Dataset Information

Moving in the Right Direction: Protein Vibrations Steering Function.

ABSTRACT: Nearly all protein functions require structural change, such as enzymes clamping onto substrates, and ion channels opening and closing. These motions are a target for possible new therapies; however, the control mechanisms are under debate. Calculations have indicated protein vibrations enable structural change. However, previous measurements found these vibrations only weakly depend on the functional state. By using the novel technique of anisotropic terahertz microscopy, we find that there is a dramatic change to the vibrational directionality with inhibitor binding to lysozyme, whereas the vibrational energy distribution, as measured by neutron inelastic scattering, is only slightly altered. The anisotropic terahertz measurements provide unique access to the directionality of the intramolecular vibrations, and immediately resolve the inconsistency between calculations and previous measurements, which were only sensitive to the energy distribution. The biological importance of the vibrational directions versus the energy distribution is revealed by our calculations comparing wild-type lysozyme with a higher catalytic rate double deletion mutant. The vibrational energy distribution is identical, but the more efficient mutant shows an obvious reorientation of motions. These results show that it is essential to characterize the directionality of motion to understand and control protein dynamics to optimize or inhibit function.

SUBMITTER: Niessen KA

PROVIDER: S-EPMC5355481 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Moving in the Right Direction: Protein Vibrations Steering Function.

Niessen Katherine A KA Xu Mengyang M Paciaroni Alessandro A Orecchini Andrea A Snell Edward H EH Markelz Andrea G AG

Biophysical journal 20170301 5

Nearly all protein functions require structural change, such as enzymes clamping onto substrates, and ion channels opening and closing. These motions are a target for possible new therapies; however, the control mechanisms are under debate. Calculations have indicated protein vibrations enable structural change. However, previous measurements found these vibrations only weakly depend on the functional state. By using the novel technique of anisotropic terahertz microscopy, we find that there is ...[more]

PMID: 28297652

Similar Datasets

Project description:Following the suggestion that a command encoding current target location feeds the oculomotor system during interceptive saccades, we tested the involvement of the deep superior colliculus (dSC). Extracellular activity of 52 saccade-related neurons was recorded in three monkeys while they generated saccades to targets that were static or moving along the preferred axis, away from (outward) or toward (inward) a fixated target with a constant speed (20°/s). Vertical and horizontal motions were tested when possible. Movement field (MF) parameters (boundaries, preferred vector, and firing rate) were estimated after spline fitting of the relation between the average firing rate during the motor burst and saccade amplitude. During radial target motions, the inner MF boundary shifted in the motion direction for some, but not all, neurons. Likewise, for some neurons, the lower boundaries were shifted upward during upward motions and the upper boundaries downward during downward motions. No consistent change was observed during horizontal motions. For some neurons, the preferred vectors were also shifted in the motion direction for outward, upward, and "toward the midline" target motions. The shifts of boundary and preferred vector were not correlated. The burst firing rate was consistently reduced during interceptive saccades. Our study demonstrates an involvement of dSC neurons in steering the interceptive saccade. When observed, the shifts of boundary in the direction of target motion correspond to commands related to past target locations. The absence of shift in the opposite direction implies that dSC activity does not issue predictive commands related to future target location.NEW & NOTEWORTHY The deep superior colliculus is involved in steering the saccade toward the current location of a moving target. During interceptive saccades, the active population consists of a continuum of cells ranging from neurons issuing commands related to past locations of the target to neurons issuing commands related to its current location. The motor burst of collicular neurons does not contain commands related to the future location of a moving target.

Project description:The treatment of advanced, solid-tumor oncology has been reshaped over the last eight years with the development and FDA approval of several immune checkpoint inhibitors (ICIs) comprised of monoclonal antibodies targeting either PD-1, PD-L1, or CTLA-4 across numerous disease states and indications. Yet, despite their vast expansion of use in both solid-tumor and hematologic malignancies, gastrointestinal cancers have had limited approvals to date. This review article will focus on the use of the currently studied, approved uses and the potential future roles of ICIs in the treatment of cancers of the upper gastrointestinal tract through recent updates on ongoing studies and discussion of phase III studies underway. A single immunotherapy agent, Pembrolizumab, is the only currently approved treatment option in subset of patients with unresectable locally advanced, recurrent, or metastatic esophageal, gastroesophageal, or gastric cancers after failure or intolerance of initial systemic treatments. The only patients who are currently considered for treatment with ICI are those with tumors that are either microsatellite instability-high (MSI-H), DNA mismatch repair deficient (dMMR), or in those with esophageal, GEJ, or gastric adenocarcinomas that have at least one-percent expression of PD-L1 after failing at least two lines of systemic therapy based on early results from the KEYNOTE-059 trial released in 2017, or second-line treatment of locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) with combined positive score (CPS) of 10 or greater based on the combined results from KEYNOTE-180 and KEYNOTE-181 in 2019. However, despite these limited successes thus far, there are numerous ongoing studies evaluating several ICIs for efficacy and safety in esophageal, GEJ, and gastric cancers. These agents are being studied in countless aspects of these malignancies: from neoadjuvant and adjuvant treatment in resectable disease to first-line treatment and beyond in the advanced, unresectable, or metastatic setting. In this article we will review the currently approved agents as well as ongoing clinical trials that will be approaching completion in the next 5 years, potentially altering the landscape of treatment in upper GI malignancies.

Project description:Intra-articular injections of platelet-rich plasma (PRP) and other novel blood-derived products developed specifically for osteoarthritis (OA) can provide pain relief and potential benefits in disease progression. Meta-analyses show the clinical superiority of PRP compared with other intra-articular injections, but results are modest and the effect sizes are small. PRP injections in knee OA are performed indiscriminately, but the clinical response varies enormously between patients because of an array of mixed OA phenotypes. Subgroup analyses are scarce; some studies stratify patients according to radiographic severity and found better results in early OA, without consensus for more advanced stages of the condition. Parallel identification of soluble and imaging biomarkers is essential to personalise and leverage PRP therapies. The inflammatory phenotype is most interesting from the PRP perspective because PRPs modulate inflammation by releasing a large pool of chemokines and cytokines, which interact with synovial fibroblasts and macrophages; in addition, they can modulate the innate immune response. No soluble biomarkers have been discovered that have implications for OA research and PRP interventions. Clinical examination of patients based on their inflammatory phenotype and imaging identification of pain sources and structural alterations could help discern who will respond to PRP. Synovial inflammation and bone marrow lesions are sources of pain, and intra-articular injections of PRP combined with subchondral bone injection can enhance clinical outcomes. Further refining ultrasound phenotypes may aid in personalising PRP therapies. Intra-articular delivery combined with injections in altered ligamentous structures, medial and coronal ligaments or premeniscal pes anserinus showed positive clinical outcomes. Although the evidence supporting these approaches are weak, they merit further consideration to refine PRP protocols and target the right OA phenotypes.

Dataset Information

Moving in the Right Direction: Protein Vibrations Steering Function.

Publications

Moving in the Right Direction: Protein Vibrations Steering Function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets