Computational Evolution Protocol for Peptide Design

Computational peptide design is useful for therapeutics, diagnostics, and vaccine development. To select the most promising peptide candidates, the key is describing accurately the peptide-target interactions at the molecular level. We here review a computational peptide design protocol whose key feature is the use of all-atom explicit solvent molecular dynamics for describing the different peptide-target complexes explored during the optimization. We describe the milestones behind the development of this protocol, which is now implemented in an open-source code called PARCE. We provide a basic tutorial to run the code for an antibody fragment design example. Finally, we describe three additional applications of the method to design peptides for different targets, illustrating the broad scope of the proposed approach

New Strategies for the Prevention of Urinary Tract Infections by Uropathogenic <em>Escherichia coli</em>

Uropathogenic Escherichia coli (UPEC) is the leading causal agent of urinary tract infections (UTIs), which present high morbidity and limitations in antibiotic treatments. UTIs can also manifest as recurrent (RUTIs) in children and adults and represent a severe public health problem, mainly because there are no treatment and control alternatives that are 100% effective. Patients with RUTIs have a decreased quality of life and are prone to significant complications of UTIs, such as pyelonephritis and urosepsis. Recently, we described UPEC clinical strains related to UTI that have a high profile of antibiotic resistance [multidrug-resistant (MDR) and extensively drug-resistant (XDR)] and genes encoding several fimbrial adhesins, such as FimH of type 1 fimbriae, PapG of fimbriae P, and CsgA of Curli fimbriae. Recently, the expression of fimbrial adhesins (FimH, CsgA, and PapG) was shown to be involved in the release of the interleukins (IL) 6 and IL-8 in vitro. This work aims to present a broad overview and description of the pathogenic attributes of UPEC, including the infection processes, pathogenicity mechanisms, and host immune responses, as well as an integral perspective to generate new studies that would contribute to the implementation of preventive strategies against UTI

Incidence of community-acquired lower respiratory tract infections and pneumonia among older adults in the United Kingdom: a population-based study.

Community-acquired lower respiratory tract infections (LRTI) and pneumonia (CAP) are common causes of morbidity and mortality among those aged ≥65 years; a growing population in many countries. Detailed incidence estimates for these infections among older adults in the United Kingdom (UK) are lacking. We used electronic general practice records from the Clinical Practice Research Data link, linked to Hospital Episode Statistics inpatient data, to estimate incidence of community-acquired LRTI and CAP among UK older adults between April 1997-March 2011, by age, sex, region and deprivation quintile. Levels of antibiotic prescribing were also assessed. LRTI incidence increased with fluctuations over time, was higher in men than women aged ≥70 and increased with age from 92.21 episodes/1000 person-years (65-69 years) to 187.91/1000 (85-89 years). CAP incidence increased more markedly with age, from 2.81 to 21.81 episodes/1000 person-years respectively, and was higher among men. For both infection groups, increases over time were attenuated after age-standardisation, indicating that these rises were largely due to population aging. Rates among those in the most deprived quintile were around 70% higher than the least deprived and were generally higher in the North of England. GP antibiotic prescribing rates were high for LRTI but lower for CAP (mostly due to immediate hospitalisation). This is the first study to provide long-term detailed incidence estimates of community-acquired LRTI and CAP in UK older individuals, taking person-time at risk into account. The summary incidence commonly presented for the ≥65 age group considerably underestimates LRTI/CAP rates, particularly among older individuals within this group. Our methodology and findings are likely to be highly relevant to health planners and researchers in other countries with aging populations

Effects of lng Mutations on LngA Expression, Processing, and CS21 Assembly in Enterotoxigenic Escherichia coli E9034A

Enterotoxigenic Escherichia coli (ETEC) is a major cause of morbidity in children under 5 years of age in low- and middle-income countries and a leading cause of traveler's diarrhea worldwide. The ability of ETEC to colonize the intestinal epithelium is mediated by fimbrial adhesins, such as CS21 (Longus). This adhesin is a type IVb pilus involved in adherence to intestinal cells in vitro and bacterial self-aggregation. Fourteen open reading frames have been proposed to be involved in CS21 assembly, hitherto only the lngA and lngB genes, coding for the major (LngA) and minor (LngB) structural subunit, have been characterized. In this study, we investigated the role of the LngA, LngB, LngC, LngD, LngH, and LngP proteins in the assembly of CS21 in ETEC strain E9034A. The deletion of the lngA, lngB, lngC, lngD, lngH, or lngP genes, abolished CS21 assembly in ETEC strain E9034A and adherence to HT-29 cells was reduced 90%, compared to wild-type strain. Subcellular localization prediction of CS21 proteins was similar to other well-known type IV pili homologues. We showed that LngP is the prepilin peptidase of LngA, and that ETEC strain E9034A has another peptidase capable of processing LngA, although with less efficiency. Additionally, we present immuno-electron microscopy imagens to show that the LngB protein could be localized at the tip of CS21, and probably helps to control CS21 length. In conclusion, our results demonstrate that the LngA, LngB, LngC, LngD, LngH, and LngP proteins are essential for CS21 assembly, as well as for bacterial aggregation and adherence to HT-29 cells

Molecular Epidemiology of Multidrug-Resistant Uropathogenic Escherichia coli O25b Strains Associated with Complicated Urinary Tract Infection in Children.

BACKGROUND: Uropathogenic Escherichia coli (UPEC) has increased the incidence of urinary tract infection (UTI). It is the cause of more than 80% of community-acquired cystitis cases and more than 70% of uncomplicated acute pyelonephritis cases. AIM: The present study describes the molecular epidemiology of UPEC O25b clinical strains based on their resistance profiles, virulence genes, and genetic diversity. METHODS: Resistance profiles were identified using the Kirby-Bauer method, including the phenotypic production of extended-spectrum β-lactamases (ESBLs) and metallo-β-lactamases (MBLs). The UPEC serogroups, phylogenetic groups, virulence genes, and integrons were determined via multiplex PCR. Genetic diversity was established using pulsed-field gel electrophoresis (PFGE), and sequence type (ST) was determined via multilocus sequence typing (MLST). RESULTS: UPEC strains (n = 126) from hospitalized children with complicated UTIs (cUTIs) were identified as O25b, of which 41.27% were multidrug resistant (MDR) and 15.87% were extensively drug resistant (XDR). The O25b strains harbored the fimH (95.23%), csgA (91.26%), papGII (80.95%), chuA (95.23%), iutD (88.09%), satA (84.92%), and intl1 (47.61%) genes. Moreover, 64.28% were producers of ESBLs and had high genetic diversity. ST131 (63.63%) was associated primarily with phylogenetic group B2, and ST69 (100%) was associated primarily with phylogenetic group D. CONCLUSION: UPEC O25b/ST131 harbors a wide genetic diversity of virulence and resistance genes, which contribute to cUTIs in pediatrics

Stunting is preceded by intestinal mucosal damage and microbiome changes and Is associated with systemic inflammation in a cohort of Peruvian infants

Stunting, defined as height-for-ag

A bioinformatic approach to identify confirmed and probable CRISPR–Cas systems in the Acinetobacter calcoaceticus–Acinetobacter baumannii complex genomes

IntroductionThe Acinetobacter calcoaceticus–Acinetobacter baumannii complex, or Acb complex, consists of six species: Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter nosocomialis, Acinetobacter pittii, Acinetobacter seifertii, and Acinetobacter lactucae. A. baumannii is the most clinically significant of these species and is frequently related to healthcare-associated infections (HCAIs). Clustered regularly interspaced short palindromic repeat (CRISPR) arrays and associated genes (cas) constitute bacterial adaptive immune systems and function as variable genetic elements. This study aimed to conduct a genomic analysis of Acb complex genomes available in databases to describe and characterize CRISPR systems and cas genes.MethodsAcb complex genomes available in the NCBI and BV-BRC databases, the identification and characterization of CRISPR-Cas systems were performed using CRISPRCasFinder, CRISPRminer, and CRISPRDetect. Sequence types (STs) were determined using the Oxford scheme and ribosomal multilocus sequence typing (rMLST). Prophages were identified using PHASTER and Prophage Hunter.ResultsA total of 293 genomes representing six Acb species exhibited CRISPR-related sequences. These genomes originate from various sources, including clinical specimens, animals, medical devices, and environmental samples. Sequence typing identified 145 ribosomal multilocus sequence types (rSTs). CRISPR–Cas systems were confirmed in 26.3% of the genomes, classified as subtypes I-Fa, I-Fb and I-Fv. Probable CRISPR arrays and cas genes associated with CRISPR–Cas subtypes III-A, I-B, and III-B were also detected. Some of the CRISPR–Cas systems are associated with genomic regions related to Cap4 proteins, and toxin–antitoxin systems. Moreover, prophage sequences were prevalent in 68.9% of the genomes. Analysis revealed a connection between these prophages and CRISPR–Cas systems, indicating an ongoing arms race between the bacteria and their bacteriophages. Furthermore, proteins associated with anti-CRISPR systems, such as AcrF11 and AcrF7, were identified in the A. baumannii and A. pittii genomes.DiscussionThis study elucidates CRISPR–Cas systems and defense mechanisms within the Acb complex, highlighting their diverse distribution and interactions with prophages and other genetic elements. This study also provides valuable insights into the evolution and adaptation of these microorganisms in various environments and clinical settings

A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study

The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3-80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7-74.5]; OR 1.34 [95% CI: 0.46-3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 μmol/L, 95% CI: 3.6-8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin-containing regimen; 13% of patients in arm A dropped out because of metformin-related gastrointestinal symptoms. The most common adverse events (AEs) of grade ≥3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution

Self-harm consultations during the first year of COVID-19 pandemic: Study in four Argentine provinces

INTRODUCCIÓN: Es objeto de debate si la conducta suicida se vio impactada por la pandemia por COVID-19 y las medidas de aislamiento asociadas. Una vía para caracterizar la conducta suicida son las consultas a los servicios de emergencia en salud por lesiones autoinfligidas. El objetivo fue describir y analizar las consultas por conducta suicida, comparando los períodos de pandemia y prepandemia. MÉTODOS: Se realizó un estudio descriptivo de corte transversal con análisis de fuentes secundarias en tres hospitales generales y tres neuropsiquiátricos de cuatro provincias argentinas. Se relevaron consultas de febrero, julio y octubre del período de estudio. Se midieron variables sociodemográficas y referidas al episodio autolesivo. Se utilizaron frecuencias relativas y tasas para el análisis. RESULTADOS: Se analizaron 411 casos de consulta por lesión autoinfligida. El 73% fue del período previo a 2020. Al comparar los períodos prepandemia y pandemia, se observó un aumento en la tasa de consultas en el segundo, particularmente significativo en los hospitales neuropsiquiátricos. La derivación a otro establecimiento fue mayor en el período de pandemia. El envenenamiento fue el mecanismo de ocurrencia más habitual en ambos períodos, pero disminuyó durante la pandemia, cuando creció el uso de objetos cortantes. DISCUSIÓN: Se requiere continuar con el monitoreo de las consultas por lesiones autoinfligidas y abordar las diferencias de demanda entre hospitales generales y especializados.INTRODUCTION: The impact of COVID-19 pandemic and associated lockdowns on suicide behavior has been a matter of debate. Self-harm consultations to emergency departments are a way to analyze suicidal behavior. The objective was to describe and analyze self-harm consultations, comparing the pandemic and pre-pandemic periods. METHODS: A cross-sectional descriptive study was conducted with secondary source analysis in three general hospitals and three neuropsychiatric hospitals from four Argentine provinces. Consultations reported in February, July and October over the analyzed period were considered for the study. Data gathered included sociodemographic variables and those related to the self-harm event. Relative frequencies and rates were used for the analysis. RESULTS: A total of 411 self-harm consultations were included in the analysis, 73% of them were from the pre-pandemic period. Consultation rates were higher in the pandemic period, with a particularly significant increase in neuropsychiatric hospitals. Referral to another facility was higher during the pandemic. Poisoning was the most frequently used mechanism in both periods, even though it diminished during the pandemic period, when the use of sharp objects increased. DISCUSSION: It is necessary to continue monitoring self-harm consultations, and the differences between demand to general and specialized neuropsychiatric hospitals.Fil: Bonano, Daniela. Instituto Universidad de la Fundación "Héctor Barceló"; ArgentinaFil: Ochoa, Leandro Javier. Instituto Universidad de la Fundación "Héctor Barceló"; ArgentinaFil: Orzuza, Natalia. Gobierno de la Provincia de Entre Rios. Ministerio de Salud.; ArgentinaFil: Fernández, Marina A.. Universidad de Buenos Aires. Facultad de Psicología. Instituto de Investigaciones; ArgentinaFil: Morra, Ana Paula. Instituto Universidad de la Fundación "Héctor Barceló"; ArgentinaFil: Castro Valdez, Joaquín. Centro de Estudios Legales y Sociales.; ArgentinaFil: Badano, Florencia Maite. Autoridad de Cuenca Matanza Riachuelo.; ArgentinaFil: Ferrando, Fernanda. Gobierno de la Provincia de Entre Rios. Ministerio de Salud.; ArgentinaFil: Bernasconi, Silvina Virginia. Gobierno de la Ciudad Autonoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich.; ArgentinaFil: Turriani, Martín. Gobierno de la Provincia de Entre Rios. Ministerio de Salud.; ArgentinaFil: Simonini, Claudia. Provincia de Córdoba. Ministerio de Salud; ArgentinaFil: Duarte, Paula. Gobierno de la Provincia de Entre Rios. Ministerio de Salud.; ArgentinaFil: Ardila Gómez, Sara Elena. Universidad de Buenos Aires. Facultad de Psicología. Instituto de Investigaciones; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin