The Nuclear Network: Multiplex Network Analysis for Interconnected Systems

States facing the decision to develop a nuclear weapons program do so within a broader context of their relationships with other countries. How these diplomatic, economic, and strategic relationships impact proliferation decisions, however, remains under-specified. Adding to the existing empirical literature that attempts to model state proliferation decisions, this article introduces the first quantitative heterogeneous network analysis of how networks of conflict, alliances, trade, and nuclear cooperation interact to spur or deter nuclear proliferation. Using a multiplex network model, we conceptualize states as nodes linked by different modes of interaction represented on individual network layers. Node strength is used to quantify factors correlated with nuclear proliferation and these are combined in a weighted sum across layers to provide a metric characterizing the proliferation behavior of the state. This multiplex network modeling approach provides a means for identifying states with the highest relative likelihood of proliferation—based only on their relationships to other states. This work demonstrates that latent conflict and nuclear cooperation are positively correlated with proliferation, while an increased trade dependence suggests a decreased proliferation likelihood. A case study on Iran’s controversial nuclear program and past nuclear activity is also provided. These findings have clear, policy-relevant conclusions related to alliance posture, sanctions policy, and nuclear assistance. Abstract ©The Authors

Promiscuous Aggregate-Based Inhibitors Promote Enzyme Unfolding

One of the leading sources of false positives in early drug discovery is the formation of organic small molecule aggregates, which inhibit enzymes nonspecifically at micromolar concentrations in aqueous solution. The molecular basis for this widespread problem remains hazy. To investigate the mechanism of inhibition at a molecular level, we determined changes in solvent accessibility that occur when an enzyme binds to an aggregate using hydrogen-deuterium exchange mass spectrometry. For AmpC beta-lactamase, binding to aggregates of the small molecule rottlerin increased the deuterium exchange of all 10 reproducibly detectable peptides, which covered 41% of the sequence of beta-lactamase. This suggested a global increase in proton accessibility upon aggregate binding, consistent with denaturation. We then investigated whether enzyme-aggregate complexes were more susceptible to proteolysis than uninhibited enzyme. For five aggregators, trypsin degradation of beta-lactamase increased substantially when beta-lactamase was inhibited by aggregates, whereas uninhibited enzyme was generally stable to digestion. Combined, these results suggest that the mechanism of action of aggregate-based inhibitors proceeds via partial protein unfolding when bound to an aggregate particle

Oxidative protein labeling in mass-spectrometry-based proteomics

Oxidation of proteins and peptides is a common phenomenon, and can be employed as a labeling technique for mass-spectrometry-based proteomics. Nonspecific oxidative labeling methods can modify almost any amino acid residue in a protein or only surface-exposed regions. Specific agents may label reactive functional groups in amino acids, primarily cysteine, methionine, tyrosine, and tryptophan. Nonspecific radical intermediates (reactive oxygen, nitrogen, or halogen species) can be produced by chemical, photochemical, electrochemical, or enzymatic methods. More targeted oxidation can be achieved by chemical reagents but also by direct electrochemical oxidation, which opens the way to instrumental labeling methods. Oxidative labeling of amino acids in the context of liquid chromatography(LC)–mass spectrometry (MS) based proteomics allows for differential LC separation, improved MS ionization, and label-specific fragmentation and detection. Oxidation of proteins can create new reactive groups which are useful for secondary, more conventional derivatization reactions with, e.g., fluorescent labels. This review summarizes reactions of oxidizing agents with peptides and proteins, the corresponding methodologies and instrumentation, and the major, innovative applications of oxidative protein labeling described in selected literature from the last decade

Carbon disulfide. Just toxic or also bioregulatory and/or therapeutic?

The overview presented here has the goal of examining whether carbon disulfide (CS2) may play a role as an endogenously generated bioregulator and/or has therapeutic value. The neuro- and reproductive system toxicity of CS2 has been documented from its long-term use in the viscose rayon industry. CS2 is also used in the production of dithiocarbamates (DTCs), which are potent fungicides and pesticides, thus raising concern that CS2 may be an environmental toxin. However, DTCs also have recognized medicinal use in the treatment of heavy metal poisonings as well as having potency for reducing inflammation. Three known small molecule bioregulators (SMBs) nitric oxide, carbon monoxide, and hydrogen sulfide were initially viewed as environmental toxins. Yet each is now recognized as having intricate, though not fully elucidated, biological functions at concentration regimes far lower than the toxic doses. The literature also implies that the mammalian chemical biology of CS2 has broader implications from inflammatory states to the gut microbiome. On these bases, we suggest that the very nature of CS2 poisoning may be related to interrupting or overwhelming relevant regulatory or signaling process(es), much like other SMBs

Case of the disappearing drusen

A 66-year-old man with age-related macular degeneration was admitted for new left cerebellar and right parietal hemorrhagic tumours. Excisional biopsy of the left cerebellar lesion demonstrated primary CNS lymphoma (PCNSL) of diffuse large B-cell morphology. No intraocular inflammation was present. Fundus examination revealed numerous drusen at the posterior pole of the left eye only, confirmed as sub–retinal pigment epithelium (sub-RPE) deposits on optical coherence tomography. Complete resolution of these unilateral sub-RPE drusenoid deposits occurred with systemic treatment for PCNSL alone using methotrexate, cytarabine, thioepta, and rituximab (MATRix) chemotherapy. No diagnostic vitrectomy was needed. In this photo essay we illustrate the spontaneous resolution of sub-RPE drusenoid deposits with systemic chemotherapy