Structural and Chemical Profiling of the Human Cytosolic Sulfotransferases

The human cytosolic sulfotransfases (hSULTs) comprise a family of 12 phase II enzymes involved in the metabolism of drugs and hormones, the bioactivation of carcinogens, and the detoxification of xenobiotics. Knowledge of the structural and mechanistic basis of substrate specificity and activity is crucial for understanding steroid and hormone metabolism, drug sensitivity, pharmacogenomics, and response to environmental toxins. We have determined the crystal structures of five hSULTs for which structural information was lacking, and screened nine of the 12 hSULTs for binding and activity toward a panel of potential substrates and inhibitors, revealing unique “chemical fingerprints” for each protein. The family-wide analysis of the screening and structural data provides a comprehensive, high-level view of the determinants of substrate binding, the mechanisms of inhibition by substrates and environmental toxins, and the functions of the orphan family members SULT1C3 and SULT4A1. Evidence is provided for structural “priming” of the enzyme active site by cofactor binding, which influences the spectrum of small molecules that can bind to each enzyme. The data help explain substrate promiscuity in this family and, at the same time, reveal new similarities between hSULT family members that were previously unrecognized by sequence or structure comparison alone

ЛУЧЕВАЯ ДИАГНОСТИКА ПОРОКА РАЗВИТИЯ ПЕЧЕНИ

Hepatic malformations are rare. We review the pathogenesis, morphology, classification, clinical presentation, and diagnosis of these malformations. We report a case of an accessory hepatic lobe masquerading as an abdominal tumor and detected with multilayer spiral CT and MRI. We discuss diagnostic signs as well as advantages and limitations of the two methods. The diagnosis was verified by pathology following an unconventional laparoscopic resection of the left hepatic lobe.Пороки развития печени - редкая врожденная патология. В работе приведена краткая информация о механизме возникновения таких аномалий и морфологических формах, о классификациях, клинической картине и возможностях их распознавания. Представлено собственное наблюдение одного из пороков развития печени, а именно наличие добавочной доли печени у пациентки, симулирующей новообразование брюшной полости. Для его идентификации были применены мультиспиральная компьютерная томография и магнитно-резонансная томография. Описана лучевая семиотика выявленной патологии. Отмечены достоинства и ограничения этих методов. Окончательный диагноз был поставлен на основании результатов лапароскопической атипичной резекции левой доли печени и последующего гистологического исследования операционного материала

Structural Biology of Human H3K9 Methyltransferases

SET domain methyltransferases deposit methyl marks on specific histone tail lysine residues and play a major role in epigenetic regulation of gene transcription. We solved the structures of the catalytic domains of GLP, G9a, Suv39H2 and PRDM2, four of the eight known human H3K9 methyltransferases in their apo conformation or in complex with the methyl donating cofactor, and peptide substrates. We analyzed the structural determinants for methylation state specificity, and designed a G9a mutant able to tri-methylate H3K9. We show that the I-SET domain acts as a rigid docking platform, while induced-fit of the Post-SET domain is necessary to achieve a catalytically competent conformation. We also propose a model where long-range electrostatics bring enzyme and histone substrate together, while the presence of an arginine upstream of the target lysine is critical for binding and specificity. Enhanced version: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available i

The effect of climate change on avian offspring production: A global meta-analysis

Climate change affects timing of reproduction in many bird species, but few studies have investigated its influence on annual reproductive output. Here, we assess changes in the annual production of young by female breeders in 201 populations of 104 bird species (N = 745,962 clutches) covering all continents between 1970 and 2019. Overall, average offspring production has declined in recent decades, but considerable differences were found among species and populations. A total of 56.7% of populations showed a declining trend in offspring production (significant in 17.4%), whereas 43.3% exhibited an increase (significant in 10.4%). The results show that climatic changes affect offspring production through compounded effects on ecological and life history traits of species. Migratory and larger-bodied species experienced reduced offspring production with increasing temperatures during the chick-rearing period, whereas smaller-bodied, sedentary species tended to produce more offspring. Likewise, multi-brooded species showed increased breeding success with increasing temperatures, whereas rising temperatures were unrelated to repro- ductive success in single-brooded species. Our study suggests that rapid declines in size of bird populations reported by many studies from different parts of the world are driven only to a small degree by changes in the production of young

Losing the battle: perceived status loss and contemplated or attempted suicide in older adults

Objective: While loss of socioeconomic status (SES) has been linked to suicidal behavior, it is unclear whether this experience is merely a downstream effect of psychopathology (“downward drift”), a sign of hardship, or an independent psychological contributor to suicide risk. We examined the association between the subjective experience of status loss and suicidal behavior and ideation in old age, while accounting for potential confounders. We were also interested in whether status loss was associated with mere thoughts of suicide vs. suicidal behavior. Methods: Fifty older (55+) depressed suicide attempters, 29 depressed suicide ideators with no history of attempted suicide, 38 non-suicidal depressed participants and 45 non-psychiatric controls underwent detailed clinical characterization and reported their current and highest lifetime SES. Results: Suicide attempters were more likely to report a decline in their SES compared to healthy controls and non-suicidal depressed older adults, while not differing from suicide ideators. This difference was not explained by objective predictors of SES, including education, financial difficulties, and the presence of addiction. Interestingly, while the current SES of suicide attempters was much lower than that of comparison groups, their reported highest lifetime SES was just as high, despite the differences in education. Conclusion: In older adults, the experience of status loss is associated with contemplated and attempted suicide even after accounting for objective indicators of social status and psychopathology. It is possible that suicidal individuals retrospectively inflate their previous status, making their current standing appear even worse by comparison

Losing the battle: perceived status loss and contemplated or attempted suicide in older adults

Objective: While loss of socioeconomic status (SES) has been linked to suicidal behavior, it is unclear whether this experience is merely a downstream effect of psychopathology (“downward drift”), a sign of hardship, or an independent psychological contributor to suicide risk. We examined the association between the subjective experience of status loss and suicidal behavior and ideation in old age, while accounting for potential confounders. We were also interested in whether status loss was associated with mere thoughts of suicide vs. suicidal behavior. Methods: Fifty older (55+) depressed suicide attempters, 29 depressed suicide ideators with no history of attempted suicide, 38 non-suicidal depressed participants and 45 non-psychiatric controls underwent detailed clinical characterization and reported their current and highest lifetime SES. Results: Suicide attempters were more likely to report a decline in their SES compared to healthy controls and non-suicidal depressed older adults, while not differing from suicide ideators. This difference was not explained by objective predictors of SES, including education, financial difficulties, and the presence of addiction. Interestingly, while the current SES of suicide attempters was much lower than that of comparison groups, their reported highest lifetime SES was just as high, despite the differences in education. Conclusion: In older adults, the experience of status loss is associated with contemplated and attempted suicide even after accounting for objective indicators of social status and psychopathology. It is possible that suicidal individuals retrospectively inflate their previous status, making their current standing appear even worse by comparison