SUMMARY Pantothenate kinase (PanK) catalyzes the rate-controlling step in coenzyme A (CoA) biosynthesis. PanK3 is stringently regulated by acetyl-CoA and uses an ordered kinetic mechanism with ATP as the leading substrate. Biochemical analysis of site-directed mutants indicates that pantothenate binds in a tunnel adjacent to the active site that is occupied by the pantothenate moiety of the acetyl-CoA regulator in the PanK3•acetyl-CoA binary complex. A high-throughput screen for PanK3 inhibitors and activators was applied to a bioactive compound library. Thiazolidinediones, sulfonylureas and steroids were inhibitors, and fatty acyl-amides and tamoxifen were activators. The PanK3 activators and inhibitors either stimulated or repressed CoA biosynthesis in HepG2/C3A cells. The flexible allosteric acetyl-CoA regulatory domain of PanK3 also binds the substrates, pantothenate and pantetheine, and small molecule inhibitors and activators to modulate PanK3 activity.
Lung development depends upon the differentiation and expansion of a variety of specialized epithelial cell types, including distal type I and type II pneumocytes in the late term. Previous studies have shown a strict dependence on the choline cytidylyltransferase ␣ isoform (CCT␣) to mediate membrane phospholipid formation in cultured cells and during preimplantation embryogenesis. CCT␣ expression is highest in lung, and there has long been speculation about its precise role, due to the dual requirement for phospholipid in proliferating cell membranes and for lung surfactant production from alveolar type II cells. We investigated the function of CCT␣ in lung development, using an inducible, epithelial cell-specific CCT␣ knockout mouse line. Deletion of CCT␣ beginning at embryonic day 7.5 did not restrict lung development but resulted in severe respiratory failure at birth. Alveolar lavage and lung lipid analyses showed significant decreases in the major surfactant phospholipid, dipalmitoyl-phosphatidylcholine. The fatty acids destined for the surfactant phospholipid were redirected to an expanded triglyceride pool. Transcripts encoding type II cell-specific markers were expressed in the knockout mice, indicating the expected progression of differentiation in lung epithelia. However, surfactant protein levels were reduced, with the exception of that for surfactant protein B, which was elevated. Ultrastructural analysis of the type II cells showed Golgi complex abnormalities and aberrant lamellar bodies, which deliver surfactant lipid and protein to the alveolar lumen. Thus, CCT␣ was not required for the proliferation or differentiation of lung epithelia but was essential for the secretory component of phospholipid synthesis and critical for the proper formation of lamellar bodies and surfactant protein homeostasis.
Amblyomma americanum (the lone star tick) is a pathogen vector, mainly from eastern North America, that bites humans. With global integration and climate change, some ticks that are currently confined to a certain place may begin to spread out; some reports have shown that they are undergoing rapid range expansion. The difference in the potential geographic distribution of A. americanum under current and future climatic conditions is dependent on environment variables such as temperature and precipitation, which can affect their survival. In this study, we used a maximum entropy (MaxEnt) model to predict the potential geographic distribution of A. americanum. The MaxEnt model was calibrated at the native range of A. americanum using occurrence data and the current climatic conditions. Seven WorldClim climatic variables were selected by the jackknife method and tested in MaxEnt using different combinations of model feature class functions and regularization multiplier values. The best model was chosen based on the omission rate and the lowest Akaike information criterion. The resulting model was then projected onto the global scale using the current and future climate conditions modeled under four greenhouse gas emission scenarios.
Glossina morsitans is a vector for Human African Trypanosomiasis (HAT), which is mainly distributed in sub-Saharan Africa at present. Our objective was to project the historical and future potentially suitable areas globally and explore the influence of climatic factors. The maximum entropy model (MaxEnt) was utilized to evaluate the contribution rates of bio-climatic factors and to project suitable habitats for G. morsitans. We found that Isothermality and Precipitation of Wettest Quarter contributed most to the distribution of G. morsitans. The predicted potentially suitable areas for G. morsitans under historical climate conditions would be 14.5 million km2, including a large area of Africa which is near and below the equator, small equatorial regions of southern Asia, America, and Oceania. Under future climate conditions, the potentially suitable areas are expected to decline by about −5.38 ± 1.00% overall, under all shared socioeconomic pathways, compared with 1970–2000. The potentially suitable habitats of G. morsitans may not be limited to Africa. Necessary surveillance and preventive measures should be taken in high-risk regions.
ImportanceAssociations between heat waves and preterm birth (PTB) have been reported. However, associations of daytime-only, nighttime-only, and compound heat waves with PTB have yet to be explored at a national level. Furthermore, possible heterogeneity across urban-rural communities with different socioeconomic statuses needs to be explored.ObjectiveTo examine the association between daytime-only, nighttime-only, and compound heat waves and PTB in China and to find variations between urban and rural regions.Design, Setting, and ParticipantsThis case-crossover study used nationwide representative birth data between January 1, 2012, and December 31, 2019, from China’s National Maternal Near Miss Surveillance System. This multisite study covered 30 provinces in China and ensured the representation of urban and rural populations across 3 socioeconomic regions. Singleton live births delivered in the warm seasons from April to October during the study period were included. Exclusion criteria consisted of gestational age younger than 20 or older than 45 weeks, maternal ages younger than 13 or older than 50 years, conception dates earlier than 20 weeks before January 1, 2012, and later than 45 weeks before December 31, 2019, and an inconsistent combination of birthweight and gestational age according to growth standard curves of Chinese newborns. Data were analyzed from September 10, 2021, to April 25, 2023.ExposuresEighteen definitions of heat waves by 3 distinct types, including daytime only (only daily maximum temperature exceeds thresholds), nighttime only (only daily minimum temperature exceeds thresholds), and compound (both daily maximum and minimum temperature exceeds thresholds) heat waves, and 6 indexes, including 75th percentile of daily temperature thresholds for 2 or more (75th-D2), 3 or more (75th-D3), or 4 or more (75th-D4) consecutive days and 90th percentile of daily temperature thresholds for 2 or more (90th-D2), 3 or more (90th-D3), and 4 or more (90th-D4) consecutive days.Main Outcomes and MeasuresPreterm births with less than 37 completed weeks of gestation.ResultsAmong the 5 446 088 singleton births in the final analytic sample (maternal mean [SD] age, 28.8 [4.8] years), 310 384 were PTBs (maternal mean [SD] age, 29.5 [5.5] years). Compared with unexposed women, exposure of pregnant women to compound heat waves in the last week before delivery was associated with higher risk for PTB, with the adjusted odds ratios (AORs) ranging from 1.02 (95% CI, 1.00-1.03) to 1.04 (95% CI, 1.01-1.07) in 6 indexes. For daytime-only heat wave exposures, AORs ranged from 1.03 (95% CI, 1.01-1.05) to 1.04 (95% CI, 1.01-1.08) in the 75th-D4, 90th-D2, 90th-D3, and 90th-D4 indexes. Such associations varied by rural (AOR range, 1.05 [95% CI, 1.01-1.09] to 1.09 [95% CI, 1.04-1.14]) and urban (AOR range, 1.00 [95% CI, 0.98-1.02] to 1.01 [95% CI, 0.99-1.04]) regions during exposure to daytime-only heat waves in the 75th-D3 and 90th-D3 indexes.Conclusions and RelevanceIn this case-crossover study, exposure to compound and daytime-only heat waves in the last week before delivery were associated with PTB, particularly for pregnant women in rural regions exposed to daytime-only heat waves. These findings suggest that tailored urban-rural preventive measures may improve maternal health in the context of climate change.
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