PrlaeA Affects the Production of Roquefortine C, Mycophenolic Acid, and Andrastin A in Penicillium roqueforti, but It Has Little Impact on Asexual Development.

The regulation of fungal specialized metabolism is a complex process involving various regulators. Among these regulators, LaeA, a methyltransferase protein originally discovered in Aspergillus spp., plays a crucial role. Although the role of LaeA in specialized metabolism has been studied in different fungi, its function in Penicillium roqueforti remains unknown. In this study, we employed CRISPR-Cas9 technology to disrupt the laeA gene in P. roqueforti (PrlaeA) aiming to investigate its impact on the production of the specialized metabolites roquefortine C, mycophenolic acid, and andrastin A, as well as on asexual development, because they are processes that occur in the same temporal stages within the physiology of the fungus. Our results demonstrate a substantial reduction in the production of the three metabolites upon disruption of PrlaeA, suggesting a positive regulatory role of LaeA in their biosynthesis. These findings were further supported by qRT-PCR analysis, which revealed significant downregulation in the expression of genes associated with the biosynthetic gene clusters (BGCs) responsible for producing roquefortine C, mycophenolic acid, and andrastin A in the ΔPrlaeA strains compared with the wild-type P. roqueforti. Regarding asexual development, the disruption of PrlaeA led to a slight decrease in colony growth rate, while conidiation and conidial germination remained unaffected. Taken together, our results suggest that LaeA positively regulates the expression of the analyzed BGCs and the production of their corresponding metabolites in P. roqueforti, but it has little impact on asexual development.

Leading causes of excess mortality in Mexico during the COVID-19 pandemic 2020-2021: A death certificates study in a middle-income country.

Background: The death toll after SARS-CoV-2 emergence includes deaths directly or indirectly associated with COVID-19. Mexico reported 325,415 excess deaths, 34.4% of them not directly related to COVID-19 in 2020. In this work, we aimed to analyse temporal changes in the distribution of the leading causes of mortality produced by COVID-19 pandemic in Mexico to understand excess mortality not directly related to the virus infection. Methods: We did a longitudinal retrospective study of the leading causes of mortality and their variation with respect to cause-specific expected deaths in Mexico from January 2020 through December 2021 using death certificate information. We fitted a Poisson regression model to predict cause-specific mortality during the pandemic period, based on the 2015-2019 registered mortality. We estimated excess deaths as a weekly difference between expected and observed deaths and added up for the entire period. We expressed all-cause and cause-specific excess mortality as a percentage change with respect to predicted deaths by our model. Findings: COVID-19 was the leading cause of death in 2020-2021 (439,582 deaths). All-cause total excess mortality was 600,590 deaths (38⋅2% [95% CI: 36·0 to 40·4] over expected). The largest increases in cause-specific mortality, occurred in diabetes (36·8% over expected), respiratory infections (33·3%), ischaemic heart diseases (32·5%) and hypertensive diseases (25·0%). The cause-groups that experienced significant decreases with respect to the expected pre-pandemic mortality were infectious and parasitic diseases (-20·8%), skin diseases (-17·5%), non-traffic related accidents (-16·7%) and malignant neoplasm (-5·3%). Interpretation: Mortality from COVID-19 became the first cause of death in 2020-2021, the increase in other causes of death may be explained by changes in the health service utilization patterns caused by hospital conversion or fear of the population using them. Cause-misclassification cannot be ruled out. Funding: This study was funded by Conacyt.

The Association of Obesity, Type 2 Diabetes, and Hypertension with Severe Coronavirus Disease 2019 on Admission Among Mexican Patients.

OBJECTIVE: This study's aim was to explore the association of obesity, type 2 diabetes, and hypertension with severe coronavirus disease 2019 (COVID-19) on admission. METHODS: In the present study, a total of 23,593 patient samples were evaluated by a laboratory from the Mexican Institute of Epidemiological Diagnosis and Reference. Of these, 18,443 were negative for COVID-19, 3,844 were positive for COVID-19, and 1,306 were positive for other respiratory viruses. Severe types of respiratory disease were defined by the presence of pneumonia and other organ failure that requires intensive care. Multivariable logistic regression models were used to explore factors associated with severe COVID-19 on admission. RESULTS: Patients who tested positive for COVID-19 had a higher proportion of obesity (17.4%), diabetes (14.5%), and hypertension (18.9%) compared with those without a confirmed diagnosis. Compared with patients without obesity, those with obesity showed a 1.43-fold higher odds of developing severe COVID-19 on admission, whereas subjects with diabetes and hypertension showed a 1.87-fold and 1.77-fold higher odds of developing severe COVID-19 on admission, respectively. CONCLUSIONS: Obesity, diabetes, and hypertension were significantly associated with severe COVID-19 on admission and the association of obesity was stronger in patients < 50 years of age.