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Skin color affects light penetration leading to differences in its absorption and scattering properties. COVID-19 highlighted the importance of understanding of the interaction of light with different skin types, e.g., pulse oximetry (PO) unreliably determined oxygen saturation levels in people from Black and ethnic minority backgrounds. Furthermore, with increased use of other medical wearables using light to provide disease information and photodynamic therapies to treat skin cancers, a thorough understanding of the effect skin color has on light is important for reducing healthcare disparities. The aim of this work is to perform a thorough review on the effect of skin color on optical properties and the implication of variation on optical medical technologies. Published optical coefficients associated with different skin colors were collated and their effects on optical penetration depth and transport mean free path (TMFP) assessed. Variation among reported values is significant. We show that absorption coefficients for dark skin are to 74% greater than for light skin in the 400 to 1000 nm spectrum. Beyond 600 nm, the TMFP for light skin is greater than for dark skin. Maximum transmission for all skin types was beyond 940 nm in this spectrum. There are significant losses of light with increasing skin depth; in this spectrum, depending upon Fitzpatrick skin type (FST), on average 14% to 18% of light is lost by a depth of 0.1 mm compared with 90% to 97% of the remaining light being lost by a depth of 1.93 mm. Current published data suggest that at wavelengths beyond 940 nm light transmission is greatest for all FSTs. Data beyond 1000 nm are minimal and further study is required. It is possible that the amount of light transmitted through skin for all skin colors will converge with increasing wavelength enabling optical medical technologies to become independent of skin color.

Bernard Keavney, Judith Goodship and colleagues report a genome-wide association study of congenital heart disease and identify a region on chromosome 4p16 associated with risk of atrial septal defect. We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated ( P = 9.5 × 10 −7 ) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort ( N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10 −5 ; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19–1.65; combined P = 2.6 × 10 −10 ). Genotype accounted for ∼9% of the population-attributable risk of ASD.

This report presents an optical fibre-based endo-microscopic imaging tool that simultaneously measures the topographic profile and 3D viscoelastic properties of biological specimens through the phenomenon of time-resolved Brillouin scattering. This uses the intrinsic viscoelasticity of the specimen as a contrast mechanism without fluorescent tags or photoacoustic contrast mechanisms. We demonstrate 2 μm lateral resolution and 320 nm axial resolution for the 3D imaging of biological cells and Caenorhabditis elegans larvae. This has enabled the first ever 3D stiffness imaging and characterisation of the C. elegans larva cuticle in-situ. A label-free, subcellular resolution, and endoscopic compatible technique that reveals structural biologically-relevant material properties of tissue could pave the way toward in-vivo elasticity-based diagnostics down to the single cell level. A hair-thin fibre-optic imaging system that can image the mechanical properties of single-cellular and multi-cellular organisms in 3D with sufficient resolution to identify 300 nm structures in the C. elegans cuticle.

Matthew Hurles and colleagues report exome sequencing of 1,891 individuals with syndromic or nonsyndromic congenital heart defects (CHD). They found that nonsyndromic CHD patients were enriched for protein-truncating variants in CHD-associated genes inherited from unaffected parents and identified three new syndromic CHD disorders caused by de novo mutations. Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1% (refs. 1 , 2 ). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%) 3 , suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance 4 , 5 . De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations 6 , 7 . We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings 8 . Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4 , CDK13 and PRKD1 . Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

Rapid advances in medical imaging technology, particularly the development of optical systems with non-linear imaging modalities, are boosting deep tissue imaging. The development of reliable standards and phantoms is critical for validation and optimization of these cutting-edge imaging techniques. We aim to design and fabricate flexible, multi-layered hydrogel-based optical standards and evaluate advanced optical imaging techniques at depth. Standards were made using a robust double-network hydrogel matrix consisting of agarose and polyacrylamide. The materials generated ranged from single layers to more complex constructs consisting of up to seven layers, with modality-specific markers embedded between the layers. These standards proved useful in the determination of the axial scaling factor for light microscopy and allowed for depth evaluation for different imaging modalities (conventional one-photon excitation fluorescence imaging, two-photon excitation fluorescence imaging, second harmonic generation imaging, and coherent anti-Stokes Raman scattering) achieving actual depths of 1550, 1550, 1240, and , respectively. Once fabricated, the phantoms were found to be stable for many months. The ability to image at depth, the phantom's robustness and flexible layered structure, and the ready incorporation of \"optical markers\" make these ideal depth standards for the validation of a variety of imaging modalities.

There is strong evidence from familial recurrence studies for a genetic predisposition to sporadic, non-syndromic Tetralogy of Fallot (TOF). TOF is the most common, cyanotic congenital heart disease (CHD) phenotype yet the cause for the majority of cases remains elusive. Rare genetic variants have been identified as important contributors to the risk of CHD, but relatively small numbers of TOF cases have been studied to date. 829 TOF patients underwent whole exome sequencing (WES), the largest cohort of non-syndromic TOF patients reported to date. The prevalence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database (gnomAD) and a scaled combined annotation-dependent depletion (CADD) score of ≥20. Clustering analysis of variants revealed that two genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5 × 10-8), after correction for multiple comparisons. NOTCH1 was most frequently found to harbour unique, deleterious variants. 31 variants were observed in 37 probands (4.5%; 95% confidence interval [CI]: 3.2–6.1%) and included seven loss-of-function variants, 22 missense variants and two in-frame indels. Sanger sequencing of the unaffected parents of seven cases identified five de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y and p.N1875S) were subjected to functional evaluation and two showed a reduction in Jagged1-induced NOTCH signalling. FLT4 variants were found in 2.4% (95% CI:1.6–3.8%) of TOF patients, with 21 patients harbouring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other biologically plausible candidate genes. In summary, the NOTCH1 locus is the most frequent site of genetic variants predisposing to non-syndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.

Microrheology, the study of fluids on micron length-scales, promises to reveal insights into cellular biology, including mechanical biomarkers of disease and the interplay between biomechanics and cellular function. Here a minimally-invasive passive microrheology technique is applied to individual living cells by chemically binding a bead to the surface of a cell, and observing the mean squared displacement of the bead at timescales ranging from milliseconds to 100s of seconds. Measurements are repeated over the course of hours, and presented alongside novel analysis to quantify changes in the cells' low-frequency elastic modulus and the cell's dynamics over the time window from around 0.01s to 10s. An analogy to optical trapping allows verification of the invariant viscosity of HeLa S3 cells under control conditions and after cytoskeletal disruption. Stiffening of the cell is observed during cytoskeletal rearrangement in the control case, and cell softening when the actin cytoskeleton is disrupted by Latrunculin B. These data correlate with conventional understanding that integrin binding and recruitment triggers cytoskeletal rearrangement. This is, to our knowledge, the first time that cell stiffening has been measured during focal adhesion maturation, and the longest time over which such stiffening has been quantified by any means.

A number of approaches have been taken towards the development of a vaccine protective against serogroup B meningococcal disease but, as yet, none have been successful. The commensal bacterium, Neisseria lactamica, shares many surface structures with N. meningitidis and N. lactamica may therefore provide an alternative approach to vaccinating against serogroup B disease. Immunological evidence suggests that carriage of N. lactamica is involved in natural protection against disease caused by N. meningitidis. This study presents the important observation that N. lactamica vaccines protect mice against meningococcal challenge. To identify the components responsible for protection, the outer membrane proteins of N. lactamica, extracted from whole cells, were separated by preparative electrophoresis and pooled into low <43 kDa), medium (43-65 kDa) and high (>67 kDa) molecular weight protein groups. The low molecular weight group provided the best protection of these groups, and further separation of this group indicated that proteins of 25-43 kDa provided the observed protection. Serum raised against N. lactamica proteins was cross-reactive with meningococci of different serogroups, serotypes and serosubtypes. N. lactamica antisera raised in mice were not bactericidal and although sera raised in rabbits showed some bactericidal activity, titres did not correlate with protection. Meningococcal proteins cross-reactive with N. lactamica antisera were identified using surface enhance laser-desorption ionisation time-of-flight mass spectroscopy. The cross-reactive proteins had molecular masses of approximately 11.2 kDa, 13.7 kDa, 26.8 kDa, 17.4 kDa, 28.1 kDa, 33.1 kDa, 53.2 kDa and 66.6 kDa. Several meningococcal proteins of unknown function and others that have previously been considered as vaccine antigens (PorB and TbpB) were putatively identified. Proteins with epitopes homologous to these proteins are likely to be present in N. lactamica and may be involved in protection against meningococcal challenge. The identity of the 66.6 kDa protein as TbpB was confirmed by comparing the cross-reactivity of N. meningitidis OMPs from wild-type and TbpB knockout strains with N. lactamica antisera. Using a N. lactamica genomic expression library, the DNA sequences of recombinant N. lactamica proteins cross-reactive with N. lactamica antiserum were obtained. Meningococcal proteins with homology to the N. lactamica sequences were identified by comparison with the complete genome sequences of N. meningitidis serogroups A and B. Fifteen cross-reactive sequences coded, either partially or completely, for 23 different proteins. This study demonstrates that N. lactamica provides an effective vaccine in mice against lethal meningococcal challenge and that N. lactamica may provide an alternative approach to vaccination against serogroup B meningococcal disease. Putative identifications of the proteins involved in this protection have been made.