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Studies evaluating students’ UX of applications that will influence their continuance use of educational systems in Higher Educational Institutions (HEIs) have not been sufficiently addressed in the African region, specifically in Ghana. Thus, conducting a study on students’ UX of systems in HEIs will enhance students’ interest in continuing to use such systems. Therefore, this study examines students’ user experience (UX) and how it impacts their continued use of the Student Management Information System (SMIS). The study proposed a research model by integrating user experience questionnaire (UEQ) constructs with continuance intention to use. The study adopted an online questionnaire to collect data from 415 students at Koforidua Technical University (KTU). The partial least square-structural equation model (PLS-SEM) method was used to evaluate the proposed model’s reliability, validity, and relationship among the constructs. The UEQ data analysis tool was used in analysing the data. The study’s findings showed that attractiveness, perspicuity, efficiency, stimulation, and novelty significantly influenced students’ continuance intention to use the SMIS. However, dependability did not significantly affect students’ continuance intention to use the SMIS. Also, the study’s findings on the benchmark results showed that attractiveness, perspicuity, and stimulation were categorized as good, while dependability, efficiency, and novelty were categorized as excellent. These findings offer valuable insights for UX designers and developers aiming to create engaging and intuitive SMIS solutions. Also, it will provide students feedback on system UX that can be incorporated into future release updates. Furthermore, this research contributes significantly to the understanding of student UX with SMIS in developing country HEIs and its impact on continued usage.

Joubert Syndrome (JBTS) is a neurodevelopmental ciliopathy defined by a highly specific midbrain-hindbrain malformation, variably associated with additional neurological features. JBTS displays prominent genetic heterogeneity with >40 causative genes that encode proteins localising to the primary cilium, a sensory organelle that is essential for transduction of signalling pathways during neurodevelopment, among other vital functions. JBTS proteins localise to distinct ciliary subcompartments, suggesting diverse functions in cilium biology. Currently, there is no unifying pathomechanism to explain how dysfunction of such diverse primary cilia-related proteins results in such a highly specific brain abnormality. To identify the shared consequence of JBTS gene dysfunction, we carried out transcriptomic analysis using zebrafish mutants for the JBTS-causative genes cc2d2aw38, cep290fh297, inpp5ezh506, talpid3i264 and togaram1zh510 and the Bardet-Biedl syndrome-causative gene bbs1k742. We identified no commonly dysregulated signalling pathways in these mutants and yet all mutants displayed an enrichment of altered gene sets related to central nervous system function. We found that JBTS mutants have altered primary cilia throughout the brain but do not display abnormal brain morphology. Nonetheless, behavioural analyses revealed reduced locomotion and loss of postural control which, together with the transcriptomic results, hint at underlying abnormalities in neuronal activity and/or neuronal circuit function. These zebrafish models therefore offer the unique opportunity to study the role of primary cilia in neuronal function beyond early patterning, proliferation and differentiation., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Chemokines are proteins important for a range of biological processes from cell-directed migration (chemotaxis) to cell activation and differentiation. Chemokine C-C ligand 5 (CCL5) is an important pro-inflammatory chemokine attracting immune cells towards inflammatory sites through interaction with its receptors CCR1/3/5. Recombinant production of large quantities of CCL5 in Escherichia coli is challenging due to formation of inclusion bodies which necessitates refolding, often leading to low recovery of biologically active protein. To combat this, we have developed a method for CCL5 production that utilises the purification of SUMO tagged CCL5 from E. coli SHuffle cells avoiding the need to reform disulfide bonds through inclusion body purification and yields high quantities of CCL5 (~ 25 mg/L). We demonstrated that the CCL5 produced was fully functional by assessing well-established cellular changes triggered by CCL5 binding to CCR5, including receptor phosphorylation and internalisation, intracellular signalling leading to calcium flux, as well as cell migration. Overall, we demonstrate that the use of solubility tags, SHuffle cells and low pH dialysis constitutes an approach that increases purification yields of active CCL5 with low endotoxin contamination for biological studies., (© 2024. The Author(s).)

Prostate cancer is the most common cancer in men in the UK with over 50 000 new cases diagnosed each year and although therapeutic advances in surgery, anti-androgens, radio- and chemotherapy have increased survival rates, there still remains a need for new treatments to combat the most aggressive forms of the disease. Gene therapy offers promise as an alternative approach but is reliant on selective targeting to the cancer cell surface. Herein we describe the novel construction of a prostate specific membrane antigen (PSMA) binding bioconjugate-polyplex, based on a glutamate-urea peptide scaffold using 'click' chemistry, which we demonstrate is capable of targeted delivery of a GFP gene to PSMA overexpressing prostate cancer cells, and therefore may have potential future application as part of a prostate cancer gene delivery therapy., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Nucleoside analogues are established treatments for cancer and viral infection. Gemcitabine is a commonly employed nucleoside analogue displaying anticancer properties against a range of tumor types but is rapidly inactivated in vivo . Efforts to bolster its pharmaceutical profile include investigating prodrug forms. Herein, we explore the synthesis of a novel glucose-gemcitabine glycoconjugate, targeting uptake via glucose transport. We select a redox-reactive disulfide linker for conjugation of gemcitabine (through N 4-cytosine) with glucose. Evaluation of this glycoconjugate reveals increased toxicity against androgen insensitive PC3 prostate cancer cells compared to LNCaP (which have lower levels of glucose transporter GLUT1). These preliminary results suggest that glycoconjugation of nucleosides may be an effective approach to targeting cells which display increased uptake and metabolism of glucose., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Spectral ripple discrimination tasks are commonly used to probe spectral resolution in cochlear implant (CI), normal-hearing (NH), and hearing-impaired individuals. In addition, these tasks have also been used to examine spectral resolution development in NH and CI children. In this work, stimulus sine-wave carrier density was identified as a critical variable in an example spectral ripple-based task, the Spectro-Temporally Modulated Ripple (SMR) Test, and it was demonstrated that previous uses of it in NH listeners sometimes used values insufficient to represent relevant ripple densities. Insufficient carry densities produced spectral under-sampling that both eliminated ripple cues at high ripple densities and introduced unintended structured interference between the carriers and intended ripples at particular ripple densities. It was found that this effect produced non-monotonic psychometric functions for NH listeners that would cause systematic underestimation of thresholds with adaptive techniques. Studies of spectral ripple detection in CI users probe a density regime below where this source of aliasing occurs, as CI signal processing limits dense ripple representation. While these analyses and experiments focused on the SMR Test, any task in which discrete pure-tone carriers spanning frequency space are modulated to approximate a desired pattern must be designed with the consideration of the described spectral aliasing effect.

Background: Phospholipases D1 and D2 (PLD1/2) are implicated in tumorigenesis through their generation of the signalling lipid phosphatidic acid and its downstream effects. Inhibition of PLD1 blocks prostate cell growth and colony formation. Here a role for PLD2 in prostate cancer (PCa), the major cancer of men in the western world, is examined., Methods: PLD2 expression was analysed by immunohistochemistry and western blotting. The effects of PLD2 inhibition on PCa cell viability and cell motility were measured using MTS, colony forming and wound-healing assays., Results: PLD2 protein is expressed about equally in luminal and basal prostate epithelial cells. In cells from different Gleason-scored PCa tissue PLD2 protein expression is generally higher than in non-tumorigenic cells and increases in PCa tissue scored Gleason 6-8. PLD2 protein is detected in the cytosol and nucleus and had a punctate appearance. In BPH tissue stromal cells as well as basal and luminal cells express PLD2. PLD2 protein co-expresses with chromogranin A in castrate-resistant PCa tissue. PLD2 inhibition reduces PCa cell viability, colony forming ability and directional cell movement., Conclusions: PLD2 expression correlates with increasing Gleason score to GS8. PLD2 inhibition has the potential to reduce PCa progression.

Background: Phospholipases D1 and D2 (PLD1/2) hydrolyse cell membrane glycerophospholipids to generate phosphatidic acid, a signalling lipid, which regulates cell growth and cancer progression through effects on mTOR and PKB/Akt. PLD expression and/or activity is raised in breast, colorectal, gastric, kidney and thyroid carcinomas but its role in prostate cancer (PCa), the major cancer of men in the western world, is unclear., Methods: PLD1 protein expression in cultured PNT2C2, PNT1A, P4E6, LNCaP, PC3, PC3M, VCaP, 22RV1 cell lines and patient-derived PCa cells was analysed by western blotting. PLD1 protein localisation in normal, benign prostatic hyperplasia (BPH), and castrate-resistant prostate cancer (CRPC) tissue sections and in a PCa tissue microarray (TMA) was examined by immunohistochemistry. PLD activity in PCa tissue was assayed using an Amplex Red method. The effect of PLD inhibitors on PCa cell viability was measured using MTS and colony forming assays., Results: PLD1 protein expression was low in the luminal prostate cell lines (LNCaP, VCaP, 22RV1) compared with basal lines (PC3 and PC3M). PLD1 protein expression was elevated in BPH biopsy tissue relative to normal and PCa samples. In normal and BPH tissue, PLD1 was predominantly detected in basal cells as well in some stromal cells, rather than in luminal cells. In PCa tissue, luminal cells expressed PLD1. In a PCa TMA, the mean peroxidase intensity per DAB-stained Gleason 6 and 7 tissue section was significantly higher than in sections graded Gleason 9. In CRPC tissue, PLD1 was expressed prominently in the stromal compartment, in luminal cells in occasional glands and in an expanding population of cells that co-expressed chromogranin A and neurone-specific enolase. Levels of PLD activity in normal and PCa tissue samples were similar. A specific PLD1 inhibitor markedly reduced the survival of both prostate cell lines and patient-derived PCa cells compared with two dual PLD1/PLD2 inhibitors. Short-term exposure of PCa cells to the same specific PLD1 inhibitor significantly reduced colony formation., Conclusions: A new specific inhibitor of PLD1, which is well tolerated in mice, reduces PCa cell survival and thus has potential as a novel therapeutic agent to reduce prostate cancer progression. Increased PLD1 expression may contribute to the hyperplasia characteristic of BPH and in the progression of castrate-resistant PCa, where an expanding population of neuroendocrine-like cells express PLD1.

Background: Achieving locoregional control in high-risk patients with head and neck cancer who are poor candidates for standard continuous-course (chemo) radiotherapy due to advanced age, comorbidities, or very advanced disease is challenging. At our Institution, we have significant experience with a regimen of split-course, accelerated, hypofractionated radiotherapy (SCAHRT) for these patients., Patients and Methods: The SCAHRT regimen consisted of 60-72 Gy in 20-24 fractions separated by several weeks mid-course to allow for toxicity recovery and disease reassessment. It was used for patients with advanced age, significant co-morbidities, anticipated intolerance to definitive (chemo)radiation, and those with oligometastatic disease. Disease-free and overall survival rates were calculated using Kaplan-Meier analysis., Results: Fifty-eight out of 65 patients (89%) completed both courses of treatment. Patients without metastatic or recurrent disease were evaluated for treatment response and survival (n=39). Among this group, total tumor response was 91%, and median locoregional failure-free survival and overall survival were 25.7 and 8.9 months, respectively., Conclusion: In high-risk patients unable to tolerate continuous-course definitive (chemo)radiation, SCAHRT is a safe, well-tolerated and effective method of achieving durable locoregional disease control. In properly selected patients, this regimen is preferable to purely palliative approaches., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: The purpose of the present study was to identify variables associated with high risk of failure in patients with locally advanced squamous cell carcinoma of the oral cavity (SCC-OC)., Patients and Methods: This retrospective study included 191 patients with stage III-IVb SCC-OC treated with post-operative radiotherapy (RT) or chemoradiotherapy (CRT) between 1995 and 2013. Disease-free (DFS) and overall survival (OS) were analyzed; variables associated with inferior DFS were identified., Results: Seventy-five patients (39%) recurred. DFS and five-year OS were 52% and 54%, respectively. Poorly differentiated tumors (p=0.03), recurrent tumors (p=0.02) and high nodal ratio (p=0.02) were associated with an increased risk of recurrence. CRT was associated with improved DFS in patients with positive margins and/or extracapsular extension (p=0.021)., Conclusion: Tumors that are recurrent, high grade, or have high nodal ratio are at risk of recurrence. Presence of these disease features should be taken into consideration for better risk stratification., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Tumor human papillomavirus (HPV) status has emerged as one of the most powerful prognostic factors for disease control and survival in patients with oropharyngeal squamous cell carcinoma (OPSCC). We reviewed our experience in patients with OPSCC and known tumor HPV status treated with definitive chemoradiotherapy (CRT)., Methods: Patients with stage III-IVb OPSCC and known tumor HPV status treated with CRT between 2006 and 2011 were identified from an IRB approved registry for this retrospective review. Outcomes were estimated using the Kaplan-Meier method and compared between HPV-positive and negative patients using the log-rank test., Results: Of the 121 pts (89% male, 93% Caucasian) included in this study, median age was 57 (range: 40-73) and median follow-up was 21 months (range: 6-63). Ninety-seven (80%) patients were HPV-positive and 24 (20%) were HPV-negative. Primary site was base of tongue (55%), tonsil (44%), and oropharyngeal wall (2%). Two year rates of locoregional recurrence (3% vs. 26%; p = 0.002), disease free survival (93% vs. 64%; p = 0.001) and overall survival (94% vs 73%; p = 0.002) were superior in HPV-positive patients, while rates of distant recurrence were similar (3% vs. 5%; p = 0.98). While acute toxicities were similar between both groups, patients with HPV-positive disease were more likely to resume a normal diet (90% vs. 65%; p = 0.017) at last follow up. Also, no HPV-positive patient required a feeding tube beyond 6 months after treatment, compared with 24% of HPV-negative patients., Conclusions: Definitive CRT produces excellent rates of disease control with minimal late toxicity for patients with HPV-positive OPSCC. Studies of OPSCC should account for tumor HPV status when identifying factors prognostic for outcome.

Purpose: Long-term clinical studies have now shown that tight control of blood pressure in type 2 diabetes reduces the risk of diabetes-related death and common diabetic complications, including diabetic retinopathy. However, the mechanisms by which hypertension enhances diabetic microvascular disease, especially diabetic retinopathy, are poorly understood. We developed an experimental model of hypertension in diabetic rats and studied the early ultrastructural changes in retinal capillaries under these conditions., Methods: Hypertension was induced in diabetic BioBreeding (BB) rats by unilateral nephrectomy, weekly subcutaneous mineralocorticoid and 0.9% oral saline. Serial blood pressures and ultrastructural features of retinal capillaries were recorded in four groups: normotensive Wistar rats, normotensive diabetic rats, hypertensive Wistar rats and hypertensive diabetic rats., Results: A significant and sustained increase in systolic blood pressure occurred in both groups of nephrectomised rats. There was a significant increase in the number of caveolae (i) in both pericytes and endothelial cells in animals with hypertension and diabetes together compared with all other groups and (ii) in pericytes in animals with diabetes alone. The number of direct contacts between pericytes and endothelial cells was reduced in diabetic and hypertensive diabetic animals. Hypertension and diabetes had an interactive effect in producing retinal capillary basement membrane thickening., Conclusions: In the BB rat hypertension and diabetes have an interactive effect in increasing the number of caveolae in both endothelial cells and pericytes. We speculate that this may be a reflection of changes in calcium and nitric oxide metabolism in these animals.

The role of cGMP as a second messenger for renin secretion is contentious. This was investigated using a superfused collagenase-dispersed rat kidney cortex cell preparation devoid of indirect influences on renin secretion. Nitroprusside, atriopeptin II and 8-Br-cGMP all increased renin release but the dose-response relationships were biphasic. At low dose ranges there was a positive correlation between increasing drug concentration and renin secretion, but at high drug concentrations, a negative correlation was apparent. Methylene blue, a guanylate cyclase inhibitor, also suppressed baseline renin release at 10(-5) and 10(-6) M, but stimulated release at 10(-3) M. Using mid-range drug concentrations, the cGMP specific phosphodiesterase inhibitor MB22948 potentiated renin release in response to nitroprusside and 8-Br-cGMP. Inhibition of guanylate cyclase with either methylene blue or LY83583 attenuated renin release in response to nitroprusside, but, as expected, had no effect on 8-Br-cGMP induced release. We conclude that, under physiological conditions, cGMP is a stimulatory second messenger for renin release. This activity is mimicked at low dose ranges by 8-Br-cGMP, nitroprusside and atriopeptin II. In response to high doses of these drugs an unknown inhibitory pathway is activated and this opposes, in a dose-related manner, the stimulatory actions of cGMP for renin release.

1. Dietary sodium depletion and subsequent repletion was studied in rabbits. Potassium intake was maintained constant. 2. during sodium depletion and repletion blood pressure, packed cell volume, food consumption and body weight remained at control values. 3. Decreased sodium excretion was observed in both urine and faeces during sodium depletion and the physiological control of these changes is discussed in relation to the renin-angiotensin-aldosterone system. 4. Potassium excretion during sodium depletion initially fell as a result of reduced urine volume and gradually returned to normal. Urine potassium concentration remained constant. 5. Faecal excretion of potassium rose by 63% during sodium depletion and there was a rise from a control value of 17-25% in the proportion of total potassium excretion accounted for by the faecal component. 6. Water consumption and urine volume both decreased in the initial phase of sodium depletion and then returned to control levels. 7. It is important to consider both urinary and faecal excretion of sodium and potassium when calculating balance status for either ion. Faecal excretion, as well as kidney function, shows important physiological adaptations.

Release of active and inactive renin by rabbit kidney cortex slices was investigated. Inactive renin was estimated as the increase in renin activity after acidification (pH 2.8) of slice supernatant solutions. For kidney slices incubated in complete Krebs bicarbonate buffer, the Na-K-ATPase inhibitor ouabain (100 microM) reduced the secretion of both active (-19.2%) and inactive (-78.9%) forms of renin. In low Na buffers ([Na+] = 23 mM) active renin release was increased and inactive renin was suppressed. Both of these changes were abolished by addition of ouabain (100 microM). The reduction in inactive renin secretion produced by ouabain in complete Krebs buffer did not occur in low [Na+] buffers. In zero Ca2+ buffers containing EGTA (5 mM), secretion of both active and inactive renin was increased but these changes were abolished by addition of ouabain (100 microM). Incubating kidney slices in low Na+, zero Ca2+ media revealed differences between the secretion control mechanisms for the two forms of renin. The separate stimulatory effects of low Na+ and low Ca2+ were not additive for the release of active renin and inclusion of ouabain resulted in similar secretion rates to those under control conditions. For inactive renin secretion, in the absence of Ca2+ release mechanisms still respond to reduction in Na+ with decreased secretion. Conversely, in low Na+ buffers, removal of Ca2+ still promotes inactive renin secretion. These changes were abolished by the addition of ouabain (100 microM). Slices did not change in weight during incubation in media which did not contain ouabain. Addition of this inhibitor to control buffers and low Na buffers did result in an increase in weight. This correlated with the presence of Ca2+ in the buffer and did not appear to be related to [Na+]. These studies again show that the mechanisms regulating the secretion of active and inactive renin are not identical and support the hypothesis that Na+ have differing roles to play in the regulation of these two forms of renin.

1. Active and inactive renin release by rabbit kidney cortex slices was investigated. Inactive renin was estimated as the increase in renin activity after acidification (pH 2 . 8) of slice supernatant solutions. 2. Active renin release was increased when incubation medium [Na+] was reduced. This relationship was linear (r2 = 0 . 96) over the range [Na+] = 23-133 mM. 3. For the same range of [Na+] inactive renin secretion decreased when medium [Na+] was reduced (r2 = 0 . 92). Therefore, the proportion of total renin which was in the inactive form decreased linearly as [Na+] was reduced (r2 = 0 . 97). 4. Chloride ions did not appear to be important in altering the secretion of either active or inactive renin. 5. Adding furosemide to the incubation medium in concentrations up to 40 micrograms/ml. did not change secretion of either form of renin. The action of furosemide on secretion of active and inactive renin in vivo is therefore secondary to altered renal function. 6. Regulation of the relative amount of active and inactive renin in plasma could be entirely an intrarenal event. It is not essential to invoke a plasma activating enzyme for inactive renin in order to explain changes in plasma levels of the two forms of renin. 7. This paper supports the hypothesis that release of inactive renin by the kidney is controlled by a sodium-sensitive mechanism.

Regulation of plasma levels of active and inactive renin was investigated using sheep with indwelling artery, vein and bladder catheters. Control and experimental studies were carried out in the same animals on different days. Volume depletion during any single experiment was limited to a maximum of 50 ml. Despite large changes in sodium and water excretion, the diuretic furosemide at two dose levels, 1 and 10 mg/kg, failed to alter plasma levels of either active or inactive renin in conscious sheep. Induction of pentobarbitone anaesthesia in the sheep did not, per se, alter either plasma active or inactive renin. Furosemide (10 mg/kg) in anaesthetized animals produced a similar diuresis and natriuresis response to conscious sheep, but plasma active renin increased by 270% and inactive renin decreased to zero. In conscious sheep given an infusion of papaverine, furosemide also produced an increase in plasma active renin and a concurrent decrease in the inactive form. In both anaesthetized animals and in conscious sheep infused with papaverine, furosemide-induced intrarenal vasodilation, as evidenced by changes in clearance of p-aminohippuric acid, was much reduced in comparison to the conscious animals. This may be significant in relation to the control of renin secretion. It appears that the macula densa sodium receptor, which is considered to regulate renin release, will only function after it has been primed by other intra- or extrarenal factors. This is discussed, particularly in relation to the possible role played by the prostaglandin system.

Release of active and inactive renin by rabbit kidney cortex slices was investigated. Inactive renin was estimated as the increase in renin activity after acidification (pH 2.8) of slice supernatant solutions. In Ca2+-free media, release of both active and inactive renin was increased but the changes in inactive renin were more marked. The percentage of total renin released which was inactive ranged from 8.3% ([Ca2+] = 9.2 mM) to 34.5% (zero [Ca2+]) with a linear relationship (r = -0.96) over the range of [Ca2+] studied. Depolarizing media ([K+] = 20 mM) suppressed release of inactive renin more than release of the active form. This effect, for both forms of renin, was lost when Ca2+ ions were omitted from the incubation media. This suggests that influx of Ca2+ ions was responsible for the reduced renin secretion following depolarization of the juxtaglomerular cells. Reducing the [K+] of the incubation buffer from 5.7 mM (control) to 1.0 mM did not alter active renin but increased release of inactive renin. Low [K+] media abolished the stimulatory effect of low [Ca2+] on release of both forms of renin. In incubation media with low [Ca2+] or with low [K+] the mixture of renins released by the kidney cortex slices correlated with that found in extracts of non-incubated kidney: that is, about 35% of the total renin was in the inactive form. Mechanisms controlling the secretion of active and inactive renins by the kidney are at least partially independent. Differential secretion of the two forms, perhaps linked to regulation of the activation of inactive renin before release, appears to be the basis of a control step in the over-all expression of the renin-angiotensin system. This may be coupled in some way to juxtaglomerular cell Na+ ion flux.

1. Active and acid-activatable (inactive) renins were measured in rabbit plasma under control conditions and during sodium depletion with subsequent repletion. 2. Active renin increased by 97% during sodium depletion and returned to control levels on repletion. Both changes were complete within 1 day of changing the diet. 3. During dietary sodium depletion inactive renin levels initially fell to zero and then increased until, after 13 days, inactive renin was again 10% of total renin levels, a proportion comparable to the control values. 4. Sodium repletion caused plasma inactive renin to return to control levels over about 13 days, a quite different time course to active renin. Therefore, in the first phase of repletion the proportion of total renin in the inactive form rose to 19%. 5. These changes are discussed in relation to concurrent changes in sodium, potassium and water metabolism.