bluuebunny/crossref_metadata_2025 huggingface dataset:
Significant dissociation of expression patterns of the basic helix–loop–helix transcription factors Dec1 and Dec2 in rat kidney
Authors: Wu Tao , Ni Yinhua , ZhuGe Fen , Sun Lu , Xu Bin , Kato Hisanori , Fu Zhengwei
Published: March 2011

Dec1 and Dec2 are regulators of the mammalian molecular clock that show robust circadian rhythms in the suprachiasmatic nucleus and various peripheral tissues. Although the expression of Dec1 and Dec2 is altered by multiple stimuli in different organs, their transcriptional regulatory mechanisms have not been fully elucidated for the kidney. In the present study, we describe for the first time significant dissociation of expression patterns with arrhythmic expression of Dec1 and rhythmic expression of Dec2 in rat kidney under a normal light–dark (LD) cycle. Daytime restricted feeding (RF) significantly altered the expression patterns of these two clock genes, and even induced circadian expression of Dec1 with an amplitude of 2.2 on day 3 and 4.2 on day 7. However, when a reversed feeding schedule was coupled with a reversed LD cycle, the expression of Dec1 but not Dec2 reverted to being arrhythmic. Moreover, exogenous injection of the glucocorticoid analogue dexamethasone (Dex) at certain times of the day resulted in rhythmic expression of Dec1, which was similar to that seen following RF for 7 days. In contrast, endogenous disruption of glucocorticoids by adrenalectomy abolished RF-induced rhythmic expression of Dec1 in the kidney. These observations suggest the existence of a glucocorticoid gating mechanism in the circadian expression of Dec1 in rat kidney.
Hibernating above the permafrost: effects of ambient temperature and season on expression of metabolic genes in liver and brown adipose tissue of arctic ground squirrels
Authors: Williams Cory T. , Goropashnaya Anna V. , Buck C. Loren , Fedorov Vadim B. , Kohl Franziska , Lee Trixie N. , Barnes Brian M.
Published: March 2011

Hibernating arctic ground squirrels (Urocitellus parryii), overwintering in frozen soils, maintain large gradients between ambient temperature (Ta) and body temperature (Tb) by substantially increasing metabolic rate during torpor while maintaining a subzero Tb. We used quantitative reverse-transcription PCR (qRT-PCR) to determine how the expression of 56 metabolic genes was affected by season (active in summer vs hibernating), metabolic load during torpor (imposed by differences in Ta: +2 vs –10°C) and hibernation state (torpid vs after arousal). Compared with active ground squirrels sampled in summer, liver from hibernators showed increased expression of genes associated with fatty acid catabolism (CPT1A, FABP1 and ACAT1), ketogenesis (HMGCS2) and gluconeogenesis (PCK1) and decreased expression of genes associated with fatty acid synthesis (ACACB, SCD and ELOVL6), amino acid metabolism, the urea cycle (PAH, BCKDHA and OTC), glycolysis (PDK1 and PFKM) and lipid metabolism (ACAT2). Stage of hibernation (torpid vs aroused) had a much smaller effect, with only one gene associated with glycogen synthesis (GSY1) in liver showing consistent differences in expression levels between temperature treatments. Despite the more than eightfold increase in energetic demand associated with defending Tb during torpor at a Ta of –10 vs +2°C, transcript levels in liver and brown adipose tissue differed little. Our results are inconsistent with a hypothesized switch to use of non-lipid fuels when ambient temperatures drop below freezing.
Reversible remodeling of lung tissue during hibernation in the Syrian hamster
Authors: Talaei Fatemeh , Hylkema Machteld N. , Bouma Hjalmar R. , Boerema Ate S. , Strijkstra Arjen M. , Henning Rob H. , Schmidt Martina
Published: March 2011

During hibernation, small rodents such as hamsters cycle through phases of strongly suppressed metabolism with low body temperature (torpor) and full restoration of metabolism and body temperature (arousal). Remarkably, the repetitive stress of cooling–rewarming and hypoxia does not cause irreversible organ damage. To identify adaptive mechanisms protecting the lungs, we assessed histological changes as well as the expression and localization of proteins involved in tissue remodeling in lungs from Syrian hamsters at different phases of hibernation using immunohistochemical staining and western blot analysis. In torpor (early and late) phase, a reversible increased expression of smooth muscle actin, collagen, angiotensin converting enzyme and transforming growth factor-β was found, whereas expression of the epidermal growth factor receptor and caveolin-1 was low. Importantly, all these alterations were restored during arousal. This study demonstrates substantial alterations in protein expression mainly in epithelial cells of lungs from hibernating Syrian hamsters. These structural changes of the bronchial airway structure are termed airway remodeling and often occur in obstructive lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung fibrosis. Unraveling the molecular mechanism leading to reversal of airway remodeling by the end of torpor may identify possible therapeutic targets to reduce progression of this process in patients suffering from asthma, chronic obstructive pulmonary disease and lung fibrosis.
Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) show microstructural bone loss during hibernation but preserve bone macrostructural geometry and strength
Authors: McGee-Lawrence Meghan E. , Stoll Danielle M. , Mantila Emily R. , Fahrner Bryna K. , Carey Hannah V. , Donahue Seth W.
Published: March 2011

Lack of activity causes bone loss In most animals. Hibernating bears have physiological processes to prevent cortical and trabecular bone loss associated with reduced physical activity, but different mechanisms of torpor among hibernating species may lead to differences in skeletal responses to hibernation. There are conflicting reports regarding whether small mammals experience bone loss during hibernation. To investigate this phenomenon, we measured cortical and trabecular bone properties in physically active and hibernating juvenile and adult 13-lined ground squirrels (Ictidomys tridecemlineatus, previous genus name Spermophilus). Cortical bone geometry, strength and mineral content were similar in hibernating compared with active squirrels, suggesting that hibernation did not cause macrostructural cortical bone loss. Osteocyte lacunar size increased (linear regression, P=0.001) over the course of hibernation in juvenile squirrels, which may indicate an osteocytic role in mineral homeostasis during hibernation. Osteocyte lacunar density and porosity were greater (+44 and +59%, respectively; P<0.0001) in hibernating compared with active squirrels, which may reflect a decrease in osteoblastic activity (per cell) during hibernation. Trabecular bone volume fraction in the proximal tibia was decreased (–20%; P=0.028) in hibernating compared with physically active adult squirrels, but was not different between hibernating and active juvenile squirrels. Taken together, these data suggest that 13-lined ground squirrels may be unable to prevent microstructural losses of cortical and trabecular bone during hibernation, but importantly may possess a biological mechanism to preserve cortical bone macrostructure and strength during hibernation, thus preventing an increased risk of bone fracture during remobilization in the spring.
Consumer Understanding of Prescription Drug Information: An Illustration Using an Antidepressant Medication
Authors: Shiffman Saul , Gerlach Karen K , Sembower Mark A , Rohay Jeffrey M
Published: March 2011

Background

Patient education and warnings have emerged as prominent interventions for improving drug safety. As part of the provision of information and guidance on safe use of drugs, patients often receive multiple pieces of written information when they obtain a prescription medication, including a Food and Drug Administration (FDA)–mandated medication guide (MG), consumer medication information (CMI), and patient package insert (PPI).

Objective:

To determine whether patients understand the materials providing drug information and whether the materials convey the intended information.

Methods:

Fifty-two adults with a high school education or less were shown an actual (blinded) MG, CMI, and PPI for a marketed antidepressant medication. Comprehension was tested with methods used by the FDA to assess label comprehension for nonprescription products.

Results:

The majority of participants (88.2%) looked at all 3 pieces of information provided. The mean (SD) time spent reviewing the CMI was 5.2 (4.8) minutes (range 0-21.9). 16.5(13.3) minutes for the PPI (range 0-43.0), and 2.5 (1.6) minutes for the MG (range 0-7.6). Less than 20% of participants were able to identify the symptoms of a rare but potentially life-threatening situation that can occur with this medication and only 61.5% recalled the risk of teen suicide, which is the sole focus of the MG. Respondents with lower literacy scores performed more poorly than those with higher literacy scores.

Conclusions:

Information provided with at least some prescription drugs is not adequately understood by less-educated consumers and does not effectively communicate critical safety messages or directions.
The Role of Angiotensin Receptor Blockers in Patients with Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema
Authors: Beavers Craig James , Dunn Steven P , Macaulay Tracy E
Published: March 2011

Objective:

To assess the safety of using angiotensin II receptor blockers (ARBs) in patients who develop angioedema with the use of angiotensin-converting enzyme inhibitors (ACEIs).

Data Sources:

A literature search was performed using MEDLINE (1977-January 2011) and Cochrane Library, using the terms angiotensin receptor blocker, angiotensin-converting enzyme inhibitor, and angioedema. In addition, reference citations from publications identified were reviewed.

Study Selection and Data Extraction:

Only English-language publications were included. Randomized controlled trial data, observational studies (retrospective and prospective), and case reports on adults who received ACEI therapy and then an ARB as an alternative therapy were reviewed.

Data Synthesis:

Two randomized controlled trials and 1 meta-analysis evaluated ARB use in patients intolerant to ACEIs. Taken together, there is a conservative estimate of a 10% or less incidence of cross reactivity of angioedema in patients who receive an ARB after experiencing ACEI-associated angioedema. Angioedema related to ARBs is reported to be less severe and occurs earlier compared to angioedema that develops during ACEI therapy

Conclusions:

ARBS may be an alternative for patients who develop angioedema white using an ACEI but should be reserved for patients with high therapeutic need for angiotensin inhibition. Treatment should be started with observation, patients should be educated on the signs of angioedema, and proper emergency management should be emphasized to patients and care providers.
Prevalence of Blood Doping in Samples Collected from Elite Track and Field Athletes
Authors: Sottas Pierre-Edouard , Robinson Neil , Fischetto Giuseppe , Dollé Gabriel , Alonso Juan Manuel , Saugy Martial
Published: March 2011

BACKGROUND

No reliable estimate of the prevalence of doping in elite sports has been published. Since 2001, the international governing body for athletics has implemented a blood-testing program to detect altered hematological profiles in the world's top-level athletes.

METHODS

A total of 7289 blood samples were collected from 2737 athletes out of and during international athletic competitions. Data were collected in parallel on each sample, including the age, sex, nationality, and birth date of the athlete; testing date; sport; venue; and instrument technology. Period prevalence of blood-doping in samples was estimated by comparing empirical cumulative distribution functions of the abnormal blood profile score computed for subpopulations with stratified reference cumulative distribution functions.

RESULTS

In addition to an expected difference between endurance and nonendurance athletes, we found nationality to be the major factor of heterogeneity. Estimates of the prevalence of blood doping ranged from 1% to 48% for subpopulations of samples and a mean of 14% for the entire study population. Extreme cases of secondary polycythemia highlighted the health risks associated with blood manipulations.

CONCLUSIONS

When applied at a population level, in this case the population of samples, hematological data can be used to estimate period prevalence of blood doping in elite sports. We found that the world's top-level athletes are not only heterogeneous in physiological and anthropometric factors but also in their doping behavior, with contrasting attitudes toward doping between countries. When applied at the individual level, the same biomarkers, as formalized in the Athlete Biological Passport paradigm, can be used in analysis of the observed different physiological characteristics and behavioral heterogeneities.
Screening for small molecule modulators of Hsp70 chaperone activity using protein aggregation suppression assays: inhibition of the plasmodial chaperone PfHsp70-1
Authors: Cockburn Ingrid L. , Pesce Eva-Rachele , Pryzborski Jude M. , Davies-Coleman Michael T. , Clark Peter G.K. , Keyzers Robert A. , Stephens Linda L. , Blatch Gregory L.
Published: March 2011

Plasmodium falciparum heat shock protein 70 (PfHsp70-1) is thought to play an essential role in parasite survival and virulence in the human host, making it a potential antimalarial drug target. A malate dehydrogenase based aggregation suppression assay was adapted for the screening of small molecule modulators of Hsp70. A number of small molecules of natural (marine prenylated alkaloids and terrestrial plant naphthoquinones) and related synthetic origin were screened for their effects on the protein aggregation suppression activity of purified recombinant PfHsp70-1. Five compounds (malonganenone A-C, lapachol and bromo-β-lapachona) were found to inhibit the chaperone activity of PfHsp70-1 in a concentration dependent manner, with lapachol preferentially inhibiting PfHsp70-1 compared to another control Hsp70. Using growth inhibition assays on P. falciparum infected erythrocytes, all of the compounds, except for malonganenone B, were found to inhibit parasite growth with IC50 values in the low micromolar range. Overall, this study has identified two novel classes of small molecule inhibitors of PfHsp70-1, one representing a new class of antiplasmodial compounds (malonganenones). In addition to demonstrating the validity of PfHsp70-1 as a possible drug target, the compounds reported in this study will be potentially useful as molecular probes for fundamental studies on Hsp70 chaperone function.
In VivoPositron Emission Tomographic Imaging of Glial Responses to Amyloid-β and Tau Pathologies in Mouse Models of Alzheimer's Disease and Related Disorders
Authors: Maeda Jun , Zhang Ming-Rong , Okauchi Takashi , Ji Bin , Ono Maiko , Hattori Satoko , Kumata Katsushi , Iwata Nobuhisa , Saido Takaomi C. , Trojanowski John Q. , Lee Virginia M.-Y. , Staufenbiel Matthias , Tomiyama Takami , Mori Hiroshi , Fukumura Toshimitsu , Suhara Tetsuya , Higuchi Makoto
Published: March 2011

Core pathologies of Alzheimer's disease (AD) are aggregated amyloid-β peptides (Aβ) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18 kDa translocator protein (TSPO). Here, we elucidated contributions of Aβ and tau deposits toin vivoTSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-positive microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals before occurrence of brain atrophy and thioflavin-S-positive tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomography (PET) with two classes of TSPO radioligands, [11C]AC-5216 and [18F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was observed in aged mice modeling Aβ plaque deposition, despite the notably enhancedin vivobinding of amyloid radiotracer, [11C]Pittsburgh Compound-B, to plaques. In these animals, [11C]AC-5216 yielded better TSPO contrasts than [18F]fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance TSPO probes. Furthermore, an additional line of mice modeling intraneuronal Aβ accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. Our data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aβ pathologies.
Interphotoreceptor Retinoid-Binding Protein as the Physiologically Relevant Carrier of 11-cis-Retinol in the Cone Visual Cycle
Authors: Parker Ryan , Wang Jin-Shan , Kefalov Vladimir J. , Crouch Rosalie K.
Published: March 2011

Cones function in constant light and are responsible for mediating daytime human vision. Like rods, cones use the photosensitive molecule 11-cis-retinal to detect light, and in constant illumination, a continuous supply of 11-cis-retinal is needed. A retina visual cycle is thought to provide a privileged supply of 11-cis-retinal to cones by using 11-cis-retinol generated in Müller cells. In the cycle, 11-cis-retinol is transported from Müller cells to cone inner segments, where it is oxidized to 11-cis-retinal. This oxidation step is only performed in cones, thus rendering the cycle cone-specific. Interphotoreceptor retinoid-binding protein (IRBP) is a retinoid-binding protein in the subretinal space that binds 11-cis-retinol endogenously. Cones inIrbp−/−mice are retinoid-deficient under photopic conditions, and it is possible that 11-cis-retinol supplies are disrupted in the absence of IRBP. We tested the hypothesis that IRBP facilitates the delivery of 11-cis-retinol to cones by preserving the isomeric state of 11-cis-retinol in light. With electrophysiology, we show that the cone-like photoreceptors ofNrl−/−mice use the cone visual cycle similarly to wild-type cones. Then, using oxidation assays in isolatedNrl−/−Rpe65−/−retinas, we show that IRBP delivers 11-cis-retinol for oxidation in cones and improves the efficiency of the oxidation reaction. Finally, we show that IRBP protects the isomeric state of 11-cis-retinol in the presence of light. Together, these findings suggest that IRBP plays an important role in the delivery of 11-cis-retinol to cones and can facilitate cone function in the presence of light.
Gata2 Is Required for Migration and Differentiation of Retinorecipient Neurons in the Superior Colliculus
Authors: Willett Ryan T. , Greene Lloyd A.
Published: March 2011

The superior colliculus (SC)/optic tectum of the dorsal mesencephalon plays a major role in responses to visual input, yet regulation of neuronal differentiation within this layered structure is only partially understood. Here, we show that the zinc finger transcription factor Gata2 is required for normal SC development. Starting at embryonic day 15 (E15) (corresponding to the times at which neurons of the outer and intermediate layers of the SC are generated), Gata2 is transiently expressed in the rat embryonic dorsal mesencephalon within a restricted region between proliferating cells of the ventricular zone and the deepest neuronal layers of the developing SC. The Gata2-positive cells are postmitotic and lack markers of differentiated neurons, but express markers for immature neuronal precursors including Ascl1 and Pax3/7.In uteroelectroporation with Gata2 small hairpin RNAs at E16 into cells along the dorsal mesencephalic ventricle interferes with their normal migration into the SC and maintains them in a state characterized by retention of Pax3 expression and the absence of mature neuronal markers. Collectively, these findings indicate that Gata2 plays a required role in the transition of postmitotic neuronal precursor cells of the retinorecipient layers of the SC into mature neurons and that loss of Gata2 arrests them at an intermediate stage of differentiation.
In VivoImaging of Dorsal Root Regeneration: Rapid Immobilization and Presynaptic Differentiation at the CNS/PNS Border
Authors: Di Maio Alessandro , Skuba Andrew , Himes B. Timothy , Bhagat Srishiti L. , Hyun Jung Keun , Tessler Alan , Bishop Derron , Son Young-Jin
Published: March 2011

Dorsal root (DR) axons regenerate in the PNS but turn around or stop at the dorsal root entry zone (DREZ), the entrance into the CNS. Earlier studies that relied on conventional tracing techniques or postmortem analyses attributed the regeneration failure to growth inhibitors and lack of intrinsic growth potential. Here, we report the firstin vivoimaging study of DR regeneration. Fluorescently labeled, large-diameter DR axons inthy1-YFPH mice elongated through a DR crush site, but not a transection site, and grew along the root at >1.5 mm/d with little variability. Surprisingly, they rarely turned around at the DREZ upon encountering astrocytes, but penetrated deeper into the CNS territory, where they rapidly stalled and then remained completely immobile or stable, even after conditioning lesions that enhanced growth along the root. Stalled axon tips and adjacent shafts were intensely immunolabeled with synapse markers. Ultrastructural analysis targeted to the DREZ enriched with recently arrived axons additionally revealed abundant axonal profiles exhibiting presynaptic features such as synaptic vesicles aggregated at active zones, but not postsynaptic features. These data suggest that axons are neither repelled nor continuously inhibited at the DREZ by growth-inhibitory molecules but are rapidly stabilized as they invade the CNS territory of the DREZ, forming presynaptic terminal endings on non-neuronal cells. Our work introduces a new experimental paradigm to the investigation of DR regeneration and may help to induce significant regeneration after spinal root injuries.
Anterior Hippocampus and Goal-Directed Spatial Decision Making
Authors: Viard Armelle , Doeller Christian F. , Hartley Tom , Bird Chris M. , Burgess Neil
Published: March 2011

Planning spatial paths through our environment is an important part of everyday life and is supported by a neural system including the hippocampus and prefrontal cortex. Here we investigated the precise functional roles of the components of this system in humans by using fMRI as participants performed a simple goal-directed route-planning task. Participants had to choose the shorter of two routes to a goal in a visual scene that might contain a barrier blocking the most direct route, requiring a detour, or might be obscured by a curtain, requiring memory for the scene. The participant's start position was varied to parametrically manipulate their proximity to the goal and the difference in length of the two routes. Activity in medial prefrontal cortex, precuneus, and left posterior parietal cortex was associated with detour planning, regardless of difficulty, whereas activity in parahippocampal gyrus was associated with remembering the spatial layout of the visual scene. Activity in bilateral anterior hippocampal formation showed a strong increase the closer the start position was to the goal, together with medial prefrontal, medial and posterior parietal cortices. Our results are consistent with computational models in which goal proximity is used to guide subsequent navigation and with the association of anterior hippocampal areas with nonspatial functions such as arousal and reward expectancy. They illustrate how spatial and nonspatial functions combine within the anterior hippocampus, and how these functions interact with parahippocampal, parietal, and prefrontal areas in decision making and mnemonic function.
This Is the Rhythm of Your Eyes: The Phase of Ongoing Electroencephalogram Oscillations Modulates Saccadic Reaction Time
Authors: Drewes Jan , VanRullen Rufin
Published: March 2011

Motor reaction times in humans are highly variable from one trial to the next, even for simple and automatic tasks, such as shifting your gaze to a suddenly appearing target. Although classic models of reaction time generation consider this variability to reflect intrinsic noise, some portion of it could also be attributed to ongoing neuronal processes. For example, variations of alpha rhythm frequency (8–12 Hz) across individuals, or alpha amplitude across trials, have been related previously to manual reaction time variability. Here we investigate the trial-by-trial influence of oscillatory phase, a dynamic marker of ongoing activity, on saccadic reaction time in three paradigms of increasing cognitive demand (simple reaction time, choice reaction time, and visual discrimination tasks). The phase of ongoing prestimulus activity in the high alpha/low beta range (11–17 Hz) at frontocentral locations was strongly associated with saccadic response latencies. This relation, present in all three paradigms, peaked for phases recorded ∼50 ms before fixation point offset and 250 ms before target onset. Reaction times in the most demanding discrimination task fell into two distinct modes reflecting a fast but inaccurate strategy or a slow and efficient one. The phase effect was markedly stronger in the group of subjects using the faster strategy. We conclude that periodic fluctuations of electrical activity attributable to neuronal oscillations can modulate the efficiency of the oculomotor system on a rapid timescale; however, this relation may be obscured when cognitive load also adds a significant contribution to response time variability.
Progressive Motor Cortex Functional Reorganization Following 6-Hydroxydopamine Lesioning in Rats
Authors: Viaro Riccardo , Morari Michele , Franchi Gianfranco
Published: March 2011

Many studies have attempted to correlate changes of motor cortex activity with progression of Parkinson's disease, although results have been controversial. In the present study we used intracortical microstimulation (ICMS) combined with behavioral testing in 6-hydroxydopamine hemilesioned rats to evaluate the impact of dopamine depletion on movement representations in primary motor cortex (M1) and motor behavior. ICMS allows for motor-effective stimulation of corticofugal neurons in motor areas so as to obtain topographic movements representations based on movement type, area size, and threshold currents. Rats received unilateral 6-hydroxydopamine in the nigrostriatal bundle, causing motor impairment. Changes in M1 were time dependent and bilateral, although stronger in the lesioned than the intact hemisphere. Representation size and threshold current were maximally impaired at 15 d, although inhibition was still detectable at 60–120 d after lesion. Proximal forelimb movements emerged at the expense of the distal ones. Movement lateralization was lost mainly at 30 d after lesion. Systemicl-3,4-dihydroxyphenylalanine partially attenuated motor impairment and cortical changes, particularly in the caudal forelimb area, and completely rescued distal forelimb movements. Local application of the GABAAantagonist bicuculline partially restored cortical changes, particularly in the rostral forelimb area. The local anesthetic lidocaine injected into the M1 of the intact hemisphere restored movement lateralization in the lesioned hemisphere. This study provides evidence for motor cortex remodeling after unilateral dopamine denervation, suggesting that cortical changes were associated with dopamine denervation, pathogenic intracortical GABA inhibition, and altered interhemispheric activity.
An RNA Interference-Based Screen of Transcription Factor Genes Identifies Pathways Necessary for Sensory Regeneration in the Avian Inner Ear
Authors: Alvarado David M. , Hawkins R. David , Bashiardes Stavros , Veile Rose A. , Ku Yuan-Chieh , Powder Kara E. , Spriggs Meghan K. , Speck Judith D. , Warchol Mark E. , Lovett Michael
Published: March 2011

Sensory hair cells of the inner ear are the mechanoelectric transducers of sound and head motion. In mammals, damage to sensory hair cells leads to hearing or balance deficits. Nonmammalian vertebrates such as birds can regenerate hair cells after injury. In a previous study, we characterized transcription factor gene expression during chicken hair cell regeneration. In those studies, a laser microbeam or ototoxic antibiotics were used to damage the sensory epithelia (SE). The current study focused on 27 genes that were upregulated in regenerating SEs compared to untreated SEs in the previous study. Those genes were knocked down by siRNA to determine their requirement for supporting cell proliferation and to measure resulting changes in the larger network of gene expression. We identified 11 genes necessary for proliferation and also identified novel interactive relationships between many of them. Defined components of theWNT,PAX, andAP1pathways were shown to be required for supporting cell proliferation. These pathways intersect onWNT4, which is also necessary for proliferation. Among the required genes, the CCAAT enhancer binding protein,CEBPG, acts downstream of Jun Kinase andJUNDin theAP1pathway. TheWNTcoreceptorLRP5acts downstream ofCEBPG, as does the transcription factorBTAF1. Both of these genes are also necessary for supporting cell proliferation. This is the first large-scale screen of its type and suggests an important intersection between theAP1pathway, thePAXpathway, andWNTsignaling in the regulation of supporting cell proliferation during inner ear hair cell regeneration.
Feature-Specific Attentional Priority Signals in Human Cortex
Authors: Liu Taosheng , Hospadaruk Luke , Zhu David C. , Gardner Justin L.
Published: March 2011

Human can flexibly attend to a variety of stimulus dimensions, including spatial location and various features such as color and direction of motion. Although the locus of spatial attention has been hypothesized to be represented by priority maps encoded in several dorsal frontal and parietal areas, it is unknown how the brain represents attended features. Here we examined the distribution and organization of neural signals related to deployment of feature-based attention. Subjects viewed a compound stimulus containing two superimposed motion directions (or colors) and were instructed to perform an attention-demanding task on one of the directions (or colors). We found elevated and sustained functional magnetic resonance imaging response for the attention task compared with a neutral condition, without reliable differences in overall response amplitude between attending to different features. However, using multivoxel pattern analysis, we were able to decode the attended feature in both early visual areas (primary visual cortex to human motion complex hMT+) and frontal and parietal areas (e.g., intraparietal sulcus areas IPS1–IPS4 and frontal eye fields) that are commonly associated with spatial attention. Furthermore, analysis of the classifier weight maps showed that attending to motion and color evoked different patterns of activity, suggesting that different neuronal subpopulations in these regions are recruited for attending to different feature dimensions. Thus, our finding suggests that, rather than a purely spatial representation of priority, frontal and parietal cortical areas also contain multiplexed signals related to the priority of different nonspatial features.
The Relative Roles of Diffusion and Uptake in Clearing Synaptically Released Glutamate Change during Early Postnatal Development
Authors: Thomas Christopher G. , Tian Hua , Diamond Jeffrey S.
Published: March 2011

Glutamate uptake by transporters expressed in astrocytes combines with synaptic structure to regulate the time that synaptically released glutamate remains in the extracellular space and, consequently, the duration and location of postsynaptic receptor activation. Both factors change greatly in the rodent hippocampus during the second postnatal week when most synapses become established and begin to mature, processes that are influenced by synaptically released glutamate. Transporter expression increases, potentially speeding removal of synaptically released glutamate, whereas extracellular space decreases, thereby slowing dilution. We investigated whether these competing changes influence the glutamate concentration time course and postsynaptic responses in the CA1 region of the mouse hippocampus during this critical period of synaptic development. Our results suggest that the glutamate concentration time course remains relatively consistent over this period, although the primary mechanisms regulating glutamate clearance change. Before the second postnatal week, clearance of synaptically released glutamate depends primarily on diffusion into large extracellular spaces, whereas later in development it relies more on increased uptake capacity. Thus, increased transporter expression during this period accompanies structural changes in the neuropil, preserving a relatively consistent glutamate concentration time course and ensuring that postsynaptic receptor activation remains brief and primarily localized to receptors close to release sites.
Input-Specific Critical Periods for Experience-Dependent Plasticity in Layer 2/3 Pyramidal Neurons
Authors: Wen Jing A. , Barth Alison L.
Published: March 2011

Critical periods for experience-dependent plasticity have been well characterized within sensory cortex, in which the ability of altered sensory input to drive firing rate changes has been demonstrated across brain areas. Here we show that rapid experience-dependent changes in the strength of excitatory synapses within mouse primary somatosensory cortex exhibit a critical period that is input specific and mechanistically distinct in layer 2/3 pyramidal neurons. Removal of all but a single whisker [single whisker experience (SWE)] can trigger the strengthening of individual glutamatergic synaptic contacts onto layer 2/3 neurons only during a short window during the second and third postnatal week. At both layer 4 and putative 2/3 inputs, SWE-triggered plasticity has a discrete onset, before which it cannot be induced. SWE synaptic strengthening is concluded at both inputs after the beginning of the third postnatal week, indicating that both types of inputs display a critical period for experience-dependent plasticity. Importantly, the timing of this critical period is both delayed and prolonged for layer 2/3-2/3 versus layer 4-2/3 excitatory synapses. Furthermore, plasticity at layer 2/3 inputs does not invoke the trafficking of calcium-permeable, GluR2-lacking AMPA receptors, whereas it sometimes does at layer 4 inputs. The dissociation of critical period timing and plasticity mechanisms at layer 4 and layer 2/3 synapses, despite the close apposition of these inputs along the dendrite, suggests remarkable specificity for the developmental regulation of plasticityin vivo.
CLIP-170 and IQGAP1 Cooperatively Regulate Dendrite Morphology
Authors: Swiech Lukasz , Blazejczyk Magdalena , Urbanska Malgorzata , Pietruszka Patrycja , Dortland Bjorn R. , Malik Anna R. , Wulf Phebe S. , Hoogenraad Casper C. , Jaworski Jacek
Published: March 2011

Dendritic arbors are compartments of neurons dedicated to receiving synaptic inputs. Their shape is an outcome of both the intrinsic genetic program and environmental signals. The microtubules and actin cytoskeleton are both crucial for proper dendritic morphology, but how they interact is unclear. The present study demonstrates that microtubule plus-end tracking protein CLIP-170 and actin-binding protein IQGAP1 regulate dendrite morphology of rat neurons by coordinating the interaction between microtubules and the actin cytoskeleton. Moreover, we show that mTOR kinase interacts with CLIP-170 and is needed for efficient formation of a protein complex containing CLIP-170 and IQGAP1. Dynamic microtubules, CLIP-170, and IQGAP1 are required for proper dendritic arbor morphology and PI3K-mTOR-induced increase in dendritic arbor complexity. Moreover, CLIP-170 and IQGAP1 knockdown modulates dendritic arbor growth via regulation of the actin cytoskeleton. We postulate that mTOR controls dendritic arbor morphology by enhancing cross talk between dynamic microtubules and actin through CLIP-170 and IQGAP1.
Youth at Risk for Obesity Show Greater Activation of Striatal and Somatosensory Regions to Food
Authors: Stice Eric , Yokum Sonja , Burger Kyle S. , Epstein Leonard H. , Small Dana M.
Published: March 2011

Obese humans, compared with normal-weight humans, have less striatal D2 receptors and striatal response to food intake; weaker striatal response to food predicts weight gain for individuals at genetic risk for reduced dopamine (DA) signaling, consistent with the reward-deficit theory of obesity. Yet these may not be initial vulnerability factors, as overeating reduces D2 receptor density, D2 sensitivity, reward sensitivity, and striatal response to food. Obese humans also show greater striatal, amygdalar, orbitofrontal cortex, and somatosensory region response to food images than normal-weight humans do, which predicts weight gain for those not at genetic risk for compromised dopamine signaling, consonant with the reward-surfeit theory of obesity. However, after pairings of palatable food intake and predictive cues, DA signaling increases in response to the cues, implying that eating palatable food contributes to increased responsivity. Using fMRI, we tested whether normal-weight adolescents at high- versus low-risk for obesity showed aberrant activation of reward circuitry in response to receipt and anticipated receipt of palatable food and monetary reward. High-risk youth showed greater activation in the caudate, parietal operculum, and frontal operculum in response to food intake and in the caudate, putamen, insula, thalamus, and orbitofrontal cortex in response to monetary reward. No differences emerged in response to anticipated food or monetary reward. Data indicate that youth at risk for obesity show elevated reward circuitry responsivity in general, coupled with elevated somatosensory region responsivity to food, which may lead to overeating that produces blunted dopamine signaling and elevated responsivity to food cues.
mTOR inhibition, a potential novel approach for bronchial carcinoids
Authors: Dong Mei , Yao James C
Published: March 2011

Although targeted therapy, including inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor, being developed for carcinoids arised from the gastrointestinal tract, treatment for locally advanced or metastatic bronchial carcinoids (BCs) remains lacking. Traditional cytotoxic chemotherapy offers essentially minimal benefit to this largely under-characterized tumor. In the September issue of Endocrine-Related Cancer, Zatelli et al. reported an anti-proliferative effect of mTOR inhibitor, everolimus, in cultured primary BC tumor cells by attenuation of IGF signaling pathway. This effect is more significant in aggressive tumors that carry higher levels of mTOR, and is consistent with the therapeutic benefit of everolimus for patients with BC observed in our phase II and III clinical trials. Although adding somatostatin analog to mTOR inhibitor did not provide a synergistic anti-tumor effect, development of rational combinations is highly warranted to further improve the outcome for patients with neuroendocrine tumors.
Islamic Mode of Regulation
Authors: Abraham Ibrahim
Published: March 2011

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When Did the Word "Culture" Become a Synonym for the Word "Bullshit"
Authors: Weep Reed
Published: March 2011

Humor Column
Sexual dimorphism of structures showing indeterminate growth: tusks of American mastodons (Mammut americanum)
Authors: Smith Kathlyn M. , Fisher Daniel C.
Published: March 2011

Documenting sexual dimorphism for structures that exhibit indeterminate growth can be more difficult than for structures exhibiting determinate growth. Most proboscidean tusks are ever-growing structures that change size and shape throughout life. Sexual dimorphism is pronounced in tusks of mature individuals, but the external form of tusks offers no clear evidence of maturation, and it is difficult to distinguish a young male's tusk from that of an older female. Thus, with previous approaches, knowledge of age was often required to assess sex from tusk measurements. This study examines sexual dimorphism of American mastodon (Mammut americanum) tusks through principal components analysis to determine which aspects of tusk form contribute most strongly to the variance among measurements and to explore the relationship between tusk form and individual age and sex. Twenty-one mastodon tusks from the Great Lakes region were evaluated in two analyses, the first focusing on geometrically distinct aspects of tusk form and the second adding measurements that reflect ontogenetic changes in a single aspect of morphology (circumference). Both analyses separated mastodons by sex (PC-I) and sorted them by age (PC-II). The distribution of tusks on the PC-II versus PC-I plane provides better discrimination of sex than univariate or bivariate methods because tusks of similar size and opposite sex appear near opposite ends of an age spectrum. The second analysis enhances sorting by age, thereby clarifying assessment of sex. This work contributes to studies of mastodon paleobiology by presenting a reliable method for assessing the sex of an individual from tusk measurements without requiring independent knowledge of age.
Stream channel network analysis applied to colony-wide feeding structures in a Permian bryozoan from Greenland
Authors: Key Marcus M. , Jackson Patrick N. Wyse , Vitiello Louis J.
Published: March 2011

Colony-wide feeding currents are a common feature of many bryozoan colonies. These feeding currents are centered on excurrent macular chimneys that expel previously filtered water away from the colony surface. In some bryozoans these macular chimneys consist of a branching channel network that converges at a point in the center of the chimney. The bifurcating channels of the maculae are analogous to a stream channel network in a closed basin with centripetal drainage. The classical methods of stream channel network analysis from geomorphology are here used to quantitatively analyze the number and length of macular channels in bryozoans. This approach is applied to a giant branch of the trepostome bryozoanTabuliporafrom the Early Permian Kim Fjelde Formation in North Greenland. Its large size allowed 18 serial tangential peels to be made through the 8-mm-thick exozone. The peels intersected two stellate maculae as defined by contiguous exilapores. The lengths of 1460 channels radiating from the maculae were measured and their Horton-Strahler stream order and Shreve magnitude scored.

We hypothesize that if fossil bryozoan maculae function as excurrent water chimneys, then they should conform to Horton's laws of stream networks and behave like closed basins with centripetal drainage. Results indicate that the stellate maculae in this bryozoan behaved liked stream channel networks exhibiting landscape maturation and stream capture. They conformed to the Law of Stream Number. They have a Bifurcation Ratio that falls within the range of natural stream channel networks. They showed a pattern opposite that expected by the Law of Stream Lengths in response to behavior characteristic of a centripetal drainage pattern in a closed basin. Thus, the stellate maculae in this bryozoan probably functioned as excurrent water chimneys with the radiating channels serving to efficiently collect the previously filtered water, conducting it to the central chimney for expulsion away from the colony surface.
Impact of Globalization on Income Distribution Inequality in 60 Countries
Authors: Zhou Lei , Biswas Basudeb , Bowles Tyler , Saunders Peter J.
Published: March 2011

This paper investigates the impact of globalization on income inequality distribution in 60 developed, transitional, and developing countries. Using Kearney's (2002, 2003 and 2004) data and principal component analysis (PCA), two globalization indices are created. One of these indices is the equally weighted index. The other index is derived from the principal component analysis. The Gini coefficient of a country is regressed on each index, respectively, in all 60 test cases.

The main contribution of this paper is its finding of a negative relationship between both globalization indices and the Gini coefficient for all 60 countries under investigation. Furthermore, test results indicate that this relationship is robust. Therefore, the empirical evidence presented in this paper supports the claim that globalization helps reduce income distribution inequality within countries.
The Taylor Rule in Estimating the Performance of Inflation Targeting Programs: The Case of Turkey
Authors: Erdem Ekrem , Kayhan Selim
Published: March 2011

In this study, we aim to analyse the performance of inflation targeting program named “A Transition Program into a Powerful Economy” in particular since 2002 until the end of 2009 by using Taylor rule in a different way. We divide inflation targeting period in accordance with the governors of the CBRT, Sureyya Serdengecti and Durmus Yilmaz, as a most important element that affects inflation targeting program among other factors.

Results imply that Mr. Serdengecti did not follow a pure Taylor rule while Mr. Yilmaz does. In Serdengecti period, the CBRT does not take in account output gap movements and exchange rate while deciding short term interest rate as said in Taylor rule. But the CBRT takes into account outgap movements and exchange rate movements in Yilmaz period, and these variables have important portion in discussing of short term interest rate while it is not so necessary in Serdengecti period.
Review of Disconnect: The Truth about Cell Phone Radiation, What the Industry Has Done to Hide It, and How to Protect Your Family
Authors: Tachover Dafna , Stein Richard A.
Published: March 2011

Review of Disconnect reveals an alarming public policy disconnect in approaching the well‐established health hazards from cell phones and describes how industry money manipulates science, public policy decision makers, and the public.
A Review of Hurricane Disaster Planning for the Elderly
Authors: McCann David GC
Published: March 2011

Frail elderly people are particularly vulnerable during hurricanes. Of the 1,330 people known to have perished along the Gulf Coast as a result of Hurricane Katrina, 71% of those in Louisiana were older than 60 years, 47% were older than 75 years, and at least 68 died in nursing homes. Unfortunately, community disaster planning frequently fails to allow for the needs of the frail elderly before, during, and after hurricanes. This paper discusses the particular vulnerabilities of the frail elderly, especially those with chronic diseases, those in residential care facilities, and those who are dialysis‐dependent. The importance of the Incident Management System (IMS) is discussed, and those who care for the frail elderly in long‐term care facilities must understand and use IMS in dealing with hurricane‐related disasters. Recommendations are made that will improve hurricane disaster planning for the frail elderly. From a policy viewpoint, it is critical that the elderly, especially those with chronic diseases, be included in disaster planning at the federal, state, and local levels to ensure that a repeat of the Hurricane Katrina debacle does not occur.