Miracle-dz/UniFAR-FTUs huggingface dataset:
A 6.4 Mb duplication of the α-synuclein locus causing frontotemporal dementia and Parkinsonism: phenotype-genotype correlations.

IMPORTANCE α-Synuclein (SNCA) locus duplications are associated with variable clinical features and reduced penetrance but the reasons underlying this variability are unknown. OBJECTIVES To report a novel family carrying a heterozygous 6.4 Mb duplication of the SNCA locus with an atypical clinical presentation strongly reminiscent of frontotemporal dementia and late-onset pallidopyramidal syndromes and study phenotype-genotype correlations in SNCA locus duplications. DESIGN, SETTING, AND PARTICIPANTS We report the clinical and neuropathologic features of a family carrying a 6.4 Mb duplication of the SNCA locus. To identify candidate disease modifiers, we completed a genetic analysis of the family and conducted statistical analysis on previously published cases carrying SNCA locus duplications using regression modeling with robust standard errors to account for clustering at the family level. MAIN OUTCOMES AND MEASURES We assessed whether length of the SNCA locus duplication influences disease penetrance and severity and whether extraduplication factors have a disease-modifying role. RESULTS We identified a large 6.4 Mb duplication of the SNCA locus in this family. Neuropathological analysis showed extensive α-synuclein pathology with minimal phospho-tau pathology. Genetic analysis showed an increased burden of Parkinson disease-related risk factors and the disease-predisposing H1/H1 microtubule-associated protein tau haplotype. Statistical analysis of previously published cases suggested there is a trend toward increasing disease severity and disease penetrance with increasing duplication size. The corresponding odds ratios from the univariable analyses were 1.17 (95% CI, 0.81-1.68) and 1.34 (95% CI, 0.78-2.31), respectively. Sex was significantly associated with both disease risk and severity; men compared with women had increased disease risk and severity and the corresponding odds ratios from the univariable analyses were 8.36 (95% CI, 1.97-35.42) and 5.55 (95% CI, 1.39-22.22), respectively. CONCLUSIONS AND RELEVANCE These findings further expand the phenotypic spectrum of SNCA locus duplications. Increased dosage of genes located within the duplicated region probably cannot increase disease risk and disease severity without the contribution of additional risk factors. Identification of disease modifiers accounting for the substantial phenotypic heterogeneity of patients with SNCA locus duplications could provide insight into molecular events involved in α-synuclein aggregation.
Tratamiento de Chagas con benznidazol y ácido tióctico

Se realizo un ensayo clinico controlado, multicentrico, a triple ciego, para evaluar si el tratamiento oral combinado del acido tioctico (AT), reduce la incidencia de los efectos secundarios asociados al tratamiento con benznidazol (BZ) en pacientes infectados con Trypanosoma cruzi. Cuatro esquemas fueron asignados al azar pareados por edad, administrando placebo o AT por via oral a razon de 50-100 mg dia a dosis e intervalos variables (con y sin periodo pre-induccion) en combinacion con BZ a dosis de 5 mg/kg/dia por 30 dias. Se realizaron evaluaciones en los dias 10, 20, 37 y 52 de iniciado el tratamiento. Fueron enrolados 249 pacientes con edades entre 15 y 44 anos. El 70.3% de los pacientes completo el tratamiento y el 17.7% restante debio suspender la medicacion por causas relacionadas al BZ. La proporcion de personas afectadas por al menos un efecto adverso, fue semejante entre los 4 grupos: entre 54.8 y 58%, aunque en ninguno de ellos resulto de caracter grave. Las manifestaciones clinicas adversas fueron: exantema morbiliforme (28%); prurito (13.6%); cefalea (8%); epigastralgia (6.2%); fiebre (6.2%); astenia (4.3%); nauseas (4.0%); mialgias (4.3%); vomitos (3.2%); otros (21.5%). La incidencia de experiencias adversas no difirio significativamente entre los 4 esquemas terapeuticos, ni entre los diferentes intervalos de edad de los pacientes. La asociacion con acido tioctico no demostro prevenir las manifestaciones de intolerancia a este agente. No obstante, la administracion de BZ en un ciclo mensual unico a pacientes infectados logro una elevada tasa de adherencia al tratamiento ambulatorio.
ESTIMATING UNCERTAINTY IN MULTIVARIATE RESPONSES TO SELECTION

Predicting the responses to natural selection is one of the key goals of evolutionary biology. Two of the challenges in fulfilling this goal have been the realization that many estimates of natural selection might be highly biased by environmentally induced covariances between traits and fitness, and that many estimated responses to selection do not incorporate or report uncertainty in the estimates. Here we describe the application of a framework that blends the merits of the Robertson–Price Identity approach and the multivariate breeder's equation to address these challenges. The approach allows genetic covariance matrices, selection differentials, selection gradients, and responses to selection to be estimated without environmentally induced bias, direct and indirect selection and responses to selection to be distinguished, and if implemented in a Bayesian‐MCMC framework, statistically robust estimates of uncertainty on all of these parameters to be made. We illustrate our approach with a worked example of previously published data. More generally, we suggest that applying both the Robertson–Price Identity and the multivariate breeder's equation will facilitate hypothesis testing about natural selection, genetic constraints, and evolutionary responses.
Participación y atrición en proyectos de investigación del VIH/SIDA: Una Experiencia puertorriqueña

En Puerto Rico es dificil lograr que la gente participe de investigacion sobre VIH/SIDA. Este estudio presenta datos de una intervencion grupal de 12 sesiones, realizada entre 1997 y 1999 con hombres homosexuales VIH+ (n=50). El 34% de ellos no asistio a la intervencion, el 36% asistio parcialmente y el 30% la completo. La edad de los participantes y la duracion de la intervencion estuvieron asociadas con la asistencia. Los participantes mas jovenes asistieron a menos sesiones que los mayores. La intervencion corta obtuvo mas asistencia que la larga. Algunos obstaculos mencionados para asistir a la intervencion fueron: estado de salud, efectos secundarios de los medicamentos, condiciones del clima y logistica para llegar al lugar de reunion.
MUSCLE TRADE‐OFFS IN A POWER‐AMPLIFIED PREY CAPTURE SYSTEM

Should animals operating at great speeds and accelerations use fast or slow muscles? The answer hinges on a fundamental trade‐off: muscles can be maximally fast or forceful, but not both. Direct lever systems offer a straightforward manifestation of this trade‐off, yet the fastest organisms use power amplification, not direct lever action. Power‐amplified systems typically use slow, forceful muscles to preload springs, which then rapidly release elastic potential energy to generate high speeds and accelerations. However, a fast response to a stimulus may necessitate fast spring‐loading. Across 22 mantis shrimp species (Stomatopoda), this study examined how muscle anatomy correlates with spring mechanics and appendage type. We found that muscle force is maximized through physiological cross‐sectional area, but not through sarcomere length. Sit‐and‐wait predators (spearers) had the shortest sarcomere lengths (fastest contractions) and the slowest strike speeds. The species that crush shells (smashers) had the fastest speeds, most forceful springs, and longest sarcomeres. The origin of the smasher clade yielded dazzlingly high accelerations, perhaps due to the release from fast spring‐loading for evasive prey capture. This study offers a new window into the dynamics of force–speed trade‐offs in muscles in the biomechanical, comparative evolutionary framework of power‐amplified systems.
Conselho de administração: Que funções?

A separacao da propriedade e da gestao das empresas levou a criacao de um orgao interno conhecido como conselho de administracao. A essencia das funcoes deste orgao consiste em arbitrar solucoes para objetivos e reivindicacoes em conflito, as quais exigem complexos equilibrios (juizos de gestao) sobre um amplo conjunto de metas e meios para as alcancar. Sao de destacar tres funcoes: institucional, de governacao e estrategica. A funcao institucional, externa, legitima as atividades da empresa com o seu meio envolvente, instigada pela obtencao de recursos. A funcao de governacao, interna, procura conciliar os interesses dos diferentes constituintes organizacionais. A funcao estrategica consubstancia-se na tomada das decisoes estrategicas, visando a adaptacao da empresa ao seu meio envolvente. Contudo, as funcoes deverao evoluir, no sentido de se adaptarem as novas configuracoes organizacionais e aos novos processos de criacao de valor.
INTERMITTENT BREEDING AND CONSTRAINTS ON LITTER SIZE: CONSEQUENCES FOR EFFECTIVE POPULATION SIZE PER GENERATION (Ne) AND PER REPRODUCTIVE CYCLE (Nb)

In iteroparous species, it is easier to estimate Nb (effective number of breeders in one reproductive cycle) than Ne (effective population size per generation). Nb can be used as a proxy for Ne and also can provide crucial insights into eco‐evolutionary processes that occur during reproduction. We used analytical and numerical methods to evaluate effects of intermittent breeding and litter/clutch size on inbreeding Nb and Ne. Fixed or random litter sizes ≥ 3 have little effect on either effective‐size parameter; however, in species (e.g., many large mammals) in which females can produce only one offspring per cycle, female Nb = ∞ and overall Nb = 4Nb(male). Intermittent breeding reduces the pool of female breeders, which reduces both female and overall Nb; reductions are larger in high‐fecundity species with high juvenile mortality and increase when multiple reproductive cycles are skipped. Simulated data for six model species showed that both intermittent breeding and litter‐size constraints increase Ne, but only slightly. We show how to quantitatively account for these effects, which are important to consider when (1) using Nb to estimate Ne, or (2) drawing inferences about male reproductive success based on estimates of female Nb.
ON THE EVOLUTION OF MIGRATION IN HETEROGENEOUS ENVIRONMENTS

Populations often experience variable conditions, both in time and space. Here we develop a novel theoretical framework to study the evolution of migration under the influence of spatially and temporally variable selection and genetic drift. First, we examine when polymorphism is maintained at a locus under heterogeneous selection, as a function of the pattern of spatial heterogeneity and the migration rate. In a second step, we study how levels of migration evolve under the joint action of kin competition and local adaptation at a polymorphic locus. This analysis reveals the existence of evolutionary bistability, whereby a low or a high migration rate may evolve depending on the initial conditions. Last, we relax several assumptions regarding selection heterogeneity commonly made in previous studies and explore the consequences of more complex spatial and temporal patterns of variability in selection on the evolution of migration. We found that small modifications in the pattern of environmental heterogeneity may have dramatic effects on the evolution of migration. This work highlights the importance of considering more general scenarios of environmental heterogeneity when studying the evolution of life‐history traits in ecologically complex settings.
COARSE DARK PATTERNING FUNCTIONALLY CONSTRAINS ADAPTIVE SHIFTS FROM APOSEMATISM TO CRYPSIS IN STRAWBERRY POISON FROGS

Ecological specialization often requires tight coevolution of several traits, which may constrain future evolutionary pathways and make species more prone to extinction. Aposematism and crypsis represent two specialized adaptations to avoid predation. We tested whether the combined effects of color and pattern on prey conspicuousness functionally constrain or facilitate shifts between these two adaptations. We combined data from 17 natural populations of strawberry poison frogs, Oophaga pumilio with an experimental approach using digitalized images of frogs and chickens as predators. We show that bright coloration often co‐occurs with coarse patterning among the natural populations. Dull green frogs with coarse patterning are rare in nature but in the experiment they were as easily detected as bright red frogs suggesting that this trait combination represents a transient evolutionary state toward aposematism. Hence, a gain of either bright color or coarse patterning leads to conspicuousness, but a transition back to crypsis would be functionally constrained in populations with both bright color and coarse patterning by requiring simultaneous changes in two traits. Thus, populations (or species) signaling aposematism by conspicuous color should be less likely to face an evolutionary dead end and more likely to radiate than populations with both conspicuous color and coarse patterning.
Noise affects the shape of female preference functions for acoustic signals

The shape of female mate preference functions influences the speed and direction of sexual signal evolution. However, the expression of female preferences is modulated by interactions between environmental conditions and the female's sensory processing system. Noise is an especially relevant environmental condition because it interferes directly with the neural processing of signals. Although noise is therefore likely a significant force in the evolution of communication systems, little is known about its effects on preference function shape. In the grasshopper Chorthippus biguttulus, female preferences for male calling song characteristics are likely to be affected by noise because its auditory system is sensitive to fine temporal details of songs. We measured female preference functions for variation in male song characteristics in several levels of masking noise and found strong effects of noise on preference function shape. The overall responsiveness to signals in noise generally decreased. Preference strength increased for some signal characteristics and decreased for others, largely corresponding to expectations based on neurophysiological studies of acoustic signal processing. These results suggest that different signal characteristics will be favored under different noise conditions, and thus that signal evolution may proceed differently depending on the extent and temporal patterning of environmental noise.
Essentials of Nitric Oxide for the Pediatric (Cardiac) Anesthesiologist

Short- and long-term survival rates for the operative treat ment of congenital heart disease (CHD) have improved significantly in the past 2 decades. The increasing sophisti cation of the pediatric cardiologist's diagnostic armamen tarium has led to more pervasive use of fetal screening with echocardiography. Early diagnosis and pre-emptive care of the neonate with complex CHD have allowed interventional strategies in the catheterization suite or the operating room to be optimized in both the timing and the quality of pallia tive or corrective procedures. Medications such as prosta glandin E and ventilator strategies using hypoxic and hyper carbic inspired gases exemplify therapies benefitting the contemporary neonate with CHD, often allowing stabiliza tion of the patient before surgery. Surgical care of neonates, infants, and children with CHD has also improved. Insights into maturational differences in myocardial and autonomic function have led to more appropriate myocardial protection strategies and pharmacologic support of the circulation. Recognition of those anomalies in which total correction in the neonate is desirable has stimulated improvements in the technical and cognitive skills of pediatric cardiovascular sur geons and pediatric cardiac anesthesiologists to meet these challenges. The goal of this article is to provide the pediatric anesthesiologist with an overview of inhaled nitric oxide and its relevance to clinical practice.
Quantifying hummingbird preference for floral trait combinations: The role of selection on trait interactions in the evolution of pollination syndromes

Darwin recognized the flower's importance for the study of adaptation and emphasized that the flower's functionality reflects the coordinated action of multiple traits. Here we use a multitrait manipulative approach to quantify the potential role of selection acting on floral trait combinations underlying the divergence and maintenance of three related North American species of Silene (Caryophyllaceae). We artificially generated 48 plant phenotypes corresponding to all combinations of key attractive traits differing among the three Silene species (color, height, inflorescence architecture, flower orientation, and corolla‐tube width). We quantified main and interaction effects of trait manipulation on hummingbird visitation preference using experimental arrays. The main effects of floral display height and floral orientation strongly influenced hummingbird visitation, with hummingbirds preferring flowers held high above the ground and vertically to the sky. Hummingbirds also prefer traits in a nonadditive manner as multiple two‐way and higher order interaction effects were important predictors of hummingbird visitation. Contemporary trait combinations found in hummingbird pollinated S. virginica are mostly preferred. Our study demonstrates the likelihood of pollination syndromes evolving due to selection on trait combinations and highlights the importance of trait interactions in understanding the evolution of complex adaptations.
Relationships of diversity, disparity, and their evolutionary rates in squirrels (Sciuridae)

Several theories predict that rapidly diversifying clades will also rapidly diverge phenotypically; yet, there are also reasons for suspecting that diversification and divergence might not be correlated. In the widely distributed squirrel clade (Sciuridae), we test for correlations between per lineage speciation rates, species richness, disparity, and a time‐invariant measure of disparity that allows for comparing rates when evolutionary modes differ, as they do in squirrels. We find that species richness and speciation rates are not correlated with clade age or with each other. Disparity appears to be positively correlated with clade age because young, rapidly diversifying Nearctic grassland clades are strongly pulled to a single stable optimum but older, slowly diversifying Paleotropical forest clades contain lineages that diverge along multiple ecological and morphological lines. That contrast is likely due to both the environments they inhabit and their phylogenetic community structure. Our results argue against a shared explanation for diversity and disparity in favor of geographically mediated modes of speciation and ecologically mediated modes of phenotypic evolution.
Centromere‐associated meiotic drive and female fitness variation in Mimulus

Female meiotic drive, in which chromosomal variants preferentially segregate to the egg pole during asymmetric female meiosis, is a theoretically pervasive but still mysterious form of selfish evolution. Like other selfish genetic elements, driving chromosomes may be maintained as balanced polymorphisms by pleiotropic or linked fitness costs. A centromere‐associated driver (D) with a ∼58:42 female‐specific transmission advantage occurs at intermediate frequency (32–40%) in the Iron Mountain population of the yellow monkeyflower, Mimulus guttatus. Previously determined male fertility costs are sufficient to prevent the fixation of D, but predict a higher equilibrium frequency. To better understand the dynamics and effects of D, we developed a new population genetic model and measured genotype‐specific lifetime female fitness in the wild. In three of four years, and across all years, D imposed significant recessive seedset costs, most likely due to hitchhiking by deleterious mutations. With both male and female costs as measured, and 58:42 drive, our model predicts an equilibrium frequency of D (38%) very close to the observed value. Thus, D represents a rare selfish genetic element whose local population genetic dynamics have been fully parameterized, and the observation of equilibrium sets the stage for investigations of coevolution with suppressors.
The genetic basis of color‐related local adaptation in a ring‐like colonization around the Mediterranean

Uncovering the genetic basis of phenotypic variation and the population history under which it established is key to understand the trajectories along which local adaptation evolves. Here, we investigated the genetic basis and evolutionary history of a clinal plumage color polymorphism in European barn owls (Tyto alba). Our results suggest that barn owls colonized the Western Palearctic in a ring‐like manner around the Mediterranean and meet in secondary contact in Greece. Rufous coloration appears to be linked to a recently evolved nonsynonymous‐derived variant of the melanocortin 1 receptor (MC1R) gene, which according to quantitative genetic analyses evolved under local adaptation during or following the colonization of Central Europe. Admixture patterns and linkage disequilibrium between the neutral genetic background and color found exclusively within the secondary contact zone suggest limited introgression at secondary contact. These results from a system reminiscent of ring species provide a striking example of how local adaptation can evolve from derived genetic variation.
Receiver discriminability drives the evolution of complex sexual signals by sexual selection

A hallmark of sexual selection by mate choice is the evolution of exaggerated traits, such as longer tails in birds and more acoustic components in the calls of birds and frogs. Trait elaboration can be opposed by costs such as increased metabolism and greater predation risk, but cognitive processes of the receiver can also put a brake on trait elaboration. For example, according to Weber's Law traits of a fixed absolute difference will be more difficult to discriminate as the absolute magnitude increases. Here, we show that in the Emei music frog (Babina daunchina) increases in the fundamental frequency between successive notes in the male advertisement call, which increases the spectral complexity of the call, facilitates the female's ability to compare the number of notes between calls. These results suggest that female's discriminability provides the impetus to switch from enhancement of signaling magnitude (i.e., adding more notes into calls) to employing a new signal feature (i.e., increasing frequency among notes) to increase complexity. We suggest that increasing the spectral complexity of notes ameliorates some of the effects of Weber's Law, and highlights how perceptual and cognitive biases of choosers can have important influences on the evolution of courtship signals.