Why is tcp complex

We analyze the reason of problems mentioned above before and after packet loss. Before the packet loss, the traditional TCP presents low adaptability and poor flexibility. As we all know, TCP has many constant initial values when the transmission starts. For example, the initial value of cwnd is set as 1 mss maximum segment size and the initial value of ssthresh is set as bytes.

For instance, the value of ssthresh, which is the threshold between SS slow start phase and CA congestion avoidance phase. On one hand, if the initial value of ssthresh is relatively small in the environment of large bandwidth, small delay and light link load, then TCP flow will end the SS phase and step into the CA phase prematurely which will cause low link utilization.

On the other hand, if the ssthresh is too large for current link state, the sender will enhance the sending rate which may cause link congestion and packet loss. In wired network, most packet losses are caused by congestion, but in wireless or heterogeneous networks, BER is another important reason of packet loss which can also cause performance degradation of TCP [ 3 ]. To solve the problem of poor flexibility caused by constant initial settings, we assume that a dynamic and appropriate setting of initial value will make the complex network transmission change to an easy-handled system.

As a precondition, TCP transmission must be sensitive to the initial value. It is generally known that sensitive to the initial value is an important characteristic of chaos system. So we should confirm whether TCP protocol behaves chaotically in heterogeneous network. In recent years, a large body of researches on analyzing the nature of TCP protocol has been published in literatures.

Zhao used phase-space reconstruction in chaos theory to detect covert channel in TCP initial sequence numbers and solved the problem of testing covert channel [ 4 ].

Wang verified the bifurcation and chaos character in RED-AQM, and proved the existence of communication delay threshold to determine whether the system is stable [ 5 ]. Veres pointed out that the congestion control of TCP performs certain periodicity and predictability, and confirmed the chaotic nature of TCP in wired network [ 6 ]. Next section will demonstrate the chaotic nature of TCP congestion control in heterogeneous network.

In order to calculate the initial value more scientifically and intelligently and improve the flexibility of TCP in heterogeneous network, we employ the idea from nature-inspired algorithm. Nature-inspired algorithm has characters such as self-organization, robustness, scalability and adaptability, which are highly desired by complex network environment [ 7 ]. Besides, nature-inspired algorithms have been applied in many areas such as network security, pervasive computing, sensor network and artificial intelligence which had made remarkable achievements [ 8 — 9 ].

After the analysis of nature-inspired algorithms and congestion control mechanisms, we propose a novel structure of TCP congestion control model based on prey-predator algorithm [ 10 ]. In this model, TCP parameters are initialized with calculated values, which will make the TCP stay in an effective operating state and utilize the available network bandwidth maximally.

The rest of this paper is organized as follows. In section 2 the chaotic characteristic of TCP congestion control in heterogeneous network is analysed and verified. In section 3 the theoretical basises and structure of IPPM are presented.

Section 4 is dedicated to analyzing the parameters of proposed model. In section 5 the simulation results are exposed and discussed, focusing on the throughput, fairness and packet loss rate of IPPM. At last, we make a summary of this paper as well as the future work.

If a system shows the characteristics of periodicity, strange attractor and initial value sensitivity, we confirm this system as a chaotic system [ 11 ]. Next, we will find out whether does TCP congestion control in heterogeneous network hold these characteristics using NS2.

The network environment is shown as Fig 1 , where, S denotes sender, AP Access Point represents the last jump of the wireless access point, D indicates the wireless receiver. We can prove the chaotic nature of the system through analyzing the attractor of one dimension [ 12 ]. Because cwnd is just one of the numerous parameters in the whole system, and not continuous, which means that cwnd cannot describe the properties of a complex system effectively, especially the hidden nature of the system.

It is particularly important to expresses the current operating condition of the system more accurately. Literature [ 13 ] proposed a time shift algorithm to reconstruct the phase space of the parameter, so as to show some hidden properties in complex system effectively.

The algorithm is shown as follows: 1 2 where x and y represent two TCP flows. This method holds two advantages:. So this time shift algorithm can express the property of system more accurately and continuously. After using the above algorithm to reconstruct the phase space of cwnd, we can get Fig 2 , where, x [i] and y[i] represent a pair of values produced by time shift algorithm at a certain moment.

Fig 2 indicates that the attractor appears after a sufficient running time, and it performs steady in some plausible disordered status. The common method to confirm a attractor as a strange attractor is to find out whether the attractor has fractal structure [ 14 ]. The fractal dimension of the attractor can be calculated by the method of box dimension as following. Then the box dimension of above attractor D F can be expressed as follows: 3 4.

This box dimension is non-integer dimension, indicating that the attractor has a fractal structure which we called strange attractor.

The strange attractor is one of the main characteristics of chaos, so it contradicts our hypothesis, and therefore proves the result. The initial value sensitivity refers to a minor change at the beginning which results in a tremendous difference in the end. It is one of the important properties of chaotic system, namely, butterfly effect. Simulation results are compared among four groups of experiments.

In each group, TCP 0 begins to send data from 0. Experimental results are shown in Fig 3. Fig 3 shows the changes of cwnd in the scenarios of two flows when starting at different time. This uses up the current usable window since the client has sent the full amount the receiver can handle. Next, the server acknowledges the first 30 bytes.

The sender slides its send window right by 30 and updates its usable window to account for the acknowledged bytes 4. If the server then processes everything in its buffer, it will acknowledge the next 70 bytes and update its receive window to bytes. The client increases its send window and usable window to match and slides them both to the right.

The client then transmits another bytes 5. In reality, chunks of data called segments, each with a TCP header, are transmitted between a sender and receiver. Additionally, the speed with which the send window slides through the client's buffer varies depending on how quickly the client gets data from the sending application, how quickly the server processes the data in its receive buffer, if any packets are lost in transmission, and the specifics of the sliding window protocol implementation and congestion control algorithms.

TCP is complex but is used extensively by applications that depend on its reliability, so problems like misconfigured settings can have wide-ranging impacts on your network.

Visibility into your network and knowledge of how the protocol operates can help minimize troubleshooting time and make problems easier to identify. ExtraHop is the only solution that combines real-time visibility through wire data analytics which covers every transaction on your network with machine learning to automatically detect and correlate anomalous behavior. Instead of fixing problems with TCP and other critical but complicated protocols through time-consuming trial and error, ExtraHop helps you identify and resolve issues proactively and in less than a third of the time it would have taken you otherwise.

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A compromised VPN client infects a print server and accesses a critical networking admin tool, ExtraHop Reveal x detectors fire. The vulnerability to vCenter Server presents serious risk to organizations. Reactome - a knowledgebase of biological pathways and processes More Reactome i. Homo sapiens Human. This is known as the 'taxonomic identifier' or 'taxid'. It lists the nodes as they appear top-down in the taxonomic tree, with the more general grouping listed first.

Human Gene Nomenclature Database More HGNC i. MIM i. VEuPathDB i. DisGeNET i. Open Targets More OpenTargets i. PharmGKB i. Pharos i. BioMuta curated single-nucleotide variation and disease association database More BioMuta i. DMDM i. Phosphoserine Combined sources Manual assertion inferred from combination of experimental and computational evidence i Ref. Phosphotyrosine Combined sources Manual assertion inferred from combination of experimental and computational evidence i Ref.

N6-acetyllysine Combined sources Manual assertion inferred from combination of experimental and computational evidence i Ref. Encyclopedia of Proteome Dynamics More EPD i. MassIVE i. MaxQB i. PaxDb, a database of protein abundance averages across all three domains of life More PaxDb i. PeptideAtlas More PeptideAtlas i. PRIDE i. ProteomicsDB: a multi-organism proteome resource More ProteomicsDB i. OGP i. IPI P MetOSite database of methionine sulfoxide sites More MetOSite i.

PhosphoSitePlus i. SwissPalm database of S-palmitoylation events More SwissPalm i. To determine transfection efficiency, the generated plasmids were designed to independently express GFP. K cells were used for evaluation of initial transduction efficiency, which was acceptable for both constructs as determined by flow cytometry Fig. Increased expression of CCT2 had pleiotropic effects on the cells. Note that these are qualitative not quantitative assessments. Increased migration Fig.

Tubulin levels were quantified per cell based on the mean pixel intensity. Data shown is representative of three experiments. S3 for full blot and total protein images used for signal normalization. The bar graphs represent protein levels relative to Parental cells. Signal was normalized to total protein as previously described 14 and in Materials and Methods. Error bars represent the mean with s.

Representative data of at least three independent experiments is shown. Refer to Supplemental Fig. S3 for full blot images. Blot images, replicates, and total protein are shown in Supplemental Data Fig.

These results do suggest that CCT2-FLAG was influencing the levels of other CCT subunits, likely as part of the oligomeric complex, and while additional activities as a monomer cannot be ruled out, CCT2, is essential for the activity of the chaperonin complex and bears further investigation.

We show this through a bioinformatics analysis of possible CCT interactors that are involved in cell cycling and whose expression co-occurs with CCT2 in breast cancer Table 1. To determine whether expressing CCT2 could promote cell growth, we examined cell division using a dye dilution method.

In our initial assessment of cell division, we observed that cells stably expressing the control lentiviral plasmid no CCT2-FLAG grew more slowly compared to non-transduced parental cells Fig. This was shown by others and could be an effect attributed to the use of polybrene We realized that to detect a pro-growth effect mediated by CCT2 in the lentiviral transduced cells, we would need to evaluate cells after several passages to enable the protein-folding activity to rescue proliferation.

This was observed as shown in Fig. Blot images and total protein are shown in Supplemental Data Fig. We concluded that expressing the single CCT2 subunit induced cell proliferation likely through the activity of the chaperonin complex that increased key cell cycling proteins like CDKs and others. The percent of original cells post-generation 1 is shown. Representative data of three experiments is shown.

The bar graphs represent protein levels relative to the control cells in each dataset. Signal was normalized to total protein as previously described 14 and in Methods.

Blots were performed once with technical replicates for each lysate. Cropped blot for CDKs is shown. S4C,D for full blot images. Having shown the role of CCT2 in promoting growth and invasiveness of cells, we next examined the effects of CCT2 loss.

Outcomes were loss of viability, as evidenced by reduced adherence Fig. S6C and migration Fig. Total protein image corresponding to the blot above shows equal load between the lanes.

Images were cropped to show CCT2 band only. S7A,B for full blot images. Representative data of three independent experiments is shown. We previously established that the doxy chow had no impact on tumor growth in mice not shown. This experiment was repeated with similar results. Note that the tumors that did grow in the cct2- silenced mice were smaller Fig.

We found that these tumors had detectable levels of CCT2 that were comparable to control mice Fig. We concluded that, in these mice, cct2 -gene silencing was less efficient, enabling tumors to grow. These results confirm the data shown herein that CCT2 is an essential component of the chaperonin complex and supports the tumorigenic process. Representative data is shown. Our focus on CCT2 as a potential therapeutic target for inhibition of chaperonin activity initiated upon discovering correlations between CCT2 expression and reduced breast cancer patient survival.

Increased CCT2 expression was sustained through all breast cancer stages and correlated with poor prognosis in patients. Since the CCT complex is formed by eight different subunits, the importance of a single subunit, like CCT2, was undetermined. By overexpressing CCT2 in select breast epithelial and luminal A breast cancer cell lines, we showed that expression of CCT2 could drive cell proliferation and invasiveness, overcoming the initial slowing of growth caused by the lentiviral transduction system Most of the overexpressed CCT2 was incorporated in the chaperonin oligomeric complex and variably influenced the levels of other CCT subunits.

Inducible loss of CCT2 in tumor cells implanted in mice impaired tumor growth, indicating that CCT2 is essential for the in vivo replication of tumor cells. CCT is thus a viable target for therapeutic intervention in cancer due to its function as a critical protein-folding complex, and the inhibition of CCT could be achieved through direct targeting of the CCT2 subunit. The function of CCT in support of the cytoskeleton is well known but its activity promoting other cell functions is still being determined.

Actin and tubulin are obligate client proteins and loss of CCT activity is known to change cell motility, morphology, and proliferation We found that overexpressing CCT2 promoted the migration of cells that were not inherently motile, which is in line with our previous report of loss of actin and tubulin upon targeting of CCT with CT20p 16 , The use of siRNAs to target different CCT subunits was previously explored by others in select cell lines and resulted in growth arrest that was independent of checkpoint inhibition and reductions in tubulin but not actin Moreover, the CCT chaperonin was recently found to have role in the disassembly of mitotic checkpoint complexes 48 as well as mediating calcium signaling through Orai1 trafficking Our finding that overexpressing CCT2 promoted the proliferation of breast cancer and breast epithelial cells is among the first to demonstrate that an increase in cancer cell growth and upregulation of select CDKs as well as other CCT subunits resulted from overexpressing this single CCT subunit.

The role of CCT in many diseases, including cancer, is far from fully characterized. One study that examined CCT levels in different cell lines found that cancer cells generally had higher expression of CCT protein, but this did not always correlate with protein-folding activity Another group found that overexpressing CCT1 in yeast did not affect levels of assembled complex, but that the CCT1 subunits remained soluble in the cytosol and had inherent protein-folding activity While the oligomeric activity of CCT is the most investigated, the ability of select CCT subunits to act as monomers is supported by several studies.

For example, CCT4 produced a protusion phenotype by interactions with pglued and microtubules 52 , However, the monomeric activity of CCT2 is unknown.

Our study revealed that the overexpressed FLAG-tagged CCT2 subunit associated with other CCT subunits, promoting functional effects such as migration and proliferation that are suggestive of increased protein-folding activity. Although this is indicative of oligomeric-driven effects, this does not rule out possible CCT2-driven monomeric activities, such as interactions with the actin filament capping and severing protein, gelsolin While we found that most of the CCT2-FLAG in cells was in the oligomeric complex, some also was in monomeric form, and could be further studied.

Others found that depletion of CCT subunits e. Hence, it remains unclear what regulates CCT subunit expression and chaperonin activity but could involve interplay between other chaperones and partitioning of client proteins 50 or the response to conditions of stress Our research with CCT2 suggests that the individual CCT subunits may have different roles in the activity of the chaperonin complex in cancer cells that remain to be studied.

The mechanisms by which CCT subunit expression is regulated are also poorly understood. However, it is clear that CCT is an essential complex needed by cancer cells to survive and grow. Key questions remain — is CCT a general cytosolic chaperone or are its substrates highly restricted, as some studies suggest 30 , and is the activity of the complex driven by the demands for protein folding to support cell cycling, cytoskeletal rearrangements or chromatin remodeling?

If the latter, do cancer cells usurp the restricted activities of CCT that are driven by oncogenic processes, becoming more susceptible to inhibition of the chaperonin than healthy cells?

Are there unique monomeric activities of CCT subunits? As a step towards answers, our study identifies CCT2 as a potential target for therapeutic inhibition as well as diagnostic development, whose loss could impede the activity of the chaperonin complex in a manner that is detrimental to cancer cells. Cells were used between passages 2 and The MCF10A, MCF7, T47D, and K cells, transduced with the lentiviral particles prepared as described below, were cultured in the same medium as the wild-type parental lines with the addition of 0.

Envelope vector pMD2. Lentiviral particle preparations were purchased Dharmacon. The following day, cells were washed twice with 1X phosphate-buffered saline Corning and medium replaced with standard media for recovery.