This enhancement diminishes linearly with increasing SOA. These results suggest that letters and speech-sounds are processed as compound stimuli early and automatically in the auditory association cortex of fluent readers and that this processing is strongly dependent on timing. (c) 2007 Elsevier Ireland Ltd. All rights reserved.”
“Purpose: Considerable controversy exists regarding the recently published high prevalence of cryptorchidism and the actual orchiopexy rate in Denmark. Therefore, we carried out another prevalence study.

Materials and Methods: The study population included 1,094 consecutive

males delivered alive at Glostrup University Hospital during 2002, with a 4-year review of patient data and telephone contact with primary physicians.

Results: EPZ5676 price At birth the www.selleckchem.com/products/jsh-23.html overall frequency of cryptorchidism was 2.4% (26 of 1,088 cases, 23% bilateral). The frequency of cryptorchidism in singletons was 2.4% (24 of 1,012 patients). The frequency of cryptorchidism in patients with a birth weight of 2,500 gm or more was 2.1%, compared to 8.2% in those with a birth weight of less than 2,500 gm (chi-square p<0.05). The frequency of cryptorchidism in twins was 2.6% (2 of 76). The frequency of birth weight below 2,500 gin was 51% (39 of 76) in twins and 4.9% (50 of 1,012) in singletons (chi-square p<0.00005). The weight of the placenta was higher in twins (median 1,000 gm) than in singletons (650

gm). At age 4 years 1.6% of the boys had undergone or were waiting to undergo surgery for cryptorchidism, and 0.6% had a diagnosis of retractile testes.

Conclusions: In a small cohort of newborns the incidence of cryptorchidism in Denmark has not changed, and is similar to previous reports from why the 1950s. The risk is higher in low birth weight singleton neonates but does not appear to be higher in twins, despite lower birth weight and prematurity.”
“Most cold-sensitive subnucleus caudalis (Vc) neurons are also excited

by the TRPM8 agonist menthol and the TRPA1 agonist cinnamaldehyde (CA). We investigated how interactions among menthol, CA and noxious cooling and heating of the tongue affected responses of superficial Vc units recorded in thiopental-anesthetized rats. Units responded to 1% CA which enhanced cold- and heat-evoked responses 5 min later. They responded more strongly to 10% CA which initially depressed cold responses, followed by enhancement at 5 min without affecting responses to heat. Following 10% CA, the mean response to 1% menthol was significantly lower than when menthol was tested first. After menthol, the subsequent response to CA was significantly weaker compared to the mean CA-evoked response when it was tested first. These results demonstrate mutual cross-desensitization between CA and menthol. The response to CA was enhanced following prior application of 10% ethanol (menthol vehicle).

Leukemia (2012) 26, 23-33; doi:10.1038/leu.2011.184; published online 26 July 2011″
“Two of the primary responses in a

cell when perturbed are modulation of the dynamics of its constituent LCL161 gene expression and protein abundance to restore steady-state homeostasis. To obtain a detailed model of the restoration of this balance, it is necessary to examine the kinetics of transcription and translation, thus going beyond establishing mere abundance levels of transcripts and proteins. In this review we discuss proteomic approaches that utilize genomic tagging and metabolic labeling to reveal turnover kinetics for cellular proteins in a high-throughput manner. Novel metabolic and multiplexed labeling techniques coupled to mass spectrometry, in combination with next-generation sequencing approaches, provide tools for studying the principles of cellular adaptation and dynamics in unprecedented detail.”
“The brain vascular endothelium operates as a dynamic regulatory interface to maintain the cell environment of the nervous system. In the vicinity of astrocytes, brain endothelial cells develop characteristic

features conferring a strong cellular impermeability which limits the penetration of various compounds. The aim of our study was to determine selleck chemical by differential proteomic analysis the changes occurring in bovine brain capillary endothelial cells (BBCEC) differentiated in co-culture with astrocytes compared with endothelial cells cultured alone. In

Ulixertinib clinical trial order to obtain reproducible and meaningful protein profiles of in vitro blood-brain barrier models, three sample preparation procedures were carried out to provide the first 2-D comparative proteomic study of BBCEC. Our study highlights advantages and drawbacks of each procedure. The cellular proteins prepared from mechanical scraping of collagen-seeded BBCEC were strongly contaminated by serum proteins. Enzymatic dissociation of BBCEC by trypsin or collagenase solved this problem. A comparative 2-DE profile study of collagenase-harvested BBCEC revealed that cytoskeleton-related proteins (actin, gelsolin and filamin-A) show the most significant quantitative changes in the Triton soluble protein fraction from BBCEC that exhibit characteristics closest to the in vivo situation.”
“Histamine in the adult central nervous system (CNS) acts as a neurotransmitter. This amine is one of the first neurotransmitters to appear during development reaching its maximum concentration simultaneously with neuron differentiation peak. This suggests that HA plays an important role in neurogenesis. We have previously shown that HA is able to increase neuronal differentiation of neural stem cells (NSCs) in vitro, by activating the histamine type 1 receptor. However the mechanism(s) by which HA has a neurogenic effect on NSCs has not been explored. Here we explore how HA is able to increase neuron phenotype.

We searched studies on

healthy (non-clinical) populations that used the TCI (version 9), and that had a required sample size of at least 100. The search resulted in 16 articles. The resulted pooled correlation coefficient was medium level between NS and HA (-0.27). Correlations were small for HA-P (-0.20), NS-P (-0.14), NS-RD (0.10), RD-P (0.05) and HA-RD (0.04). In meta-regression, the correlation NS-P was significantly affected by the location of the study (Asian/other) and by the gender distribution of the sample. In the HA-P correlation, the mean age of the sample affected the correlation. In conclusion, we found a medium level negative correlation between NS and HA; other correlations between the dimensions were small. These findings mainly support Cloninger’s theory of independent dimensions. (C) 2007 Elsevier Ireland Ltd. All click here rights reserved.”
“The

current study presents an organotypic rat midbrain slice culture that served as a consistent and informative framework, where the STN neurons and their interconnectivity were closely examined with respect to electrophysiological and pharmacological properties. From multi-electrode array recordings, it was found that MLN2238 research buy the majority of STN neurons spontaneously fired in bursts rather than tonically under control conditions, and the neural activity between pairs of burst-firing STN neurons was tightly correlated. This spontaneous synchronized burst firing Taselisib purchase was also affected by a glutamate receptor antagonist, yet unaffected by a GABA receptor antagonist. Moreover, even when the STN was isolated from all its known external inputs, spontaneous

synchronized burst firing was still observed under control conditions and consistently switched to tonic firing following the application of a glutamate receptor antagonist. Therefore, the results indicated the existence of glutamatergic projections to the STN in the slice preparation, and these excitatory synaptic connections appeared to originate from axon collaterals within the STN rather than other basal ganglia nuclei. It could be concluded that the STN neurons and their interconnectivity are essential requirements in the rat brain slice preparation to produce spontaneous synchronized burst firing. (C) 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.”
“Recent evidence demonstrates important maternal effects on an offspring’s risk of developing metabolic disease. These effects extend across the full range of maternal environments and partly involve epigenetic mechanisms. The maternal effects can be explained in evolutionary terms, and there is some evidence for their transmission into succeeding generations. Unbalanced maternal diet or body composition, ranging from poor to rich environments, adversely influences the offspring’s response to later challenges such as an obesogenic diet or physical inactivity, increasing the risk of disease.

Testosterone administration in rats is a suitable tool for investigating hormone dependent benign Nepicastat ic50 prostatic hyperplasia. We performed a comparison experiment between Serenoa repens and the lycopene-Se-Serenoa repens combination on prostate growth induced in rats by testosterone administration.

Materials and Methods: Rats were treated daily with testosterone propionate (3 mg/kg subcutaneously) or its vehicle for 14 days. Testosterone administered animals were randomized to receive vehicle, Serenoa repens (25 mg/kg subcutaneously)

or the combination of lycopene (3 mg/kg subcutaneously), Se (3 mg/kg subcutaneously) and Serenoa repens for 14 days. The rats were sacrificed and

the prostate was removed for analysis.

Results: Lycopene-Se-Serenoa repens was more effective than Serenoa repens alone for decreasing prostate weight and hyperplasia, augmenting pro-apoptotic Bax and caspase-9, and blunting anti-apoptotic Bcl-2 mRNA. Lycopene-Se-Serenoa repens also markedly decreased epidermal growth factor and vascular endothelial growth factor expression.

Conclusions: The data indicate that the Stattic ic50 lycopene-Se-Serenoa repens combination is superior to Serenoa repens alone for decreasing hormone dependent prostatic growth.”
“Recent studies have shown that PLA2G6 is a causative gene for PARK14-linked autosomal recessive early-onset complicated dystonia-parkinsonism, early-onset parkinsonism with frontotemporal dementia and autosomal recessive early-onset Parkinsonism without added complicated clinical features. In order to investigate the characteristics of PLA2G6 gene mutations in Chinese selleck screening library sporadic early-onset parkinsonism (FOP) patients, we performed polymerase chain reaction

and DNA direct sequencing on a cohort of sporadic EOP patients from Chinese population. In this study, we found a novel heterozygous varient (p.G679V). Bioinformatics demonstrates that p.G679V exhibits highly conserved residues across species, which hints it might be a pathogenic mutation. Our result indicated that PLA2G6 mutations might not be a main cause of Chinese sporadic EOP. (C) 2012 Elsevier Ireland Ltd. All rights reserved.”
“Objective: To test if the covariance of hypothalamus-oituitary-adrenal (HPA) axis and subjective-psycho logical responses to stress is dependent on different dynamics of these systems. Although stress theories typically assume substantial correlations of psychological and endocrine stress responses, studies have produced inconsistent results. One reason for this might be imperfect coupling of the different stress response systems. However, inconsistent correlations might also be a result of different on-/offsets of these stress responses, i.e., specific dynamics of the systems.

Materials and Methods:

We performed a retrospective analysis of 155 patients diagnosed with isolated primary high grade carcinoma in situ at a tertiary center from 1990 to 2008 who underwent transurethral resection followed by intravesical bacillus Calmette-Guerin therapy. The end points included time to disease recurrence, time to progression to invasive disease (cT1 or higher) or to muscle invasive disease (cT2 or higher), or early radical cystectomy. Predictors included gender, age, race, smoking history, presenting symptoms, carcinoma in situ pattern (focal, multiple or diffuse) and response to bacillus Calmette-Guerin.

Results: A total of 155 patients received bacillus Calmette-Guerin therapy within 6 months. The 5-year cumulative incidence of progression to cT1 or higher was 45% (95% CI 37-55) and to cT2 or higher was 17% (95% CI 12-25) adjusting for the competing risk of radical cystectomy. Of 130 patients Selleck SBI-0206965 evaluated for response to bacillus Calmette-Guerin 81 (62%) were considered responders. Response to bacillus Calmette-Guerin was significantly associated with progression to cT1 or higher/radical cystectomy (HR 0.59, 95% CI 0.36-0.95, p = 0.029) and to cT2 or higher/radical cystectomy (HR 0.53, 95%

CI 0.32-0.88, p = 0.015). This association was largely driven by the higher rate of early radical cystectomy among nonresponders.

Conclusions: Despite bacillus Calmette-Guerin therapy and early radical cystectomy, patients with primary carcinoma in situ had a high rate of disease progression. HER2 inhibitor Response to bacillus Calmette-Guerin was significantly associated SB431542 order with a lower rate of disease progression or early radical cystectomy.”
“Background:

Failure to generate phagocyte-derived superoxide and related reactive oxygen intermediates (ROIs) is the major defect in chronic granulomatous disease, causing recurrent infections and granulomatous complications. Chronic granulomatous disease is caused by missense, nonsense, frameshift, splice, or deletion mutations in the genes for p22(sup phox), p40(sup phox), p47(sup phox), p67(sup phox) (autosomal chronic granulomatous disease), or gp91(sup phox) (X-linked chronic granulomatous disease), which result in variable production of neutrophil-derived ROIs. We hypothesized that residual ROI production might be linked to survival in patients with chronic granulomatous disease.

Methods: We assessed the risks of illness and death among 287 patients with chronic granulomatous disease from 244 kindreds. Residual ROI production was measured with the use of superoxide-dependent ferricytochrome c reduction and flow cytometry with dihydrorhodamine oxidation assays. Expression of NADPH oxidase component protein was detected by means of immunoblotting, and the affected genes were sequenced to identify causal mutations.

05). Thirteen of 26 (50%) patients with a tear >1.9 cm(2) had aortic branch malperfusion (P = .032). Ten of 14(71%) patients with a tear >4.86 cm2 (mean plus one standard deviation) had aortic branch malperfusion (P =.002). The location of tears ranged from-6 mm to +459.2 mm from the left selleck inhibitor subclavian artery orifice: 80.5% (n = 99) of these tears were above the reference origin of the celiac artery. Eight of 13 panents (62%) with a tear distal to 282 mm (the orifice of the celiac artery) had aortic branch malperfusion in

(P = .04). A classification for the location of intimomedial tears is proposed with potential clinical relevance to endovascular repair: type I has no identifiable tears; type 2 has one or more tears with no tears distal to the orifice of the celiac artery; type 3 has tears involving the branch vessels of the abdominal aorta, and type 4 has intimomedial

tears distal to the aortic bifurcation.

Conclusions. Characterization and location of intimomedial tears using see more computed tomography (CT) imaging is feasible and represents an important step in the management of type B aortic dissection. The location and surface area of tears is associated with malperfusion. Based on the proposed classification and anatomic reference data, three out of every four-patients may have a favorable constellation of intimomedial tears (type 1 or 2) that would be amenable to endovascular repair and reverse aortic remodeling. The clinical correlation will be established in upcoming studies. (J Vase Surg 2010; 52:562-8.)”
“Objectives. Octogenarians and even patients over

70 years old have unexplained poor outcomes with carotid angioplasty and stenting (CAS). We sought to evaluate whether older patients may have compromised intracramal collaterals and cerebral reserve and be intolerant to otherwise clinically silent emboli generated during CAS.

Methods: One thousand twenty-four cerebral blood flow (CBF) studies performed between 1991 and 2001 with stable xenon computed Ribonucleotide reductase tomography scans (Xe/CT) were reviewed. CBF. was measured before and after 1 gm intravenous acetazolamide (ACZ), a cerebral vasodilator. The normal response to ACZ is an increase in CBF. In areas of significant compromise of cerebral reserve (CR), CBF drops, representing a “”steal”" phenomenon. CBF changes were categorized as normal or abnormal and correlated with age, gender, cerebral symptoms, and with intracranial, carotid, or vertebral artery disease. Logistic regression was used to determine the effect of age on CR in the entire group and a subgroup of 179 patients with significant carotid stenosis of >50%.

Results: Nine hundred sixteen studies were suitable for analysis. Carotid occlusion was predictive of decreased reserve (OR, 3.9; P = .03) regardless of age.

Signs of endomysial

microangiopathy are frequently reported. Necrotizing autoimmune myopathies can be associated with antisignal recognition particle (SRP) antibodies or more rarely with the usual inflammatory myopathy antibodies. Paraneoplasic forms are described but remain exceptional. Lastly, necrotizing autoimmune myopathies, sometimes associated with statin therapy, have been recently described. They are linked with an antibody directed against 3-hydroxy-3-methyglutaryl-coenzyme A. Treatment is based on corticosteroid therapy, immunosuppressive drugs or intravenous immunoglobulins. Response is variable, depending on the clinical form. (C) 2013 Elsevier Masson SAS. All rights reserved.”
“Introduction. – Idiopathic myopathies are a group of acquired muscular diseases considered as autoimmune this website disorders. Characteristic histopathologic features allow the classification into myositis (polymyositis, dermatomyositis, and inclusion body myositis) and immune-mediated necrotizing myopathies.. But overlapping

histological features may be observed between different idiopathic myopathies and even between acquired and genetic muscular diseases. In the group of idiopathic myopathies important discrepancies can be observed concerning extra-muscular involvement and prognosis.

State of art. – The learn more discovery of myositis-specific antibodies and myositis-associated antibodies has led to a serologic approach complementary to histological classification, because see more striking associations of myositis-specific antibodies with clinical features and survival were observed. Here we reviewed the myositis-specific

antibodies including autoantibodies directed against the aminoacyl tRNA-synthetase enzymes, the Mi-2 protein and the signal recognition particle, and the main myositis-associated autoantibodies, that can be tested in clinical practice.

Perspectives. – We will also focus on newly described dermatomyositis-associated antibodies (directed against: transcription intermediary factor 1 family proteins, small ubiquitin-like modifier activating enzyme, and melanoma differentiation-associated gene 5), and immune-mediated necrotizing myopathy-associated antibodies (directed against HMGcoA-reductase).

Conclusion. – Myositis-specific antibodies and myositis-associated antibodies are useful for the diagnosis of forms of autoimmune myopathies with distinct clinical features. They may help to define patients into clinical syndromes with specific outcomes and thus influence treatment strategies. (C) 2013 Published by Elsevier Masson SAS.”
“Introduction. – Exercise intolerance (EI) is a frequent motive for seeking neuromuscular consultation and may be a sign of metabolic disease or, rarely, muscular dystrophy. The diagnosis is not established in many patients with a typical clinical presentation.

Understanding

this relation is central to both evolutionary biology and developmental genetics. Von Baer’s ideas have been both a source of inspiration this website to generations of biologists and a target of continuous criticism over many years. With advances in multiple fields, including paleontology, cladistics, phylogenetics, genomics, and cell and developmental biology, it is now possible to examine carefully the significance of von Baer’s law and its predictions. In this review, I argue that, 185 years after von Baer’s law was first formulated, its main concepts after proper refurbishing remain surprisingly relevant in revealing the fundamentals of the evolution development connection, and suggest that their explanation should become the focus of renewed research.”
“Nicotine is the main active component of tobacco, and has both acute and chronic pharmacological effects that can contribute to its abuse potential in humans. The aim of the present study was to evaluate a possible role of GABA(B) receptors in acute and chronic responses to nicotine administration, VE-821 molecular weight by comparing GABA(B1) knockout mice and their wild-type littermates. In wild-type mice, acute nicotine administration (0.5, 1, 3 and 6 mg/kg, sc) dose-dependently decreased locomotor activity, and induced antinociceptive

responses in the tail-immersion and hot-plate tests. In GABA(B1) knockout mice, the hypolocomotive effect was observed only with the highest dose of nicotine, and the antinociceptive responses in both tests were significantly reduced in GABA(B1) knockout mice compared to their wild-type littermate. Additionally, nicotine elicited anxiolytic- (0.05 mg/kg) and anxiogenic-like (0.8 mg/kg) responses in the elevated plus-maze test in wild-type mice, while selectively the anxiolytic-like effect was abolished in GABA(B1) knockout mice. We further investigated nicotine withdrawal in mice chronically treated with nicotine (25 mg/kg/day, sc). Mecamylamine (1 mg/kg, sc) precipitated several somatic signs of nicotine withdrawal in wild-type

mice. However, signs of nicotine withdrawal were missing in GABA(B1) knockout mice. Finally, there was a decreased immunoreactivity of Fos-positive nuclei in the bed nucleus of the stria terminalis, basolateral amygdaloid nucleus and hippocampal dentate gyrus in abstinent MK-0518 mouse wildtype but not in GABA(B1) knockout mice. These results reveal an interaction between the GABA(B) system and the neurochemical systems through which nicotine exerts its acute and long-term effects. (C) 2012 Elsevier Ltd. All rights reserved.”
“Background: The clinical importance of classifying myocardial infarction (MI) into non-Q-wave (NQWMI) vs. Q-wave (QWMI) subsets is controversial and might depend on the therapeutic reperfusion strategy employed. The prognostic implications of NQWMI development following primary percutaneous coronary intervention (PCI) have not been reported.

We hypothesized that this interpersonal synchronous behavior would not be observed in individuals with autism spectrum disorders (ASD), which are characterized by impaired social communication. To test this hypothesis, we examined eyeblink entrainments in adults with ASD. As we reported previously, the eyeblinks of adults without ASD were significantly synchronized

with the speaker’s eyeblinks at pauses in his speech when they viewed the speaker’s entire face. However, the significant eyeblink synchronization disappeared when adults without ASD viewed only the speaker’s eyes or mouth, suggesting that information from the whole face, including information from both the eyes and the mouth, was necessary for eyeblink entrainment. By contrast, the ASD participants did not show any eyeblink synchronization with the speaker,

even when viewing the speaker’s MK-4827 eyes and mouth simultaneously. The lack of eyeblink entrainment to the speaker in individuals with ASD suggests that they are not able to temporally attune themselves to others’ behaviors. The deficits in temporal coordination may impair effective social communication with others. (C) 2011 Elsevier Ltd. All rights reserved.”
“Background: Endothelial progenitor-derived cells (EPC) are a cell therapy tool in peripheral arterial disease and for C646 reendothelialization of bypasses and stents. Objective: To assess EPC behavior under flow conditions normally found in vivo. Results: EPC were isolated from human cord blood, cultured on compliant tubes and exposed in an in vitro flow system mimicking hemodynamic environments normally found in medium and large arteries. EPC exposed for 24 h to unidirectional (0.3 +/- 0.1 or 6 +/- 3 dynes/cm(2)) shear stress oriented along flow direction,

while those exposed to bidirectional shear stress (0.3 +/- 3 dynes/cm(2)) or static conditions had random orientation. Under bidirectional flow, tissue factor (TF) activity and mRNA expression were significantly increased (2.5- Staurosporine and 7.0-fold) compared to static conditions. Under low shear unidirectional flow TF mRNA increased 4.9 +/- 0.5-fold. Similar flow-induced increases were observed for TF in mature umbilical vein-derived endothelial cells. Expression of tissue-type plasminogen activator (t-PA), urokinase (u-PA) and monocyte chemotactic protein 1 (MCP1) were reduced by 40-60% in late outgrowth endothelial progenitor-derived cells (LO-EPC) exposed to any flow environment, while MCP1, but not t-PA or u-PA, was decreased in HUVEC. Conclusions: Flow, in particular bidirectional, modifies the hemostatic balance in LO-EPC with increased TF and decreased plasminogen activator expression. Copyright (C) 2011 S. Karger AG, Basel”
“Psychogenic tremor is the commonest psychogenic movement disorder, yet little is known of its pathophysiology.

Viral export was also found https://www.selleckchem.com/products/pexidartinib-plx3397.html to be markedly vectorial in N6 but not C11 cells. However, rather than being exported from the apical domain as expected, more than 95% of HAV was exported via the basolateral domain of N6 cells, suggesting that virus is first excreted from infected hepatocytes into the bloodstream rather than to the biliary tree. Enteric excretion of HAV may therefore rely on reuptake and transcytosis of progeny HAV across hepatocytes into the bile. These studies provide the first example of the interactions between viruses and polarized hepatocytes.”
“Memory enhancement is a matter of concern

in general, and in particular to people suffering from cognitive dysfunction. In this Study, we investigated the effect of Nelumbo nucifera rhizome extract on learning and memory function. A step-through

passive avoidance test was performed with Wistar rats. In addition, immunohistochemistry was used to investigate cell proliferation and differentiation in the dentate gyrus of the hippocampus. The methanol extract of N. nucifera rhizome (MNR) resulted in significant improvements of memory functions and neurogenesis in the dentate gyrus. In the passive avoidance test, the retention time of MNR-treated rats was significantly longer than that of controls. Immunohistochemical analyses using BrdU, Ki-67, and DCX showed significantly increased cell proliferation and cell differentiation in the dentate gyrus. These results suggest that N. nucifera rhizome extract may Tideglusib cost improve learning and memory with enhancing neurogenesis in the DG of the hippocampus. (c) 2008 Elsevier

Ireland Ltd. All rights reserved.”
“The human polynucleotide cytidine deaminases APOBEC3G (hA3G) and APOBEC3F (hA3F) are antiviral restriction factors capable of inducing extensive plus-strand guanine-to-adenine (G-to-A) hypermutation in a variety of retroviruses and retroelements, including human immunodeficiency virus type 1 (HIV-1). They differ in target specificity, favoring plus-strand 5′GG and 5′GA dinucleotide motifs, respectively. To characterize their mutational preferences in detail, we analyzed single-copy, near-full-length HIV-1 proviruses which had been hypermutated SB203580 nmr in vitro by hA3G or hA3F. hA3-induced G-to-A mutation rates were significantly influenced by the wider sequence context of the target G. Moreover, hA3G, and to a lesser extent hA3F, displayed clear tetranucleotide preference hierarchies, irrespective of the genomic region examined and overall hypermutation rate. We similarly analyzed patient-derived hypermutated HIV-1 genomes using a new method for estimating reference sequences. The majority of these, regardless of subtype, carried signatures of hypermutation that strongly correlated with those induced in vitro by hA3G. Analysis of genome-wide hA3-induced mutational profiles confirmed that hypermutation levels were reduced downstream of the polypurine tracts.