Quantitative Analysis of Pedogenic Thresholds and Domains in Volcanic Soils

Ecosystems - Pedogenic thresholds describe where soil properties or processes change in an abrupt/nonlinear fashion in response to small changes in environmental forcing. Contrastingly, soil...     

Thermodynamics of neutral protein evolution

Naturally evolving proteins gradually accumulate mutations while continuing to fold to stable structures. This process of neutral evolution is an important mode of genetic change and forms the basis for the molecular clock. We present a mathematical theory that predicts the number of accumulated mutations, the index of dispersion, and the distribution of stabilities in an evolving protein population from knowledge of the stability effects (delta deltaG values) for single mutations. Our theory quantitatively describes how neutral evolution leads to marginally stable proteins and provides formulas for calculating how fluctuations in stability can overdisperse the molecular clock. It also shows that the structural influences on the rate of sequence evolution observed in earlier simulations can be calculated using just the single-mutation delta deltaG values. We consider both the case when the product of the population size and mutation rate is small and the case when this product is large, and show that in the latter case the proteins evolve excess mutational robustness that is manifested by extra stability and an increase in the rate of sequence evolution. All our theoretical predictions are confirmed by simulations with lattice proteins. Our work provides a mathematical foundation for understanding how protein biophysics shapes the process of evolution.     

Slow base excision by human alkyladenine DNA glycosylase limits the rate of formation of AP sites and AP endonuclease 1 does not stimulate base excision

The base excision repair pathway removes damaged DNA bases and resynthesizes DNA to replace the damage. Human alkyladenine DNA glycosylase (AAG) is one of several damage-specific DNA glycosylases that recognizes and excises damaged DNA bases. AAG removes primarily damaged adenine residues. Human AP endonuclease 1 (APE1) recognizes AP sites produced by DNA glycosylases and incises the phophodiester bond 5' to the damaged site. The repair process is completed by a DNA polymerase and DNA ligase. If not tightly coordinated, base excision repair could generate intermediates that are more deleterious to the cell than the initial DNA damage. The kinetics of AAG-catalyzed excision of two damaged bases, hypoxanthine and 1,N6-ethenoadenine, were measured in the presence and absence of APE1 to investigate the mechanism by which the base excision activity of AAG is coordinated with the AP incision activity of APE1. 1,N6-ethenoadenine is excised significantly slower than hypoxanthine and the rate of excision is not affected by APE1. The excision of hypoxanthine is inhibited to a small degree by accumulated product, and APE1 stimulates multiple turnovers by alleviating product inhibition. These results show that APE1 does not significantly affect the kinetics of base excision by AAG. It is likely that slow excision by AAG limits the rate of AP site formation in vivo such that AP sites are not created faster than can be processed by APE1.     

Hypertension awareness,treatment, and control and their association with healthcare access in the middle-aged and older Indian population: A nationwide cohort study

BackgroundHypertension is the most important cardiovascular risk factor in India, and representative studies of middle-aged and older Indian adults have been lacking. Our objectives were to estimate the proportions of hypertensive adults who had been diagnosed, took antihypertensive medication, and achieved control in the middle-aged and older Indian population and to investigate the association between access to healthcare and hypertension management.Methods and findingsWe designed a nationally representative cohort study of the middle-aged and older Indian population, the Longitudinal Aging Study in India (LASI), and analyzed data from the 2017–2019 baseline wave (N = 72,262) and the 2010 pilot wave (N = 1,683). Hypertension was defined as self-reported physician diagnosis or elevated blood pressure (BP) on measurement, defined as systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg. Among hypertensive individuals, awareness, treatment, and control were defined based on self-reports of having been diagnosed, taking antihypertensive medication, and not having elevated BP, respectively. The estimated prevalence of hypertension for the Indian population aged 45 years and older was 45.9% (95% CI 45.4%–46.5%). Among hypertensive individuals, 55.7% (95% CI 54.9%–56.5%) had been diagnosed, 38.9% (95% CI 38.1%–39.6%) took antihypertensive medication, and 31.7% (95% CI 31.0%–32.4%) achieved BP control. In multivariable logistic regression models, access to public healthcare was a key predictor of hypertension treatment (odds ratio [OR] = 1.35, 95% CI 1.14–1.60, p = 0.001), especially in the most economically disadvantaged group (OR of the interaction for middle economic status = 0.76, 95% CI 0.61–0.94, p = 0.013; OR of the interaction for high economic status = 0.84, 95% CI 0.68–1.05, p = 0.124). Having health insurance was not associated with improved hypertension awareness among those with low economic status (OR = 0.96, 95% CI 0.86–1.07, p = 0.437) and those with middle economic status (OR of the interaction = 1.15, 95% CI 1.00–1.33, p = 0.051), but it was among those with high economic status (OR of the interaction = 1.28, 95% CI 1.10–1.48, p = 0.001). Comparing hypertension awareness, treatment, and control rates in the 4 pilot states, we found statistically significant (p < 0.001) improvement in hypertension management from 2010 to 2017–2019. The limitations of this study include the pilot sample being relatively small and that it recruited from only 4 states.ConclusionsAlthough considerable variations in hypertension diagnosis, treatment, and control exist across different sociodemographic groups and geographic areas, reducing uncontrolled hypertension remains a public health priority in India. Access to healthcare is closely tied to both hypertension diagnosis and treatment.

Jinkook Lee and colleagues investigate hypertension management and its association with healthcare access in middle-aged and older adults in India.     

Inhibition of H3K27me3-Specific Histone Demethylases JMJD3 and UTX Blocks Reactivation of Herpes Simplex Virus 1 in Trigeminal Ganglion Neurons

Herpes simplex virus 1 (HSV-1) genomes are associated with the repressive heterochromatic marks H3K9me2/me3 and H3K27me3 during latency. Previous studies have demonstrated that inhibitors of H3K9me2/me3 histone demethylases reduce the ability of HSV-1 to reactivate from latency. Here we demonstrate that GSK-J4, a specific inhibitor of the H3K27me3 histone demethylases UTX and JMJD3, inhibits HSV-1 reactivation from sensory neurons in vitro. These results indicate that removal of the H3K27me3 mark plays a key role in HSV-1 reactivation.     

Granulysin, a T cell product, kills bacteria by altering membrane permeability

Granulysin, a protein located in the acidic granules of human NK cells and cytotoxic T cells, has antimicrobial activity against a broad spectrum of microbial pathogens. A predicted model generated from the nuclear magnetic resonance structure of a related protein, NK lysin, suggested that granulysin contains a four alpha helical bundle motif, with the alpha helices enriched for positively charged amino acids, including arginine and lysine residues. Denaturation of the polypeptide reduced the alpha helical content from 49 to 18% resulted in complete inhibition of antimicrobial activity. Chemical modification of the arginine, but not the lysine, residues also blocked the antimicrobial activity and interfered with the ability of granulysin to adhere to Escherichia coli and Mycobacterium tuberculosis. Granulysin increased the permeability of bacterial membranes, as judged by its ability to allow access of cytosolic ss-galactosidase to its impermeant substrate. By electron microscopy, granulysin triggered fluid accumulation in the periplasm of M. tuberculosis, consistent with osmotic perturbation. These data suggest that the ability of granulysin to kill microbial pathogens is dependent on direct interaction with the microbial cell wall and/or membrane, leading to increased permeability and lysis.     

Dyskerin,tRNA genes,and condensin tether pericentric chromatin to the spindle axis in mitosis

Condensin is enriched in the pericentromere of budding yeast chromosomes where it is constrained to the spindle axis in metaphase. Pericentric condensin contributes to chromatin compaction, resistance to microtubule-based spindle forces, and spindle length and variance regulation. Condensin is clustered along the spindle axis in a heterogeneous fashion. We demonstrate that pericentric enrichment of condensin is mediated by interactions with transfer ribonucleic acid (tRNA) genes and their regulatory factors. This recruitment is important for generating axial tension on the pericentromere and coordinating movement between pericentromeres from different chromosomes. The interaction between condensin and tRNA genes in the pericentromere reveals a feature of yeast centromeres that has profound implications for the function and evolution of mitotic segregation mechanisms.     

Stable kinetochore-microtubule attachment constrains centromere positioning in metaphase

With a single microtubule attachment, budding-yeast kinetochores provide an excellent system for understanding the coordinated linkage to dynamic microtubule plus ends for chromosome oscillation and positioning. Fluorescent tagging of kinetochore proteins indicates that, on average, all centromeres are clustered, distinctly separated from their sisters, and positioned equidistant from their respective spindle poles during metaphase. However, individual fluorescent chromosome markers near the centromere transiently reassociate with their sisters and oscillate from one spindle half to the other. To reconcile the apparent disparity between the average centromere position and individual centromere proximal markers, we utilized fluorescence recovery after photobleaching to measure stability of the histone-H3 variant Cse4p/CENP-A. Newly synthesized Cse4p replaces old protein during DNA replication. Once assembled, Cse4-GFP is a physically stable component of centromeres during mitosis. This allowed us to follow centromere dynamics within each spindle half. Kinetochores remain stably attached to dynamic microtubules and exhibit a low incidence of switching orientation or position between the spindle halves. Switching of sister chromatid attachment may be contemporaneous with Cse4p exchange and early kinetochore assembly during S phase; this would promote mixing of chromosome attachment to each spindle pole. Once biorientation is attained, centromeres rarely make excursions beyond their proximal half spindle.     

The 15 N-terminal amino acids of hexokinase II are not required for in vivo function: analysis of a truncated form of hexokinase II in Saccharomyces cerevisiae

The function of the N-terminal amino acids of Saccharomyces cerevisiae hexokinase II was studied in vivo using strains producing a form of hexokinase II lacking its first 15 amino acids (short form). This short form of hexokinase II was produced from a fusion between the promoter region of the PGK1 gene and the HXK2 coding sequence except the first 15 codons. As expected, the in vitro analysis of the short form protein by gel filtration chromatography indicates that the short protein does not form dimers under conditions where the wild-type protein dimerizes. Kinetic studies show that the enzymatic activities are very similar to wild-type behavior. The physiological experiments performed on the strains containing the fusion allele demonstrate that the short form of the enzyme is similar to the wild-type both in terms of phosphorylation of hexoses and glucose repression. We conclude that the N-terminal amino acids of hexokinase II are not required in vivo either for phosphorylation of hexoses or for glucose repression.     

Physiological, chemical, morphological, and plant infectivity characteristics of Frankia isolates from Myrica pennsylvanica: correlation to DNA restriction patterns.

The filter exclusion method was used to isolate Frankia strains from Myrica pennsylvanica (bayberry) root nodules collected at diverse sites in New Jersey. A total of 16 isolates from five locations were cultured. The isolates were characterized by morphological, chemical, physiological, and plant infectivity criteria and compared with genomic DNA restriction pattern data, which were used to assign the isolates into gel groups (see accompanying paper). The isolates from M. pennsylvanica evaluated in this study were characteristic of Frankia physiological group B strains and were indistinguishable on the basis of whole-cell wall chemistry and diaminopimelic acid isomer analysis. Distinct differences in the spectrum of utilized organic acids and carbohydrates were observed among the isolates and were the only phenotypic criteria by which the isolates could be separated and assigned into separate groups. In general, isolates within a restriction pattern gel group had identical utilization patterns, whereas intragroup isolates had different utilization patterns. Correlation of these phenotypic characteristics with the results of molecular analysis revealed an exclusive carbohydrate and organic acid utilization pattern for each gel group as established by restriction pattern analysis.