Networks of High Mutual Information Define the Structural Proximity of Catalytic Sites: Implications for Catalytic Residue Identification

Identification of catalytic residues (CR) is essential for the characterization of enzyme function. CR are, in general, conserved and located in the functional site of a protein in order to attain their function. However, many non-catalytic residues are highly conserved and not all CR are conserved throughout a given protein family making identification of CR a challenging task. Here, we put forward the hypothesis that CR carry a particular signature defined by networks of close proximity residues with high mutual information (MI), and that this signature can be applied to distinguish functional from other non-functional conserved residues. Using a data set of 434 Pfam families included in the catalytic site atlas (CSA) database, we tested this hypothesis and demonstrated that MI can complement amino acid conservation scores to detect CR. The Kullback-Leibler (KL) conservation measurement was shown to significantly outperform both the Shannon entropy and maximal frequency measurements. Residues in the proximity of catalytic sites were shown to be rich in shared MI. A structural proximity MI average score (termed pMI) was demonstrated to be a strong predictor for CR, thus confirming the proposed hypothesis. A structural proximity conservation average score (termed pC) was also calculated and demonstrated to carry distinct information from pMI. A catalytic likeliness score (Cls), combining the KL, pC and pMI measures, was shown to lead to significantly improved prediction accuracy. At a specificity of 0.90, the Cls method was found to have a sensitivity of 0.816. In summary, we demonstrate that networks of residues with high MI provide a distinct signature on CR and propose that such a signature should be present in other classes of functional residues where the requirement to maintain a particular function places limitations on the diversification of the structural environment along the course of evolution

Estimated impact of maternal vaccination on global paediatric influenza-related in-hospital mortality: A retrospective case series

BACKGROUND: Influenza virus infection is an important cause of under-five mortality. Maternal vaccination protects children younger than 3 months of age from influenza infection. However, it is unknown to what extent paediatric influenza-related mortality may be prevented by a maternal vaccine since global age-stratified mortality data are lacking. METHODS: We invited clinicians and researchers to share clinical and demographic characteristics from children younger than 5 years who died with laboratory-confirmed influenza infection between January 1, 1995 and March 31, 2020. We evaluated the potential impact of maternal vaccination by estimating the number of children younger than 3 months with in-hospital influenza-related death using published global mortality estimates. FINDINGS: We included 314 children from 31 countries. Comorbidities were present in 166 (53%) children and 41 (13%) children were born prematurely. Median age at death was 8·6 (IQR 4·5-16·6), 11·5 (IQR 4·3-24·0), and 15·5 (IQR 7·4-27·0) months for children from low- and lower-middle-income countries (LMICs), upper-middle-income countries (UMICs), and high-income countries (HICs), respectively. The proportion of children younger than 3 months at time of death was 17% in LMICs, 12% in UMICs, and 7% in HICs. We estimated that 3339 annual influenza-related in-hospital deaths occur in the first 3 months of life globally. INTERPRETATION: In our study, less than 20% of children is younger than 3 months at time of influenza-related death. Although maternal influenza vaccination may impact maternal and infant influenza disease burden, additional immunisation strategies are needed to prevent global influenza-related childhood mortality. The missing data, global coverage, and data quality in this study should be taken into consideration for further interpretation of the results. FUNDING: Bill & Melinda Gates Foundation

The Distribution of Debt Across Euro Area Countries: The Role of Individual Characteristics, Institutions and Credit Conditions

The aim of this paper is twofold. First, we present an up-to-date assessment of the differences across euro area countries in the distributions of various measures of debt conditional on household characteristics. We consider three different outcomes: the probability of holding debt, the amount of debt held and, in the case of secured debt, the interest rate paid on the main mortgage. Second, we examine the role of legal and economic institutions in accounting for these differences. We use data from the first wave of a new survey of household finances, the Household Finance and Consumption Survey, to achieve these aims. We find that the patterns of secured and unsecured debt outcomes vary markedly across countries. Among all the institutions considered, the length of asset repossession periods best accounts for the features of the distribution of secured debt. In countries with longer repossession periods, the fraction of people who borrow is smaller, the youngest group of households borrow lower amounts (conditional on borrowing), and the mortgage interest rates paid by low-income households are higher. Regulatory loan-to-value ratios, the taxation of mortgages and the prevalence of interest-only or fixed-rate mortgages deliver less robust results

Consideraciones prácticas en la conformación robusta del parámetro de Youla para el diseño algebraico de controladores

The Youla-Kucera parameterization is used to find the family of controllers for which a feedback control system is internally stable. Then, by employing loopshaping techniques, the robust performance problem is solved for minimum phase plants and the problem of robust stability with asymptotic tracking for the case of non-minimum phase plants. The proposed methodology allows considering practical aspects in the design of feedback control systems such as tracking, disturbance rejection, input constraints, noise suppression and plant uncertainty.La parametrización de Youla-Kucera es utilizada en la determinación de la familia de controladores que estabiliza internamente un sistema de control. Luego, mediante el empleo de técnicas de conformación del lazo se resuelve el problema de desempeño robusto, en el caso de plantas de fase mínima; y el problema de estabilidad robusta y seguimiento asintótico en el caso de plantas de fase no mínima. La metodología propuesta permite considerar aspectos prácticos del diseño de sistemas de control tales como el seguimiento, el rechazo a perturbaciones, la limitación del esfuerzo de control, la supresión del ruido y la robustez

Focus on 5 Years of the Acceptance and Adhesion to Prostaglandin El Auto-Intracavernosal Injection in Patients with Erectile Disfunction

From 5/98 to 5/03, of the 1310 patients taking a medical therapy for erectile dysfunction (E.D.), only 137 took autointracavernosal injection (auto. ICI). 134 patients were contacted by phone and were asked to answer a definite questionnaire. Results 49 patients (36.5%) still perform auto-ICI therapy while 85 (63.5%) had given up. 53% of the patients still using auto-ICI make the injection 4, or more times a month, with an erection lasting a considerable time (30–60 minutes). Nobody referred the presence of corpora cavernosa fibrosis. The reasons put forward by patients who stopped the therapy were: a perception of ineffectiveness, therapy rejection, fear of injections and the appearance of intolerable side effects. Conclusions Auto-ICI therapy remains a valid option for patients with E.D. not responding to oral therapy but it needs greater involvement by the physician in order to evaluate the patient's psychological discomfort and reduce or eliminate intolerable side effects. </jats:sec

Dexamethasone for Pediatric Critical Asthma: A Multicenter Descriptive Study

Background Systemic corticosteroids are vital to critical asthma management. While intravenous methylprednisolone is routinely used in the pediatric intensive care unit (PICU) setting, recent data supports dexamethasone as an alternative. Using the Pediatric Health Information System (PHIS) registry, we assessed trends and variation in corticosteroid prescribing among children hospitalized for critical asthma. Methods We performed a multicenter retrospective cohort study using PHIS data among children 3-17 years of age admitted for critical asthma from 2011 through 2019. Primary outcomes were corticosteroid prescribing rates by year and participating sites. Exploratory outcomes were corticosteroid-related adverse effects, rates of adjunctive pharmaceutical and respiratory interventions, mortality and length of stay. Results Of the 49 children's hospitals assessed, 26 907 encounters were included for study. Mean dexamethasone exposure rates were 18.1 ± 2.4% where 2.4 ± 1.2% represented dexamethasone-alone prescribing. Dexamethasone alone prescribing exhibited a linear trend (annual increase of 0.5 ± 0.1% annually R2 = 0.845) without correlation to cumulative site critical asthma admission rates. Compared to encounters prescribed solely methylprednisolone or a combination of dexamethasone and methylprednisolone, subjects provided dexamethasone alone had reduced asthma severity indices, length of stay, and exposure rates to adjunctive asthma interventions. Adverse events were rare and the dexamethasone-alone group less frequently experienced gastritis and hyperglycemia. Conclusions In this multicenter retrospective study from 49 children's hospitals, dexamethasone prescribing rates appear increasing for pediatric critical asthma. Observed variability in corticosteroid prescribing implies a continued need for controlled prospective comparative analyses to define ideal corticosteroid regimens for pediatric critical asthma. </jats:sec

Adenoid cystic/basal cell carcinoma of the prostate: case report

Although most prostate carcinomas belong to the conventional acinar type, unusual variants have been reported. The adenoid cystic/basal cell carcinoma of the prostate is a rare tumor with distinctive histopathologic features. There are quite few publications in the literature concerning the diagnosis, treatment, and prognosis of this neoplasm. Methods. A 71-year-old man had an increased PSA value (5.11 ng/dL); the prostatic biopsy examination was positive for adenoid cystic/basal cell carcinoma. For this reason we proceeded with radical prostatectomy. The histology examination showed an acinar conventional carcinoma and adenoid cystic/basal cell carcinoma. At eight months the patient did not show any recurrence. Conclusions. Various histologic and immunohistochemical features are helpful in recognizing the adenoid cystic/basal cell carcinoma of the prostate. Clinically, the only difference from a conventional adenocarcinoma is that the PSA value is usually normal or only slightly increased. This tumor has a biological potential that can result in metastases in some cases; the current treatment consists primarily in the surgical resection. A close, long-term follow-up is strongly recommended. </jats:sec

Tomato Apical Leaf Curl Virus: A Novel, Monopartite Geminivirus Detected in Tomatoes in Argentina

Plant viruses that are members of the Geminiviridae family have circular single-stranded DNA (ssDNA) genome and are responsible for major crop diseases worldwide. We have identified and characterized a novel monopartite geminivirus infecting tomato in Argentina. The full-length genome was cloned and sequenced. The genome-wide pairwise identity calculation that resulted in a maximum of 63% identity with all of other known geminiviruses indicated that it is a new geminivirus species. Biolistic infected plants presented interveinal yellowing, apical leaf curling and extreme root hypotrophy. Thus, the name proposed for this species is tomato apical leaf curl virus (ToALCV). The phylogenetic inferences suggested different evolutionary relationships for the replication-associated protein (Rep) and the coat protein (CP). Besides, the sequence similarity network (SSN) protein analyses showed that the complementary-sense gene products (RepA, Rep and C3) are similar to capulavirus while the viron-sense gene products (CP, MP and V3) are similar to topocuvirus, curtovirus and becurtovirus. Based on the data presented, ToALCV genome appears to have “modular organization” supported by its recombination origin. Analyses of the specificity-determining positions (SDPs) of the CP of geminiviruses defined nine subgroups that include geminiviruses that share the same type of insect vector. Our sequences were clustered with the sequences of topocuvirus, whose vector is the treehopper, Micrutalis malleifera. Also, a set of the highest scored amino acid residues was predicted for the CP, which could determine differences in virus transmission specificity. We predict that a treehopper could be the vector of ToALCV, but transmission assays need to be performed to confirm this. Given everything we demonstrate in this paper, ToALCV can be considered a type member of a new putative genus of the Geminiviridae family