Molecular Network Analysis Research Articles

Microbial community structural response to variations in physicochemical features of different aquifers.

The community structure of groundwater microorganisms has a significant impact on groundwater quality. However, the relationships between the microbial communities and environmental variables in groundwater of different recharge and disturbance types are not fully understood. In this study, measurements of groundwater physicochemical parameters and 16S rDNA high-throughput sequencing technology were used to assess the interactions between hydrogeochemical conditions and microbial diversity in Longkou coastal aquifer (LK), Cele arid zone aquifer (CL), and Wuhan riverside hyporheic zone aquifer (WH). Redundancy analysis indicated that the primary chemical parameters affecting the microbial community composition were NO3 -, Cl-, and HCO3 -. The species and quantity of microorganisms in the river-groundwater interaction area were considerably higher than those in areas with high salinity [Shannon: WH (6.28) > LK (4.11) > CL (3.96); Chao1: WH (4,868) > CL (1510) > LK (1,222)]. Molecular ecological network analysis demonstrated that the change in microbial interactions caused by evaporation was less than that caused by seawater invasion under high-salinity conditions [(nodes, links): LK (71,192) > CL (51,198)], whereas the scale and nodes of the microbial network were greatly expanded under low-salinity conditions [(nodes, links): WH (279,694)]. Microbial community analysis revealed that distinct differences existed in the classification levels of the different dominant microorganism species in the three aquifers. Environmental physical and chemical conditions selected the dominant species according to microbial functions. Gallionellaceae, which is associated with iron oxidation, dominated in the arid zones, while Rhodocyclaceae, which is related to denitrification, led in the coastal zones, and Desulfurivibrio, which is related to sulfur conversion, prevailed in the hyporheic zones. Therefore, dominant local bacterial communities can be used as indicators of local environmental conditions.

Effect of Deep Vertical Rotary Tillage on Soil Bacterial Community Diversity and Microbial Network Structure in Cultivated Land

The aim of this study was to understand the effect of deep vertical rotary tillage on the diversity and structural distribution of a soil bacterial community in cultivated land, as well as the interactions between microbial ecological molecular network and species. In this study, the cultivated soil under different tillage methods in the Yellow River diversion irrigation area in Ningxia was selected as the research object, and two treatments were set up, namely, deep vertical rotary tillage (DVRT) and conventional tillage (CT). Then, Illumina MiSeq technology was used to analyze the molecular ecological network of soil bacterial community under different tillage methods in the Ningxia Yellow River irrigation area. The results showed that DVRT significantly increased the contents of total organic carbon (TOC), total nitrogen (TN), alkali-hydrolyzed nitrogen (AN), total phosphorus (TP), available phosphorus (AP), and total potassium (TK) in the 0-20 cm soil layer compared with those in the CT treatment. Compared with those in the CT treatment, DVRT significantly increased the contents of TOC, TN, TP, AP, TK, and available potassium (AK) in the 20-40 cm soil layer. DVRT treatment significantly increased water content (WC) by 8.13%-13.30% and decreased pH and electrical conductivity (EC) by 4.51%-5.85% and 12.5%-13.33%, respectively. In different growth stages and soil layers of maize, the Shannon and Ace indices were increased in the DVRT treatments. The dominant bacterial phyla were:Actinobacteria, Proteobacteria, Chloroflexi, Acidobacteriota, and Gemmatimonadota. The results of bacterial community β diversity showed that DVRT and CT had significant differences in bacterial community structure. The redundancy analysis and Partial Mantel test results showed that pH, EC, and TP were the key environmental factors affecting the structural diversity of bacterial communities. Molecular ecological network analysis revealed that DVRT treatment microbial networks consisted of more functionally related microbial modules, and the topological roles of key microorganisms were different from those in the CT treatment. In conclusion, DVRT can enhance soil nutrients and WC in different soil layers, reduce pH and EC, improve soil bacterial community diversity and microbial network structure, and also enhance the potential ecosystem functions in cultivated soil.

Improving Methane Production from Waste Activated Sludge Assisted by Fe(II)-Activated Peroxydisulfate Pretreatment via Anaerobic Digestion: Role of Interspecific Syntrophism Mediated by Sulfate-Reducing Bacteria

Sulfate radical generated via peroxydisulfate (PDS) activation has been extensively applied to energy recovery from waste activated sludge (WAS) during anaerobic digestion (AD), while the residual sulfate is still a limitation for its further application. In this study, a novel coupling strategy of Fe(II)-activated PDS pretreatment [Fe(II)_PDS] with sulfate-reducing bacteria (SRB) mediated was explored to enhance methane yield from WAS during AD. Results showed that the similar methane yield was obtained in Fe(II)_PDS + SRB (16.6 mL/g VSS) and zero-valent iron (ZVI)_PDS + SRB (16.9 mL/g VSS), which enhanced by 19.9–56.5% than other groups, while the hydrolysis rate constant (0.0065 h–1) in Fe(II)_PDS + SRB was much higher than that observed in ZVI_PDS + SRB (0.0046 h–1). Meanwhile, the concentration of short-chain fatty acids (SCFAs) peaked at 360.9 mg COD/g VSS (5 d) in the Fe(II)_PDS + SRB group, with the acetic acid (HAc) and propionic acid (HPr) accumulative proportion of 73.5%, and the total concentration promoted by 28.5% than that of the ZVI_PDS + SRB group, which provided a more ideal substrate for methanogens. The ultimate utilization efficiency of SCFAs reached 62.4% in the Fe(II)_PDS + SRB group. Moreover, MiSeq sequencing, canonical correspondence analysis, and molecular ecological network analysis revealed the intrinsic interaction of the functional microbial consortia, that is, anaerobic fermentation bacteria, SRB, nitrate-reducing bacterium, and acetotrophic methanogen, with the abundances of 9.52, 2.4, 4.93, and 77.7% in the Fe(II)_PDS + SRB group. Considering the treatment performance and the difficulty of the subsequent disposal, Fe(II) may be the superior activator than ZVI for free radicals (i.e., SO4•– and HO•) generation from PDS and further played the important role for interspecific syntrophism coupling with SRB during AD. Results of this study may provide a promising way for energy recovery from WAS.

Shallow- and Deep-Water Ophiura Species Produce a Panel of Chlorin Compounds with Potent Photodynamic Anticancer Activities.

A Pacific brittle star Ophiura sarsii has previously been shown to produce a chlorin (3S,4S)-14-Ethyl-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid (ETPA) (1) with potent phototoxic activities, making it applicable to photodynamic therapy. Using extensive LC-MS metabolite profiling, molecular network analysis, and targeted isolation with de novo NMR structure elucidation, we herein identify five additional chlorin compounds from O. sarsii and its deep-sea relative O. ooplax: 10S-Hydroxypheophorbide a (2), Pheophorbide a (3), Pyropheophorbide a (4), (3S,4S,21R)-14-Ethyl-9-(hydroxymethyl)-21-(methoxycarbonyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid (5), and (3S,4S,21R)-14-Ethyl-21-hydroxy-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid (6). Chlorins 5 and 6 have not been previously reported in natural sources. Interestingly, low amounts of chlorins 1-4 and 6 could also be identified in a distant species, the basket star Gorgonocephalus cf. eucnemis, demonstrating that chlorins are produced by a wide spectrum of marine invertebrates of the class Ophiuroidea. Following the purification of these major Ophiura chlorin metabolites, we discovered the significant singlet oxygen quantum yield upon their photoinduction and the resulting phototoxicity against triple-negative breast cancer BT-20 cells. These studies identify an arsenal of brittle star chlorins as natural photosensitizers with potential photodynamic therapy applications.

Investigation of the mechanism of anammox granules alleviating the inhibition of organic matter in pharmaceutical wastewater

In current study, the reactor performance, granular characteristics and microbial community succession were investigated in an anaerobic ammonium oxidation (anammox) granular system treating pharmaceutical wastewater under varying COD/N ratios. The results showed that the optimal nitrogen removal performance was achieved with COD/N of 0.63, indicating the feasibility of anammox granular system to treat pharmaceutical wastewater. As the COD/N ratio increased to 1.31, the nitrogen removal efficiency declined to 49.2%. However, the reactor recovered rapidly after 60 days, because that stable granular structure retained high biomass. It was found that AnAOB secreted more extracellular protein, especially a specific humic acid-like substance to form fine and coarse granules as response to the inhibitory conditions. The population of anammox species has shifted significantly. Besides, the key genera and the symbiotic genera with AnAOB were confirmed by molecular ecological networks analysis.

New acylated flavonoid isolated from Thai bee pollen using molecular networking analysis and determination of its catechol-O-methyltransferase inhibitory activity

New acylated flavonoid isolated from Thai bee pollen using molecular networking analysis and determination of its catechol-O-methyltransferase inhibitory activity

Delineating the conformational landscape of cannabinoid receptor 1 (CB1R) using gaussian accelerated molecular dynamics and network analysis.

The cannabinoid receptor 1, CB1R, is a class A GPCR implicated in various disease states, including pain and inflammation. Interestingly, both the agonists, which can alleviate pain, and the antagonists, which can lead to appetite suppression in obese patients, have substantial therapeutic benefits. Crystal structures for the CB1R have also been determined in the inactive and active states. However, the role of these ligands in stabilizing these different states and how they contribute to this shift in equilibria is relatively unknown. The free energy surface for these transitions has also not been determined. Using Gaussian Accelerated MD, we have explored the different conformational states of the CB1R, exploring both the effects of orthosteric and allosteric ligands on the free energy landscape. Furthermore, we have analyzed the residue contacts and performed network analysis to determine the information flow pertinent to the transition between states. The results provide unprecedented insights into the activation of CB1R, and the critical residues involved in this process. These results can help to guide structure-based drug design where potential drugs can be evaluated on their ability to stabilize a preferred conformation of the receptor of focus.

Isolation and Characterization of Compounds from Ochreinauclea maingayi (Hook. f.) Ridsd. (Rubiaceae) with the Aid of LCMS/MS Molecular Networking

Phytochemical investigation of the dichloromethane crude extract from the bark of Ochreinauclea maingayi with the aid of LCMS/MS-based molecular networking guided the isolation and accelerated the elucidation of known and new indole alkaloids. The molecular networking analysis produces two main clusters, along with 41 non-prioritized clusters and self-loop nodes. Each cluster has several nodes which depict the fractions contained within those nodes. An implementation of a fraction mapping for each node represents the molecular weight and key fragment data of each compound. From the analysis of each cluster and node, we can deduce the indole alkaloids are the scaffold of interest. Indole scaffold can be found between F5 and F10 that contain several types of indole alkaloids. In total, we have successfully purified nine indole alkaloids, including 9H-β-carboline-4-carboxylate 2, norharmane 3, harmane 4, naucledine 10, neonaucline 15, 1,2,3,4-tetranorharmane-1-one 16, naulafine 19, cadambine 9, and a new monoterpene indole alkaloid dihyrodeglycocadambine 7 from F5 to F10 using a chromatographic technique. Their structures were confirmed by 1D-NMR, 2D-NMR, UV, IR, LCMS, and MS2LDA. Several clusters and nodes contain ions that could not be annotated, suggesting that they may possess novel compounds that are yet to be discovered.

Electrostimulation triggers an increase in cross-niche microbial associations toward enhancing organic nitrogen wastewater treatment

As an efficient wastewater pretreatment biotechnology, electrostimulated hydrolysis acidification (eHA) has been used to accelerate the removal of refractory pollutants, which is closely related to the effects of electrostimulation on microbial interspecies associations. However, the ecological processes underpinning such linkages remain unresolved, especially for the microbial communities derived from different niches, such as the electrode surface and plankton. Herein, the principles of cross-niche microbial associations and community assembly were investigated using molecular ecological network and phylogenetic bin-based null model analysis (iCAMP) based on 16S rRNA gene sequences. The electrostimulated planktonic sludge and electrode biofilm displayed significantly (P < 0.05) 1.67 and 1.53 times higher organic nitrogen pollutant (azo dye Alizarin Yellow R) degradation efficiency than non-electrostimulation group, and the corresponding microbial community composition and structure were significantly (P < 0.05) changed. Electroactive bacteria and functional degraders were enriched in the electrode biofilm and planktonic sludge, respectively. Notably, electrostimulation strengthened the synergistic microbial associations (1.8 times more links) between sludge and biofilm members. Additionally, both electrostimulation and cross-niche microbial associations induced greater importance of deterministic assembly. Overall, this study highlights the specificity of cross-electrode surface microbial associations and ecological processes with electrostimulation and advances our understanding of the manipulation of sludge microbiomes in engineered wastewater treatment systems.

Food webs reveal coexistence mechanisms and community organization in carnivores

Globally, massive carnivore guild extirpations have led to trophic downgrading and compromised ecosystem services. However, the complexity of multi-carnivore food webs complicates accurate identification of species interactions and community organization. Here, we used fecal DNA metabarcoding to investigate three communities that together encompass eight large- and meso-carnivore species and their 44 prey taxa of the Qinghai-Tibet Plateau (QTP), one of the last places on Earth that still harbors intact carnivore assemblages. Quantitative food-web analyses revealed pronounced interspecific variations in the carnivores' prey compositions and dietary partitioning both between and within guilds. Additionally, body masses of the carnivores and their prey exhibited consistent hump-shaped correlations across communities. Overall, differences in prey diversity, size category, and proportional utilization among the carnivore species result in trophic niche segregation that likely promotes carnivore coexistence in the harsh QTP environment. Network structure analyses detected significant modularity in all food webs but nestedness in only one. Furthermore, network characterization identified pikas (Ochotona spp.), bharal (Pseudois nayaur), and domestic yak (Bos grunniens) as potential keystone prey across the areas. Our results paint a holistic and detailed picture of the QTP carnivore assemblages' trophic networks and demonstrate that the combined use of the molecular dietary approach and network analysis can generate structural insights into carnivore coexistence and can identify functionally important species in complex communities. Such knowledge can help safeguard carnivore guild integrity and enhance community resilience to environmental perturbations in the sensitive QTP ecosystems.

Unique Habitat of Karst Tiankengs Changes the Taxonomy and Potential Metabolism of Soil Microbial Communities.

Microbial communities in karst ecosystems have been extensively studied. However, in a class of deep-lying habitats with unique climates (karst tiankeng), the structure and ecological functions of microorganisms receive little attention, which is essential for understanding the biogeochemistry of karst tiankeng. Herein, microorganisms from inside (ITK) and outside (OTK) karst tiankengs were analyzed by high-throughput sequencing and multivariate statistical analysis. The results showed that the structure and function of soil bacterial communities inside and outside karst tiankengs were significantly different. The ITK microbial communities presented significantly higher Shannon diversity due to the abundant nutrients in karst tiankeng soil. Random molecular ecological network analysis revealed that the ITK network was simpler and more vulnerable and may be susceptible to environmental changes. More positive links within the network indicate that microorganisms adapt to the karst tiankeng through synergies. The keystones in karst tiankeng were mainly involved in the decomposition of soil organic matter and carbon/nitrogen cycles. Although soil total phosphorus and available potassium regulate microbial community structure variation, dispersal limitation is the predominant ecological process within the microbial community in karst tiankeng. In addition, the functional profiles of the microbial communities reveal that some human diseases (such as infectious diseases) exist in OTK. Collectively, these findings have enhanced our understanding of microbial interactions, ecological functions, and community composition processes in karst tiankeng ecosystems. IMPORTANCE Constrained by the trapped terrain, a unique ecosystem has formed in karst tiankeng. Soil microorganisms are essential for the formation and maintenance of ecosystems, but soil microbial ecology research in karst tiankeng is still lacking. In this study, representative habitats inside and outside karst tiankeng were selected to study the taxonomy and potential metabolism of soil microbial communities. The results show that the unique habitat of karst tiankeng reshapes the composition, structure, and function of soil microbial communities. Our results contribute to enhancing our understanding of sustainable recovery strategies in fragile ecosystems and understanding the biodiversity value of karst tiankeng under climate change.

Genomic and Metabolite Profiling Reveal a Novel Streptomyces Strain, QHH-9511, from the Qinghai-Tibet Plateau.

The prevalence of superbugs, represented by methicillin-resistant Staphylococcus aureus (MRSA), has become a serious clinical and public safety concern with rising incidence in hospitals. Polyketides with diverse chemical structures harbor many antimicrobial activities, including those of rifampin and rapamycin against MRSA. Streptomyces sp. QHH-9511 was isolated from a niche habitat in the Qinghai-Tibet Plateau and used to produce antibacterial metabolites. Herein, an integrated approach combining genome mining and metabolic analysis were employed to decipher the chemical origin of the antibacterial components with pigmented properties in strain QHH-9511, a novel Streptomyces species from a lichen symbiont on the Qinghai-Tibet Plateau. Genomic phylogeny assembled at the chromosome level revealed its unique evolutionary state. Further genome mining uncovered 36 candidate gene clusters, most of which were uncharacterized. Meanwhile, based on liquid chromatography coupled to diode array detection mass spectrometry, a series of granaticins, BSMs, chromones, phaeochromycins, and related molecules were discovered by using the Global Natural Product Social molecular networking platform. Subsequently, several pigment compounds were isolated and identified by high-resolution mass spectrometry and/or nuclear magnetic resonance, among which the structure-activity relationships of seven aromatic polyketides showed that the fused lactone ring of the C-2 carboxyl group could increase antibacterial activity. Genetic experiments indicated that all seven aromatic polyketides are a series of metabolic shunts produced by a single type II polyketide synthase (PKS) cluster. Comparative genomic analysis of granaticin producers showed that the granaticin gene cluster is widely distributed. This study provides an efficient method to combine genome mining and metabolic profiling techniques to uncover bioactive metabolites derived from specific habitats, while deepening our understanding of aromatic polyketide biosynthesis. IMPORTANCE Undescribed microorganisms from special habitats are being screened for anti-superbug drug molecules. In a project to screen actinomycetes for anti-MRSA activity, we isolated a Streptomyces strain from Qinghai Lake lichens. The phylogeny based on the genome assembled at the chromosome level revealed this strain's unique evolutionary state. The chemical origins of the antibacterial components with pigment properties in strain QHH-9511 were determined using an integrated approach combining genome mining and metabolic analysis. Further genome mining uncovered 36 secondary metabolite gene clusters, the majority of which were previously unknown. A series of aromatic compounds were discovered using molecular network analysis, separation, and extraction. Genetic experiments revealed that all seven aromatic polyketides are a series of metabolic shunts produced by a single cluster of type II PKSs. This study describes a method for identifying novel Streptomyces from specific habitats by combining genome mining with metabolic profiling techniques.

High expression of KNL1 in prostate adenocarcinoma is associated with poor prognosis and immune infiltration.

Prostate adenocarcinoma (PRAD) is a common malignancy with increasing morbidity and mortality. Kinetochore scaffold 1 (KNL1) has been reported to be involved in tumor progression and prognosis in other tumors, but its role in PRAD has not been reported in detail. KNL1 expression analysis, clinicopathological parameters analysis, prognostic correlation analysis, molecular interaction network and functional abdominal muscle analysis and immune infiltration analysis by using multiple online databases and downloaded expression profile. The results suggest that KNL1 is highly expressed in PRAD, which is associated with worse prognosis in PRAD patients. KnL1-related genes are highly enriched in mitotic function, which is considered to be highly related to the development of cancer. Finally, KNL1 expression is associated with a variety of tumor infiltrating immune cells, especially Treg and Th2 cells. In conclusion, our findings provide preliminary evidence that KNL1 may be an independent prognostic predictor of PRAD and is associated with immune infiltration.

Fungi and cercozoa regulate methane-associated prokaryotes in wetland methane emissions.

Wetlands are natural sources of methane (CH4) emissions, providing the largest contribution to the atmospheric CH4 pool. Changes in the ecohydrological environment of coastal salt marshes, especially the surface inundation level, cause instability in the CH4 emission levels of coastal ecosystems. Although soil methane-associated microorganisms play key roles in both CH4 generation and metabolism, how other microorganisms regulate methane emission and their responses to inundation has not been investigated. Here, we studied the responses of prokaryotic, fungal and cercozoan communities following 5 years of inundation treatments in a wetland experimental site, and molecular ecological networks analysis (MENs) was constructed to characterize the interdomain relationship. The result showed that the degree of inundation significantly altered the CH4 emissions, and the abundance of the pmoA gene for methanotrophs shifted more significantly than the mcrA gene for methanogens, and they both showed significant positive correlations to methane flux. Additionally, we found inundation significantly altered the diversity of the prokaryotic and fungal communities, as well as the composition of key species in interactions within prokaryotic, fungal, and cercozoan communities. Mantel tests indicated that the structure of the three communities showed significant correlations to methane emissions (p < 0.05), suggesting that all three microbial communities directly or indirectly contributed to the methane emissions of this ecosystem. Correspondingly, the interdomain networks among microbial communities revealed that methane-associated prokaryotic and cercozoan OTUs were all keystone taxa. Methane-associated OTUs were more likely to interact in pairs and correlated negatively with the fungal and cercozoan communities. In addition, the modules significantly positively correlated with methane flux were affected by environmental stress (i.e., pH) and soil nutrients (i.e., total nitrogen, total phosphorus and organic matter), suggesting that these factors tend to positively regulate methane flux by regulating microbial relationships under inundation. Our findings demonstrated that the inundation altered microbial communities in coastal wetlands, and the fungal and cercozoan communities played vital roles in regulating methane emission through microbial interactions with the methane-associated community.

Integrative strategy for quality control of Radix Bupleuri based on non-targeted metabolomic profiling and molecular networking.

Quality control of Radix Bupleuri (RB) can be challenging due to the complexity of origin, the similar morphological characteristics, and the diversity of the multiple components. In this study, an integrated strategy for extensive identification of metabolites in plants based on multiple data processing methods was proposed to distinguish four commercially available RB species. First, the pre-processed mass spectrometry data was uploaded to Global Natural Products Social Molecular Networking (GNPS) for spectral library search and molecular network analysis, which can effectively differentiate isomers and reduce molecular redundancy. Second, the possible cleavage mode was summarized from the characteristic MS/MS fragment ions of saikoside standard, and then the possible structure of saikoside in the sample was deduced according to the cleavage patterns. Third, collected all kinds of RB components reported in the literature and matched the information in the samples to obtain more comprehensive information about metabolites. Finally, chemical markers were found employing chemometrics. This strategy not only increases the variety and number of identified components, but also improves the accuracy of the data. Based on this strategy, a total of 132 components were identified from different species of RB, and 14 chemical constituents were considered to be potential chemical markers to distinguish four kinds of RB. Among them, saikogenin a, hydroxy-saikosaponin a, hydroxy-saikosaponin d, and rutinum were of great significance for identification. The method proposed in this study not only successfully identified and distinguished four species of RB, but also laid a good theoretical foundation for regulating the RB market. This strategy provides promising perspectives in the accurate analysis of the ingredients of traditional Chinese medicine.

Using molecular network analysis to understand current HIV-1 transmission characteristics in an inland area of Yunnan, China.

HIV-1 molecular surveillance provides a new approach to explore transmission risks and targeted interventions. From January to June 2021, 663 newly reported HIV-1 cases were recruited in Zhaotong City, Yunnan Province, China. The distribution characteristics of HIV-1 subtypes and HIV-1 molecular network were analysed. Of 542 successfully subtyped samples, 12 HIV-1 strains were identified. The main strains were CRF08_BC (47.0%, 255/542), CRF01_AE (17.0%, 92/542), CRF07_BC (17.0%, 92/542), URFs (8.7%, 47/542), and CRF85_BC (6.5%, 35/542). CRF08_BC was commonly detected among Zhaotong natives, illiterates, and non-farmers and was mostly detected in Zhaoyang County. CRF01_AE was frequently detected among married and homosexual individuals and mostly detected in Weixin and Zhenxiong counties. Among the 516 pol sequences, 187 (36.2%) were clustered. Zhaotong natives, individuals aged ≥60years, and illiterate individuals were more likely to be found in the network. Assortativity analysis showed that individuals were more likely to be genetically associated when stratified by age, education level, occupation, and reporting area. The genetic diversity of HIV-1 reflects the complexity of local HIV epidemics. Molecular network analyses revealed the subpopulations to focus on and the characteristics of the risk networks. The results will help optimise local prevention and control strategies.

Inhibition of colorectal cancer targets IL-6, CTLA-4, & B7-2 by Tislelizumab: molecular docking, dynamics, & STRING protein-protein network analysis

As a DNA mismatch repair deficit (dMMR) anticancer medication, and a humanized monoclonal antibody (hmAb), Tislelizumab has attracted significant interest in recent years. The programmed cell death protein-1 (PD-1) and its ligands (PD-L1/CD274/B7-H1 and PDL2/CD273) may bind to each other with great affinity. This binding prevents activated T-cells from continuing to proliferate, produce cytokines, and engage in cytotoxic action. The B7:PD-1 inhibitory immunological checkpoint receptor binds to the B7-2(CD86) B-lymphocyte activation antigen. This paper presents Tislelizumab's molecular docking and dynamics simulations with the receptor B7-2(CD86) and its downstream signaling proteins CTLA-4 and IL-6. When docked to B cell stimulatory factor-2 soluble IL-6 receptor alpha (sIL6Ra/CD126), Tislelizumab had a strong binding affinity of 329 kcal/mol and provided an excellent quality model with an LGscore of 4.54. The type I membrane protein B7-2(CD86), a member of the immunoglobulin superfamily, responded to docking with an affinity of −332.35 kcal/mol and LGscore of 2.54. Docking to the immune checkpoint protein receptor cytotoxic T-lymphocyte-associated protein-4 (CTLA-4/CD152) had a binding affinity of −305.91 kcal/mol, facilitating immunological control and cellular dissociation. Tislelizumab and these target proteins exhibited persistent and advantageous interactions in molecular dynamics studies. The STRING functional protein-protein network analysis supported our in silico docking and dynamic simulation results. This analysis also included comparisons of the binding modes of mAbs to protein receptors involved in the cancer hallmark mechanism(s), demonstrating that IL-6, B7-2, and CTLA-4 act and are inhibited in group-mode. Functional enrichment analysis and molecular modelling supported the relationship between the hallmarks of the tumor microenvironment that link inflammation to immunity. Tislelizumab may therefore be able to prevent these three proteins from acting. These findings may also shine light on Dostarlimab's mode of action, which in 2022 achieved ground-breaking success in a clinical study for colorectal cancer.

Dynamic self-assembly of supramolecular catalysts from precision macromolecules.

We show the emergence of strong catalytic activity at low concentrations in dynamic libraries of complementary sequence-defined oligomeric chains comprising pendant functional catalytic groups and terminal recognition units. In solution, the dynamic constitutional library created from pairs of such complementary oligomers comprises free oligomers, self-assembled di(oligomeric) macrocycles, and a virtually infinite collection of linear poly(oligomeric) chains. We demonstrate, on an exemplary catalytic system requiring the cooperation of no less than five chemical groups, that supramolecular di(oligomeric) macrocycles exhibit a catalytic turnover frequency ca. 20 times larger than the whole collection of linear poly(oligomers) and free chains. Molecular dynamics simulations and network analysis indicate that self-assembled supramolecular di(oligomeric) macrocycles are stabilized by different interactions, among which chain end pairing. We mathematically model the catalytic properties of such complex dynamic libraries with a small set of physically relevant parameters, which provides guidelines for the synthesis of oligomers capable to self-assemble into functionally-active supramolecular macrocycles over a larger range of concentrations.

Molecular network analysis of hormonal contraceptives side effects via database integration

Hormonal contraceptives (HCs) have been shown to be safe and effective when used correctly and consistently, however, as other classes of drugs, they are also associated with adverse health outcomes. In this study, we aim to explain the occurrence of common and unexpected HCs side effects (SEs) integrating drug-target, drug-SE and protein-protein interaction (PPI) public databases. We created a tripartite network that includes three types of vertices: SEs, drugs, and targets. The three layers are linked by means of the inter-layer associations drug-target and drug-SE, whereas only the target layer is characterized also by intra-layer links (PPIs). We exploited the drug-mediated association SE-target to identify the side effect modules defined as a network connected component composed of target proteins plus the proteins needed to connect them. We found that module proteins are associated with diseases/phenotypes and/or KEGG pathways related to the SEs. In particular, in many cases, targets are not enriched in SE features, whereas investigating their neighborhood (here defined as the proteins that allow the targets' connection) we found SE-related pathways. These results show that HCs action can perturb the targets’ neighborhood inducing unwanted reaction and that the proposed approach can help to understand how, and through which molecular mechanisms, side effects can occur. The approach is general in its nature: it can be applied to other drugs categories providing a support in identifying a subject-specific therapy that takes into account comorbidities and lifestyle to reduce or avoid the most undesired side effects.

Combining molecular network analysis and field epidemiology to quantify local HIV transmission and highlight ongoing epidemics

This study aimed to establish a collaborative approach to quantify local HIV transmission, which is an issue of great concern to public health. We linked HIV-1 pol gene sequences to demographic information and epidemiological investigations in Hangzhou (a central city in East China). We estimated local acquisition rates from a collaboration of molecular network analysis (with a distance-based approach) and epidemiological investigations. Among 1064 newly diagnosed patients with HIV, 857 pol sequences were acquired and subsequently analyzed. Multiple subtypes were identified, with circulating recombinant form (CRF)07_BC (42.5%) and CRF01_AE (39.2%) predominating, followed by 13 other subtypes and 26 unique recombinant forms. By integrating the molecular network analysis and epidemiological investigations, we estimated that the proportion of local infection was 63.2%. The multivariable analyses revealed that individuals in clusters were more likely to be local residents, be aged 50 years or older, work as farmers, and have a higher first cluster of differentiation 4 count level (P <0.05). The proportions of local acquisitions over 70% were observed in local residents (79.9%, 242/303), individuals aged 50 years or older (73.6%, 181/246), and farmers (75.6%, 99/131). The molecular network analysis can augment traditional HIV epidemic surveillance. This study establishes a paradigm for quantifying local HIV transmission for generalization in other areas.