Miracle-dz/UniFAR-FTUs huggingface dataset:
Rate theories for biologists

Abstract Some of the rate theories that are most useful for modeling biological processes are reviewed. By delving into some of the details and subtleties in the development of the theories, the review will hopefully help the reader gain a more than superficial perspective. Examples are presented to illustrate how rate theories can be used to generate insight at the microscopic level into biomolecular behaviors. An attempt is made to clear up a number of misconceptions in the literature regarding popular rate theories, including the appearance of Planck's constant in the transition-state theory and the Smoluchowski result as an upper limit for protein–protein and protein–DNA association rate constants. Future work in combining the implementation of rate theories through computer simulations with experimental probes of rate processes, and in modeling effects of intracellular environments so that theories can be used for generating rate constants for systems biology studies is particularly exciting.
Prediction of hERG Liability – Using SVM Classification, Bootstrapping and Jackknifing

Drug‐induced QT prolongation leads to life‐threatening cardiotoxicity, mostly through blockage of the human ether‐à‐go‐go‐related gene (hERG) encoded potassium ion (K+) channels. The hERG channel is one of the most important antitargets to be addressed in the early stage of drug discovery process, in order to avoid more costly failures in the development phase. Using a thallium flux assay, 4,323 molecules were screened for hERG channel inhibition in a quantitative high throughput screening (qHTS) format. Here, we present support vector classification (SVC) models of hERG channel inhibition with the averaged area under the receiver operator characteristics curve (AUC‐ROC) of 0.93 for the tested compounds. Both Jackknifing and bootstrapping have been employed to rebalance the heavily biased training datasets, and the impact of these two under‐sampling rebalance methods on the performance of the predictive models is discussed. Our results indicated that the rebalancing techniques did not enhance the predictive power of the resulting models; instead, adoption of optimal cutoffs could restore the desirable balance of sensitivity and specificity of the binary classifiers. In an external validation set of 66 drug molecules, the SVC model exhibited an AUC‐ROC of 0.86, further demonstrating the utility of this modeling approach to predict hERG liabilities.
Lesões do sistema urinário em 1.063 cães

The aim of this study was to determine the prevalence, epidemiology, clinical significance, and possible associated causes of the urinary system lesions in dogs necropsied between January 1999 and December 2010 at the Laboratorio de Patologia Veterinaria of the Universidade Federal de Santa Maria (LPV-UFSM). To accomplish this, the necropsy reports were analyzed retrospectively. In this time frame, 3,189 dogs were necropsied and about 30% had lesions in the urinary system. In most of the dogs (79.1%), lesions were single and in about 21% they were multiple, totalizing 1,373 lesions. Out of them, 1,014 (73.8%) were observed in the kidney and 359 (26.2%) were in the lower urinary tract (LUT). One third of the lesions in the urinary system were causes of spontaneous death or reason for euthanasia (SD/EUTH) of the affected dogs. The other two third of the lesions were considered incidental findings. The main renal lesions diagnosed, in descending order of prevalence, were: tubulointerstitial nephritis, infarct, granulomatous nephritis (parasitary), glomerulonephritis, metastatic/multicentric neoplasms, pyelonephritis/pyelitis, and hydronephrosis. The main LUT lesions, in descending order of prevalence, were: cystitis, presence of viral inclusions bodies (morbillivirus), urolithiasis, urinary bladder dilatation, urinary bladder rupture (with uroperitoneum), and metastatic/multicentric neoplasms. Epidemiological aspects such as gender, breed, and age of affected dogs had expressive variations according to the type of lesion diagnosed. Uremia was observed in a significant number of cases of SD/EUTH and was mostly due to renal lesions.
Fast protein folding kinetics

Abstract Fast-folding proteins have been a major focus of computational and experimental study because they are accessible to both techniques: they are small and fast enough to be reasonably simulated with current computational power, but have dynamics slow enough to be observed with specially developed experimental techniques. This coupled study of fast-folding proteins has provided insight into the mechanisms, which allow some proteins to find their native conformation well <1 ms and has uncovered examples of theoretically predicted phenomena such as downhill folding. The study of fast folders also informs our understanding of even ‘slow’ folding processes: fast folders are small; relatively simple protein domains and the principles that govern their folding also govern the folding of more complex systems. This review summarizes the major theoretical and experimental techniques used to study fast-folding proteins and provides an overview of the major findings of fast-folding research. Finally, we examine the themes that have emerged from studying fast folders and briefly summarize their application to protein folding in general, as well as some work that is left to do.
2-aminopurine as a fluorescent probe of DNA conformation and the DNA–enzyme interface

Abstract Nearly 50 years since its potential as a fluorescent base analogue was first recognized, 2-aminopurine (2AP) continues to be the most widely used fluorescent probe of DNA structure and the perturbation of that structure by interaction with enzymes and other molecules. In this review, we begin by considering the origin of the dramatic and intriguing difference in photophysical properties between 2AP and its structural isomer, adenine; although 2AP differs from the natural base only in the position of the exocyclic amine group, its fluorescence intensity is one thousand times greater. We then discuss the mechanism of interbase quenching of 2AP fluorescence in DNA, which is the basis of its use as a conformational probe but remains imperfectly understood. There are hundreds of examples in the literature of the use of changes in the fluorescence intensity of 2AP as the basis of assays of conformational change; however, in this review we will consider in detail only a few intensity-based studies. Our primary aim is to highlight the use of time-resolved fluorescence measurements, and the interpretation of fluorescence decay parameters, to explore the structure and dynamics of DNA. We discuss the salient features of the fluorescence decay of 2AP when incorporated in DNA and review the use of decay measurements in studying duplexes, single strands and other structures. We survey the use of 2AP as a probe of DNA-enzyme interaction and enzyme-induced distortion, focusing particularly on its use to study base flipping and the enhanced mechanistic insights that can be gained by a detailed analysis of the decay parameters, rather than merely monitoring changes in fluorescence intensity. Finally we reflect on the merits and shortcomings of 2AP and the prospects for its wider adoption as a fluorescence-decay-based probe.
Unraveling amyloid formation paths of Parkinson's disease protein α-synuclein triggered by anionic vesicles

Abstract Amyloid formation of the synaptic brain protein α-synuclein (αS) is related to degeneration of dopaminergic neurons in Parkinson's disease patients. αS is thought to function in vesicle transport and fusion and it binds strongly to negatively charged vesicles in vitro. Here we combined circular dichroism, fluorescence and imaging methods in vitro to characterize the interaction of αS with negatively charged vesicles of DOPS (1,2-dioleoyl-sn-glycero-3-phospho-L-serine, sodium salt) and DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol), sodium salt) and the consequences of such interactions on αS amyloid formation. We found that lipid head-group chemistry modulates αS interactions and also affects amyloid fiber formation. During the course of the experiments, we made the unexpected discovery that pre-formed αS oligomers, typically present in a small amount in the αS starting material, acted as templates for linear growth of anomalous amyloid fibers in the presence of vesicles. At the same time, the remaining αS monomers were restricted from vesicle-mediated nucleation of amyloid fibers. Although not a dominant process in bulk experiments, this hidden αS aggregation pathway may be of importance in vivo.
Outcome of Cataract Surgery in Patients with Pseudoexfoliation

Purpose: To study the surgical outcome & the complica ons encountered during & a er cataract surgery in Indian pa ents with pseudoexfolia on. Materials & Methods: In this hospital based retrospec ve study, 50 pa ents above 50 years of age having cataract with pseudoexfolia on & having normal Intraocular Pressure (IOP) who underwent extracapsular catract surgery were included. Pa ents with other associated ocular pathology were excluded. Pa ents were followed up for various complica ons up to 30th postopera ve day. Results: Fi y pa ents with pseudoexfolia on underwent extra capsular cataract surgery. Problems encountered during surgery were small nondila ng pupil (26%), zonular dialysis (2%), posterior capsular rupture (6%), vitreous loss (4%), residual lens ma er (10%), iridodialysis (4%) hyphema (2%). Post-opera ve complica ons were irregular pupil due to sphincterotomy (8%), signifi cant anterior chamber reac on (30%), and exuda ve membrane forma on (6%), corneal oedema with striate keratopathy (32%), iris pigment dispersion (16%), raised intraocular pressure (6%), posterior synechiae (2%) and intraocular lens decentra on (2%). Conclusion: Pa ents with pseudoexfolia on are at increased risk for development of surgical and postsurgical complica ons. Awareness about complica ons and ability to manage these complica ons by experienced surgeon is key to success. Del J Ophthalmol 2012;23(3):183-186.
Childhood Mycosis Fungoides: Experience of 28 Patients and Response to Phototherapy

Mycosis fungoides (MF), the most common cutaneous T‐cell lymphoma (CTCL), is rare in childhood. The prognosis and response to treatment are poorly described in children. The objective of the current study was to evaluate the response to phototherapy in a pediatric cohort. A retrospective cohort study of all patients diagnosed with MF before the age of 18 years and referred to the regional CTCL phototherapy service was performed between January 1990 and April 2012. Twenty‐eight patients were identified (13 boys, 15 girls). The mean age at presentation was 11.6 ± 3.9 years. The hypopigmented variant was noted in 79% of patients. All patients had stage I disease (IA = 10, IB = 17, unknown = 1). The median follow‐up after diagnosis was 43 months (range 6–274 mos). Narrowband ultraviolet B (NbUVB; 311 nm) was used as first‐line phototherapy in 18 patients and psoralen (bath) plus ultraviolet A (PUVA) was used in 8 patients. Complete or partial response was observed in 19 of 22 patients (86%). A further course of phototherapy was required in 7 of 12 patients (58%) treated with NbUVB after a median of 4 months (range 4–29 mos). A further course of phototherapy was required in four of eight patients (50%) successfully treated with PUVA after a median of 45.5 months (range 30–87 mos). No disease progression was noted over the follow‐up (median 43 mos). The majority of patients in our cohort had hypopigmented MF. Phototherapy offers an effective option for treatment of childhood MF, although the period of remission may be greater in patients treated with PUVA.
A nationwide survey of radiation oncologists' management practices of radiation-induced skin reaction (RISK)

Abstract Purpose: A questionnaire was developed to explore variations among radiation oncologists in managing early-stage breast cancer, specifically radiation-induced skin reaction (RISK). Materials and methods: A survey was designed to target a database of 962 radiation oncologists, self-identified as ‘interested in treatment of breast cancer’. This database was obtained from the American Society of Therapeutic Radiology & Oncology (ASTRO). Participants submitted the survey online or by mail. Overall response to the survey was 282 out of 962 (29.3%). Data were handled as rates. Results: Out of 282 respondents, 275 (97.5%) agreed on delivering 4500–5040 cGy. The most frequently employed dose was 5040/180 cGy. Three-dimensional-conformal (3DCRT) treatment was used by 55.4%, intensity-modulated radiotherapy (IMRT) by 24.5%, and conventional by 20.1%. Almost all (92.5%) agreed on using boost in ductal carcinoma in situ (DCIS). Image-guided boost placement (IGBP) was used by 87.3%. Boost dose included variations: 50.2, 7.3, and 18% used 1000, 1200, and 1400 cGy, respectively; the remaining used higher doses. In management of RISK, Aquaphor was the most popular agent (72.1%). Other agents were utilized either alone or in combination. Almost all (99%) agreed that large breast size increases RISK. Conclusion: This survey offers a glimpse of management practices in early-stage breast cancer amongst a cross-section of radiation oncologists in the United States. Although there appears to be an overall congruence on the doses and techniques of radiation delivery, the management of RISK is varied. Additional efforts are warranted to standardize practices in order to practice evidence based medicine in a cost-effective manner.
A psychologically implausible architecture that is always conscious, always active

s The book presents the case that cognitive science should turn its attention to developing theories of human cognition that cover the full range of human perceptual, cognitive, and action phenomena. Cognitive science has now produced a massive number of high-quality regularities with many micro theories that reveal important mechanisms. The need for integration is pressing and will continue to increase. Equally important, cognitive science now has the theoretical concepts and tools to support serious attempts at unified theories. The argument is made entirely by presenting an exemplar unified theory of cognition both to show what a real unified theory would be like and to provide convincing evidence that such theories are feasible. The exemplar is SOAR, a cognitive architecture, which is realized as a software system. After a detailed discussion of the architecture and its properties, with its relation to the constraints on cognition in the real world and to existing ideas in cognitive science, SOAR is used as theory for a wide range of cognitive phenomena: immediate responses (stimulus-response compatibility and the Sternberg phenomena); discrete motor skills (transcription typing); memory and learning (episodic memory and the acquisition of skill through practice); problem solving (cryptarithmetic puzzles and syllogistic reasoning); language (sentence verification and taking instructions); and development (transitions in the balance beam task). The treatments vary in depth and adequacy, but they clearly reveal a single, highly specific, operational theory that works over the entire range of human cognition, SOAR is presented as an exemplar unified theory, not as the sole candidate. Cognitive science is not ready yet for a single theory there must be multiple attempts. But cognitive science must begin to work toward such unified theories. Keywords^ artificial intelligence; chunking; cognition; cognitive science; computation; problem solving; production systems; SOAR; symbol systems The book begins by urging on psychology unified theories of cognition: Psychology has arrived at the possibility of unified theories of cognition theories that gain their power by positing a single system of mechanisms that operate together to produce the full range of human cognition. I do not say they are here, but they are within reach and we should strive to attain them. My goal is to convince the reader that unified theories of cognition are really worth striving for now, as we move into the nineties. This cannot be done just by talking about it. An exemplar candidate is put forth to illustrate concretely what a unified theory of cognition means and why it should be a goal for cognitive science. The candidate is a theory (and system) called SOAR (Laird et al. 1987). The book is the written version of the William James Lectures, delivered at Harvard University in spring 1987. Its stance is personal, reflecting the author's thirty years of research in cognitive science, although this precis will be unable to convey much of this flavor.
Unified cognition misses language

s The book presents the case that cognitive science should turn its attention to developing theories of human cognition that cover the full range of human perceptual, cognitive, and action phenomena. Cognitive science has now produced a massive number of high-quality regularities with many micro theories that reveal important mechanisms. The need for integration is pressing and will continue to increase. Equally important, cognitive science now has the theoretical concepts and tools to support serious attempts at unified theories. The argument is made entirely by presenting an exemplar unified theory of cognition both to show what a real unified theory would be like and to provide convincing evidence that such theories are feasible. The exemplar is SOAR, a cognitive architecture, which is realized as a software system. After a detailed discussion of the architecture and its properties, with its relation to the constraints on cognition in the real world and to existing ideas in cognitive science, SOAR is used as theory for a wide range of cognitive phenomena: immediate responses (stimulus-response compatibility and the Sternberg phenomena); discrete motor skills (transcription typing); memory and learning (episodic memory and the acquisition of skill through practice); problem solving (cryptarithmetic puzzles and syllogistic reasoning); language (sentence verification and taking instructions); and development (transitions in the balance beam task). The treatments vary in depth and adequacy, but they clearly reveal a single, highly specific, operational theory that works over the entire range of human cognition, SOAR is presented as an exemplar unified theory, not as the sole candidate. Cognitive science is not ready yet for a single theory there must be multiple attempts. But cognitive science must begin to work toward such unified theories. Keywords^ artificial intelligence; chunking; cognition; cognitive science; computation; problem solving; production systems; SOAR; symbol systems The book begins by urging on psychology unified theories of cognition: Psychology has arrived at the possibility of unified theories of cognition theories that gain their power by positing a single system of mechanisms that operate together to produce the full range of human cognition. I do not say they are here, but they are within reach and we should strive to attain them. My goal is to convince the reader that unified theories of cognition are really worth striving for now, as we move into the nineties. This cannot be done just by talking about it. An exemplar candidate is put forth to illustrate concretely what a unified theory of cognition means and why it should be a goal for cognitive science. The candidate is a theory (and system) called SOAR (Laird et al. 1987). The book is the written version of the William James Lectures, delivered at Harvard University in spring 1987. Its stance is personal, reflecting the author's thirty years of research in cognitive science, although this precis will be unable to convey much of this flavor.
Unified psychobiological theory

s The book presents the case that cognitive science should turn its attention to developing theories of human cognition that cover the full range of human perceptual, cognitive, and action phenomena. Cognitive science has now produced a massive number of high-quality regularities with many micro theories that reveal important mechanisms. The need for integration is pressing and will continue to increase. Equally important, cognitive science now has the theoretical concepts and tools to support serious attempts at unified theories. The argument is made entirely by presenting an exemplar unified theory of cognition both to show what a real unified theory would be like and to provide convincing evidence that such theories are feasible. The exemplar is SOAR, a cognitive architecture, which is realized as a software system. After a detailed discussion of the architecture and its properties, with its relation to the constraints on cognition in the real world and to existing ideas in cognitive science, SOAR is used as theory for a wide range of cognitive phenomena: immediate responses (stimulus-response compatibility and the Sternberg phenomena); discrete motor skills (transcription typing); memory and learning (episodic memory and the acquisition of skill through practice); problem solving (cryptarithmetic puzzles and syllogistic reasoning); language (sentence verification and taking instructions); and development (transitions in the balance beam task). The treatments vary in depth and adequacy, but they clearly reveal a single, highly specific, operational theory that works over the entire range of human cognition, SOAR is presented as an exemplar unified theory, not as the sole candidate. Cognitive science is not ready yet for a single theory there must be multiple attempts. But cognitive science must begin to work toward such unified theories. Keywords^ artificial intelligence; chunking; cognition; cognitive science; computation; problem solving; production systems; SOAR; symbol systems The book begins by urging on psychology unified theories of cognition: Psychology has arrived at the possibility of unified theories of cognition theories that gain their power by positing a single system of mechanisms that operate together to produce the full range of human cognition. I do not say they are here, but they are within reach and we should strive to attain them. My goal is to convince the reader that unified theories of cognition are really worth striving for now, as we move into the nineties. This cannot be done just by talking about it. An exemplar candidate is put forth to illustrate concretely what a unified theory of cognition means and why it should be a goal for cognitive science. The candidate is a theory (and system) called SOAR (Laird et al. 1987). The book is the written version of the William James Lectures, delivered at Harvard University in spring 1987. Its stance is personal, reflecting the author's thirty years of research in cognitive science, although this precis will be unable to convey much of this flavor.