We present the discovery and characterization of two warm mini-Neptunes transiting the K3V star TOI-815 in a K–M binary system. Analysis of its spectra and rotation period reveal the star to be young, with an age of 200−200+400 Myr. TOI-8l5b has a 11.2-day period and a radius of 2.94 ± 0.05 R⊕ with transits observed by TESS, CHEOPS, ASTEP, and LCOGT. The outer planet, TOI-8l5c, has a radius of 2.62 ± 0.10 R⊕, based on observations of three nonconsecutive transits with TESS; targeted CHEOPS photometry and radial velocity follow-up with ESPRESSO were required to confirm the 35-day period. ESPRESSO confirmed the planetary nature of both planets and measured masses of 7.6 ± 1.5 M⊕ (ρP = 1.64−0.31+0.33 g cm−3) and 23.5 ± 2.4 M⊕ (ρP = 7.2−1.0+1.1 g cm−3), respectively. Thus, the planets have very different masses, which is unusual for compact multi-planet systems. Moreover, our statistical analysis of mini-Neptunes orbiting FGK stars suggests that weakly irradiated planets tend to have higher bulk densities compared to those undergoing strong irradiation. This could be ascribed to their cooler atmospheres, which are more compressed and denser. Internal structure modeling of TOI-815b suggests it likely has a H-He atmosphere that constitutes a few percent of the total planet mass, or higher if the planet is assumed to have no water. In contrast, the measured mass and radius of TOI-815c can be explained without invoking any atmosphere, challenging planetary formation theories. Finally, we infer from our measurements that the star is viewed close to pole-on, which implies a spin-orbit misalignment at the 3σ level. This emphasizes the peculiarity of the system’s orbital architecture, and probably hints at an eventful dynamical history.
View lessBiological invasions pose a rapidly expanding threat to the persistence, functioning and service provisioning of ecosystems globally, and to socio-economic interests. The stages of successful invasions are driven by the same mechanism that underlies adaptive changes across species in general—via natural selection on intraspecific variation in traits that influence survival and reproductive performance (i.e., fitness). Surprisingly, however, the rapid progress in the field of invasion science has resulted in a predominance of species-level approaches (such as deny lists), often irrespective of natural selection theory, local adaptation and other population-level processes that govern successful invasions. To address these issues, we analyse non-native species dynamics at the population level by employing a database of European freshwater macroinvertebrate time series, to investigate spreading speed, abundance dynamics and impact assessments among populations. Our findings reveal substantial variability in spreading speed and abundance trends within and between macroinvertebrate species across biogeographic regions, indicating that levels of invasiveness and impact differ markedly. Discrepancies and inconsistencies among species-level risk screenings and real population-level data were also identified, highlighting the inherent challenges in accurately assessing population-level effects through species-level assessments. In recognition of the importance of population-level assessments, we urge a shift in invasive species management frameworks, which should account for the dynamics of different populations and their environmental context. Adopting an adaptive, region-specific and population-focused approach is imperative, considering the diverse ecological contexts and varying degrees of susceptibility. Such an approach could improve and refine risk assessments while promoting mechanistic understandings of risks and impacts, thereby enabling the development of more effective conservation and management strategies.
View lessGiven the multitude of challenges Earth is facing, sustainability science is of key importance to our continued existence. Evolution is the fundamental biological process underlying the origin of all biodiversity. This phylogenetic diversity fosters the resilience of ecosystems to environmental change, and provides numerous resources to society, and options for the future. Genetic diversity within species is also key to the ability of populations to evolve and adapt to environmental change. Yet, the value of evolutionary processes and the consequences of their impairment have not generally been considered in sustainability research. We argue that biological evolution is important for sustainability and that the concepts, theory, data, and methodological approaches used in evolutionary biology can, in crucial ways, contribute to achieving the UN Sustainable Development Goals (SDGs). We discuss how evolutionary principles are relevant to understanding, maintaining, and improving Nature Contributions to People (NCP) and how they contribute to the SDGs. We highlight specific applications of evolution, evolutionary theory, and evolutionary biology's diverse toolbox, grouped into four major routes through which evolution and evolutionary insights can impact sustainability. We argue that information on both within-species evolutionary potential and among-species phylogenetic diversity is necessary to predict population, community, and ecosystem responses to global change and to make informed decisions on sustainable production, health, and well-being. We provide examples of how evolutionary insights and the tools developed by evolutionary biology can not only inspire and enhance progress on the trajectory to sustainability, but also highlight some obstacles that hitherto seem to have impeded an efficient uptake of evolutionary insights in sustainability research and actions to sustain SDGs. We call for enhanced collaboration between sustainability science and evolutionary biology to understand how integrating these disciplines can help achieve the sustainable future envisioned by the UN SDGs.
View lessHydrogel-integrated graphene superstructures (GSSs) represent a promising platform for applications in tissue engineering and regenerative medicine. Graphene, a two-dimensional carbon-based material, possesses remarkable mechanical, thermal, and electrical characteristics, making it a strong candidate for application in biomedicine. Researchers have pursued the integration of graphene with hydrogels, known for their biocompatibility and ability to provide a conducive environment for cellular growth, to craft sophisticated scaffolds tailored to tissue engineering needs. The integration of hydrogels and graphene enables the construction of 3D frameworks that closely mimic the natural extracellular matrix (ECM) found in biological tissues. Hydrogels furnish a biocompatible, well-hydrated environment, while the graphene component bolsters the scaffold's mechanical integrity and electrical conductivity. This amalgamation enhances cellular adhesion, differentiation, and proliferation, thereby facilitating tissue regeneration. A notable advantage of hydrogel-integrated GSSs lies in their capacity to support the growth and differentiation of a variety of cell types such as PC12, MG-63, U-87, and MC3T3-E1 cell lines. Overall, hydrogel-integrated GSSs exhibit great potential for advancing biomimetic tissue engineering and regenerative medicine. The combination of the unique properties of graphene with the biocompatibility of hydrogels enables the development of advanced scaffold systems for tissue regeneration. Further research and development in this domain will play a crucial role in advancing regenerative medicine and the treatment of various diseases and injuries.
View lessDust emission fluxes during wind soil erosion are usually estimated using a dust concentration vertical gradient, by assuming a constant dust flux layer between the surface and the dust measurement levels. Here, we investigate the existence of this layer during erosion events recorded in Iceland and Jordan. Size-resolved dust fluxes were estimated at three levels between 2 and 4 m using the eddy-covariance method. Dust fluxes were found mainly constant only between the two upper levels in Iceland, the lower dust flux being often stronger and richer in coarse particles, while dust fluxes in Jordan were nearly constant across all levels. The wind dynamics could not explain the absence of a constant dust flux layer in Iceland. We show that the presence of stationary dust source patches in Iceland, related to surface humidity, created a non-uniform dust layer near the surface, named dust roughness sublayer (DRSL), where individual plumes behind each patch interact but do not fully mix. The lowest dust measurement level was probably located within this sublayer while the upper ones were located above, such that there the emitted dust became spatially well-mixed. This explains near the surface in Iceland, the more intermittent dust concentration, its low correlation with the dust concentrations above, and the richer dust flux in coarse particles due to their lower deposition contribution. Our findings highlight the importance of estimating dust fluxes above a dust blending height whose characteristics depend on the dust source patchiness caused by surface humidity or the presence of sparse non-erosive elements.
View lessThe adoption of agri-environment practices (AEPs) is crucial for safeguarding the long-term sustainability of ecosystem services within European agricultural landscapes. However, the tailoring of agri-environment policies to the unique characteristics of farming systems is a challenging task, often neglecting local farm parameters or requiring extensive farm survey data. Here, we develop a simplified typology of farming system archetypes (FSAs), using field-level data on farms' economic size and specialisation derived from the Integrated Administration and Control System in three case studies in Germany, Czechia and the United Kingdom. Our typology identifies groups of farms that are assumed to react similarly to agricultural policy measures, bridging the gap between efforts to understand individual farm behaviour and broad agri-environmental typologies. We assess the usefulness of our approach by quantifying the spatial association of identified archetypes of farming systems with ecologically relevant AEPs (cover crops, fallow, organic farming, grassland maintenance, vegetation buffers, conversion of cropland to grassland and forest) to understand the rates of AEP adoption by different types of farms. Our results show that of the 20 archetypes, economically large farms specialised in general cropping dominate the agricultural land in all case studies, covering 56% to 85% of the total agricultural area. Despite regional differences, we found consistent trends in AEP adoption across diverse contexts. Economically large farms and those specialising in grazing livestock were more likely to adopt AEPs, with economically larger farms demonstrating a proclivity for a wider range of measures. In contrast, economically smaller farms usually focused on a narrower spectrum of AEPs and, together with farms with an economic value <2 000 EUR, accounted for 70% of all farms with no AEP uptake. These insights indicate the potential of the FSA typology as a framework to infer key patterns of AEP adoption, thus providing relevant information to policy-makers for more direct identification of policy target groups and ultimately for developing more tailored agri-environment policies.
View lessA relevant question concerning inter-areal communication in the cortex is whether these interactions are synergistic. Synergy refers to the complementary effect of multiple brain signals conveying more information than the sum of each isolated signal. Redundancy, on the other hand, refers to the common information shared between brain signals. Here, we dissociated cortical interactions encoding complementary information (synergy) from those sharing common information (redundancy) during prediction error (PE) processing. We analyzed auditory and frontal electrocorticography (ECoG) signals in five common awake marmosets performing two distinct auditory oddball tasks and investigated to what extent event-related potentials (ERP) and broadband (BB) dynamics encoded synergistic and redundant information about PE processing. The information conveyed by ERPs and BB signals was synergistic even at lower stages of the hierarchy in the auditory cortex and between auditory and frontal regions. Using a brain-constrained neural network, we simulated the synergy and redundancy observed in the experimental results and demonstrated that the emergence of synergy between auditory and frontal regions requires the presence of strong, long-distance, feedback, and feedforward connections. These results indicate that distributed representations of PE signals across the cortical hierarchy can be highly synergistic.
View lessBackground
Extended-spectrum cephalosporins (ESCs) are third and fourth generation cephalosporin antimicrobials used in humans and animals to treat infections due to multidrug-resistant (MDR) bacteria. Resistance to ESCs (ESC-R) in Enterobacterales is predominantly due to the production of extended-spectrum β-lactamases (ESBLs) and plasmid-mediated AmpC β-lactamases (AmpCs). The dynamics of ESBLs and AmpCs are changing across countries and host species, the result of global transmission of ESC-R genes. Plasmids are known to play a key role in this dissemination, but the relative importance of different types of plasmids is not fully understood.
Methods
In this study, Escherichia coli with the major ESC-R genes blaCTX-M-1, blaCTX-M-15, blaCTX-M-14 (ESBLs) and blaCMY-2 (AmpC), were selected from diverse host species and other sources across Canada, France and Germany, collected between 2003 and 2017. To examine in detail the vehicles of transmission of the ESC-R genes, long- and short-read sequences were generated to obtain complete contiguous chromosome and plasmid sequences (n = 192 ESC-R E. coli). The types, gene composition and genetic relatedness of these plasmids were investigated, along with association with isolate year, source and geographical origin, and put in context with publicly available plasmid sequences.
Findings
We identified five epidemic resistance plasmid subtypes with distinct genetic properties that are associated with the global dissemination of ESC-R genes across multiple E. coli lineages and host species. The IncI1 pST3 blaCTX-M-1 plasmid subtype was found in more diverse sources than the other main plasmid subtypes, whereas IncI1 pST12 blaCMY-2 was more frequent in Canadian and German human and chicken isolates. Clonal expansion also contributed to the dissemination of the IncI1 pST12 blaCMY-2 plasmid in ST131 and ST117 E. coli harbouring this plasmid. The IncI1 pST2 blaCMY-2 subtype was predominant in isolates from humans in France, while the IncF F31:A4:B1 blaCTX-M-15 and F2:A-:B- blaCTX-M-14 plasmid subtypes were frequent in human and cattle isolates across multiple countries. Beyond their epidemic nature with respect to ESC-R genes, in our collection almost all IncI1 pST3 blaCTX-M-1 and IncF F31:A4:B1 blaCTX-M-15 epidemic plasmids also carried multiple antimicrobial resistance (AMR) genes conferring resistance to other antimicrobial classes. Finally, we found genetic signatures in the regions surrounding specific ESC-R genes, identifying the predominant mechanisms of ESC-R gene movement, and using publicly available databases, we identified these epidemic plasmids from widespread bacterial species, host species, countries and continents.
Interpretation
We provide evidence that epidemic resistance plasmid subtypes contribute to the global dissemination of ESC-R genes, and in addition, some of these epidemic plasmids confer resistance to multiple other antimicrobial classes. The success of these plasmids suggests that they may have a fitness advantage over other plasmid types and subtypes. Identification and understanding of the vehicles of AMR transmission are crucial to develop and target strategies and interventions to reduce the spread of AMR.
View lessAn Electroencephalography (EEG) dataset utilizing rich text stimuli can advance the understanding of how the brain encodes semantic information and contribute to semantic decoding in brain-computer interface (BCI). Addressing the scarcity of EEG datasets featuring Chinese linguistic stimuli, we present the ChineseEEG dataset, a high-density EEG dataset complemented by simultaneous eye-tracking recordings. This dataset was compiled while 10 participants silently read approximately 13 hours of Chinese text from two well-known novels. This dataset provides long-duration EEG recordings, along with pre-processed EEG sensor-level data and semantic embeddings of reading materials extracted by a pre-trained natural language processing (NLP) model. As a pilot EEG dataset derived from natural Chinese linguistic stimuli, ChineseEEG can significantly support research across neuroscience, NLP, and linguistics. It establishes a benchmark dataset for Chinese semantic decoding, aids in the development of BCIs, and facilitates the exploration of alignment between large language models and human cognitive processes. It can also aid research into the brain’s mechanisms of language processing within the context of the Chinese natural language.
View less“Dragon stones” are prehistoric basalt stelae carved with animal imagery found in Armenia and surrounding regions. These monuments have a complex history of use and reuse across millennia, and the original date of creation is still a matter of debate. In this article, we present a unique dragon stone context excavated at the site of Lchashen, Armenia, where a three-and-a-half-meter high basalt stela with an image of a sacrificed bovid was found above a burial dating to the 16th century BC. The burial stands out among hundreds from this site as the only one in connection with a “dragon stone”, and one of very few containing the remains of newborn babies. Furthermore, our analyses of ancient DNA extracted from the well-preserved skeletal remains of two 0–2-month-old individuals showed them to be second-degree related females with identical mitochondrial sequences of the haplogroup U5a1a1 lineage, thus indicating that the infants are closely related. Additionally, we assessed that the buried individuals displayed genetic ancestry profiles similar to other Bronze Age individuals from the region.
View lessBackground: There is evidence from meta-analyses and systematic reviews that digital mental health interventions for depression, anxiety, and stress-related disorders tend to be cost-effective. However, no such evidence exists for guided digital mental health care in low and middle-income countries (LMICs) facing humanitarian crises, where the needs are highest. Step-by-Step (SbS), a digital mental health intervention for depression, anxiety, and stress-related disorders, proved to be effective for Lebanese citizens and war-affected Syrians residing in Lebanon. Assessing the cost-effectiveness of SbS is crucial because Lebanon’s overstretched health care system must prioritize cost-effective treatment options in the face of continuing humanitarian and economic crises.
Objective: This study aims to assess the cost-effectiveness of SbS in a randomized comparison with enhanced usual care (EUC).
Methods: The cost-effectiveness analysis was conducted alongside a pragmatic randomized controlled trial in 2 parallel groups comparing SbS (n=614) with EUC (n=635). The primary outcome was cost (in US $ for the reference year 2019) per treatment response of depressive symptoms, defined as >50% reduction of depressive symptoms measured using the Patient Health Questionnaire (PHQ). The secondary outcome was cost per remission of depressive symptoms, defined as a PHQ score <5 at last follow-up (5 months post baseline). The evaluation was conducted first from the health care perspective then from the societal perspective.
Results: Taking the health care perspective, SbS had an 80% probability to be regarded as cost-effective compared with EUC when there is a willingness to pay US $220 per additional treatment response or US $840 per additional remission. Taking the wider societal perspective, SbS had a >75% probability to be cost-saving while gaining response or remission.
Conclusions: To our knowledge, this study is the first cost-effectiveness analysis based on a large randomized controlled trial (n=1249) of a guided digital mental health intervention in an LMIC. From the principal findings, 2 implications flowed, from the (1) health care perspective and (2) wider societal perspective. First, our findings suggest that SbS is associated with greater health benefits, albeit for higher costs than EUC. It is up to decision makers in health care to decide if they find the balance between additional health gains and additional health care costs acceptable. Second, as seen from the wider societal perspective, there is a substantial likelihood that SbS is not costing more than EUC but is associated with cost-savings as SBS participants become more productive, thus offsetting their health care costs. This finding may suggest to policy makers that it is in the interest of both population health and the wider Lebanese economy to implement SbS on a wide scale. In brief, SbS may offer a scalable, potentially cost-saving response to humanitarian emergencies in an LMIC.
View lessLong-standing questions about human brain evolution may only be resolved through comparisons with close living evolutionary relatives, such as chimpanzees. This applies in particular to structural white matter (WM) connectivity, which continuously expanded throughout evolution. However, due to legal restrictions on chimpanzee research, neuroscience research currently relies largely on data with limited detail or on comparisons with evolutionarily distant monkeys. Here, we present a detailed magnetic resonance imaging resource to study structural WM connectivity in the chimpanzee. This open-access resource contains (1) WM reconstructions of a postmortem chimpanzee brain, using the highest-quality diffusion magnetic resonance imaging data yet acquired from great apes; (2) an optimized and validated method for high-quality fiber orientation reconstructions; and (3) major fiber tract segmentations for cross-species morphological comparisons. This dataset enabled us to identify phylogenetically relevant details of the chimpanzee connectome, and we anticipate that it will substantially contribute to understanding human brain evolution.
View lessWe consider the classical shadows task for pure states in the setting of both joint and independent measurements. The task is to measure few copies of an unknown pure state ρ in order to learn a classical description which suffices to later estimate expectation values of observables. Specifically, the goal is to approximate Tr(Oρ) for any Hermitian observable O to within additive error ϵ provided Tr(O2)≤B and ∥O∥=1. Our main result applies to the joint measurement setting, where we show ~Θ(√Bϵ−1+ϵ−2) samples of ρ are necessary and sufficient to succeed with high probability. The upper bound is a quadratic improvement on the previous best sample complexity known for this problem. For the lower bound, we see that the bottleneck is not how fast we can learn the state but rather how much any classical description of ρ can be compressed for observable estimation. In the independent measurement setting, we show that O(√Bdϵ−1+ϵ−2) samples suffice. Notably, this implies that the random Clifford measurements algorithm of Huang, Kueng, and Preskill, which is sample-optimal for mixed states, is not optimal for pure states. Interestingly, our result also uses the same random Clifford measurements but employs a different estimator.
View lessThe present study aims to understand the impact of submarine groundwater discharge (SGD) on a coastal area with different lithology and degrees of SGD. Sampling campaigns took place in Puck Bay and the Gulf of Gdańsk, southern Baltic Sea encompassing years between 2009 and 2021. The methodological approach combined geophysical characterization of the surface sediments with detailed spatial and temporal (isotope) biogeochemical investigations of pore and surface waters, and was supported by nearshore groundwater and river surveys. Acoustic investigations identified areas of disturbance that may indicate zones of preferential SGD release. The composition of porewater and the differences in the bay's surface waters disclosed SGD as common phenomenon in the study area. Regional SGD was estimated through a radium mass balance. Local estimation of SGD, based on porewater profiles, revealed highest SGD fluxes at the sandy shoreline, but relatively low elemental fluxes. Though SGD was low at the muddy sites corresponding elemental fluxes of nutrients and dissolved carbon exceeded those determined at the sandy sites due to intense diagenesis in the top sediments. SGD appears to be sourced from different freshwater endmembers; however, diagenesis in surface sediments substantially modified the composition of the mixed solutions that are finally discharged to coastal waters. Overall, this study provides a better understanding of the SGD dynamics in the region by a multi-approach and emphasizes the need to understand the processes occurring at the sediment-water interface when estimating SGD.
View lessHeparin, a widely used clinical anticoagulant, is generally well-tolerated; however, approximately 1% of patients develop heparin-induced thrombocytopenia (HIT), a serious side effect. While efforts to understand the role of chemokines in HIT development are ongoing, certain aspects remain less studied, such as the stabilization of chemokine oligomers by heparin. Here, we conducted a combined ion mobility-native mass spectrometry study to investigate the stability of chemokine oligomers and their complexes with fondaparinux, a synthetic heparin analog. Collision-induced dissociation and unfolding experiments provided clarity on the specificity and relevance of chemokine oligomers and their fondaparinux complexes with varying stoichiometries, as well as the stabilizing effects of fondaparinux binding.
View lessAltered heart rate (HR) and heart rate variability (HRV) are common observations in psychiatric disorders. Yet, few studies have examined these cardiac measures in obsessive-compulsive disorder (OCD). The current study aimed to investigate HR and HRV, indexed by the root mean square of successive differences (RMSSD) and further time domain indices, as putative biological characteristics of OCD. Electrocardiogram was recorded during a five-minute resting state. Group differences between patients with OCD (n = 96), healthy participants (n = 112), and unaffected first-degree relatives of patients with OCD (n = 47) were analyzed. As potential moderators of group differences, we examined the influence of age and medication, respectively. As results indicated, patients with OCD showed higher HR and lower HRV compared to healthy participants. These group differences were not moderated by age. Importantly, subgroup analyses showed that only medicated patients displayed lower HRV compared to healthy individuals, while HR alterations were evident in unmedicated patients. Regarding unaffected first-degree relatives, group differences in HRV remained at trend level. Further, an age-moderated group differentiation showed that higher HRV distinguished relatives from healthy individuals in young adulthood, whereas at higher age lower HRV was indicative of relatives. Both the role of familial risk and medication in HRV alterations need further elucidation. Pending future studies, alterations in HR and potentially HRV might serve as useful indices to characterize the pathophysiology of OCD.
View lessIn order to determine optimal parameters of vacuum thermal processing of superconducting radiofrequency niobium cavities exhaustive information on the initial chemical state of niobium and its modification upon a vacuum heat treatment is required. In the present work the chemical composition of the niobium surface upon ultra-high vacuum baking at 200 C-degrees-400 C-degrees similar to 'medium-temperature baking' and 'furnace baking' of cavities is explored in-situ by synchrotron x-ray photoelectron spectroscopy (XPS). Our findings imply that below the critical thickness of the Nb2O5 layer (approximate to 1nm) niobium starts to interact actively with surface impurities, such as carbon and phosphorus. By studying the kinetics of the native oxide reduction, the activation energy and the rate-constant relation have been determined and used for the calculation of the oxygen-concentration depth profiles. It has been established that the controlled diffusion of oxygen is realized at temperatures 200 C-degrees-300 C-degrees, and the native-oxide layer represents an oxygen source, while at 400 C-degrees the pentoxide is completely reduced and the doping level is determined by an ambient oxygen partial pressure. Fluorine (F to Nb atomic ratio is 0.2) after the buffered chemical polishing was found to be incorporated into the surface layer probed by XPS (approximate to 4.6nm), and its concentration increased during the low-temperature baking (F/Nb = 0.35 at 230 C-degrees) and depleted at higher temperatures (F/Nb = 0.11 at 400 C-degrees). Thus, the influence of fluorine on the performance of mid-T baked, nitrogen-doped and particularly mild-baked (120 C-degrees/48 h) cavities must be considered. The possible role of fluorine in the educed Nb+5 -> Nb+4 reaction under the impact of an x-ray beam at room temperature and during the thermal treatment is also discussed. The range of temperature and duration parameters of the thermal treatment at which the niobium surface would not be contaminated with impurities is determined.
View lessTropical theileriosis is a fatal leukemic-like disease of cattle caused by the tick-transmitted protozoan parasite Theileria annulata. The economics of cattle meat and milk production is severely affected by theileriosis in endemic areas. The hydroxynaphtoquinone buparvaquone (BPQ) is the only available drug currently used to treat clinical theileriosis, whilst BPQ resistance is emerging and spreading in endemic areas. Here, we chronically exposed T. annulata-transformed macrophages in vitro to BPQ and monitored the emergence of drug-resistant parasites. Surviving parasites revealed a significant increase in BPQ IC50 compared to the wild type parasites. Drug resistant parasites from two independent cloned lines had an identical single mutation, M128I, in the gene coding for T. annulata cytochrome B (Tacytb). This in vitro generated mutation has not been reported in resistant field isolates previously, but is reminiscent of the methionine to isoleucine mutation in atovaquone-resistant Plasmodium and Babesia. The M128I mutation did not appear to exert any deleterious effect on parasite fitness (proliferation and differentiation to merozoites). To gain insight into whether drug-resistance could have resulted from altered drug binding to TaCytB we generated in silico a 3D-model of wild type TaCytB and docked BPQ to the predicted 3D-structure. Potential binding sites cluster in four areas of the protein structure including the Q01 site. The bound drug in the Q01 site is expected to pack against an alpha helix, which included M128, suggesting that the change in amino acid in this position may alter drug-binding. The in vitro generated BPQ resistant T. annulata is a useful tool to determine the contribution of the various predicted docking sites to BPQ resistance and will also allow testing novel drugs against theileriosis for their potential to overcome BPQ resistance.
View lessGlioblastoma (GB) is one of the most lethal types of neoplasms with unique anatomic, physiologic, and pathologic features that usually persist after exposure to standard therapeutic modalities. It is biologically aggressive, and the existence of the blood-brain barrier (BBB) limits the efficacy of standard therapies. In this work, we hypothesize the potential of surface-functionalized ultra-small nanostructured lipid carriers (usNLCs) with charge-switchable cell-penetrating peptides (CPPs) to overcome this biological barrier and improve targeted delivery to brain tumor tissues. The big question is: what is the potential of CPPs in directing nanoparticles toward brain tumor tissue? To answer this question, the usNLCs were functionalized with distinct biomolecules [five CPPs, c(RGDfK) and transferrin, Tf] through electrostatic interaction and its ability as a targeting approach to BBB (HBMEC) and glioma cells (U87 cells) evaluated in terms of physicochemical properties, cellular uptake, permeability in a 2D-BBB model, and tumor growth inhibition. Monte Carlo simulations elucidated CPP adsorption patterns. The permeability studies revealed that targeted usNLCs, especially usNLCsTf and usNLCsCPP4, exhibited an increased permeability coefficient compared to the non-targeted usNLCs. Functionalized usNLCs evidenced enhanced uptake in BBB cells, with smaller CPPs showing higher internalization (CPP1 and CPP2). Similarly, functionalized usNLCs exhibited more significant cytotoxicity in glioma cells, with specific CPPs promoting favorable internalization. Analysis of the endocytic pathway indicated that usNLCsCPPs were mainly internalized by direct translocation and caveolae-mediated endocytosis. Optimal usNLCs with dual targeting capabilities to both BBB and GB cells provide a promising therapeutic strategy for GB.
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