Perturbation of the Dimer Interface of Triosephosphate Isomerase and its Effect on Trypanosoma cruzi

Most of the enzymes of parasites have their counterpart in the host. Throughout evolution, the three-dimensional architecture of enzymes and their catalytic sites are highly conserved. Thus, identifying molecules that act exclusively on the active sites of the enzymes from parasites is a difficult task. However, it is documented that the majority of enzymes consist of various subunits, and that conservation in the interface of the subunits is lower than in the catalytic site. Indeed, we found that there are significant differences in the interface between the two subunits of triosephosphate isomerase from Homo sapiens and Trypanosoma cruzi (TcTIM), which causes Chagas disease in the American continent. In the search for agents that specifically inhibit TcTIM, we found that 2,2′-dithioaniline (DTDA) is far more effective in inactivating TcTIM than the human enzyme, and that its detrimental effect is due to perturbation of the dimer interface. Remarkably, DTDA prevented the growth of Escherichia coli cells that had TcTIM instead of their own TIM and killed T. cruzi epimastigotes in culture. Thus, this study highlights a new approach base of targeting molecular interfaces of dimers

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Enfermedad periodontal como factor de riesgo para presentar resultados perinatales adversos

Objetivo: Determinar si la enfermedad periodontal (EP) es un factor de riesgo que pudiera ejercer alguna influencia en la presentación de resultados perinatales adversos en la población general. Método: Estudio prospectivo de cohorte, en el cual se incluyeron 282 pacientes que acudieron al Hospital Universitario "Dr. José Eleuterio González", Monterrey, Nuevo León, México, para atención del parto. Se realizó examen dental clasificándolas como sanas o enfermas. Para el análisis estadístico se utilizó estadística descriptiva, medidas de tendencia central y de dispersión, X² y riesgo relativo (RR) para establecer asociación entre la enfermedad periodontal y las variables de estudio. Resultados: La incidencia de EP fue de 15%. La edad promedio de 22,1 años. El RR para parto prematuro fue 0,67 (IC 95% 0,19-2,33; p=0,81), preeclampsia 1,17 (IC 95% 0,45-3,02; p=0,35), ruptura prematura de membranas 0,842 (IC 95% 0,80-0,88; p=0,76), bajo peso al nacer 0,85 (IC 95% 0,33-2,51; p=0,71). Conclusión: En nuestro estudio no encontramos asociación entre pacientes con enfermedad periodontal y resultados perinatales adversos.<br>Objective: To determine the relationship between maternal periodontal disease and the development of adverse perinatal outcomes. Methods: A prospective cohort study was performed; 282 patients were included, who were assisted for their birth delivery at the Hospital Universitario "Dr. José Eleuterio González", Monterrey, Nuevo León, Mexico. A dental examination was done classifying them as healthy or sick. A descriptive and statistic study was done looking for the association between periodontal disease and the variables of the study were compared using X² and relative risk. Results: The incidence of periondontal disease was 15%. The average age was 22.1 years. The risk ratio for preterm delivery was 0.67 (CI 95% 0.19-2.33; p=0.81), preeclampisa 1.17 (CI 95% 0.45-3.02; p=0.35), premature rupture of membranes 0.842 (CI 95% 0.80-0.88; p=0.76), low birthweight 0.85 (CI 95% 0.33-2.51; p=0.71). Conclusion: No significant association was seen between periodontal disease and the adverse perinatal outcomes

(Table T1) Depths and ages of datum levels at ODP Leg 182 sites

The first and last appearances of Quaternary planktonic foraminifers in the Great Australian Bight were evaluated using datum levels from magnetostatigraphy, oxygen isotope stratigraphy, and calcareous nannofossil biostratigraphy to determine whether they were synchronous or diachronous with open-ocean biostratigraphic events. The first appearance of Globorotalia truncatulinoides is diachronous at 1.6-1.7 Ma at Site 1127 and 1.1-1.2 at Sites 1129 and 1132, similar to other local appearances in high latitudes. All other datum levels, however, are synchronous with open-ocean events, including the first appearance of Globorotalia hirsuta and the last appearances of Globorotalia tosaensis and pink Globigerinoides ruber in the Indo-Pacific region. A local reappearance of Gt. hirsuta at ~0.12 Ma and the disappearance of Globorotalia crassaformis at ~0.10 Ma were found to be useful for local biostratigraphy. Age control at the bottom of all of the sections is poor at this time, but results suggest that sedimentation recommenced starting at ~1.9 Ma above the regional unconformity that marks the base of seismostratigraphic Sequence 2. Sediment accumulation is distinctly reduced in the lower Pleistocene compared to the upper Pleistocene, perhaps in part because of processes associated with several omission surfaces

Biology of three species of North American Triatominae (Hemiptera: Reduviidae: Triatominae) fed on rabbits

Aspects related to hatching, lifetime, number of blood meals for molting, mortality, feeding time, and postfeeding defecation delay were evaluated and compared in each instar of three North American Triatominae: Triatoma gerstaeckeri, Triatoma lecticularia and Triatoma protracta, all of them fed on rabbits. No significant differences (p > 0.05) were found among the three species regarding mean hatching rate, which was close to 20 days. Egg-to-adult development times were significantly shorter (p < 0.05) for T. lecticularia. Number of blood meals for molting to next instar ranged from one to five for T. protracta, and from one to six for T. gerstaeckeri and T. lecticularia. Mortality rates were higher in younger nymphs of T. lecticularia and T. protracta, while rates in T. gerstaeckeri were higher in fifth-instar nymphs. Mean feeding time was longest in T. gerstaeckeri, followed by T. lecticularia. More than twice the number of T. gerstaeckeri nymphs completed the development process, if compared to the nymphs from the other two species. Defecation delay was less than 10 min for T. lecticularia, T. protracta and the youngest nymphs of T. gerstaeckeri. Results point out that these three species may be important potential vectors of Trypanosoma cruzi for human populations, in areas of Mexico where these species are currently present

Breast cancer treatment: A phased approach to implementation

Optimal treatment outcomes for breast cancer are dependent on a timely diagnosis followed by an organized, multidisciplinary approach to care. However, in many low‐ and middle‐income countries, effective care management pathways can be difficult to follow because of financial constraints, a lack of resources, an insufficiently trained workforce, and/or poor infrastructure. On the basis of prior work by the Breast Health Global Initiative, this article proposes a phased implementation strategy for developing sustainable approaches to enhancing patient care in limited‐resource settings by creating roadmaps that are individualized and adapted to the baseline environment. This strategy proposes that, after a situational analysis, implementation phases begin with bolstering palliative care capacity, especially in settings where a late‐stage diagnosis is common. This is followed by strengthening the patient pathway, with consideration given to a dynamic balance between centralization of services into centers of excellence to achieve better quality and decentralization of services to increase patient access. The use of resource checklists ensures that comprehensive therapy or palliative care can be delivered safely and effectively. Episodic or continuous monitoring with established process and quality metrics facilitates ongoing assessment, which should drive continual process improvements. A series of case studies provides a snapshot of country experiences with enhancing patient care, including the implementation of national cancer control plans in Kenya, palliative care in Romania, the introduction of a 1‐stop clinic for diagnosis in Brazil, the surgical management of breast cancer in India, and the establishment of a women\u27s cancer center in Ghana