Miracle-dz/UniFAR-FTUs huggingface dataset:
Predicting Transdermal Fentanyl Delivery Using Mechanistic Simulations for Tailored Therapy

Transdermal drug delivery is a key technology for administering drugs. However, most devices are “one-size-fits-all”, even though drug diffusion through the skin varies significantly from person-to-person. For next-generation devices, personalization for optimal drug release would benefit from an augmented insight into the drug release and percutaneous uptake kinetics. Our objective was to quantify the changes in transdermal fentanyl uptake with regards to the patient’s age and the anatomical location where the patch was placed. We also explored to which extent the drug flux from the patch could be altered by miniaturizing the contact surface area of the patch reservoir with the skin. To this end, we used validated mechanistic modeling of fentanyl diffusion, storage, and partitioning in the epidermis to quantify drug release from the patch and the uptake within the skin. A superior spatiotemporal resolution compared to experimental methods enabled in-silico identification of peak concentrations and fluxes, and the amount of stored drug and bioavailability. The patients’ drug uptake showed a 36% difference between different anatomical locations after 72 h, but there was a strong interpatient variability. With aging, the drug uptake from the transdermal patch became slower and less potent. A 70-year-old patient received 26% less drug over the 72-h application period, compared to an 18-year-old patient. Additionally, a novel concept of using micron-sized drug reservoirs was explored in silico. These reservoirs induced a much higher local flux (µg cm-2 h-1) than conventional patches. Up to a 200-fold increase in the drug flux was obtained from these small reservoirs. This effect was mainly caused by transverse diffusion in the stratum corneum, which is not relevant for much larger conventional patches. These micron-sized drug reservoirs open new ways to individualize reservoir design and thus transdermal therapy. Such computer-aided engineering tools also have great potential for in-silico design and precise control of drug delivery systems. Here, the validated mechanistic models can serve as a key building block for developing digital twins for transdermal drug delivery systems.
Using plant traits to understand the contribution of biodiversity effects to community productivity in an agricultural system

Increasing biodiversity generally enhances productivity through selection and complementarity effects not only in natural but also in agricultural systems. However, explaining why diversity enhances productivity remains a central goal in agricultural science. In a field experiment, we constructed monocultures, 2- and 4-species mixtures from eight crop species with and without fertilizer and both in temperate Switzerland and semi-arid Spain. We measured environmental factors and plant traits and related these in structural equation models to selection and complementarity effects to explain yield differences between monocultures and mixtures. Increased crop diversity increased yield in Switzerland. This positive biodiversity effect was driven to almost same extents by selection and complementarity effects, which increased with plant height and C:N ratio, respectively. Also, ecological processes driving yield increases from monocultures to mixtures differed from those responsible for yield increases through the diversification of mixtures. While selection effects were mainly driven by one species, complementarity effects were linked to higher productivity per unit N. Yield increases due to mixture diversification were driven only by complementarity and were not mediated through the measured traits, suggesting that ecological processes beyond those measured in this study were responsible for positive diversity effects on yield beyond 2-species mixtures.
Spatially-specific working memory activity in the human superior colliculus

Theoretically, working memory (WM) representations are encoded by population activity of neurons with distributed tuning across the stored feature. Here, we leverage computational neuroimaging approaches to map the topographic organization of human superior colliculus (SC) and model how population activity in SC encodes WM representations. We first modeled receptive field properties of voxels in SC, deriving a detailed topographic organization resembling that of the primate SC. Neural activity within male and female human SC persisted throughout a retention interval of several types of modified memory-guided saccade tasks. Assuming an underlying neural architecture of the SC based on its retinotopic organization, we used an encoding model to show that the pattern of activity in human SC represents locations stored in WM. Our tasks and models allowed us to dissociate the locations of visual targets and the motor metrics of memory-guided saccades from the spatial locations stored in WM, thus confirming that human SC represents true WM information. These data have several important implications. They add the SC to a growing number of cortical and subcortical brain areas that form distributed networks supporting WM functions. Moreover, they specify a clear neural mechanism by which topographically organized SC encodes WM representations. Significance Statement Using computational neuroimaging approaches, we mapped the topographic organization of human superior colliculus (SC) and modeled how population activity in SC encodes working memory (WM) representations, rather than simpler visual or motor properties that have been traditionally associated with the laminar maps in the primate SC. Together, these data both position the human SC into a distributed network of brain areas supporting WM and elucidate the neural mechanisms by which the SC supports WM.
A visual atlas of meiotic protein dynamics in living fission yeast

Meiosis is a carefully choreographed dynamic process that re-purposes proteins from somatic/vegetative cell division, as well as meiosis-specific factors, to carry out the differentiation and recombination pathway common to sexually reproducing eukaryotes. Studies of individual proteins from a variety of different experimental protocols can make it difficult to compare details between them. Using a consistent protocol in otherwise wild type fission yeast cells, this report provides an atlas of dynamic protein behavior of representative proteins at different stages during normal zygotic meiosis in fission yeast. This establishes common landmarks to facilitate comparison of different proteins and shows that initiation of S phase likely occurs prior to nuclear fusion/karyogamy. Summary Meiosis is an important process for sexually reproducing organisms. Unique dynamics of recombination and chromosome segregation are required for this differentiation process. Fission yeast is an excellent model to study meiotic progression and chromosome dynamics. Historically, different methodologies have been used to examine protein dynamics in fixed or live cells, which makes comparisons more difficult. In this report, we use fluorescently tagged proteins and live-cell microscopy under uniform conditions to compare meiotic signposts that define dynamic behavior of proteins during meiotic DNA synthesis, nuclear fusion, chromosome alignment, genetic recombination, metaphase, and meiosis. This establishes a reference atlas of protein behavior during meiotic differentiation.
Otolith Chemistry Discriminates among Hatchery-Reared and Tributary-Spawned Salmonines in a Tailwater System

Abstract The Little Red River tailwater (LRRT) system in Arkansas supports a naturally reproducing population of brown trout Salmo trutta and an economically valuable fishery. Natural reproduction by stocked brook trout Salvelinus fontinalis and rainbow trout Oncorhynchus mykiss is unknown but assumed to be negligible. An artificial tributary to the LRRT was constructed to provide a spawning and nursery refuge for stocked trouts, and shortly thereafter we observed spawning adults and emergent fry in the tributary. As a first step in determining the relative contributions of hatchery- and tributary-produced brook and rainbow trouts recruiting to the LRRT fishery, we distinguished hatchery-reared fry from tributary-spawned fry via otolith chemistry. We used laser ablation inductively coupled plasma mass spectrometry to measure the abundances of cations in otoliths. Significant differences between hatchery and wild stocks were found for six element : Ca ratios. A five-variable (Mg, Mn, Zn, Sr, and Ba) discri.
Structure-based modelling and dynamics of MurM, a Streptococcus pneumoniae penicillin resistance determinant that functions at the cytoplasmic membrane interface

MurM is an aminoacyl-tRNA dependant ligase that aminoacylates the Lipid II peptidoglycan precursor, in the human pathogen Streptococcus pneumoniae. MurM is required for the generation of branched peptidoglycan precursors enabling indirect cross-links in the peptidoglycan and is found to be essential for penicillin resistance. In this study we have solved the X-ray crystal structure of Staphylococcus aureus FemX, an isofunctional homologue of MurM, and used this as a template to generate a homology model of MurM. Using this model, we perform molecular docking and molecular dynamics to examine the interaction of the protein with the phospholipid bilayer and the membrane embedded Lipid II substrate of MurM. Our model suggests that MurM is associated with the major membrane phospholipid cardiolipin, and we confirm this with experimental evidence that the activity of MurM is enhanced by this phospholipid and inhibited by its direct precursor phosphatidylglycerol. This suggests that the spatial association of pneumococcal membrane phospholipids and their impact on MurM activity may be a critical to the final architecture of the peptidoglycan and the expression of clinically relevant penicillin resistance in this pathogen.
Extracellular GABA waves regulate coincidence detection in excitatory circuits

Coincidence detection of excitatory inputs by principal neurons underpins the rules of signal integration and Hebbian plasticity in the brain. In the hippocampal circuitry, detection fidelity is thought to depend on the GABAergic synaptic input through a feed-forward inhibitory circuit also involving the hyperpolarization-activated Ih current. However, afferent connections often bypass feed-forward circuitry, suggesting that a different GABAergic mechanism might control coincidence detection in such cases. To test whether fluctuations in the extracellular GABA concentration [GABA] could play a regulatory role here, we use a GABA ‘sniffer’ patch in acute hippocampal slices of the rat and document strong dependence of [GABA] on network activity. We find that blocking GABAergic signalling strongly reduces the coincidence detection window of direct excitatory inputs to pyramidal cells whereas increasing [GABA] through GABA uptake blockade expands it. The underlying mechanism involves membrane-shunting tonic GABAA receptor current; it does not have to rely on Ih but depends strongly on the neuronal GABA transporter GAT-1. We use dendrite-soma dual patch-clamp recordings to show that the strong effect of membrane shunting on coincidence detection relies on nonlinear amplification of changes in the decay of dendritic synaptic currents when they reach the soma. Our results suggest that, by dynamically regulating extracellular GABA, brain network activity can optimise signal integration rules in local excitatory circuits.
Metagenomic Characterization of Soil Microbial Communities in the Luquillo Experimental Forest (Puerto Rico) and Implications for Nitrogen Cycling

Tropical rainforests are the largest terrestrial sinks of atmospheric CO2 and the largest natural source of N2O emissions, two greenhouse gases that are critical for the climate. The microbial communities of rainforest soils that directly or indirectly, through affecting plant growth, contribute to these fluxes remain poorly described by cultured-independent methods. ABSTRACT The phylogenetic and functional diversities of microbial communities in tropical rainforests and how these differ from those of temperate communities remain poorly described but are directly related to the increased fluxes of greenhouse gases such as nitrous oxide (N2O) from the tropics. Toward closing these knowledge gaps, we analyzed replicated shotgun metagenomes representing distinct life zones and an elevation gradient from four locations in the Luquillo Experimental Forest (LEF), Puerto Rico. These soils had a distinct microbial community composition and lower species diversity compared to those of temperate grasslands or agricultural soils. In contrast to the overall distinct community composition, the relative abundances and nucleotide sequences of N2O reductases (nosZ) were highly similar between tropical forest and temperate soils. However, respiratory NO reductase (norB) was 2-fold more abundant in the tropical soils, which might be relatable to their greater N2O emissions. Nitrogen fixation (nifH) also showed higher relative abundance in rainforest than in temperate soils, i.e., 20% versus 0.1 to 0.3% of bacterial genomes in each soil type harbored the gene, respectively. Finally, unlike temperate soils, LEF soils showed little stratification with depth in the first 0 to 30 cm, with ∼45% of community composition differences explained solely by location. Collectively, these results advance our understanding of spatial diversity and metabolic repertoire of tropical rainforest soil communities and should facilitate future ecological studies of these ecosystems. IMPORTANCE Tropical rainforests are the largest terrestrial sinks of atmospheric CO2 and the largest natural source of N2O emissions, two greenhouse gases that are critical for the climate. The microbial communities of rainforest soils that directly or indirectly, through affecting plant growth, contribute to these fluxes remain poorly described by cultured-independent methods. To close this knowledge gap, the present study applied shotgun metagenomics to samples selected from three distinct life zones within the Puerto Rico rainforest. The results advance our understanding of microbial community diversity in rainforest soils and should facilitate future studies of natural or manipulated perturbations of these critical ecosystems.
Maternal glucocorticoid levels during incubation predict breeding success, but not reproductive investment, in a free-ranging bird

ABSTRACT The hormone corticosterone (CORT) has been hypothesized to be linked with fitness, but the directionality of the relationship is unclear. The ‘CORT-fitness hypothesis’ proposes that high levels of CORT arise from challenging environmental conditions, resulting in lower reproductive success (a negative relationship). In contrast, the CORT-adaptation hypothesis suggests that, during energetically demanding periods, CORT will mediate physiological or behavioral changes that result in increased reproductive investment and success (a positive relationship). During two breeding seasons, we experimentally manipulated circulating CORT levels in female tree swallows (Tachycineta bicolor) prior to egg laying, and measured subsequent reproductive effort, breeding success, and maternal survival. When females were recaptured during egg incubation and again during the nestling stage, the CORT levels were similar among individuals in each treatment group, and maternal treatment had no effect on indices of fitness. By considering variation among females, we found support for the CORT-adaptation hypothesis; there was a significant positive relationship between CORT levels during incubation and hatching and fledging success. During the nestling stage CORT levels were unrelated to any measure of investment or success. Within the environmental context of our study, relationships between maternal glucocorticoid levels and indices of fitness vary across reproductive stages. Summary: Levels of the stress biomarker corticosterone predict breeding success in female tree swallows. However, correlations between hormone levels and fitness differ between life-history stages.
Pigmentler ve Et Rengi

Renkli bilesikler icerisinde et rengi icin en onemli olanlari hemoglobin ve myoglobindir ve miktar olarak da en fazla bulunan pigmentlerdir. Myoglobin ve hemoglobin’in her ikisi de protein komplekslerdir. Bu pigmentlerin kimyasal yapilarinin birbirine benzemesi yaninda canli dokulardaki fonksiyonlari da birbirine benzer. Cunku, hayvanin metabolik aktivitesi icin gerek myoglobin, gerekse hemoglobin oksijen ile birlesmek zorundadir. Myoglobin ve hemoglobinin fonksiyonlari birbirine benzemesine ragmen islevleri tamamen farklidir. Hemoglobin; kan dolasiminda dokulara oksijen tasiyici olarak rol alir. Bu nedenle hemoglobin, “kan pigmenti” olarak isimlendirilir. Buna karsilik myoglobin, kaslarda dominant pigmenttir ve oksijenin kas hucrelerinde depolanmasinda rol alir. Bu nedenle myoglobin, “kas pigmenti” olarak isimlendirilir.
Impact of virus subtype and host IFNL4 genotype on large-scale RNA structure formation in the genome of hepatitis C virus

Mechanisms underlying the ability of hepatitis C virus (HCV) to establish persistent infections and induce progressive liver disease remain poorly understood. HCV is one of several positive-stranded RNA viruses capable of establishing persistence in their immunocompetent vertebrate hosts, an attribute associated with formation of large scale RNA structure in their genomic RNA. We developed novel methods to analyse and visualise genome-scale ordered RNA structure (GORS) predicted from the increasingly large datasets of complete genome sequences of HCV. Structurally conserved RNA secondary structure in coding regions of HCV localised exclusively to polyprotein ends (core, NS5B). Coding regions elsewhere were also intensely structured based on elevated minimum folding energy difference (MFED) values, but the actual stem-loop elements involved in genome folding were structurally entirely distinct, even between subtypes 1a and 1b. Dynamic remodelling was further evident from comparison of HCV strains in different host genetic background. Significantly higher MFED values, greater suppression of UpA dinucleotide frequencies and restricted diversification were found in subjects with the TT genotype of the rs12979860 SNP in the IFNL4 gene compared to the CC (non-expressing) allele. These structural and compositional associations with expression of interferon-λ4 were recapitulated on a larger scale by higher MFED values and greater UpA suppression of genotype 1 compared to genotype 3a, associated with previously reported HCV genotype-associated differences in hepatic interferon-stimulated gene induction. Associations between innate cellular responses with HCV structure and further evolutionary constraints represents an important new element in RNA virus evolution and the adaptive interplay between virus and host.
Nicotinic acetylcholine receptor ligands as potential therapeutics

The nicotinic acetylcholine receptors (nAChRs) belong to a superfamily of ligand-gated ion channels. Neuronal nAChRs are involved in a variety of complex cognitive processes (learning and memory) and therefore in CNS disorders. These include, for example, Alzheimer’s and Parkinson’s disease, attention deficit hyperactivity disorder, Tourette’s syndrome, schizophrenia, depression, pain and tobacco dependence. Thus, nAChRs present a rational target for the treatment of these pathological processes. Over the past years an increasing number of ligands, especially for the α4β2 subtype has been synthesised. Recent developments reveal increased interest in α7 ligands for the treatment of CNS diseases as well as for pain and inflammation. Unfortunately, only a few companies provide biological data in detail, especially regarding subtype selectivity and functionality. This review provides an overview of the recent patent literature focusing mainly on small molecule ligands.
ZZ Top: faster and more adaptive Z chromosome evolution in two Lepidoptera

The rate of divergence for Z or X chromosomes is theoretically predicted to be greater than autosomes, but the possible explanations for this pattern vary, as do empirical results from diverse taxa. Even among moths and butterflies (Lepidoptera), which generally share a single-origin Z chromosome, the handful of available studies give mixed support for faster or more adaptive evolution of the Z chromosome, depending on the species assayed. Here, we examine the molecular evolution of Z chromosomes in two additional lepidopteran species: the Carolina sphinx moth and the monarch butterfly, the latter of which possesses a recent chromosomal fusion yielding a segment of newly Z-linked DNA. We find evidence for both faster and more adaptive Z chromosome evolution in both species, though this effect is strongest in the neo-Z portion of the monarch sex chromosome. The neo-Z is less male-biased than expected of a Z chromosome, and unbiased and female-biased genes drive the signal for adaptive evolution here. Together these results suggest that male-biased gene accumulation and haploid selection have opposing effects on long-term rates of adaptation and may help explain the discrepancies in previous findings as well as the repeated evolution of neo-sex chromosomes in Lepidoptera.
Seasonal Metabolic Acclimatization in a Northern Population of Free-Ranging Snowshoe Hares, Lepus americanus

Abstract Seasonal acclimatization in high-latitude endotherms may involve increases or reductions in body size and metabolic rate to, respectively, augment thermoregulatory capacity or reduce energy requirements. We investigated seasonal acclimatization in a northern population of wild snowshoe hares (Lepus americanus) that is exposed to low food availability and extremely cold temperatures in winter. Snowshoe hares were livetrapped and transported to a nearby mobile laboratory. Hares were placed in a metabolic chamber and oxygen consumption was measured for 55 min at each of the following temperatures: 10°C, 0°C, −10°C, −15°C, and −20°C. Hair length and density were measured on a sample of collected hares. Snowshoe hares maintained similar body mass and body temperature between the seasons, but average resting metabolic rate and thermal conductance were, respectively, 20% and 32% lower in winter than in autumn. The lower critical temperature was −10°C to −15°C in winter and 0°C to −10°C in autumn. Guard hairs were 36% longer and 148% denser in winter than autumn, whereas downy hairs were the same length but 128% denser in winter than autumn. Collectively, these results suggest that resource constraints associated with a herbivorous diet in regions and seasons of poor forage quality favors an energetically conservative approach to winter acclimatization.
Network-based metrics of resilience and ecological memory in lake ecosystems

Some ecosystems undergo abrupt transitions to a new regime after passing a tipping point in an exogenous stressor, for example lakes shifting from a clear to turbid ‘eutrophic’ state in response to nutrient-enrichment. Metrics-based resilience indicators have been developed as early warning signals of these shifts but have not always proved reliable indicators. Alternative approaches focus on changes in the composition and structure of an ecosystem, which can require long-term food-web observations that are typically beyond the scope of monitoring. Here we prototype a network-based algorithm for estimating ecosystem resilience, which reconstructs past ecological networks solely from palaeoecological abundance data. Resilience is estimated using local stability analysis, and eco-net energy: a neural network-based proxy for ‘ecological memory’. We test the algorithm on modelled (PCLake+) and empirical (lake Erhai) data. The metrics identify increasing diatom community instability during eutrophication in both cases, with eco-net energy revealing complex eco-memory dynamics. The concept of ecological memory opens a new dimension for understanding ecosystem resilience and regime shifts, with eco-memory potentially increasing ecosystem resilience by allowing past memorised eco-network states to be recovered after disruptions.