Self-organisation in LTE networks : an investigation

Mobile telecommunications networks based on Long Term Evolution (LTE) technology promise faster throughput to their users. LTE networks are however susceptible to a phenomenon known as inter-cell interference which can greatly reduce the throughput of the network causing unacceptable degradation of performance for cell edge users. A number of approaches to mitigating or minimising inter-cell interference have been presented in the literature such as randomisation, cancellation and coordination. The possibility of coordination between network nodes in an LTE network is made possible through the introduction of the X2 network link. This thesis explores approaches to reducing the effect of inter-cell interference on the throughput of LTE networks by using the X2 link to coordinate the scheduling of radio resources. Three approaches to the reduction of inter-cell interference were developed. Localised organisation is a centralised scheme in which a scheduler is optimised by a Genetic Algorithm (GA) to reduce interference. Networked organisation makes use of the X2 communications link to enable the network nodes to exchange scheduling information in a way that lowers the level of interference across the whole network. Finally a more distributed and de-centralised approach is taken in which each of the network nodes optimises its own scheduling in coordination with its neighbours. An LTE network simulator was built to allow for experimental comparison between these techniques and a number of existing approaches and to serve as a test bed for future algorithm development. These approaches were found to significantly improve the throughput of the cell edge users who were most affected by intereference. In particular the networked aspect of these approaches yielded the best initial results showing clear improvement over the existing state of the art. The distributed approach shows significant promise given further development.EPSR

Additional file 3: Figure S2. of Long-term leukocyte reconstitution in NSG mice transplanted with human cord blood hematopoietic stem and progenitor cells

Comparison of human cell chimerism between peripheral blood and spleen or bone marrow. Paired t test (left) and correlation (right) analyses were performed of human cell chimerism in peripheral blood and spleen (A) or bone marrow (B) (TIF 9278 kb

Additional file 6: Figure S6. of Long-term leukocyte reconstitution in NSG mice transplanted with human cord blood hematopoietic stem and progenitor cells

Gating strategy for assessment of engraftment of HSPCs in bone marrow. A representative example for the assessment of engraftment of HSPCs in bone marrow is shown. Percentages of cell populations were determined as follows: Total HSPCs: Í34+ cells (of CD45+ cells), more primitive cells: Í38- or CD90+ cells (of CD45 + CD34+ or CD45+ cells). (TIF 5264 kb

Emergence of resistance in the mice under monotherapy with TMC278-LA.

*<p>S = susceptible (wildtype strain).</p>**<p>#192 showed suppressed HIV RNA under TMC278-LA monotherapy.</p>***<p>#191, 224 showed viral failure under the ART regimen of 3TC, TDF and TMC278-LA. #190 gave a positive signal for HIV RNA but below the limit of detection (<800 copies/ml)</p><p>#221, 245 only baseline analyses have been done, and therefore data from these mice were not integrated in the table.</p><p>¶#n.d. = not done.</p

Recovery of cell-associated HIV DNA (A) and increase of HIV mRNA transcripts in vitro from splenic tissue obtained from HIV-infected mice with suppressed HIV RNA following activation.

<p>(A) DNA from infected HeLa cells (HeLa inf) and from the spleen of HIV-infected mice served as positive controls, DNA from an uninfected humanized mouse (uninf) served as negative control. The specimens of the treated and HIV-infected mice were from the experiments investigating the antiviral potency of the double long-acting drugs; (MNE = mean normalized expression). B) Splenic tissue specimens from either HIV infected ART naïve hu mice (HIV), ART treated mice (ART) or mice treated with the two long acting drugs (Double-LA) were subjected to mitogens (PMA, PHA) in concert with anti-CD3/28 and IL-7. 18 hours later RNA was extracted and real-time PCR done for quantifying HIV Gag transcripts. Specimens of two mice which were treated with double LA drugs did not show any HIV transcript at all (data not shown in the graph); in five mice we did not detect any HIV transcripts prior to stimulation. The real-time PCRs were done in duplicates. *this specimen is from a mouse (#417) with detectable HIV RNA at the time of euthanization (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038853#pone-0038853-t002" target="_blank">Table 2</a>).</p

HIV RNA load at the terminal bleeding in mice on ART or on double long-acting drugs.

*<p>n.d.  =  non-detectable.</p><p>- Humanized mice were sacrificed 151 days after HIV infection and 114 days after starting ART or double long-acting drugs.</p><p>- Detection limit: the volume of plasma available was slightly different for the mice euthanized and thus the lower detection limit varied accordingly between 40 and 60 copies/ml.</p

Humanized mice with viral failure under ART with 3TC, TDF and TMC278-LA show consecutive or simultaneous emergence of the key mutation to 3TC or TMC278.

<p>A), B), C) and D) show the four mice with emergence of resistance under ART. The black dots indicate that resistance testing had been done, white dots no resistance testing done.</p

Two long-acting drugs, TMC278-LA (160 mg/kg) and TMC181-LA (400 mg/kg), are highly effective as maintenance therapy.

<p>(A) Response to a quadruple ART consisting of 3TC, TDF, TMC278-LA and TMC181-LA over a treatment period of 150 days (the black circles identifies the mice which remained over the entire time on ART (n = 7), the white circles identify the mice which were subsequently switched to a treatment with double long-acting drugs (see (B)). (B) Sustained successful suppression of HIV RNA after switching mice with suppressed HIV RNA under quadruple ART to a treatment with double long-acting drugs (n = 8). (C) Mock-treated HIV infected mice (n = 5). (D) CD4+ T-cells as determined by the CD4/CD8 cell ratio in all treated mice (ART and double long-acting drugs) and mock-treated mice at the end of the experiment.</p

ART is highly efficient in disseminated high-titer HIV infection in hu mice.

<p>(A) Response to ART with AZT, 3TC and RTV, followed by 3TC, TDF and TMC278-LA. Note that the initial regimen was poorly tolerated by the hu mice that resulted in reduced food uptake and thus a somewhat lower response rate. (B) Mock-treated HIV-infected mice (n = 8). (C and D) Mice with suppressed HIV RNA were either kept on ART (n = 11) (C) or switched to monotherapy with TMC278-LA alone (n = 10) (D). ART and monotherapy were interrupted to monitor the mice for viral rebound. We included two mice with viral failure into the group treated with TMC-278-LA alone. ┼ indicates that one mouse died within one week of bleeding. (E and F) Weight monitoring of mice either constantly on combined ART (E) or switched subsequently to monotherapy with TMC278-LA (F). Compilation of weight loss over time of all mice, i.e., mice on ART with viral failure (VF), mice on ART with suppressed HIV RNA and untreated HIV-infected mice (controls) (G). Grey-spotted area indicates the time period hu mice were on ART with AZT, 3TC and RTV, grey-plain shaded the time period on ART with 3TC, TDF and TMC278-LA. The coloured circles indicate the mice with viral failure.</p

PK data for 3TC, TDF, TMC278-LA and TMC181-LA.

<p>(A and C) Plasma levels of 3TC and TDF, respectively, over a day of mice on food pellets containing 0.5 mg/g food of 3TC or TDF for 2 weeks. (B and D) Decay rate of 3TC (t½ = 5.5 h) and TDF (t½ = 3.5 h), respectively, when replacing the food containing 3TC or TDF with standard food. (E and F) Plasma levels after one dose of either TMC278-LA (160 mg/kg) or TMC181-LA (white dots: 200mg/kg; black dots: 400mg/kg) administered s.c. The data were obtained with mice on ART-containing food pellets for at least 2 weeks to permit PK equilibration. The shaded area in (A–D) indicates the therapeutic range as defined in humans <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038853#pone.0038853-Fletcher1" target="_blank">[42]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038853#pone.0038853-Chittick1" target="_blank">[43]</a>. The dashed line in (E and F) indicates the target concentration (C target). Median effective concentration (EC) 50 values of TMC278 and TMC181 are 4.95 ng/ml and 1.29 ng/ml respectively <i>in vitro</i> in MT4 cells cultured with 50% human serum. The different colours indicate the experiments done with the same food batch, and whether we used mice transplanted with human CD34+ cells or not (White, red and yellow dots indicate humanized mice, green and blue dots indicate mice without transplantation of human CD34+ cells).</p