bluuebunny/crossref_metadata_2025 huggingface dataset:
Numerical solution of the multidimensional Gelfand–Levitan equation
Authors: Kabanikhin Sergey I. , Sabelfeld Karl K. , Novikov Nikita S. , Shishlenin Maxim A.
Published: September 2015

The coefficient inverse problem for the two-dimensional wave equation is solved.
We apply the Gelfand–Levitan approach to transform the nonlinear inverse problem to a family of linear integral equations.
We consider the Monte Carlo method for solving the Gelfand–Levitan equation. We obtain the estimation of the solution of the Gelfand–Levitan equation in one specific point, due to the properties of the method. That allows the Monte Carlo method to be more effective in terms of span cost, compared with regular methods of solving linear system. Results of numerical simulations are presented.
Russell's Notes on Frege for Appendix A of The Principles of Mathematics
Authors: Linsky Bernard
Published: September 2015

This article presents notes that Russell made while reading the works of Gottlob Frege in 1902. These works include Frege’s books as well as the packet of offprints Frege sent at Russell’s request in June of that year. Russell relied on these notes while composing “Appendix A: The Logical and Arithmetical Doctrines of Frege” to add to The Principles of Mathematics, which was then in press. A transcription of the marginal comments in those works of Frege appeared in the previous issue of this journal.
Russell and Wittgenstein on Incongruent Counterparts and Incompatible Colours
Authors: Lugg Andrew
Published: September 2015

Russell (in Principles of Mathematics) and Wittgenstein (in Tractatus
Logico-Philosophicus) largely agree on the twin questions of why pairs of
congruent objects cannot always be made to coincide and why surfaces
can never be uniformly two colours at once. Both philosophers take
space and colour to be mathematically representable, construe the relevant
impossibilities as mathematical and hold that mathematical impossibility
is at root logical. It is not by chance that Russell says nothing
about the phenomena in his Introduction to the Tractatus or surprising
that Wittgenstein was unmoved by the objection that his account of colour
incompatibility puts paid to his early philosophy.
Effect of Whey Protein in Conjunction With a Caloric-Restricted Diet and Resistance Training
Authors: Dudgeon Wesley D. , Kelley Elizabeth P. , Scheett Timothy P.
Published: September 2015

Dudgeon, WD, Kelley, EP, and Scheett, TP. Effect of whey protein in conjunction with a caloric-restricted diet and resistance training. J Strength Cond Res 31(5): 1353–1361, 2017—Caloric-restricted weight loss, especially rapid weight loss, results from a decrease in both lean and fat mass (FM). The goal for many is to lose FM while retaining lean body mass (LBM) and muscular performance thus many turn to supplements. Sixteen resistance-trained men (24 ± 1.6 years of age) completed a 4 d·wk−1 body building style split resistance training program for 8 weeks in conjunction with a pre-exercise, periexercise, and postexercise ingestion of whey protein (WHEY) nutritional supplement or carbohydrate (CON)-based nutritional supplement. There were no differences in body mass change between the WHEY and CON groups although both groups lost body mass (p ≤ 0.05); however, WHEY group maintained LBM whereas the CON group lost (p ≤ 0.05), and the WHEY group lost FM (p > 0.05) and the CON group did not, although the change in FM between groups was not different. Both the WHEY and CON (p ≤ 0.05) groups significantly increased lower-body strength. The WHEY group increased upper-body strength (p ≤ 0.05), whereas the CON did not change. Both groups (p ≤ 0.05) increased lower-body repetitions to fatigue with the increase greater in the CON group (p ≤ 0.05). The CON group also increased upper-body repetitions (p ≤ 0.05) whereas WHEY did not. WHEY group lost body mass, composed of FM, whereas CON also experienced a loss in body mass, but this loss was due to decrease in LBM. Neither group experienced a loss in muscle performance, with the WHEY group tending to show improvement in strength and CON group in endurance. These data indicate WHEY supplementation compared with carbohydrate supplementation, during a caloric-restricted “cut” diet can assist in maintaining LBM while allowing for the loss of FM.
Validity and Reliability of a Portable Isometric Mid-Thigh Clean Pull
Authors: James Lachlan P. , Roberts Llion A. , Haff G. Gregory , Kelly Vincent G. , Beckman Emma M.
Published: September 2015

James, LP, Roberts, LA, Haff, GG, Kelly, VG, and Beckman, EM. Validity and reliability of a portable isometric mid-thigh clean pull. J Strength Cond Res 31(5): 1378–1386, 2017—This study investigated the test-retest reliability and criterion validity of force-time curve variables collected through a portable isometric mid-thigh clean pull (IMTP) device equipped with a single-axial load cell. Fifteen males with ≥6 months of resistance training experience attended two testing sessions. In each session, participants performed an IMTP in 2 separate conditions in a randomized counterbalanced manner. The criterion condition consisted of a closed-chain IMTP configured with a force plate (IMTPf), whereas the experimental test was undertaken using a portable IMTP with data acquired through a single-axial load cell (IMTPl). A very high reliability (coefficient of variation [CV] = 3.10, 90% confidence interval [CI]: 2.4–4.6%; intraclass correlation coefficient [ICC] = 0.96, 90% CI: 0.90–0.98) and acceptable validity (CV = 9.2, 90% CI: 7–14%; ICC = 0.88, 90% CI: 0.71–0.95) were found in the experimental condition for the measure of peak force. However, significant differences were present between the IMTPf and IMTPl (p < 0.0001). Alternate force-time curve variables did not reach acceptable levels of validity or reliability in the experimental condition. The IMTPl is a valid and highly reliable method for assessing peak force. This provides evidence supporting the use of an IMTPl as a cost-effective and portable alternative for those who wish to assess maximal force production in a similar fashion to a traditional IMTP. However, practitioners should be aware that these are slightly different tests.
CSF and Blood Levels of GFAP in Alexander Disease
Authors: Jany Paige L. , Agosta Guillermo E. , Benko William S. , Eickhoff Jens C. , Keller Stephanie R. , Köehler Wolfgang , Koeller David , Mar Soe , Naidu Sakkubai , Marie Ness Jayne , Pareyson Davide , Renaud Deborah L. , Salsano Ettore , Schiffmann Raphael , Simon Julie , Vanderver Adeline , Eichler Florian , van der Knaap Marjo S. , Messing Albee
Published: September 2015

Alexander disease is a rare, progressive, and generally fatal neurological disorder that results from dominant mutations affecting the coding region ofGFAP, the gene encoding glial fibrillary acidic protein, the major intermediate filament protein of astrocytes in the CNS. A key step in pathogenesis appears to be the accumulation of GFAP within astrocytes to excessive levels. Studies using mouse models indicate that the severity of the phenotype correlates with the level of expression, and suppression of GFAP expression and/or accumulation is one strategy that is being pursued as a potential treatment. With the goal of identifying biomarkers that indirectly reflect the levels of GFAP in brain parenchyma, we have assayed GFAP levels in two body fluids in humans that are readily accessible as biopsy sites: CSF and blood. We find that GFAP levels are consistently elevated in the CSF of patients with Alexander disease, but only occasionally and modestly elevated in blood. These results provide the foundation for future studies that will explore whether GFAP levels can serve as a convenient means to monitor the progression of disease and the response to treatment.
Arginine Methyltransferase 1 in the Nucleus Accumbens Regulates Behavioral Effects of Cocaine
Authors: Li Yan , Zhu Ruiming , Wang Wenjing , Fu Dengqi , Hou Jing , Ji Sen , Chen Bo , Hu Zhengtao , Shao Xue , Yu Xuri , Zhao Qian , Zhang Baolai , Du Changman , Bu Qian , Hu Chunyan , Tang Yun , Zhong Lei , Yang Shengyong , Zhao Yinglan , Cen Xiaobo
Published: September 2015

Recent evidence suggests that histone modifications play a role in the behavioral effects of cocaine in rodent models. Histone arginine is known to be methylated by protein arginineN-methyltransferases (PRMTs). Evidence shows that PRMT1 contributes to >90% of cellular PRMT activity, which regulates histone H4 arginine 3 asymmetric dimethylation (H4R3me2a). Though histone arginine methylation represents a chemical modification that is relatively stable compared with other histone alterations, it is less well studied in the setting of addiction. Here, we demonstrate that repeated noncontingent cocaine injections increase PRMT1 activity in the nucleus accumbens (NAc) of C57BL/6 mice. We, subsequently, identify a selective inhibitor of PRMT1, SKLB-639, and show that systemic injections of the drug decrease cocaine-induced conditioned place preference to levels observed with genetic knockdown of PRMT1. NAc-specific downregulation of PRMT1 leads to hypomethylation of H4R3me2a, and hypoacetylation of histone H3 lysine 9 and 14. We also found that H4R3me2a is upregulated in NAc after repeated cocaine administration, and that H4R3me2a upregulation in turn controls the expression ofCdk5andCaMKII. Additionally, the suppression of PRMT1 in NAc with lentiviral-short hairpin PMRT1 decreases levels ofCaMKIIandCdk5in the cocaine-treated group, demonstrating that PRMT1 affects the ability of cocaine to induceCaMKIIandCdk5in NAc. Notably, increased H4R3me2a by repeated cocaine injections is relatively long-lived, as increased expression was observed for up to 7 d after the last cocaine injection. These results show the role of PRMT1 in the behavioral effects of cocaine.

SIGNIFICANCE STATEMENTThis work demonstrated that repeated cocaine injections led to an increase of protein arginineN-methyltransferase (PRMT1) in nucleus accumbens (NAc). We then identified a selective inhibitor of PRMT1 (SKLB-639), which inhibited cocaine-induced conditioned place preference (CPP). Additionally, genetic downregulation of PRMT1 in NAc also attenuated cocaine-caused CPP and locomotion activity, which was associated with decreased expression of histone H4 arginine 3 asymmetric demethylation (H4R3me2a) and hypoacetylation of histone H3 lysine 9 and 14 (acH3K9/K14). This study also showed that H4R3me2a controlled transcriptions of Cdk5 and CaMKII, and that PRMT1 negatively affected the ability of cocaine to induce CaMKII and Cdk5 in NAc. Notably, increased H4R3me2a by repeated cocaine injection was relatively long-lived as increased expression was observed up to 7 d after withdrawal from cocaine. Together, this study suggests that PRMT1 inhibition may serve as a potential therapeutic strategy for cocaine addiction.
A Simple Network Architecture Accounts for Diverse Reward Time Responses in Primary Visual Cortex
Authors: Huertas Marco A. , Hussain Shuler Marshall G. , Shouval Harel Z.
Published: September 2015

Many actions performed by animals and humans depend on an ability to learn, estimate, and produce temporal intervals of behavioral relevance. Exemplifying such learning of cued expectancies is the observation of reward-timing activity in the primary visual cortex (V1) of rodents, wherein neural responses to visual cues come to predict the time of future reward as behaviorally experienced in the past. These reward-timing responses exhibit significant heterogeneity in at least three qualitatively distinct classes: sustained increase or sustained decrease in firing rate until the time of expected reward, and a class of cells that reach a peak in firing at the expected delay. We elaborate upon our existing model by including inhibitory and excitatory units while imposing simple connectivity rules to demonstrate what role these inhibitory elements and the simple architectures play in sculpting the response dynamics of the network. We find that simply adding inhibition is not sufficient for obtaining the different distinct response classes, and that a broad distribution of inhibitory projections is necessary for obtaining peak-type responses. Furthermore, although changes in connection strength that modulate the effects of inhibition onto excitatory units have a strong impact on the firing rate profile of these peaked responses, the network exhibits robustness in its overall ability to predict the expected time of reward. Finally, we demonstrate how the magnitude of expected reward can be encoded at the expected delay in the network and how peaked responses express this reward expectancy.

SIGNIFICANCE STATEMENTHeterogeneity in single-neuron responses is a common feature of neuronal systems, although sometimes, in theoretical approaches, it is treated as a nuisance and seldom considered as conveying a different aspect of a signal. In this study, we focus on the heterogeneous responses in the primary visual cortex of rodents trained with a predictable delayed reward time. We describe under what conditions this heterogeneity can arise by self-organization, and what information it can convey. This study, while focusing on a specific system, provides insight onto how heterogeneity can arise in general while also shedding light onto mechanisms of reinforcement learning using realistic biological assumptions.
“Visual” Cortex of Congenitally Blind Adults Responds to Syntactic Movement
Authors: Lane Connor , Kanjlia Shipra , Omaki Akira , Bedny Marina
Published: September 2015

Human cortex is comprised of specialized networks that support functions, such as visual motion perception and language processing. How do genes and experience contribute to this specialization? Studies of plasticity offer unique insights into this question. In congenitally blind individuals, “visual” cortex responds to auditory and tactile stimuli. Remarkably, recent evidence suggests that occipital areas participate in language processing. We asked whether in blindness, occipital cortices: (1) develop domain-specific responses to language and (2) respond to a highly specialized aspect of language–syntactic movement. Nineteen congenitally blind and 18 sighted participants took part in two fMRI experiments. We report that in congenitally blind individuals, but not in sighted controls, “visual” cortex is more active during sentence comprehension than during a sequence memory task with nonwords, or a symbolic math task. This suggests that areas of occipital cortex become selective for language, relative to other similar higher-cognitive tasks. Crucially, we find that these occipital areas respond more to sentences with syntactic movement but do not respond to the difficulty of math equations. We conclude that regions within the visual cortex of blind adults are involved in syntactic processing. Our findings suggest that the cognitive function of human cortical areas is largely determined by input during development.

SIGNIFICANCE STATEMENTHuman cortex is made up of specialized regions that perform different functions, such as visual motion perception and language processing. How do genes and experience contribute to this specialization? Studies of plasticity show that cortical areas can change function from one sensory modality to another. Here we demonstrate that input during development can alter cortical function even more dramatically. In blindness a subset of “visual” areas becomes specialized for language processing. Crucially, we find that the same “visual” areas respond to a highly specialized and uniquely human aspect of language–syntactic movement. These data suggest that human cortex has broad functional capacity during development, and input plays a major role in determining functional specialization.
Spontaneous Activity Patterns in Primary Visual Cortex Predispose to Visual Hallucinations
Authors: Pajani Auréliane , Kok Peter , Kouider Sid , de Lange Floris P.
Published: September 2015

According to theoretical frameworks casting perception as inference, vision results from the integration of bottom-up visual input with top-down expectations. Under conditions of strongly degraded sensory input, this may occasionally result in false perceptions in the absence of a sensory signal, also termed “hallucinations.” Here, we investigated whether spontaneous prestimulus activity patterns in sensory circuits, which may embody a participant's prior expectations, predispose the observer toward false perceptions. Specifically, we used fMRI to investigate whether the representational content of prestimulus activity in early visual cortex is linked to subsequent perception during a challenging detection task. Human participants were asked to detect oriented gratings of a particular orientation that were embedded in noise. We found two characteristics of prestimulus activity that predisposed participants to hallucinations: overall lower prestimulus activity and a bias in the prestimulus activity patterns toward the to-be-detected (expected) grating. These results suggest that perceptual hallucinations may be due to an imprecise and biased state of sensory circuits preceding sensory evidence collection.

SIGNIFICANCE STATEMENTWhen sensory stimulation is strongly degraded, we occasionally misperceive a stimulus when only noise is present: a perceptual hallucination. Using fMRI in healthy participants, we investigated whether the state of early visual cortex preceding stimulus onset predisposes an observer to hallucinations. We found two characteristics of prestimulus activity that predisposed participants to hallucinations: overall lower prestimulus activity and a bias in the prestimulus activity patterns toward the expected grating. These results suggest that perceptual hallucinations are due to an imprecise and biased state of sensory circuits preceding sensation.
Dynamic Changes from Depolarizing to Hyperpolarizing GABAergic Actions during Giant Depolarizing Potentials in the Neonatal Rat Hippocampus
Authors: Khalilov Ilgam , Minlebaev Marat , Mukhtarov Marat , Khazipov Roustem
Published: September 2015

During development, GABA exerts depolarizing action on immature neurons and, acting in synergy with glutamate, drives giant depolarizing potentials (GDPs) in the hippocampal network. Yet, blockade of the GABA(A) receptors transforms GDPs to epileptiform discharges suggesting dual, both excitatory and inhibitory, actions of GABA in the immature hippocampal network. However, the nature of this dualism in early GABA actions is poorly understood. Here we characterized the dynamics of synaptic currents mediated by GABA(A) and glutamate receptors through an estimation of the changes in their conductance and driving forces in neonatal rat CA3 pyramidal cells during GDPs. We found that depolarizing GABAergic and glutamatergic currents act in synergy at the GDPs' onset. However, during the peak of the population discharge, the inward synaptic current was essentially mediated by glutamate receptors whereas GABA currents transiently switched their direction from depolarizing to hyperpolarizing as a result of neuronal depolarization above the GABA(A) reversal potential. Thus, the action of GABA on CA3 pyramidal cells dynamically changes during GDPs from excitatory at the GDPs' onset to inhibitory at the GDPs' peak. We propose that the dynamic changes in GABA actions occurring during GDPs enable GABAergic interneurons not only to initiate the discharge of pyramidal cells but also to control excitation in the recurrent CA3 network preventing epileptiform synchronization.

SIGNIFICANCE STATEMENTDuring development GABA exerts a depolarizing action on immature neurons. However, at the network level the effects of GABA are complex involving both excitatory and inhibitory actions. Here we show that GABA actions critically depend on the network state. Although GABA depolarizes neurons at rest and at the onset of population bursts, it transiently becomes hyperpolarizing at the peak of the population bursts. These dynamic changes in GABA actions enable GABAergic interneurons not only to initiate the network discharge but also to control excitation to prevent epileptiform synchronization.
Impaired Cholinergic Excitation of Prefrontal Attention Circuitry in the TgCRND8 Model of Alzheimer's Disease
Authors: Proulx Éliane , Fraser Paul , McLaurin JoAnne , Lambe Evelyn K.
Published: September 2015

Attention deficits in Alzheimer's disease can exacerbate its other cognitive symptoms, yet relevant disruptions of key prefrontal circuitry are not well understood. Here, in the TgCRND8 mouse model of this neurological disorder, we demonstrate and characterize a disruption of cholinergic excitation in the major corticothalamic layer of the prefrontal cortex, in which modulation by acetylcholine is essential for optimal attentional function. Using electrophysiology with concurrent multiphoton imaging, we show that layer 6 pyramidal cells are unable to sustain cholinergic excitation to the same extent as their nontransgenic littermate controls, as a result of the excessive activation of calcium-activated hyperpolarizing conductances. We report that cholinergic excitation can be improved in TgCRND8 cortex by pharmacological blockade of SK channels, suggesting a novel target for the treatment of cognitive dysfunction in Alzheimer's disease.

SIGNIFICANCE STATEMENTAlzheimer's disease is accompanied by attention deficits that exacerbate its other cognitive symptoms. In brain slices of a mouse model of this neurological disorder, we demonstrate, characterize, and rescue impaired cholinergic excitation of neurons essential for optimal attentional performance. In particular, we show that the excessive activation of a calcium-activated potassium conductance disrupts the acetylcholine excitation of prefrontal layer 6 pyramidal neurons and that its blockade normalizes responses. These findings point to a novel potential target for the treatment of cognitive dysfunction in Alzheimer's disease.
From Jerash to New York
Authors: Macaulay-Lewis Elizabeth , Simard Jared
Published: September 2015

From Jerash to New York: Columns, Archaeology, and Politics at the 1964–65 World’s Fair analyzes the Column of Jerash, presented to New York City by the government of Jordan as a permanent memento of that country’s participation in the 1964–65 New York World’s Fair. Elizabeth Macaulay-Lewis and Jared Simard offer the first scholarly documentation and assessment of the column, which still stands at the site of the fair in Flushing Meadows Corona Park in Queens, New York, and confirm that it originated from Jerash, but not from the Temple of Artemis. The gift of the column was part of King Hussein of Jordan’s policy of archaeological diplomacy, which included the donation of artifacts to American cities and universities to strengthen ties between Jordan and the United States. Macaulay-Lewis and Simard explore the competing narratives of biblical and classical history and archaeology in the American-Israel and Jordan Pavilions at the 1964–65 World’s Fair and the controversy that erupted over the inclusion of a mural about Palestinian refugees in the Jordan Pavilion.
“A Better Civilization” through Tourism
Authors: Ochonicky Adam
Published: September 2015

Adam Ochonicky, “‘A Better Civilization’ through Tourism: Cultural Appropriation in The Marble Faun” (pp. 221–237)

This essay argues that Nathaniel Hawthorne’s The Marble Faun: Or, The Romance of Monte Beni (1860) is an attempt to situate the United States within a lineage of “great” nations via the depiction of tourism abroad in the nineteenth century. In The Marble Faun, Hawthorne suggests that the historical legacies of nations are dependent on the production of art objects, literature, and cultural sites that demonstrate the sophistication of a given national identity. As such, the novel’s narrative revolves around the experiences of a pair of American artists, Hilda and Kenyon, during their stay in Rome. Hawthorne continually emphasizes the duo’s remarkable skills as evaluators and copyists of Italian art in order to legitimize their—and, by proxy, the United States’—appropriation of Italy’s culture and historical stature. Throughout the novel, Hawthorne disparages the degraded state of then-contemporary Rome, while elevating the comparatively youthful United States as the rightful inheritor of Italy’s illustrious past. Essentially, by situating critical work on the nineteenth-century “realm of leisure” alongside twenty-first-century theories of tourism, this essay provides a framework for understanding the complex interconnections between transnational tourism and the development of American cultural identity in The Marble Faun.
Alternative Hfq‐sRNA interaction modes dictate alternative mRNA recognition
Authors: Schu Daniel J , Zhang Aixia , Gottesman Susan , Storz Gisela
Published: September 2015

Many bacteria use small RNAs (sRNAs) and the RNA chaperone Hfq to regulate mRNA stability and translation. Hfq, a ring‐shaped homohexamer, has multiple faces that can bind both sRNAs and their mRNA targets. We find that Hfq has at least two distinct ways in which it interacts with sRNAs; these different binding properties have strong effects on the stability of the sRNA in vivo and the sequence requirements of regulated mRNAs. Class I sRNAs depend on proximal and rim Hfq sites for stability and turn over rapidly. Class II sRNAs are more stable and depend on the proximal and distal Hfq sites for stabilization. Using deletions and chimeras, we find that while Class I sRNAs regulate mRNA targets with previously defined ARN repeats, Class II sRNAs regulate mRNAs carrying UA‐rich rim‐binding sites. We discuss how these different binding modes may correlate with different roles in the cell, with Class I sRNAs acting as emergency responders and Class II sRNAs acting as silencers.
Five-year prospective evaluation of thyroid function in girls with subclinical mild hypothyroidism of different etiology
Authors: Wasniewska Malgorzata , Aversa Tommaso , Salerno Mariacarolina , Corrias Andrea , Messina Maria Francesca , Mussa Alessandro , Capalbo Donatella , De Luca Filippo , Valenzise Mariella
Published: September 2015

Aim

To follow-up for 5 years thyroid status evolution in 127 girls with mild (TSH 5–10 mU/l) subclinical hypothyroidism (SH) of different etiologies.

Patients

The population was divided into two age-matched groups of 42 and 85 girls with either idiopathic (group A) or Hashimoto's thyroiditis (HT)-related SH (group B). Group B was in turn divided into three subgroups, according to whether SH was either isolated or associated with Turner syndrome (TS) or Down syndrome (DS).

Results

At the end of follow-up the rate of girls who became euthyroid was higher in group A (61.9% vs 10.6%), whereas the rates of patients who remained SH (55.3% vs 26.2%), became overtly hypothyroid (30.6% vs 11.9%) or required levothyroxine (l-T4) therapy (63.5% vs 23.8%) were higher in group B. Among the girls of group B, the risk of remaining SH or developing overt hypothyroidism was higher in the subgroups with TS or DS than in those with isolated HT.

Conclusions

Long-term prognosis of mild and idiopathic SH is frequently benign, even though a l-T4 treatment may be needed throughout follow-up in almost a quarter of cases; long-term prognosis is different in the girls with either idiopathic or HT-related SH; and the association with either TS or DS impairs the outcome of HT-related SH.
Safety and tolerability of sorafenib in patients with radioiodine-refractory thyroid cancer
Authors: Worden Francis , Fassnacht Martin , Shi Yuankai , Hadjieva Tatiana , Bonichon Françoise , Gao Ming , Fugazzola Laura , Ando Yuichi , Hasegawa Yasuhisa , Park Do Joon , Shong Young Kee , Smit Johannes W A , Chung John , Kappeler Christian , Meinhardt Gerold , Schlumberger Martin , Brose Marcia S
Published: September 2015

Effective adverse event (AE) management is critical to maintaining patients on anticancer therapies. The DECISION trial was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 trial which investigated sorafenib for treatment of progressive, advanced, or metastatic radioactive iodine-refractory, differentiated thyroid carcinoma. Four hundred and seventeen adult patients were randomized (1:1) to receive oral sorafenib (400 mg, twice daily) or placebo, until progression, unacceptable toxicity, noncompliance, or withdrawal. Progression-free survival, the primary endpoint of DECISION, was reported previously. To elucidate the patterns and management of AEs in sorafenib-treated patients in the DECISION trial, this report describes detailed, by-treatment-cycle analyses of the incidence, prevalence, and severity of hand–foot skin reaction (HFSR), rash/desquamation, hypertension, diarrhea, fatigue, weight loss, increased serum thyroid stimulating hormone, and hypocalcemia, as well as the interventions used to manage these AEs. By-cycle incidence of the above-selected AEs with sorafenib was generally highest in cycle 1 or 2 then decreased. AE prevalence generally increased over cycles 2–6 then stabilized or declined. Among these AEs, only weight loss tended to increase in severity (from grade 1 to 2) over time; severity of HFSR and rash/desquamation declined over time. AEs were mostly grade 1 or 2, and were generally managed with dose interruptions/reductions, and concomitant medications (e.g. antidiarrheals, antihypertensives, dermatologic preparations). Most dose interruptions/reductions occurred in early cycles. In conclusion, AEs with sorafenib in DECISION were typically grade 1 or 2, occurred early during the treatment course, and were manageable over time.
Polymorphism of IL37 gene as a protective factor for autoimmune thyroid disease
Authors: Yan Ni , Meng Shuai , Song Rong-Hua , Qin Qiu , Wang Xuan , Yao Qiuming , Jiang Yanfei , Jiang Wenjuan , Shi Liangfeng , Xu Jian , Zhang Jinan
Published: September 2015

Autoimmune thyroid disease (AITD) comprises Graves' disease (GD) and Hashimoto's thyroiditis (HT). IL37 has been recently proved to be a natural suppressor for innate immunity and acquired immunity. Therefore, this study was conducted to identify the association of IL37 genetic polymorphisms with AITD in Chinese Han population. Polymorphisms of rs3811046/rs3811047/rs2723176/rs272186 in the IL37 gene were assessed in a case–control study comprising 701 GD patients, 301 HT patients and 939 controls. Genetic variants were genotyped by multiplex polymerase chain reaction and ligase detection reaction. The frequencies of the minor allele A of rs2723176 and A of rs2723186 were significantly lower in the GD patients than in the controls (P=0.014, OR=0.774; P=0.014, OR=0.777). After gender stratification, the rs3811046 G allele and the rs3811047/rs2723186 A allele were both significantly associated with a decreased risk of GD in female patients (P=0.030, OR=0.777; P=0.023, OR=0.774; P=0.029, OR=0.761). However, none of the four single nucleotide polymorphisms of IL37 gene showed any significant association with HT. Moreover, haplotype analysis revealed the GCG haplotype conferred increased risk for GD as a whole and in female GD patients (OR=1.213; OR=1.320). The ACG haplotype was associated with an increased risk of HT as a whole (OR=1.567) and in male GD patients (OR=1.820). In contrast, the AAA haplotype showed a protective role for GD as a whole (OR=0.760) and in female GD patients (OR=0.765). Our study strongly supports that the IL37 gene variants are associated with the susceptibility to AITD.
Similar Efficacies of Selection Shape Mitochondrial and Nuclear Genes in BothDrosophila melanogasterandHomo sapiens
Authors: Cooper Brandon S , Burrus Chad R , Ji Chao , Hahn Matthew W , Montooth Kristi L
Published: September 2015

Deleterious mutations contribute to polymorphism even when selection effectively prevents their fixation. The efficacy of selection in removing deleterious mitochondrial mutations from populations depends on the effective population size (Ne) of the mitochondrial DNA and the degree to which a lack of recombination magnifies the effects of linked selection. Using complete mitochondrial genomes from Drosophila melanogaster and nuclear data available from the same samples, we reexamine the hypothesis that nonrecombining animal mitochondrial DNA harbor an excess of deleterious polymorphisms relative to the nuclear genome. We find no evidence of recombination in the mitochondrial genome, and the much-reduced level of mitochondrial synonymous polymorphism relative to nuclear genes is consistent with a reduction in Ne. Nevertheless, we find that the neutrality index, a measure of the excess of nonsynonymous polymorphism relative to the neutral expectation, is only weakly significantly different between mitochondrial and nuclear loci. This difference is likely the result of the larger proportion of beneficial mutations in X-linked relative to autosomal loci, and we find little to no difference between mitochondrial and autosomal neutrality indices. Reanalysis of published data from Homo sapiens reveals a similar lack of a difference between the two genomes, although previous studies have suggested a strong difference in both species. Thus, despite a smaller Ne, mitochondrial loci of both flies and humans appear to experience similar efficacies of purifying selection as do loci in the recombining nuclear genome.
Genetic Linkage Mapping of Economically Important Traits in Cultivated Tetraploid Potato (Solanum tuberosum L.)
Authors: Massa Alicia N , Manrique-Carpintero Norma C , Coombs Joseph J , Zarka Daniel G , Boone Anne E , Kirk William W , Hackett Christine A , Bryan Glenn J , Douches David S
Published: September 2015

The objective of this study was to construct a single nucleotide polymorphism (SNP)-based genetic map at the cultivated tetraploid level to locate quantitative trait loci (QTL) contributing to economically important traits in potato (Solanum tuberosum L.). The 156 F1 progeny and parents of a cross (MSL603) between “Jacqueline Lee” and “MSG227-2” were genotyped using the Infinium 8303 Potato Array. Furthermore, the progeny and parents were evaluated for foliar late blight reaction to isolates of the US-8 genotype of Phytophthora infestans (Mont.) de Bary and vine maturity. Linkage analyses and QTL mapping were performed using a novel approach that incorporates allele dosage information. The resulting genetic maps contained 1972 SNP markers with an average density of 1.36 marker per cM. QTL mapping identified the major source of late blight resistance in “Jacqueline Lee.” The best SNP marker mapped ∼0.54 Mb from a resistance hotspot on the long arm of chromosome 9. For vine maturity, the major-effect QTL was located on chromosome 5 with allelic effects from both parents. A candidate SNP marker for this trait mapped ∼0.25 Mb from the StCDF1 gene, which is a candidate gene for the maturity trait. The identification of markers for P. infestans resistance will enable the introgression of multiple sources of resistance through marker-assisted selection. Moreover, the discovery of a QTL for late blight resistance not linked to the QTL for vine maturity provides the opportunity to use marker-assisted selection for resistance independent of the selection for vine maturity classifications.
Identification and Correction of Sample Mix-Ups in Expression Genetic Data: A Case Study
Authors: Broman Karl W , Keller Mark P , Broman Aimee Teo , Kendziorski Christina , Yandell Brian S , Sen Śaunak , Attie Alan D
Published: September 2015

In a mouse intercross with more than 500 animals and genome-wide gene expression data on six tissues, we identified a high proportion (18%) of sample mix-ups in the genotype data. Local expression quantitative trait loci (eQTL; genetic loci influencing gene expression) with extremely large effect were used to form a classifier to predict an individual’s eQTL genotype based on expression data alone. By considering multiple eQTL and their related transcripts, we identified numerous individuals whose predicted eQTL genotypes (based on their expression data) did not match their observed genotypes, and then went on to identify other individuals whose genotypes did match the predicted eQTL genotypes. The concordance of predictions across six tissues indicated that the problem was due to mix-ups in the genotypes (although we further identified a small number of sample mix-ups in each of the six panels of gene expression microarrays). Consideration of the plate positions of the DNA samples indicated a number of off-by-one and off-by-two errors, likely the result of pipetting errors. Such sample mix-ups can be a problem in any genetic study, but eQTL data allow us to identify, and even correct, such problems. Our methods have been implemented in an R package, R/lineup.
bz-rates: A Web Tool to Estimate Mutation Rates from Fluctuation Analysis
Authors: Gillet-Markowska Alexandre , Louvel Guillaume , Fischer Gilles
Published: September 2015

Fluctuation analysis is the standard experimental method for measuring mutation rates in micro-organisms. The appearance of mutants is classically described by a Luria-Delbrück distribution composed of two parameters: the number of mutations per culture (m) and the differential growth rate between mutant and wild-type cells (b). A precise estimation of these two parameters is a prerequisite to the calculation of the mutation rate. Here, we developed bz-rates, a Web tool to calculate mutation rates that provides three useful advances over existing Web tools. First, it allows taking into account b, the differential growth rate between mutant and wild-type cells, in the estimation of m with the generating function. Second, bz-rates allows the user to take into account a deviation from the Luria-Delbrück distribution called z, the plating efficiency, in the estimation of m. Finally, the Web site provides a graphical visualization of the goodness-of-fit between the experimental data and the model. bz-rates is accessible at http://www.lcqb.upmc.fr/bzrates.
Ultra-High Density, Transcript-Based Genetic Maps of Pepper Define Recombination in the Genome and Synteny Among Related Species
Authors: Hill Theresa , Ashrafi Hamid , Chin-Wo Sebastian Reyes , Stoffel Kevin , Truco Maria-Jose , Kozik Alexander , Michelmore Richard , Van Deynze Allen
Published: September 2015

Our ability to assemble complex genomes and construct ultradense genetic maps now allows the determination of recombination rates, translocations, and the extent of genomic collinearity between populations, species, and genera. We developed two ultradense genetic linkage maps for pepper from single-position polymorphisms (SPPs) identified de novo with a 30,173 unigene pepper genotyping array. The Capsicum frutescens × C. annuum interspecific and the C. annuum intraspecific genetic maps were constructed comprising 16,167 and 3,878 unigene markers in 2108 and 783 genetic bins, respectively. Accuracies of marker groupings and orders are validated by the high degree of collinearity between the two maps. Marker density was sufficient to locate the chromosomal breakpoint resulting in the P1/P8 translocation between C. frutescens and C. annuum to a single bin. The two maps aligned to the pepper genome showed varying marker density along the chromosomes. There were extensive chromosomal regions with suppressed recombination and reduced intraspecific marker density. These regions corresponded to the pronounced nonrecombining pericentromeric regions in tomato, a related Solanaceous species. Similar to tomato, the extent of reduced recombination appears to be more pronounced in pepper than in other plant species. Alignment of maps with the tomato and potato genomes shows the presence of previously known translocations and a translocation event that was not observed in previous genetic maps of pepper.
SNP Assay Development for Linkage Map Construction, Anchoring Whole-Genome Sequence, and Other Genetic and Genomic Applications in Common Bean
Authors: Song Qijian , Jia Gaofeng , Hyten David L , Jenkins Jerry , Hwang Eun-Young , Schroeder Steven G , Osorno Juan M , Schmutz Jeremy , Jackson Scott A , McClean Phillip E , Cregan Perry B
Published: September 2015

A total of 992,682 single-nucleotide polymorphisms (SNPs) was identified as ideal for Illumina Infinium II BeadChip design after sequencing a diverse set of 17 common bean (Phaseolus vulgaris L) varieties with the aid of next-generation sequencing technology. From these, two BeadChips each with >5000 SNPs were designed. The BARCBean6K_1 BeadChip was selected for the purpose of optimizing polymorphism among market classes and, when possible, SNPs were targeted to sequence scaffolds in the Phaseolus vulgaris 14× genome assembly with sequence lengths >10 kb. The BARCBean6K_2 BeadChip was designed with the objective of anchoring additional scaffolds and to facilitate orientation of large scaffolds. Analysis of 267 F2 plants from a cross of varieties Stampede × Red Hawk with the two BeadChips resulted in linkage maps with a total of 7040 markers including 7015 SNPs. With the linkage map, a total of 432.3 Mb of sequence from 2766 scaffolds was anchored to create the Phaseolus vulgaris v1.0 assembly, which accounted for approximately 89% of the 487 Mb of available sequence scaffolds of the Phaseolus vulgaris v0.9 assembly. A core set of 6000 SNPs (BARCBean6K_3 BeadChip) with high genotyping quality and polymorphism was selected based on the genotyping of 365 dry bean and 134 snap bean accessions with the BARCBean6K_1 and BARCBean6K_2 BeadChips. The BARCBean6K_3 BeadChip is a useful tool for genetics and genomics research and it is widely used by breeders and geneticists in the United States and abroad.
Evolutionary Fate of the Androgen Receptor−Signaling Pathway in Ray-Finned Fishes with a Special Focus on Cichlids
Authors: Lorin Thibault , Salzburger Walter , Böhne Astrid
Published: September 2015

The emergence of the steroid system is coupled to the evolution of multicellular animals. In vertebrates in particular, the steroid receptor repertoire has been shaped by genome duplications characteristic to this lineage. Here, we investigate for the first time the composition of the androgen receptor–signaling pathway in ray-finned fish genomes by focusing in particular on duplicates that emerged from the teleost-specific whole-genome duplication. We trace lineage- and species-specific duplications and gene losses for the genomic and nongenomic pathway of androgen signaling and subsequently investigate the sequence evolution of these genes. In one particular fish lineage, the cichlids, we find evidence for differing selection pressures acting on teleost-specific whole-genome duplication paralogs at a derived evolutionary stage. We then look into the expression of these duplicated genes in four cichlid species from Lake Tanganyika indicating, once more, rapid changes in expression patterns in closely related fish species. We focus on a particular case, the cichlid specific duplication of the rac1 GTPase, which shows possible signs of a neofunctionalization event.
Flux Control in a Defense Pathway inArabidopsis thalianaIs Robust to Environmental Perturbations and Controls Variation in Adaptive Traits
Authors: Olson-Manning Carrie F , Strock Christopher F , Mitchell-Olds Thomas
Published: September 2015

The connections leading from genotype to fitness are not well understood, yet they are crucial for a diverse set of disciplines. Uncovering the general properties of biochemical pathways that influence ecologically important traits is an effective way to understand these connections. Enzyme flux control (or, control over pathway output) is one such pathway property. The flux-controlling enzyme in the antiherbivory aliphatic glucosinolate pathway of Arabidopsis thaliana has majority flux control under benign greenhouse conditions and has evidence of nonneutral evolution. However, it is unknown how patterns of flux control may change in different environments, or if insect herbivores respond to differences in pathway flux. We test this, first through genetic manipulation of the loci that code for the aliphatic glucosinolate pathway enzymes under a variety of environments (reduced water, reduced soil nutrients, leaf wounding and methyl jasmonate treatments), and find that flux control is consistently in the first enzyme of the pathway. We also find that a generalist herbivore, Trichoplusia ni, modifies its feeding behavior depending on the flux through the glucosinolate pathway. The influence over herbivore behavior combined with the consistency of flux control suggests that genes controlling flux might be repeatedly targeted by natural selection in diverse environments and species.
Tres decenios de profesionalización de los estudios literarios en México: algunas consecuencias
Authors: Higashi Alejandro
Published: September 2015

En este trabajo, reflexiono sobre distintos aspectos relacionados con la profesionalización del campo de los estudios literarios en México después la fundación del Sistema Nacional de Investigadores, institución federal que por primera vez definió el perfil deseable de la investigación a través de una plantilla homologada de requisitos cuantificables, mediante estímulos económicos. Atiendo, principalmente, a la forma en que fue recibida esta nueva fuerza trabajadora en el campo cultural de los estudios literarios por una hegemonía intelectual prolífica y dominante fuera de la universidad y a las opiniones que recibió la formación de lenguajes teóricos especializados y su capacidad para formar profesionales dentro de sus aulas (que no necesariamente coincidían con la figura del crítico acuñada en años previos). La profesionalización, en todo caso, condujo a la crítica a la especialización y abrió los caminos para mantener dicho estilo de discurso y difundirlo entre los miembros de su comunidad académica.
Crisis y transformación de la educación superior: el lugar de las humanidades en Latinoamérica
Authors: García Herrera Alejandra
Published: September 2015

Este artículo analiza las transformaciones recientes de la universidad en Latinoamérica, como resultado de las propuestas de organismos internacionales, a finales del siglo pasado, que conciben la educación como base para el desarrollo económico. A través del estudio de la creciente bibliografía sobre la crisis de la educación superior en el continente, este trabajo busca esclarecer el vínculo entre universidad y sociedad que el enfoque corporativo ha propiciado y que ha puesto en riesgo la función social o intelectual de la universidad latinoamericana. 
No hay salida fácil: crisis, excelencia, valor y el futuro de las humanidades en la educación universitaria
Authors: Wager Joseph
Published: September 2015

Este ensayo hace hincapié en la manera en la que las humanidades han sido cuestionadas y, lo que es más preocupante aún, en la manera en la que han asumido una necesidad de legitimarse mediante la búsqueda de valores íntimos o utilitaristas. Esta búsqueda del valor es, a su vez, la piedra de toque en el mundo actual. Sin embargo, las humanidades no representan la única faceta que ha sido trastocada por el afán de la producción, un afán que resulta de una cosmovisión que algunos tacharían de mercantilista. Aunque con frecuencia los defensores de las humanidades enfatizan la forma en la que ellas abren el camino para tener una vida más plena y una sociedad más democrática (lo cual las justifica), al plantear el asunto así se sucumbe a la lógica productiva de la cosmovisión dominante. Este texto pretende comprender, explicar y ofrecer algunas percepciones en torno a las humanidades de hoy en día y del futuro, a partir de una amplia variedad de referencias culturales, personales y literarias.