Accurate Determination of Conformational Transitions in Oligomeric Membrane Proteins

The structural dynamics governing collective motions in oligomeric membrane proteins play key roles in vital biomolecular processes at cellular membranes. In this study, we present a structural refinement approach that combines solid-state NMR experiments and molecular simulations to accurately describe concerted conformational transitions identifying the overall structural, dynamical, and topological states of oligomeric membrane proteins. The accuracy of the structural ensembles generated with this method is shown to reach the statistical error limit, and is further demonstrated by correctly reproducing orthogonal NMR data. We demonstrate the accuracy of this approach by characterising the pentameric state of phospholamban, a key player in the regulation of calcium uptake in the sarcoplasmic reticulum, and by probing its dynamical activation upon phosphorylation. Our results underline the importance of using an ensemble approach to characterise the conformational transitions that are often responsible for the biological function of oligomeric membrane protein states

Explosions of water clusters in intense laser fields

Energetic, highly-charged oxygen ions, $O^{q+}$ ($q\leq 6$), are copiously produced upon laser field-induced disassembly of highly-charged water clusters, $(H_2O)_n$ and $(D_2O)_n$, $n\sim$ 60, that are formed by seeding high-pressure helium or argon with water vapor. $Ar_n$ clusters (n$\sim$40000) formed under similar experimental conditions are found undergo disassembly in the Coulomb explosion regime, with the energies of $Ar^{q+}$ ions showing a $q^2$ dependence. Water clusters, which are argued to be considerably smaller in size, should also disassemble in the same regime, but the energies of fragment O$^{q+}$ ions are found to depend linearly on $q$ which, according to prevailing wisdom, ought to be a signature of hydrodynamic expansion that is expected of much larger clusters. The implication of these observations on our understanding of the two cluster explosion regimes, Coulomb explosion and hydrodynamic expansion, is discussed. Our results indicate that charge state dependences of ion energy do not constitute an unambiguous experimental signature of cluster explosion regime.Comment: Submitted to Phys. Rev.

Polymorphism rs3088232 in the BRDT gene is associated with idiopathic male infertility in the West Siberian Region of Russia

Allelic variants of genes involved in spermatogenesis can contribute to the genetic predisposition to idiopathic male infertility. In the present study we investigated the association of polymorphism rs3088232 in the BRDT gene with the risk of this pathology on the sample of 105 infertile patients and 230 healthy controls. We revealed the association of allele G (OR = 1.80; CI 1.16—2.80; p = 0.008) and genotype GG (OR = 6.47; CI 1.23—34.15; p = 0.01) with idiopathic male infertility

Transmembrane helix dynamics of bacterial chemoreceptors supports a piston model of signalling.

Transmembrane α-helices play a key role in many receptors, transmitting a signal from one side to the other of the lipid bilayer membrane. Bacterial chemoreceptors are one of the best studied such systems, with a wealth of biophysical and mutational data indicating a key role for the TM2 helix in signalling. In particular, aromatic (Trp and Tyr) and basic (Arg) residues help to lock α-helices into a membrane. Mutants in TM2 of E. coli Tar and related chemoreceptors involving these residues implicate changes in helix location and/or orientation in signalling. We have investigated the detailed structural basis of this via high throughput coarse-grained molecular dynamics (CG-MD) of Tar TM2 and its mutants in lipid bilayers. We focus on the position (shift) and orientation (tilt, rotation) of TM2 relative to the bilayer and how these are perturbed in mutants relative to the wildtype. The simulations reveal a clear correlation between small (ca. 1.5 Å) shift in position of TM2 along the bilayer normal and downstream changes in signalling activity. Weaker correlations are seen with helix tilt, and little/none between signalling and helix twist. This analysis of relatively subtle changes was only possible because the high throughput simulation method allowed us to run large (n = 100) ensembles for substantial numbers of different helix sequences, amounting to ca. 2000 simulations in total. Overall, this analysis supports a swinging-piston model of transmembrane signalling by Tar and related chemoreceptors

Analysis of the dynamics and structure of morbidity of athletes of the national teams of Moscow based on the results of medical examination

Objective: The aim of the study was to analyze the structure and dynamics of morbidity of athletes, members of sports teams of the city of Moscow based on the results of an in-depth medical examination in the period 2017–2021.Materials and methods: The data of the medical examination of athletes, which took place at the Moscow scientific and Practical Center for Medical Rehabilitation, restorative and sports medicine, including instrumental, functional and laboratory studies from 2017 to 2021, were analyzed. In 2017, 15176 athletes were examined, in 2018 and 2019, 11200, in 2020, 10080 people and in 2021–11922 athletes.Results: The results of the study showed an increase in the proportion of amenorrhea within the triad of athletes, an increase in general therapeutic morbidity, diseases of the gastrointestinal tract, among which the proportion of secondary hyperbilirubinemia in 2021 increased 3 times compared to 2020, which, in our opinion, is also due to the impact of the pandemic and quarantine restrictions.The high prevalence of ophthalmological morbidity of athletes and changes in the cardiovascular system is shown. During 2017–2021, a change in the structure of cardiac morbidity was revealed in the form of an increase in the proportion of cardiac arrhythmias and hypertensive response to stress.An increase in the endocrine morbidity of athletes in 2021 was revealed due to an increase in the proportion of hypothyroidism and more frequent detection of hyperthyroidism, possibly related to the COVID-19 pandemic, which requires further research.There was also an increase in diseases of the skin and genitourinary system in athletes. Psychological problems of athletes increased during the observation period from 2017 to 2021. There was no significant dynamics of surgical and traumatological diseases, otolaryngological pathologу.Conclusion: The results of the study indicate the importance of regular full-fledged examination of athletes, identification of various functional disorders and diseases for their timely prevention and treatment in order to preserve the health of athletes and improve athletic performance

The Cerebral Microvasculature in Schizophrenia: A Laser Capture Microdissection Study

BACKGROUND: Previous studies of brain and peripheral tissues in schizophrenia patients have indicated impaired energy supply to the brain. A number of studies have also demonstrated dysfunction of the microvasculature in schizophrenia patients. Together these findings are consistent with a hypothesis of blood-brain barrier dysfunction in schizophrenia. In this study, we have investigated the cerebral vascular endothelium of schizophrenia patients at the level of transcriptomics. METHODOLOGY/PRINCIPAL FINDINGS: We used laser capture microdissection to isolate both microvascular endothelial cells and neurons from post mortem brain tissue from schizophrenia patients and healthy controls. RNA was isolated from these cell populations, amplified, and analysed using two independent microarray platforms, Affymetrix HG133plus2.0 GeneChips and CodeLink Whole Human Genome arrays. In the first instance, we used the dataset to compare the neuronal and endothelial data, in order to demonstrate that the predicted differences between cell types could be detected using this methodology. We then compared neuronal and endothelial data separately between schizophrenic subjects and controls. Analysis of the endothelial samples showed differences in gene expression between schizophrenics and controls which were reproducible in a second microarray platform. Functional profiling revealed that these changes were primarily found in genes relating to inflammatory processes. CONCLUSIONS/SIGNIFICANCE: This study provides preliminary evidence of molecular alterations of the cerebral microvasculature in schizophrenia patients, suggestive of a hypo-inflammatory state in this tissue type. Further investigation of the blood-brain barrier in schizophrenia is warranted

Orientation and dynamics of transmembrane peptides: the power of simple models

In this review we discuss recent insights obtained from well-characterized model systems into the factors that determine the orientation and tilt angles of transmembrane peptides in lipid bilayers. We will compare tilt angles of synthetic peptides with those of natural peptides and proteins, and we will discuss how tilt can be modulated by hydrophobic mismatch between the thickness of the bilayer and the length of the membrane spanning part of the peptide or protein. In particular, we will focus on results obtained on tryptophan-flanked model peptides (WALP peptides) as a case study to illustrate possible consequences of hydrophobic mismatch in molecular detail and to highlight the importance of peptide dynamics for the experimental determination of tilt angles. We will conclude with discussing some future prospects and challenges concerning the use of simple peptide/lipid model systems as a tool to understand membrane structure and function