Display omitted
•Triazole-based ‘click’ chemistry is a versatile tool in ligand design.•Triazole-based ligands enable access to rich coordination chemistry.•Facile tuning of photophysical luminescent ...properties through ‘click’ chemistry design.•Diverse applications from cellular imaging to light-emitting and photovoltaic devices.•Triazole-based ligand enables access to highly novel photochemistry.
The copper-catalysed cycloaddition of alkynes and azides to form 1,2,3-triazoles has emerged as a powerful tool in ligand design and the synthesis of novel transition metal complexes. In this review we focus on the photophysical properties of metal complexes bearing 1,2,3-triazole-based ligands with a particular emphasis on those of d6 metals including rhenium(I), iron(II), ruthenium(II), osmium(II) and iridium(III). We also highlight key examples of triazole complexes of platinum(II) and palladium(II) as well as the lanthanides and coinage metals.
Long COVID remains a broadly defined syndrome, with estimates of prevalence and duration varying widely. We use data from rounds 3-5 of the REACT-2 study (n = 508,707; September 2020 - February ...2021), a representative community survey of adults in England, and replication data from round 6 (n = 97,717; May 2021) to estimate the prevalence and identify predictors of persistent symptoms lasting 12 weeks or more; and unsupervised learning to cluster individuals by reported symptoms. At 12 weeks in rounds 3-5, 37.7% experienced at least one symptom, falling to 21.6% in round 6. Female sex, increasing age, obesity, smoking, vaping, hospitalisation with COVID-19, deprivation, and being a healthcare worker are associated with higher probability of persistent symptoms in rounds 3-5, and Asian ethnicity with lower probability. Clustering analysis identifies a subset of participants with predominantly respiratory symptoms. Managing the long-term sequelae of COVID-19 will remain a major challenge for affected individuals and their families and for health services.
The sensitivity of both nuclear magnetic resonance spectroscopy and magnetic resonance imaging is very low because the detected signal strength depends on the small population difference between spin ...states even in high magnetic fields. Hyperpolarization methods can be used to increase this difference and thereby enhance signal strength. This has been achieved previously by incorporating the molecular spin singlet para-hydrogen into hydrogenation reaction products. We show here that a metal complex can facilitate the reversible interaction of para-hydrogen with a suitable organic substrate such that up to an 800-fold increase in proton, carbon, and nitrogen signal strengths are seen for the substrate without its hydrogenation. These polarized signals can be selectively detected when combined with methods that suppress background signals.
Sixteen ovarian tumor (OTU) family deubiquitinases (DUBs) exist in humans, and most members regulate cell-signaling cascades. Several OTU DUBs were reported to be ubiquitin (Ub) chain linkage ...specific, but comprehensive analyses are missing, and the underlying mechanisms of linkage specificity are unclear. Using Ub chains of all eight linkage types, we reveal that most human OTU enzymes are linkage specific, preferring one, two, or a defined subset of linkage types, including unstudied atypical Ub chains. Biochemical analysis and five crystal structures of OTU DUBs with or without Ub substrates reveal four mechanisms of linkage specificity. Additional Ub-binding domains, the ubiquitinated sequence in the substrate, and defined S1’ and S2 Ub-binding sites on the OTU domain enable OTU DUBs to distinguish linkage types. We introduce Ub chain restriction analysis, in which OTU DUBs are used as restriction enzymes to reveal linkage type and the relative abundance of Ub chains on substrates.
Display omitted
•The 16 human OTU DUBs cleave distinct sets of ubiquitin chain types•Five crystal structures of three human OTU DUBs reveal uncharacterized Ub-binding sites•We reveal four distinct mechanisms of linkage specificity in OTU DUBs•OTU DUBs can be used to identify the linkage types on a ubiquitinated substrate
OTU deubiquitinases use four distinct mechanisms of linkage specificity to hydrolyze ubiquitin, and, due to their specificity, OTU DUBs can be used in ubiquitin chain restriction analysis to characterize the chain types on ubiquitinated proteins.
Cellular uptake, luminescence imaging and antimicrobial activity against clinically relevant methicillin-resistant
S. aureus
(MRSA) bacteria are reported. The osmium(
ii
) complexes Os(
N
^
N
)
3
2+
...(
N
^
N
= 1-benzyl-4-(pyrid-2-yl)-1,2,3-triazole (
1
2+
); 1-benzyl-4-(pyrimidin-2-yl)-1,2,3-triazole (
2
2+
); 1-benzyl-4-(pyrazin-2-yl)-1,2,3-triazole (
3
2+
)) were prepared and isolated as the chloride salts of their meridional and facial isomers. The complexes display prominent spin-forbidden ground state to triplet metal-to-ligand charge transfer (
3
MLCT) state absorption bands enabling excitation as low as 600 nm for
fac
/
mer
-
3
2+
and observation of emission in aqueous solution in the deep-red/near-IR regions of the spectrum. Cellular uptake studies within MRSA cells show antimicrobial activity for
1
2+
and
2
2+
with greater toxicity for the meridional isomers in each case and
mer
-
1
2+
showing the greatest potency (32 μg mL
−1
in defined minimal media). Super-resolution imaging experiments demonstrate binding of
mer
- and
fac
-
1
2+
to bacterial DNA with high Pearson's colocalisation coefficients (up to 0.95 using DAPI). Phototoxicity studies showed the complexes exhibited a higher antimicrobial activity upon irradiation with light.
Cellular uptake, luminescence imaging and antimicrobial activity of facial and meridional isomers of Os(
ii
) triazole-based complexes against methicillin-resistant
S. aureus
, MRSA.
Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of ...middle and old age.
The incremental value of polygenic risk scores in addition to well-established risk prediction models for coronary artery disease (CAD) is uncertain.
To examine whether a polygenic risk score for CAD ...improves risk prediction beyond pooled cohort equations.
Observational study of UK Biobank participants enrolled from 2006 to 2010. A case-control sample of 15 947 prevalent CAD cases and equal number of age and sex frequency-matched controls was used to optimize the predictive performance of a polygenic risk score for CAD based on summary statistics from published genome-wide association studies. A separate cohort of 352 660 individuals (with follow-up to 2017) was used to evaluate the predictive accuracy of the polygenic risk score, pooled cohort equations, and both combined for incident CAD.
Polygenic risk score for CAD, pooled cohort equations, and both combined.
CAD (myocardial infarction and its related sequelae). Discrimination, calibration, and reclassification using a risk threshold of 7.5% were assessed.
In the cohort of 352 660 participants (mean age, 55.9 years; 205 297 women 58.2%) used to evaluate the predictive accuracy of the examined models, there were 6272 incident CAD events over a median of 8 years of follow-up. CAD discrimination for polygenic risk score, pooled cohort equations, and both combined resulted in C statistics of 0.61 (95% CI, 0.60 to 0.62), 0.76 (95% CI, 0.75 to 0.77), and 0.78 (95% CI, 0.77 to 0.79), respectively. The change in C statistic between the latter 2 models was 0.02 (95% CI, 0.01 to 0.03). Calibration of the models showed overestimation of risk by pooled cohort equations, which was corrected after recalibration. Using a risk threshold of 7.5%, addition of the polygenic risk score to pooled cohort equations resulted in a net reclassification improvement of 4.4% (95% CI, 3.5% to 5.3%) for cases and -0.4% (95% CI, -0.5% to -0.4%) for noncases (overall net reclassification improvement, 4.0% 95% CI, 3.1% to 4.9%).
The addition of a polygenic risk score for CAD to pooled cohort equations was associated with a statistically significant, yet modest, improvement in the predictive accuracy for incident CAD and improved risk stratification for only a small proportion of individuals. The use of genetic information over the pooled cohort equations model warrants further investigation before clinical implementation.
Methionine-1 (M1)-linked ubiquitin chains regulate the activity of NF-κB, immune homeostasis, and responses to infection. The importance of negative regulators of M1-linked chains in vivo remains ...poorly understood. Here, we show that the M1-specific deubiquitinase OTULIN is essential for preventing TNF-associated systemic inflammation in humans and mice. A homozygous hypomorphic mutation in human OTULIN causes a potentially fatal autoinflammatory condition termed OTULIN-related autoinflammatory syndrome (ORAS). Four independent OTULIN mouse models reveal that OTULIN deficiency in immune cells results in cell-type-specific effects, ranging from over-production of inflammatory cytokines and autoimmunity due to accumulation of M1-linked polyubiquitin and spontaneous NF-κB activation in myeloid cells to downregulation of M1-polyubiquitin signaling by degradation of LUBAC in B and T cells. Remarkably, treatment with anti-TNF neutralizing antibodies ameliorates inflammation in ORAS patients and rescues mouse phenotypes. Hence, OTULIN is critical for restraining life-threatening spontaneous inflammation and maintaining immune homeostasis.
Display omitted
•Mutation of OTULIN causes OTULIN-related autoinflammatory syndrome (ORAS) in humans•Anti-TNF treatment reverses inflammation in ORAS patient and OTULIN-deficient mice•OTULIN deficiency deregulates M1-polyUb signaling and causes sterile inflammation•Loss of OTULIN has cell-type-specific effects on LUBAC abundance and signaling
A homozygous hypomorphic mutation in the deubiquitinase OTULIN causes a potentially fatal autoinflammatory disorder, which is reconciled in mouse models.
The linear ubiquitin chain assembly complex (LUBAC) regulates immune signaling, and its function is regulated by the deubiquitinases OTULIN and CYLD, which associate with the catalytic subunit HOIP. ...However, the mechanism through which CYLD interacts with HOIP is unclear. We here show that CYLD interacts with HOIP via spermatogenesis-associated protein 2 (SPATA2). SPATA2 interacts with CYLD through its non-canonical PUB domain, which binds the catalytic CYLD USP domain in a CYLD B-box-dependent manner. Significantly, SPATA2 binding activates CYLD-mediated hydrolysis of ubiquitin chains. SPATA2 also harbors a conserved PUB-interacting motif that selectively docks into the HOIP PUB domain. In cells, SPATA2 is recruited to the TNF receptor 1 signaling complex and is required for CYLD recruitment. Loss of SPATA2 increases ubiquitination of LUBAC substrates and results in enhanced NOD2 signaling. Our data reveal SPATA2 as a high-affinity binding partner of CYLD and HOIP, and a regulatory component of LUBAC-mediated NF-κB signaling.
Display omitted
•CYLD recruitment to LUBAC and the TNF receptor 1 complex is mediated by SPATA2•SPATA2 forms a high-affinity complex with CYLD and stimulates CYLD’s activity•SPATA2, like OTULIN, uses a conserved PIM to dock to the HOIP PUB domain•SPATA2 limits ubiquitination of LUBAC substrates to regulate inflammatory signaling
Elliott et al. show that SPATA2 bridges CYLD with LUBAC to regulate substrate ubiquitination and inflammatory signaling. Structural and biochemical work defines SPATA2-CYLD and SPATA2-HOIP interfaces, reveals SPATA2-mediated CYLD activation, and provides first insights into stoichiometry of LUBAC complexes.
PDF
