are several well established scores for the assessment of the prognosis of major trauma patients that all have in common that they can be calculated at the earliest during intensive care unit stay. We intended to develop a sequential trauma score (STS) that allows prognosis at several early stages based on the information that is available at a particular time.</p> <p>Study design</p> <p>In a retrospective, multicenter study using data derived from the Trauma Registry of the German Trauma Society (2002-2006), we identified the most relevant prognostic factors from the patients basic data (P), prehospital phase (A), early (B1), and late (B2) trauma room phase. Univariate and logistic regression models as well as score quality criteria and the explanatory power have been calculated.</p> <p>Results</p> <p>A total of 2,354 patients with complete data were identified. From the patients basic data (P), logistic regression showed that age was a significant predictor of survival (AUC_{model p}, area under the curve = 0.63). Logistic regression of the prehospital data (A) showed that blood pressure, pulse rate, Glasgow coma scale (GCS), and anisocoria were significant predictors (AUC_{model A}= 0.76; AUC_{model P + A}= 0.82). Logistic regression of the early trauma room phase (B1) showed that peripheral oxygen saturation, GCS, anisocoria, base excess, and thromboplastin time to be significant predictors of survival (AUC_{model B1}= 0.78; AUC_{model P +A + B1}= 0.85). Multivariate analysis of the late trauma room phase (B2) detected cardiac massage, abbreviated injury score (AIS) of the head ≥ 3, the maximum AIS, the need for transfusion or massive blood transfusion, to be the most important predictors (AUCmodel B2 = 0.84; AUCfinal model P + A + B1 + B2 = 0.90). The explanatory power - a tool for the assessment of the relative impact of each segment to mortality - is 25% for P, 7% for A, 17% for B1 and 51% for B2. A spreadsheet for the easy calculation of the sequential trauma score is available at: <url>http://www.sequential-trauma-score.com</url></p> <p>Conclusions</p> <p>This score is the first sequential, dynamic score to provide a prognosis for patients with blunt major trauma at several points in time. With every additional piece of information the precision increases. The medical team has a simple, useful tool to identify patients at high risk and to predict the prognosis of an individual patient with major trauma very early, quickly and precisely.</p

Spectroscopy of 35^{35}P using the one-proton knockout reaction

The structure of $^{35}$P was studied with a one-proton knockout reaction at88~MeV/u from a $^{36}$S projectile beam at NSCL. The $\gamma$ rays from thedepopulation of excited states in $^{35}$P were detected with GRETINA, whilethe $^{35}$P nuclei were identified event-by-event in the focal plane of theS800 spectrograph. The level scheme of $^{35}$P was deduced up to 7.5 MeV using$\gamma-\gamma$ coincidences. The observed levels were attributed to protonremovals from the $sd$-shell and also from the deeply-bound $p\_{1/2}$ orbital.The orbital angular momentum of each state was derived from the comparisonbetween experimental and calculated shapes of individual ($\gamma$-gated)parallel momentum distributions. Despite the use of different reactions andtheir associate models, spectroscopic factors, $C^2S$, derived from the$^{36}$S $(-1p)$ knockout reaction agree with those obtained earlier from$^{36}$S($d$,\nuc{3}{He}) transfer, if a reduction factor $R\_s$, as deducedfrom inclusive one-nucleon removal cross sections, is applied to the knockout transitions.In addition to the expected proton-hole configurations, other states were observedwith individual cross sections of the order of 0.5~mb. Based on their shiftedparallel momentum distributions, their decay modes to negative parity states,their high excitation energy (around 4.7~MeV) and the fact that they were notobserved in the ($d$,\nuc{3}{He}) reaction, we propose that they may resultfrom a two-step mechanism or a nucleon-exchange reaction with subsequent neutronevaporation. Regardless of the mechanism, that could not yet be clarified, thesestates likely correspond to neutron core excitations in \nuc{35}{P}. Thisnewly-identified pathway, although weak, offers the possibility to selectivelypopulate certain intruder configurations that are otherwise hard to produceand identify.Comment: 5 figures, 1 table, accepted for publication in Physical Review

The Role of the Subgenual Anterior Cingulate Cortex and Amygdala in Environmental Sensitivity to Infant Crying

This work was supported by the Swiss National Science Foundation (SNF): Grant 51A240-104890 to FHW and ES, and the Swiss National Science Foundation (SNF): Grant PA00P1_145418 to IM and the Freiwillige Akademische Gesellschaft to IM