The αβ T-cell receptor (TCR) on each T lymphocyte mediates exquisite specificity for a particular foreign peptide bound to a major histocompatibility complex molecule (pMHC) displayed on the surface of altered cells. This recognition stimulates protection in the mammalian host against intracellular pathogens, including viruses, and involves piconewton forces that accompany pMHC ligation. Physical forces are generated by T-lymphocyte movement during immune surveillance as well as by cytoskeletal rearrangements at the immunological synapse following cessation of cell migration. The mechanistic explanation for how TCRs distinguish between foreign and self-peptides bound to a given MHC molecule is unclear: peptide residues themselves comprise few of the TCR contacts on the pMHC, and pathogen-derived peptides are scant among myriad self-peptides bound to the same MHC class arrayed on infected cells. Using optical tweezers and DNA tether spacer technology that permit piconewton force application and nanometer scale precision, we have determined how bioforces relate to self versus nonself discrimination. Single-molecule analyses involving isolated αβ-heterodimers as well as complete TCR complexes on T lymphocytes reveal that the FG loop in the β-subunit constant domain allosterically controls both the variable domain module's catch bond lifetime and peptide discrimination via force-driven conformational transition. In contrast to integrins, the TCR interrogates its ligand via a strong force-loaded state with release through a weakened, extended state. Our work defines a key element of TCR mechanotransduction, explaining why the FG loop structure evolved for adaptive immunity in αβ but not γδTCRs or immunoglobulins.mechanosensor | T-cell receptor | peptide discrimination | optical tweezers | catch bond A ntigen recognition by T lymphocytes is a crucial feature of adaptive immunity. This process requires the interaction of a clone-specific T-cell receptor (TCR) via its membrane distal variable module with a cognate peptide bound to a major histocompatibility complex molecule (pMHC) (refs. 1 and 2 and references therein). "Foreign" peptide antigens derived from infectious or other cell-altering processes including oncogenic transformation are presented either on a surface of the perturbed cell directly or indirectly via cross-presentation on antigen-presenting cells (APC). In either case, ligation of the relevant TCRαβ heterodimer initiates a cascade of T-cell signaling events following exposure of the immunoreceptor tyrosine-based activation motif (ITAM) elements in the cytoplasmic tail of the noncovalently associated subunits (CD3eγ, CD3eδ, and CD3ζζ) composing the TCR complex in 1:1:1:1 dimer stoichiometry. This accessibility allows the active kinase, Lck, to bind and phosphorylate ITAMs followed by recruitment and activation of a second tyrosine kinase, ZAP-70 (3-6). In turn, multiple downstream pathways are engaged, including transcriptional regulators controlling activation and differentiation of T cells (7,8). Thym...

Influenza hemagglutinin (HA) is the canonical type I viral envelope glycoprotein and provides a template for the membrane-fusion mechanisms of numerous viruses. The current model of HA-mediated membrane fusion describes a static "spring-loaded" fusion domain (HA2) at neutral pH. Acidic pH triggers a singular irreversible conformational rearrangement in HA2 that fuses viral and cellular membranes. Here, using single-molecule Förster resonance energy transfer (smFRET)-imaging, we directly visualized pH-triggered conformational changes of HA trimers on the viral surface. Our analyses reveal reversible exchange between the pre-fusion and two intermediate conformations of HA2. Acidification of pH and receptor binding shifts the dynamic equilibrium of HA2 in favor of forward progression along the membrane-fusion reaction coordinate. Interaction with the target membrane promotes irreversible transition of HA2 to the post-fusion state. The reversibility of HA2 conformation may protect against transition to the post-fusion state prior to arrival at the target membrane.

The search for efficient low-molecular-weight gelators (LMWGs) with possible structure-activity correlation is on the rise. The present work reports a novel set of amphiphilic dipeptide-based carboxylic acids capable of efficiently gelating organic solvents. More interestingly, their sodium salts showed enhanced efficiency in organogelation with the additional ability to gelate water. Electrostatic interactions present in the aggregation of the sodium carboxylates of amphiphilic dipeptides seem to be important because some of the nongelator carboxylic acids turned out to be excellent gelators upon salt formation. The combinations and sequence of the amino acids in the dipeptide moiety were systematically altered to understand the collective importance of the nonpolar aliphatic/aromatic substitution in amino acids in the self-assembling behavior of amphiphiles. Almost a 20-fold enhancement in the gelation ability was observed on reversing the sequence of the amino acid residues, and in some cases, nongelators were transformed to efficient gelators. Spectroscopic and microscopic studies of these thermoreversible organo/hydrogels revealed that balanced participation of the noncovalent interactions including hydrogen bonding and van der Waals interactions are crucial for organo/hydrogelation. These dipeptides selectively gelate organic solvents from their mixtures with water, and the xerogels prepared from these organogels showed time-dependent adsorption of dyes such as crystal violet. The most remarkable feature of these gelators is the pH responsiveness, which was aptly utilized for the pH-dependent phase-selective gelation of either solvent in a biphasic mixture of oil and water. The dissimilar gelation ability of the acid and its salt originating from the pH responsiveness of the amphiphilic dipeptide was employed in the instant removal of large amounts of dyes for wastewater treatment.

The present work reports a new class of antibacterial hydrogelators based on anti-inflammatory N-fluorenyl-9-methoxycarbonyl (Fmoc) amino acid/peptides functionalized cationic amphiphiles. These positively charged hydrogelators were rationally designed and developed by the incorporation of a pyridinium moiety at the C-terminal of Fmoc amino acid/peptides, because the pyridinium-based amphiphiles are a known antibacterial agent due to their cell membrane penetration properties. The Fmoc amino acid/peptide-based cationic amphiphiles efficiently gelate (minimum gelation concentration approximately 0.6-2.2%, w/v) water at room temperature. Judicious variation of amino acid and their sequences revealed the architectural dependence of the molecules on their gelation ability. Several microscopic techniques like field-emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) were used to obtain the visual insight of the morphology of the gel network. A number of spectroscopic techniques like circular dichroism, FTIR, photoluminescence, and XRD were utilized to know the involvement of several noncovalent interactions and participation of the different segments of the molecules during gelation. Spectroscopic results showed that the pi-pi interaction and intermolecular hydrogen bonding are the major responsible factors for the self-assembled gelation process that are oriented through an antiparallel beta-sheet arrangement of the peptide backbone. These Fmoc-based cationic molecules exhibited efficient antibacterial activity against both Gram-positive and Gram-negative bacteria.

The race to develop newer materials with superior properties/applications in diversified fields is gathering momentum in modern day science. In this context, an exciting avenue of research deals with the development of hybrid materials resulting from the combination of gels with nanoparticles of different origins. These varying kinds of nanoparticles (inorganic nanoparticles, Au/Ag based nanoparticles and carbonaceous nanostructures like carbon nanotube and graphene) are being used in conjunction with diverse self-assemblies to develop gel-nanocomposites with the scope of generating advanced applications. The present review will track the noteworthy progress of gel-nanocomposites and also will highlight the recent advances in their synthesis, improved properties/features and applications for developing mechanically robust materials to antimicrobial hydrogels.