Bio-inspired Chemical Space Exploration of Terpenoids

Many computational methods are used to expand the open-ended border of chemical spaces. Natural products and their derivatives are an important source for drug discovery, and some algorithms are devoted to rapidly generating pseudo-natural products, while their accessibility and chemical interpretation were often ignored or underestimated, thus hampering experimental synthesis in practice. Herein, a bio-inspired strategy (named TeroGen) is proposed, in which the cyclization and decoration stage of terpenoid biosynthesis were mimicked by meta-dynamics simulations and deep learning models respectively, to explore their chemical space. In the protocol of TeroGen, the synthetic accessibility is validated by reaction energetics (reaction barrier and reaction heat) based on the GFN2-xTB methods. Chemical interpretation is an intrinsic feature as the reaction pathway is bioinspired and triggered by the RMSD-PP method in conjunction with an encoder-decoder architecture. This is quite distinct from conventional library/fragment-based or rule-based strategies, by using TeroGen, new reaction routes are feasibly explored to increase the structural diversity. For example, only a rather limited number of sesterterpenoids in our training set is included in this work, but our TeroGen would predict more than 30000 sesterterpenoids and map out the reaction network with super efficiency, ten times as many as the known sesterterpenoids (less than 2500). In sum, TeroGen not only greatly expands the chemical space of terpenoids but also provides various plausible biosynthetic pathways, which are crucial clues for heterologous biosynthesis, bio-mimic and chemical synthesis of complicated terpenoids.

On Mass Spectra of Primordial Black Holes

Evidence for the primordial black holes (PBH) presence in the early Universe renews permanently. New limits on their mass spectrum challenge existing models of PBH formation. One of the known models is based on the closed walls collapse after the inflationary epoch. Its intrinsic feature is the multiple production of small mass PBH which might contradict observations in the nearest future. We show that the mechanism of walls collapse can be applied to produce substantially different PBH mass spectra if one takes into account the classical motion of scalar fields together with their quantum fluctuations at the inflationary stage. Analytical formulas have been developed that contain both quantum and classical contributions.

Counterspaces of Resistance: Peter Carey’s Bliss

The article discusses how Peter Carey’s 1980 novel Bliss constructs and exam- ines various counterspaces both in and beyond the text. First, it shows how the plot jux- taposes the consumerist middle-class suburban model of life with an alternative lifestyle, presenting the attractions and limitations of both, yet preferring rather the latter. Secondly, at the level of literary convention, the text activates the strategies of comic social realism only to juxtapose them with elements of fantasy, fairy tale and myth, thus undermining the representational powers of the former and hinting at other possibilities of representation. Finally, the film adaptation of the novel shows how even rebellious or critical texts may become ‘domesticated’ or absorbed by the dominating logic of cultural production, thus once again demonstrating the ambivalent position of works of art in general, and this nov- el in particular. The article argues that the ambivalence engrained in the text is an intrinsic feature, not only of Australian culture or heterotopias but of most cultural products and practices inevitably entangled in the double logic of conforming and resistance.

Cortical hyperexcitability drives dying forward ALS symptoms and pathology in mice

Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder caused by degeneration of motor neurons in the cortex and spinal cord. The origin of ALS in the central nervous system is unclear, however cortical hyperexcitability appears as an early and intrinsic feature of ALS and has been linked to degeneration of spinal motor neurons via a dying-forward mechanism. Here, we implement chemogenetics to validate the dying forward hypothesis of ALS in mice. We show that chronic hyperexcitability of corticomotoneurons induced by excitatory chemogenetics results in motor symptoms and core neuropathological hallmarks of ALS, including corticomotoneuron loss, corticospinal tract degeneration and reactive gliosis. Importantly, corticomotoneuron loss was sufficient to drive degeneration of spinal motor neurons and neuromuscular junctions (NMJs), associated with cytoplasmic TAR DNA binding protein 43 (TDP-43) pathology. These findings establish a cortical origin of ALS mediated by neuronal hyperexcitability, consistent with a dying forward mechanism of neurodegeneration.

Bridging Capillary-Driven Fragmentation and Grain Transport with Mixed Columnar-Equiaxed Solidification

In this study, a first attempt is made to bridge capillary-driven fragmentation and grain transport using a mixed columnar-equiaxed solidification model. Grain transport is an intrinsic feature of the employed solidification model which has been extensively investigated over the years. Regarding the capillary-driven fragmentation event, a new correlation between the number of fragments and interfacial area density of the columnar structure was recently established by Cool and Voorhees (2017) based on experimental research under isothermal conditions. Here, we propose to modify Cool and Voorhees’ equation to extend its range of applicability to the solidification-dominant stage without destroying the agreement with the reported measurements in the coarsening-dominant stage. With this improvement in the mixed columnar-equiaxed solidification model, capillary effects can be isolated from the motion of the phases during fragmentation events, which facilitates understanding of the results. Under pure diffusive solidification conditions (no flow or crystal sedimentation), the simulation results were validated against phase-field simulations. In more realistic scenarios where liquid flow and fragment sedimentation are both considered, the simulations indicate very reasonable results for the detection of columnar-to-equiaxed transition, which suggests that the newly proposed model can be an important tool for industrial casting applications. Moreover, flow direction and intensity were shown to affect the potential for local fragmentation. Graphic Abstract

Development of Synthetic Strategies to Access Optically Pure Feringa’s Motors

Light-driven unidirectional molecular motor has gained enormous attention since the pioneering work by Prof. Ben L. Feringa in 1999 and it holds great promise in next generation smart materials. The intrinsic feature of point chirality and helicity of these motor molecules requires efficient strategies to access their optically pure form especially when chirality-sensitive materials are fabricated. In this short review, we will summarize synthetic strategies to access optically pure first and second generation molecular motors. Generally, three strategies will be discussed including direct asymmetric synthesis, chiral auxiliary method and resolving agent aided chiral separation. We expect this review can ignite the enthusiasm of synthetic chemists to address very fundamental but unavoidable synthetic questions for chiral alkene based molecular motors concerning their large scale applications.

neoDL: a novel neoantigen intrinsic feature-based deep learning model identifies IDH wild-type glioblastomas with the longest survival

Background Neoantigen based personalized immune therapies achieve promising results in melanoma and lung cancer, but few neoantigen based models perform well in IDH wild-type GBM, and the association between neoantigen intrinsic features and prognosis remain unclear in IDH wild-type GBM. We presented a novel neoantigen intrinsic feature-based deep learning model (neoDL) to stratify IDH wild-type GBMs into subgroups with different survivals. Results We first derived intrinsic features for each neoantigen associated with survival, followed by applying neoDL in TCGA data cohort(AUC = 0.988, p value < 0.0001). Leave one out cross validation (LOOCV) in TCGA demonstrated that neoDL successfully classified IDH wild-type GBMs into different prognostic subgroups, which was further validated in an independent data cohort from Asian population. Long-term survival IDH wild-type GBMs identified by neoDL were found characterized by 12 protective neoantigen intrinsic features and enriched in development and cell cycle. Conclusions The model can be therapeutically exploited to identify IDH wild-type GBM with good prognosis who will most likely benefit from neoantigen based personalized immunetherapy. Furthermore, the prognostic intrinsic features of the neoantigens inferred from this study can be used for identifying neoantigens with high potentials of immunogenicity.

Subjective Character as the Origo a Quo of Phenomenal Consciousness

This article contributes to the debate on self-consciousness, inner awareness, and subjective character. Philosophers puzzle over whether subjective character has a monadic or a relational form. But the present article deploys formal ontology to show that this is a false dichotomy. From this vantage, a common objection to non-relational views is deflated. The common objection is that one-level, non-relational views are either unexplanatory or smuggle in resources from higher-order and/or relational views. The author uses an argument from formal ontology to suggest that such objections stem from a category error. The result is that first-order non-relational views need not lapse into higher order or relational views – subjective character can be a structured and intrinsic feature involved in the ontological constitution of mental acts. Ultimately, the author emphasizes the need to conceive of subjective character as the source of intentionality, and not the result of a prior intentional relation.

Evolution of the Earth Microbial Co-occurrence Network

Background: Co-occurrence pattern provides vital insight into complex microbial interactions of microbiomes. Although network analysis offers useful tools for describing microbial co-occurrence pattern, evolution of co-occurrence networks remains largely uncharacterized. Here, we simulated the evolution of the Earth microbial co-occurrence network and estimated topological fitness of its nodes based on the degree growth exponent.Results: We showed that the Earth microbial co-occurrence network evolved following Bianconi-Barabasi model. The Earth microbial co-occurrence network had reached to a stable status with around 500 nodes. Degree growth exponent was the major determinant of accumulated degree of taxa. The positive correlation between topological fitness and gene numbers in corresponding genomes suggests the intrinsic feature of topological fitness. The gamma distribution of topological fitness suggests the extinction of taxa with low topological fitness. We then examined the impact of node extinction and decay, finding that the link acquisition of hub nodes was not affected.Conclusions: This study glimpses the evolution feature of Earth microbial co-occurrence network and provides a framework for predicting potential hubs in the evolving network in future.