bluuebunny/crossref_metadata_2025 huggingface dataset:
Choice of Comparator in Active Control Trials of New Drugs
Authors: Luijn Johan CF van , Loenen Arie C van , Gribnau Frank WJ , Leufkens Hubert GM
Published: October 2008

Background:

When choosing the active control group in a randomized that, it is important to maintain standard treatment for the therapeutic indication for which a medicine is studied. This choice is relevant not only for demonstrating the efficacy and safety of a new drug, but also for assessing Its place in therapy in comparison with existing medicines. Comparative information is important for decisions on prescribing and reimbursement. However, choosing the most suitable comparator is difficult when recommendations on drugs of first choice vary depending on clinical settings and times.

Objective:

To evaluate the choice of comparator in premarketing randomized active control trials (RaCTs) in comparison with recommendations lor standard treatment.

Methods:

We evaluated drugs that were authorized for use in the European Union market between 1999 and 2005. Information on active comparators in RaCTs was extracted from the European Public Assessment Reports and information on recommendations regarding standard treatment was retrieved from the annual editions of the Dutch reference book on pharmacotherapy. Data on prescribing and indications at the time of authorization and 3 years before authorization were included. The comparator was considered to be in line with standard treatment if there was a similarity in both active substance or therapeutic class and the dosage.

Results:

For 58 new medications identified, treatment in the active control group was in line with the recommended standard treatment in 108 of 153 (71%) RaCTs at the time of the drug's authorization; 47 (81%) of the new drugs had been compared with the recommended standard treatment in at least one trial. When dissimilarities occurred, none of the comparators had been recommended as standard treatment 3 years earlier (the supposed time of defining the trials' protocol).

Conclusions:

Most comparators in the premarketing RaCTs of new medicines were in line with the recommended standard treatment at the moment of marketing authorization. In view of this similarity, most of these trials are also fit for postmarketing decision-making on prescribing and on inclusion in clinical guidelines and reimbursement systems.
Use of Leflunomide in the Treatment of Polyomavirus BK-Associated Nephropathy
Authors: Wu Judy K , Harris Matthew T
Published: October 2008

Objective:

To review the available literature describing the use of leflunomide for the treatment of Polyomavirus BK-associated nephropathy (BKVAN) in renal transplant recipients.

Data Sources:

Relevant literature was obtained through MEDLINE (1950–May 2008) and Science Citation Index Expanded (1900–May 2008) by using search terms leflunomide, Arava, Polyomavirus, polyoma, BK virus, and transplant. Additional articles were identified through a manual search of the reference lists of the articles obtained.

Study Selection and Data Extraction:

All articles that were written in English and discussed leflunomide use for BKVAN In renal transplant recipients were evaluated. Case reports and in vitro studies were included in this review.

Data Synthesis:

BKVAN has emerged as a problematic infectious complication with limited treatment options in renal transplant recipients. Leflunomide, used off-label for refractory BKVAN, is postulated to possess both antiviral and immunosuppressive properties. Two in vitro culture studies, 5 case reports/series, 2 retrospective cohort studies, and 3 prospective observational trials that described leflunomide use in BKVAN were identified. Available literature suggests that leflunomide at target blood concentrations of around 40 mg/L, in addition to immunosuppressive reduction, reduces BK viremia/viruria and graft failure, with few dose-limiting adverse events. It is highly recommended that routine complete blood cell counts, hepatic function panels, and drug concentrations be monitored to detect toxicity.

Conclusions:

Leflunomide appears to be promising as adjunctive treatment of BKVAN in renal transplant patients. Due to the tack of controlled randomized trials, however, use of leflunomide as first-line treatment cannot be routinely recommended.
Evaluation of Sodium Nitroprusside Toxicity in Pediatric Cardiac Surgical Patients
Authors: Moffett Brady Scott , Price Jack F
Published: October 2008

Background:

Sodium nitroprusside (SNP) is often used in postoperative pediatric cardiac surgical patients. Cyanide toxicity may occur with the use of SNP. There is a paucity of literature describing dosing parameters or physical signs and symptoms of toxicity with SNP.

Objective:

To determine the incidence of cyanide toxicity in postoperative pediatric cardiac surgical patients treated with SNP and identify dosing parameters and physical signs and symptoms that may predict elevated cyanide concentrations.

Methods:

Medical records of patients who received SNP in the pediatric cardiac intensive care unit from January 2002 through December 2002 were identified and evaluated for cyanide and thiocyanate levels, dosing, and signs and symptoms of toxicity. Patients were included if they had received SNP after cardiac surgery, were 18 years of age or less, and had at least one cyanide or thiocyanate level determined while receiving therapy. Patients were excluded if they had received sodium thiosulfate. The Mann-Whitney U test was used to determine significant differences in mean dose, duration of infusion, renal function, serum lactate, and acid-base status between groups with elevated or nonelevated levels. Logistic regression and receiver operator curve were used to determine variables associated with elevated levels. Relationships between signs and symptoms of toxicity and elevated levels were evaluated with Fisher's exact test.

Results:

Cyanide concentrations were in the toxic range in 7 of 63 (11%) patients. Patients with elevated concentrations had significantly higher mean dose, cumulative dose, and acid-base excess values. Elevated cyanide levels were independently predicted by mean dose, cumulative dose, and acid-base excess values, and a dose of 1.8 μg/kg/min predicted an elevated cyanide concentration with 89% sensitivity and 88% specificity. Adverse events were not reliable predictors of elevated cyanide levels.

Conclusions:

Mean dose of SNP is the best predictor of elevated cyanide levels. Adverse events commonly associated with cyanide toxicity may not be reliable indicators of elevated cyanide concentrations.
Serotonin Syndrome Risks When Combining SSRI/SNRI Drugs and Triptans: is the FDA's Alert Warranted?
Authors: Wenzel Richard G , Tepper Stewart , Korab William E , Freitag Fredrick
Published: October 2008

In 2006 the Food and Drug Administration (FDA) issued an alert, based on 27 case reports gathered over a 5-year span, regarding serotonin syndrome resulting from concurrent use of either a selective serotonin-re uptake inhibitor (SSRI) or a selective serotonin/norepinephrine reuptake inhibitor (SNRI) with a triptan. These diagnoses have been subsequently challenged as not meeting validated criteria for serotonin syndrome, in part because the FDA has yet to publicly disseminate important case report data. As a result of the FDA's alert, some clinicians are reluctant or refuse to provide these drugs concomitantly to patients. We believe that withholding these medications due to fears of serotonin syndrome is difficult to justify. In contrast to the small number of case reports, research shows that approximately 700,000 patients annually take SSRIs or SNRIs with triptans and that this drug combination has been effectively used by millions of individuals over the past decade. We encourage healthcare professionals to familiarize themselves with data on serotonin syndrome and to administer SSRIs/SNRIs with triptans when clinically appropriate.
Motion Adaptation Enhances Object-Induced Neural Activity in Three-Dimensional Virtual Environment
Authors: Liang Pei , Kern Roland , Egelhaaf Martin
Published: October 2008

Many response characteristics of neurons sensitive to visual motion depend on stimulus history and change during prolonged stimulation. Although the changes are usually regarded as adaptive, their functional significance is still not fully understood. With experimenter-defined stimuli, previous research on motion adaptation has mainly focused on enhancing the detection of changes in the stimulus domain, on preventing output saturation and on energy efficient coding. Here we will analyze in the blowfly visual system the functional significance of motion adaptation under the complex stimulus conditions encountered in the three-dimensional world. Identified motion sensitive neurons are confronted with seminatural optic flow as is seen by semi-free-flying animals as well as targeted modifications of it. Motion adaptation is shown to enhance object-induced neural responses in a three-dimensional environment although the overall neuronal response amplitude decreases during prolonged motion stimulation.
Formin-Dependent Synaptic Growth: Evidence That Dlar Signals via Diaphanous to Modulate Synaptic Actin and Dynamic Pioneer Microtubules
Authors: Pawson Catherine , Eaton Benjamin A. , Davis Graeme W.
Published: October 2008

Thediaphanousgene is the founding member of a family of Diaphanous-related formin proteins (DRFs). We identifieddiaphanousin a screen for genes that are necessary for the normal growth and stabilization of theDrosophilaneuromuscular junction (NMJ). Here, we demonstrate thatdiaphanousmutations perturb synaptic growth at the NMJ. Diaphanous protein is present both presynaptically and postsynaptically. However, genetic rescue experiments in combination with additional genetic interaction experiments support the conclusion thatdiais necessary presynaptically for normal NMJ growth. We then document defects in both the actin and microtubule cytoskeletons indiamutant nerve terminals. In so doing, we define and characterize a population of dynamic pioneer microtubules within the NMJ that are distinct from the bundled core of microtubules identified by the MAP1b-like protein Futsch. Defects in both synaptic actin and dynamic pioneer microtubules are correlated with impaired synaptic growth indiamutants. Finally, we present genetic evidence that Dia functions downstream of the presynaptic receptor tyrosine phosphatase Dlar and the Rho-type GEF (guanine nucleotide exchange factor)trioto control NMJ growth. Based on the established function of DRFs as Rho-GTPase-dependent regulators of the cell cytoskeleton, we propose a model in which Diaphanous links receptor tyrosine phosphatase signaling at the plasma membrane to growth-dependent modulation of the synaptic actin and microtubule cytoskeletons.
Excitatory Local Connections of Superficial Neurons in Rat Auditory Cortex
Authors: Barbour Dennis L. , Callaway Edward M.
Published: October 2008

The mammalian cerebral cortex consists of multiple areas specialized for processing information for many different sensory modalities. Although the basic structure is similar for each cortical area, specialized neural connections likely mediate unique information processing requirements. Relative to primary visual (V1) and somatosensory (S1) cortices, little is known about the intrinsic connectivity of primary auditory cortex (A1). To better understand the flow of information from the thalamus to and through rat A1, we made use of a rapid, high-throughput screening method exploiting laser-induced uncaging of glutamate to construct excitatory input maps of individual neurons. We found that excitatory inputs to layer 2/3 pyramidal neurons were similar to those in V1 and S1; these cells received strong excitation primarily from layers 2–4. Both anatomical and physiological observations, however, indicate that inputs and outputs of layer 4 excitatory neurons in A1 contrast with those in V1 and S1. Layer 2/3 pyramids in A1 have substantial axonal arbors in layer 4, and photostimulation demonstrates that these pyramids can connect to layer 4 excitatory neurons. Furthermore, most or all of these layer 4 excitatory neurons project out of the local cortical circuit. Unlike S1 and V1, where feedback to layer 4 is mediated exclusively by indirect local circuits involving layer 2/3 projections to deep layers and deep feedback to layer 4, layer 4 of A1 integrates thalamic and strong layer 4 recurrent excitatory input with relatively direct feedback from layer 2/3 and provides direct cortical output.
Inhibition of M Current in Sensory Neurons by Exogenous Proteases: A Signaling Pathway Mediating Inflammatory Nociception
Authors: Linley John E. , Rose Kirstin , Patil Mayur , Robertson Brian , Akopian Armen N. , Gamper Nikita
Published: October 2008

Inflammatory pain is thought to be mediated in part through the action of inflammatory mediators on membrane receptors of peripheral nerve terminals, however, the downstream signaling events which lead to pain are poorly understood. In this study we investigated the nociceptive pathways induced by activation of protease-activated receptor 2 (PAR-2) in damage-sensing (nociceptive) neurons from rat dorsal root ganglion (DRG). We found that activation of PAR-2 in these cells strongly inhibited M-type potassium currents (conducted by Kv7 potassium channels). Such inhibition caused depolarization of the neuronal resting membrane potential leading, ultimately, to nociception. Consistent with this mechanism, injection of the specific M channel blocker XE991 into rat paw induced nociception in a concentration-dependent manner. Injection of a PAR-2 agonist peptide also induced nociception but coinjection of XE991 and the PAR-2 agonist did not result in summation of nociception, suggesting that the action of both agents may share a similar mechanism. We also studied the signaling pathway of M current inhibition by PAR-2 using patch-clamp and fluorescence imaging of DRG neurons. These experiments revealed that the PAR-2 effect was mediated by phospholipase C (PLC). Further experiments demonstrated that M current inhibition required concurrent rises in cytosolic Ca2+concentration and depletion of membrane phosphatidylinositol 4,5-bisphosphate (PIP2). We propose that PLC- and Ca2+/PIP2-mediated inhibition of M current in sensory neurons may represent one of the general mechanisms underlying pain produced by inflammatory mediators, and may therefore open up a new therapeutic window for treatment of this major clinical problem.
Monoamine Oxidase A Genotype Predicts Human Serotonin 1A Receptor AvailabilityIn Vivo
Authors: Mickey Brian J. , Ducci Francesca , Hodgkinson Colin A. , Langenecker Scott A. , Goldman David , Zubieta Jon-Kar
Published: October 2008

The serotonergic system, including the serotonin 1A (5-HT1A) receptor, has been implicated in the pathophysiology of a number of neuropsychiatric disorders. Current data show substantial interindividual variation in the regional concentration of this receptor site, the source of which is unclear. Monoamine oxidase A (MAO-A) is a key regulator of serotonin metabolism, and polymorphic variation in the X-linked MAO-A gene influences its expression. We hypothesized that polymorphism in the MAO-A gene would be associated with sex-specific variation in 5-HT1Areceptor expression. We used positron emission tomography and [11C]WAY-100635 to quantify 5-HT1Areceptors in a group of 31 healthy and unmedicated depressed individuals. The same individuals were genotyped for an upstream variable number tandem repeat polymorphism in the promoter of the MAO-A gene. ANOVA of 5-HT1Areceptor availability demonstrated a significant effect of MAO-A genotype in the raphe nuclei, medial and inferior temporal cortex, insula, medial prefrontal cortex, and anterior cingulate (p< 0.05). The effect persisted when age, race, body mass index, and diagnosis were included in the model. Genotypes with greater putative MAO-A activity were associated with greater 5-HT1Areceptor availability in women, but not in men. Genotype predicted a substantial 42–74% of the variance in receptor availability in women, depending on the brain region (p< 0.05). Depression diagnosis was not associated with MAO-A genotype or 5-HT1Areceptor availability in these regions. These results demonstrate a sex-specific interaction between two key molecules of the human serotonergic system, and suggest a neurobiological basis for sexual dimorphism in serotonin-modulated phenotypes.
Multivoxel Pattern Selectivity for Perceptually Relevant Binocular Disparities in the Human Brain
Authors: Preston Tim J. , Li Sheng , Kourtzi Zoe , Welchman Andrew E.
Published: October 2008

Processing of binocular disparity is thought to be widespread throughout cortex, highlighting its importance for perception and action. Yet the computations and functional roles underlying this activity across areas remain largely unknown. Here, we trace the neural representations mediating depth perception across human brain areas using multivariate analysis methods and high-resolution imaging. Presenting disparity-defined planes, we determine functional magnetic resonance imaging (fMRI) selectivity to near versus far depth positions. First, we test the perceptual relevance of this selectivity, comparing the pattern-based decoding of fMRI responses evoked by random dot stereograms that support depth perception (correlated RDS) with the decoding of stimuli containing disparities to which the perceptual system is blind (anticorrelated RDS). Preferential disparity selectivity for correlated stimuli in dorsal (visual and parietal) areas and higher ventral area LO (lateral occipital area) suggests encoding of perceptually relevant information, in contrast to early (V1, V2) and intermediate ventral (V3v, V4) visual cortical areas that show similar selectivity for both correlated and anticorrelated stimuli. Second, manipulating disparity parametrically, we show that dorsal areas encode the metric disparity structure of the viewed stimuli (i.e., disparity magnitude), whereas ventral area LO appears to represent depth position in a categorical manner (i.e., disparity sign). Our findings suggest that activity in both visual streams is commensurate with the use of disparity for depth perception but the neural computations may differ. Intriguingly, perceptually relevant responses in the dorsal stream are tuned to disparity content and emerge at a comparatively earlier stage than categorical representations for depth position in the ventral stream.
A Dopaminergic Axon Lattice in the Striatum and Its Relationship with Cortical and Thalamic Terminals
Authors: Moss Jonathan , Bolam J. Paul
Published: October 2008

Interactions between glutamatergic corticostriatal afferents and dopaminergic nigrostriatal afferents are central to basal ganglia function. The thalamostriatal projection provides a glutamatergic innervation of similar magnitude to the corticostriatal projection. We tested the hypotheses that (1) thalamostriatal synapses have similar spatial relationships with dopaminergic axons as corticostriatal synapses do and (2) the spatial relationships between excitatory synapses and dopaminergic axons are selective associations. We examined at the electron microscopic level rat striatum immunolabeled to reveal vesicular glutamate transporters (VGluTs) 1 and 2, markers of corticostriatal and thalamostriatal terminals, respectively, together with tyrosine hydroxylase (TH) to reveal dopaminergic axons. Over 80% of VGluT-positive synapses were within 1 μm of a TH-positive axon and >40% were within 1 μm of a TH-positive synapse. Of structures postsynaptic to VGluT1- or VGluT2-positive terminals, 21 and 27%, respectively, were apposed by a TH-positive axon and about half of these made synaptic contact. When structures postsynaptic to VGluT-positive terminals and VGluT-positive terminals themselves were normalized for length of plasma membrane, the probability of them being apposed by, or in synaptic contact with, a TH-positive axon was similar to that of randomly selected structures. Extrapolation of the experimental data to more closely reflect the distribution in 3D reveals that all structures in the striatum are within ∼1 μm of a TH-positive synapse. We conclude that (1) thalamostriatal synapses are in a position to be influenced by released dopamine to a similar degree as corticostriatal synapses are and (2) these associations arise from a nonselective dopaminergic axon lattice.
A Decrease in Anandamide Signaling Contributes to the Maintenance of Cutaneous Mechanical Hyperalgesia in a Model of Bone Cancer Pain
Authors: Khasabova Iryna A. , Khasabov Sergey G. , Harding-Rose Catherine , Coicou Lia G. , Seybold Bryan A. , Lindberg Amy E. , Steevens Christopher D. , Simone Donald A. , Seybold Virginia S.
Published: October 2008

Tumors in bone are associated with pain in humans. Data generated in a murine model of bone cancer pain suggest that a disturbance of local endocannabinoid signaling contributes to the pain. When tumors formed after injection of osteolytic fibrosarcoma cells into the calcaneus bone of mice, cutaneous mechanical hyperalgesia was associated with a decrease in the level of anandamide (AEA) in plantar paw skin ipsilateral to tumors. The decrease in AEA occurred in conjunction with increased degradation of AEA by fatty acid amide hydrolase (FAAH). Intraplantar injection of AEA reduced the hyperalgesia, and intraplantar injection of URB597, an inhibitor of FAAH, increased the local level of AEA and also reduced hyperalgesia. An increase in FAAH mRNA and enzyme activity in dorsal root ganglia (DRG) L3–L5 ipsilateral to the affected paw suggests DRG neurons contribute to the increased FAAH activity in skin in tumor-bearing mice. Importantly, the anti-hyperalgesic effects of AEA and URB597 were blocked by a CB1 receptor antagonist. Increased expression of CB1 receptors by DRG neurons ipsilateral to tumor-bearing limbs may contribute to the anti-hyperalgesic effect of elevated AEA levels. Furthermore, CB1 receptor protein-immunoreactivity as well as inhibitory effects of AEA and URB597 on the depolarization-evoked Ca2+transient were increased in small DRG neurons cocultured with fibrosarcoma cells indicating that fibrosarcoma cells are sufficient to evoke phenotypic changes in AEA signaling in DRG neurons. Together, the data provide evidence that manipulation of peripheral endocannabinoid signaling is a promising strategy for the management of bone cancer pain.
Unmasking the CA1 Ensemble Place Code by Exposures to Small and Large Environments: More Place Cells and Multiple, Irregularly Arranged, and Expanded Place Fields in the Larger Space
Authors: Fenton André A. , Kao Hsin-Yi , Neymotin Samuel A. , Olypher Andrey , Vayntrub Yevgeniy , Lytton William W. , Ludvig Nandor
Published: October 2008

In standard experimental environments, a constant proportion of CA1 principal cells are place cells, each with a spatial receptive field called a place field. Although the properties of place cells are a basis for understanding the mammalian representation of spatial knowledge, there is no consensus on which of the two fundamental neural-coding hypotheses correctly accounts for how place cells encode spatial information. Within the dedicated-coding hypothesis, the current activity of each cell is an independent estimate of the location with respect to its place field. The average of the location estimates from many cells represents current location, so a dedicated place code would degrade if single cells had multiple place fields. Within the alternative, ensemble-coding hypothesis, the concurrent discharge of many place cells is a vector that represents current location. An ensemble place code is not degraded if single cells have multiple place fields as long as the discharge vector at each location is unique. Place cells with multiple place fields might be required to represent the substantially larger space in more natural environments. To distinguish between the dedicated-coding and ensemble-coding hypotheses, we compared the characteristics of CA1 place fields in a standard cylinder and an approximately six times larger chamber. Compared with the cylinder, in the chamber, more CA1 neurons were place cells, each with multiple, irregularly arranged, and enlarged place fields. The results indicate that multiple place fields is a fundamental feature of CA1 place cell activity and that, consequently, an ensemble place code is required for CA1 discharge to accurately signal location.
Genetic Dissection of γ-Secretase-Dependent and-Independent Functions of Presenilin in Regulating Neuronal Cell Cycle and Cell Death
Authors: Kallhoff-Munoz Verena , Hu Lingyun , Chen Xiaoli , Pautler Robia G. , Zheng Hui
Published: October 2008

Cell cycle markers have been shown to be upregulated and proposed to lead to apoptosis of postmitotic neurons in Alzheimer's disease (AD). Presenilin (PS) plays a critical role in AD pathogenesis, and loss-of-function studies in mice established a potent effect of PS in cell proliferation in peripheral tissues. Whether PS has a similar activity in the neuronal cell cycle has not been investigated. PS exhibits γ-secretase-dependent and -independent functions; the former requires aspartate 257 (D257) as part of the active site, and the latter involves the hydrophilic loop domain encoded by exon 10. We used two novel mouse models, one expressing the PS1 D257A mutation on a postnatal PS conditional knock-out background and the other deleting exon 10 ofPS1, to dissect the γ-secretase-dependent and -independent activities of PS in the adult CNS. Whereas γ-secretase plays a dominant role in neuronal survival, our studies reveal potent neuronal cell cycle regulation mediated by the PS1 hydrophilic loop. Although neurons expressing cell cycle markers do not directly succumb to apoptosis, they are more vulnerable under stress conditions. Importantly, our data identify a novel pool of cytoplasmic p53 as a downstream mediator of this cellular vulnerability. These results support a model whereby the PS γ-secretase activity is essential in maintaining neuronal viability, and the PS1 loop domain modulates neuronal homeostasis through cell cycle and cytoplasmic p53 control.
Vibrissa Sensation in Superior Colliculus: Wide-Field Sensitivity and State-Dependent Cortical Feedback
Authors: Cohen Jeremy D. , Hirata Akio , Castro-Alamancos Manuel A.
Published: October 2008

Rodents use their vibrissae (whiskers) to sense and navigate the environment. A main target of this sensory information is the superior colliculus in the midbrain, which rats can use to detect meaningful whisker stimuli in behavioral contexts. Here, we used field potential, single-unit, and intracellular recordings to show that, although cells in the intermediate layers of the superior colliculus respond relatively effectively to single whiskers, the cells respond much more robustly to simultaneous, or nearly simultaneous, wide-field (multiwhisker) stimuli. The enhanced multiwhisker response is temporally stereotyped, consisting of two short latency peaks caused by convergent trigeminal synaptic inputs and cortical feedback, respectively. The cells are highly sensitive to the degree of temporal dispersion and contact order of multiwhisker stimuli, which makes them excellent detectors of initial multiwhisker contact. In addition, their output is most robust during quiescent states because of the dependence of cortical feedback on forebrain activation, and this may serve as an alerting signal to drive orienting responses.
Concepts Are More than Percepts: The Case of Action Verbs
Authors: Bedny Marina , Caramazza Alfonso , Grossman Emily , Pascual-Leone Alvaro , Saxe Rebecca
Published: October 2008

Several regions of the posterior-lateral-temporal cortex (PLTC) are reliably recruited when participants read or listen to action verbs, relative to other word and nonword types. This PLTC activation is generally interpreted as reflecting the retrieval of visual-motion features of actions. This interpretation supports the broader theory, that concepts are comprised of sensory–motor features. We investigated an alternative interpretation of the same activations: PLTC activity for action verbs reflects the retrieval of modality-independent representations of event concepts, or the grammatical types associated with them, i.e., verbs. During a functional magnetic resonance imaging scan, participants made semantic-relatedness judgments on word pairs varying in amount of visual-motion information. Replicating previous results, several PLTC regions showed higher responses to words that describe actions versus objects. However, we found that these PLTC regions did not overlap with visual-motion regions. Moreover, their response was higher for verbs than nouns, regardless of visual-motion features. For example, the response of the PLTC is equally high to action verbs (e.g., to run) and mental verbs (e.g., to think), and equally low to animal nouns (e.g., the cat) and inanimate natural kind nouns (e.g., the rock). Thus, PLTC activity for action verbs might reflect the retrieval of event concepts, or the grammatical information associated with verbs. We conclude that concepts are abstracted away from sensory–motor experience and organized according to conceptual properties.
Neural Substrates for Reversing Stimulus–Outcome and Stimulus–Response Associations
Authors: Xue Gui , Ghahremani Dara G. , Poldrack Russell A.
Published: October 2008

Adaptive goal-directed actions require the ability to quickly relearn behaviors in a changing environment, yet how the brain supports this ability is barely understood. Using functional magnetic resonance imaging and a novel reversal learning paradigm, the present study examined the neural mechanisms associated with reversal learning for outcomes versus motor responses. Participants were extensively trained to classify novel visual symbols (Japanese Hiraganas) into two arbitrary classes (“male” or “female”), in which subjects could acquire both stimulus–outcome associations and stimulus–response associations. They were then required to relearn either the outcome or the motor response associated with the symbols, or both. The results revealed that during reversal learning, a network including anterior cingulate, posterior inferior frontal, and parietal regions showed extended activation for all types of reversal trials, whereas their activation decreased quickly for trials not involving reversal, suggesting their role in domain–general interference resolution. The later increase of right ventral lateral prefrontal cortex and caudate for reversal of stimulus–outcome associations suggests their importance in outcome reversal learning in the face of interference.
Note: A Field Assessment of the Defensive Responses of Moths to an Auditory Stimulus
Authors: St. Juliana Justin R. , Fenton Brock M. , Korine Carmi , Pinshow Berry , Wojciechowski Michal , Kravchenko Vasiliy
Published: October 2008

We examined the responses of moths to an auditory stimulus in the field with respect to moth size, moth activity state (at rest or flying), whether it responded, and response type. Moths most commonly responded by changing flight direction. Flying moths responded significantly more often to the auditory stimulus than did resting moths; small- and medium-sized moths responded significantly more often than larger ones. We found no differences in use of response types between size classes. We suggest that these behavioral responses to the auditory stimulus are likely due to evolved induced responses to detection of predatory bats.
Genetic (RAPD) Diversity Across Species Range: Core vs. Peripheral Populations of Wild Barley in Israel and Turkmenistan
Authors: Shulgina Irina , Yakubov Bahtiyor , Orlovsky Nikolai , Mendlinger Samuel , Shulgina Irina , Volisc Sergei
Published: October 2008

Populations of wild barley,Hordeum spontaneum, were collected in two countries, Israel and Turkmenistan, in environments representing two similar sharp clines of aridity. This allowed us to use the same criteria to define species core and periphery in the two regions. Plants from 21 Israeli and 11 Turkmenian populations were analyzed for 59 putative loci by randomly amplified polymorphic DNA. Extent of variation was similar in populations at species border (periphery) and in populations inhabiting favorable environments away from the border (core). In contrast, the two regions (Israel and Turkmenistan) differed in extent of genetic diversity as estimated by mean number of alleles per locus, the proportion of polymorphic loci, and the percent of expected heterozygosity, with Israel harboring more variation than Turkmenistan. The genetic population structure revealed by RAPDs did not differ between species core and periphery in each region and between the two regions. The pattern of RAPD variation corresponded to inter-population mosaic structure characterized by genetic differentiation over short geographic distances.

The major conclusion of this study is that there is no simple relationship between neutral genetic variability and population location with respect to the species range (core vs. periphery).
Adaptive Mutations In RNA-Based Regulatory Mechanisms: Computational and Experimental Investigations
Authors: Barash Danny , Sikorski Johannes , Perry Elizabeth B. , Nevo Eviatar , Nudler Evgeny
Published: October 2008

Recent discoveries of RNA-based regulatory mechanisms have prompted substantial interest in how they formed and the extent to which varying environmental conditions have influenced their evolution. One class of RNA-based regulatory mechanism that has been found in bacteria is the riboswitch, regulating the biosynthesis of certain vitamins by an RNA genetic control element that senses small molecules and responds with a structural change that affects transcription termination or translation initiation without the participation of proteins. By taking the thiamin pyrophosphate (TPP)-riboswitch inBacillus subtilisas a model system, we wish to examine whether beneficial mutations may exist at the level of RNA that will cause an improvement in organism fitness. By computationally analyzing the difference in primary and secondary structure of theB. subtilisTPP-riboswitch collected from the xeric "African" south-facing slope (SFS) vs. the mesic, "European", north-facing slope (NFS) in "Evolution Canyon" III at Nahal Shaharut, southern Israel, we wish to experimentally study the environmental effect on transcription termination in these RNA-based regulatory mechanisms that are believed to be of ancient origin in the evolutionary time scale. Computational results, so far, indicate that specific mutations affect the riboswitch conformation by causing a global rearrangement. We would like to check whether such mutations could be adaptive mutations that may have a beneficial fitness effect, taking the TPP-riboswitch as a model system at the micro-scale. Empirical results so far indicate that in the promoter region of the TPP-riboswitch, all mutations increase nucleotide GC content in the xeric SFS, whereas in the mesic NFS they increase AT content. Preliminary examination of termination efficiency of strains found exclusively on one slope or the other, reveal increased termination efficiency in the presence of TPP and at more moderate temperatures, but only a suggestion of greater termination efficiency from strains found on both slopes. We expect that further results will shed light on the mutational differences of TPP-riboswitch sequences found on opposite slopes of "Evolution Canyon" III at Nahal Shaharut, potentially leading to interesting discoveries that relate to the topic of adaptive, nonrandom mutations.
Evolution of the Circadian Clock Mechanism in Prokaryotes
Authors: Dvornyk Volodymyr
Published: October 2008

The circadian system of prokaryotes is probably the oldest among the circadian systems of living organisms. The genes comprising the system are very different in their evolutionary histories. The reconstruction of macroevolution of the circadian genes in cyanobacteria suggests that there are probably at least two types of circadian systems, based either on the threekaigenes (kaiA, kaiB, andkaiC) or onkaiBandkaiC.When referred to the recently published results about a genomic timescale of prokaryote evolution, the origin ofkaiBandsasAcorresponds to the appearance of anoxygenic photosynthesis, while the origin of thekaiBCoperon corresponds to the time when oxygenic photosynthesis evolved.

The results of the studies performed so far suggest that major steps in macroevolution of the circadian system in cyanobacteria have been related to global changes in the environment and to keystone advances in biological evolution. This macroevolution has involved selection, multiple lateral transfers, gene duplications, and fusions as its primary driving forces. The proposed scenario of the circadian system's macroevolution is far from complete and will be updated as new genomic and sequence data are accumulated.
Biodiversity of Earthworms in the Levant
Authors: Pavlíček Tomáš , Csuzdi Csaba , Nevo Eviatar
Published: October 2008

Today, 37 species, 16 genera, and five families (Acanthodrilidae, Criodrilidae, Lumbricidae, Ocnerodrilidae, and Megascolecidae) of earthworms are known to be present in the Levant. Out of all recorded species, 35-43% (13-16 species) have been directly or indirectly introduced by humans and 57-65% (21-24 species) seem to be autochthonous. Twelve to fourteen (50-67%) autochthonous species are endemic to the Levant (generaDendrobaena, Healyella, Helodrilus, andPerelia). The autochthonous Levantine earthworm fauna is exclusively Palearctic, and species mainly show zoogeographic affinities to Anatolia-Caucasus and Europe. No observed earthworm endemism above the species level corresponds to the expected origin of earthworm fauna in the Levant between Rupelian (30-28 Mya) and Tortonian (11.5-6 Mya) (Oligocene-Miocene). In spite of the fact that speciation in earthworms might take millions of years, the observed new species isolated in the desert oases and along the Negev and Sinai Desert borders might change this perception if we can differentiate between relicts surviving the expansion of the Arabo-Syrian desert belt and subsequent speciation.
Modeling the Evolutionary and Ecological Consequences of Selection and Adaptation in Heterogeneous Environments
Authors: Cohen Dan
Published: October 2008

The evolution of adaptations of natural populations in heterogeneous environments poses many challenges. According to the conventional paradigm of adaptive evolution, most traits of existing organisms should be well adapted to the whole wide range of conditions to which they are exposed in their natural environments. However, many traits in most organisms appear to be poorly adapted at many specific conditions, while many other traits appear to be well adapted to conditions that occur only very rarely or not at all in their natural environment. At the same time, many apparently available resources are exploited very little or not at all by the existing species in ecological communities.

To help account for these discrepancies and contradictions, I model the effects of the frequency distribution of the contributions to reproductive output of different conditions, habitats, and events, and the major effects of the correlations between the selection forces at different conditions on the selection and adaptation of each of the characteristic traits of species in naturally heterogeneous environments.

The force of selection at any one condition i is proportional to the reproductive output fraction Fi of the exposed population. Fi is the product of the population fraction Hi and the individual reproductive output Ri.

Selection at any one locus or trait A in a large mixed population establishes an allele or trait A* that maximizes the mean fitness

W⁁(A) = Σi[(Wi(A)Fi], weighted over all conditions according to the product of their fitness functions and relative reproductive outputs. Consequently, the adaptation of any trait to any one rare specific condition depends very little on the specific selection coefficient! Specific adaptations depend almost only on the correlations between the fitness of the overall optimal trait A* and the fitness of the specific optimal trait Ai* at the specific condition. Thus, species are expected to be better adapted and to exploit mostly their more abundant and more positively correlated resources.

The consequences for ecological communities are that superior competitive species are not likely to evolve to exclude coexisting rare species that exploit rare negatively correlated habitats.

Also, the exploitation by any one species of a range of resources with negatively correlated fitness functions is genetically and ecologically unstable. Such resources may remain unexploited by existing species. Opening a large new habitat may select against adaptation for some previously utilized resources with negatively correlated fitness functions, but may select for adaptation for some previously unutilized rare resources or habitats with positively correlated fitness functions. The opposite effects are predicted for the elimination of some large utilized resource.
"Evolution Canyon": A Microcosm of Life's Evolution Focusing on Adaptation and Speciation
Authors: Nevo Eviatar
Published: October 2008

Local microcosmic natural laboratories, dubbed "Evolution Canyon" (EC) models, reinforce studies of regional and global macrocosmic ecological theaters across life and unravelevolution in action.The EC model laboratories permit genomic, proteomic, and phenomic studies highlighting speciation and adaptation at a microscale. Critical transplant experiment tests can evaluate interslope differential fitness. Novel techniques of genetic mapping, sequence nucleotide polymorphisms (SNPs), and wide genome coding and noncoding expressions can unravel evolutionary dynamics. Finally, fundamental problems such as stress effects on nonrandom mutations, lateral transfers, splicing variations, sex, and social evolutions, and adaptive strategies of prokaryotes and eukaryotes are testable. We are studying four "Evolution Canyons" (EC I-IV) in the Carmel, Galilee, Negev, and Golan mountains. We've identified 2,500 species in EC I (Carmel) from bacteria to mammals in an area of 7,000 m. Higher terrestrial species richness was found on the more stressful tropical "African" slope (AS). Aquatic species richness was higher on the milder, temperate "European" slope (ES). In soil fungi we found interslope local and regional adaptive divergence in sex, melanism, and conidia. In nine out of 14 (64%) model organisms across life we identified largely higher genetic polymorphisms on the more stressful "African" slope. In some model species we found higher mutation rates, gene conversion, recombination, DNA repair, and larger genome size as well as interslope divergent micro-satellites, molecular polymorphisms, retrotransposons, and wide-genome gene expression on the more stressful AS. Remarkably, interslope incipient sympatric speciation was found across life. The "Evolution Canyon" model represents the Israeli ecological equivalent of the Galapagos Islands. Micro-climatic selection overrides drift and drives both interslope adaptive radiation and incipient sympatric speciation. The EC model could potentially highlight many mysteries of evolutionary biology.
On The Necessity to Study Natural Bacterial Populations-The Model of Bacillus Simplex From "Evolution Canyons" I and II, Israel
Authors: Sikorski Johannes , Nevo Eviatar
Published: October 2008

How do bacteria evolve and speciate in natural environments? How does bacterial evolution relate to bacterial systematics? Exploring these answers is essential because bacteria profoundly impact life in general and, in particular, that of humans. Much insight into bacterial microevolution has come from theoretical and computational studies and from multigenerational laboratory systems ("Experimental Evolution"). These studies, however, do not take into account the diversity of modes of how bacteria can evolve under the complexity of the real world, i.e., nature. We argue, therefore, that for a comprehensive understanding of bacterial microevolution, it is essential to study natural populations. We underline our argument by introducing theBacillus simplexmodel from "Evolution Canyon", Israel. This metapopulation splits into different evolutionary lineages that have adapted to the microclimatically different slopes of "Evolution Canyon". It was shown that temperature stress is a major environmental factor driving theB. simplexadaptation and speciation progress. Therefore, this model population has proven highly suitable to study bacterial microevolution in natural habitats. Finally, we discuss theB. simplexintrapopulation divergence of lineages in light of current controversies on bacterial species concepts and taxon identification.
Moral imperialism and multi-centric clinical trials in peripheral countries
Authors: Garrafa Volnei , Lorenzo Claudio
Published: October 2008

Moral imperialism is expressed in attempts to impose moral standards from one particular culture, geopolitical region or culture onto other cultures, regions or countries. Examples of Direct Moral Imperialism can be seen in various recurrent events involving multi-centric clinical trials promoted by developed (central) countries in poor and developing (peripheral) countries, particularly projects related to the theory of double standards in research. After the WMA General Assembly refused to change the Helsinki Declaration - which would have given moral recognition to the above mentioned theory - the USA abandoned the declaration and began to promote regional seminars in peripheral countries with the aim of "training" researchers on ethical perspectives that reflect America's best interests. Individuals who received such training became transmitters of these central countries' ideas across the peripheral countries, representing a form of Indirect Moral Imperialism. The paper proposes the establishment of regulatory and social control systems for clinical trials implemented in peripheral countries, through the formulation of ethical norms that reflect the specific contexts of these countries, along with the drawing up and validation of their own national norms.