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Recombinant herpes simplex virus strains can be constructed by several methods, including homologous recombination, bacterial artificial chromosome manipulation, and yeast genetic methods. Homologous recombination may have the advantage of introducing fewer genetic alterations in the viral genome, but the low level of recombinants can make this method more time consuming if there is no screen or selection. In this study we used complementing cell lines that express Cas9 and guide RNAs targeting the parental virus to rapidly generate recombinant viruses. Analysis of the progeny viruses indicated that CRISPR-Cas9 both promoted recombination to increase recombinant viruses and selected against parental viruses in the transfection progeny viruses. This approach can also be used to enrich for recombinants made by any of the current methods.

SARS coronavirus 1 (SARS-CoV-1) causes a respiratory infection that can lead to acute respiratory distress characterized by inflammation and high levels of cytokines in the lung tissue. In this study we constructed a herpes simplex virus 1 replication-defective mutant vector expressing SARS-CoV-1 spike protein as a potential vaccine vector and to probe the effects of spike protein on host cells. The spike protein expressed from this vector is functional in that it localizes to the surface of infected cells and induces fusion of ACE2-expressing cells. In immunized mice, the recombinant vector induced antibodies that bind to spike protein in an ELISA assay and that show neutralizing activity. The spike protein expressed from this vector can induce the expression of cytokines in an ACE2-independent, MyD88-dependent process. These results argue that the SARS-CoV-1 spike protein intrinsically activates signaling pathways that induce cytokines and contribute directly to the inflammatory process of SARS.

Asphalt mixture is a skeleton filling system consisting of aggregate, asphalt, and mineral powder. High performance asphalt mixture design is directly affected by internal stress transmission of skeleton filling system. In this paper, the discrete element method based on digital image was employed to study the stress transmission. By analyzing the effect of skeleton structure on the contact force between aggregate and mortar, it is concluded that the skeleton aggregate in the asphalt mixture is the main stress transmission medium. The lower the degree of disruption, the higher the contact force of skeleton aggregate. At the same time, the variation coefficient of contact force of asphalt mortar with low filling coefficient is larger and the localization phenomenon is more serious. By analyzing the effect of mortar properties on the contact force between aggregate and mortar, it is concluded that the lower the modulus of asphalt mortar, the higher the degree of localization of contact force and the more likely to have local damage.

Journal of traffic and transportation engineering : JTTE 8(6), 815-999 (2021). doi:10.1016/j.jtte.2021.10.001, Published by Periodical Offices of Chang��an University, [S.I.]

Oropouche virus (OROV) infection of humans is associated with a debilitating febrile illness that can progress to meningitis or encephalitis. First isolated from a forest worker in Trinidad and Tobago in 1955, the arbovirus OROV has since been detected throughout the Amazon basin with an estimated 500,000 human infections. Like other members of the family Peribunyaviridae, the viral genome exists as 3 single-stranded negative-sense RNA segments. The medium sized segment encodes a viral glycoprotein complex (GPC) that is proteolytically processed into two viral envelope proteins Gn and Gc responsible for attachment and membrane fusion. There are no therapeutics or vaccines to combat OROV infection, and we have little understanding of protective immunity to infection. Here we generated a replication competent chimeric vesicular stomatitis virus (VSV), in which the endogenous glycoprotein was replaced by the GPC of OROV. Serum from mice immunized with VSV-OROV specifically neutralized wild type OROV, and using peptide arrays we mapped multiple epitopes within an N-terminal variable region of Gc recognized by the immune sera. VSV-OROV lacking this variable region of Gc was also immunogenic in mice producing neutralizing sera that recognize additional regions of Gc. Challenge of both sets of immunized mice with wild type OROV shows that the VSV-OROV chimeras reduce wild type viral infection and suggest that antibodies that recognize the variable N-terminus of Gc afford less protection than those that target more conserved regions of Gc.ImportanceOropouche virus (OROV), an orthobunyavirus found in Central and South America, is an emerging public health challenge that causes debilitating febrile illness. OROV is transmitted by arthropods, and increasing mobilization has the potential to significantly increase the spread of OROV globally. Despite this, no therapeutics or vaccines have been developed to combat infection. Using vesicular stomatitis (VSV) as a backbone, we developed a chimeric virus bearing the OROV glycoproteins (VSV-OROV) and tested its ability to elicit a neutralizing antibody response. Our results demonstrate that VSV-OROV produces a strong neutralizing antibody response that is at least partially targeted to the N-terminal region of Gc. Importantly, vaccination with VSV-OROV reduces viral loads in mice challenged with wildtype virus. This data provides the first evidence that targeting the OROV glycoproteins may be an effective vaccination strategy to combat OROV infection.

The failure of a 101.6 mm drill pipe was studied by combining experimental testing and finite element simulation. The macro analysis, metallographic structure and energy spectrum, chemical composition and a mechanical property test of the failed drill pipe sample were firstly carried out. Then, a three-dimensional finite element model of drill pipe failure was established based on the experimental results. Finally, the failure mechanism of drill pipe was analyzed and the mitigation measures were put forward. The results showed that solids settling sticking was the direct cause of fracture failure of the drill pipe joint. Due to the violent friction and wear between the drill pipe joint and the settled sand, the large amount of heat generated caused the microstructure of the joint material to undergo phase transformation and the bearing capacity to be reduced. Finally, fracture occurs under tensile and torsional loads.

Gradation measurement is important for quality control of pavement construction. Computed tomography (CT) can capture the microstructure images of asphalt mixture. However, an accuracy digital image processing method should be developed. In this study, fuzzy network, multilevel threshold and morphological methods are utilized to reduce the noise, enhance the contrast and segment images. The 2D aggregate gradation obtained from the digital image segmentation procedure is transferred into 3D gradation by stereological method. The results show that fuzzy network can balance the noise reduction and contrast enhancement. The multilevel Otsu’s threshold method can obtain the two thresholds automatically. The morphological processing and watershed transformation can fill the holes in the image and break the aggregate connections. By comparing the calculated gradation and the designed gradation, the image processing procedure proposed in this paper can be utilized to obtain the gradation information of AC, SMA and OGFC accurately and effectively.

The angularity of particles has important effects on the mechanical properties of asphalt mixture and other granular materials. To simulate these effects, the glue-sphere method was usually used to create an arbitrary polyhedron particle. Unlike other studies, this paper aims to efficiently fill a polyhedron with as few spheres as possible through optimization technology in order to reduce the cost of calculation during mixture simulation. Four contents are mainly discussed here: a) how to produce non-spherical aggregates and control their sizes with the minimal bounding box; b) how to fill convex non-spherical particles with the fewest balls as possible using the constrained nonlinear optimization method; c) how to compute the typical shape factors of these particles; and d) how the control parameters affect the filling effect. The algorithm for this study was programmed by MATLAB software and was proven to have better filling performance and less computational cost compared to other methods.

Genotyping epidermal growth factor receptor (EGFR) gene in patients with advanced non-small cell lung cancers (NSCLC) is essential for identifying those patients who may benefit from targeted therapies. Systemically evaluating EGFR mutation detection rates of different methods currently used in clinical setting will provide valuable information to clinicians and laboratory scientists who take care of NSCLC patients. This study retrospectively reviewed the EGFR data obtained in our laboratory in last 10 years. A total of 21,324 NSCLC cases successfully underwent EGFR genotyping for clinical therapeutic purpose, including 5,244 cases tested by Sanger sequencing, 13,329 cases tested by real-time PCR, and 2,751 tested by next-generation sequencing (NGS). The average EGFR mutation rate was 45.1%, with 40.3% identified by Sanger sequencing, 46.5% by real-time PCR and 47.5% by NGS. Of these cases with EGFR mutations identified, 93.3% of them harbored a single EGFR mutation (92.1% with 19del or L858R, and 7.9% with uncommon mutations) and 6.7% harbored complex EGFR mutations. Of the 72 distinct EGFR variants identified in this study, 15 of them (single or complex EGFR mutations) were newly identified in NSCLC. For these cases with EGFR mutations tested by NGS, 65.3% of them also carried tumor-related variants in some non-EGFR genes and about one third of them were considered candidates of targeted drugs. NGS method showed advantages over Sanger sequencing and real-time PCR not only by providing the highest mutation detection rate of EGFR but also by identifying actionable non-EGFR mutations with targeted drugs in clinical setting.

Colorectal cancer(CRC), which is derived from polyps, is a common malignant tumor with a high incidence and mortality. Currently the colonoscopy is the most effective approach for early detection of the colorectal cancer. With the development of object detection, some polyp detection algorithms have achieved satisfied results. However, most of them need the support of hardware accelerators such as GPU, which is unsuitable for actual clinical environment due to its high power consumption and loud noise. To solve the problem, this paper proposes a solution to implement real-time polyp detection for colonoscopy video on general-purpose computing platforms, i.e. CPU. Our solution incorporates several methods to improve efficiency of polyp detection. Firstly, by analyzing the similarity and difference between successive frames in colonoscopy videos, we use the abrupt shot detection method to reduce the unnecessary detection for frames that contain non-polyps; secondly, for the frames that need to be detected, we iterated a procedure of sparse training, pruning and knowledge distillation to search for compressed models. Our approach is evaluated with both public datasets and actual colonoscopy videos, and results show that our approach can process 35.28 frames per second on colonoscopy videos with satisfied precision on CPU.

The incidence of gastric hyperplastic polyps (HPs) has been on the rise in recent years. The contribution of Helicobacter pylori infection to this trend has remained to be elucidated. The present study aimed to explore the association between HPs and H. pylori in China, an area with a high infection rate of H. pylori. In order to study trends of HPs and H. pylori infection over the past decades, cases encountered from 2009 to 2018 were assessed and a total of 109,150 consecutive patients who underwent esophagogastroduodenoscopy at Qingdao Municipal Hospital (Qingdao, China) were enrolled. The incidence of HPs and the prevalence of H. pylori were determined and their correlation was explored. Gastric HPs were detected in 1,497 patients (1.6%) who received gastric biopsies. The incidence of HPs exhibited a rising trend, with a ~4-fold increase in the annual detection rate from 2009 to 2018. The prevalence of H. pylori infection was inversely associated with the prevalence of HPs (adjusted odds ratio, 0.66). The prevalence of H. pylori in the examined cohort decreased with time (r=-0.76, P=0.011). The decreasing trend of H. pylori infection was negatively correlated with the rising trend of HPs (r=-0.64, P=0.048), further indicating an inverse association between them. The difference in the prevalence of HPs between H. pylori-negative and -positive patients increased with age (r=0.80, P=0.018). The age-associated increase was slower in H. pylori-infected patients. The decline in H. pylori infection with time appeared to not be associated with the birth cohort effect, suggesting the decline was not caused by exposure to environmental factors during an early period of life. The present results indicated that the incidence of gastric HPs increased with the decline in H. pylori infection, demonstrating an inverse association between the occurrence of HPs and the infection.

In order to study the effects of aggregate shape on the strength of mixtures, the glue-sphered ellipsoid particles were used to create cylinder samples, and triaxial tests were simulated using the ...

Porous asphalt pavement is defined as an asphalt concrete with air voids content of around 20% and capable of forming drainage channels inside the mixture. It consists of an open-graded asphalt mixture composed predominantly of embedded-occluded single-sized macadam from interlocking processes, and is also known as porous asphalt mixture. In China, Marshall Design Method for porous asphalt mixture is the most widely used mixture design method for laboratory experimental study at present. The main parameters of Marshall Design Method are compaction work (number of compactions) and compaction temperature, i.e. this method can work out the air voids content meeting the performance requirements under uniform standard compaction work and given range of compaction temperature in practice. However, on account of different climates and traffic volumes, the molding parameters of Marshall Design shall be adjusted correspondingly to satisfy the pavement performance of mixture. For this purpose, limestone, which is of relatively low strength, is used as aggregate in porous asphalt mixture for experimental study, and the feasibility of limestone used in porous asphalt is also analyzed and verified. By analyzing the influences of Marshall molding parameters (compaction temperature and number of compactions) on the air voids content of porous asphalt mixture, the ranges of molding parameters of Marshall Design Method suitable for porous asphalt using limestone as coarse aggregate is found. Through analyzing the influence rules of Marshall molding parameters (compaction temperature and number of compactions) on the properties of porous asphalt mixture (high temperature stability, water stability and low temperature stability), combining with the ranges of molding parameters calculated with air voids content, the molding parameters for the Marshall test specimen applicable to the limestone porous asphalt mixture in Chinese region is proposed.

e13637 Background: Genotyping epidermal growth factor receptor ( EGFR) gene in patients with advanced non-small cell lung cancers (NSCLC) is essential to identify those patients who may benefit from targeted treatments. However, the testing methodology is still a puzzle for many clinicians. This study retrospectively reviewed the EGFR data from testing patients with NSCLC in our laboratory in 10 years. Methods: A total of 21,324 NSCLC cases successfully underwent EGFR genotyping in our laboratory for clinical therapeutic purpose, including 5,244 cases tested by Sanger sequencing, 13,329 cases tested by real-time PCR, and 2,751 tested by next generation sequencing-NGS. Results: 54.6%, 20% and 2.3% samples were recorded with tumor cell content (TCC) of < 40%, < 20% and 1% respectively. The average EGFR mutation rate was 45.1%, with 40.3% identified by Sanger sequencing, 46.5% by real-time PCR and 47.5% by NGS. Comparable EGFR mutation rates were observed in cases with 1%-20% TCC from real-time PCR and NGS platforms. In these cases with EGFR mutations, 93.3% of them carried a single EGFR mutation (92.1% with a classical mutation as 19del or L858R, and 7.9% with an uncommon mutation) and 6.7% harbored complex EGFR mutations. 65.3% of the cases carrying EGFR mutations identified by NGS also have tumor related variants in other genes. 26.5% more cases were found to have oncogenic driver mutations with therapeutic significance beyond EGFR by NGS. Conclusions: NGS may be the most optimal methodology to detect EGFR mutations in patients with NSCLC compared with Sanger sequencing and real-time PCR platforms from accuracy and comprehensiveness aspects, but some other issues, such as Turn Around Time (TAT), still should be considered in clinical practice.

Background/aims The function of regulatory T cells (Treg) and helper T cells 17 (Th17) related indexes, such as interleukin (IL)-6, IL-17, transforming growth factor (TGF)-β1, and forkhead box protein 3(FoxP3) in gastric adenocarcinoma tissues remains undefined. We investigated and analyzed the relevance of the proteins with the clinicopathological characteristics and the interactions among them in gastric cancer. Materials and methods A total 68 gastric cancer patients and 40 healthy controls were enrolled. Immunohistochemistry (IHC) as well as quantitative real-time reverse transcription- polymerase chain reaction (RT-PCR) was used to determine the expression levels of IL-6, TGF-β1, IL-17, and FoxP3 in the prepared tissues. Statistical analysis included ANOVA and chi-square test. Results The expression levels of IL-6, IL-17, FoxP3, and TGF-β1 had significantly increased in cancer tissues compared to controls. Clinical staging of gastric cancer were correlated with the rise of IL-6, IL-17, FoxP3, and TGF-β1 levels expressed in cancer tissues. The expression level of TGF-β1 and IL-6 was positively related to that of IL-17 and FoxP3, similar to FoxP3 and IL-17 in gastric cancer tissues. Conclusion IL-6, TGF-β1, FoxP3, and IL-17 may promote the progression of gastric cancer individually or jointly and have complex interactions.

Low temperature asphalt (LTA) technologies, such as warm-mixed asphalt mixes, are utilized in the paving industry to lower energy demands and greenhouse gas emissions during asphalt mixing and pavement construction. However, the asphalt mixes developed that incorporate LTA additives are more sensitive than hot-mixed asphalts to temperature reduction during compaction, which leads to inadequate compaction and subsequent poor pavement performance. The induction heating-assisted compaction of pavement structures appears to be an effective way to ameliorate such issues and to improve mix compactability at lower temperatures. Considering that induction-assisted compaction is a complex process, a computational methodology is proposed in this paper. A porous asphalt concrete mix was considered as case material. For the pavement compaction analyses after induction, the temperature field generated by electromagnetic induction was predicted and the material parameters of asphalt mortar were adjusted. The effect of induction heating on asphalt compaction effectiveness, the tendency of mix density changing, the increase in compactor passes, and the influence of temperature on compaction at different locations in the pavement were studied as well.

Circulating follicular helper T (cTfh) cells are a novel subset of cluster of differentiation (CD)4+ helper T cells. Interleukin (IL)-21 and C-X-C motif chemokine ligand (CXCL)13 are the principal effectors and chemotactic regulatory factors of Tfh. However, the roles of IL-21 and CXCL13 in gastric cancer have not yet been completely elucidated. The aim of the present study was to investigate the distribution of cTfh cells, and the expression of IL-21 and CXCL13 in patients with gastric cancer was evaluated in order to ascertain the significance and potential mechanisms of these effectors in gastric cancer. A total of 50 patients with gastric cancer were enrolled as the study subjects, with 30 healthy individuals selected as controls. The percentage of cTfh cells (cTfh%) in the peripheral blood was calculated using flow cytometry. They are identified in the present study as CD4+ chemokine C-X-C receptor (CXCR)5+ inducible T cell co-stimulator (ICOS)+ cells. The serum levels of IL-21 and CXCL13 were determined by ELISA. The cTfh% in the peripheral blood and the concentration of IL-21 and CXCL13 in the serum were significantly higher in patients with gastric cancer compared with the control group. cTfh% was significantly higher in patients with lymph node metastasis, Tumor-Node-Metastasis (TNM) stage III-IV and low differentiation. The concentrations of IL-21 and CXCL13 in patients with lymph node metastasis and/or TNM III-IV were significantly higher than in those without lymph node metastasis or with TNM I-II. There was a positive correlation between cTfh%/CXCL13 and IL-21/CXCL13, while there was no correlation between cTfh%/IL-21. cTfh cells and associated factors (IL-21/CXCL13) may be involved in the development and progression of gastric cancer. There may be mutual regulation among cTfh cells, IL-21 and CXCL13.

Accurate determination of structural responses plays a critical role in a mechanistic-empirical pavement design. A new distress model, top-down fatigue cracking, has been incorporated in the newly developed Mechanistic-Empirical Pavement Design Guide. The critical response for top-down cracking is the horizontal tensile stress or strain at the pavement surface. However, the poor convergence of analytical layered elastic solutions in the vicinity of the pavement surface may result in large errors in response results. This study uses the Lucas algorithm to effectively solve this problem. The algorithm converts the complicated oscillating behaviour of the product of Bessel functions to regular oscillations by separating the integrand into high- and low-frequency components. Thus, extrapolation techniques can be effectively applied to accelerate the convergence. A computer code is developed to implement the proposed procedure. The computer code is verified against the boundary conditions and finite element re...

Load-induced top-down cracking is one of the major types of asphalt pavement deterioration; however, its initiation mechanisms have not been fully understood so far, which makes it very difficult to effectively consider this failure pattern in the pavement design procedures. To address this issue, the present study developed a two-dimensional microstructure-based multiscale finite element model, in which material properties on two physical length scales, i.e., the local (mixture level) and global (pavement level) scales, were incorporated in the computation and linked through a homogenization process. A digital image processing (DIP) technology was employed to develop the two-dimensional local-scale representative volume element (RVE) model that considered the realistic heterogeneous microstructure of asphalt concrete (AC), and a bilinear cohesive zone model was applied to simulating the local-scale damage initiation and evolution in the RVEs. Two typical pavement structures, with cement-treated base (CTB) and granular base (GB) respectively, were taken into account to interpret the influence of the global-scale pavement configurations on top-down cracking performance. The results showed that the significant near-surface transverse tensile stress just outside the tire edge could be the primary cause of the top-down cracking. For the pavement with CTB, the top-down cracking was the predominant type of fatigue failure, whereas for the pavement with GB, the bottom-up cracking was the main pattern of fatigue failure. Besides, as the temperature increased, more damage was induced under the same traffic loading due to the reduced tensile strength of AC. It was also found on the local scale that the significant tensile stress within the mortar matrix phase probably acted as the driving force of the microcrack initiation and propagation and the effects of the shear traction on the damage evolution in the AC layer increased with the temperature.

The mechanistic-empirical pavement design guide (MEPDG) developed under National Cooperative Highway Research Program Project 1-37A requires the use of axle load spectra or load distribution factors (LDFs) for pavement thickness designs. The MEPDG allows for various levels of LDF inputs, varying from site-specific (level 1) to regional average (level 2) and national average (level 3). There exists a concern that the MEPDG level 2 and level 3 inputs do not take any site-specific information into consideration and thus may result in erroneous thickness design. This study proposed a new approach to determine the axle LDF and number of axles per truck (NAPT) for level 2 and level 3 inputs. The proposed approach requires that the design guide provide default LDFs and NAPTs for both normally loaded and overloaded trucks for various axle types and vehicle classes. Thus, design engineers can estimate LDFs and NAPTs for a particular project site based on the percentages of overloaded trucks of that site which are ...

A new quantitative structure-activity relationship (QSAR) model for the classification of 161 skin sensitizers has been developed with adaptive boosting (Adaboost). The selection of variables for each descriptor was performed with particle swarm optimization (PSO). Among all descriptors in the model, the Radial Distribution Function+3DMolecular Representation of Structure based on Electron diffraction(RDF+3D-MoRSE) descriptor exhibited the highest accuracy in the predictions. On a known compound data set, the AdaBoost model improved the prediction accuracy of the training set and the test set to 100.0% and 89.8%, up from 100.0% and 85.7% when only the support vector machine (SVM) was applied.

Old World monkey TRIM5alpha proteins are known to block the replication of human immunodeficiency virus and other retroviruses in a species-specific fashion. In this report, we show that specific forms of simian TRIM5alpha proteins can restrict herpes simplex virus (HSV) infection. To define the effect of TRIM5alpha on HSV replication, we examined HSV infection in HeLa cell lines that stably express simian and human orthologs of TRIM5alpha proteins. We demonstrated that several simian TRIM5alpha proteins can restrict HSV replication, with the TRIM5alpha protein of rhesus macaques showing the strongest inhibition of HSV infection. We also found that the level of the inhibition of virus replication was viral strain-specific. TRIM5alpha is likely to inhibit HSV at the early stage of infection; however, at later times of infection, the levels of TRIM5alpha are significantly decreased. Thus, some TRIM5alpha proteins exhibit antiviral effects that extend beyond retroviral infections, but HSV may be able to reduce this restriction by reducing TRIM5alpha levels during the later phases of virus replication. Our results also argue that TRIM5alpha is only part of the reduced level of HSV replication in rhesus macaques, which are known to be less susceptible to HSV infection than other primates.

In the present work, the support vector machine (SVM) and Adaboost-SVM have been used to develop a classification model as a potential screening mechanism for a novel series of 5-HT(1A) selective ligands. Each compound is represented by calculated structural descriptors that encode topological features. The particle swarm optimization (PSO) and the stepwise multiple linear regression (Stepwise-MLR) methods have been used to search descriptor space and select the descriptors which are responsible for the inhibitory activity of these compounds. The model containing seven descriptors found by Adaboost-SVM, has showed better predictive capability than the other models. The total accuracy in prediction for the training and test set is 100.0% and 95.0% for PSO-Adaboost-SVM, 99.1% and 92.5% for PSO-SVM, 99.1% and 82.5% for Stepwise-MLR-Adaboost-SVM, 99.1% and 77.5% for Stepwise-MLR-SVM, respectively. The results indicate that Adaboost-SVM can be used as a useful modeling tool for QSAR studies.

Adult T-cell leukemia (ATL) is an aggressive malignancy that is associated with human T-cell lymphotropic virus I (HTLV-I) infection. HTLV-I transformed T-cell lines and fresh ATL cells are characterized by constitutive activation of the interleukin-2 receptor (IL-2R) signaling pathway however, the mechanism(s) responsible for constitutive IL-2R activation are unknown. To further examine the cause of this signaling pathway deregulation, we measured mRNA and protein expression levels by real-time PCR and Western blots, respectively, of four negative regulators of the IL-2R signaling pathway including src homology 2 (SH2)-containing phosphatase (SHP1), cytokine-inducible (CIS) SH2-containing protein, suppressor of cytokine signaling-1 (SOCS1) and protein inhibitor of activated signal transducer and activator of transcription 3 (STAT3) (PIAS3) in six HTLV-1 negative and seven HTLV-1 positive T-cell leukemia lines. The activation status of the JAK/STAT pathway was also examined. SHP1 mRNA and protein expression levels were selectively down regulated in all HTLV-1-infected transformed cell lines, while CIS, SOCS1, and PIAS3 protein expression were markedly but variably upregulated and the cells showed evidence of constitutive STAT3 activation. In acutely HTLV-1 infected primary CD4+ T-cells there was a gradual loss of SHP1 expression over 10 weeks in culture which correlated with progression from immortalization to transformation and loss of IL-2 dependence for growth. Two transformed cell lines that were established following HTLV-1 infection showed loss of SHP1 expression and overexpression of CIS, SOCS1, PIAS3. However, this overexpression was not adequate to block constitutive activation of the JAK/STAT pathway. Thus, multiple levels of IL-2 receptor signal deregulation are found in HTLV-1 transformed cells, which may be a result of early loss of SHP1 expression.