Subsets of Slow Dynamic Modes Reveal Global Information Sources as Allosteric Sites.

Allostery is a key biological control mechanism, and dynamic information flow provides a perspective to describe allosteric interactions in causal relationships. Here, as a novel implementation of the Gaussian Network Model (GNM) based Transfer Entropy (TE) calculations, we show that the dissection of dynamic information into subsets of slow dynamic modes discloses different layers of multi-directional allosteric pathways inherent in a given protein structure. In these subsets of slow modes, the degree of collectivity (Col) in the information transfer of residues with their TE values (TECol score) identifies distinct residues as powerful effectors, global information sources; showing themselves with a high dynamic capacity to collectively disseminate information to others. As exemplified on aspartate transcarbamoylase (ATCase), Na+/K+-adenosine triphosphatase (Na+/K+-ATPase), and human transient receptor potential melastatin 2 (TRPM2) along with a dataset of 20 proteins, these specific residues are associated with known active and allosteric sites. These information source residues, which collectively control others and lead allosteric communication pathways, hint at plausible binding sites for structure-based rational drug design.

Structural insight into host plasma membrane association and assembly of HIV-1 matrix protein.

Oligomerization of Pr55Gag is a critical step of the late stage of the HIV life cycle. It has been known that the binding of IP6, an abundant endogenous cyclitol molecule at the MA domain, has been linked to the oligomerization of Pr55Gag. However, the exact binding site of IP6 on MA remains unknown and the structural details of this interaction are missing. Here, we present three high-resolution crystal structures of the MA domain in complex with IP6 molecules to reveal its binding mode. Additionally, extensive Differential Scanning Fluorimetry analysis combined with cryo- and ambient-temperature X-ray crystallography and GNM-based transfer entropy calculations identify the key residues that participate in IP6 binding. Our data provide novel insights about the multilayered HIV-1 virion assembly process that involves the interplay of IP6 with PIP2, a phosphoinositide essential for the binding of Pr55Gag to membrane. IP6 and PIP2 have neighboring alternate binding sites within the same highly basic region (residues 18-33). This indicates that IP6 and PIP2 bindings are not mutually exclusive and may play a key role in coordinating virion particles' membrane localization. Based on our three different IP6-MA complex crystal structures, we propose a new model that involves IP6 coordination of the oligomerization of outer MA and inner CA domain's 2D layers during assembly and budding.

Turkish Pediatricians' Awareness of Children's Oral Health.

Purpose: To assess the level of knowledge about the common approaches to children's oral and dental health in a sample of Turkish pediatricians.
Methods: A total of 130 pediatricians responded to an 18-question electronic survey about their personal information and knowledge about children's oral health. The data obtained were analyzed using the Mann-Whitney U, Kruskal-Wallis, and multiple linear regression analysis tests.
Results: The mean pediatricians' knowledge score was 7.99±1.67 (range: zero to 11) and the median score was eight. There were no statistically signification relationships between the pediatricians' mean knowledge, their sociodemographic factors and their educational background about children's oral health.
Conclusion: Turkish pediatricians need more pediatric oral health education.

Effect of different doses of radiation on morphogical, mechanical and chemical properties of primary and permanent teeth-an in vitro study.

BACKGROUND: Radiotherapy, applied to the head and neck region, can cause radiation side effects such as reduction of saliva and radiation caries. The aim of this study was to perform an in vitro assessment of the effects of radiation therapy on the morphological, mechanical, and chemical properties of primary and permanent teeth. METHODS: One hundred four extracted human teeth (52 impacted wisdom teeth, 52 primary molar teeth) were used. The teeth were divided into two parts in the mesiodistal direction. Of the 98 teeth, the vestibular sections were used for the vickers analysis and lingual sections were used for the Inductively Coupled Plasma-Optical Emission Spectrometry (ICP-OES) analysis. The teeth in the experimental group were fixed to wax models. Each model had an equal number of teeth (n = 7). The doses were applied to the teeth for 6 weeks; 5 week days and 2Gy daily. After the radiotherapy was conducted weekly, a wax model was taken from radiation reception. Along with the elemental contents (Na, K, Mg, P, and Ca) of the teeth, enamel and dentin microhardness was evaluated, and SEM analyzes were performed on 6 teeth. RESULTS: Radiation caused a decrease in microhardness of enamel and dentin (p < 0.05). In the elemental analysis by ICP-OES, it was observed that there were decreases in all elements after 60Gy compared to the control group (p < 0.05). In the experimental groups, amorphous structures were encountered in SEM images. CONCLUSIONS: Radiation has negative effects on the teeth structure and additional studies are needed in this regard. This study indicates that radiotherapy patients are at a higher risk for dental caries.

Distinct Allosteric Networks Underlie Mechanistic Speciation of ABC Transporters.

ABC transporters couple the energy of ATP hydrolysis to the transmembrane transport of biomolecules. Here, we investigated the allosteric networks of three representative ABC transporters using a hybrid molecular simulations approach validated by experiments. Each of the three transporters uses a different allosteric network: in the constitutive B12 importer BtuCD, ATP binding is the main driver of allostery and docking/undocking of the substrate-binding protein (SBP) is the driven event. The allosteric signal originates at the cytoplasmic side of the membrane before propagating to the extracellular side. In the substrate-controlled maltose transporter, the SBP is the main driver of allostery, ATP binding is the driven event, and the allosteric signal propagates from the extracellular to the cytoplasmic side of the membrane. In the lipid flippase PglK, a cyclic crosstalk between ATP and substrate binding underlies allostery. These results demonstrate speciation of biological functions may arise from variations in allosteric connectivity.

Single-molecule probing of the conformational homogeneity of the ABC transporter BtuCD.

ATP-binding cassette (ABC) transporters use the energy of ATP hydrolysis to move molecules through cellular membranes. They are directly linked to human diseases, cancer multidrug resistance, and bacterial virulence. Very little is known of the conformational dynamics of ABC transporters, especially at the single-molecule level. Here, we combine single-molecule spectroscopy and a novel molecular simulation approach to investigate the conformational dynamics of the ABC transporter BtuCD. We observe a single dominant population of molecules in each step of the transport cycle and tight coupling between conformational transitions and ligand binding. We uncover transient conformational changes that allow substrate to enter the transporter. This is followed by a 'squeezing' motion propagating from the extracellular to the intracellular side of the translocation cavity. This coordinated sequence of events provides a mechanism for the unidirectional transport of vitamin B12 by BtuCD.

Sequence-specific random coil chemical shifts of intrinsically disordered proteins.

Although intrinsically disordered proteins (IDPs) are widespread in nature and play diverse and important roles in biology, they have to date been little characterized structurally. Auspiciously, intensified efforts using NMR spectroscopy have started to uncover the breadth of their conformational landscape. In particular, polypeptide backbone chemical shifts are emerging as powerful descriptors of local dynamic deviations from the "random coil" state toward canonical types of secondary structure. These digressions, in turn, can be connected to functional or dysfunctional protein states, for example, in adaptive molecular recognition and protein aggregation. Here we describe a first inventory of IDP backbone (15)N, (1)H(N), (1)H(α), (13)C(O), (13)C(ß), and (13)C(α) chemical shifts using data obtained for a set of 14 proteins of unrelated sequence and function. Singular value decomposition was used to parametrize this database of 6903 measured shifts collectively in terms of 20 amino acid-specific random coil chemical shifts and 40 sequence-dependent left- and right-neighbor correction factors, affording the ncIDP library. For natively unfolded proteins, random coil backbone chemical shifts computed from the primary sequence displayed root-mean-square deviations of 0.65, 0.14, 0.12, 0.50, 0.36, and 0.41 ppm from the experimentally measured values for the (15)N, (1)H(N), (1)H(α), (13)C(O), (13)C(ß), and (13)C(α) chemical shifts, respectively. The ncIDP prediction accuracy is significantly higher than that obtained with libraries for small peptides or "coil" regions of folded proteins.

Predictors of suicidal behavior in a sample of Turkish suicide attempters.

In a Turkish sample, 100 suicide attempters, were compared with 60 healthy controls on measures of hopelessness, depression, and suicidal ideation. Suicide attempters were more depressive, more hopeless, and displayed greater suicidal ideation than healthy controls. Depression severity rather than hopelessness correlated with suicidal intent. Suicide lethality was independent of depression severity, hopelessness, and suicidal ideation and intent, suggesting that lethality is likely due to chance.

Alexithymia and suicidal behavior.

A number of factors including hopelessness have been identified as amplifying suicide risk. Alexithymia has recently been investigated as a predictor of suicidal behavior. The prevalence of the personality trait alexithymia in suicide attempters as well as other predictors of suicidal behavior were investigated in this study. One hundred suicide attempters were compared to 60 healthy controls on the measures of hopelessness, alexithymia, depression and suicidal ideation. First-timers and repetitive suicide attempters, males and females, married and unmarried suicide attempters were compared to each other in the suicide attempter group. The correlations of hopelessness, depression and alexithymia with suicidal intent and suicide lethality were investigated. The suicide attempter group did not display significantly higher scores on the alexithymia measure, compared to healthy controls. Alexithymia neither seemed to be a prevalent personality trait in suicide attempters nor a sensitive predictor of suicidality. The subscales of Toronto Alexithymia Scale measuring difficulty in identification and expression of feelings also did not reveal a significant difference between the two groups. Suicide attempters were more depressive, more hopeless and displayed greater suicidal ideation than healthy controls. Severity of depression was a stronger predictor of suicidal intent than hopelessness in the suicide attempter group. The lethality of the suicide attempt did not correlate with any of the psychometric measures. These findings propose that difficulty in the identification and articulation of feelings does not comprise a risk factor for suicidal behavior.