Unveiling mutation effects on the structural dynamics of the main protease from SARS-CoV-2 with hybrid simulation methods.

The main protease of SARS-CoV-2 (called Mpro or 3CLpro) is essential for processing polyproteins encoded by viral RNA. Several Mpro mutations were found in SARS-CoV-2 variants, which are related to higher transmissibility, pathogenicity, and resistance to neutralization antibodies. Macromolecules adopt several favored conformations in solution depending on their structure and shape, determining their dynamics and function. In this study, we used a hybrid simulation method to generate intermediate structures along the six lowest frequency normal modes and sample the conformational space and characterize the structural dynamics and global motions of WT SARS-CoV-2 Mpro and 48 mutations, including mutations found in P.1, B.1.1.7, B.1.351, B.1.525 and B.1.429+B.1.427 variants. We tried to contribute to the elucidation of the effects of mutation in the structural dynamics of SARS-CoV-2 Mpro. A machine learning analysis was performed following the investigation regarding the influence of the K90R, P99L, P108S, and N151D mutations on the dimeric interface assembling of the SARS-CoV-2 Mpro. The parameters allowed the selection of potential structurally stable dimers, which demonstrated that some single surface aa substitutions not located at the dimeric interface (K90R, P99L, P108S, and N151D) are able to induce significant quaternary changes. Furthermore, our results demonstrated, by a Quantum Mechanics method, the influence of SARS-CoV-2 Mpro mutations on the catalytic mechanism, confirming that only one of the chains of the WT and mutant SARS-CoV-2 Mpros are prone to cleave substrates. Finally, it was also possible to identify the aa residue F140 as an important factor related to the increasing enzymatic reactivity of a significant number of SARS-CoV-2 Mpro conformations generated by the normal modes-based simulations.

Effect of phosphorylation on the structural dynamics, thermal stability of human dopamine transporter: A simulation study using normal modes, molecular dynamics and Markov State Model.

The Human Dopamine Transporter (hDAT) plays an essential role in modulating the Influx/Efflux of dopamine, and it is involved in the mechanism of certain neurodegenerative diseases such as Parkinson's disease. Several studies have reported important states for Dopamine transport: outward-facing open state (OFo), the outward-facing closed state (OFc), the holo-occluded state closed (holo), and the inward-facing open state (IFo). Furthermore, experimental assays have shown that different phosphorylation conditions in hDAT can affect the rate of dopamine absorption. We present a protocol using hybrid simulation methods to study the conformational dynamics and stability of states of hDAT under different phosphorylation sites. With this protocol, we explored the conformational space of hDAT, identified the states, and evaluated the free energy differences and the transition probabilities between them in each of the phosphorylation cases. We also presented the conformational changes and correlated them with those described in the literature. There is a thesis/hypothesis that the phosphorylation condition corresponding to NP-333 system (where all sites Ser/Thr from residue 2 to 62 and 254 to 613 are phosphorylated, except residue 333) would decrease the rate of dopamine transport from the extracellular medium to the intracellular medium by hDAT as previously described in the literature by Lin et al., 2003. Our results corroborated this thesis/hypothesis and the data reported. It is probably due to the affectation/changes/alteration of the conformational dynamics of this system that makes the intermediate states more likely and makes it difficult to initial states associated with the uptake of dopamine in the extracellular medium, corroborating the experimental results. Furthermore, our results showed that just single phosphorylation/dephosphorylation could alter intrinsic protein motions affecting the sampling of one or more states necessary for dopamine transport. In this sense, the modification of phosphorylation influences protein movements and conformational preferences, affecting the stability of states and the transition between them and, therefore, the transport.

Multifractal Downscaling of Rainfall Using Normalized Difference Vegetation Index (NDVI) in the Andes Plateau.

In this paper, a multifractal downscaling technique is applied to adequately transformed and lag corrected normalized difference vegetation index (NDVI) in order to obtain daily estimates of rainfall in an area of the Peruvian Andean high plateau. This downscaling procedure is temporal in nature since the original NDVI information is provided at an irregular temporal sampling period between 8 and 11 days, and the desired final scale is 1 day. The spatial resolution of approximately 1 km remains the same throughout the downscaling process. The results were validated against on-site measurements of meteorological stations distributed in the area under study.

Improving potato drought tolerance through the induction of long-term water stress memory.

Knowledge of drought tolerance in potato is limited and very little is known about stress memory in this crop. In the present study, long-term stress memory was tested on tuber yield and drought tolerance related traits in three potato varieties (Unica, Désirée and Sarnav) with contrasted yields under water restriction. Seed tubers produced by plants grown under non-restricted (non-primed tubers) and restricted (primed tubers) water conditions were sown and exposed to similar watering treatments. Tuber yield and leaf greenness of plants from primed and non-primed seeds as well as tuber carbon isotope discrimination (Δ(13)C) and antioxidant activity (AA) responses to watering treatments were compared. Higher tuber yield, both under non-restricted and restricted water regimes, was produced by primed Sarnav plants. The decrease of tuber yield and Δ(13)C with water restriction was lower in primed Unica plants. Long-term stress memory consequently appears to be highly genotype-dependent in potato. Its expression in plants originated from primed tubers and facing water restriction seems to be positively associated to the degree of inherent capability of the cultivar to yield under water restriction. However, other effects of priming appear to be genotype-independent as priming enhanced the tuber AA in response to water restriction in the three varieties.

Exposición a plaguicidas y prácticas de uso y protección en embarazadas de zona rurales en control de atención primaria en la región de Valparaíso, Chile / Exposure to pesticides and use and protection practices in pregnant women from rural areas in primary care control in the Valparaíso region, Chile

ANTECEDENTES: Los trabajadores agrícolas y habitantes rurales están expuestos a productos plaguicidas. Aun cuando las políticas sanitarias se preocupan de normarlos, diversos estudios demuestran exposición en trabajadores y residentes cercanos a las zonas productivas. Entre ellos se encuentran mujeres gestantes, consideradas población particularmente vulnerable frente a plaguicidas. OBJETIVO: Identificar el contacto con plaguicidas, así como conductas asociadas a su uso, en mujeres gestantes de dos comunas agrícolas de la V Región en control prenatal en Centros de Salud Familiar. MÉTODO: Estudio observacional transversal, realizado en una muestra de ochenta gestantes que ingresaron a control entre mayo 2013 y abril 2014. El instrumento de recolección de datos fue una encuesta, aplicada por el equipo de salud al ingreso. RESULTADOS: Las gestantes, en su gran mayoría, alguna vez han tenido contacto con plaguicidas, y cerca de la mitad lo tuvo en el mismo año en que se aplicó la encuesta. La exposición a plaguicidas se da tanto en los espacios productivos, como residenciales. Se observó que las medidas preventivas asociadas al contacto con agrotóxicos son insuficientes. A la vez, destaca la exposición a fumigaciones aéreas, frente a las cuales la posibilidad de prevención es aún menor. CONCLUSIÓN: En comunas rurales puede existir un contacto permanente de la población femenina gestante con plaguicidas, lo cual sucede sin las medidas de protección adecuadas, incrementando el riesgo de exposición a estas sustancias. Es pertinente entonces, desarrollar una labor educativa activa para mejorar las prácticas de uso de plaguicidas.

BACKGROUND: Agriculture workers and rural dwellers are exposed to pesticide products. Sanitation policies attempt to regulate their use, but studies demonstrate that a significant percentage of workers and residents who are close to the productive zones are exposed to these chemicals. Pregnant women are particularly vulnerable to pesticides. AIM: To identify the risk of exposure to pesticides and practices of pesticide handling in women under pregnancy control programs in Family Health Care Centers in two rural districts of the 5th Region. METHOD: Cross-sectional study, conducted during May 2013 and April 2014 on eighty women, who entered pregnancy control programs in either rural district. The health professionals of the Centers collected the data in a survey. RESULTS: Most of the pregnant women declared having been in contact with pesticides at some point. Almost half of them had this contact in the same year of their interview, that is previous or during their pregnancy. The exposure to pesticides takes place in productive locations as well as residential areas. The preventive measures associated to the contact with pesticides are not sufficient. Rural populations are also exposed to aerial fumigations, which further limits preventive measures. CONCLUSION: Pregnant women living in a rural district may be permanently exposed to pesticides. Exposure to agrochemicals is not associated to safe prevention practices which increase the risk of exposure. Educational programs may aid to enhance safe pesticide use.

Randomized trial of benznidazole for chronic Chagas' cardiomyopathy

BACKGROUND:The role of trypanocidal therapy in patients with established Chagas' cardiomyopathy is unproven.METHODS:We conducted a prospective, multicenter, randomized study involving 2854 patients with Chagas' cardiomyopathy who received benznidazole or placebo for up to 80 days and were followed for a mean of 5.4 years. The primary outcome in the time-to-event analysis was the first event of any of the components of the composite outcome of death, resuscitated cardiac arrest, sustained ventricular tachycardia, insertion of a pacemaker or implantable cardioverter-defibrillator, cardiac transplantation, new heart failure, stroke, or other thromboembolic event.RESULTS:The primary outcome occurred in 394 patients (27.5%) in the benznidazole group and in 414 (29.1%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.07; P=0.31). At baseline, a polymerase-chain-reaction (PCR) assay was performed on blood samples obtained from 1896 patients; 60.5% had positive results for Trypanosoma cruzi on PCR. The rates of conversion to negative PCR results (PCR conversion) were 66.2% in the benznidazole group and 33.5% in the placebo group at the end of treatment, 55.4% and 35.3%, respectively, at 2 years, and 46.7% and 33.1%, respectively, at 5 years or more (P<0.001 for all comparisons)...

First report of cattle farms with gastrointestinal nematodes resistant to levamisole in Mexico.

The objectives of the present study were: (1) to report the percentage of cattle farms with gastrointestinal nematodes (GINs) resistant to levamisole in Veracruz, Mexico, (2) to identify the genera of GINs involved in resistance, and (3) to identify factors associated with these resistances. The faecal egg count reduction test (McMaster technique) was used to detect the presence of resistant GINs. A questionnaire was given to owners to understand the history of anthelmintic use. The percentage of cattle farms with GINs resistant to levamisole was 36.4% (4/11). The percentage of faecal egg count reduction on resistant farms was 91%, 82%, 42% and 88%. A similar number of cattle farms (4/11) were identified as potentially having levamisole resistance. Only three farms had GIN populations susceptible to levamisole. Cooperia spp. was the genus most commonly found to be resistant, followed by Haemonchus spp., Ostertagia spp. and Oesophagostomum spp. No factors were identified that influenced the presence of GIN resistance. However, there were identified inappropriate anthelmintic practices in cattle farms that should be improved. None of the farmers weighed their animals in order to dose them correctly with anthelmintics. Six cattle farms (54.5%) applied anthelmintics to new arriving animals. This is the first report of levamisole resistant GINs in Mexico. Improving the use of anthelmintics and measures of quarantine for infected cattle will help control the spread of resistance.

El diagnóstico de alcoholismo en estudiantes de medicina un enfoque transhispanoamericano: México, Colombia, Perú (Lima y Cuzco) y Ecuador / Diagnosis of alcoholismo in students of medicine: A transhispanic-american approach: México, Colombia, Perú (Lima and Cuzco) and Ecuador

Mediante el inventario de evaluación sussmilch (IES), previamente validado y confiabilizado, se estableció una diferencia significativa entre la teoría y la realidad de la calidad de la información publicada (1967-1999). Esto señala que esos resultados no pueden generalizarse ni dentro ni fuera de las muestras de estudiantes, también de medicina. En contraste, con base en el principio de que resultados negativos también son resultados, en este ejercicio de demostró empíricamente que los resultados obtenidos representan bien a las muestras de estudiantes que fueron admitidos a cinco facultades de medicina hispanoamericana (FMH). Se desarrolló el indice de alcoholismo de pregrado (IAPG) integrado por cuatro (ó cinco) reactivos con respuestas dicotómicas, capaces de discernir, con error conocido, entre estudiantes de medicina no-alcohólicos (NOH), sospechosos (SOH) y alcohólicos (OH). El perfil psicométrico del IAPG exhibió una equivalente entre las Facultades de Medicina de la Universidad Nacional Autónoma de México (UNAM), Universidad Nacional de Colombia (UNC), Universidad Peruana Cayetano Heredia(UPCH), universidad Nacional de San Antonio Abad del Cuzco (UNSAAC) y Universidad de Cuenca(UC).

[Massive hypertrophy of the mammary gland. Report of 6 cases]. / Hipertrofia masiva de la glándula mamaria. Presentación de seis casos.

In the period of January of 1985 to January of 1995, 6 cases of massive hypertrophy of the mammary gland were diagnosed from 60,000 patients seen in the External Consultation of the Service of Gynecological Oncology. The age oscillated between 11 and 27 years old, with an average of 20.8 years. One case was unilateral and the 5 remaining, bilateral; 3 coexisted with pregnancy. The treatment consisted of reductive mammoplasty. This pathology is a rare entity, with not very well defined etiology in which apparently there are involved hormonals receptors and an unusual sensibility to hormones although they are at normal serum levels.

[Carcinoma of fallopian tubes. Presentation of 2 cases]. / Carcinoma de trompa de Falopio. Presentación de dos casos.

The carcinoma of the Fallopian tube is at the present time, one of the most rare gynecologic tumors, representing approximately less than 1% in world literature, being in our experience of 0.15%. We presented two cases of adenocarcinoma of the Fallopian tube, seen in a lapse of 25 years, not diagnosed preoperatorily with the clinical trial of abnormal bleeding, negative biopsy of endometrium and adnexal mass. As it is written in the literature, the diagnosis is rarely established previous to the operation and it usually corresponded to an adenocarcinoma. The classification of the FIGO for the stage is used. In relation to the survival follow-up: the stages I and II present 60% approximately of survival to the five years and it is suggested radiotherapy additional to the surgery; however, according to some authors this doesn't improve the survival.

Influenza. Comportamiento en Panamá (1989-1992) / Influenza. Behaviour in Panamá (1989-1992)

Se realiza una revisión de la influenza, las características del virus, el comportamiento epidemiológico, el cuadro clínico, el tratamiento y la prevención. Se analiza su comportamiento epidemiológico en Panamá durante los últimos cuatro años. Se concluye que la influenza continúa siendo un problema importante de salud pública y ejerce gran influencia en la morbilidad por neumonía en niños

Diagnóstico in vitro de Haemonchus contortus resistente al albendazol, fenbendazol, oxfendazol y febantel en tres rebaños ovinos Tabasco o Pelibuey / In vitro diagnosis of resistant Haemonchus contortus to benzimidazoles in three flocks of Tabasco or Pellibuey breed sheep

El objetivo del estudio fue: a) detectar mediante una prueba in vitro, poblaciones de nematodos resistentes a bencimidazoles y prodencimidazoles en ovinos de raza Tabasco o Pelibuey y b) determinar los factores de manejo de animales y antihelmínticos que contribuyeron a la selección de los nematodos resistentes. La prueba in vitro básicamente puso en contacto huevos de H. contortus con diferentes concentraciones en ppm de tiabendazol; los resultados se sometieron a análisis Probit. El índice de resitencia alcanzado por las tres poblaciones de nematodos resistentes fue: 21.6, 17.5 y 19.2. Los factores que contribuyeron a la selección de nematodos fueron: sobrepastoreo, dosis subletales y carencia de refugio larvario. Los antihelmínticos involucrados son: albendazol, fenbendazol, oxfendazol y fabantel.

Enfermedad inflamatoria pélvica en mujeres del Area Metropolitana de Panamá / Inflammatory pelvic disease in women of the Area Metropolitana de Panamá

La enfermedad inflamatoria pélvica (EIP) es un síndrome que se presenta en mujeres sexualmente activas o en edad reproductiva, causada principalmente por los agentes causantes de las enfermedades transmitidas sexualmente (ETS). Este trabajo presenta la información epidemiológica obtenida en 16 mujeres atendidas en el Cuarto de Urgencia de Ginecología del Complejo Hospitalario Metropolitano de la Caja de Seguro Social de la Ciudad de Panamá, con un diagnóstico inicial de EIP aguda y que representaron el 19 (por ciento) (16/84) de todos los casos de EIP reportados en el Area Metropolitana de Panamá en 1986. Los casos se presentaron en mujeres de 16 a 42 años. No se observó ninguna asociación entre EIP aguda y variables tales como raza, estado marital ni número de compañeros sexuales. Tres casos tenían antecedentes de ETS y uno informó el uso de dispositivo intrauterino. Se detectaron tres casos de EIP aguda gonocóccica. No se obtuvieron cultivos positivos por Chlamydia trachomatis ni por Mycoplasma hominis

Selection among nonlinear models for rate of passage studies in ruminants.

Eight Toggenburg wether goats were fed either Coastal bermudagrass (Cynodon dactylon) or orchardgrass (Dactylis glomerata)-alfalfa (Medicago sativa) hay (57:43%) in a reversal design. Four markers were used to study the movement of different digesta fractions: erbium for large particles greater than 1,700 microns; ytterbium for medium particles less than 1,700 microns and greater than 500 microns; chromium for small particles less than 500 microns and greater than 32 microns; and cobalt to follow liquid passage. Fecal samples were collected every 4 h for 6 d. The excretion curves obtained for every marker in each animal were used for model selection. One-compartment gamma age-dependent models (gamma 2, 3 and 4 age-dependent), two-compartment (gamma 2 and gamma 3 age-dependent, age-independent) models and a biexponential model were fitted to the data. Residual sums of squares and the Davidson and MacKinnon test were used to select the most appropriate models. These procedures indicated that the models best describing the movement of different digesta fractions through the gastrointestinal tract of goats, in this experiment, were the biexponential model for liquids, gamma 2 two-compartment model for small and medium particles and gamma 3 two-compartment model for large particles. To accurately describe the behavior of different components of digesta in the digestive tract, different mathematical models are required. In general, models that describe the movement of large particles have higher orders of age-dependency than models that describe the passage of liquids or small particles.