132 research outputs found
Understanding the roles of glia and circulating leukocytes in neurodegenerative diseases
https://www.frontiersin.org/research-topics/11664/understanding-the-roles-of-glia-and-circulating-leukocytes-in-neurodegenerative-disease
Leishmaniasis
Leishmaniasis is a major global health challenge, affecting approximately 12 million of the poorest people in 100 countries. It is a deforming and fatal disease in the visceral form. Therapies for leishmaniasis are numerically restricted, basically consisting of the administration of miltefosine, pentavalent antimonials, amphotericin B, or pentamidine. This is an important vulnerability against therapy efficiency that must be overcome by the scientific community. This book discusses important aspects of the disease, such as treatment, epidemiology, and molecular and cell biology. The information contained herein is important for young researchers as they seek to develop safe and effective treatments for this neglected tropical disease
Neuroprotection: Rescue from Neuronal Death in the Brain
Dear Colleagues, The brain is vulnerable to injury. Following injury in the brain, apoptosis or necrosis may occur easily, leading to various functional disabilities. Neuronal death is associated with a number of neurological disorders including hypoxic ischemia, epileptic seizures, and neurodegenerative diseases. The brain subjected to injury is regarded to be responsible for the alterations in neurotransmission processes, resulting in functional changes. Oxidative stress produced by reactive oxygen species has been shown to be related to the death of neurons in traumatic injury, stroke, and neurodegenerative diseases. Therefore, scavenging or decreasing free radicals may be crucial for preventing neural tissues from harmful adversities in the brain. Neurotrophic factors, bioactive compounds, dietary nutrients, or cell engineering may ameliorate the pathological processes related to neuronal death or neurodegeneration and appear beneficial for improving neuroprotection. As a result of neuronal death or neuroprotection, the brain undergoes activity-dependent long-lasting changes in synaptic transmission, which is also known as functional plasticity. Neuroprotection implying the rescue from neuronal death is now becoming one of global health concerns. This Special Issue attempts to explore the recent advances in neuroprotection related to the brain. This Special Issue welcomes original research or review papers demonstrating the mechanisms of neuroprotection against brain injury using in vivo or in vitro models of animals as well as in clinical settings. The issues in a paper should be supported by sufficient data or evidence. Prof. Bae Hwan Lee Guest Edito
Spatial And Temporal Control Of The Kinesin Motors Kif11 And Kif22 In Mitosis
Mitosis requires the control of mechanical forces generated by kinesin motors to ensure equal segregation of chromosomes into two daughter cells. Two kinesins contributing to these forces are KIF11 (or Eg5), which crosslinks and slides anti-parallel microtubules, and KIF22 (or Kid), which binds to microtubules and chromosome arms. This work addresses how post-translational modifications and pathogenic mutations alter the structure and function of KIF11 and KIF22.
The homotetrameric kinesin KIF11 is subject to acetylation at lysine 146, a residue in the a2 helix of the motor domain. The effect of this acetylation was assessed at the single molecule and cellular levels using an acetylation mimetic mutant, KIF11 K146Q. In single molecule optical trapping assays, KIF11 K146Q dimers are more likely than wild type (WT) dimers to stall rather than dissociate from the microtubule under load. Based on these results, acetylated KIF11 motors would be predicted to stall microtubule sliding during spindle formation, acting as a brake and slowing pole separation. To test this prediction, mCherry (mCh) tagged KIF11 WT and K146Q motors were expressed at low levels in HeLa cells. To compare the functional activity of WT and K146Q KIF11, cells were treated with the KIF11 inhibitor monastrol, resulting in mitotic arrest and the formation of monopolar spindles. Bipolar spindle formation following monastrol washout was then imaged and measured. While spindle lengths at the completion of pole separation were similar in cells expressing mCh-KIF11 WT or K146Q, pole separation occurred at a significantly slower velocity in cells expressing mCh-KIF11 K146Q than in cells expressing mCh-KIF11 WT. This velocity difference is consistent with KIF11 acetylated at K146 stalling rather than dissociating from the microtubule and acting as a brake during pole separation. Acetylation at a2 helix lysine 146 represents a mechanism by which the activity of KIF11 may be controlled in mitotic cells.
Structural changes in the a2 helix also affect the activity of KIF22. Point mutations at P148 and R149 in this domain, as well as at V475 in the tail of the motor, dominantly cause a skeletal developmental disorder. The effect of these pathogenic mutations on the function of KIF22 in mitosis was investigated. KIF22 uses plus end-directed motility and direct binding to chromosome arms to generate polar ejection forces, which contribute to chromosome congression and alignment in metaphase. Mutant KIF22 generated forces to move chromosomes toward microtubule plus ends in prometaphase, indicating that mutant motors are active. As cells proceeded through mitosis, however, mutations disrupted anaphase chromosome segregation and caused chromosome recongression, which resulted in reduced proliferation, abnormal daughter cell nuclear morphology, and, in a subset of cells, cytokinesis failure. This phenotype could be explained by a failure of KIF22 to inactivate in anaphase, resulting in continued generation of polar ejection forces and impaired anaphase chromosome segregation. Consistent with this model, a phosphomimetic mutation in the tail of KIF22 which constitutively activates the motor phenocopied the effect of pathogenic mutations. Mimicking the phosphorylation of a2 helix residue T158 also prevented the inactivation of KIF22 in anaphase, demonstrating the importance of this region of the motor domain in controlling KIF22 activity
Path Reweighting Methods for underdamped Langevin Dynamics for Molecular Systems
Knowledge about the dynamical properties of biomolecules is essential to understand their function in biological processes. This thesis approaches the task to compute dynamical properties with two different strategies. Part A focuses on Molecular Dynamics (MD) simulations combined with path reweighting. Three of the most widely used underdamped Langevin integrators for MD simulations are the splitting methods BAOAB and BAOA which are available in the MD packages OpenMM and AMBER and the Gromacs Stochastic Dynamics (GSD) integrator implemented in GROMACS. We found that all three integrators are equivalent configurational sampling algorithms and thus yield configurational properties at equivalent accuracy. MD simulations with stochastic integrators such as Langevin integrators offer the possibility to reweight estimated dynamical properties using path reweighting. With path reweighting we can for example recover the original dynamics from MD simulation that have been conducted with enhanced sampling methods. The key component of path reweighting is the path reweighting factor M which strongly depends on the chosen integrator. We derive M_L for underdamped Langevin dynamics propagated by a variant of the Langevin Leapfrog integrator. Additionally, we present two strategies which can be used as blueprints to straightforwardly derive M_L for other Langevin integrators. The previously reported path reweighting factor matches the Euler-Maruyama integrator for overdamped Langevin dynamics and was used as standard reweighting factor even though the MD simulation was conducted with an underdamped Langevin integrator. We prove that this path reweighting factors differs from the exact M_L only by O(ξ^4 ∆t^4) and thus yields highly accurate dynamical reweighting results (∆t is the integration time step, and ξ is the collision rate.).
Part B of this thesis combines experimental and theoretical approaches to investigate Multiple Inositol Polyphosphate Phosphatase 1 (MINPP1)-mediated inositol polyphosphate (InsP) networks. We use 13C-labeling experiments combined with nuclear magnetic resonance spectroscopy (NMR) to uncover a novel branch of InsP dephosphorylation in human cells. Additionally, we extract the corresponding reaction rates using a Markovian kinetic scheme as theoretical model to describe the network
PROGRAM and PROCEEDINGS THE NEBRASKA ACADEMY OF SCIENCES -- April 22, 2022
Aeronautics & Space Science -- Chairperson(s): Dr. Scott Tarry & Michaela Lucas
ANTHROPOLOGY SECTION Chairperson: Dr. Taylor Livingston
APPLIED SCIENCE & TECHNOLOGY SECTION Chairperson: Mary Ettel
BIOLOGICAL SCIENCES SECTION Chairperson: Therese McGinn
BIOMEDICAL SCIENCES SECTION Chairperson: Annemarie Shibata
CHEMISTRY SECTION Chairperson: Nathanael Fackler
EARTH SCIENCES SECTION Chairperson: Irina Filina
ENVIRONMENTAL SCIENCES SECTION Chairperson: Mark Hammer
PHYSICS SECTION Chairperson: Adam Davis
FRIENDS OF THE ACADEMY
2022 Maiben Lecturer: Dan Sitzman
2022 FRIEND OF SCIENCE AWARD TO: Julie Sigmon and Chris Schabe
The Use of Protein Modification and Ion Mobility-Mass Spectrometry to Probe Protein Structure
Mass spectrometry (MS) is considered to be indispensable technology for the use in modern pharmaceutical drug discovery and development processes. However, MS is rarely used as a screening technology for protein structure. In this project, ion mobility-mass spectrometry (IM-MS) methods are developed to investigate protein structure with the use of chemical modification and genetic modification.
Collision induced unfolding (CIU) method was optimised for measuring the mobility of ubiquitin (Ub) drift traces and the collision cross section (CCS) was calculated. The mobility was measured in the trap by acquiring several voltages and monitoring the drift trace of the lower state ion ([M+6H]6+ and [M+5H]5+. By combining the CIU method and chemical modification of proteins we can enhance the understanding of protein structure in the gas phase.
Acetylation was carried out first on ubiquitin, the results showed a difference in the drift trace for ubiquitin after acetylation. This led to inspection of the MS/MS spectrum of intact Ub. The b-ion, corresponding to fragmentation at lysine residue K6, showed this residue to have importance for the structural integrity of the protein. Therefore, different K6 mutant were obtained and their CIU were acquired. The results confirmed that the K6 reside is indeed crucial in the ubiquitin unfolding pathway. Acetylation of this residue, or its replacement with alanine (K6A Ub) produced a conformationally destabilised form of the protein, which unfolded at lower collision energies. Wild type Ub and its mutant K6O mutant shared the fact the K6 is present, and the result showed they have the same CIU unfolding profile, In contrast the NoK and K6R mutant where the K6 has been modified to R, resulted in a more stable compact structure as evidenced by the CIU profile.
Diethylpyrocarbonate modification of the single the histidine residue in Ub, which was postulated to interact with K6 in the gas phase structure resulted in modest destabilisation of compact Ub, while succinylation of the N-terminus had no clear effect on stability of the protein structure. Studies of molecular dynamics and charge distribution support the experimental data by rationalising the importance of protonated K6 and H68 interaction in the gas-phase stabilization of the native folding of Ub.
Finally, the ubiquitin associating domain UBA2 was destabilised by adding an acetyl group to the N-terminus of the protein. The observation was interpreted by the breaking of a key intramolecular interaction between the N-terminus and the glutamate residue E22. Moreover, the behavious of different in charge states showed the important of addition of charge on the structure of proteins
Urological Cancer 2021
Cancer of the urological sphere is a disease continuously increasing in numbers in the statistics of tumor malignancies in Western countries. Although this fact is mainly due to the contemporary increase of life expectancy of the people in these geographic areas, many other factors do contribute as well to this growth. Urological cancer is a complex and varied disease of different organs and mainly affects the male population. In fact, kidney, prostate, and bladder cancer are regularly included in the top-ten list of the most frequent neoplasms in males in most statistics. The female population, however, has also increasingly found itself affected by renal and bladder cancer in the last decade. Considering these altogether, urological cancer is a problem of major concern in developed societies. This Topic Issue of Cancers intends to shed some light into the complexity of this field and will consider all useful and appropriate contributions that scientists and clinicians may provide to improve urological cancer knowledge for patients’ benefit. The precise identification of the molecular routes involved, the diagnostic pathological criteria in the grey zones, the dilemma of T1G3 management, and the possible treatment options between superficial, nonmuscle-invasive and muscle-invasive diseases will be particularly welcomed in this Issue
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