The benefit of symbols: monkeys show linear, human-like, accuracy when using symbols to represent scalar value

When humans and animals estimate numbers of items, their error rate is proportional to the number. To date, however, only humans show the capacity to represent large numbers symbolically, which endows them with increased precision, especially for large numbers, and with tools for manipulating numbers. This ability depends critically on our capacity to acquire and represent explicit symbols. Here we show that when rhesus monkeys are trained to use an explicit symbol system, they too show more precise, and linear, scaling than they do using a one-to-one corresponding numerosity representation. We also found that when taught two different types of representations for reward amount, the monkeys systematically undervalued the less precise representation. The results indicate that monkeys, like humans, can learn alternative mechanisms for representing a single value scale and that performance variability and relative value depend on the distinguishability of each representation

Distinct Properties of Hexameric but Functionally Conserved Mycobacterium tuberculosis Transcription-Repair Coupling Factor

Transcription coupled nucleotide excision repair (TC-NER) is involved in correcting UV-induced damage and other road-blocks encountered in the transcribed strand. Mutation frequency decline (Mfd) is a transcription repair coupling factor, involved in repair of template strand during transcription. Mfd from M. tuberculosis (MtbMfd) is 1234 amino-acids long harboring characteristic modules for different activities. Mtbmfd complemented Escherichia coli mfd (Ecomfd) deficient strain, enhanced survival of UV irradiated cells and increased the road-block repression in vivo. The protein exhibited ATPase activity, which was stimulated ∼1.5-fold in the presence of DNA. While the C-terminal domain (CTD) comprising amino acids 630 to 1234 showed ∼2-fold elevated ATPase activity than MtbMfd, the N-terminal domain (NTD) containing the first 433 amino acid residues was able to bind ATP but deficient in hydrolysis. Overexpression of NTD of MtbMfd led to growth defect and hypersensitivity to UV light. Deletion of 184 amino acids from the C-terminal end of MtbMfd (MfdΔC) increased the ATPase activity by ∼10-fold and correspondingly exhibited efficient translocation along DNA as compared to the MtbMfd and CTD. Surprisingly, MtbMfd was found to be distributed in monomer and hexamer forms both in vivo and in vitro and the monomer showed increased susceptibility to proteases compared to the hexamer. MfdΔC, on the other hand, was predominantly monomeric in solution implicating the extreme C-terminal region in oligomerization of the protein. Thus, although the MtbMfd resembles EcoMfd in many of its reaction characteristics, some of its hitherto unknown distinct properties hint at its species specific role in mycobacteria during transcription-coupled repair

Fitness Landscape Transformation through a Single Amino Acid Change in the Rho Terminator

Regulatory networks allow organisms to match adaptive behavior to the complex and dynamic contingencies of their native habitats. Upon a sudden transition to a novel environment, the mismatch between the native behavior and the new niche provides selective pressure for adaptive evolution through mutations in elements that control gene expression. In the case of core components of cellular regulation and metabolism, with broad control over diverse biological processes, such mutations may have substantial pleiotropic consequences. Through extensive phenotypic analyses, we have characterized the systems-level consequences of one such mutation (rho*) in the global transcriptional terminator Rho of Escherichia coli. We find that a single amino acid change in Rho results in a massive change in the fitness landscape of the cell, with widely discrepant fitness consequences of identical single locus perturbations in rho* versus rhoWT backgrounds. Our observations reveal the extent to which a single regulatory mutation can transform the entire fitness landscape of the cell, causing a massive change in the interpretation of individual mutations and altering the evolutionary trajectories which may be accessible to a bacterial population

Resistive Exercise for Arthritic Cartilage Health (REACH): A randomized double-blind, sham-exercise controlled trial

<p>Abstract</p> <p>Background</p> <p>This article provides the rationale and methodology, of the first randomised controlled trial to our knowledge designed to assess the efficacy of progressive resistance training on cartilage morphology in women with knee osteoarthritis.</p> <p>Development and progression of osteoarthritis is multifactorial, with obesity, quadriceps weakness, joint malalignment, and abnormal mechanical joint forces particularly relevant to this study. Progressive resistance training has been reported to improve pain and disability in osteoarthritic cohorts. However, the disease-modifying potential of progressive resistance training for the articular cartilage degeneration characteristic of osteoarthritis is unknown. Our aim was to investigate the effect of high intensity progressive resistance training on articular cartilage degeneration in women with knee osteoarthritis.</p> <p>Methods</p> <p>Our cohort consisted of women over 40 years of age with primary knee osteoarthritis, according to the American College of Rheumatology clinical criteria. Primary outcome was blinded measurement of cartilage morphology via magnetic resonance imaging scan of the tibiofemoral joint. Secondary outcomes included walking endurance, balance, muscle strength, endurance, power, and velocity, body composition, pain, disability, depressive symptoms, and quality of life.</p> <p>Participants were randomized into a supervised progressive resistance training or sham-exercise group. The progressive resistance training group trained muscles around the hip and knee at 80% of their peak strength and progressed 3% per session, 3 days per week for 6 months. The sham-exercise group completed all exercises except hip adduction, but without added resistance or progression. Outcomes were repeated at 3 and 6 months, except for the magnetic resonance imaging scan, which was only repeated at 6 months.</p> <p>Discussion</p> <p>Our results will provide an evaluation of the disease-modifying potential of progressive resistance training for osteoarthritis.</p> <p>Trial Registration</p> <p>ANZCTR Reference No. 12605000116628</p

Linking Oviposition Site Choice to Offspring Fitness in Aedes aegypti: Consequences for Targeted Larval Control of Dengue Vectors

Controlling the mosquito Aedes aegypti, the predominant dengue vector, requires understanding the ecological and behavioral factors that influence population abundance. Females of several mosquito species are able to identify high-quality egg-laying sites, resulting in enhanced offspring development and survival, and ultimately promoting population growth. Here, the authors investigated egg-laying decisions of Ae. aegypti. Paradoxically, they found that larval survival and development were poorest in the containers females most often selected for egg deposition. Thus, egg-laying decisions may contribute to crowding of larvae and play a role in regulating mosquito populations. The authors also tested whether removal of the containers producing the most adult mosquitoes, a World Health Organization-recommended dengue prevention strategy, changes the pattern of how females allocate their eggs. Elimination of the most productive containers led to a more even distribution of eggs in one trial, but not another. These results suggest that behavioral adjustments by egg-laying females may lessen the effectiveness of a common mosquito control tactic. The authors advocate incorporating control strategies that take advantage of the natural egg-laying preferences of this vector species, such as luring egg-laying females to traps or places where their eggs will accumulate, but not develop

The E-cadherin repressor slug and progression of human extrahepatic hilar cholangiocarcinoma

<p>Abstract</p> <p>Objectives</p> <p>This study explored the expression and function of Slug in human extrahepatic hilar cholangiocarcinoma (EHC) to identify its role in tumor progression.</p> <p>Methods</p> <p>The expression of Snail and Slug mRNA in 52 human tissue samples of EHC was investigated. The mRNA of Snail and Slug were quantified using reverse transcriptase-PCR, and correlations with E-cadherin expression and clinicopathological factors were investigated. We then investigated transfection of Slug cDNA in endogenous E-cadherin-positive human EHC FRH0201 cells, selectively induced the loss of E-cadherin protein expression, and then small interfering RNA (siRNA) for inhibition of Slug expression in endogenous Slug-positive human EHC QBC939 cells, selectively induced the loss of Slug protein expression. A Boyden chamber transwell assay was used for invasion.</p> <p>Results</p> <p>Slug mRNA was overexpressed in 18 cases (34.6%) of EHC compared with adjacent noncancerous tissue. E-Cadherin protein expression determined in the same 52 cases by immunohistochemistry was significantly down-regulated in those cases with Slug mRNA overexpression (P = 0.0001). The tumor and nontumor ratio of Slug mRNA was correlated with nodal metastasis(p = 0.0102), distant metastasis (p = 0.0001)and Survival time(p = 0.0443). However, Snail mRNA correlated with neither E-cadherin expression nor tumor invasiveness. By inhibiting Slug expression by RNA interference, we found that reduced Slug levels upregulated E-cadherin and decreased invasion in QBC939 cell. When the QBC939 cells was infected with Slug cDNA,, significant E-cadherin was downregulated and increased invasion in QBC939 cell.</p> <p>Conclusions</p> <p>The results suggested that Slug expression plays an important role in both the regulation of E-cadherin expression and in the acquisition of invasive potential in human EHC. Slug is possibly a potential target for an antitumor therapy blocking the functions of invasion and metastasis in human EHCs.</p

Revealing Dissociable Attention Biases in Chronic Smokers Through an Individual-Differences Approach

Addiction is accompanied by attentional biases (AB), wherein drug-related cues grab attention independently of their perceptual salience. AB have emerged in different flavours depending on the experimental approach, and their clinical relevance is still debated. In chronic smokers we sought evidence for dissociable attention abnormalities that may play distinct roles in the clinical manifestations of the disorder. Fifty smokers performed a modified visual probe-task measuring two forms of AB and their temporal dynamics, and data on their personality traits and smoking history/ status were collected. Two fully dissociable AB effects were found: A Global effect, reflecting the overall impact of smoke cues on attention, and a Location-specific effect, indexing the impact of smoke cues on visuospatial orienting. Importantly, the two effects could be neatly separated from one another as they: (i) unfolded with dissimilar temporal dynamics, (ii) were accounted for by different sets of predictors associated with personality traits and smoking history and (iii) were not correlated with one another. Importantly, the relevance of each of these two components in the single individual depends on a complex blend of personality traits and smoking habits, a result that future efforts addressing the clinical relevance of addiction-related AB should take into careful consideration.This study was supported by funding provided by the University of Verona to CDL, CC and L

Replication Fork Reversal after Replication–Transcription Collision

Replication fork arrest is a recognized source of genetic instability, and transcription is one of the most prominent causes of replication impediment. We analyze here the requirement for recombination proteins in Escherichia coli when replication–transcription head-on collisions are induced at a specific site by the inversion of a highly expressed ribosomal operon (rrn). RecBC is the only recombination protein required for cell viability under these conditions of increased replication-transcription collisions. In its absence, fork breakage occurs at the site of collision, and the resulting linear DNA is not repaired and is slowly degraded by the RecJ exonuclease. Lethal fork breakage is also observed in cells that lack RecA and RecD, i.e. when both homologous recombination and the potent exonuclease V activity of the RecBCD complex are inactivated, with a slow degradation of the resulting linear DNA by the combined action of the RecBC helicase and the RecJ exonuclease. The sizes of the major linear fragments indicate that DNA degradation is slowed down by the encounter with another rrn operon. The amount of linear DNA decreases nearly two-fold when the Holliday junction resolvase RuvABC is inactivated in recB, as well as in recA recD mutants, indicating that part of the linear DNA is formed by resolution of a Holliday junction. Our results suggest that replication fork reversal occurs after replication–transcription head-on collision, and we propose that it promotes the action of the accessory replicative helicases that dislodge the obstacle

Steroid Concentrations in Plasma, Whole Blood and Brain: Effects of Saline Perfusion to Remove Blood Contamination from Brain

The brain and other organs locally synthesize steroids. Local synthesis is suggested when steroid levels are higher in tissue than in the circulation. However, measurement of both circulating and tissue steroid levels are subject to methodological considerations. For example, plasma samples are commonly used to estimate circulating steroid levels in whole blood, but steroid levels in plasma and whole blood could differ. In addition, tissue steroid measurements might be affected by blood contamination, which can be addressed experimentally by using saline perfusion to remove blood. In Study 1, we measured corticosterone and testosterone (T) levels in zebra finch (Taeniopygia guttata) plasma, whole blood, and red blood cells (RBC). We also compared corticosterone in plasma, whole blood, and RBC at baseline and after 60 min restraint stress. In Study 2, we quantified corticosterone, dehydroepiandrosterone (DHEA), T, and 17β-estradiol (E2) levels in the brains of sham-perfused or saline-perfused subjects. In Study 1, corticosterone and T concentrations were highest in plasma, significantly lower in whole blood, and lowest in RBC. In Study 2, saline perfusion unexpectedly increased corticosterone levels in the rostral telencephalon but not other regions. In contrast, saline perfusion decreased DHEA levels in caudal telencephalon and diencephalon. Saline perfusion also increased E2 levels in caudal telencephalon. In summary, when comparing local and systemic steroid levels, the inclusion of whole blood samples should prove useful. Moreover, blood contamination has little or no effect on measurement of brain steroid levels, suggesting that saline perfusion is not necessary prior to brain collection. Indeed, saline perfusion itself may elevate and lower steroid concentrations in a rapid, region-specific manner