Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluating the adaptive‐filter model of the cerebellum

Abstract The adaptive‐filter model of the cerebellar microcircuit is in widespread use, combining as it does an explanation of key microcircuit features with well‐specified computational power. Here we consider two methods for its evaluation. One is to test its predictions concerning relations between cerebellar inputs and outputs. Where the relevant experimental data are available, e.g. for the floccular role in image stabilization, the predictions appear to be upheld. However, for the majority of cerebellar microzones these data have yet to be obtained. The second method is to test model predictions about details of the microcircuit. We focus on features apparently incompatible with the model, in particular non‐linear patterns in Purkinje cell simple‐spike firing. Analysis of these patterns suggests the following three conclusions. (i) It is important to establish whether they can be observed during task‐related behaviour. (ii) Highly non‐linear models based on these patterns are unlikely to be universal, because they would be incompatible with the (approximately) linear nature of floccular function. (iii) The control tasks for which these models are computationally suited need to be identified. At present, therefore, the adaptive filter remains a candidate model of at least some cerebellar microzones, and its evaluation suggests promising lines for future enquiry.
CD 26 , APN / CD 13 and related enzymes as regulators of T cell immunity : implications for experimental encephalomyelitis and multiple sclerosis

1 Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Germany, 2 IMTM GmbH, Department Immunopharm, Magdeburg, Germany, 3 University Clinic of Dermatology and Venereology, Otto-von-Guericke University Magdeburg, Germany, 4 Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, Germany, 5 Institute of Biochemistry and Biotechnology, Department of Natural Sciences I, Martin-Luther-University HalleWittenberg, Halle, Germany, 6 Departments of Immunology and Pharmacology, University of Connecticut Health Center, Farmington, CT
Earliest Steps in Primary Tumor Formation and Micrometastasis Resolved with Histochemical Markers of Gene-tagged Tumor Cells

To facilitate detection of tumor cells at the highest resolution in any organ in athymic nude mouse model systems, a histochemical marker gene [bacterial IacZ or human placental alkaline phosphatase (ALP)] was transfected into specified transformed/tumor cells (fibrosarcoma or neuroblastoma). The fates of tumor cells were followed qualitatively and quantitatively by histochemical staining of whole organs or organ sections. Primary tumors developed initially via formation of “curly-haired” complexes of cells in the subcutis or dermis, followed by division of a large fraction of cells. When two tumor classes were mixed before injection, outgrowth occurred in regional concentrations of the primary tumor. Blood microvessels were detectable within 72 hr of injection, growing into tumor regions. IV injection routinely yielded multicellular foci in the lungs within minutes as precursors of experimental metastases. Micrometastasis was further resolved with cells “inactivated” by different treatments and by co-injection of two different tagged cell types. These approaches using different histochemical marker genes to “tag” different tumor cell classes, along with more advanced molecular biological approaches, permit us to characterize gene expression and its reversibility during the earliest stages of primary tumor formation and micrometastasis to virtually any organ in the recipient animal.
Patterns of Early Involvement in Expert and Nonexpert Masters Triathletes

The ultraendurance triathlon presents a unique sport for examining Masters-level involvement. On the one hand, involvement in this sport represents a fairly extreme form of physical activity with applicability to a small cohort of athletes, while on the other its general structure promotes continued participation across the lifespan, unlike sports such as gymnastics and figure skating. Here, Baker, Cote, and Deakin explore the early involvement and training in triathlon-related sports as well as other activities in a group of male Masters-level triathletes.
Cutaneous reactions in patients with solitary cysticercus granuloma on phenytoin sodium

Several medical conditions are believed to be associated with an increased risk of cutaneous adverse reactions to anti-epileptic drugs. The aim of this study was to study the frequency and nature of cutaneous reactions in a cohort of patients being treated with phenytoin sodium for seizures, who were divided into those with a solitary cysticercus granuloma (SCG) and those with a condition other than SCG, to determine if the presence of SCG increases the risk of cutaneous adverse reaction to phenytoin. A cohort of 117, consecutively begun on treatment with phenytoin for seizure control, were followed up prospectively for the development of cutaneous reactions. There were 63 patients with SCG upon imaging and 54 patients to whom phenytoin was administered for seizures due to causes other than SCG or multiple neurocysticercosis. Cutaneous reactions were significantly more common (p = 0.02) in patients with SCG (9/63 patients; 14.3%) than in controls (2/54 patients; 3.7%). The spectrum of skin reactions in patients with SCG included benign skin rash (n = 3), anticonvulsant hypersensitivity syndrome (n = 4), Stevens-Johnson syndrome (n = 1), and urticaria (n = 1). Individuals with seizures due to SCG have a high incidence of cutaneous adverse reactions to phenytoin. This fact should be kept in mind when initiating them on treatment with this anti-epileptic drug.
Molecular Genetics of Soft-Tissue Sarcomas: A Brief Overview for Clinical Oncologists

AbstractSoft-tissue sarcomas (STSs) are a heterogeneous group of tumors with distinct lines of differentiation and biologic behavior. Currently, histological analysis is still the main diagnostic approach for the classification of STSs. However, ancillary molecular genetic methods are becoming increasingly important for diagnostic confirmation and therapeutic considerations. Herein, we provide a brief overview of clinically relevant molecular abnormalities of STSs for the general clinical oncologist.
Transforming from service providers to solution providers: implications for provider-customer relationships and customer-induced solution innovation

There is a rich body of literature investigating the integration of customers into innovation processes. The various strands of this literature converge on the notion that integrating customers creates access to use-related knowledge that is needed to better target future customers. In a similar vein, solution selling has emerged as a means to provide solutions that fulfil customers' demands as an alternative to selling products and services to an unknown, anonymous customer. Here, most research adopts a producer-centric view. Yet, little research exists that: 1) combines customer integration and solution selling; 2) considers service companies. Thus, the authors' aim was to investigate whether and how a transformation from being a service provider to being a solution provider influences the provider's relationship with the customer, affects customer-induced service and solution innovation, and shapes the provider's absorptive capacity. The authors employ a case study design and investigate a German medium-sized IT consulting firm. The main result is the identification of testable propositions stemming from expert interviews and additional company data. At the end of the article, the authors discuss theoretical and managerial implications.
Pharmacologic induction of fetal hemoglobin: raising the therapeutic bar in sickle cell disease

The favorable effects of high levels of fetal hemoglobin (Hb F) in sickle cell disease have been recognized for several decades. This has been an important incentive for the development of therapeutic agents that increase Hb F production. 5-Azacytidine, the first such agent in clinical use, was proposed based on a molecular understanding of the role of DNA methylation in globin gene regulation. Controversy over the mechanism of Hb F induction by 5-azacytidine led to the identification of hydroxyurea as another agent that can increase Hb F production. Although the clinical benefit of hydroxyurea has been demonstrated in a randomized clinical trial, greater increases in Hb F are clearly needed for optimal therapeutic effect. Butyrates also increase Hb F levels, and their use in combination with hydroxyurea appears to be synergistic. Now that multiple therapeutic agents are available for Hb F induction, the use of combination therapy to increase Hb F levels sufficiently to prevent all the complications of sickle cell disease has become a realistic goal.
Iro/IRX transcription factors negatively regulate Dpp/TGF‐β pathway activity during intestinal tumorigenesis

Activating mutations in Wnt and EGFR/Ras signaling pathways are common in colorectal cancer (CRC). Remarkably, clonal co‐activation of these pathways in the adult Drosophila midgut induces “tumor‐like” overgrowths. Here, we show that, in these clones and in CRC cell lines, Dpp/TGF‐β acts as a tumor suppressor. Moreover, we discover that the Iroquois/IRX‐family‐protein Mirror downregulates the transcription of core components of the Dpp pathway, reducing its tumor suppressor activity. We also show that this genetic interaction is conserved in human CRC cells, where the Iro/IRX proteins IRX3 and IRX5 diminish the response to TGF‐β. IRX3 and IRX5 are upregulated in human adenomas, and their levels correlate inversely with the gene expression signature of response to TGF‐β. In addition, Irx5 expression confers a growth advantage in the presence of TGF‐β, but is selected against in its absence. Together, our results identify a set of Iro/IRX proteins as conserved negative regulators of Dpp/TGF‐β activity. We propose that during the characteristic adenoma‐to‐carcinoma transition of human CRC, the activity of IRX proteins could reduce the sensitivity to the cytostatic effect of TGF‐β, conferring a growth advantage to tumor cells prior to the acquisition of mutations in TGF‐β pathway components.
Ubiquitination in signaling to and activation of IKK

Summary: A role for polyubiquitination in the activation of inhibitor of NF‐κB (IκB) kinase (IKK) through a proteasome‐independent mechanism was first reported in 1996, but the physiological significance of this finding was not clear until 2000 when TRAF6 was found to be a ubiquitin E3 ligase that catalyzes lysine‐63 (K63) polyubiquitination. Since then, several proteins known to regulate IKK have been linked to the ubiquitin pathway. These include the deubiquitination enzymes CYLD and A20 that inhibit IKK, and the ubiquitin binding proteins NEMO and TAB2 which are the regulatory subunits of IKK and TAK1 kinase complexes, respectively. Now accumulating evidence strongly supports a central role of K63 polyubiquitination in IKK activation by multiple immune and inflammatory pathways. Interestingly, recent research suggests that some alternative ubiquitin chains such as linear or K11 ubiquitin chains may also play a role in certain pathways such as the TNF pathway. Here I present a historical narrative of the discovery of the role of ubiquitin in IKK activation, review recent advances in understanding the role and mechanism of ubiquitin‐mediated IKK activation, and raise some questions to be resolved in future research.
GAS EXCHANGE , METABOLITE STATUS AND EXCESS POST-EXERCISE OXYGEN CONSUMPTION AFTER REPETITIVE BOUTS OF EXHAUSTIVE EXERCISE IN JUVENILE RAINBOW TROUT

Juvenile rainbow trout (approximately 6 g) were exercised to exhaustion in two 5min bouts given 6h apart. Resting levels of whole-body lactate and glycogen were restored prior to the second bout. The rate of O2 consumption increased about threefold 5min after each bout of exercise, while recovery time decreased from 4h after the first bout to 2-3h after the second. The excess post-exercise oxygen consumption, i.e. 'oxygen debt', was significantly reduced by 40% after the second exercise bout, despite almost identical rates of lactate clearance and glycogen resynthesis. The rates of CO2 and ammonia excretion increased sixfold and threefold, and recovery times decreased from 4-6 h to 3h and from 3h to 1.5 h, respectively. After the first bout, whole-body lactate levels peaked at 5min post-exercise at about 8.5 times pre-exercise levels. After the second bout, lactate levels peaked at Omin post-exercise and fell more rapidly during recovery. Wholebody glycogen levels decreased by 70 % and 80 % and ATP levels decreased by 75 % and 65 % after the first and second bouts, respectively, while glucose levels increased about 1.5-fold immediately after both bouts. Creatine phosphate levels decreased by 70% and 80% after the first and second bouts, respectively. After 6h of recovery, creatine phosphate levels were higher after the second bout than after the first. These findings suggest that exhaustive exercise may cause a 'nonspecific' increase in metabolic rate not directly related to the processing of metabolites, which is reduced upon a subsequent exercise bout. This is in contrast with the classical 'oxygen debt hypothesis', which states that the oxygen debt and lactate clearance are linked. Furthermore, it appears that two sequential exercise bouts are sufficient to induce a 'training effect', i.e. improved rates of metabolic recovery.
Hepatotoxicity Associated with Antiretroviral Therapy Containing HIV-1 Protease Inhibitors

Human immunodeficiency virus 1 (HIV-1) protease inhibitors are important components of highly active antiretroviral therapy and have had a profound impact on the natural history of HIV and AIDS. However, in the era of highly active antiretroviral therapy (HAART), drug-induced hepatotoxicity or liver injury has emerged as an important potential complication of combination antiretroviral therapy, particularly those regimens containing protease inhibitors (PIs). Liver injury has been associated each of the six PIs currently approved by the U. S. Food and Drug Administration (FDA), most commonly with administration of full dose ritonavir (600 mg bid or 400 mg bid with saquinavir). However, this regimen has been largely replaced by the use of low-dose ritonavir (</= 200 mg bid) to pharmacologically "boost" other PI, such as lopinavir or indinavir, which has not been associated with an increased risk of hepatotoxicity compared with other PIs. Coinfection with hepatitis C virus (HCV) and B virus (HBV) remains an important risk factor for the development of HAART-associated liver injury. Although studies indicate that coinfected patients can be safely treated with PIs, such patients should be closely monitored. In addition, although unsubstantiated, some experts recommend evaluation or treatment, or both, of underlying chronic viral hepatitis prior to the initiation of antiretroviral therapy. Further research is needed to understand the etiopathogenesis of PI-associated liver injury, particularly among patients with hepatitis B or C infection.
Evaluation of narrow-band UVB phototherapy in 150 patients with vitiligo.

BACKGROUND Very few studies have been performed to evaluate the efficacy and safety of narrow-band ultraviolet B (NBUVB) therapy in Indian patients with vitiligo and are of small sample size. AIMS The purpose of this study is to know the efficacy and safety of NBUVB in 150 vitiligo patients of various age groups. METHODS One hundred fifty patients (69 males, 81 females), aged 3-70 years, with vitiligo were treated twice weekly with NBUVB. The starting dose was 250 mJ/cm2 in adults and 150 mJ/cm2 in children, with 20% dose increments at each subsequent visit given for a maximum period of 1 year and were followed-up for 6 months for stability of repigmentation. Statistical methods were employed to establish the relation between the response and the number of exposures, duration of treatment, cumulative dose and the compliance. RESULTS Analysis of our study showed that a majority of our cases, about 73, achieved 25-75% repigmentation, with an average of 51+/-19 exposures, 51 had <25% repigmentation, with an average of 19+/-11 exposures and 26 had >75% repigmentation, with an average of 74+/-24 exposures. Good response to therapy was directly associated with good compliance, more number of exposures and increasing cumulative dose, which was statistically significant (P<0.01). Adverse effects were minimal. Only three patients developed depigmentation of repigmented sites during follow-up. CONCLUSION Our study proves that NBUVB therapy is an effective and safe tool in the management of vitiligo, with good stability of repigmentation and cosmetic appearance.
Examining speech production using masked priming

The time to initiate naming a printed target word is reduced when preceded by an identical masked prime (match prime) or by one that has the same initial letter (onset prime) compared to an all letter different control. Masked priming has been examined using vocal response time but offers an opportunity to examine speech production dynamics before the onset of speech acoustics. We tracked tongue-dorsum, tongue-tip and lip motion from four participants pronouncing 19 targets in match, onset and unrelated control prime conditions. Control primes were selected so their articulation involved a different tongue gesture than the target. Prime influence was measured by tongue-dorsum height at gestural onset and peak velocity of the subsequent gesture. Results showed that relative to targets in the match condition, control targets had a significantly different tongue dorsum height and the peak velocity was greater when the subsequent gesture was achieved.
The accuracy of the rectal examination in the diagnosis of prostate carcinoma.

BEFORE 1920 the only diagnostic test for prostate cancer was the digital rectal examination. If the prostate was nodular, irregular, or stone-hard, a presumptive diagnosis of cancer was made, to be confirmed by biopsy. Since then diagnostic procedures have increased in number, complexity, and expense. It can reasonably be asked whether the accuracy of these tests is better than that of digital rectal examination. Assessment of the accuracy (or efficiency) of a screening test involves several factors, including the sensitivity and specificity of the test and the prevalence of the suspected disease in the population tested. From these factors the .
Forbidden Fruit

Acknowledgments ix PART ONE Chapter One: Making Sense of the World 3 Chapter Two: Counterfactual Thought Experiments 29 PART TWO Chapter Three: Franz Ferdinand Found Alive: World War I Unnecessary 69 Chapter Four: Leadership and the End of the Cold War: Did It Have to End This Way? 103 Coauthored with George W. Breslauer PART THREE Chapter Five: Scholars and Causation 1 137 Coauthored with Philip E. Tetlock Chapter Six: Scholars and Causation 2 166 APPENDIX Experiment 4, Instrument 1: Unmaking American Tragedies 196 Chapter Seven: If Mozart Had Died at Your Age: Psycho-logic versus Statistical Inference 205 Chapter Eight: Heil to the Chief: Sinclair Lewis, Philip Roth, and Fascism 222 Conclusions 259 Notes 287 Index 329
Incorporating PRO: a Defective-Goal Analysis ∗

In this paper I propose a novel account of the obligatory silence of PRO, based on the notion of defective goal in Roberts (2010). While languages differ with respect to the availability of null subject pronouns in matrix clauses , PRO is silent crosslinguisti- cally. I propose that the obligatory silence of PRO follows from its featural makeup— PRO is aP with unvalued �-features. PRO must enter into an Agree relation to have its �-features valued, and in this Agree relation PRO is a defective goal. A defective goal contains no features that are not shared with its probe, which makes the goal equivalent to a copy in a chain. I propose that PRO is silent for the same reason that, generally, only one copy of an element is expressed overtly; in an Agree relation PRO is treated as the lower copy in a chain that contains its probe , and PRO is deleted in the same way that lower copies are deleted. The present proposal is able to account for the silence of infinitival subjects in both obligatory an d non-obligatory control con- structions. A significant advantage of the present proposal is that it correctly predicts the existence of overt PRO in configurations where PRO bears a feature, such as focus, which it does not share with its probe.
Detection and Serotyping of Dengue Virus in Serum Samples by Multiplex Reverse Transcriptase PCR-Ligase Detection Reaction Assay

ABSTRACT The detection and successful typing of dengue virus (DENV) from patients with suspected dengue fever is important both for the diagnosis of the disease and for the implementation of epidemiologic control measures. A technique for the multiplex detection and typing of DENV serotypes 1 to 4 (DENV-1 to DENV-4) from clinical samples by PCR-ligase detection reaction (LDR) has been developed. A serotype-specific PCR amplifies the regions of genes C and E simultaneously. The two amplicons are targeted in a multiplex LDR, and the resultant fluorescently labeled ligation products are detected on a universal array. The assay was optimized using 38 DENV strains and was evaluated with 350 archived acute-phase serum samples. The sensitivity of the assay was 98.7%, and its specificity was 98.4%, relative to the results of real-time PCR. The detection threshold was 0.017 PFU for DENV-1, 0.004 PFU for DENV-2, 0.8 PFU for DENV-3, and 0.7 PFU for DENV-4. The assay is specific; it does not cross-react with the other flaviviruses tested (West Nile virus, St. Louis encephalitis virus, Japanese encephalitis virus, Kunjin virus, Murray Valley virus, Powassan virus, and yellow fever virus). All but 1 of 26 genotypic variants of DENV serotypes in a global DENV panel from different geographic regions were successfully identified. The PCR-LDR assay is a rapid, sensitive, specific, and high-throughput technique for the simultaneous detection of all four serotypes of DENV.
Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels.

OBJECTIVE Dopamine agonists normalize prolactin (PRL) levels and reduce tumour size in responsive prolactinoma. However, several cases have shown resistance to dopamine agonists upon initial treatment. Infrequently, prolactinoma initially responds, but then becomes refractory to prolonged treatment (secondary resistance). We investigated the possible mechanisms of resistance to dopamine agonists. SUBJECTS AND METHODS Twelve cases of prolactinoma were surgically resected and classified according to the responsiveness of PRL levels and tumour size to dopamine agonists: good responders (n = 5), poor responders (n = 5), or secondary resistance (n = 2). We examined the expression of dopamine D(2) receptor (D(2)R) isoform (short: D(2)S and long: D(2)L) mRNA and protein. We investigated DNA methylation patterns in the promoter region of the DRD2 gene. RESULTS The predominant D(2)R isoform expressed in prolactinoma was D(2)L. Levels of D(2)L mRNA were significantly lower in secondary resistance and poor responders than in good responders. Expression of D(2)R protein was variable among cases. Almost no CpG sites of the DRD2 gene promoter region were methylated. CONCLUSION Resistance of prolactinoma to dopamine agonists is correlated with a reduction in D(2)L isoform mRNA levels. Silencing of the DRD2 gene by methylation in the promoter region is unlikely to play a role in dopamine agonist resistance in prolactinoma.