UV-sensitive syndrome (UV(S)S) is an autosomal recessive disorder characterized by photosensitivity and deficiency in transcription-coupled repair (TCR), a subpathway of nucleotide-excision repair ...that rapidly removes transcription-blocking DNA damage. Cockayne syndrome is a related disorder with defective TCR and consists of two complementation groups, Cockayne syndrome (CS)-A and CS-B, which are caused by mutations in ERCC8 (CSA) and ERCC6 (CSB), respectively. UV(S)S comprises three groups, UV(S)S/CS-A, UV(S)S/CS-B and UV(S)S-A, caused by mutations in ERCC8, ERCC6 and an unidentified gene, respectively. Here, we report the cloning of the gene mutated in UV(S)S-A by microcell-mediated chromosome transfer. The predicted human gene UVSSA (formerly known as KIAA1530)(7) corrects defective TCR in UV(S)S-A cells. We identify three nonsense and frameshift UVSSA mutations in individuals with UV(S)S-A, indicating that UVSSA is the causative gene for this syndrome. The UVSSA protein forms a complex with USP7 (ref. 8), stabilizes ERCC6 and restores the hypophosphorylated form of RNA polymerase II after UV irradiation.
Hydrogen is an established anti-oxidant that prevents acute oxidative stress. To clarify the mechanism of hydrogen’s effect in the brain, we administered hydrogen-rich pure water (H
2) to senescence ...marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice, which cannot synthesize vitamin C (VC), also a well-known anti-oxidant. These KO mice were divided into three groups; recipients of H
2, VC, or pure water (H
2O), administered for 33 days. VC levels in H
2 and H
2O groups were <6% of those in the VC group. Subsequently, superoxide formation during hypoxia-reoxygenation treatment of brain slices from these groups was estimated by a real-time biography imaging system, which models living brain tissues, with Lucigenin used as chemiluminescence probe for superoxide. A significant 27.2% less superoxide formed in the H
2 group subjected to ischemia–reperfusion than in the H
2O group. Thus hydrogen-rich pure water acts as an anti-oxidant in the brain slices and prevents superoxide formation.
The spatial organization of gut microbiota is crucial for the functioning of the gut ecosystem, although the mechanisms that organize gut bacterial communities in microhabitats are only partially ...understood. The gut of the insect Riptortus pedestris has a characteristic microbiota biogeography with a multispecies community in the anterior midgut and a monospecific bacterial population in the posterior midgut. We show that the posterior midgut region produces massively hundreds of specific antimicrobial peptides (AMPs), the Crypt-specific Cysteine-Rich peptides (CCRs) that have membrane-damaging antimicrobial activity against diverse bacteria but posterior midgut symbionts have elevated resistance. We determined by transposon-sequencing the genetic repertoire in the symbiont Caballeronia insecticola to manage CCR stress, identifying different independent pathways, including AMP-resistance pathways unrelated to known membrane homeostasis functions as well as cell envelope functions. Mutants in the corresponding genes have reduced capacity to colonize the posterior midgut, demonstrating that CCRs create a selective barrier and resistance is crucial in gut symbionts. Moreover, once established in the gut, the bacteria differentiate into a CCR-sensitive state, suggesting a second function of the CCR peptide arsenal in protecting the gut epithelia or mediating metabolic exchanges between the host and the gut symbionts. Our study highlights the evolution of an extreme diverse AMP family that likely contributes to establish and control the gut microbiota.
Heart-kidney crosstalk is recognized as the cardiorenal syndrome. We examined the association of cardiac function and structure with the risk of kidney failure with replacement therapy (KFRT) in a ...chronic kidney disease (CKD) population.
Prospective observational cohort study.
3,027 participants from the Chronic Renal Insufficiency Cohort Study.
Five preselected variables that assess different aspects of cardiac structure and function: left ventricular mass index (LVMI), LV volume, left atrial (LA) area, peak tricuspid regurgitation (TR) velocity, and left ventricular ejection fraction (EF) as assessed by echocardiography.
Incident KFRT (primary outcome), and annual estimated glomerular filtration rate (eGFR) slope (secondary outcome).
Multivariable Cox models and mixed-effects models.
The mean age of the participants was 59±11 SD years, 54% were men, and mean eGFR was 43±17mL/min/1.73m2. Between 2003 and 2018 (median follow-up, 9.9 years), 883 participants developed KFRT. Higher LVMI, LV volume, LA area, peak TR velocity, and lower EF were each statistically significantly associated with an increased risk of KFRT, with corresponding HRs for the highest versus lowest quartiles (lowest vs highest for EF) of 1.70 (95% CI, 1.27-2.26), 1.50 (95% CI, 1.19-1.90), 1.43 (95% CI, 1.11-1.84), 1.45 (95% CI, 1.06-1.96), and 1.26 (95% CI, 1.03-1.56), respectively. For the secondary outcome, participants in the highest versus lowest quartiles (lowest vs highest for EF) had a statistically significantly faster eGFR decline, except for LA area (ΔeGFR slope per year, −0.57 95% CI, −0.68 to−0.46 mL/min/1.73m2 for LVMI, −0.25 95% CI, −0.35 to−0.15 mL/min/1.73m2 for LV volume, −0.01 95% CI, −0.12 to−0.01 mL/min/1.73m2 for LA area, −0.42 95% CI, −0.56 to−0.28 mL/min/1.73m2 for peak TR velocity, and −0.11 95% CI, −0.20 to−0.01 mL/min/1.73m2 for EF, respectively).
The possibility of residual confounding.
Multiple aspects of cardiac structure and function were statistically significantly associated with the risk of KFRT. These findings suggest that cardiac abnormalities and incidence of KFRT are potentially on the same causal pathway related to the interaction between hypertension, heart failure, and coronary artery diseases.
Heart disease and kidney disease are known to interact with each other. In this study, we examined whether cardiac abnormalities, as assessed by echocardiography, were linked to the subsequent progression of kidney disease among people living with chronic kidney disease (CKD). We found that people with abnormalities in heart structure and function had a greater risk of progression to advanced CKD that required kidney replacement therapy and had a faster rate of decline in kidney function. Our study indicates the potential role of abnormal heart structure and function in the progression of kidney disease among people living with CKD.
Cytochrome c oxidase (CcO) is a large membrane-bound hemeprotein that catalyzes the reduction of dioxygen to water. Unlike classical dioxygen binding hemeproteins with a heme b group in their active ...sites, CcO has a unique binuclear center (BNC) composed of a copper atom (CuB) and a heme a 3 iron, where O2 binds and is reduced to water. CO is a versatile O2 surrogate in ligand binding and escape reactions. Previous time-resolved spectroscopic studies of the CO complexes of bovine CcO (bCcO) revealed that photolyzing CO from the heme a 3 iron leads to a metastable intermediate (CuB-CO), where CO is bound to CuB, before it escapes out of the BNC. Here, with a pump-probe based time-resolved serial femtosecond X-ray crystallography, we detected a geminate photoproduct of the bCcO–CO complex, where CO is dissociated from the heme a 3 iron and moved to a temporary binding site midway between the CuB and the heme a 3 iron, while the locations of the two metal centers and the conformation of Helix-X, housing the proximal histidine ligand of the heme a 3 iron, remain in the CO complex state. This new structure, combined with other reported structures of bCcO, allows for a clearer definition of the ligand dissociation trajectory as well as the associated protein dynamics.
Little information is available regarding incidence and severity of pulmonary embolism (PE) across the periods of ancestral strain, Alpha, Delta, and Omicron variants. The aim of this study is to ...investigate the incidence and severity of PE over the dominant periods of ancestral strain and Alpha, Delta, and Omicron variants. We hypothesized that the incidence and the severity by proximity of PE in patients with the newer variants and vaccination would be decreased compared with those in ancestral and earlier variants. Patients with COVID-19 diagnosis between March 2020 and February 2022 and computed tomography pulmonary angiogram performed within a 6-week window around the diagnosis (-2 to +4 weeks) were studied retrospectively. The primary endpoints were the associations of the incidence and location of PE with the ancestral strain and each variant. Of the 720 coronavirus disease 2019 patients with computed tomography pulmonary angiogram (58.6 ± 17.2 years; 374 females), PE was diagnosed among 42/358 (12%) during the ancestral strain period, 5/60 (8%) during the Alpha variant period, 16/152 (11%) during the Delta variant period, and 13/150 (9%) during the Omicron variant period. The most proximal PE (ancestral strain vs variants) was located in the main/lobar arteries (31% vs 6%-40%), in the segmental arteries (52% vs 60%-75%), and in the subsegmental arteries (17% vs 0%-19%). There was no significant difference in both the incidence and location of PE across the periods, confirmed by multivariable logistic regression models. In summary, the incidence and severity of PE did not significantly differ across the periods of ancestral strain and Alpha, Delta, and Omicron variants.
PDF
