Non-Equilibrium Polar Localization of Proteins in Bacterial Cells

Many proteins are observed to localize to the poles within bacterial cells. Some bacteria show unipolar localization, yet under different conditions bipolar patterns can emerge. One mechanism for spontaneous polar localization has been shown to involve the combination of protein aggregation and nucleoid occlusion. Whether the different observed patterns represent global energy minima for the cellular system remains to be determined. In this paper we show that for a model consisting only of protein aggregation along with an excluded volume effect due to the DNA polymer, that unipolar patterns are the global energy ground state regardless of protein concentration and DNA density. We extend the model to allow for proteins to be added to the cellular volume at a constant rate and show that bipolar (or multi-foci) patterns emerge as the result of the system being kinetically trapped in a local energy minimum. Lastly we also consider the situation of a growing cell that starts with a pre-existing aggregate at one of the poles and determine conditions under which either unipolar or bipolar patterns can exist at the point when it is ready to divide. This work sheds new interpretations on recently published experimental data and suggests experiments to test whether such a mechanism can drive patterning in bacteria

Probing Long-Range Interactions by Extracting Free Energies From Genome-Wide Chromosome Conformation Capture Data

Background A variety of DNA binding proteins are involved in regulating and shaping the packing of chromatin. They aid the formation of loops in the DNA that function to isolate different structural domains. A recent experimental technique, Hi-C, provides a method for determining the frequency of such looping between all distant parts of the genome. Given that the binding locations of many chromatin associated proteins have also been measured, it has been possible to make estimates for their influence on the long-range interactions as measured by Hi-C. However, a challenge in this analysis is the predominance of non-specific contacts that mask out the specific interactions of interest. Results We show that transforming the Hi-C contact frequencies into free energies gives a natural method for separating out the distance dependent non-specific interactions. In particular we apply Principal Component Analysis (PCA) to the transformed free energy matrix to identify the dominant modes of interaction. PCA identifies systematic effects as well as high frequency spatial noise in the Hi-C data which can be filtered out. Thus it can be used as a data driven approach for normalizing Hi-C data. We assess this PCA based normalization approach, along with several other normalization schemes, by fitting the transformed Hi-C data using a pairwise interaction model that takes as input the known locations of bound chromatin factors. The result of fitting is a set of predictions for the coupling energies between the various chromatin factors and their effect on the energetics of looping. We show that the quality of the fit can be used as a means to determine how much PCA filtering should be applied to the Hi-C data. Conclusions We find that the different normalizations of the Hi-C data vary in the quality of fit to the pairwise interaction model. PCA filtering can improve the fit, and the predicted coupling energies lead to biologically meaningful insights for how various chromatin bound factors influence the stability of DNA loops in chromatin

Localization of aggregating proteins in bacteria depends on the rate of addition

Many proteins are observed to localize to specific subcellular regions within bacteria. Recent experiments have shown that proteins that have self-interactions that lead them to aggregate tend to localize to the poles. Theoretical modeling of the localization of aggregating protein within bacterial cell geometries shows that aggregates can spontaneously localize to the pole due to nucleoid occlusion. The resulting polar localization, whether it be to a single pole or to both was shown to depend on the rate of protein addition. Motivated by these predictions we selected a set of genes from E. coli, whose protein products have been reported to localize when tagged with GFP, and explored the dynamics of their localization. We induced protein expression from each gene at different rates and found that in all cases unipolar patterning is favored at low rates of expression whereas bipolar is favored at higher rates of expression. Our findings are consistent with the predictions of the model, suggesting that localization may be due to aggregation plus nucleoid occlusion. When we expressed GFP by itself under the same conditions, no localization was observed. These experiments highlight the potential importance of protein aggregation, nucleoid occlusion and rate of protein expression in driving polar localization of functional proteins in bacteria

Analysis of Spatial Justice in Access to Urban Services Case study: Yasouj city

Given that the urban spatial structure has a coherent system and is made up of a variety of components and elements, it appears necessary to emphasize its aspects in terms of different service indicators.The instability of any one of these components can have an impact on the entire complex and urban structure.Given the significance of the issue of spatial justice inthe distribution of urban services,the present study aims to investigate how urban services are distributed inYasoujcity and to pinpoint imbalances and inequalities at the of the city.This article used a descriptive-analytical research method.The mean nearest neighbor index was employed to identify the distribution pattern of urban services,and network analysis in Arc GIS software was used to evaluate the status of the city in terms of access to public services.The results of the study indicate the location of service clusters in Yasouj city.In this manner, the service distribution is beneficial in the areas of the city that are in District1 of Region1 and District1 of Region2, but it is unfavorable in the areas of the city that are in the east and northeast as well as the southern neighborhoods.The research's overall findings indicate that Yasouj city's service distribution is in poor shape and that the outskirt areas are less prosperous than the city center neighborhoods.Therefore, it is advised reviewing the urban development plans, paying attention to the present needs and necessities, avoiding the place, spatial, and economic requirements in the location of services, and redistributing services and giving the disadvantaged neighborhoods priorit

Orthopedic oncology residency education, how broad and how deep?

Orthopedic residency training has long been an area of active research and discussion, and as the knowledge and concepts in subspecialties evolve, it is crucial to investigate the implications of these advancements in the musculoskeletal oncology field. It is important to note that the acquisition of surgical skills and scientific knowledge from orthopedic texts alone is not sufficient in this area. Orthopedic residents must also acquire multidisciplinary communication and leadership skills, as well as the mental capacity to make sound clinical decisions. Therefore, this commentary highlights the importance of assessing whether the current curriculum provides adequate preparation for residents’ future careers, despite the fact that the expansion of subspecialties in orthopedic education has undoubtedly enhanced the depth of knowledge and concepts in the field. In addition, orthopedic residents must adopt an open-minded and scientific approach toward orthopedic oncology, which has unique principles. Moreover, it is crucial that general orthopedic surgeons have the necessary skills to manage patients and know when to refer them. By exploring these issues, we hope to continually contribute to ongoing discussions about how to improve orthopedic residencyeducation

Subcutaneous granulocyte colony-stimulating factor administration for subacute traumatic spinal cord injuries, report of neurological and functional outcomes: a double-blind randomized controlled clinical trial

OBJECTIVEGranulocyte-colony stimulating factor (G-CSF) is a major cytokine that has already been clinically verified for chronic traumatic spinal cord injuries (TSCIs). In this study, the authors set out to determine the safety and efficacy of G-CSF administration for neurological and functional improvement in subacute, incomplete TSCI.METHODSThis phase II/III, prospective, double-blind, placebo-controlled, parallel randomized clinical trial was performed in 60 eligible patients (30 treatment, 30 placebo). Patients with incomplete subacute TSCIs with American Spinal Injury Association Impairment Scale (AIS) grades B, C, and D were enrolled. Patients were assessed using the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) scale, Spinal Cord Independence Measure (SCIM-III) and International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS), just before intervention and at 1, 3, and 6 months, after 7 daily subcutaneous administrations of 300 μg/day of G-CSF in the treatment group and placebo in the control group.RESULTSAmong 60 participants, 28 patients (93.3%) in the G-CSF group and 26 patients (86.6%) in the placebo group completed the study protocol. After 6 months of follow-up, the AIS grade remained unchanged in the placebo group, while in the G-CSF group 5 patients (45.5%) improved from AIS grade B to C, 5 (45.5%) improved from AIS grade C to grade D, and 1 patient (16.7%) improved from AIS grade D to E. The mean ± SEM change in ISNCSCI motor score in the G-CSF group was 14.9 ± 2.6 points, which was significantly greater than in the placebo group (1.4 ± 0.34 points, p < 0.001). The mean ± SEM light-touch and pinprick sensory scores improved by 8.8 ± 1.9 and 10.7 ± 2.6 points in the G-CSF group, while those in the placebo group improved by 2.5 ± 0.60 and 1.2 ± 0.40 points, (p = 0.005 and 0.002, respectively). Evaluation of functional improvement according to the IANR-SCIFRS instrument revealed significantly more functional improvement in the G-CSF group (10.3 ± 1.3 points than in the placebo group (3.0 ± 0.81 points; p < 0.001). A significant difference was also observed between the 2 groups as measured by the SCIM-III instrument (29.6 ± 4.1 vs 10.3 ± 2.2, p < 0.001).CONCLUSIONSIncomplete subacute TSCI is associated with significant motor, sensory, and functional improvement after administration of G-CSF.Clinical trial registration no.: IRCT201407177441N3 (www.irct.ir