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Interaction network resilience can be defined as the ability of interacting organisms to maintain their functions, processes or populations after experiencing a disturbance. Studies on mutualistic interactions between plants and pollinators along environmental gradients are essential to understand the provision of ecosystem services and the mechanisms challenging their network resilience. However, it remains unknown to what level ecological changes along climatic gradients constrain the network resilience of mutualistic organisms, especially along elevation gradients. We surveyed bee species and recorded their interactions with plants throughout the four major seasons (i.e. long and short rainy, and long and short dry) on 50 study sites positioned along an elevation gradient (525 m to 2,530 m asl) in the Eastern Afromontane Biodiversity Hotspots in Kenya, East Africa. We calculated bee and plant network resilience using the network resilience parameter (βeff) and assessed changes in bee and plant network resilience along the elevation gradient using generalised additive models (gams). We quantified the effects of climate, bee and plant diversity, bee functional traits, network structure, and landscape configuration on bee and plant network resilience using a set of multi-model inference frameworks followed by structural equation models (SEM). We found that bee and plant species exhibited higher levels of network resilience at higher elevations. While bee network resilience increased linearly across the elevation gradient, plant network resilience increased exponentially from ∼1500 m and higher. Bee and plant network resilience increased in areas with reduced mean annual temperature (MAT) and decreased in areas with lower mean annual precipitation (MAP). Our SEM model showed that increasing temperatures indirectly influenced plant network resilience via network modularity and community assemblage of bees. We also found that MAP had a direct positive effect on plant diversity and network resilience, while the fragmentation of habitats reduced richness of plant communities and enhanced network modularity. In conclusion, we revealed that mutualistic networks showed higher network resilience at higher elevations. We also unveiled that climate and habitat fragmentation directly or indirectly influences the network resilience of plants and bees via the modulation of community assemblages and interaction networks. These influences are lower at higher elevations such that these systems seem better able to buffer against extinction cascades. We thus suggest that, management efforts should be geared at consolidating natural habitats. In contrast, restoration efforts should aim at mitigating climate change effects and harnessing the ability of mutualists to reconnect broken links to improve the network resilience and functioning of East-African montane ecosystems.

As large language models (LLMs) have become more deeply integrated into various sectors, understanding how they make moral judgements has become crucial, particularly in the realm of autonomous driving. This study used the moral machine framework to investigate the ethical decision-making tendencies of prominent LLMs, including GPT-3.5, GPT-4, PaLM 2 and Llama 2, to compare their responses with human preferences. While LLMs' and humans' preferences such as prioritizing humans over pets and favouring saving more lives are broadly aligned, PaLM 2 and Llama 2, especially, evidence distinct deviations. Additionally, despite the qualitative similarities between the LLM and human preferences, there are significant quantitative disparities, suggesting that LLMs might lean toward more uncompromising decisions, compared with the milder inclinations of humans. These insights elucidate the ethical frameworks of LLMs and their potential implications for autonomous driving.

Although ChatGPT promises wide-ranging applications, there is a concern that it is politically biased; in particular, that it has a left-libertarian orientation. Nevertheless, following recent trends in attempts to reduce such biases, this study re-evaluated the political biases of ChatGPT using political orientation tests and the application programming interface. The effects of the languages used in the system as well as gender and race settings were evaluated. The results indicate that ChatGPT manifests less political bias than previously assumed; however, they did not entirely dismiss the political bias. The languages used in the system, and the gender and race settings may induce political biases. These findings enhance our understanding of the political biases of ChatGPT and may be useful for bias evaluation and designing the operational strategy of ChatGPT.

Large Language Models (LLMs), such as ChatGPT, encounter ‘jailbreak’ challenges, wherein safeguards are circumvented to generate ethically harmful prompts. This study introduces a straightforward black-box method for efficiently crafting jailbreak prompts that bypass LLM defenses. Our technique iteratively transforms harmful prompts into benign expressions directly utilizing the target LLM, predicated on the hypothesis that LLMs can autonomously generate expressions that evade safeguards. Through experiments conducted with ChatGPT (GPT-3.5 and GPT-4) and Gemini-Pro, our method consistently achieved an attack success rate exceeding 80% within an average of five iterations for forbidden questions and proved to be robust against model updates. The jailbreak prompts generated were not only naturally worded and succinct, but also challenging to defend against. These findings suggest that the creation of effective jailbreak prompts is less complex than previously believed, underscoring the heightened risk posed by black-box jailbreak attacks.

Abstract Background Deep neural networks (DNNs) are widely investigated in medical image classification to achieve automated support for clinical diagnosis. It is necessary to evaluate the robustness of medical DNN tasks against adversarial attacks, as high-stake decision-making will be made based on the diagnosis. Several previous studies have considered simple adversarial attacks. However, the vulnerability of DNNs to more realistic and higher risk attacks, such as universal adversarial perturbation (UAP), which is a single perturbation that can induce DNN failure in most classification tasks has not been evaluated yet. Methods We focus on three representative DNN-based medical image classification tasks (i.e., skin cancer, referable diabetic retinopathy, and pneumonia classifications) and investigate their vulnerability to the seven model architectures of UAPs. Results We demonstrate that DNNs are vulnerable to both nontargeted UAPs, which cause a task failure resulting in an input being assigned an incorrect class, and to targeted UAPs, which cause the DNN to classify an input into a specific class. The almost imperceptible UAPs achieved > 80% success rates for nontargeted and targeted attacks. The vulnerability to UAPs depended very little on the model architecture. Moreover, we discovered that adversarial retraining, which is known to be an effective method for adversarial defenses, increased DNNs’ robustness against UAPs in only very few cases. Conclusion Unlike previous assumptions, the results indicate that DNN-based clinical diagnosis is easier to deceive because of adversarial attacks. Adversaries can cause failed diagnoses at lower costs (e.g., without consideration of data distribution); moreover, they can affect the diagnosis. The effects of adversarial defenses may not be limited. Our findings emphasize that more careful consideration is required in developing DNNs for medical imaging and their practical applications.

Voter model dynamics in complex networks are vulnerable to adversarial attacks. In particular, the voting outcome can be inverted by adding extremely small perturbations that are strategically generated in social networks, even when one opinion is dominant over the other. However, the mitigation of adversarial attacks on the voter model dynamics in complex networks has not been thoroughly investigated. Thus, we examined network structures that could mitigate adversarial attacks using model networks and real-world networks, considering that the network structure affects the voter model dynamics. Numerical simulations demonstrated that the heterogeneity of node degrees in the networks (degree heterogeneity) significantly mitigates adversarial attacks. In particular, for complex networks with a power-law degree distribution $P(k)\sim k^{-\gamma}$ , the mitigation effect is significant for $\gamma \leqslant 3$ . However, the mitigation effect of the degree heterogeneity was relatively weak for large and dense networks. The degree correlation and clustering in the networks exhibited almost no mitigation effect. The results enhance our understanding of how opinion dynamics and collective decision-making are distorted in social networks and may be useful for considering defense strategies against adversarial attacks.

Backdoor attacks are a serious security threat to open-source and outsourced development of computational systems based on deep neural networks (DNNs). In particular, the transferability of backdoors is remarkable; that is, they can remain effective after transfer learning is performed. Given that transfer learning from natural images is widely used in real-world applications, the question of whether backdoors can be transferred from neural models pretrained on natural images involves considerable security implications. However, this topic has not been evaluated rigorously in prior studies. Hence, in this study, we configured backdoors in 10 representative DNN models pretrained on a natural image dataset, and then fine-tuned the backdoored models via transfer learning for four real-world applications, including pneumonia classification from chest X-ray images, emergency response monitoring from aerial images, facial recognition, and age classification from images of faces. Our experimental results show that the backdoors generally remained effective after transfer learning from natural images, except for small DNN models. Moreover, the backdoors were difficult to detect using a common method. Our findings indicate that backdoor attacks can exhibit remarkable transferability in more realistic transfer learning processes, and highlight the need for the development of more advanced security countermeasures in developing systems using DNN models for sensitive or mission-critical applications.

Abstract Background Co-occurrence networks—ecological associations between sampled populations of microbial communities inferred from taxonomic composition data obtained from high-throughput sequencing techniques—are widely used in microbial ecology. Several co-occurrence network methods have been proposed. Co-occurrence network methods only infer ecological associations and are often used to discuss species interactions. However, validity of this application of co-occurrence network methods is currently debated. In particular, they simply evaluate using parametric statistical models, even though microbial compositions are determined through population dynamics. Results We comprehensively evaluated the validity of common methods for inferring microbial ecological networks through realistic simulations. We evaluated how correctly nine widely used methods describe interaction patterns in ecological communities. Contrary to previous studies, the performance of the co-occurrence network methods on compositional data was almost equal to or less than that of classical methods (e.g., Pearson’s correlation). The methods described the interaction patterns in dense and/or heterogeneous networks rather inadequately. Co-occurrence network performance also depended upon interaction types; specifically, the interaction patterns in competitive communities were relatively accurately predicted while those in predator–prey (parasitic) communities were relatively inadequately predicted. Conclusions Our findings indicated that co-occurrence network approaches may be insufficient in interpreting species interactions in microbiome studies. However, the results do not diminish the importance of these approaches. Rather, they highlight the need for further careful evaluation of the validity of these much-used methods and the development of more suitable methods for inferring microbial ecological networks.

Background Although structural correlation network (SCN) analysis is an approach to evaluate brain networks, the neurobiological interpretation of SCNs is still problematic. Brain-derived neurotrophic factor (BDNF) is well-established as a representative protein related to neuronal differentiation, maturation, and survival. Since a valine-to-methionine substitution at codon 66 of the BDNF gene (BDNF Val66Met single nucleotide polymorphism (SNP)) is well-known to have effects on brain structure and function, we hypothesized that SCNs are affected by the BDNF Val66Met SNP. To gain insight into SCN analysis, we investigated potential differences between BDNF valine (Val) homozygotes and methionine (Met) carriers in the organization of their SCNs derived from inter-regional cortical thickness correlations. Methods Forty-nine healthy adult subjects (mean age = 41.1 years old) were divided into two groups according to their genotype (n: Val homozygotes = 16, Met carriers = 33). We obtained regional cortical thickness from their brain T1 weighted images. Based on the inter-regional cortical thickness correlations, we generated SCNs and used graph theoretical measures to assess differences between the two groups in terms of network integration, segregation, and modularity. Results The average local efficiency, a measure of network segregation, of BDNF Met carriers’ network was significantly higher than that of the Val homozygotes’ (permutation p-value = 0.002). Average shortest path lengths (a measure of integration), average local clustering coefficient (another measure of network segregation), small-worldness (a balance between integration and segregation), and modularity (a representative measure for modular architecture) were not significantly different between group (permutation p-values ≧ 0.01). Discussion and Conclusion Our results suggest that the BDNF Val66Met polymorphism may potentially influence the pattern of brain regional morphometric (cortical thickness) correlations. Comparing networks derived from inter-regional cortical thickness correlations, Met carrier SCNs have denser connections with neighbors and are more distant from random networks than Val homozygote networks. Thus, it may be necessary to consider potential effects of BDNF gene mutations in SCN analyses. This is the first study to demonstrate a difference between Val homozygotes and Met carriers in brain SCNs.

The absence of genome complexity in prokaryotes, being the evolutionary precursors to eukaryotic cells comprising all complex life (the prokaryote–eukaryote divide), is a long-standing question in evolutionary biology. A previous study hypothesized that the divide exists because prokaryotic genome size is constrained by bioenergetics (prokaryotic power per gene or genome being significantly lower than eukaryotic ones). However, this hypothesis was evaluated using a relatively small dataset due to lack of data availability at the time, and is therefore controversial. Accordingly, we constructed a larger dataset of genomes, metabolic rates, cell sizes and ploidy levels to investigate whether an energetic barrier to genome complexity exists between eukaryotes and prokaryotes while statistically controlling for the confounding effects of cell size and phylogenetic signals. Notably, we showed that the differences in bioenergetics between prokaryotes and eukaryotes were less significant than those previously reported. More importantly, we found a limited contribution of power per genome and power per gene to the prokaryote–eukaryote dichotomy. Our findings indicate that the prokaryote–eukaryote divide is hard to explain from the energetic perspective. However, our findings may not entirely discount the traditional hypothesis; in contrast, they indicate the need for more careful examination.

Universal adversarial attacks, which hinder most deep neural network (DNN) tasks using only a single perturbation called universal adversarial perturbation (UAP), are a realistic security threat to the practical application of a DNN for medical imaging. Given that computer-based systems are generally operated under a black-box condition in which only input queries are allowed and outputs are accessible, the impact of UAPs seems to be limited because well-used algorithms for generating UAPs are limited to white-box conditions in which adversaries can access model parameters. Nevertheless, we propose a method for generating UAPs using a simple hill-climbing search based only on DNN outputs to demonstrate that UAPs are easily generatable using a relatively small dataset under black-box conditions with representative DNN-based medical image classifications. Black-box UAPs can be used to conduct both nontargeted and targeted attacks. Overall, the black-box UAPs showed high attack success rates (40–90%). The vulnerability of the black-box UAPs was observed in several model architectures. The results indicate that adversaries can also generate UAPs through a simple procedure under the black-box condition to foil or control diagnostic medical imaging systems based on DNNs, and that UAPs are a more serious security threat.

Open-source deep neural networks (DNNs) for medical imaging are significant in emergent situations, such as during the pandemic of the 2019 novel coronavirus disease (COVID-19), since they accelerate the development of high-performance DNN-based systems. However, adversarial attacks are not negligible during open-source development. Since DNNs are used as computer-aided systems for COVID-19 screening from radiography images, we investigated the vulnerability of the COVID-Net model, a representative open-source DNN for COVID-19 detection from chest X-ray images to backdoor attacks that modify DNN models and cause their misclassification when a specific trigger input is added. The results showed that backdoors for both non-targeted attacks, for which DNNs classify inputs into incorrect labels, and targeted attacks, for which DNNs classify inputs into a specific target class, could be established in the COVID-Net model using a small trigger and small fraction of training data. Moreover, the backdoors were effective for models fine-tuned from the backdoored COVID-Net models, although the performance of non-targeted attacks was limited. This indicated that backdoored models could be spread via fine-tuning (thereby becoming a significant security threat). The findings showed that emphasis is required on open-source development and practical applications of DNNs for COVID-19 detection.

Abstract Background Host–pathogen interactions are important in a wide range of research fields. Given the importance of metabolic crosstalk between hosts and pathogens, a metabolic network-based reverse ecology method was proposed to infer these interactions. However, the validity of this method remains unclear because of the various explanations presented and the influence of potentially confounding factors that have thus far been neglected. Results We re-evaluated the importance of the reverse ecology method for evaluating host–pathogen interactions while statistically controlling for confounding effects using oxygen requirement, genome, metabolic network, and phylogeny data. Our data analyses showed that host–pathogen interactions were more strongly influenced by genome size, primary network parameters (e.g., number of edges), oxygen requirement, and phylogeny than the reserve ecology-based measures. Conclusion These results indicate the limitations of the reverse ecology method; however, they do not discount the importance of adopting reverse ecology approaches altogether. Rather, we highlight the need for developing more suitable methods for inferring host–pathogen interactions and conducting more careful examinations of the relationships between metabolic networks and host–pathogen interactions.

Owing the epidemic of the novel coronavirus disease 2019 (COVID-19), chest X-ray computed tomography imaging is being used for effectively screening COVID-19 patients. The development of computer-aided systems based on deep neural networks (DNNs) has become an advanced open source to rapidly and accurately detect COVID-19 cases because the need for expert radiologists, who are limited in number, forms a bottleneck for screening. However, thus far, the vulnerability of DNN-based systems has been poorly evaluated, although realistic and high-risk attacks using universal adversarial perturbation (UAP), a single (input image agnostic) perturbation that can induce DNN failure in most classification tasks, are available. Thus, we focus on representative DNN models for detecting COVID-19 cases from chest X-ray images and evaluate their vulnerability to UAPs. We consider non-targeted UAPs, which cause a task failure, resulting in an input being assigned an incorrect label, and targeted UAPs, which cause the DNN to classify an input into a specific class. The results demonstrate that the models are vulnerable to non-targeted and targeted UAPs, even in the case of small UAPs. In particular, the 2% norm of the UAPs to the average norm of an image in the image dataset achieves >85% and >90% success rates for the non-targeted and targeted attacks, respectively. Owing to the non-targeted UAPs, the DNN models judge most chest X-ray images as COVID-19 cases. The targeted UAPs allow the DNN models to classify most chest X-ray images into a specified target class. The results indicate that careful consideration is required in practical applications of DNNs to COVID-19 diagnosis; in particular, they emphasize the need for strategies to address security concerns. As an example, we show that iterative fine-tuning of DNN models using UAPs improves the robustness of DNN models against UAPs.

Understanding global soil bacterial diversity is important because of its role in maintaining a healthy global ecosystem. Given the effects of environmental changes (e.g., warming and human impact) on the diversity of animals and plants, effects on soil bacterial diversity are expected; however, they have been poorly evaluated at the global scale to date. Thus, in this study, we focused on the dominant soil bacteria, which are likely critical drivers of key soil processes worldwide, and investigated the effects of warming velocity and human activities on their diversity. Using a global dataset of bacteria, we performed spatial analysis to evaluate the effects of warming velocity and human activities, while statistically controlling for the potentially confounding effects of current climate and geographic parameters with global climate and geographic data. We demonstrated that the diversity of the dominant soil bacteria was influenced globally, not only by the aridity index (dryness) and pH but also by warming velocity from the Last Glacial Maximum (21,000 years ago) to the present, showing significant increases. The increase in bacterial diversity with warming velocity was particularly significant in forests and grasslands. An effect of human activity was also observed, but it was secondary to warming velocity. These findings provide robust evidence and advance our understanding of the effects of environmental changes (particularly global warming) on soil bacterial diversity at the global scale.

Deep neural networks (DNNs) are vulnerable to adversarial attacks. In particular, a single perturbation known as the universal adversarial perturbation (UAP) can foil most classification tasks conducted by DNNs. Thus, different methods for generating UAPs are required to fully evaluate the vulnerability of DNNs. A realistic evaluation would be with cases that consider targeted attacks; wherein the generated UAP causes the DNN to classify an input into a specific class. However, the development of UAPs for targeted attacks has largely fallen behind that of UAPs for non-targeted attacks. Therefore, we propose a simple iterative method to generate UAPs for targeted attacks. Our method combines the simple iterative method for generating non-targeted UAPs and the fast gradient sign method for generating a targeted adversarial perturbation for an input. We applied the proposed method to state-of-the-art DNN models for image classification and proved the existence of almost imperceptible UAPs for targeted attacks; further, we demonstrated that such UAPs can be easily generated.

Body-size relationships between predators and their prey are important in ecological studies because they reflect the structure and function of food webs. Inspired by studies on the impact of global warming on food webs, the effects of temperature on body-size relationships have been widely investigated; however, the impact of environmental factors on body-size relationships has not been fully evaluated because climate warming affects various ocean environments. Thus, here, we comprehensively investigated the effects of ocean environments and predator–prey body-size relationships by integrating a large-scale dataset of predator–prey body-size relationships in marine food webs with global oceanographic data. We showed that various oceanographic parameters influence prey size selection. In particular, oxygen concentration, primary production and salinity, in addition to temperature, significantly alter body-size relationships. Furthermore, we demonstrated that variability (seasonality) of ocean environments significantly affects body-size relationships. The effects of ocean environments on body-size relationships were generally remarkable for small body sizes, but were also significant for large body sizes and were relatively weak for intermediate body sizes, in the cases of temperature seasonality, oxygen concentration and salinity variability. These findings break down the complex effects of ocean environments on body-size relationships, advancing our understanding of how ocean environments influence the structure and functioning of food webs.

It is theorized that a mutualistic ecosystem's resilience against perturbations (e.g. species extinction) is determined by a single macroscopic parameter (network resilience), calculable from the network. Given that such perturbations occur owing to environmental changes (e.g. climate change and human impact), it has been predicted that mutualistic ecosystems that exist despite extensive environmental changes exhibit higher network resilience; however, such a prediction has not been confirmed using real-world data. Thus, in this study, the effects of climate change velocity and human activities on mutualistic network resilience were investigated. A global dataset of plant–animal mutualistic networks was used, and spatial analysis was performed to examine the effects. Moreover, the potential confounding effects of network size, current climate and altitude were statistically controlled. It was demonstrated that mutualistic network resilience was globally influenced by warming velocity and human impact, in addition to current climate. Specifically, pollination network resilience increased in response to human impact, and seed-dispersal network resilience increased with warming velocity. The effect of environmental changes on network resilience for plants was remarkable. The results confirmed the prediction obtained based on the theory and imply that real-world mutualistic networks have a structure that increases ecosystem resilience against environmental changes. These findings will enhance the understanding of ecosystem resilience.

Oxygen is thought to promote species and biomolecule diversity. Previous studies have suggested that oxygen expands metabolic networks by acquiring metabolites with different chemical properties (higher hydrophobicity, for example). However, such conclusions are typically based on biased evaluation, and are therefore non-conclusive. Thus, we re-investigated the effect of oxygen on metabolic evolution using a phylogenetic comparative method and metadata analysis to reduce the bias as much as possible. Notably, we found no difference in metabolic network expansion between aerobes and anaerobes when evaluating phylogenetic relationships. Furthermore, we showed that previous studies have overestimated or underestimated the degrees of differences in the chemical properties (e.g., hydrophobicity) between oxic and anoxic metabolites in metabolic networks of unicellular organisms; however, such overestimation was not observed when considering the metabolic networks of multicellular organisms. These findings indicate that the contribution of oxygen to increased chemical diversity in metabolic networks is lower than previously thought; rather, phylogenetic signals and cell-cell communication result in increased chemical diversity. However, this conclusion does not contradict the effect of oxygen on metabolic evolution; instead, it provides a deeper understanding of how oxygen contributes to metabolic evolution despite several limitations in data analysis methods.

Factors determining habitat variability are poorly understood despite possible explanations based on genome and physiology. This is because previous studies only focused on primary measures such as genome size and body size. In this study, we hypothesize that specific gene functions determine habitat variability in order to explore new factors beyond primary measures. We comprehensively evaluate the relationship between gene functions and the climate envelope while statistically controlling for potentially confounding effects by using data on the habitat range, genome, body size and metabolism of various mammals. Our analyses show that the number of proteins and RNAs contained in exosomes is predominantly associated with the climate envelope. This finding indicates the importance of exosomes to habitat range expansion of mammals and provides a new hypothesis for the relationship between the genome and habitat variability.

Formation and adaptation of metabolic networks has been a long-standing question in biology. With recent developments in biotechnology and bioinformatics, the understanding of metabolism is progressively becoming clearer from a network perspective. This review introduces the comprehensive metabolic world that has been revealed by a wide range of data analyses and theoretical studies; in particular, it illustrates the role of evolutionary events, such as gene duplication and horizontal gene transfer, and environmental factors, such as nutrient availability and growth conditions, in evolution of the metabolic network. Furthermore, the mathematical models for the formation and adaptation of metabolic networks have also been described, according to the current understanding from a perspective of metabolic networks. These recent findings are helpful in not only understanding the formation of metabolic networks and their adaptation, but also metabolic engineering.

Network controllability is an important topic in wide-ranging research fields. However, the relationship between controllability and network structure is poorly understood, although degree heterogeneity is known to determine the controllability. We focus on the size of a minimum dominating set (MDS), a measure of network controllability, and investigate the effect of degree-degree correlation, which is universally observed in real-world networks, on the size of an MDS. We show that disassortativity or negative degree-degree correlation reduces the size of an MDS using analytical treatments and numerical simulation, whereas positive correlations hardly affect the size of an MDS. This result suggests that disassortativity enhances network controllability. Furthermore, apart from the controllability issue, the developed techniques provide new ways of analyzing complex networks with degree-degree correlations.

Theoretical studies have indicated that nestedness and modularity-non-random structural patterns of ecological networks-influence the stability of ecosystems against perturbations; as such, climate change and human activity, as well as other sources of environmental perturbations, affect the nestedness and modularity of ecological networks. However, the effects of climate change and human activities on ecological networks are poorly understood. Here, we used a spatial analysis approach to examine the effects of climate change and human activities on the structural patterns of food webs and mutualistic networks, and found that ecological network structure is globally affected by climate change and human impacts, in addition to current climate. In pollination networks, for instance, nestedness increased and modularity decreased in response to increased human impacts. Modularity in seed-dispersal networks decreased with temperature change (i.e., warming), whereas food web nestedness increased and modularity declined in response to global warming. Although our findings are preliminary owing to data-analysis limitations, they enhance our understanding of the effects of environmental change on ecological communities.

Elucidation of tumour suppression mechanisms is a major challenge in cancer biology. Therefore, Peto's paradox, or low cancer incidence in large animals, has attracted focus. According to the gene-abundance hypothesis, which considers the increase/decrease in cancer-related genes with body size, researchers evaluated the associations between gene abundance and body size. However, previous studies only focused on a few specific gene functions and have ignored the alternative hypothesis (metabolic rate hypothesis): in this hypothesis, the cellular metabolic rate and subsequent oxidative stress decreases with increasing body size. In this study, we have elected to explore the gene-abundance hypothesis taking into account the metabolic rate hypothesis. Thus, we comprehensively investigated the correlation between the number of genes in various functional categories and body size while at the same time correcting for the mass-specific metabolic rate (Bc). A number of gene functions that correlated with body size were initially identified, but they were found to be artefactual due to the decrease in Bc with increasing body size. By contrast, immune system-related genes were found to increase with increasing body size when the correlation included this correction for Bc. These findings support the gene-abundance hypothesis and emphasize the importance of also taking into account the metabolic rate when evaluating gene abundance–body size relationships. This finding may be useful for understanding cancer evolution and tumour suppression mechanisms as well as for determining cancer-related genes and functions.

In this study, the metabolic and physiological potential evaluator system based on Kyoto Encyclopedia of Genes and Genomes (KEGG) functional modules was employed to establish a functional classification of archaeal species and to determine the comprehensive functions (functionome) of the previously uncultivated thermophile "Candidatus Caldiarchaeum subterraneum" (Ca. C. subterraneum). A phylogenetic analysis based on the concatenated sequences of proteins common among 142 archaea and 2 bacteria, and among 137 archaea and 13 unicellular eukaryotes suggested that Ca. C. subterraneum is closely related to thaumarchaeotic species. Consistent with the results of the phylogenetic analysis, clustering and principal component analyses based on the completion ratio patterns for all KEGG modules in 79 archaeal species suggested that the overall metabolic and physiological potential of Ca. C. subterraneum is similar to that of thaumarchaeotic species. However, Ca. C. subterraneum possessed almost no genes in the modules required for nitrification and the hydroxypropionate-hydroxybutyrate cycle for carbon fixation, unlike thaumarchaeotic species. However, it possessed all genes in the modules required for central carbohydrate metabolism, such as glycolysis, pyruvate oxidation, the tricarboxylic acid (TCA) cycle, and the glyoxylate cycle, as well as multiple sets of sugar and branched chain amino acid ABC transporters. These metabolic and physiological features appear to support the predominantly aerobic character of Ca. C. subterraneum, which lives in a subsurface thermophilic microbial mat community with a heterotrophic lifestyle.

The hypothesis that variability in natural habitats promotes modular organization is widely accepted for cellular networks. However, results of some data analyses and theoretical studies have begun to cast doubt on the impact of habitat variability on modularity in metabolic networks. Therefore, we re-evaluated this hypothesis using statistical data analysis and current metabolic information. We were unable to conclude that an increase in modularity was the result of habitat variability. Although horizontal gene transfer was also considered because it may contribute for survival in a variety of environments, closely related to habitat variability, and is known to be positively correlated with network modularity, such a positive correlation was not concluded in the latest version of metabolic networks. Furthermore, we demonstrated that the previously observed increase in network modularity due to habitat variability and horizontal gene transfer was probably due to a lack of available data on metabolic reactions. Instead, we determined that modularity in metabolic networks is dependent on species growth conditions. These results may not entirely discount the impact of habitat variability and horizontal gene transfer. Rather, they highlight the need for a more suitable definition of habitat variability and a more careful examination of relationships of the network modularity with horizontal gene transfer, habitats, and environments.

Single amino acid variants (SAVs) are the most abundant form of known genetic variations associated with human disease. Successful prediction of the functional impact of SAVs from sequences can thus lead to an improved understanding of the underlying mechanisms of why a SAV may be associated with certain disease. In this work, we constructed a high-quality structural dataset that contained 679 high-quality protein structures with 2,048 SAVs by collecting the human genetic variant data from multiple resources and dividing them into two categories, i.e., disease-associated and neutral variants. We built a two-stage random forest (RF) model, termed as FunSAV, to predict the functional effect of SAVs by combining sequence, structure and residue-contact network features with other additional features that were not explored in previous studies. Importantly, a two-step feature selection procedure was proposed to select the most important and informative features that contribute to the prediction of disease association of SAVs. In cross-validation experiments on the benchmark dataset, FunSAV achieved a good prediction performance with the area under the curve (AUC) of 0.882, which is competitive with and in some cases better than other existing tools including SIFT, SNAP, Polyphen2, PANTHER, nsSNPAnalyzer and PhD-SNP. The sourcecodes of FunSAV and the datasets can be downloaded at http://sunflower.kuicr.kyoto-u.ac.jp/sjn/FunSAV.

Zinc-binding proteins are the most abundant metalloproteins in the Protein Data Bank where the zinc ions usually have catalytic, regulatory or structural roles critical for the function of the protein. Accurate prediction of zinc-binding sites is not only useful for the inference of protein function but also important for the prediction of 3D structure. Here, we present a new integrative framework that combines multiple sequence and structural properties and graph-theoretic network features, followed by an efficient feature selection to improve prediction of zinc-binding sites. We investigate what information can be retrieved from the sequence, structure and network levels that is relevant to zinc-binding site prediction. We perform a two-step feature selection using random forest to remove redundant features and quantify the relative importance of the retrieved features. Benchmarking on a high-quality structural dataset containing 1,103 protein chains and 484 zinc-binding residues, our method achieved >80% recall at a precision of 75% for the zinc-binding residues Cys, His, Glu and Asp on 5-fold cross-validation tests, which is a 10%-28% higher recall at the 75% equal precision compared to SitePredict and zincfinder at residue level using the same dataset. The independent test also indicates that our method has achieved recall of 0.790 and 0.759 at residue and protein levels, respectively, which is a performance better than the other two methods. Moreover, AUC (the Area Under the Curve) and AURPC (the Area Under the Recall-Precision Curve) by our method are also respectively better than those of the other two methods. Our method can not only be applied to large-scale identification of zinc-binding sites when structural information of the target is available, but also give valuable insights into important features arising from different levels that collectively characterize the zinc-binding sites. The scripts and datasets are available at http://protein.cau.edu.cn/zincidentifier/.

Network modularity is an important structural feature in metabolic networks. A previous study suggested that the variability in natural habitat promotes metabolic network modularity in bacteria. However, since many factors influence the structure of the metabolic network, this phenomenon might be limited and there may be other explanations for the change in metabolic network modularity. Therefore, we focus on archaea because they belong to another domain of prokaryotes and show variability in growth conditions (e.g., trophic requirement and optimal growth temperature), but not in habitats because of their specialized growth conditions (e.g., high growth temperature). The relationship between biological features and metabolic network modularity is examined in detail. We first show the absence of a relationship between network modularity and habitat variability in archaea, as archaeal habitats are more limited than bacterial habitats. Although this finding implies the need for further studies regarding the differences in network modularity, it does not contradict previous work. Further investigations reveal alternative explanations. Specifically, growth conditions, trophic requirement, and optimal growth temperature, in particular, affect metabolic network modularity. We have discussed the mechanisms for the growth condition-dependant changes in network modularity. Our findings suggest different explanations for the changes in network modularity and provide new insights into adaptation and evolution in metabolic networks, despite several limitations of data analysis.