Down-regulation of MHC class I by papillomavirus E5 proteins

Like many viruses, papillomaviruses are totally dependent upon host biosynthetic machinery for replicating their genomes and establishing infection. These processes are associated with the production of antigenic proteins that make the virus vulnerable to immune surveillance which ultimately results in elimination of viral infection. However, papillomaviruses have developed mechanisms to escape the cellular immune recognition of the virally-infected cells by encoding proteins that interfere with antigen presentation to immune cells. Papillomavirus E5 are small oncoproteins of 42 to 83 amino acids in BPV-4 and HPV-16 respectively, expressed at low levels mainly in the deep layers of infected epithelia and down-regulate the expression and transport to the cell surface of the major histocompatibility complex class I (MHC I). The BPV-4 E5 protein inhibits transcription of heavy chain, retains MHC class I in the Golgi apparatus and prevents its transport to the cell surface. In this study, we investigated expression of MHC class I in natural infection by BPV-4. We determined that MHC I is not expressed in cells expressing BPV-4E5. We also determined that expression of BPV-4E5 is accompanied by expression of the proliferation marker (Ki67) also in the differentiated cells of upper layers of papillomas. Down-regulation of MHC class I in papilloma cells expressing E5 would allow escaping recognition by cytotoxic T lymphocytes (CTL). Cells lacking MHC I are subjected to NK cells attack, which recognise and destroy cells lacking surface expression of MHC I unless non classical MHC class I molecules are presented on the cell surface. Because of the impossibility to investigate expression of non classical MHC class I in cells expressing classical MHC class I due to the absence of appropriate antibodies, we investigated the effect of BPV-4E5 on expression of bovine classical (N*01301)or non classical (N*50001) MHC class I in transfected mouse mastocytoma cells. We determined that E5 does not retain N*50001 MHC class I complex in the Golgi, and does not inhibit the transport of the complex to the cell surface. We also determined that E5 induces degradation of N*01301 heavy chain but does not affect the stability of N*50001 heavy chain. We also determined that retention of MHC class I in the Golgi and thus prevention of its transport to the cell surface requires the C-terminus domain of E5. We also investigated the relationship between HPV-16E5 and HLA class I. HPV-16E5 down-regulates surface expression of HLA-A, but not of HLA-C/E. Because of a lack of antibodies capable of distinguishing C and E, we introduced either HLA-A2 or HLA-E cDNA in mouse mastocytoma cells expressing HPV-16E5. We confirmed that HPV-16E5 down-regulates HLA-A2 by retaining it in the Golgi and inhibits its transport to the cell surface but it does not affect HLA-E. We extended our observations to investigate the effect of HPV-16E5 on expression of MHC class I in cervical intraepithelial neoplasia grade I (CIN I). We determined that in some CIN cells, expression of E5 and HLA class I was incompatible, while in other cases E5 and HLA class I were co-expressed. Expression of E5 in some cells was accompanied by expression of Ki67. We also determined that down-regulation of HLA class I by E5 is independent of expression of HPV-16E7 in raft cultures of HaCaT cells expressing HPV-16E5 only. E5 does not affect expression of HLA-E. Therefore down-regulation of classical MHC class I by PVE5 proteins on the surface of infected cells would allow escaping recognition by CTL while, undisturbed expression of non-classical MHC I on the cell surface would escape destruction by NK cells. It remains to be determined if E5 expressing cells do avoid being killed by both CTL and NK cells

Effect of Diameter of Micropile on the Minaret Behavior during Earthquake, Virtual study

This study aims to suggest a technique for soil properties improvement of AL- Kadhimin shrine Minaret and to support the foundation, which has a tilt of roughly 80 cm from the vertical axis. The shrine of the AL- Kadhimin is made up of four minarets with two domes set in a large courtyard. The four minarets have skewed to varying degrees due to uncontrolled dewatering inside the shrine in recent years. However, the northeast minaret was the most inclined due to its proximity to the well placed inside shrine courtyard. When the well near the minaret is operated, the water level drops, increasing the effective stresses of the soil and causing differential settling of the minaret foundation. To maintain the minaret's foundation from potential lateral stresses, a micropile system has been proposed around it. PLAXIS 3D is used to do a three-dimensional numerical analysis in this study. A micropile system of several diameters has been considered for the suggested technique. In the analysis, the modeling and verification findings revealed that the suggested micropile system plays a significant role in incrementing the minaret's lateral load resistance (earthquake)

The Behavior of the Al-Kadhim Minaret during Earthquakes: A Virtual Study

The study focuses on the causes of minaret tilting as well as possible solutions. The major aims of this study are to improve knowledge of historical tall structure stability and rehabilitation operations using the finite element approach to model the soil and minaret (PLAXIS 3D 2020), a platform for computational soil investigation and modeling. The numerical analysis aims to identify stresses, settlement, and deformation of the soil and minaret in various scenarios like Earthquakes, explosions, and winds. The simulation of the problem by the PLAXIS 3D revealed that the greatest lateral displacement computed at the Top Minaret is 5.5 cm, and the greatest vertical movement is calculated to be 3 cm. Seismic settlement is the effect of earthquake shaking, causing densification of soil with lower relative density

Arabic Language Learning (All) for kids

Arabic Language has an exceptional position in Islam.It is the language of Quran, thus the need to learn and understand Arabic amongst Muslims is of paramount importance. For countries where their native language is not Arabic, the language is only taught in special schools. Arabic language needs to be introduced to children at early ages such as in the kindergarten.With the advent of computer technology, various kind of multimedia tools have been developed for the purpose of language learning.Since children are attracted to computer applications especially those that involve multimedia, there is a need to develop Arabic language learning applications for them.Even though there are few applications available in the market for that purpose, most of them do not fully utilize the multimedia elements.The prime objective of this study was to propose an Arabic Language Learning (ALL) for kids of ages between 4 to 6 years old that enable them to learn the language.In the process, an interactive field-tested ALL for kids has been developed as an alternative to the traditional learning tools.The results of user evaluation on the ALL indicate that it has good usability in terms of Learn ability, Usefulness, Ease of Use and Outcome/Future Use.The results also indicate that there is a significant difference between novice and expert users for Usefulness and Ease of Use, while no significant difference for learn ability and Outcome/Future Use

Effects of humidity on sand and dust storm attenuation predictions based on 14 GHz measurement

Several models were proposed to predict the attenuation of microwave signals due to sand and dust storms. Those models were developed based on theoretical assumptions like Rayleigh approximation, Mie equations or numerical methods. This paper presents a comparison between attenuation predicted by three different theoretical models with measured attenuation at 14 GHz. Dielectric constant of dust particles is one of the important parameter in prediction models. This constant is estimated from measured dust samples and is utilized for predictions. All models are found largely underestimating the measurement. Humidity is also monitored and has been observed higher during dust storm. Hence dielectric constants are re-estimated with relative humidity conditions using available conversion model. The prediction has a great impact of humidity and predicted attenuations are found much higher in humid than dry dust condition. However, all models underestimate the measurement even considering 100% of relative humidity. Hence it is recommended to investigate the models by considering humidity and other environmental factors that change during dust storm

Effects of humidity on sand and dust storm attenuation predictions based on 14 GHz measurement

Several models were proposed to predict the attenuation of microwave signals due to sand and dust storms. Those models were developed based on theoretical assumptions like Rayleigh approximation, Mie equations or numerical methods. This paper presents a comparison between attenuation predicted by three different theoretical models with measured attenuation at 14 GHz. Dielectric constant of dust particles is one of the important parameter in prediction models. This constant is estimated from measured dust samples and is utilized for predictions. All models are found largely underestimating the measurement. Humidity is also monitored and has been observed higher during dust storm. Hence dielectric constants are re-estimated with relative humidity conditions using available conversion model. The prediction has a great impact of humidity and predicted attenuations are found much higher in humid than dry dust condition. However, all models underestimate the measurement even considering 100% of relative humidity. Hence it is recommended to investigate the models by considering humidity and other environmental factors that change during dust storm

Demographics and Epidemiology of Hepatitis B in the State of Qatar: A Five-Year Surveillance-Based Incidence Study

Background: Expatriates represent >80% of Qatar’s population, mostly arriving from countries in Africa and Asia that are endemic with many diseases. This increases the risk for introducing new pathogens into the country and provides a platform for maintenance of endemic pathogen circulation. Here, we report on the incidence and epidemiological characteristics of hepatitis B in Qatar between 2010 and 2014. Methods: We performed a retrospective epidemiological data analysis using the data available at the surveillance system of the Ministry of Public Health (MOPH) in Qatar. Data were collected from distinctive public and private incorporates around the nation. Reported cases of hepatitis B patients represent those who met the stringent case definition as per World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) guidelines and eventually reported to MOPH. Results: The annual incidence rates of hepatitis B cases were 30.0, 34.2, 30.5, 39.4, and 19.8 per 100,000 population in 2010, 2011, 2012, 2013, and 2014, respectively. There was no specific trend or seasonality for the reported cases. The incidence rates were higher in females compared to males between 2010 and 2012, but similar in 2013 and 2014. The highest incidence rates were reported among individuals between 25 and 34 years of age. No cases were reported in children younger than five years in 2013 and 2014. Rates of hepatitis B cases declined dramatically in 2014, in both Qataris and non-Qataris, as compared to the previous years. Conclusion: Our results indicate a dramatic decline of hepatitis B cases in Qatar but mandate improved surveillance and vaccination efforts in expatriates in the nation. View Full-TextMOP

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Global, regional, and national incidence of six major immune-mediated inflammatory diseases: findings from the global burden of disease study 2019

BACKGROUND: The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019. METHODS: We collected detailed information on six major causes of IMIDs, including asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, psoriasis, and atopic dermatitis, between 1990 and 2019, derived from the Global Burden of Disease study in 2019. The average annual percent change (AAPC) in number of incidents and age standardized incidence rate (ASR) on IMIDs, by sex, age, region, and causes, were calculated to quantify the temporal trends. FINDINGS: In 2019, rheumatoid arthritis, atopic dermatitis, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease accounted 1.59%, 36.17%, 54.71%, 0.09%, 6.84%, 0.60% of overall new IMIDs cases, respectively. The ASR of IMIDs showed substantial regional and global variation with the highest in High SDI region, High-income North America, and United States of America. Throughout human lifespan, the age distribution of incident cases from six IMIDs was quite different. Globally, incident cases of IMIDs increased with an AAPC of 0.68 and the ASR decreased with an AAPC of −0.34 from 1990 to 2019. The incident cases increased across six IMIDs, the ASR of rheumatoid arthritis increased (0.21, 95% CI 0.18, 0.25), while the ASR of asthma (AAPC = −0.41), inflammatory bowel disease (AAPC = −0.72), multiple sclerosis (AAPC = −0.26), psoriasis (AAPC = −0.77), and atopic dermatitis (AAPC = −0.15) decreased. The ASR of overall and six individual IMID increased with SDI at regional and global level. Countries with higher ASR in 1990 experienced a more rapid decrease in ASR. INTERPRETATION: The incidence patterns of IMIDs varied considerably across the world. Innovative prevention and integrative management strategy are urgently needed to mitigate the increasing ASR of rheumatoid arthritis and upsurging new cases of other five IMIDs, respectively. FUNDING: The Global Burden of Disease Study is funded by the Bill and Melinda Gates Foundation. The project funded by Scientific Research Fund of Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (2022QN38)