Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein

During biosynthesis, proteins can begin folding co-translationally to acquire their biologically-active structures. Folding, however, is an imperfect process and in many cases misfolding results in disease. Less is understood of how misfolding begins during biosynthesis. The human protein, alpha-1-antitrypsin (AAT) folds under kinetic control via a folding intermediate; its pathological variants readily form self-associated polymers at the site of synthesis, leading to alpha-1-antitrypsin deficiency. We observe that AAT nascent polypeptides stall during their biosynthesis, resulting in full-length nascent chains that remain bound to ribosome, forming a persistent ribosome-nascent chain complex (RNC) prior to release. We analyse the structure of these RNCs, which reveals compacted, partially-folded co-translational folding intermediates possessing molten-globule characteristics. We find that the highly-polymerogenic mutant, Z AAT, forms a distinct co-translational folding intermediate relative to wild-type. Its very modest structural differences suggests that the ribosome uniquely tempers the impact of deleterious mutations during nascent chain emergence. Following nascent chain release however, these co-translational folding intermediates guide post-translational folding outcomes thus suggesting that Z’s misfolding is initiated from co-translational structure. Our findings demonstrate that co-translational folding intermediates drive how some proteins fold under kinetic control, and may thus also serve as tractable therapeutic targets for human disease

An analysis of the three-dimensional kinetics and kinematics of maximal effort punches among amateur boxers.

This is an Accepted Manuscript of an article published by Taylor & Francis in International Journal of Performance Analysis in Sport on 27-9-18, available online: https://doi.org/10.1080/24748668.2018.1525651The purpose of this study was to quantify the 3D kinetics and kinematics of six punch types among amateur boxers. Fifteen males (age: 24.9 ± 4.2 years; stature: 1.78 ± 0.1 m; body mass: 75.3 ± 13.4 kg; boxing experience: 6.3 ± 2.8 years) performed maximal effort punches against a suspended punch bag during which upper body kinematics were assessed via a 3D motion capture system, and ground reaction forces (GRF) of the lead and rear legs via two force plates. For all variables except elbowjoint angular velocity, analysis revealed significant (P < 0.05) differences between straight, hook and uppercut punches. The lead hook exhibited the greatest peak fist velocity (11.95 ± 1.84 m/s), the jab the shortest delivery time (405 ± 0.15 ms), the rear uppercut the greatest shoulder-joint angular velocity (1069.8 ± 104.5°/s), and the lead uppercut the greatest elbow angular velocity (651.0 ± 357.5°/s). Peak resultant GRF differed significantly (P < 0.05) between rear and lead legs for the jab punch only. Whilst these findings provide novel descriptive data for coaches and boxers, future research should examine if physical and physiological capabilities relate to the key biomechanical qualities associated with maximal punching performance

Morbidity and outcomes of foreign travelers in Zakynthos island, Greece: a retrospective study.

BACKGROUND: Although there is satisfactory recording of diseases affecting travelers visiting developing countries, little is known regarding morbidity of travelers when visiting developed countries. We sought to evaluate the morbidity of foreign travelers in Zakynthos, a popular Greek island attracting large number of foreign tourists every summer. METHODS: Data from foreign travelers that accommodated in Zakynthos and sought medical services from the private offices of Zante Medical Care from May 1 to October 30 2012 were retrospectively analyzed. RESULTS: Two thousand six hundred and eighty-eight patients were included in the study. The mean age (± SD) of the patients whom the age was recorded was 29.6 (± 18.3) and 51.5% of them were from 18 to 40 years old. Disorders of the respiratory tract (32.7%), dermatologic conditions (21.1%), musculoskeletal injuries (16.4%), and gastrointestinal disorders (16.3%) were the four most prevalent clinical categories among patients. Ear disorder was the most common syndromic description (14.5%) among which 81.2% were ear infections; otitis externa and otitis media were diagnosed in 8.5% and 3.3% patients in total. The most common specific diagnosis was gastroenteritis (14.3%). Insect bite and sunburn were the most common diagnosis (6.5% and 3.8%, respectively) among patients with a dermatologic condition. Ear infection was the most common diagnosis in pediatric patients. CONCLUSION: Disorders mainly of the upper respiratory tract were the predominant causes of illness among foreign travelers in Zakynthos. Traveler's diarrhea was the most common specific diagnosis but the prevalence within the total population was not very high

Multivariate analysis regarding the development of the 4 most common categories of disease in 2,688 patients.

<p>^* Data on age, gender, and duration of travel was not available for 92, 7, and 137 patients, respectively.</p><p><b>Abbreviations</b></p><p>y: year, F: female, d: day, UK: United Kingdom, SRB: Serbia, HU: Hungary, OR: odds ratio, CI: confidence interval, Aug: August, Sept: September, October.</p

Morbidity of 2,688 patients by clinical category and most common specific diagnosis within each category.

<p><b>Abbreviations</b></p><p>SD: standard deviation, y: year, F: female, UK: United Kingdom, SRB: Serbia, HU: Hungary, OR: odds ratio, CI: confidence interval.</p

Univariate and multivariate analyses regarding observation and need for hospitalization of 2,688 patients.

<p>^* Data on age, gender, and duration of travel was not available for 92, 7, and 137 patients, respectively.</p><p>^** The remaining clinical categories are reported in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094416#pone-0094416-t002" target="_blank">Tables 2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0094416#pone-0094416-t003" target="_blank">3</a>.</p><p><b>Abbreviations</b></p><p>y: year, F: female, d: day, UK: United Kingdom, SRB: Serbia, HU: Hungary, OR: odds ratio, CI: confidence interval.</p

Morbidity and univariate analysis of 2,688 patients according to age, gender, month of travel, and duration of stay.

<p>^* Data on age, gender, and duration of travel was not available for 92, 7, and 137 patients, respectively.</p><p><b>Abbreviations</b></p><p>y: year, F: female, M: male, d: day, UK: United Kingdom, SRB: Serbia, HU: Hungary, OR: odds ratio, CI: confidence interval, Aug: August, Sept: September, October.</p

Demographic characteristics of 2,688 patients.

<p>^*Age was not recorded for 92 patients, while gender was not recorded for 7 patients.</p><p>^** The remaining travelers were from Italy (36), former Yugoslav Republic of Macedonia (30), Finland (29), Sweden (27), Slovenia (26), Ireland (24), Bulgaria (17), Austria (16), Belgium (10), Germany (10), Norway (10), Croatia (11), Switzerland (5), Slovakia (2), Lithuania (2), Australia (1), France (1), Ukraine (2), Brazil (1), Bosnia (1), while relevant data was not recorded from 5 travelers.</p><p><b>Abbreviations</b></p><p>SD: standard deviation, y: year, F: female, UK: United Kingdom, SRB: Serbia, HU: Hungary, OR: odds ratio, CI: confidence interval</p

Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global pooled analysis

Background Since the start of the 2009 influenza A pandemic (H1N1pdm), the World Health Organization and its member states have gathered information to characterize the clinical severity of H1N1pdm infection and to assist policy makers to determine risk groups for targeted control measures. Methods and Findings Data were collected on approximately 70,000 laboratory-confirmed hospitalized H1N1pdm patients, 9,700 patients admitted to intensive care units (ICUs), and 2,500 deaths reported between 1 April 2009 and 1 January 2010 from 19 countries or administrative regions—Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong SAR, Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom—to characterize and compare the distribution of risk factors among H1N1pdm patients at three levels of severity: hospitalizations, ICU admissions, and deaths. The median age of patients increased with severity of disease. The highest per capita risk of hospitalization was among patients <5 y and 5–14 y (relative risk [RR] = 3.3 and 3.2, respectively, compared to the general population), whereas the highest risk of death per capita was in the age groups 50–64 y and ≥65 y (RR = 1.5 and 1.6, respectively, compared to the general population). Similarly, the ratio of H1N1pdm deaths to hospitalizations increased with age and was the highest in the ≥65-y-old age group, indicating that while infection rates have been observed to be very low in the oldest age group, risk of death in those over the age of 64 y who became infected was higher than in younger groups. The proportion of H1N1pdm patients with one or more reported chronic conditions increased with severity (median = 31.1%, 52.3%, and 61.8% of hospitalized, ICU-admitted, and fatal H1N1pdm cases, respectively). With the exception of the risk factors asthma, pregnancy, and obesity, the proportion of patients with each risk factor increased with severity level. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. Our findings suggest that morbid obesity might be a risk factor for ICU admission and fatal outcome (RR = 36.3). Conclusions Our results demonstrate that risk factors for severe H1N1pdm infection are similar to those for seasonal influenza, with some notable differences, such as younger age groups and obesity, and reinforce the need to identify and protect groups at highest risk of severe outcomes