Recent developments in translational imaging of in vivo gene therapy outcomes.

Gene therapy achieves therapeutic benefits by delivering genetic materials, packaged within a delivery vehicle, to target cells with defective genes. This approach has shown promise in treating various conditions, including cancer, metabolic disorders, and tissue-degenerative diseases. Over the past 5 years, molecular imaging has increasingly supported gene therapy development in both preclinical and clinical studies.

Novel Quantification Protocol for Cardiovascular Calcification Progression Using Longitudinal MicroPET/MicroCT Images.

Micro positron emission tomography (PET) and micro computed tomography (CT) imaging are powerful, ideal research tools for following the progression of cardiovascular calcification. Due to their non-invasive nature, small research animals can be imaged at multiple time points. The challenge lies in the accurate quantification of cardiovascular calcification.

Fluorescence of Half-Twisted 10-Acyl-1-methyltetrahydrobenzoquinolines.

The steric interference of proximal dialkyl amino and acyl groups at the peri (1,8) positions of naphthalene affects the intramolecular charge transfer fluorescence. Previous studies indicate that acyl and freely rotating dimethyl amino groups twist toward coplanarity with the naphthalene ring in the excited state. The present study examines the effect of constraining the amino group in a ring.

Daily testing for contacts of individuals with SARS-CoV-2 infection and attendance and SARS-CoV-2 transmission in English secondary schools and colleges: an open-label, cluster-randomised trial.

Background: School-based COVID-19 contacts in England have been asked to self-isolate at home, missing key educational opportunities. We trialled daily testing of contacts as an alternative to assess whether this resulted in similar control of transmission, while allowing more school attendance.

Methods: We did an open-label, cluster-randomised, controlled trial in secondary schools and further education colleges in England.

Deliberately Losing Control of C-H Activation Processes in the Design of Small-Molecule-Fragment Arrays Targeting Peroxisomal Metabolism.

Combined photochemical arylation, "nuisance effect" (S Ar) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein-ligand structure determination. Reactions were deliberately allowed to run "out of control" in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with S Ar processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.

A Ca/CaM-regulated transcriptional switch modulates stomatal development in response to water deficit.

Calcium (Ca) signals are decoded by the Ca-sensor protein calmodulin (CaM) and are transduced to Ca/CaM-binding transcription factors to directly regulate gene expression necessary for acclimation responses in plants. The molecular mechanisms of Ca/CaM signal transduction processes and their functional significance remains enigmatic. Here we report a novel Ca/CaM signal transduction mechanism that allosterically regulates DNA-binding activity of GT2-LIKE 1 (GTL1), a transrepressor of STOMATAL DENSITY AND DISTRIBUTION 1 (SDD1), to repress stomatal development in response to water stress.

Possible positive effect of the APOE ε2 allele on cognition in early to mid-adult life.

Background: ε4 allele possession is associated with an increased risk of Alzheimer's disease. Its effects earlier in life are less well understood. Previous studies have reported both detrimental effects and a lack of effect on cognition outside dementia.

Synthesis of kinase inhibitors containing a pentafluorosulfanyl moiety.

A series of 3-methylidene-1H-indol-2(3H)-ones substituted with a 5- or 6-pentafluorosulfanyl group has been synthesized by a Knoevenagel condensation reaction of SF-substituted oxindoles with a range of aldehydes. The resulting products were characterized by X-ray crystallography studies and were tested for biological activity versus a panel of cell lines and protein kinases. Some exhibited single digit nM activity.

Production of Phloroglucinol, a Platform Chemical, in Arabidopsis using a Bacterial Gene.

Phloroglucinol (1,3,5-trihydroxybenzene; PG) and its derivatives are phenolic compounds that are used for various industrial applications. Current methods to synthesize PG are not sustainable due to the requirement for carbon-based precursors and co-production of toxic byproducts. Here, we describe a more sustainable production of PG using plants expressing a native bacterial or a codon-optimized synthetic PhlD targeted to either the cytosol or chloroplasts.

HAPRAP: a haplotype-based iterative method for statistical fine mapping using GWAS summary statistics.

Motivation: Fine mapping is a widely used approach for identifying the causal variant(s) at disease-associated loci. Standard methods (e.g.

Frequency of KLK3 gene deletions in the general population.

Background One of the kallikrein genes ( KLK3) encodes prostate-specific antigen, a key biomarker for prostate cancer. A number of factors, both genetic and non-genetic, determine variation of serum prostate-specific antigen concentrations in the population. We have recently found three KLK3 deletions in individuals with very low prostate-specific antigen concentrations, suggesting a link between abnormally reduced KLK3 expression and deletions of KLK3.

A critical role for the self-assembly of Amyloid-β1-42 in neurodegeneration.

Amyloid β1-42 (Aβ1-42) plays a central role in Alzheimer's disease. The link between structure, assembly and neuronal toxicity of this peptide is of major current interest but still poorly defined. Here, we explored this relationship by rationally designing a variant form of Aβ1-42 (vAβ1-42) differing in only two amino acids.

Mendelian Randomisation study of the influence of eGFR on coronary heart disease.

Impaired kidney function, as measured by reduced estimated glomerular filtration rate (eGFR), has been associated with increased risk of coronary heart disease (CHD) in observational studies, but it is unclear whether this association is causal or the result of confounding or reverse causation. In this study we applied Mendelian randomisation analysis using 17 genetic variants previously associated with eGFR to investigate the causal role of kidney function on CHD. We used 13,145 participants from the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium and 194,427 participants from the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease (CARDIoGRAMplusC4D) consortium.

Size-exclusion chromatographic NMR under HR-MAS.

The addition of stationary phases or sample modifiers can be used to modify the separation achievable in the diffusion domain of diffusion NMR experiments or provide information on the nature of the analyte-sample modifier interaction. Unfortunately, the addition of insoluble chromatographic stationary phases can lead to line broadening and degradation in spectral resolution, largely because of differences in magnetic susceptibility between the sample and the stationary phase. High-resolution magic angle spinning (HR-MAS) techniques can be used to remove this broadening.

A synthetic, catalytic and theoretical investigation of an unsymmetrical SCN pincer palladacycle.

The SCN ligand 2-{3-[(methylsulfanyl)methyl]phenyl}pyridine, 1, has been synthesized starting from an initial Suzuki-Miyaura (SM) coupling between 3-((hydroxymethyl)phenyl)boronic acid and 2-bromopyridine. The C-H activation of 1 with in situ formed Pd(MeCN)4(BF4)2 has been studied and leads to a mixture of palladacycles, which were characterized by X-ray crystallography. The monomeric palladacycle LPdCl 6, where L-H = 1, has been synthesized, and tested in SM couplings of aryl bromides, where it showed moderate activity.

Importance of Genetic Studies in Consanguineous Populations for the Characterization of Novel Human Gene Functions.

Consanguineous offspring have elevated levels of homozygosity. Autozygous stretches within their genome are likely to harbour loss of function (LoF) mutations which will lead to complete inactivation or dysfunction of genes. Studying consanguineous offspring with clinical phenotypes has been very useful for identifying disease causal mutations.

A study of common Mendelian disease carriers across ageing British cohorts: meta-analyses reveal heterozygosity for alpha 1-antitrypsin deficiency increases respiratory capacity and height.

Background: Several recessive Mendelian disorders are common in Europeans, including cystic fibrosis (CFTR), medium-chain-acyl-Co-A-dehydrogenase deficiency (ACADM), phenylketonuria (PAH) and alpha 1-antitrypsin deficiency (SERPINA1).

Methods: In a multicohort study of >19,000 older individuals, we investigated the relevant phenotypes in heterozygotes for these genes: lung function (forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC)) for CFTR and SERPINA1; cognitive measures for ACADM and PAH; and physical capability for ACADM, PAH and SERPINA1.

Results: Findings were mostly negative but lung function in SERPINA1 (protease inhibitor (PI) Z allele, rs28929474) showed enhanced FEV1 and FVC (0.

Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis.

Background: Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis.

Methods: We first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease.

Effect of smoking on physical and cognitive capability in later life: a multicohort study using observational and genetic approaches.

Objectives: The observed associations between smoking and functional measures at older ages are vulnerable to bias and confounding. Mendelian randomisation (MR) uses genotype as an instrumental variable to estimate unconfounded causal associations. We conducted a meta-analysis of the observational associations and implemented an MR approach using the smoking-related single nucleotide polymorphism rs16969968 to explore their causal nature.

Possible Association of APOE Genotype with Working Memory in Young Adults.

Background: Possession of the ε4 allele of the Apolipoprotein E (APOE) gene is associated with an increased risk of Alzheimer's disease. Early adult life effects of ε4 are less well understood. Working memory has been relatively little studied (compared to episodic memory) in relation to APOE genotype despite its importance in cognitive functioning.

Identifying Highly Penetrant Disease Causal Mutations Using Next Generation Sequencing: Guide to Whole Process.

Recent technological advances have created challenges for geneticists and a need to adapt to a wide range of new bioinformatics tools and an expanding wealth of publicly available data (e.g., mutation databases, and software).