Early Promoter Research Articles

DNA methylation profiles in urothelial bladder cancer tissues and children with schistosomiasis from Eggua, Ogun State, Nigeria

BackgroundSquamous cell carcinoma has been attributed to chronic schistosomiasis and is the predominant type of bladder cancer in schistosomiasis endemic areas. The aim of this study was to assess early promoter DNA methylation in selected genes implicated in schistosomiasis-associated bladder cancer (SABC).MethodsA total of 159 urine samples were collected from school-aged children in Eggua Community of Ogun State and examined by microscopy for Schistosoma haematobium eggs. From this sample, a subset of 34 (21.1%) urine samples positive for S. haematobium, age and sex-matched with negative urine control samples, and 16 formalin-fixed paraffin-embedded bladder cancer tissues obtained from the University College Hospital were subjected to DNA isolation and bisulphite DNA conversion. Quantitative methylation-specific PCR was used to determine the methylation status of APC, RARβ2, RASSF1A, and TIMP3 in the samples.ResultsHigh degrees of methylation of RARβ2(67.7%), RASSF1A (38.2%), and TIMP3(52.9%) was more common in urogenital schistosomiasis (UGS)-positive urine samples than negative urine (control) samples and in bladder cancer tissues. Promoter DNA methylation in the positive urine samples was 1.4-fold, 13.3-fold, 3.4-fold, and 3.8-fold higher in APC, RARβ2, RASSF1A, and TIMP3, respectively, than in the matched controls. The odds of promoter methylation were likely to increase with age group for APC (OR: 1.615) and TIMP3(OR: 2.000); sex for TIMP3(OR: 2.644); and haematuria for RARβ2(OR: 1.094), RASSF1A (OR: 1.143), and TIMP3(OR: 1.842), although there were no significant associations. Conclusions: Gene promoter DNA methylation in tumour suppressor genes was observed in schistosomiasis cases. Hence, promoter DNA methylation may occur during active schistosomiasis in children. This result may serve as an early non-invasive biomarker to detect and hint at the risk of developing SABC later in life.

Identification of target cells of human papillomavirus 18 using squamocolumnar junction organoids.

Human papillomavirus 18 (HPV18) is a highly malignant HPV genotype among high-risk HPVs, characterized by the difficulty of detecting it in precancerous lesions and its high prevalence in adenocarcinomas. The cellular targets and molecular mechanisms underlying its infection remain unclear. In this study, we aimed to identify the cells targeted by HPV18 and elucidate the molecular mechanisms underlying HPV18 replication. Initially, we established a lentiviral vector (HPV18LCR-GFP vector) containing the HPV18 long control region promoter located upstream of EGFP. Subsequently, HPV18LCR-GFP vectors were transduced into patient-derived squamocolumnar junction organoids, and the presence of GFP-positive cells was evaluated. Single-cell RNA sequencing of GFP-positive and GFP-negative cells was conducted. Differentially expressed gene analysis revealed that 169 and 484 genes were significantly upregulated in GFP-positive and GFP-negative cells, respectively. Pathway analysis showed that pathways associated with cell cycle and viral carcinogenesis were upregulated in GFP-positive cells, whereas keratinization and mitophagy/autophagy-related pathways were upregulated in GFP-negative cells. siRNA-mediated luciferase reporter assay and HPV18 genome replication assay validated that, among the upregulated genes, ADNP, FHL2, and NPM3 were significantly associated with the activation of the HPV18 early promoter and maintenance of the HPV18 genome. Among them, NPM3 showed substantially higher expression in HPV-related cervical adenocarcinomas than in squamous cell carcinomas, and NPM3 knockdown of HPV18-infected cells downregulated stem cell-related genes. Our new experimental model allows us to identify novel genes involved in HPV18 early promoter activities. These molecules might serve as therapeutic targets in HPV18-infected cervical lesions.

Early Literacy Promotion Using Automated Hovering Among Young Minority Children

ObjectiveTo determine feasibility, acceptability, and explore outcomes of behavioral economic (BE) strategies to increase parent-child shared reading within a Reach Out and Read program. MethodsWe conducted rapid-cycle interviews with 10 parents to assess text messages followed by an 8-week randomized controlled trial of 3 BE strategies at 2 urban primary care practices: daily text messages (texting); daily text messages and regret messaging (regret); or daily text messages, regret messaging, and lottery participation (lottery). Parent-child dyads were eligible if children were <24 months old, Medicaid-eligible, and had access to phones capable of receiving and sending text messages. Parents completed the Read Subscale of the StimQ and Parenting Stress Index-short form (PSI-SF) pre- and postintervention, MacArthur Communicative Development Inventory (CDI), Devereux Early Childhood Assessment (DECA), and a satisfaction measure postintervention. Differences between groups were assessed using intention-to-treat analysis. ResultsOf 45 dyads randomized, 41 (91%) completed the study. Most participants were Black with incomes <$55,000. Parents reported reading on average 4 d/wk with no change in the reading frequency over time. StimQ scores increased over time, but there were no significant differences in StimQ, PSI-SF, CDI, and DECA scores between groups. Parents in all 3 groups reported satisfaction (3.8/5.0) with the intervention. ConclusionsImplementation of BE strategies in 2 Reach Out and Read programs was feasible, near acceptable, and improved home reading environment scores. Future study should investigate BE strategies vis-à-vis usual care and be of sufficient duration and intensity to engage participants to assess its impact on patient and parent outcomes.

MORC3 represses the HCMV major immediate early promoter in myeloid cells in the absence of PML nuclear bodies.

Human cytomegalovirus (HCMV) can undergo either a latent or a lytic infection in cells of the myeloid lineage. Whilst the molecular mechanisms which determine the outcome of infection are far from clear, it is well established that a key factor is the differential regulation of the major immediate early promoter (MIEP) responsible for driving lytic immediate early gene expression. Using a myelomonocytic cell line stably transduced with a GFP reporter under the control of the MIEP, which recapitulates MIEP regulation in the context of virus infection, we have used an unbiased CRISPR-Cas9 sub-genomic, epigenetic library screen to identify novel cellular factors involved in MIEP repression during establishment and maintenance of latency in myeloid cells. One such cellular factor identified was MORC3. Consistent with MORC3 being a robust repressor of the MIEP, we show that THP1 cells devoid of MORC3 fail to establish latency. We also show that MORC3 is induced during latent infection, recruited to the MIEP and forms MORC3 nuclear bodies (MORC3-NBs) which, interestingly, co-localize with viral genomes. Finally, we show that the latency-associated functions of MORC3 are regulated by the deSUMOylase activity of the viral latency-associated LUNA protein likely to prevent untimely HCMV reactivation.

Mobility outcomes and associated factors of acute geriatric care in hospitalized older patients: results from the PAGER study

Key summary pointsAimTo examine different mobility outcomes of acute geriatric care in acutely hospitalized older adults and identify associated factors.FindingsPatients showed significant increases in locomotor capacity, physical activity, and life-space mobility from hospital admission to discharge, for which frailty was consistently identified as a negative independent predictor. A higher mean daily physical activity level was independently predictive of improvements in locomotor capacity.MessageOlder hospitalized patients benefit from acute geriatric care in terms of distinct mobility outcomes; however, frailty-specific adaptations may be needed for frail patients to optimize their mobility outcomes.

Effects at 12 months of a primary care intervention using finger puppets to support early language promotion: A pilot study

ObjectiveTo determine if introducing finger puppets in the primary care setting during infancy improves parenting and language outcomes at 12 months. MethodsIntervention cohorts were enrolled at ages 2 (early) and 6 (late) months, given a puppet, and followed two weeks later to assess dosage. High dosage was defined as using the puppet daily. At 12 months, a usual care cohort was enrolled and outcome measures were collected for all participants, including maternal depression (PHQ-9), the cognitive home environment (StimQ-T), preverbal skills (CSBS-DP-IT), and vocabulary development (CDI SF). ResultsOf 413 families screened, 248 (60%) were eligible, 180 (73%) enrolled, and 154 (86%) completed the 12-month visit. Most children (84%) were on government-sponsored insurance. There were no differences between early and late intervention outcomes. In intention-to-treat analysis, the intervention cohorts scored better than usual care on the Availability of Learning Materials (ALM) (5.50 vs. 5.02, p = 0.04) and Parental Involvement in Developmental Advance (PIDA) (8.30 vs. 7.58, p = 0.02) StimQ-T subscales and receptive vocabulary (CDI SF English) (61.0 vs. 50.1, p = 0.05). In per protocol analysis, high dosage scored better than low dosage and usual care on the StimQ-T ALM (5.83, 5.08, 5.02, p = 0.01), preverbal communication (CSBS-DP-IT) (72.3, 57.2, 59.2, p = 0.01), and receptive vocabulary (CDI SF English) (73.4, 56.1, 50.1, p = 0.0002). ConclusionsFinger puppets distributed in infancy were associated with an enhanced cognitive home environment and better preverbal and receptive language at 12 months, especially for families using the puppet daily. Additional study should determine if impacts are generalizable and maintained.

Repression of the major immediate early promoter of human cytomegalovirus allows transcription from an alternate promoter.

Following infection, the human cytomegalovirus (HCMV) genome becomes rapidly associated with host histones which can contribute to the regulation of viral gene expression. This can be seen clearly during HCMV latency where silencing of the major immediate early promoter (MIEP), normally responsible for expression of the key lytic proteins IE72 and IE86, is mediated by histone methylation and recruitment of heterochromatin protein 1. Crucially, reversal of these histone modifications coupled with histone acetylation drives viral reactivation which can be blocked with specific histone acetyltransferase inhibitors (HATi). In lytic infection, a role for HATi is less clear despite the well-established enhancement of viral replication observed with histone deacetylase inhibitors. Here we report that a number of different broad-acting HATi have a minor impact on viral infection and replication during lytic infection with the more overt phenotypes observed at lower multiplicities of infection. However, specific analyses of the regulation of major immediate early (MIE) gene expression reveal that the HATi C646, which targets p300/CBP, transiently repressed MIE gene expression via inhibition of the MIEP but by 24 h post-infection MIE gene expression was rescued due to compensatory activation of an alternative IE promoter, ip2. This suggested that silencing of the MIEP promoted alternative ip2 promoter activity in lytic infection and, consistent with this, ip2 transcription is impaired in cells infected with a recombinant HCMV that does not auto-repress the MIEP at late times of infection. Furthermore, inhibition of the histone methyltransferases known to be responsible for auto-repression is similarly inhibitory to ip2 transcription in wild-type infected cells. We also observe that these discrete transcriptional activities of the MIEP and ip2 promoter are also reflected in reactivation; essentially in cells where the MIEP is silenced, ip2 activity is easier to detect at very early times post-reactivation whereas in cells where robust activation of the MIEP is observed ip2 transcription is reduced or delayed. Finally, we observe that inhibition of pathways demonstrated to be important for reactivation of HCMV in dendritic cells, e.g. in response to IL-6, are preferentially important for activation of the MIEP and not the ip2 promoter. Together, these data add to the hypothesis that the existence of multiple promoters within the MIE region of HCMV can drive reactivation in a cell type- and ligand-specific manner and also suggest that inter-dependent regulatory activity between the two promoters exists.

The Human Cytomegalovirus Latency-Associated Gene Product Latency Unique Natural Antigen Regulates Latent Gene Expression.

Human cytomegalovirus (HCMV) infection can lead to either lytic or latent infection, which is dependent on the regulation of the viral major immediate early promoter (MIEP). Suppression of the MIEP is a pre-requisite for latency and is driven by repressive epigenetic modifications at the MIEP during latent infection. However, other viral genes are expressed during latency and this is correlated with activatory epigenetic modifications at latent gene promoters. Yet the molecular basis of the differential regulation of latent and lytic gene expression by epigenetics is unclear. LUNA, a latent viral transcript, has been suggested to be important for HCMV latency and has also been shown to be important for efficient reactivation likely through its known deSUMOylase activity. Intriguingly, we and others have also observed that LUNA enhances latency-associated expression of the viral UL138 gene. Here, we show that in the absence of LUNA, the expression of multiple latency-associated transcripts is reduced during latent infection, which is correlated with a lack of activatory marks at their promoters. Interestingly, we also show that LUNA interacts with the hematopoietic transcription factor GATA-2, which has previously been shown to bind to a number of latency-associated gene promoters, and that this interaction is dependent on the deSUMOylase domain of LUNA. Finally, we show that the deSUMOylase activity of LUNA is required for the establishment and/or maintenance of an open chromatin configuration around latency-associated gene promoters. As such, LUNA plays a key role in efficient latency-associated viral gene expression and carriage of viral genome during latent carriage.

Perspectives of professional experts in relation to the development of community-based exercise for young adults with schizophrenia: a qualitative study

Physical activity is a key modifiable factor in protecting physical and mental health in people with severe mental illness including schizophrenia. Therefore, early promotion of physical activity is recommended and...

Disease severity of COVID-19 in different phases of the pandemic: Do healthcare workers have better outcomes?

BackgroundThis study aimed to characterize and compare the demographics, clinical profile, and COVID-19 outcomes between healthcare workers (HCWs) and non-HCWs COVID-19 patients diagnosed in different phases of the pandemic defined by the vaccine rollout policy and different variants that circulated in South Carolina (SC). MethodsExtracted from the statewide electronic health record data, we analyzed the clinical outcome of 34,502 HCWs and 1,071,020 non-HCWs adults diagnosed with SARS-CoV-2 between March 2, 2020 to April 14, 2022. Logistic regression models were used to explore the association between different pandemic phases and COVID-19 severity-related outcomes. ResultsSubstantial reductions in mortality were observed following the vaccine rollout in non-HCWs and HCWs. Compared to the pre-vaccination period, non-HCWs patients diagnosed during post-vaccination with Alpha predominance (adjusted odds ratio [aOR]: 1.10; 95%CI: 1.04–1.16) were more likely to be hospitalized, but the reduced mortality rates were observed in all post-vaccination periods. Regarding HCWs, a reduced mortality rate was only observed in the pre-Alpha (aOR: 0.33; 95%CI: 0.13–0.84) and Omicron periods (aOR: 0.21; 95%CI: 0.05–0.89). ConclusionsThe declining protection effect of vaccines informs the importance of early promotion of the booster dose of the COVID-19 vaccine for HCWs who have more occupational exposure.

The readmission of a parturient with natural delivery after discharge due to residual fetal membrane: A case report.

Placental residue is a relatively common and sophisticated disease among obstetric delivery complications. A failure to detect placental residue in time may cause poor outcomes such as postpartum hemorrhage and puerperal infection. We present the case of a 33-year-old full-term singleton parturient with placental residue. Upon precipitate labor and childbirth, the placenta and fetal membranes were examined to be intact. However, 1 day after discharge, she felt that there was discharge from the vagina and thus presented to our emergency department. The patient was diagnosed with residual membranes and readmitted to the hospital for uterine curettage. Uterine curettage was performed under B-ultrasound guidance. The patient was discharged smoothly without any postoperative complications. This paper can provide significant enlightenment for the prevention and early treatment of placental residue, including enhancing the risk awareness of high-risk patients, standardizing the process of clinical examination of the placenta, and early uterine contraction promotion to assist in the discharge of residual tissue, so as to reduce the occurrence of placental residue.

Francis S. Morrison MD-Tribute to an apheresis leader.

Francis S. Morrison MD was among the early developers and promoters of the American Society for Apheresis (ASFA). His work was pivotal in creating a lasting institutional structure from which American apheresis medical practice would develop decades after his death. Francis Morrison is honored each year at the ASFA annual meeting as ASFA awards the Francis S. Morrison MD Memorial Award Lecture to an individual who stands out as among its most accomplished members. This tribute seeks to describe the person and the key accomplishments of Francis S. Morrison in the historical context of a time when the future of apheresis medicine was uncertain.

Early Counseling to Improve Oral Health Behavior in Children with Major Congenital Heart Defects: A Randomized Controlled Trial

Maintaining optimal oral health behavior in children with a congenital heart defect (CHD) is important in managing the risk for caries development and infective endocarditis. The aim of this study was to evaluate the impact of an early and repeat oral health promotion intervention (OHPI) among children with major CHD. Randomized controlled trial including 72 out of 91 children born in Finland April 1, 2017–October 31, 2020 with (a) major CHD potentially included in the criteria of endocarditis prophylaxis or (b) any CHD with surgical repair combined with a chromosomal syndrome. A parallel passive control (C) group of 87 healthy children were recruited at birth. CHD children were randomized 1:1 to intervention (CHD-I) and control (CHD-C) groups. The OHPI included counseling by motivational interviewing, home delivered toothpaste and toothbrushes, and written information, and was provided at baseline, 6, 12, and 18 months of age to CHD-I group. The primary outcome measure at 24 months was child’s oral health behavior (toothbrushing, sugar intake, and dental care contact). The secondary outcome measures were parents’ awareness of the importance of oral health behavior, and oral health behavior as a predictor for child behavior. At 24 months, toothbrushing was performed twice a day in 20/27 (74%) among CHD-I, in 13/30 (43%) among CHD-C (CHD-I vs. CHD-C p = 0.03), and in 37/50 (74%) among healthy comparisons (CHD-C vs. C p = 0.01). Electric toothbrush use was 12/27 (44%) in CHD-I, 5/30 (17%) in CHD-C (CHD-I vs. CHD-C p = 0.04), and 7/50 (14%) in healthy comparison (CHD-C vs. C p = 0.76) children. Among CHD-I, toothbrushing and use of electric toothbrush improved between 12 months and 24 months. Sugar drink intake was more common among CHD-C (CHD-C vs. C p = 0.02), but comparable to CHD-I children. Parental toothbrushing predicted child toothbrushing twice a day. There were no statistical group differences in dental care contact. Children with CHD are at risk for poor oral health behavior. This could be improved with early and repeat oral health promotion parental counseling.

Weak promoters to drive selection marker expression: Improvement of cell line development process for therapeutic protein production in CHO-K1 cells.

Chinese Hamster Ovary cells have been widely used as host cells for production of recombinant therapeutic molecules. Cell line development is a decisive step, which must be carried out with an efficient process. In particular, degree of selection stringency is an important parameter for identification of rare, high-producing cell lines. In the CHOZN® CHO K1 platform, selection of top-producing clones is based on puromycin resistance, whose expression is driven by Simian Virus 40 Early (SV40E) promoter. In this study, novel promoters have been identified to drive expression of selection marker. Decrease of transcriptional activity compared to SV40E promoter was confirmed by RT-qPCR. Selection stringency was increased, as seen by decreased surviving rate of transfected mini-pools and longer recovery duration of transfected bulk pools. Several promoters led to a 1.5-fold increase of maximum titer and a 1.3-fold increase of mean specific productivity of the monoclonal antibody over the clone generation. Expression level was maintained stable over long term cultivation. Finally, productivity increase was confirmed on several monoclonal antibodies and fusion proteins. Lowering the strength of promoter for expression of selective pressure resistance is an efficient strategy to increase selection stringency, which can be applied on industrial CHO-based cell line development platforms.

Experimental Support for Human Papillomavirus Genome Amplification Early after Infectious Delivery.

Even though replication and transcription of human papillomavirus type 16 (HPV16) has been intensively studied, little is known about immediate-early events of the viral life cycle due to the lack of an efficient infection model allowing genetic dissection of viral factors. We employed the recently developed infection model (Bienkowska-Haba M, Luszczek W, Myers JE, Keiffer TR, et al. 2018. PLoS Pathog 14:e1006846) to investigate genome amplification and transcription immediately after infectious delivery of viral genome to nuclei of primary keratinocytes. Using 5-ethynyl-2'-deoxyuridine (EdU) pulse-labeling and highly sensitive fluorescence in situ hybridization, we observed that the HPV16 genome is replicated and amplified in an E1- and E2-dependent manner. Knockout of E1 resulted in failure of the viral genome to replicate and amplify. In contrast, knockout of the E8^E2 repressor led to increased viral genome copy number, confirming previous reports. Genome copy control by E8^E2 was confirmed for differentiation-induced genome amplification. Lack of functional E1 had no effect on transcription from the early promoter, suggesting that viral genome replication is not required for p97 promoter activity. However, infection with an HPV16 mutant virus defective for E2 transcriptional function revealed a requirement of E2 for efficient transcription from the early promoter. In the absence of the E8^E2 protein, early transcript levels are unaltered and even decreased when normalized to genome copy number. Surprisingly, a lack of functional E8^E2 repressor did not affect E8^E2 transcript levels when normalized to genome copy number. These data suggest that the main function of E8^E2 in the viral life cycle is to control genome copy number. IMPORTANCE It is being assumed that human papillomavirus (HPV) utilizes three different modes of replication during its life cycle: initial amplification during the establishment phase, genome maintenance, and differentiation-induced amplification. However, HPV16 initial amplification was never formally proven due to a lack of an infection model. Using our recently established infection model (Bienkowska-Haba M, Luszczek W, Myers JE, Keiffer TR, et al. 2018. PLoS Pathog 14:e1006846), we demonstrate herein that viral genome is indeed amplified in an E1- and E2-dependent manner. Furthermore, we find that the main function of the viral repressor E8^E2 is to control viral genome copy number. We did not find evidence that it regulates its own promoter in a negative feedback loop. Our data also suggest that the E2 transactivator function is required for stimulation of early promoter activity, which has been debated in the literature. Overall, this report confirms the usefulness of the infection model for studying early events of the HPV life cycle using mutational approaches.

Maternal Perceptions of Evidence-Based Early Childhood Sleep Health Promotion Recommendations: An Explanatory Sequential Study

ABSTRACT Objectives The purpose of this explanatory sequential design study was to better understand caregivers’ perceptions about and interest in evidence-based early childhood sleep health promotion recommendations. Method A purposeful sample of mothers of 20 1–5-year-old children (10 children exhibiting optimal sleep and 10 children exhibiting insufficient/fragmented sleep) attending a preschool serving a low socio-economic (SES) status metropolitan community were invited to participate in qualitative interviews. Data were coded according to a grounded theory approach and themes were identified within the optimal and suboptimal sleeper groups. Results Mothers reported different approaches to managing electronics by optimal/suboptimal sleeper group, with mothers of optimal sleepers limiting access to electronics more than mothers in the suboptimal sleep group. Other themes of sleep health practices did not differ meaningfully between groups. Conclusions Maternal perspectives about early childhood sleep health were similar across optimal and suboptimal sleepers on most elements of child sleep health. Managing child sleep was contextually influenced and these results highlight the complexities of how families living in lower SES environments perceive common sleep recommendations. Thus, sleep health education efforts should be tailored to the needs and values of specific families and communities.

Remembering Ruth Milligan Ballweg, MPA, PA-C Emeritus.

Remembering Ruth Milligan Ballweg, MPA, PA-C Emeritus.

Homage to Dr. Murray Enkin and the complexity of evidence-based medicine.

Homage to Dr. Murray Enkin and the complexity of evidence-based medicine.

Slug, a Stress-Induced Transcription Factor, Stimulates Herpes Simplex Virus 1 Replication and Transactivates a cis-Regulatory Module within the VP16 Promoter.

Stress-mediated activation of the glucocorticoid receptor (GR) and specific stress-induced transcription factors stimulate herpes simplex virus 1 (HSV-1) productive infection, explant-induced reactivation, and immediate early (IE) promoters that drive expression of infected cell protein 0 (ICP0), ICP4, and ICP27. Several published studies concluded the virion tegument protein VP16, ICP0, and/or ICP4 drives early steps of reactivation from latency. Notably, VP16 protein expression was induced in trigeminal ganglionic neurons of Swiss Webster or C57BL/6J mice during early stages of stress-induced reactivation. If VP16 mediates reactivation, we hypothesized stress-induced cellular transcription factors would stimulate its expression. To address this hypothesis, we tested whether stress-induced transcription factors transactivate a VP16 cis-regulatory module (CRM) located upstream of the VP16 TATA box (-249 to -30). Initial studies revealed the VP16 CRM cis-activated a minimal promoter more efficiently in mouse neuroblastoma cells (Neuro-2A) than mouse fibroblasts (NIH-3T3). GR and Slug, a stress-induced transcription factor that binds enhancer boxes (E-boxes), were the only stress-induced transcription factors examined that transactivated the VP16 CRM construct. GR- and Slug-mediated transactivation was reduced to basal levels when the E-box, two 1/2 GR response elements (GREs), or NF-κB binding site was mutated. Previous studies revealed GR and Slug cooperatively transactivated the ICP4 CRM, but not ICP0 or ICP27. Silencing of Slug expression in Neuro-2A cells significantly reduced viral replication, indicating Slug-mediated transactivation of ICP4 and VP16 CRM activity correlates with enhanced viral replication and reactivation from latency. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes lifelong latency in several types of neurons. Periodically cellular stressors trigger reactivation from latency. Viral regulatory proteins are not abundantly expressed during latency, indicating cellular transcription factors mediate early stages of reactivation. Notably, the glucocorticoid receptor (GR) and certain stress-induced transcription factors transactivate cis-regulatory modules (CRMs) essential for expression of infected cell protein 0 (ICP0) and ICP4, key viral transcriptional regulatory proteins linked to triggering reactivation from latency. Virion protein 16 (VP16) specifically transactivates IE promoter and was also reported to mediate early stages of reactivation from latency. GR and Slug, a stress-induced enhancer box (E-box) binding protein, transactivate a minimal promoter downstream of VP16 CRM, and these transcription factors occupy VP16 CRM sequences in transfected cells. Notably, Slug stimulates viral replication in mouse neuroblastoma cells suggesting Slug, by virtue of transactivating VP16 and ICP4 CRM sequences, can trigger reactivation in certain neurons.

Rural Tourism Under Apartheid South Africa: The Case of Transkei

Rural tourism scholarship has greatly expanded over the past two decades. One aspect of rural tourism that is undeveloped in literature is the historical evolution of rural tourism destinations. This paper uses an historical approach and archival documentary sources to examine the evolution of rural tourism under apartheid in one of the former Bantustans of South Africa, namely Transkei. It is shown tourism became a sector of policy interest because of disappointments associated with national government programmes for industrial decentralization. Early tourism promotion centred on leisure tourism around the natural beauty and attractions of Transkei’s coastal areas. With the grant of ‘independence’, however, a new institutional environment emerged which resulted in the Transkei becoming a focus for casino tourism at a time when casino gambling was prohibited in South Africa. The growth of casino tourism was, however, linked to corruption which occurred between South African tourism capital and the leadership of this Bantustan.