Hydrogenases catalyze oxidoreduction of molecular hydrogen and have potential applications for utilizing dihydrogen as an energy source. NiFe hydrogenase has two different oxidized states, Ni-A ...(unready, exhibits a lag phase in reductive activation) and Ni-B (ready). We have succeeded in converting Ni-B to Ni-A with the use of Na
2S and O
2 and determining the high-resolution crystal structures of both states. Ni-B possesses a monatomic nonprotein bridging ligand at the Ni-Fe active site, whereas Ni-A has a diatomic species. The terminal atom of the bridging species of Ni-A occupies a similar position as C of the exogenous CO in the CO complex (inhibited state). The common features of the enzyme structures at the unready (Ni-A) and inhibited (CO complex) states are proposed. These findings provide useful information on the design of new systems of biomimetic dihydrogen production and fuel cell devices.
The Aurora (Ipl1)-related kinases are universal regulators of mitosis. We now show that Aurora-A, in addition to Aurora-B, regulates kinetochore function in human cells. A two-hybrid screen ...identified the kinetochore component CENP-A as a protein that interacts with Aurora-A. Aurora-A phosphorylated CENP-A in vitro on Ser-7, a residue also known to be targeted by Aurora-B. Depletion of Aurora-A or Aurora-B by RNA interference revealed that CENP-A is initially phosphorylated in prophase in a manner dependent on Aurora-A, and that this reaction appears to be required for the subsequent Aurora-B-dependent phosphorylation of CENP-A as well as for the restriction of Aurora-B to the inner centromere in prometaphase. Prevention of CENP-A phosphorylation also led to chromosome misalignment during mitosis as a result of a defect in kinetochore attachment to microtubules. Our observations suggest that phosphorylation of CENP-A on Ser-7 by Aurora-A in prophase is essential for kinetochore function.
Tropical forests and savannas can co-occur in a range of macro-environmental conditions. In these conditions, disturbances and resource availability are thought to control savanna and forest ...transitions, although the mechanisms involved are disputed. We hypothesized that, in Neotropical regions where fire activity is high, fire is the main factor controlling functional differences between savanna and forest, as well as their relative resistance to biome shifts. We sampled plant functional traits and soil and determined fire history, for 198 plots distributed across three landscapes with distinct fire frequencies (high, mid, and low). In each landscape, plots covered a woody cover gradient (from wooded grasslands to forests). We tested whether the sharpness and the magnitude of the functional distinction between savanna and forest were affected by fire. We also computed the environmental hyperspace (niche space) to evaluate how biome relative stability changed in relation to fire. Functional thresholds were detected only in the high and mid landscapes, where savanna and forest plots formed a multidimensional bimodal distribution in functional trait space. The stability of savannas in relation to forest increased abruptly with fire, whereas functional differences between forest and savanna increased gradually. Our results suggest that savanna can occur as an alternative vegetation state to forest where a fire burns every 18 years (on average), but higher frequencies are required for savannas to occupy large unique portions of the environmental niche space.
Graphic Abstract
This photo was taken and provided by Rafael S. Oliveira, one of the authors.
Chronic exposure to cement dust may induce adverse health effects, including a significant decrease in lung function. The study investigated whether the prevalence of COPD and respiratory symptoms ...was associated with working at different tasks exposed to varying levels of cement dust. The cross-sectional study was carried out among 223 exposed and 156 less exposed workers from two cement factories from November 20 to December 15, 2016 in DRC. Workers completed a questionnaire and spirometry was performed. Multivariate analysis was performed to evaluate the association between occupation exposed to cement dust, COPD, and respiratory symptoms, after adjustment for confounders. Morning cough and cough on most days for as much as 3 months each year were significantly higher in the exposed group (
p
< 0.05) (
p
= 0.001) than in the less exposed group. As compared to the less exposed group, the prevalence of COPD was higher among the exposed group, 28.2 and 9.6% respectively (
p
< 0.001). A significant association with COPD, aOR 14.49 (5.33; 39.40), aOR 3.37 (1.44; 7.89), and aOR 3.09 (1.58; 6.05) was found among cleaning, transportation, and production workers, respectively. Working at certain tasks exposed to cement dust is associated with the higher prevalence of COPD and respiratory symptoms. A greater risk is being among cleaning, transportation, and production workers. This suggests the necessity to prioritize the quality of preventive measures in each work area.
Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer
. However, how such cycles affect the clonal composition of ...tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.
Abstract
Droughts are predicted to increase in both frequency and intensity by the end of the 21st century, but ecosystem response is not expected to be uniform across landscapes. Here we assess the ...importance of the hill-to-valley hydrologic gradient in shaping vegetation embolism resistance under different rainfall regimes using hydraulic functional traits. We demonstrate that rainfall and hydrology modulate together the embolism resistance of tree species in different sites and topographic positions. Although buffered by stable access to groundwater, valley plants are intrinsically more vulnerable to drought-induced embolism than those on hills. In all study sites, the variability in resistance to embolism is higher on hills than on valleys, suggesting that the diversity of strategies to cope with drought is more important for tree communities on hills. When comparing our results with previously published data across the tropics, we show greater variability at the local scale than previously reported. Our results reinforce the urgent need to extend sampling efforts across rainfall regimes and topographic positions to improve the characterization of ecosystem resistance to drought at finer spatial scales.
Platinum drugs and PARP inhibitors ("PARPis") are considered to be effective in BRCA-associated cancers with impaired DNA repair. These agents cause stalled and collapsed replication forks and create ...double-strand breaks effectively in the absence of repair mechanisms, resulting in arrest of the cell cycle and induction of cell death. However, recent studies have shown failure of these chemotherapeutic agents due to emerging drug resistance. In this study, we developed a stochastic model of BRCA-associated cancer progression in which there are four cancer populations: those with (i) functional BRCA, (ii) dysfunctional BRCA, (iii) functional BRCA and a growth advantage, and (iv) dysfunctional BRCA and a growth advantage. These four cancer populations expand from one cancer cell with normal repair function until the total cell number reaches a detectable amount. We derived formulas for the probability and expected numbers of each population at the time of detection. Furthermore, we extended the model to consider the tumor dynamics during treatment. Results from the model were validated and showed good agreement with clinical and experimental evidence in BRCA-associated cancers. Based on the model, we investigated conditions in which drug resistance during the treatment course originated from either a pre-existing drug-resistant population or a de novo population, due to secondary mutations. Finally, we found that platinum drugs and PARPis were effective if (i) BRCA inactivation is present, (ii) the cancer was diagnosed early, and (iii) tumor growth is rapid. Our results indicate that different types of cancers have a preferential way of acquiring resistance to platinum drugs and PARPis according to their growth and mutational characteristics.
Serine protease inhibitor Kazal type 1 (SPINK1), which is structurally similar to epidermal growth factor, is thought to inhibit trypsin activity and to prevent pancreatitis. Point mutations in the ...SPINK1 gene seem to predispose humans to pancreatitis; however, the clinical significance of SPINK1 mutations remains controversial. This study aimed to elucidate the role of SPINK1.
We generated Spink3-deficient (Spink3(-/-)) mice by gene targeting in mouse embryonic stem cells. Embryonic and neonatal pancreases were analyzed morphologically and molecularly. Specific probes were used to show the typical autophagy that occurs during acinar cell death.
In Spink3(-/-) mice, the pancreas developed normally up to 15.5 days after coitus. However, autophagic degeneration of acinar cells, but not ductal or islet cells, started from day 16.5 after coitus. Rapid onset of cell death occurred in the pancreas and duodenum within a few days after birth and resulted in death by 14.5 days after birth. There was limited inflammatory cell infiltration and no sign of apoptosis. At 7.5 days after birth, residual ductlike cells in the tubular complexes strongly expressed pancreatic duodenal homeodomain-containing protein 1, a marker of pancreatic stem cells, without any sign of acinar cell regeneration.
The progressive disappearance of acinar cells in Spink3(-/-) mice was due to autophagic cell death and impaired regeneration. Thus, Spink3 has essential roles in the maintenance of integrity and regeneration of acinar cells.
Despite the necessity of optical coherence tomography (OCT) for diagnosis and longitudinal monitoring in patients with Vogt-Koyanagi-Harada (VKH) disease, no studies have identified useful OCT ...markers for predicting recurrence in these patients. Although the precise reason for this remains unclear, one possibility is that infiltration of inflammatory cells into the choroid attenuates the OCT signal, making it difficult to precisely assess the structure of the choroid. Therefore, this study aimed to investigate changes in retinal pigment epithelium (RPE) reflectivity immediately above the choroid in eyes with acute VKH disease, as well as the association between RPE reflectivity and VKH disease recurrence.
This single-centered retrospective observational study included 20 treatment-naïve patients with acute VKH disease presenting with serous retinal detachment (SRD) in the posterior pole at the initial visit between October 2015 and January 2020, as well as 15 healthy control eyes. All patients were followed up for at least 6 months and received treatment with intravenous methylprednisolone followed by oral administration of prednisolone. Swept-source OCT images through the fovea were used to measure central retinal thickness, central choroidal thickness, and RPE reflectivity.
During an observation period of 37.2 ± 30.8 months, recurrence of inflammation was observed in 11 patients (55.0%). Initial visual acuity was worse in patients who developed recurrence than in those who did not (
=0.024). On initial OCT images, RPE reflectivity differed significantly between patients with and without recurrence (1.75 ± 0.42 vs 1.35 ± 0.20;
=0.018), while there were no significant differences in other chorioretinal parameters, such as central retinal thickness and choroidal thickness.
RPE reflectivity on OCT images may be useful for predicting the recurrence of inflammation in patients with VKH disease.
RAD51 recombinase polymerizes at the site of double-strand breaks (DSBs) where it performs DSB repair. The loss of RAD51 causes extensive chromosomal breaks, leading to apoptosis. The polymerization ...of RAD51 is regulated by a number of RAD51 mediators, such as BRCA1, BRCA2, RAD52, SFR1, SWS1, and the five RAD51 paralogs, including XRCC3. We here show that brca2-null mutant cells were able to proliferate, indicating that RAD51 can perform DSB repair in the absence of BRCA2. We disrupted the BRCA1, RAD52, SFR1, SWS1, and XRCC3 genes in the brca2-null cells. All the resulting double-mutant cells displayed a phenotype that was very similar to that of the brca2-null cells. We suggest that BRCA2 might thus serve as a platform to recruit various RAD51 mediators at the appropriate position at the DNA-damage site.
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