Basis Of Function Research Articles

Proteogenomics-guided functional venomics resolves the toxin arsenal and activity of Deinagkistrodon acutus venom

Snakebite primarily impacts rural communities of Africa, Asia, and Latin America. The sharp-nosed viper (Deinagkistrodon acutus) is among the snakes of highest medical importance in Asia. Despite various studies on its venom using modern venomics techniques, a comprehensive understanding of composition and function of this species' venom remains lacking. We combined proteogenomics with extensive bioactivity profiling to present the first genome-level catalogue of D. acutus venom proteins and their exochemistry. Our analysis identified an unusually simple venom containing 45 components from 20 distinct protein families. Relative toxin abundances indicate that C-type lectin and C-type lectin-related protein (CTL), snake venom metalloproteinase (svMP), snake venom serine protease (svSP), and phospholipase A2 (PLA2) constitute 90 % of the venom. Bioassays targeting key aspects of viperid envenomation showed considerable concentration-dependent cytotoxicity, particularly in kidney and lung cells, and potent protease and PLA2 activity. Factor Xa and thrombin activities were minor, and no plasmin activity was observed. Effects on haemolysis, intracellular calcium (Ca2+) release, and nitric oxide (NO) synthesis were negligible. Our analysis provides the first holistic genome-based overview of the toxin arsenal of D. acutus, predicting the molecular and functional basis of its life-threatening effects, and opens novel avenues for treating envenomation by this highly dangerous snake.

Exploring the molecular solvatochromism, stability, reactivity, and non-linear optical response of resveratrol.

This work analyzes the isomerization effects and solvent contributions to the stability, electronic excitations, reactivity, and non-linear optical properties (NLO) of resveratrol molecules within the formalism of the Density Functional Theory. The findings suggest that resveratrol solvatochromism is significantly influenced by solvent polarization. The electronic and free energies (E and G) indicate that trans is the most stable conformer. The system is classified as a strong nucleophile. However, the analysis of the Fukui functions and the Mulliken charges indicate that cis-trans isomerization jointly affects the reactive indices of the carbon and hydrogen atoms. The results also suggest that solvent is relevant to solvatochromism and the NLO response. Both cis and trans conformers present strong excitations that undergo a visible hypsochromic change when the polarity of the solvent increases. Once the absorption spectra are connected to the first hyperpolarization ( ) by the Oudar and Chemla relation, the hypsochromism of resveratrol is the reason for the drop in the generation of the second harmonic when the ambient polarity decreases. The CAM-B3LYP DFT results suggest that resveratrol is interesting for NLO applications. Depending on the choice of solvent, values 50 times those observed for urea ( esu), which is a standard NLO material. The optimized geometries of cis and trans isomers of resveratrol in vacuum were obtained using Density Functional Theory (DFT) with the hybrid exchange-correlation function (CAM-B3LYP) and Pople basis set functions, specifically 6-311++G(d,p). The solvent effect on the geometries of both isomers was included using the polarizable continuum model (PCM) with the same level of QM calculation. Vibrational analysis was conducted to confirm that all optimized geometries correspond to the minimum energy. Various electronic properties, including dipole moments, molecular orbitals, transition energy, dipole polarizabilities, and global reactivity parameters, were calculated using both continuum and discrete solvation models based on the sequential QM/MM methodology. All QM calculations were performed with the Gaussian 09 program and the MC simulations with the DICE program. All NLO analysis was carried out using the Multiwfn code.

Legal regulation of the asylum granting and ensuring of the refugees’ rights in the European Union

The article is devoted to the study of the legal regulation of the asylum granting and ensuring of the refugees’ rights in the European Union. Within the framework of the article, the legal basis of the Common European Asylum System functioning, the creation of which is laid down in the constituent treaties of the European Union, is investigated. In particular, it is determined that the purpose of such a common system is to establish unified standards for determining the criteria for admissibility of applications for asylum or international protection, a similar procedure for considering such applications and the grounds for refusing or suspending the status of a refugee or a person seeking temporary protection, as well as determining the state, responsible for providing asylum, uniform standards for ensuring the rights of refugees, as well as common principles of cooperation between the Member States and partner states that are not members of the Union. The key provisions of the Directive on qualification criteria, on the procedure for granting asylum and international protection, on the conditions of reception and rights of refugees, as well as the Dublin Regulation and the Eurodac Regulation were analyzed. The authors put an emphasis on the fact that because of the full-scale invasion and emergence of the war on the territory of Ukraine, significant changes were made to the process and procedures for granting refugee status and providing asylum within the framework of the legislation of the European Union. The latest Pact on Migration and Asylum was analyzed, especially regarding changes in ensuring border security, quick and effective procedures for considering and obtaining the status of a refugee or a person seeking international protection, solidarity and responsibility among countries that are obliged to provide asylum, as well as strengthening international cooperation in the field of migration. The authors express their support for those concerns regarding alleged violations that may occur after the entry into force of the Pact, in connection with the threat of violations of fundamental human rights. It was concluded that ensuring dignity and respect for human rights is a priority, considering that refugees are recognized as persons who have already suffered violations and were forced to leave their homes.

Functional characterization and structural basis of an efficient ochratoxin A-degrading amidohydrolase

Ochratoxin A (OTA) contamination in various agro-products poses a serious threat to the global food safety and human health, leading to enormous economic losses. Enzyme-mediated OTA degradation is an appealing strategy, and the search for more efficient enzymes is a prerequisite for achieving this goal. Here, a novel amidohydrolase, termed PwADH, was demonstrated to exhibit 7.3-fold higher activity than that of the most efficient OTA-degrading ADH3 previously reported. Cryo-electron microscopy structure analysis indicated that additional hydrogen-bond interactions among OTA and the adjacent residue H163, the more compact substrate-binding pocket, and the wider entry to the substrate-access cavity might account for the more efficient OTA-degrading activity of PwADH compared with that of ADH3. We conducted a structure-guided rational design of PwADH and obtained an upgraded variant, G88D, whose OTA-degrading activity was elevated by 1.2-fold. In addition, PwADH and the upgraded G88D were successfully expressed in the industrial yeast Pichia pastoris, and their catalytic activities were compared to those of their counterparts produced in E. coli, revealing the feasibility of producing PwADH and its variants in industrial yeast strains. These results illustrate the structural basis of a novel, efficient OTA-degrading amidohydrolase and will be beneficial for the development of high-efficiency OTA-degrading approaches.

Benchmarking Quantum Mechanical Levels of Theory for Valence Parametrization in Force Fields.

A wide range of density functional methods and basis sets are available to derive the electronic structure and properties of molecules. Quantum mechanical calculations are too computationally intensive for routine simulation of molecules in the condensed phase, prompting the development of computationally efficient force fields based on quantum mechanical data. Parametrizing general force fields, which cover a vast chemical space, necessitates the generation of sizable quantum mechanical data sets with optimized geometries and torsion scans. To achieve this efficiently, choosing a quantum mechanical method that balances computational cost and accuracy is crucial. In this study, we seek to assess the accuracy of quantum mechanical theory for specific properties such as conformer energies and torsion energetics. To comprehensively evaluate various methods, we focus on a representative set of 59 diverse small molecules, comparing approximately 25 combinations of functional and basis sets against the reference level coupled cluster calculations at the complete basis set limit.

Investigating acoustic startle habituation and prepulse inhibition with silent functional MRI and electromyography in young, healthy adults.

Startle habituation and prepulse inhibition (PPI) are distinct measures of different sensory information processes, yet both result in the attenuation of the startle reflex. Identifying startle habituation and PPI neural mechanisms in humans has mostly evolved from acoustic-focused rodent models. Human functional magnetic resonance imaging (fMRI) studies have used tactile startle paradigms to avoid the confounding effects of gradient-related acoustic noise on auditory paradigms and blood-oxygen-level-dependent (BOLD) measures. This study aimed to examine the neurofunctional basis of acoustic startle habituation and PPI in humans with silent fMRI. Using silent fMRI and simultaneous electromyography (EMG) to measure startle, the neural correlates of acoustic short-term startle habituation and PPI [stimulus onset asynchronies (SOA) of 60 ms and 120 ms] were investigated in 42 healthy adults (28 females). To derive stronger inferences about brain-behaviour correlations at the group-level, models included EMG-assessed measures of startle habituation (regression slope) or PPI (percentage) as a covariate. A linear temporal modulator was modelled at the individual-level to characterise functional changes in neural activity during startle habituation. Over time, participants showed a decrease in startle response (habituation), accompanied by decreasing thalamic, striatal, insula, and brainstem activity. Startle habituation was associated with the linear temporal modulation of BOLD response amplitude in several regions, with thalamus, insula, and parietal lobe activity decreasing over time, and frontal lobe, dorsal striatum, and posterior cingulate activity increasing over time. The paradigm yielded a small amount of PPI (9-13%). No significant neural activity for PPI was detected. Startle habituation was associated with the thalamus, putamen, insula, and brainstem, and with linear BOLD response modulation in thalamic, striatal, insula, parietal, frontal, and posterior cingulate regions. These findings provide insight into the mediation and functional basis of the acoustic primary startle circuit. Instead, whilst reduced compared to conventional MRI, scanner noise may have disrupted prepulse detection and processing, resulting in low PPI and impacting our ability to map its neural signatures. Our findings encourage optimisation of the MRI environment for acoustic PPI-based investigations in humans. Combining EMG and functional neuroimaging methods shows promise for mapping short-term startle habituation in healthy and clinical populations.

(Invited) Density Functional Theory Study on Molecular Structures of Polyhydroxy Fullerenes

Polyhydroxy fullerenes (PHF), also known as fullerenols or fullerols, are water-soluble fullerenes that are being studied for several applications. PHF is usually synthesized by acid or alkali method and is assumed to have only hydroxyl groups. These approaches use uncontrolled oxidation method and it is possible to have unintended functionalization. In fact, few studies have proposed presence of hemi-ketal and carbonyl groups based on NMR, XPS and FTIR studies. However, a complete understanding of their molecular structures is still lacking. Theoretical quantum chemical calculations based on density functional theory (DFT) are commonly used to predict and corroborate vibrational spectrum of molecules. Interestingly, in silico studies thus far have considered fullerenes with only hydroxyl groups with a big mismatch in their calculated vibrational energies and experimental FTIR spectrum.In this study, we investigated the presence of carbonyl and hemi-ketal functional groups on hydroxylated fullerenes using DFT. We also evaluated the influence of counterions on oxygen-containing functional groups. All DFT calculations were carried out on Gaussian19 with hybrid B3LYP functional and 6-31G(d,p) basis set. By bridging the gap between theoretical calculations and experimental measurements, we offer an alternative interpretation for the characteristic peaks observed in the FTIR spectrum. Furthermore, our theoretical calculations suggest a dynamic nature inherent in these oxygen-containing functional groups residing on the carbon cage of the fullerene structure.

The Visual Systems of Zebrafish.

The zebrafish visual system has become a paradigmatic preparation for behavioral and systems neuroscience. Around 40 types of retinal ganglion cells (RGCs) serve as matched filters for stimulus features, including light, optic flow, prey, and objects on a collision course. RGCs distribute their signals via axon collaterals to 12 retinorecipient areas in forebrain and midbrain. The major visuomotor hub, the optic tectum, harbors nine RGC input layers that combine information on multiple features. The retinotopic map in the tectum is locally adapted to visual scene statistics and visual subfield-specific behavioral demands. Tectal projections to premotor centers are topographically organized according to behavioral commands. The known connectivity in more than 20 processing streams allows us to dissect the cellular basis of elementary perceptual and cognitive functions. Visually evoked responses, such as prey capture or loom avoidance, are controlled by dedicated multistation pathways that-at least in the larva-resemble labeled lines. This architecture serves the neuronal code's purpose of driving adaptive behavior.

Spatiotemporal cerebral blood flow dynamics underlies emergence of the limbic-sensorimotor-association cortical gradient in human infancy.

Infant cerebral blood flow (CBF) delivers nutrients and oxygen to fulfill brain energy consumption requirements for the fastest period of postnatal brain development across the lifespan. However, organizing principle of whole-brain CBF dynamics during infancy remains obscure. Leveraging a unique cohort of 100+ infants with high-resolution arterial spin labeled MRI, we found the emergence of the cortical hierarchy revealed by the highest-resolution infant CBF maps available to date. Infant CBF across cortical regions increased in a biphasic pattern with initial rapid and sequentially slower rate, with break-point ages increasing along the limbic-sensorimotor-association cortical gradient. Increases in CBF in sensorimotor cortices were associated with enhanced language and motor skills, and frontoparietal association cortices for cognitive skills. The study discovered emergence of the hierarchical limbic-sensorimotor-association cortical gradient in infancy, and offers standardized reference of infant brain CBF and insight into the physiological basis of cortical specialization and real-world infant developmental functioning.

Abstract We037: GPC3-mediated metabolic rewiring of diabetic mesenchymal stromal enhances their cardioprotective functions via pyruvate kinase M2 activation

Background: Mesenchymal stromal cells (MSC) represent promising stem cell therapy for treating cardiovascular diseases. Diabetes affects the functional capability of MSC and impedes cell-based therapy. However, the impact of diabetes on MSC myocardial reparative activity, metabolic fingerprint, and the mechanism of dysfunction is still poorly understood. Therefore, our study aimed to understand the molecular basis of diabetes-induced MSC functions and their metabolic mechanism, and potential metabolic reprogramming of diabetic MSC to reverse these dysfunctions may represent a strategy to enhance cell-based therapeutics for myocardial repair in diabetic patients. Hypothesis: Our central hypothesis is that increased Glypican-3 (GPC3) mediates diabetic MSC dysfunction and diminishes energy metabolism; metabolic reprogramming of diabetic MSC with GPC3 knockdown restored diabetic MSC reparative and therapeutic activities in post-MI cardiac repair. Methods: MSCs were isolated from the bone marrow of mice from db/+ non-diabetic (WT-MSC) and diabetic mice (db/db-MSC) to compare the MSC metabolic profiles and consequent reparative function. We investigated the effect of GPC3 knockdown on db/db-MSC energy metabolism, immunosuppression, angiogenic potential in vitro, and therapeutic potential for ischemic cardiac tissue repair. Results: Intra-myocardial transplantation of db/db-MSC into the ischemic myocardium of mice does not confer cardiac benefit post-MI. The seahorse metabolic flux assays and 13 C glucose tracing studies identified defective energy metabolism in db/db-MSC. Furthermore, we found that GPC3, a heparan sulfate proteoglycan, is highly upregulated in db/db-MSC. GPC3 knockdown-db/db-MSC restored their energy metabolism, immunomodulation, and angiogenesis. Intramyocardial injection of GPC3 metabolically reprogrammed-db/db-MSC confers cardiac benefit post-MI. Conclusion: Our findings indicate that metabolic rewiring using GPC3 may be used to restore the metabolic state and functions of db/db-MSC for cell therapy applications.

Интеллектуальная технология оценки остаточного ресурса сложных технических систем

The task of estimating the residual life of complex technical systems has recently become increasingly important. For the pre-trustworthy estimation of this indicator it is required to process large arrays of data on the current state of the system under study. At the same time the task of reconstruction of the model of degradation processes development leading to the occurrence of failures requires solving a number of problems. In this regard, there is a need to use intelligent methods of data processing, which include methods of time series anomaly analysis. Purpose of the study: development of a method for detecting contextual anomalies of time series, allowing to determine the degree of development of degradation processes that lead to the occurrence of failures. Methods. An analogy was established between machine learning methods in supervised, semi-supervised and unsupervised modes and groups of anomaly detection methods differing depending on the degree of availability of labels that characterize the properties and attributes of the corresponding time series, which made it possible to evaluate the features of simple and complex anomalies from unified positions. Results. A spectral method for the analysis of contextual anomalies of time series has been developed, which, in contrast to the known spectral methods involving frequency analysis of time series, uses a special basis of exponential functions; the methodology for calculating the spectral coefficients of the investigated time series, on the basis of which a generalized attribute is calculated, allowing to attribute the investigated case to a normal or anomalous group, is outlined. Conclusion. The proposed method of estimating the residual life of complex technical systems based on the analysis of time series anomalies allows timely detection of the occurrence and development of degradation processes leading to the occurrence of failures, which increases the reliability and safety of technical systems, as well as reduces costs and time for their maintenance.

Spatial enrichment and genomic analyses reveal the link of NOMO1 with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease with uncertain genetic predisposition in most sporadic cases. The spatial architecture of cell types and gene expression are the basis of cell-cell interactions, biological function and disease pathology, but are not well investigated in the human motor cortex, a key ALS-relevant brain region. Recent studies indicated single nucleus transcriptomic features of motor neuron vulnerability in ALS motor cortex. However, the brain regional vulnerability of ALS-associated genes and the genetic link between region-specific genes and ALS risk remain largely unclear. Here, we developed an entropy-weighted differential gene expression matrix-based tool (SpatialE) to identify the spatial enrichment of gene sets in spatial transcriptomics. We benchmarked SpatialE against another enrichment tool (multimodal intersection analysis) using spatial transcriptomics data from both human and mouse brain tissues. To investigate regional vulnerability, we analysed three human motor cortex and two dorsolateral prefrontal cortex tissues for spatial enrichment of ALS-associated genes. We also used Cell2location to estimate the abundance of cell types in ALS-related cortex layers. To dissect the link of regionally expressed genes and ALS risk, we performed burden analyses of rare loss-of-function variants detected by whole-genome sequencing in ALS patients and controls, then analysed differential gene expression in the TargetALS RNA-sequencing dataset. SpatialE showed more accurate and specific spatial enrichment of regional cell type markers than multimodal intersection analysis in both mouse brain and human dorsolateral prefrontal cortex. Spatial transcriptomic analyses of human motor cortex showed heterogeneous cell types and spatial gene expression profiles. We found that 260 manually curated ALS-associated genes are significantly enriched in layer 5 of the motor cortex, with abundant expression of upper motor neurons and layer 5 excitatory neurons. Burden analyses of rare loss-of-function variants in Layer 5-associated genes nominated NOMO1 as a novel ALS-associated gene in a combined sample set of 6814 ALS patients and 3324 controls (P = 0.029). Gene expression analyses in CNS tissues revealed downregulation of NOMO1 in ALS, which is consistent with a loss-of-function disease mechanism. In conclusion, our integrated spatial transcriptomics and genomic analyses identified regional brain vulnerability in ALS and the association of a layer 5 gene (NOMO1) with ALS risk.

Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization

The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive intracellular signaling. Pharmacologically, mGluRs can be targeted at the LBDs by glutamate and synthetic orthosteric compounds or at the TMDs by allosteric modulators. Despite the potential of allosteric compounds as therapeutics, an understanding of the functional and structural basis of their effects is limited. Here we use multiple approaches to dissect the functional and structural effects of orthosteric versus allosteric ligands. We find, using electrophysiological and live cell imaging assays, that both agonists and positive allosteric modulators (PAMs) can drive activation and internalization of group II and III mGluRs. The effects of PAMs are pleiotropic, boosting the maximal response to orthosteric agonists and serving independently as internalization-biased agonists across mGluR subtypes. Motivated by this and intersubunit FRET analyses, we determine cryo-electron microscopy structures of mGluR3 in the presence of either an agonist or antagonist alone or in combination with a PAM. These structures reveal PAM-driven re-shaping of intra- and inter-subunit conformations and provide evidence for a rolling TMD dimer interface activation pathway that controls G protein and beta-arrestin coupling.

Lenvatinib targets STAT-1 to enhance the M1 polarization of TAMs during hepatocellular carcinoma progression

Lenvatinib, a multitarget kinase inhibitor, has been proven to be effective in the treatment of advanced hepatocellular carcinoma. It has been previously demonstrated that tumour associated macrophages (TAMs) in tumour tissues can promote HCC growth, invasion and metastasis. Furthermore, lenvatinib has certain immunomodulatory effects on the treatment of HCC. However, the role of lenvatinib in macrophage polarization during HCC treatment has not been fully explored. In this study, we used a variety of experimental methods both in vitro and in vivo to investigate the effect of lenvatinib on TAMs during HCC progression. This study is the first to show that lenvatinib can alter macrophage polarization in both humans and mice. Moreover, macrophages treated with lenvatinib in vitro displayed enhanced classically activated macrophages (M1) activity and suppressed liver cancer cell proliferation, invasion, and migration. Furthermore, during the progression of M1 macrophage polarization induced by lenvatinib, STAT-1 was the main target transcription factor, and inhibiting STAT-1 activity reversed the effect of lenvatinib. Overall, the present study provides a theoretical basis for the immunomodulatory function of lenvatinib in the treatment of HCC.

QUALITY ASSESSMENT OF THE SOFTWARE DEVELOPMENT PROCESS OF AN IT COMPANY BASED ON THE USE OF THE UTILITY FUNCTION

The paper considers the software development process as an object of research, which is a poorly structured system. A description of such systems is given in the form of general characteristics, which include: difficulties in building an analytical model; incompleteness, inaccuracy, unreliability and uncertainty of information; benchmarks required for assessing weakly structured systems are often absent; uniqueness of the decision-making process; dynamic nature of models of poorly structured systems, etc. In this paper, the quality assessment of the software development process is considered based on maturity model standards, which can have continuous and discrete variants. The continuous version assesses the quality of the individual focus areas and processes of the maturity models. For this purpose, a discrete point scale of the first type is used, when the assessment is carried out according to an objective criterion. The quality assessment of individual focus areas and processes characterizes the local criteria for assessing the quality of the entire software development process. Therefore, the task is to form some kind of integral quality assessment on their basis. One of the options for solving this problem is a discrete maturity model, where the scale for assessing the entire software development process has five gradations called maturity levels. Starting from the second level, each gradation is characterized by a set of focus areas with corresponding levels of capability. The availability of such a scale allows not only assessing the quality of the entire software development process, but also solving the task of planning to improve its quality. But first, it is necessary to analyse such a scale from the point of view of its balance, namely, that the distances on the scale between the gradations are approximately equal. Therefore, the paper analyses the existing scales that can be proposed for expert assessment for the quality of the software development process. Their construction can be realized on the basis of a utility function using the local criteria of maturity models formalized in this paper. For this purpose, a fundamental property of systems is used. Namely, the dependence of the utility (efficiency) of a complex system on the invested resources over the life cycle interval, which usually takes the form of a logistic curve. Further research will be devoted to using this fact to build a balanced scale for assessing the entire software development process based on maturity models.

Spline-based methods for functional data on multivariate domains

Functional data analysis is typically performed in two steps: first, functionally representing discrete observations, and then applying functional methods to the so-represented data. The initial choice of a functional representation may have a significant impact on the second phase of the analysis, as shown in recent research, where data-driven spline bases outperformed the predefined rigid choice of functional representation. The method chooses an initial functional basis by an efficient placement of the knots using a simple machine-learning algorithm. The knot selection approach does not apply directly when the data are defined on domains of a higher dimension than one such as, for example, images. The reason is that in higher dimensions the convenient and numerically efficient spline spaces use tensor bases that require knots located on a lattice. This fundamentally limits flexible knot placement which is fundamental for the approach. The goal of this research is two-fold: first, to propose modified approaches that circumvent the issue by coding the irregular knot selection into the topology of the spaces of tensor-based splines; second, to apply the approach to a classification problem workflow for functional data that utilizes knot selection. The performance is preliminarily accessed on a benchmark dataset and shown to be comparable to or better than the previous methods.

Specialization restricts the evolutionary paths available to yeast sugar transporters.

Functional innovation at the protein level is a key source of evolutionary novelties. The constraints on functional innovations are likely to be highly specific in different proteins, which are shaped by their unique histories and the extent of global epistasis that arises from their structures and biochemistries. These contextual nuances in the sequence-function relationship have implications both for a basic understanding of the evolutionary process and for engineering proteins with desirable properties. Here, we have investigated the molecular basis of novel function in a model member of an ancient, conserved, and biotechnologically relevant protein family. These Major Facilitator Superfamily sugar porters are a functionally diverse group of proteins that are thought to be highly plastic and evolvable. By dissecting a recent evolutionary innovation in an α-glucoside transporter from the yeast Saccharomyces eubayanus, we show that the ability to transport a novel substrate requires high-order interactions between many protein regions and numerous specific residues proximal to the transport channel. To reconcile the functional diversity of this family with the constrained evolution of this model protein, we generated new, state-of-the-art genome annotations for 332 Saccharomycotina yeast species spanning approximately 400 million years of evolution. By integrating phylogenetic and phenotypic analyses across these species, we show that the model yeast α-glucoside transporters likely evolved from a multifunctional ancestor and became subfunctionalized. The accumulation of additive and epistatic substitutions likely entrenched this subfunction, which made the simultaneous acquisition of multiple interacting substitutions the only reasonably accessible path to novelty.

Transcriptional, developmental, and functional parallels of lymphatic and venous smooth muscle.

Lymphatic muscle cells (LMCs) are indispensable for lymphatic vessel contraction and their aberrant recruitment or absence is associated with both primary and secondary lymphedema. Despite their critical role in lymphatic vessel function, the transcriptomic and developmental basis that confer the unique contractile properties to LMCs are largely undefined. In this study, we employed single-cell RNA sequencing (scRNAseq), lineage tracing and in vivo imaging to investigate the basis for the hybrid cardiomyocyte and blood vascular smooth muscle cell (SMC) characteristics that have been described for LMCs. Using scRNAseq, the transcriptomes of LMC and venous SMCs from the murine hindlimb exhibited more similarities than differences, although both were markedly distinct from that of arteriole SMCs in the same tissue. Functionally, both lymphatic vessels and blood vessels in the murine hindlimb displayed pulsatile contractility. However, despite expressing genes that overlap with the venous SMC transcriptome, through lineage tracing we show that LMCs do not originate from Myh11+ SMC progenitors. Previous studies have shown that LMCs express cardiac-related genes, whereas in our study we found that arteriole SMCs, but not LMCs, expressed cardiac-related genes. Through lineage tracing, we demonstrate that a subpopulation of LMCs and SMCs originate from WT1+ mesodermal progenitors, which are known to give rise to SMCs. LMCs, however, do not derive from Nkx2.5+ cardiomyocyte progenitors. Overall, our findings suggest that venous SMCs and LMCs and may derive from a related mesodermal progenitor and adopt a similar gene expression program that enable their contractile properties.

Functional traits and ecological niches as correlates of the interspecific growth–mortality trade‐off among seedlings of 14 tropical tree species

Abstract The interspecific trade‐off between growth versus mortality rates of tree species is thought to be driven by functional biology and to contribute to species ecological niche differentiation. Yet, functional trait variation is often not strongly correlated with growth and mortality, and few studies have investigated the relationships of both traits and niches, specifically encompassing above and belowground resources, to the trade‐off itself. These relationships are particularly relevant for seedlings, which must often survive resource limitation to reach larger size classes. We investigated the functional basis of the interspecific growth–mortality trade‐off and its relationship with ecological niches for seedlings of 14 tree species in a tropical forest in southwest China. We found evidence for an interspecific growth–mortality trade‐off at the seedling stage using 15 functional traits and 15 ecological niche variables. None of the organ‐level traits correlated with growth, mortality, nor the trade‐off, whereas specific stem length (SSL), a biomass allocation trait, was the only trait to have a significant correlation (positive). Moreover, light‐defined niches were not correlated with growth, mortality or the trade‐off, but soil‐defined niches did. Species at the faster growth/higher mortality end of the trade‐off were associated with higher fertility defined by lower soil bulk density and slope, and higher soil organic matter concentration and soil total nitrogen. Our findings indicate the importance of stem elongation and soil fertility for growth, mortality and their trade‐off at the seedling stage in this Asian tropical forest. Our findings contrast with analogous studies in neotropical forests showing the importance of photosynthesis‐related leaf traits related to insolation. Therefore, the functional drivers of demographic rates and trade‐offs, as well as their consequences for ecological niches, can vary among forests, likely owing to differences in biogeography, canopy disturbance rates, topography and soil properties. Moreover, the effects of functional trait variation on demographic rates and trade‐offs may be better revealed when biomass allocation is accounted for in a whole‐plant context. Read the free Plain Language Summary for this article on the Journal blog.

Autonomous multiple‐trolley collection system with nonholonomic robots: Design, control, and implementation

AbstractThe task of collecting and transporting luggage trolleys in airports, characterized by its complexity within dynamic public environments, presents both an ongoing challenge and a promising opportunity for automated service robots. Previous research has primarily developed on universal platforms with robot arms or focused on handling a single trolley, creating a gap in providing cost‐effective and efficient solutions for practical scenarios. In this paper, we propose a low‐cost mobile manipulation robot incorporated with an autonomy framework for the collection and transportation of multiple trolleys that can significantly enhance operational efficiency. The method involves a novel design of the mechanical system and a vision‐based control strategy. We design a lightweight manipulator and the docking mechanism, optimized for the sequential stacking and transportation of trolleys. On the basis of the Control Lyapunov Function and Control Barrier Function, we propose a vision‐based controller with online Quadratic Programming, which improves the docking accuracy. The practical application of our system is demonstrated in real‐world scenarios, where it successfully executes the multiple‐trolley collection task.