Search Results (7)

Leader–follower modalities and other asymmetric interactions that drive the collective motion of organisms are often quantified using information theory metrics like transfer or causation entropy. These metrics are difficult to accurately evaluate without a much larger number of data than is typically available from a time series of animal trajectories collected in the field or from experiments. In this paper, we use a generalized leader–follower model to argue that the time-separated mutual information between two organism positions can serve as an alternative metric for capturing asymmetric correlations that is much less data intensive and more accurately estimated by popular k-nearest neighbor algorithms than transfer entropy. Our model predicts a local maximum of this mutual information at a time separation value corresponding to the fundamental reaction timescale of the follower organism. We confirm this prediction by analyzing time series trajectories recorded for a pair of golden shiner fish circling an annular tank. Full article

Galectins are multifunctional effectors in cellular homeostasis and dysregulation. Oxidation of human galectin-1 (Gal-1) with its six sulfhydryls produces a disulfide-bridged oxidized form that lacks normal lectin activity yet gains new glycan-independent functionality. Nevertheless, the mechanistic details as to how Gal-1 oxidation occurs remain unclear. Here, we used ¹⁵N and ¹³C HSQC NMR spectroscopy to gain structural insight into the CuSO₄–mediated path of Gal-1 oxidation and identified a minimum two-stage conversion process. During the first phase, disulfide bridges form slowly between C16-C88 and/or C42-C66 to produce a partially oxidized, conformationally flexible intermediate that retains the ability to bind lactose. Site-directed mutagenesis of C16 to S16 impedes the onset of this overall slow process. During the second phase, increased motional dynamics of the intermediate enable the relatively distant C2 and C130 residues to form the third and final disulfide bond, leading to an unfolded state and consequent dimer dissociation. This fully oxidized end state loses the ability to bind lactose, as shown by the hemagglutination assay. Consistent with this model, we observed that the Gal-1 C2S mutant maintains intermediate-state structural features with a free sulfhydryl group at C130. Incubation with dithiothreitol reduces all disulfide bonds and allows the lectin to revert to its native state. Thus, the sequential, non-random formation of three disulfide bridges in Gal-1 in an oxidative environment acts as a molecular switch for fundamental changes to its functionality. These data inspire detailed bioactivity analysis of the structurally defined oxidized intermediate in, e.g., acute and chronic inflammation. Full article

Extra- and intra-cellular activity occurs under the direction of numerous inter-molecular interactions, and in any tissue or cell, molecules are densely packed, thus promoting those molecular interactions. Galectins and chemokines, the focus of this review, are small, protein effector molecules that mediate various cellular functions—in particular, cell adhesion and migration—as well as cell signaling/activation. In the past, researchers have reported that combinations of these (and other) effector molecules act separately, yet sometimes in concert, but nevertheless physically apart and via their individual cell receptors. This view that each effector molecule functions independently of the other limits our thinking about functional versatility and cooperation, and, in turn, ignores the prospect of physiologically important inter-molecular interactions, especially when both molecules are present or co-expressed in the same cellular environment. This review is focused on such protein-protein interactions with chemokines and galectins, the homo- and hetero-oligomeric structures that they can form, and the functional consequences of those paired interactions. Full article

Background: SARS-CoV-2 vaccines play an important role in reducing disease severity, hospitalization, and death, although they failed to prevent the transmission of SARS-CoV-2 variants. Therefore, an effective inhibitor of galectin-3 (Gal-3) could be used to treat and prevent the transmission of COVID-19. ProLectin-M (PL-M), a Gal-3 antagonist, was shown to interact with Gal-3 and thereby prevent cellular entry of SARS-CoV-2 in previous studies. Aim: The present study aimed to further evaluate the therapeutic effect of PL-M tablets in 34 subjects with COVID-19. Methods: The efficacy of PL-M was evaluated in a randomized, double-blind, placebo-controlled clinical study in patients with mild to moderately severe COVID-19. Primary endpoints included changes in the absolute RT-PCR Ct values of the nucleocapsid and open reading frame (ORF) genes from baseline to days 3 and 7. The incidence of adverse events, changes in blood biochemistry, inflammatory biomarkers, and levels of antibodies against COVID-19 were also evaluated as part of the safety evaluation. Results: PL-M treatment significantly (p = 0.001) increased RT-PCR cycle counts for N and ORF genes on days 3 (Ct values 32.09 ± 2.39 and 30.69 ± 3.38, respectively) and 7 (Ct values 34.91 ± 0.39 and 34.85 ± 0.61, respectively) compared to a placebo treatment. On day 3, 14 subjects in the PL-M group had cycle counts for the N gene above the cut-off value of 29 (target cycle count 29), whereas on day 7, all subjects had cycle counts above the cut-off value. Ct values in placebo subjects were consistently less than 29, and no placebo subjects were RT-PCR-negative until day 7. Most of the symptoms disappeared completely after receiving PL-M treatment for 7 days in more patients compared to the placebo group. Conclusion: PL-M is safe and effective for clinical use in reducing viral loads and promoting rapid viral clearance in COVID-19 patients by inhibiting SARS-CoV-2 entry into cells through the inhibition of Gal-3. Full article

PLG-007 is a developmental therapeutic compound that has been clinically shown to reduce the magnitude of postprandial glucose excursions and has the potential to be an adjunct treatment for diabetes and inflammatory-related diseases. The present investigation is aimed at understanding the molecular mechanism of action of PLG-007 and its galactomannan (GM) components GMα and GMβ (in a 1:4 mass ratio, respectively) on enzyme (i.e., α-amylase, maltase, and lactase) hydrolysis of glucose polymers using colorimetric assays and ¹³C HSQC NMR spectroscopy. The starch–iodine colorimetric assay indicated that GMα strongly inhibits α-amylase activity (~16-fold more potent than GMβ) and thus is the primary active component in PLG-007. ¹³C HSQC experiments, used to follow the α-amylase-mediated hydrolysis of starch and amylopectin, further demonstrate the α-amylase inhibitory effect of GMα via α-amylase-mediated hydrolysis of starch and amylopectin. Maltohexaose (MT6) was used to circumvent the relative kinetic complexity of starch/amylopectin degradation in Michaelis–Menten analyses. The V_max, K_M, and K_i parameters were determined using peak volume integrals from ¹³C HSQC NMR spectra. In the presence of PLG-007 with α-amylase and MT6, the increase in K_M from 7.5 ± 0.6 × 10⁻³ M (control) to 21 ± 1.4 × 10⁻³ M, with no significant change in V_max, indicates that PLG-007 is a competitive inhibitor of α-amylase. Using K_M values, K_i was estimated to be 2.1 ± 0.9 × 10⁻⁶ M; however, the microscopic K_i value of GMα is expected to be larger as the binding stoichiometry is likely to be greater than 1:1. Colorimetric assays also demonstrated that GMα is a competitive inhibitor of the enzymes maltase and lactase. Overall, this study provides insight as to how PLG-007 (GMα) is likely to function in vivo. Full article

Galectins are a family of small, highly conserved, molecular effectors that mediate various biological processes, including chemotaxis and angiogenesis, and that function by interacting with various cell surface glycoconjugates, usually targeting β-galactoside epitopes. Because of their significant involvement in various biological functions and pathologies, galectins have become a focus of therapeutic discovery for clinical intervention against cancer, among other pathological disorders. In this review, we focus on understanding galectin structure-function relationships, their mechanisms of action on the molecular level, and targeting them for therapeutic intervention against cancer. Full article

Chemokines are a family of small, highly conserved cytokines that mediate various biological processes, including chemotaxis, hematopoiesis, and angiogenesis, and that function by interacting with cell surface G-Protein Coupled Receptors (GPCRs). Because of their significant involvement in various biological functions and pathologies, chemokines and their receptors have been the focus of therapeutic discovery for clinical intervention. There are several sub-families of chemokines (e.g., CXC, CC, C, and CX3C) defined by the positions of sequentially conserved cysteine residues. Even though all chemokines also have a highly conserved, three-stranded β-sheet/α-helix tertiary structural fold, their quarternary structures vary significantly with their sub-family. Moreover, their conserved tertiary structures allow for subunit swapping within and between sub-family members, thus promoting the concept of a “chemokine interactome”. This review is focused on structural aspects of CXC and CC chemokines, their functional synergy and ability to form heterodimers within the chemokine interactome, and some recent developments in structure-based chemokine-targeted drug discovery. Full article