Construction of a Plasmodium falciparum Rab-interactome identifies CK1 and PKA as Rab-effector kinases in malaria parasites

Background information The pathology causing stages of the human malaria parasite Plasmodium falciparum reside within red blood cells that are devoid of any regulated transport system. The parasite, therefore, is entirely responsible for mediating vesicular transport within itself and in the infected erythrocyte cytoplasm, and it does so in part via its family of 11 Rab GTPases. Putative functions have been ascribed to Plasmodium Rabs due to their homology with Rabs of yeast, particularly with Saccharomyces that has an equivalent number of rab/ypt genes and where analyses of Ypt function is well characterized. Results Rabs are important regulators of vesicular traffic due to their capacity to recruit specific effectors. In order to identify P. falciparum Rab (PfRab) effectors, we first built a Ypt-interactome by exploiting genetic and physical binding data available at the Saccharomyces genome database (SGD). We then constructed a PfRab-interactome using putative parasite Rab-effectors identified by homology to Ypt-effectors. We demonstrate its potential by wet-bench testing three predictions; that casein kinase-1 (PfCK1) is a specific Rab5B interacting protein and that the catalytic subunit of cAMP-dependent protein kinase A (PfPKA-C) is a PfRab5A and PfRab7 effector. Conclusions The establishment of a shared set of physical Ypt/PfRab-effector proteins sheds light on a core set Plasmodium Rab-interactants shared with yeast. The PfRab-interactome should benefit vesicular trafficking studies in malaria parasites. The recruitment of PfCK1 to PfRab5B+ and PfPKA-C to PfRab5A+ and PfRab7+ vesicles, respectively, suggests that PfRab-recruited kinases potentially play a role in early and late endosome function in malaria parasites

Beyond the Surface: Understanding Demodex and Its Link to Blepharitis and Facial Dermatoses

Flavia Giorgiana Chioveanu,1,2 Elena Niculet,3,4 Cristina Torlac,2,5 Camelia Busila,6,7 Alin Laurentiu Tatu4,8,9 1Hexamed” Ophthalmology Clinic, Braila, Romania; 2Biomedical Doctoral School, “Dunarea de Jos” University, Galati, Romania; 3Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, “Dunarea de Jos” University, Galaţi, Romania; 4Multidisciplinary Integrated Center of Dermatological Interface Research MIC-DIR, “Dunarea de Jos” University, Galaţi, Romania; 5Individual Medical Office - Dentistry, Galati, Romania; 6Dunarea de Jos University of Galati, Faculty of Medicine and Pharmacy, Galati, Romania; 7Sf. Ioan Emergency Clinical Paediatric Hospital, Galati, Romania; 8Clinical Medical Department, Faculty of Medicine and Pharmacy, “Dunarea de Jos” University, Galaţi, Romania; 9Dermatology Department, “Sf. Cuvioasa Parascheva” Clinical Hospital of Infectious Diseases, Galaţi, RomaniaCorrespondence: Elena Niculet, Email [email protected]: Demodex represents the most frequent ectoparasite found in humans. Although Demodex mites are considered commensals of human pilosebaceous units, an abnormally high mite density can cause several ocular and cutaneous symptoms and signs, sometimes to a severe degree. Both Demodex spp. (folliculorum and brevis) play a significant part in eye pathology and facial dermatoses. These mites have been related to blepharitis, ocular rosacea, meibomian gland dysfunction and various skin diseases, including rosacea, demodicosis and seborrheic dermatitis. Understanding the importance of Demodex in both eye and skin conditions is crucial for accurate diagnosis and appropriate management strategies, which may involve targeted treatments to control the mite population and reduce associated symptoms.Keywords: eyelid inflammation, mite infestation, rosacea, demodicosi

A custom-made electronic dynamometer for evaluation of peak ankle torque after COVID-19

The negative effects of SARS-CoV-2 infection on the musculoskeletal system include symptoms of fatigue and sarcopenia. The aim of this study is to assess the impact of COVID-19 on foot muscle strength and evaluate the reproducibility of peak ankle torque measurements in time by using a custom-made electronic dynamometer. In this observational cohort study, we compare two groups of four participants, one exposed to COVID-19 throughout measurements and one unexposed. Peak ankle torque was measured using a portable custom-made electronic dynamometer. Ankle plantar flexor and dorsiflexor muscle strength was captured for both feet at different ankle angles prior and post COVID-19. Average peak torque demonstrated no significant statistical differences between initial and final moment for both groups (p = 0.945). An increase of 4.8%, p = 0.746 was obtained in the group with COVID-19 and a decrease of 1.3%, p = 0.953 was obtained in the group without COVID-19. Multivariate analysis demonstrated no significant differences between the two groups (p = 0.797). There was a very good test–retest reproducibility between the measurements in initial and final moments (ICC = 0.78, p < 0.001). In conclusion, peak torque variability is similar in both COVID-19 and non-COVID-19 groups and the custom-made electronic dynamometer is a reproducible method for repetitive ankle peak torque measurements

Efficacy of cinnamon in the treatment of orofacial conditions

Background: Cinnamon is a spice which has been in use for 1000 of years for its taste, condiment, and for its medicinal values. It has a history of medicinal use in China, Egypt, and Europe. In traditional medicine, cinnamon is used in respiratory, digestive, and skin ailments. It has anti-inflammatory, antibacterial, antidiabetic, antiarthritic, anticlotting, and immune regulatory properties. Cinnamon oil is used topically in the treatment of certain skin diseases such as acne, eczema, and pimples. In recent times, there has been a gradual rise in interest in the use and research on medicinal plants the world over due to their safety margin and minimal side and adverse effects. Aim: This paper aims to review the available scientific literature and to provide a comprehensive summary on the potential medicinal benefits of cinnamon in orofacial disease conditions. A review of the scientific literature available on cinnamon conclusively proves its efficacy in the management of several ailments including metabolic disorders like diabetes and lifestyle-associated conditions like hyperlipidemia. Conclusion: A review of its mechanism of action indicates its potential therapeutic benefit in the management of various orofacial conditions including trigeminal neuralgia and lichen planus. Clinical Significance: Cinnamon unfortunately like any medications does have its share of adverse effects and reactions, and therefore, its clinical use must be paved with caution and planned clinical trials, keeping in mind its potential adverse effects and interactions will result in a more standard formulation and protocol for the use of cinnamon as a therapeutic agent

Secondary infarction in single or in multiple vascular territories: two different entities following subarachnoid hemorrhage?

The pathogenesis of secondary infarctions (SI) after aneurysmal subarachnoid hemorrhage (SAH) is poorly understood. To assess whether SI in single (SSI) or multiple (MSI) vascular territories represent different disease entities, we compared clinical profiles of patients with these patterns of SI. CT/MRI-examinations of 448 patients were reviewed for new infarctions within 28 days after SAH, and categorized into SSI or MSI. Only patients with adequate follow-up imaging excluding any new infarctions were included for analysis (269 patients). Procedure-related infarctions were excluded. Odds ratios (ORs) with corresponding 95% confidence intervals (CI) were calculated for patients with SSI or MSI versus patients without SI to analyze differences in demographic characteristics, vascular risk factors, disease-related characteristics and treatment modalities. Thirty-six patients had SSI, 53 MSI and 180 no SI. ORs in MSI-patients were >1.5 times higher compared with ORs in SSI-patients for multiple vascular risk factors [MSI:5.4 (2.3–13) versus SSI:1.2 (0.5–2.8)], poor clinical condition on admission [MSI:4.6 (2.4–8.9) versus SSI:2.4 (1.1–5.2)], initial loss of consciousness [MSI:2.6 (1.3–5.3) versus SSI:1.1 (0.5–2.3)] and large amounts of intraventricular blood [MSI:2.9 (1.4–5.8) versus SSI:1.5 (0.7–3.2)]. In multivariate analysis ORs remained higher in MSI for presence of multiple vascular risk factors [MSI:1.9 (1.2–2.9) versus SSI:1.1 (0.8–1.7)] and initial loss of consciousness [MSI:3.0 (1.0–8.9) versus SSI:1.6 (0.6–4.0)]. Our findings suggest that SSI and MSI after SAH are not distinct disease entities. MSI was related to the same characteristics as SSI but to a larger extent, specifically to the presence of multiple vascular risk factors, initial loss of consciousness, larger amounts of intraventricular blood, and poor clinical status on admission

Sustained reduction in vaccine-type invasive pneumococcal disease despite waning effects of a catch-up campaign in Kilifi, Kenya: A mathematical model based on pre-vaccination data.

BACKGROUND: In 2011, Kenya introduced the 10-valent pneumococcal conjugate vaccine together with a catch-up campaign for children aged <5years in Kilifi County. In a post-vaccination surveillance study based in Kilifi, there was a substantial decline in invasive pneumococcal disease (IPD). However, given the continued circulation of the vaccine serotypes it is possible that vaccine-serotype disease may re-emerge once the effects of the catch-up campaign wear off. METHODS: We developed a compartmental, age-structured dynamic model of pneumococcal carriage and invasive disease for three serotype groups: the 10-valent vaccine serotypes and two groups of non-vaccine serotypes based on their susceptibility to mutual competition. The model was calibrated to age- and serotype-specific data on carriage and IPD in the pre-vaccination era and used to predict carriage prevalence and IPD up to ten years post-vaccination in Kilifi. The model was validated against the observed carriage prevalence after vaccine introduction. RESULTS: The model predicts a sustained reduction in vaccine-type pneumococcal carriage prevalence from 33% to 8% in infants and from 30% to 8% in 1-5year olds over the 10-year period following vaccine introduction. The incidence of IPD is predicted to decline across all age groups resulting in an overall reduction of 56% in the population, corresponding to 10.4 cases per 100,000 per year. The vaccine-type IPD incidence is estimated to decline by 83% while non-vaccine-type IPD incidence is predicted to increase by 52%. The model's predictions of carriage prevalence agrees well with the observed data in the first five years post-vaccination. CONCLUSION: We predict a sustained and substantial decline in IPD through PCV vaccination and that the current regimen is insufficient to fully eliminate vaccine-serotype circulation in the model. We show that the observed impact is likely to be sustained despite waning effects of the catch-up campaign

Effect of Haemophilus influenzae type b vaccination without a booster dose on invasive H influenzae type b disease, nasopharyngeal carriage, and population immunity in Kilifi, Kenya: a 15-year regional surveillance study

Background Haemophilus infl uenzae type b (Hib) conjugate vaccine, delivered as a three-dose series without a booster, was introduced into the childhood vaccination programme in Kenya in 2001. The duration of protection and need for a booster dose are unknown. We aimed to assess vaccine eff ectiveness, the impact of the vaccine on nasopharyngeal carriage, and population immunity after introduction of conjugate Hib vaccine in infancy without a booster dose in Kenya. Methods This study took place in the Kilifi Health and Demographic Surveillance System (KHDSS), an area of Kenya that has been monitored for vital events and migration every 4 months since 2000. We analysed sterile site cultures for H infl uenzae type b from children (aged ≤12 years) admitted to the Kilifi County Hospital (KCH) from Jan 1, 2000, through to Dec 31, 2014. We determined the prevalence of nasopharyngeal carriage by undertaking cross-sectional surveys in random samples of KHDSS residents (of all ages) once every year from 2009 to 2012, and measured Hib antibody concentrations in fi ve cross-sectional samples of children (aged ≤12 years) within the KHDSS (in 1998, 2000, 2004–05, 2007, and 2009). We calculated incidence rate ratios between the prevaccine era (2000–01) and the routineuse era (2004–14) and defi ned vaccine eff ectiveness as 1 minus the incidence rate ratio, expressed as a percentage. Findings 40 482 children younger than 13 years resident in KHDSS were admitted to KCH between 2000 and 2014, 38 206 (94%) of whom had their blood cultured. The incidence of invasive H infl uenzae type b disease in children younger than 5 years declined from 62·6 (95% CI 46·0–83·3) per 100 000 in 2000–01 to 4·5 (2·5–7·5) per 100 000 in 2004–14, giving a vaccine eff ectiveness of 93% (95% CI 87–96). In the fi nal 5 years of observation (2010–14), only one case of invasive H infl uenzae type b disease was detected in a child younger than 5 years. Nasopharyngeal H infl uenzae type b carriage was detected in one (0·2%) of 623 children younger than 5 years between 2009 and 2012. In the 2009 serosurvey, 92 (79%; 95% CI 70–86) of 117 children aged 4–35 months had long-term protective antibody concentrations. Interpretation In this region of Kenya, use of a three-dose primary series of Hib vaccine without a booster dose has resulted in a signifi cant and sustained reduction in invasive H infl uenzae type b disease. The prevalence of nasopharyngeal carriage is low and the profi le of Hib antibodies suggests that protection wanes only after the age at greatest risk of disease. Although continued surveillance is important to determine whether eff ective control persists, these fi ndings suggest that a booster dose is not currently required in Kenya

Exploring Light-Sensitive Nanocarriers for Simultaneous Triggered Antibiotic Release and Disruption of Biofilms Upon Generation of Laser-Induced Vapor Nanobubbles

Impaired penetration of antibiotics through bacterial biofilms is one of the reasons for failure of antimicrobial therapy. Hindered drug diffusion is caused on the one hand by interactions with the sticky biofilm matrix and on the other hand by the fact that bacterial cells are organized in densely packed clusters of cells. Binding interactions with the biofilm matrix can be avoided by encapsulating the antibiotics into nanocarriers, while interfering with the integrity of the dense cell clusters can enhance drug transport deep into the biofilm. Vapor nanobubbles (VNB), generated from laser irradiated nanoparticles, are a recently reported effective way to loosen up the biofilm structure in order to enhance drug transport and efficacy. In the present study, we explored if the disruptive force of VNB can be used simultaneously to interfere with the biofilm structure and trigger antibiotic release from light-responsive nanocarriers. The antibiotic tobramycin was incorporated in two types of light-responsive nanocarriers—liposomes functionalized with gold nanoparticles (Lip-AuNP) and graphene quantum dots (GQD)—and their efficacy was evaluated on Pseudomonas aeruginosa biofilms. Even though the anti-biofilm efficacy of tobramycin was improved by liposomal encapsulation, electrostatic functionalization with 70 nm AuNP unfortunately resulted in premature leakage of tobramycin in a matter of hours. Laser-irradiation consequently did not further improve P. aeruginosa biofilm eradication. Adsorption of tobramycin to GQD, on the other hand, did result in a stable formulation with high encapsulation efficiency, without burst release of tobramycin from the nanocarriers. However, even though laser-induced VNB formation from GQD resulted in biofilm disruption, an enhanced anti-biofilm effect was not achieved due to tobramycin not being efficiently released from GQD. Even though this study was unsuccessful in designing suitable nanocarriers for simultaneous biofilm disruption and light-triggered release of tobramycin, it provides insights into the difficulties and challenges that need to be considered for future developments in this regard

Exploring Light-Sensitive Nanocarriers for Simultaneous Triggered Antibiotic Release and Disruption of Biofilms Upon Generation of Laser-Induced Vapor Nanobubbles

Impaired penetration of antibiotics through bacterial biofilms is one of the reasons for failure of antimicrobial therapy. Hindered drug diffusion is caused on the one hand by interactions with the sticky biofilm matrix and on the other hand by the fact that bacterial cells are organized in densely packed clusters of cells. Binding interactions with the biofilm matrix can be avoided by encapsulating the antibiotics into nanocarriers, while interfering with the integrity of the dense cell clusters can enhance drug transport deep into the biofilm. Vapor nanobubbles (VNB), generated from laser irradiated nanoparticles, are a recently reported effective way to loosen up the biofilm structure in order to enhance drug transport and efficacy. In the present study, we explored if the disruptive force of VNB can be used simultaneously to interfere with the biofilm structure and trigger antibiotic release from light-responsive nanocarriers. The antibiotic tobramycin was incorporated in two types of light-responsive nanocarriers—liposomes functionalized with gold nanoparticles (Lip-AuNP) and graphene quantum dots (GQD)—and their efficacy was evaluated on Pseudomonas aeruginosa biofilms. Even though the anti-biofilm efficacy of tobramycin was improved by liposomal encapsulation, electrostatic functionalization with 70 nm AuNP unfortunately resulted in premature leakage of tobramycin in a matter of hours. Laser-irradiation consequently did not further improve P. aeruginosa biofilm eradication. Adsorption of tobramycin to GQD, on the other hand, did result in a stable formulation with high encapsulation efficiency, without burst release of tobramycin from the nanocarriers. However, even though laser-induced VNB formation from GQD resulted in biofilm disruption, an enhanced anti-biofilm effect was not achieved due to tobramycin not being efficiently released from GQD. Even though this study was unsuccessful in designing suitable nanocarriers for simultaneous biofilm disruption and light-triggered release of tobramycin, it provides insights into the difficulties and challenges that need to be considered for future developments in this regard

Cloud condensation nuclei production associated with atmospheric nucleation : a synthesis based on existing literature and new results

This paper synthesizes the available scientific information connecting atmospheric nucleation with subsequent cloud condensation nuclei (CCN) formation. We review both observations and model studies related to this topic, and discuss the potential climatic implications. We conclude that CCN production associated with atmospheric nucleation is both frequent and widespread phenomenon in many types of continental boundary layers, and probably also over a large fraction of the free troposphere. The contribution of nucleation to the global CCN budget spans a relatively large uncertainty range, which, together with our poor understanding of aerosol-cloud interactions, results in major uncertainties in the radiative forcing by atmospheric aerosols. In order to better quantify the role of atmospheric nucleation in CCN formation and Earth System behavior, more information is needed on (i) the factors controlling atmospheric CCN production and (ii) the properties of both primary and secondary CCN and their interconnections. In future investigations, more emphasis should be put on combining field measurements with regional and large-scale model studies.Peer reviewe