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BACKGROUND: Catatonia is a challenging and heterogeneous neuropsychiatric syndrome of motor, affective and behavioral dysregulation which has been associated with multiple disorders such as structural brain lesions, systemic diseases, and psychiatric disorders. This systematic review summarized and compared functional neuroimaging abnormalities in catatonia associated with psychiatric and medical conditions. METHODS: Using PRISMA methods, we completed a systematic review of 6 databases from inception to February 7th, 2024 of patients with catatonia that had functional neuroimaging performed. RESULTS: A total of 309 studies were identified through the systematic search and 62 met the criteria for full-text review. A total of 15 studies reported patients with catatonia associated with a psychiatric disorder (n = 241) and one study reported catatonia associated with another medical condition, involving patients with N-methyl-d-aspartate receptor antibody encephalitis (n = 23). Findings varied across disorders, with hyperactivity observed in areas like the prefrontal cortex (PFC), the supplementary motor area (SMA) and the ventral pre-motor cortex in acute catatonia associated to a psychiatric disorder, hypoactivity in PFC, the parietal cortex, and the SMA in catatonia associated to a medical condition, and mixed metabolic activity in the study on catatonia linked to a medical condition. CONCLUSION: Findings support the theory of dysfunction in cortico-striatal-thalamic, cortico-cerebellar, anterior cingulate-medial orbitofrontal, and lateral orbitofrontal networks in catatonia. However, the majority of the literature focuses on schizophrenia spectrum disorders, leaving the pathophysiologic characteristics of catatonia in other disorders less understood. This review highlights the need for further research to elucidate the pathophysiology of catatonia across various disorders.
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Catatonia , Neuroimagen Funcional , Catatonia/fisiopatología , Catatonia/diagnóstico por imagen , Humanos , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Trastornos Mentales/diagnóstico por imagen , Trastornos Mentales/fisiopatologíaRESUMEN
Cannabis use disorder (CUD) is a growing public health concern, with rising prevalence and significant impact on individuals across age groups. This systematic review examines 24 studies investigating pharmacological and non-pharmacological interventions for CUD among adolescents (up to 17), young adults (18-24), and older adults (25-65). Database searches were conducted for randomized controlled trials of CUD interventions reporting outcomes such as cannabis use, abstinence, withdrawal symptoms, and treatment retention. For adolescents, interventions such as contingent rewards and family engagement have shown promise, while young adults benefit from technology-based platforms and peer support. In older adults, pharmacological adjuncts combined with counseling have shown promise in enhancing treatment outcomes. However, optimal treatment combinations remain uncertain, highlighting the need for further research. Addressing CUD requires tailored interventions that acknowledge developmental stages and challenges across the lifespan. Although promising interventions exist, further comparative effectiveness research is needed to delineate the most efficacious approaches.
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Compositions of ZnO nanoparticles and polyaniline, in the form of emeraldine salt, were manufactured as thin layers by using the spin-coating method. Then, the effect of polyaniline content on their photoelectrochemical characteristics was studied. Results indicate that all the samples are sensitive to light. Besides, with 0.30% of PANI, the composite sample demonstrates the highest photocurrent density; also, its photocurrent increment starts to increase at a voltage of â 1.23 V (vs. RHE), which is approximately in accordance with the theoretical potential of water electrolysis. Furthermore, since the rate of electron-hole recombination in this composite sample is the lowest, it possesses the highest photoelectrochemical efficiency. Main findings were analyzed with respect to UV-visible absorption and photoluminescence spectra as well as SEM micrographs of the samples and Raman spectral measurements. Besides, electrochemical impedance spectroscopy analysis was applied to both pure ZnO and the sample with the best response. Effects of drying temperature and layer thickness were also investigated.
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Autism spectrum disorder (ASD) represents a panel of conditions that begin during the developmental period and result in impairments of personal, social, academic, or occupational functioning. Early diagnosis is directly related to a better prognosis. Unfortunately, the diagnosis of ASD requires a long and exhausting subjective process. We aimed to review the state of the art for automated autism diagnosis and recognition in this research. In February 2022, we searched multiple databases and sources of gray literature for eligible studies. We used an adapted version of the QUADAS-2 tool to assess the risk of bias in the studies. A brief report of the methods and results of each study is presented. Data were synthesized for each modality separately using the Split Component Synthesis (SCS) method. We assessed heterogeneity using the I 2 statistics and evaluated publication bias using trim and fill tests combined with ln DOR. Confidence in cumulative evidence was assessed using the GRADE approach for diagnostic studies. We included 344 studies from 186,020 participants (51,129 are estimated to be unique) for nine different modalities in this review, from which 232 reported sufficient data for meta-analysis. The area under the curve was in the range of 0.71-0.90 for all the modalities. The studies on EEG data provided the best accuracy, with the area under the curve ranging between 0.85 and 0.93. We found that the literature is rife with bias and methodological/reporting flaws. Recommendations are provided for future research to provide better studies and fill in the current knowledge gaps.
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Trastorno del Espectro Autista , Trastorno Autístico , Humanos , Trastorno del Espectro Autista/diagnóstico , Inteligencia ArtificialRESUMEN
OBJECTIVE: Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies. METHODS: This study summarizes the clinical, imaging, and molecular data of these patients for five years. RESULTS: The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1, and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis. CONCLUSIONS: The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042).
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ADN Mitocondrial , Mitocondrias , Niño , Humanos , ADN Mitocondrial/genética , Mutación/genética , Cuerpo CallosoRESUMEN
BACKGROUND: Shift work has been related to adverse health outcomes that can partially be attributed to physical inactivity. However, our knowledge of the influence of shift work on physical activity and sedentary behavior is inconclusive. Therefore, this study aimed to assess physical activity levels among shift and non-shift workers among a sample of Iranian adults. METHODS: Baseline data of the Ravansar Non-Communicable Disease (RaNCD) cohort study were used. All participants of RaNCD except those excluded due to unemployment or considerable disability were included in the study. We evaluated participants' physical activity levels using the PERSIAN cohort questionnaire and examined its associations with being a shift worker. RESULTS: A total of 4695 participants with a mean age of 46.1 (SD = 7.74) were included in the study. In total, 1108 (23.6%) participants were shift workers, 1420 (30.2%) had insufficient physical activity levels, and 4283 (91.2%) were male. The prevalence of physical inactivity was significantly lower among shift workers compared to non-shift workers (21% vs. 33.1%, p < 0.001). Multiple backward stepwise binary logistic regression tests indicated that being a shift worker was significantly associated with a lower chance of having insufficient physical activity levels (OR = 0.77, 95% CI = 0.65-0.92, p = 0.003). CONCLUSIONS: The prevalence of insufficient physical activity was higher among non-shift workers than shift workers in our study. By providing the factors associated with insufficient physical activity among the workers in a region of Iran, the current study findings might help policymakers target groups at higher risk of physical activity in Iran and design interventions to improve physical activity, especially among non-shift workers.
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Ejercicio Físico , Conducta Sedentaria , Adulto , Humanos , Masculino , Persona de Mediana Edad , Femenino , Irán/epidemiología , Estudios Transversales , Estudios de CohortesRESUMEN
BACKGROUND: . Low back pain is one of the major causes of morbidity worldwide. Studies on low back pain quality of care are limited. This study aimed to evaluate the quality of care of low back pain worldwide and compare gender, age, and socioeconomic groups. METHODS: . This study used GBD data from 1990 to 2017 from the Institute for Health Metrics and Evaluation (IHME) website. Extracted data included low back pain incidence, prevalence, disability-adjusted life years (DALYs), and years lived with disability (YLDs). DALYs to prevalence ratio and prevalence to incidence ratio were calculated and used in the principal component analysis (PCA) to make a proxy of the quality-of-care index (QCI). Age groups, genders, and countries with different socioeconomic statuses regarding low back pain care quality from 1990 to 2017 were compared. RESULTS: The proxy of QCI showed a slight decrease from 36.44 in 1990 to 35.20 in 2017. High- and upper-middle-income countries showed a decrease in the quality of care from 43.17 to 41.57 and from 36.37 to 36.00, respectively, from 1990 to 2017. On the other hand, low and low-middle-income countries improved, from a proxy of QCI of 20.99 to 27.89 and 27.74 to 29.36, respectively. CONCLUSION: . Despite improvements in the quality of care for low back pain in low and lower-middle-income countries between 1990 and 2017, there is still a large gap between these countries and higher-income countries. Continued steps must be taken to reduce healthcare barriers in these countries.
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Introduction: The clinical course of LBP is complex and chronicity is more frequent than once thought. Moreover, insufficient evidence was found in support of any specific approach at the level of the general population. Research question: This study aimed to evaluate the effectiveness of providing a back care package through the primary healthcare system in decreasing the rate of CLBP in the community. Material and methods: Clusters were primary healthcare units with the covered population as participants. The intervention package comprised both exercise and educational content in the form of booklets. Data regarding LBP were collected at baseline, 3 and 9-month follow-ups. The LBP prevalence and the incidence of CLBP in the intervention group compared to the control group were analyzed using logistic regression through GEE. Results: Eleven clusters were randomized including 3521 enrolled subjects. At 9 months, the intervention group showed a statistically significant decrease in both the prevalence and the incidence of CLBP, compared to the control group (OR â= â0.44; 95% CI â= â0.30-0.65; P â< â0.001 and OR â= â0.48; 95% CI â= â0.31-0.74; P â< â0.001, respectively). Discussion and conclusion: The population-based intervention was effective in reducing the LBP prevalence and CLBP incidence. Our results suggest that preventing CLBP through a primary healthcare package including exercise and educational content is achievable.
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BACKGROUND: Giant axonal neuropathy (GAN) is a progressive childhood hereditary polyneuropathy that affects both the peripheral and central nervous systems. Disease-causing variants in the gigaxonin gene (GAN) cause autosomal recessive giant axonal neuropathy. Facial weakness, nystagmus, scoliosis, kinky or curly hair, pyramidal and cerebellar signs, and sensory and motor axonal neuropathy are the main symptoms of this disorder. Here, we report two novel variants in the GAN gene from two unrelated Iranian families. METHODS: Clinical and imaging data of patients were recorded and evaluated, retrospectively. Whole-exome sequencing (WES) was undertaken in order to detect disease-causing variants in participants. Confirmation of a causative variant in all three patients and their parents was carried out using Sanger sequencing and segregation analysis. In addition, for comparing to our cases, we reviewed all relevant clinical data of previously published cases of GAN between the years 2013-2020. RESULTS: Three patients from two unrelated families were included. Using WES, we identified a novel nonsense variant [NM_022041.3:c.1162del (p.Leu388Ter)], in a 7-year-old boy of family 1, and a likely pathogenic missense variant [NM_022041.3:c.370T>A (p.Phe124Ile)], in two affected siblings of the family 2. Clinical examination revealed typical features of GAN-1 in all three patients, including walking difficulties, ataxic gait, kinky hair, sensory-motor polyneuropathy, and nonspecific neuroimaging abnormalities. Review of 63 previously reported cases of GAN indicated unique kinky hair, gait problem, hyporeflexia/areflexia, and sensory impairment were the most commonly reported clinical features. CONCLUSIONS: One homozygous nonsense variant and one homozygous missense variant in the GAN gene were discovered for the first time in two unrelated Iranian families that expand the mutation spectrum of GAN. Imaging findings are nonspecific, but the electrophysiological study in addition to history is helpful to achieve the diagnosis. The molecular test confirms the diagnosis.
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Neuropatía Axonal Gigante , Enfermedades del Sistema Nervioso Periférico , Masculino , Humanos , Niño , Neuropatía Axonal Gigante/diagnóstico , Neuropatía Axonal Gigante/genética , Neuropatía Axonal Gigante/patología , Irán , Estudios Retrospectivos , Proteínas del Citoesqueleto/genética , Mutación , Enfermedades del Sistema Nervioso Periférico/genéticaRESUMEN
Background: Balance impairment is a common problem in all age groups. There are several tools to assess balance. Functional reach test (FRT), single-leg stance (SLS) test, timed up and go (TUG) test, and TUG with the cognitive dual-task (TUGcog) are commonly employed balance tests. The current study aimed to determine the normative values of FRT, SLST, TUG, and TUGcog across age groups and genders in healthy Iranian adults. Methods: We designed a cross-sectional study, and 240 healthy adults (120 males and 120 females) in six age groups (18-29, 30-39, 40-49, 50-59, 60-69, ≥70 years) completed FRT, SLST, TUG, and TUGcog based on the Persian version of BESTest instructions. Results: There were significant age-specific declines in balance performances. Gender had effects on 18-29 years and older adults (≥60 years), and males performed better than females. Male and females had similar performance on the TUG and TUGcog tests in 60-69 years (p > 0.05). Conclusions: The normative values of FRT, SLS, TUG, and TUGcog provided for healthy Iranian adults increase the clinical utility of tests, and serve as a reference to estimating the individuals' balance performance across age and gender groups.
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BACKGROUND AND OBJECTIVES: Low back pain (LBP) is a common health condition in populations. Limited large-scale population-based studies evaluated the prevalence and predictors of LBP in developing countries. This study aimed to evaluate the prevalence and factors associated with LBP among the Iranian population. METHODS: We used baseline information from the Prospective Epidemiological Research Studies in Iran (PERSIAN), including individuals from 16 provinces of Iran. LBP was defined as the history of back pain interfering with daily activities for more than one week during an individual's lifetime. Various factors hypothesized to affect LBP, such as age, sex, marital status, educational status, ethnicity, living area, employment status, history of smoking, body mass index (BMI), physical activity, sleep duration, wealth score, history of joint pain, and history of morning stiffness in the joints were evaluated. RESULTS: In total, 163770 Iranians with a mean age of 49.37 (SD = 9.15) were included in this study, 44.8% of whom were male. The prevalence of LBP was 25.2% among participants. After adjusting for confounders, the female gender [OR:1.244(1.02-1.50)], middle and older ages [OR:1.23(1.10-1.33) and OR:1.13(1.07-1.42), respectively], being overweight or obese [OR:1.13(1.07-1.19) and OR:1.21(1.16-1.27), respectively], former and current smokers (OR:1.25(1.16-1.36) and OR:1.28(1.17-1.39), respectively], low physical activity [OR:1.07(1.01-1.14)], and short sleep duration [OR: 1.09(1.02-1.17)] were significantly associated with LBP. CONCLUSION: In this large-scale study, we found the lifetime prevalence of LBP to be lower among the Iranian population in comparison to the global prevalence of LBP; further studies are warranted to evaluate the causality of risk factors on LBP.
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Emerging evidence suggests that biofluid-based biomarkers have diagnostic and prognostic potential in traumatic brain injuries (TBI). However, owing to the lack of a conceptual framework or comprehensive review, it is difficult to visualize the breadth of materials that might be available. We conducted a systematic scoping review to map and categorize the evidence regarding biofluid-based biochemical markers of TBI. A comprehensive search was undertaken in January 2019. Of 25,354 records identified through the literature search, 1036 original human studies were included. Five hundred forty biofluid biomarkers were extracted from included studies and classified into 19 distinct categories. Three categories of biomarkers including cytokines, coagulation tests, and nerve tissue proteins were investigated more than others and assessed in almost half of the studies (560, 515, and 502 from 1036 studies, respectively). S100 beta as the most common biomarker for TBI was tested in 21.2% of studies (220 articles). Cortisol was the only biomarker measured in blood, cerebrospinal fluid, urine, and saliva. The most common sampling time was at admission and within 24 h of injury. The included studies focused mainly on biomarkers from blood and central nervous system sources, the adult population, and severe and blunt injuries. The most common outcome measures used in studies were changes in biomarker concentration level, Glasgow coma scale, Glasgow outcome scale, brain computed tomography scan, and mortality rate. Biofluid biomarkers could be clinically helpful in the diagnosis and prognosis of TBI. However, there was no single definitive biomarker with accurate characteristics. The present categorization would be a road map to investigate the biomarkers of the brain injury cascade separately and detect the most representative biomarker of each category. Also, this comprehensive categorization could provide a guiding framework to design combined panels of multiple biomarkers.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Adulto , Biomarcadores , Lesiones Traumáticas del Encéfalo/diagnóstico , Escala de Coma de Glasgow , Escala de Consecuencias de Glasgow , HumanosRESUMEN
Correction for 'Protective effects of hydroalcoholic extracts from an ancient apple variety 'Mela Rosa dei Monti Sibillini' against renal ischemia/reperfusion injury in rats' by Hasan Yousefi-Manesh et al., Food Funct., 2019, 10, 7544-7552.
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The purpose of this work was to investigate the effect of hydroalcoholic extracts from the peel (APE) and pulp (APP) of a traditional apple variety of central Italy, the 'Mela Rosa dei Monti Sibillini', on the damage caused by renal ischemia/reperfusion injury (IRI) in rats. Thirty mg per kg b.w. of the extracts were administered intraperitoneally to male adult Wistar rats 3 days before the induction of IRI by pedicle clamping. A significant decrease in the levels of malondialdehyde (MDA), tumor necrosis factor-α (TNFα), interleukin 1 beta (IL-1ß) and nuclear factor-κB (NF-κB) was observed in the groups pre-treated with APE when compared with IRI rats. The chemical composition of APE was determined by HPLC-DAD-MSn highlighting a significant amount of proanthocyanidins (52.9 mg g-1), flavonols (42.27 mg g-1) and dihydrochalcones (11.75 mg g-1). These findings indicated that this ancient apple variety is a promising source of nutraceuticals and functional foods helpful to manage complications of renal disorders.
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Frutas/química , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/etiología , Malus/química , Extractos Vegetales/farmacología , Daño por Reperfusión/tratamiento farmacológico , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Regulación hacia Abajo , Inflamación/tratamiento farmacológico , Masculino , FN-kappa B/genética , FN-kappa B/metabolismo , Extractos Vegetales/química , Ratas , Ratas WistarRESUMEN
BACKGROUND: p53 plays an important role in many areas of cellular physiology and biology, ranging from cellular development and differentiation to cell cycle arrest and apoptosis. Many of its functions are attributed to its role in assuring proper cellular division. However, since the establishment of its role in cell cycle arrest, damage repair, and apoptosis (thus also establishing its importance in cancer development), numerous reports have demonstrated additional functions of p53 in various cells. In particular, p53 appears to have important functions as it relates to neurodegeneration and synaptic plasticity. OBJECTIVE: In this review, we will address p53 functions as it relates to various neurodegenerative diseases, mainly its implications in the development of HIV-associated neurocognitive disorders. CONCLUSION: p53 plays a pivotal role in the development of neurodegenerative diseases through its interaction with cellular factors, viral factors, and/or small RNAs that have the ability to promote the development of these diseases. Hence, inhibition of p53 may present an ideal target to restore neuronal functions.
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Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Proteína p53 Supresora de Tumor/fisiología , Complejo SIDA Demencia/genética , Complejo SIDA Demencia/metabolismo , Complejo SIDA Demencia/fisiopatología , Animales , Humanos , Enfermedades Neurodegenerativas/fisiopatologíaRESUMEN
Transcriptional regulation of the human immunodeficiency virus type 1 (HIV-1) is a complex event that requires the cooperative action of both viral (e.g. Tat) and cellular (e.g. C/EBPbeta, NF-kappaB) factors. The HIV-1 Tat protein recruits the human positive transcription elongation factor P-TEFb, consisting of cdk9 and cyclin T1, to the HIV-1 transactivation response (TAR) region. In the absence of TAR, Tat activates the HIV-1 long terminal repeat (LTR) through its association with several cellular factors including C/EBPbeta. C/EBPbeta is a member of the CCAAT/enhancer-binding protein family of transcription factors and has been shown to be a critical transcriptional regulator of HIV-1 LTR. We examined whether Tat-C/EBPbeta association requires the presence of the P-TEFb complex. Using immunoprecipitation followed by Western blot, we demonstrated that C/EBPbeta-cyclin T1 association requires the presence of cdk9. Further, due to its instability, cdk9 was unable to physically interact with C/EBPbeta in the absence of cyclin T1 or Tat. Using kinase assays, we demonstrated that cdk9, but not a cdk9 dominant-negative mutant (cdk9-dn), phosphorylates C/EBPbeta. Our functional data show that co-transfection of C/EBPbeta and cdk9 leads to an increase in HIV-1 gene expression when compared to C/EBPbeta alone. Addition of C/EBP homologous protein (CHOP) inhibits C/EBPbeta transcriptional activity in the presence and absence of cdk9 and causes a delay in HIV-1 replication in T-cells. Together, our data suggest that Tat-C/EBPbeta association is mediated through cdk9, and that phosphorylated C/EBPbeta may influence AIDS progression by increasing expression of HIV-1 genes.
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Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Quinasa 9 Dependiente de la Ciclina/metabolismo , Regulación Viral de la Expresión Génica , Productos del Gen tat/metabolismo , VIH-1/patogenicidad , Proteína beta Potenciadora de Unión a CCAAT/genética , Línea Celular Tumoral , Ciclina T , Quinasa 9 Dependiente de la Ciclina/genética , Ciclinas/genética , Ciclinas/metabolismo , Productos del Gen tat/genética , Humanos , Transfección , Células U937 , Productos del Gen tat del Virus de la Inmunodeficiencia HumanaRESUMEN
Expression of the viral protein R, Vpr, of HIV-1 affects many biological events in host cells including cell cycle progression, and modulates HIV-1 gene transcription. Earlier studies implicating the cellular protein p21(WAF1) (p21) in regulation of HIV-1 transcription, led us to investigate the functional and physical interaction of Vpr and p21. Our results show that Vpr modestly activated HIV-LTR in cells lacking p21 gene. Here, we describe the mechanisms by which p21 and Vpr leading to stimulation of HIV-1 transcription. Data from the protein-protein interaction experiments revealed the ability of Vpr, p21 and p300 to form a complex. Further, we show that, Vpr interacts with the N- and the C-terminal domains of p21. Furthermore, in cells expressing Vpr, p21 localizes to both the cytoplasm and the nucleus. Interestingly, expression of Vpr alleviates p21-mediated inhibition of cell departure from G1 phase. Expression of a mutant Vpr, with arginine 73 altered to serine, did not affect the ability of p21 to cause cells arrest or its sub-cellular localization. These observations reveal a new cellular partner for Vpr, and provide a new therapeutic avenue for controlling HIV-1 expression.
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Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Regulación Viral de la Expresión Génica , Productos del Gen vpr/metabolismo , VIH-1/genética , Sitios de Unión , Ciclo Celular , Línea Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Proteína p300 Asociada a E1A/metabolismo , Productos del Gen vpr/genética , Células HCT116 , Duplicado del Terminal Largo de VIH , VIH-1/metabolismo , Humanos , Microscopía Fluorescente , Modelos Biológicos , Transfección , Productos del Gen vpr del Virus de la Inmunodeficiencia HumanaRESUMEN
The tumor suppressor p53 is an important cellular protein, which controls cell cycle progression. Phosphorylation is one of the mechanisms by which p53 is regulated. Here we report the interaction of p53 with another key regulator, cdk9, which together with cyclin T1 forms the positive transcription elongation complex, p-TEFb. This complex cooperates with the HIV-1 Tat protein to cause the phosphorylation of the carboxyl terminal domain (CTD) of RNA polymerase II and this facilitates the elongation of HIV-1 transcription. We demonstrate that cdk9 phosphorylates p53 on serine 392 through their direct physical interaction. Results from protein-protein interaction assays revealed that cdk9 interacts with the C-terminal domain (aa 361-393) of p53, while p53 interacts with the N-terminal domain of cdk9. Transfection and protein binding assays (EMSA and ChIP) demonstrated the ability of p53 to bind and activate the cdk9 promoter. Interestingly, cdk9 phosphorylates serine 392 of p53, which could be also phosphorylated by casein kinase II. Kinase assays demonstrated that cdk9 phosphorylates p53 independently of CKII. These studies demonstrate the existence of a feedback-loop between p53 and cdk9, pinpointing a novel mechanism by which p53 regulates the basal transcriptional machinery.
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Quinasa de la Caseína II/metabolismo , Quinasa 9 Dependiente de la Ciclina/metabolismo , Serina , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias Encefálicas , Línea Celular Tumoral , Glioblastoma , VIH-1/genética , Humanos , Cinética , Neoplasias Pulmonares , Fosforilación , Proteínas Recombinantes/metabolismo , Transcripción GenéticaRESUMEN
Despite the use of highly active antiretroviral therapy (HAART), neuronal cell death remains a problem that is frequently found in the brains of HIV-1-infected patients. HAART has successfully prevented many of the former end-stage complications of AIDS, however, with increased survival times, the prevalence of minor HIV-1 associated cognitive impairment appears to be rising among AIDS patients. Further, HIV-1 associated dementia (HAD) is still prevalent in treated patients as well as attenuated forms of HAD and CNS opportunistic disorders. HIV-associated cognitive impairment correlates with the increased presence in the CNS of activated, though not necessarily HIV-1-infected, microglia and CNS macrophages. This suggests that indirect mechanisms of neuronal injury and loss/death occur in HIV/AIDS as a basis for dementia since neurons are not themselves productively infected by HIV-1. In this review, we discussed the symptoms and causes leading to HAD. Outcome from this review will provide new information regarding mechanisms of neuronal loss in AIDS patients.