Correlation of Experimental and Calculated Inhibition Constants of Protease Inhibitor Complexes.

Predicting the potency of inhibitors is key to in silico screening of promising synthetic or natural compounds. Here we describe a predictive workflow that provides calculated inhibitory values, which concord well with empirical data. Calculations of the free interaction energy ΔG with the YASARA plugin FoldX were used to derive inhibition constants Ki from PDB coordinates of protease-inhibitor complexes. At the same time, corresponding KD values were obtained from the PRODIGY server. These results correlated well with the experimental values, particularly for serine proteases. In addition, analyses were performed for inhibitory complexes of cysteine and aspartic proteases, as well as of metalloproteases, whereby the PRODIGY data appeared to be more consistent. Based on our analyses, we calculated theoretical Ki values for trypsin with sunflower trypsin inhibitor (SFTI-1) variants, which yielded the more rigid Pro14 variant, with probably higher potency than the wild-type inhibitor. Moreover, a hirudin variant with an Arg1 and Trp3 is a promising basis for novel thrombin inhibitors with high potency. Further examples from antibody interaction and a cancer-related effector-receptor system demonstrate that our approach is applicable to protein interaction studies beyond the protease field.

Neural Models for Generating Natural Language Summaries from Temporal Personal Health Data.

With an increased interest in the production of personal health technologies designed to track user data (e.g., nutrient  intake, step counts), there is now more opportunity than ever to surface meaningful behavioral insights to everyday users in the form of natural language. This knowledge can increase their behavioral awareness and allow them to take action to meet their health goals. It can also bridge the gap between the vast collection of personal health data and the summary generation required to describe an individual's behavioral tendencies. Previous work has focused on rule-based time-series data summarization methods designed to generate natural language summaries of interesting patterns found within temporal personal health data. We examine recurrent, convolutional, and Transformer-based encoder-decoder models to automatically generate natural language summaries from numeric temporal personal health data. We showcase the effectiveness of our models on real user health data logged in MyFitnessPal (Weber and Achananuparp 2016) and show that we can automatically generate high-quality natural language summaries. Our work serves as a first step towards the ambitious goal of automatically generating novel and meaningful temporal summaries from personal health data.

How is Membrane Permeation of Small Ionizable Molecules Affected by Protonation Kinetics?

According to the pH-partition hypothesis, the aqueous solution adjacent to a membrane is a mixture of the ionization states of the permeating molecule at fixed Henderson-Hasselbalch concentrations, such that each state passes through the membrane in parallel with its own specific permeability. An alternative view, based on the assumption that the rate of switching ionization states is instantaneous, represents the permeation of ionizable molecules via an effective Boltzmann-weighted average potential (BWAP). Such an assumption is used in constant-pH molecular dynamics simulations. The inhomogeneous solubility-diffusion framework can be used to compute the pH-dependent membrane permeability for each of these two limiting treatments. With biased WTM-eABF molecular dynamics simulations, we computed the potential of mean force and diffusivity of each ionization state of two weakly basic small molecules: nicotine, an addictive drug, and varenicline, a therapeutic for treating nicotine addiction. At pH = 7, the BWAP effective permeability is greater than that determined by pH-partitioning by a factor of 2.5 for nicotine and 5 for varenicline. To assess the importance of ionization kinetics, we present a Smoluchowski master equation that includes explicitly the protonation and deprotonation processes coupled with the diffusive motion across the membrane. At pH = 7, the increase in permeability due to the explicit ionization kinetics is negligible for both nicotine and varenicline. This finding is reaffirmed by combined Brownian dynamics and Markov state model simulations for estimating the permeability of nicotine while allowing changes in its ionization state. We conclude that for these molecules the pH-partition hypothesis correctly captures the physics of the permeation process. The small free energy barriers for the permeation of nicotine and varenicline in their deprotonated neutral forms play a crucial role in establishing the validity of the pH-partitioning mechanism. Essentially, BWAP fails because ionization kinetics are too slow on the time scale of membrane crossing to affect the permeation of small ionizable molecules such as nicotine and varenicline. For the singly protonated state of nicotine, the computational results agree well with experimental measurements (P1 = 1.29 × 10-7 cm/s), but the agreement for neutral (P0 = 6.12 cm/s) and doubly protonated nicotine (P2 = 3.70 × 10-13 cm/s) is slightly worse, likely due to factors associated with the aqueous boundary layer (neutral form) or leaks through paracellular pathways (doubly protonated form).

A rare form of calcinosis in patients with systemic sclerosis-myositis overlap: report of four cases.

Objectives: Calcinosis is a well-described entity that occurs in patients with systemic sclerosis (SSc) and dermatomyositis (DM). Calcinosis in SSc typically occurs over pressure points and is usually nodular. We present a case series of four patients with SSc with a much rarer, diffuse form of calcinosis to illustrate this poorly recognized pattern of extensive and debilitating disease. Methods: Four patients with SSc and extensive calcinosis were identified from patients attending a tertiary rheumatology centre in the preceding 3 years. Their electronic case notes, radiographic images and medical photographs were reviewed. Results: All four patients had the diffuse cutaneous subtype of SSc (dcSSc) and additionally a myositis overlap. This was in the context of 102 of 461 (22%) patients with SSc whose clinical details had been recorded in the preceding 3 years having dcSSc. Their ages at diagnosis ranged from 27 to 65 years. Three were female, two were anti-Scl70 antibody positive, and two were anti-PMScl antibody positive. Development of calcinosis occurred between 1 and 6 years after onset of SSc. Plain radiography showed very extensive calcinosis in various sites, distributed in a pattern akin to sheets of calcium-containing deposits in the skin and subcutaneous tissue. Conclusions: Although calcinosis is common in SSc, extensive sheet-like calcinosis is very rare. Our experience suggests that when this form of calcinosis does occur, this is in the context of the diffuse cutaneous subtype of disease and with myositis overlap. The four cases described should raise awareness of this unusual and extensive pattern of disease.

Erratum: Survey of Conductive Polymers for the Fabrication of Conformation Switching Nucleic Acid-Based Electrochemical Biosensors.

[This corrects the article DOI: 10.1021/acsapm.3c02206.].

Stability and antigenicity of Chlamydia muridarum major outer membrane protein antigen at body temperature.

Chlamydia is an obligate intracellular bacterial pathogen responsible for disease and infertility across multiple species. Currently vaccines are being studied to help reduce the prevalence of this disease. The main advantage of protein subunit vaccines is their high degree of safety although this is traded off with the requirement for multiple booster doses to achieve complete protection. Although in certain populations the booster dose can be difficult and costly to administer, development of delayed vaccine delivery techniques, such as a vaccine capsule, could be the solution to this problem. One of the main drawbacks in this technology is that the antigen must remain stable at body temperature (37 °C) until release is achieved. Here we elucidate the stability of a recombinant chlamydial major outer membrane protein (MOMP) antigen and assess its antigenic and immunogenic properties after subjecting the antigen to 37 °C for four to six weeks. Through in vitro and in vivo assessment we found that the aged chlamydial MOMP was able to produce equivalent humoral and cell-mediated immune responses when compared with the unaged vaccine. It was also found that vaccines formulated with the aged antigen conferred equivalent protection against a live infection challenge as the unaged antigen. Thus ageing chlamydial MOMP antigens at 37 °C for four to six weeks did not cause any significant structural or antigenic/immunogenic degradation and recombinant C. muridarum MOMP is suitable for use in a delayed vaccine delivery system.

A TriAdj-Adjuvanted Chlamydia trachomatis CPAF Protein Vaccine Is Highly Immunogenic in Pigs.

Chlamydia trachomatis (Ct) infections are the most common sexually transmitted infection (STI). Despite effective antibiotics for Ct, undetected infections or delayed treatment can lead to infertility, ectopic pregnancies, and chronic pelvic pain. Besides humans, chlamydia poses similar health challenges in animals such as C. suis (Cs) in pigs. Based on the similarities between humans and pigs, as well as their chlamydia species, we use pigs as a large biomedical animal model for chlamydia research. In this study, we used the pig model to develop a vaccine candidate against Ct. The vaccine candidate consists of TriAdj-adjuvanted chlamydial-protease-like activity factor (CPAF) protein. We tested two weekly administration options-twice intranasal (IN) followed by twice intramuscular (IM) and twice IM followed by twice IN. We assessed the humoral immune response in both serum using CPAF-specific IgG (including antibody avidity determination) and also in cervical and rectal swabs using CPAF-specific IgG and IgA ELISAs. The systemic T-cell response was analyzed following in vitro CPAF restimulation via IFN-γ and IL-17 ELISpots, as well as intracellular cytokine staining flow cytometry. Our data demonstrate that while the IN/IM vaccination mainly led to non-significant systemic immune responses, the vaccine candidate is highly immunogenic if administered IM/IN. This vaccination strategy induced high serum anti-CPAF IgG levels with strong avidity, as well as high IgA and IgG levels in vaginal and rectal swabs and in uterine horn flushes. In addition, this vaccination strategy prompted a pronounced cellular immune response. Besides inducing IL-17 production, the vaccine candidate induced a strong IFN-γ response with CD4 T cells. In IM/IN-vaccinated pigs, these cells also significantly downregulated their CCR7 expression, a sign of differentiation into peripheral-tissue-homing effector/memory cells. Conclusively, this study demonstrates the strong immunogenicity of the IM/IN-administered TriAdj-adjuvanted Ct CPAF vaccine candidate. Future studies will test the vaccine efficacy of this promising Ct vaccine candidate. In addition, this project demonstrates the suitability of the Cs pre-exposed outbred pig model for Ct vaccine development. Thereby, we aim to open the bottleneck of large animal models to facilitate the progression of Ct vaccine candidates into clinical trials.

Viral-vectored boosting of OmcB- or CPAF-specific T-cell responses fail to enhance protection from Chlamydia muridarum in infection-immune mice and elicits a non-protective CD8-dominant response in naïve mice.

A vaccine is needed to combat the Chlamydia epidemic. Replication-deficient viral vectors are safe and induce antigen-specific T-cell memory. We tested the ability of intramuscular immunization with modified vaccinia Ankara (MVA) virus or chimpanzee adenovirus (ChAd) expressing chlamydial outer membrane protein (OmcB) or the secreted protein, chlamydial protease-like activating factor (CPAF), to enhance T-cell immunity and protection in mice previously infected with plasmid-deficient Chlamydia muridarum CM972 and elicit protection in naïve mice. MVA.OmcB or MVA.CPAF increased antigen-specific T cells in CM972-immune mice ∼150 and 50-fold, respectively, but failed to improve bacterial clearance. ChAd.OmcB/MVA.OmcB prime-boost immunization of naïve mice elicited a cluster of differentiation (CD) 8-dominant T-cell response dominated by cluster of differentiation (CD)8 T cells that failed to protect. ChAd.CPAF/ChAd.CPAF prime-boost also induced a CD8-dominant response with a marginal reduction in burden. Challenge of ChAd.CPAF-immunized mice genetically deficient in CD4 or CD8 T cells showed that protection was entirely CD4-dependent. CD4-deficient mice had prolonged infection, whereas CD8-deficient mice had higher frequencies of CPAF-specific CD4 T cells, earlier clearance, and reduced burden than wild-type controls. These data reinforce the essential nature of the CD4 T-cell response in protection from chlamydial genital infection in mice and the need for vaccine platforms that drive CD4-dominant responses.

Aplicación móvil para la enseñanza de lesiones elementales en cavidad bucal / A mobile application for teaching elementary lesions in the oral cavity

Introducción: El desarrollo de las Tecnologías de la Información y la Comunicación (TIC) y su fácil acceso, hacen de ésta una alternativa educativa que contribuye a incrementar la calidad de la educación, facilitando el proceso de enseñanza-aprendizaje con medios virtuales. Las lesiones elementales son alteraciones del tejido bucal y su conocimiento es importante para realizar un adecuado diagnóstico y manejo terapéutico. Objetivo: Diseñar, implementar y evaluar una aplicación móvil para la enseñanza de lesiones elementales en cavidad bucal. Materiales y métodos: Estudio de intervención, experimental, que evaluó una herramienta educativa sobre lesiones elementales bucales, utilizando una pre-prueba, una intervención y una prueba posterior, para el grupo control se evaluó el aprendizaje a través de la lectura de un artículo. Se compararon los resultados obtenidos mediante prueba de Chi 2 con un p≤0,05. Resultados: Ambos grupos lograron un incremento en el nivel de conocimiento sobre lesiones elementales; sin embargo, quien utilizó la aplicación móvil obtuvo resultados significativamente mejores de aprendizaje (Chi 2 p=0,014). Conclusiones: Las TIC constituyen una estrategia útil para afianzar nuevos conocimientos, se comprobó que los estudiantes que emplearon la herramienta educativa incrementaron significativamente el aprendizaje en lesiones elementales de una forma agradable y amena.

Introduction: The development and widespread access to Information and Communication Technologies (ICTs) have reinforced the view of them as didactic alternatives to improve the quality of education. These technological advances have facilitated the teaching-learning process through the use of virtual media. Knowing elementary lesions in the oral cavity tissue is important for their appropriate diagnosis and therapeutic management. Objective: To design, implement and assess the use of a mobile application in the teaching of elementary lesions of the oral cavity. Materials and methods: An intervention and experimental study that evaluated a didactic tool about oral elementary lesions, applying intervention, pre and post testing. The control group learning skills were assessed through the reading of an article. We finally compared the results via Chi2 test, with p≤0.05. Results: Although both groups showed an improvement in learning levels, the group that used the mobile application achieved significantly better results in reference to learning about elementary lesions (Chi2 p=0.014). Conclusions: ICTs have become useful strategies to strengthen new knowledge. In this study, we show that students who used the educational tool improved the learning of elementary lesions, in a significant and enjoyable way.

Immunodeficiency-associated Burkitt's lymphoma in pediatric patients: a clinical case report

Burkitt's lymphoma, a form of non-hodgkin lymphoma, is a neoplastic monoclonal proliferation of lymphoid cells in areas of the immune system. it can occur in HIV-positive patients, as AIDS is related to the development of non- hodgkin lymphoma. burkitt's lymphoma is a rare subtype, highly prevalent in patients with AIDS. incisional biopsy, in situ hybridization and computerized axial tomography are the appropriate tests to determine the characterize of the lesions. the case of a 4-year-old HIV-positive patient, who developed burkitt's lymphoma of the oral cavity, is reported in this paper. the aim of this case report is to describe the course of the pathology, taking into account its clinical imaging characteristics and treatment.