Publications by authors named "Richard J Smith"

449 Publications

Response of Amazonian forests to mid-Holocene drought: a model-data comparison.

Glob Chang Biol 2021 Oct 15. Epub 2021 Oct 15.

University of Reading, Department of Geography & Environmental Science, School of Archaeology, Geography and Environmental Science (SAGES), Whiteknights Reading, UK.

There is major concern for the fate of Amazonia over the coming century in the face of anthropogenic climate change. A key area of uncertainty is the scale of rainforest die-back to be expected under a future, drier climate. In this study, we use the middle Holocene (ca. 6,000 years before present) as an approximate analogue for a drier future, given that palaeoclimate data show much of Amazonia was significantly drier than present at this time. Here, we use an ensemble of climate and vegetation models to explore the sensitivity of Amazonian biomes to mid-Holocene climate change. For this we employ three dynamic vegetation models (JULES, IBIS, and SDGVM) forced by the bias-corrected mid-Holocene climate simulations from seven models that participated in the Paleoclimate Modelling Intercomparison Project 3 (PMIP3). These model outputs are compared with a multi-proxy palaeoecological dataset to gain a better understanding of where in Amazonia we have most confidence in the mid-Holocene vegetation simulations. A robust feature of all simulations and palaeodata is that the central Amazonian rainforest biome is unaffected by mid-Holocene drought. Greater divergence in mid-Holocene simulations exists in ecotonal eastern and southern Amazonia. Vegetation models driven with climate models that simulate a drier mid Holocene (100-150 mm per year decrease) better capture the observed (palaeodata) tropical forest die-back in these areas. Based on the relationship between simulated rainfall decrease and vegetation change, we find indications that in southern Amazonia the rate of tropical forest die-back was ~125,000 km per 100 mm rainfall decrease in the mid Holocene. This provides a baseline sensitivity of tropical forests to drought for this region (without human-driven changes to greenhouse gases, fire, and deforestation). We highlight the need for more palaeoecological and palaeoclimate data across lowland Amazonia to constrain model responses.
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http://dx.doi.org/10.1111/gcb.15929DOI Listing
October 2021

Sequential genetic testing of living related donors for inherited renal disease to promote informed choice and enhance safety of living donation.

Transpl Int 2021 Oct 10. Epub 2021 Oct 10.

Departments of Internal Medicine, University of Iowa, Iowa City, IA, USA.

Living kidney donors (LKDs) with a family history of renal disease are at risk of kidney disease as compared to LKDs without such history suggesting that some LKDs may be pre-symptomatic for monogenic kidney disease. LKDs with related transplant candidates whose kidney disease was considered genetic in origin were selected for genetic testing. In each case, the transplant candidate was first tested to verify the genetic diagnosis. A genetic diagnosis was confirmed in 12 of 24 transplant candidates (ADPKD-PKD1: 6, ALPORT-COL4A3: 2, ALPORT-COL4A5: 1: nephronophthisis-SDCCAG8: 1; CAKUT-HNF1B and ADTKD-MUC1: 1 each) and 2 had variants of unknown significance (VUS) in phenotype-relevant genes. Focused genetic testing was then done in 20 of 34 LKDs. 12 LKDs screened negative for the familial variant and were permitted to donate; 7 screened positive and were counseled against donation. One, the heterozygous carrier of a recessive disorder was also cleared. 6 of 7 LKDs with a family history of ADPKD were under 30 yr and in 5, by excluding ADPKD, allowed donation to safely proceed. The inclusion of genetic testing clarified the diagnosis in recipient candidates, improving safety or informed decision making in LKDs.
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http://dx.doi.org/10.1111/tri.14133DOI Listing
October 2021

Improving Clinical Trials for Anticomplement Therapies in Complement-Mediated Glomerulopathies: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Am J Kidney Dis 2021 Sep 24. Epub 2021 Sep 24.

University of Toronto, Toronto, Canada.

Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents a myriad of questions and challenges, not the least of which is demonstrating efficacy and safety. In light of these potential issues and because there are an increasing number of anti-complement therapy trials either planned or underway, the National Kidney Foundation (NKF) facilitated an all-virtual format scientific workshop entitled, "Improving Clinical Trials for Anti-complement Therapies in Complement-mediated Glomerulopathies." Attended by patient representatives and experts in glomerular diseases, complement physiology, and clinical trial design, the aim of this workshop was to develop standards applicable for designing and conducting clinical trials for anti-complement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, subject risk assessment and mitigation, laboratory measurements and biomarkers to support these studies, and identification of optimal outcome measures to detect benefit, specifically for trials in complement-mediated diseases. This report summarizes the discussions from this workshop and outlines consensus recommendations.
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http://dx.doi.org/10.1053/j.ajkd.2021.07.025DOI Listing
September 2021

COCH-related autosomal dominant nonsyndromic hearing loss: a phenotype-genotype study.

Hum Genet 2021 Sep 16. Epub 2021 Sep 16.

Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

This phenotype-genotype study aimed to investigate the extent of audioprofile variability related to cochlin major domains and to identify potential ethnic-specific differences associated with COCH-related hearing loss. Eight Korean families (26 cases) were diagnosed with COCH-related hearing loss by exome sequencing. Audiometric test results were combined with those from nine published East Asian families (20 cases) and compared with those from 38 European-descent families (277 cases). Audioprofiles were created by grouping audiometric test results into age ranges by age at testing and then averaging hearing loss thresholds by frequency within age ranges. The functional impact of the identified variants was assessed in vitro by examining the intracellular trafficking, secretion, and cleavage of cochlin. In both East Asian and European-descent families segregating COCH-related hearing loss, deafness-associated variants in non-LCCL domains of cochlin were associated with hearing loss that was more severe earlier in life than hearing loss caused by variants in the LCCL domain. Consistent with this phenotypic difference, functional studies demonstrated distinct pathogenic mechanisms for COCH variants in a domain-dependent manner; specifically, a cytotoxic effect was observed for the p.Phe230Leu variant, which is located in the vWFA1 domain. No ethnic-specific differences in hearing loss progression were observed, except for those attributable to an overrepresentation of presymptomatic cases in the European-descent cohort.
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http://dx.doi.org/10.1007/s00439-021-02368-yDOI Listing
September 2021

Monoclonal Gammopathy of Renal Significance Causes C3 Glomerulonephritis Via Monoclonal IgG Kappa Inhibition of Complement Factor H.

Kidney Int Rep 2021 Sep 27;6(9):2505-2509. Epub 2021 Jun 27.

Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.

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http://dx.doi.org/10.1016/j.ekir.2021.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418982PMC
September 2021

Selective Binding of Heparin/Heparan Sulfate Oligosaccharides to Factor H and Factor H-Related Proteins: Therapeutic Potential for C3 Glomerulopathies.

Front Immunol 2021 18;12:676662. Epub 2021 Aug 18.

Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

Complement dysregulation is characteristic of the renal diseases atypical hemolytic uremic syndrome (aHUS) and complement component 3 glomerulopathy (C3G). Complement regulatory protein Factor H (FH) inhibits complement activity, whereas FH-related proteins (FHRs) lack a complement regulatory domain. FH and FHRs compete for binding to host cell glycans, in particular heparan sulfates (HS). HS is a glycosaminoglycan with an immense structural variability, where distinct sulfation patterns mediate specific binding of proteins. Mutations in FH, FHRs, or an altered glomerular HS structure may disturb the FH : FHRs balance on glomerular endothelial cells, thereby leading to complement activation and the subsequent development of aHUS/C3G. In this study, we aimed to identify specific HS structures that could specifically compete off FHRs from HS glycocalyx (HS), without interfering with FH binding. FH/FHR binding to human conditionally immortalized glomerular endothelial cells (ciGEnCs) and HS purified from ciGEnC glycocalyx was assessed. HS modifications important for FH/FHR binding to HS were analyzed using selectively desulfated heparins in competition with purified HS. We further assessed effects of heparinoids on FHR1- and FHR5-mediated C3b deposition on ciGEnCs. In the presence of C3b, binding of FH, FHR1 and FHR5 to ciGEnCs was significantly increased, whereas binding of FHR2 was minimal. FHR1 and 5 competitively inhibited FH binding to HS, leading to alternative pathway dysregulation. FHR1 and FHR5 binding was primarily mediated by N-sulfation while FH binding depended on N-, 2-O- and 6-O-sulfation. Addition of 2-O-desulfated heparin significantly reduced FHR1- and FHR5-mediated C3b deposition on ciGEnCs. We identify 2-O-desulfated heparin derivatives as potential therapeutics for C3G and other diseases with dysregulated complement.
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http://dx.doi.org/10.3389/fimmu.2021.676662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416517PMC
August 2021

The natural history of OTOF-related auditory neuropathy spectrum disorders: a multicenter study.

Hum Genet 2021 Aug 23. Epub 2021 Aug 23.

Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

Pathogenic variations in the OTOF gene are a common cause of hearing loss. To refine the natural history and genotype-phenotype correlations of OTOF-related auditory neuropathy spectrum disorders (ANSD), audiograms and distortion product otoacoustic emissions (DPOAEs) were collected from a diverse cohort of individuals diagnosed with OTOF-related ANSD by comprehensive genetic testing and also reported in the literature. Comparative analysis was undertaken to define genotype-phenotype relationships using a Monte Carlo algorithm. 67 audiograms and 25 DPOAEs from 49 unique individuals positive for OTOF-related ANSD were collected. 51 unique OTOF pathogenic variants were identified of which 21 were missense and 30 were loss of function (LoF; nonsense, splice-site, copy number variants, and indels). There was a statistically significant difference in low, middle, and high frequency hearing thresholds between missense/missense and LoF/missense genotypes as compared to LoF/LoF genotypes (average hearing threshold for low, middle and high frequencies 70.9, 76.0, and 73.4 dB vs 88.5, 95.6, and 94.7 dB) via Tukey's test with age as a co-variate (P = 0.0180, 0.0327, and 0.0347, respectively). Hearing declined during adolescence with missense/missense and LoF/missense genotypes, with an annual mid-frequency threshold deterioration of 0.87 dB/year and 1.87 dB/year, respectively. 8.5% of frequencies measured via DPOAE were lost per year in individuals with serial tests. Audioprofiling of OTOF-related ANSD suggests significantly worse hearing with LoF/LoF genotypes. The unique pattern of variably progressive OTOF-related autosomal recessive ANSD may be amenable to gene therapy in selected clinical scenarios.
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http://dx.doi.org/10.1007/s00439-021-02340-wDOI Listing
August 2021

and Copy Number Variations in C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis.

Front Genet 2021 11;12:670727. Epub 2021 Jun 11.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.

C3 Glomerulopathy (C3G) and Immune Complex-Mediated Membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases characterized by glomerular deposition of C3 caused by dysregulation of the alternative pathway (AP) of complement. In approximately 20% of affected patients, dysregulation is driven by pathogenic variants in the two components of the AP C3 convertase, complement C3 () and Factor B (), or in complement Factor H () and Factor I (), two genes that encode complement regulators. Copy number variations (CNVs) involving the -related genes () that give rise to hybrid FHR proteins also have been described in a few C3G patients but not in IC-MPGN patients. In this study, we used multiplex ligation-dependent probe amplification (MLPA) to study the genomic architecture of the region and characterize CNVs in a large cohort of patients with C3G ( = 103) and IC-MPGN ( = 96) compared to healthy controls ( = 100). We identified new/rare CNVs resulting in structural variants (SVs) in 5 C3G and 2 IC-MPGN patients. Using long-read single molecule real-time sequencing (SMRT), we detected the breakpoints of three SVs. The identified SVs included: 1) a deletion of the entire in one patient with IC-MPGN; 2) an increased number of copies in one IC-MPGN and three C3G patients; 3) a deletion from -intron 3 to ' ( Δ) that results in a FHR3-FHR1 hybrid protein in a C3G patient; and 4) a hybrid gene in a C3G patient. This work highlights the contribution of CNVs to the pathogenesis of both C3G and IC-MPGN.
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http://dx.doi.org/10.3389/fgene.2021.670727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240960PMC
June 2021

Genetic Causes of Hearing Loss in a Large Cohort of Cochlear Implant Recipients.

Otolaryngol Head Neck Surg 2021 Jun 22:1945998211021308. Epub 2021 Jun 22.

Department of Otolaryngology-Head & Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.

Understanding genetic causes of hearing loss can determine the pattern and course of a patient's hearing loss and may also predict outcomes after cochlear implantation. Our goal in this study was to evaluate genetic causes of hearing loss in a large cohort of adults and children with cochlear implants. We performed comprehensive genetic testing on all patients undergoing cochlear implantation. Of the 459 patients included in the study, 128 (28%) had positive genetic testing. In total, 44 genes were identified as causative. The top 5 genes implicated were (20, 16%), (13, 10%), (10, 8%), (9, 7%), and (7, 5%). Pediatric patients had a higher diagnostic rate. This study lays the groundwork for future studies evaluating the relationship between genetic variation and cochlear implant performance.
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http://dx.doi.org/10.1177/01945998211021308DOI Listing
June 2021

Pembrolizumab Induced Acute Persistent Airway Disease in a Patient with Recurrent Respiratory Papillomatosis (RRP).

Ann Otol Rhinol Laryngol 2021 May 30:34894211021276. Epub 2021 May 30.

Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.

Objective: To present an uncommon but serious, recently identified complication of checkpoint inhibitor therapy in a patient treated with pembrolizumab infusion for disseminated recurrent respiratory papillomatosis (RRP).

Methods: Case report.

Results: A 43-year-old woman with underlying asthma developed acute hypoxic respiratory failure within 24 hours of her third infusion of pembrolizumab for treatment of intractable, disseminated recurrent respiratory papillomatosis. Pulmonary function testing revealed a severe intra-thoracic obstructive ventilatory defect. Discontinuation of pembrolizumab, ventilatory support, and treatment with systemic and inhaled corticosteroids resulted in resolution of respiratory failure; however, her underlying asthma remains poorly controlled.

Conclusion: To our knowledge, this case is the first report of pembrolizumab-induced obstructive respiratory failure in a patient being treated for RRP.
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http://dx.doi.org/10.1177/00034894211021276DOI Listing
May 2021

TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis but not hearing loss: A novel cohort study.

Am J Med Genet A 2021 08 27;185(8):2417-2433. Epub 2021 May 27.

Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, France.

Biallelic loss-of-function variants in the thrombospondin-type laminin G domain and epilepsy-associated repeats (TSPEAR) gene have recently been associated with ectodermal dysplasia and hearing loss. The first reports describing a TSPEAR disease association identified this gene is a cause of nonsyndromic hearing loss, but subsequent reports involving additional affected families have questioned this evidence and suggested a stronger association with ectodermal dysplasia. To clarify genotype-phenotype associations for TSPEAR variants, we characterized 13 individuals with biallelic TSPEAR variants. Individuals underwent either exome sequencing or panel-based genetic testing. Nearly all of these newly reported individuals (11/13) have phenotypes that include tooth agenesis or ectodermal dysplasia, while three newly reported individuals have hearing loss. Of the individuals displaying hearing loss, all have additional variants in other hearing-loss-associated genes, specifically TMPRSS3, GJB2, and GJB6, that present competing candidates for their hearing loss phenotype. When presented alongside previous reports, the overall evidence supports the association of TSPEAR variants with ectodermal dysplasia and tooth agenesis features but creates significant doubt as to whether TSPEAR variants are a monogenic cause of hearing loss. Further functional evidence is needed to evaluate this phenotypic association.
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http://dx.doi.org/10.1002/ajmg.a.62347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361973PMC
August 2021

Clinical Pharmacogenetics Implementation Consortium Guideline for the Use of Aminoglycosides Based on MT-RNR1 Genotype.

Clin Pharmacol Ther 2021 May 25. Epub 2021 May 25.

Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.

Aminoglycosides are widely used antibiotics with notable side effects, such as nephrotoxicity, vestibulotoxicity, and sensorineural hearing loss (cochleotoxicity). MT-RNR1 is a gene that encodes the 12s rRNA subunit and is the mitochondrial homologue of the prokaryotic 16s rRNA. Some MT-RNR1 variants (i.e., m.1095T>C; m.1494C>T; m.1555A>G) more closely resemble the bacterial 16s rRNA subunit and result in increased risk of aminoglycoside-induced hearing loss. Use of aminoglycosides should be avoided in individuals with an MT-RNR1 variant associated with an increased risk of aminoglycoside-induced hearing loss unless the high risk of permanent hearing loss is outweighed by the severity of infection and safe or effective alternative therapies are not available. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of aminoglycosides based on MT-RNR1 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).
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http://dx.doi.org/10.1002/cpt.2309DOI Listing
May 2021

Phonon imaging in 3D with a fibre probe.

Light Sci Appl 2021 Apr 27;10(1):91. Epub 2021 Apr 27.

Optics and Photonics Group, Faculty of Engineering, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.

We show for the first time that a single ultrasonic imaging fibre is capable of simultaneously accessing 3D spatial information and mechanical properties from microscopic objects. The novel measurement system consists of two ultrafast lasers that excite and detect high-frequency ultrasound from a nano-transducer that was fabricated onto the tip of a single-mode optical fibre. A signal processing technique was also developed to extract nanometric in-depth spatial measurements from GHz frequency acoustic waves, while still allowing Brillouin spectroscopy in the frequency domain. Label-free and non-contact imaging performance was demonstrated on various polymer microstructures. This singular device is equipped with optical lateral resolution, 2.5 μm, and a depth-profiling precision of 45 nm provided by acoustics. The endoscopic potential for this device is exhibited by extrapolating the single fibre to tens of thousands of fibres in an imaging bundle. Such a device catalyses future phonon endomicroscopy technology that brings the prospect of label-free in vivo histology within reach.
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http://dx.doi.org/10.1038/s41377-021-00532-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079419PMC
April 2021

Exome sequencing utility in defining the genetic landscape of hearing loss and novel-gene discovery in Iran.

Clin Genet 2021 07 24;100(1):59-78. Epub 2021 Mar 24.

Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.

Hearing loss (HL) is one of the most common sensory defects affecting more than 466 million individuals worldwide. It is clinically and genetically heterogeneous with over 120 genes causing non-syndromic HL identified to date. Here, we performed exome sequencing (ES) on a cohort of Iranian families with no disease-causing variants in known deafness-associated genes after screening with a targeted gene panel. We identified likely causal variants in 20 out of 71 families screened. Fifteen families segregated variants in known deafness-associated genes. Eight families segregated variants in novel candidate genes for HL: DBH, TOP3A, COX18, USP31, TCF19, SCP2, TENM1, and CARMIL1. In the three of these families, intrafamilial locus heterogeneity was observed with variants in both known and novel candidate genes. In aggregate, we were able to identify the underlying genetic cause of HL in nearly 30% of our study cohort using ES. This study corroborates the observation that high-throughput DNA sequencing in populations with high rates of consanguineous marriages represents a more appropriate strategy to elucidate the genetic etiology of heterogeneous conditions such as HL.
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http://dx.doi.org/10.1111/cge.13956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195868PMC
July 2021

The angiogenic potential of CD271+ human adipose tissue-derived mesenchymal stem cells.

Stem Cell Res Ther 2021 03 2;12(1):160. Epub 2021 Mar 2.

Blond McIndoe Laboratories, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK.

Background: Autologous fat grafting is often a crucial aspect of reconstructive and aesthetic surgeries, yet poor graft retention is a major issue with this technique. Enriching fat grafts with adipose tissue-derived mesenchymal stem cells (AD-MSCs) improves graft survival-however, AD-MSCs represent a heterogeneous population. Selection of subpopulations of AD-MSCs would allow the targeting of specific AD-MSCs that may benefit fat graft survival more than the general AD-MSC population.

Methods: Human AD-MSCs were selected for the surface marker CD271 using magnetic-activated cell sorting and compared to the CD271 negative phenotype.  These subpopulations were analysed for gene expression using Real-Time qPCR and RNA sequencing; surface marker characteristics using immunostaining; ability to form tubules when cultured with endothelial cells; and gene and protein expression of key angiogenic mediators when cultured with ex-vivo adipose tissue.

Results: Human AD-MSCs with the surface marker CD271 express angiogenic genes at higher levels, and inflammatory genes at lower levels, than the CD271- AD-MSC population. A greater proportion of CD271+ AD-MSCs also possess the typical complement of stem cell surface markers and are more likely to promote effective neoangiogenesis, compared to CD271- AD-MSCs.

Conclusion: Enriching grafts with the CD271+ AD-MSC subpopulation holds potential for the improvement of reconstructive and aesthetic surgeries involving adipose tissue.
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http://dx.doi.org/10.1186/s13287-021-02177-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927269PMC
March 2021

3D phonon microscopy with sub-micron axial-resolution.

Sci Rep 2021 02 8;11(1):3301. Epub 2021 Feb 8.

Optics and Photonics, Faculty of Engineering, University of Nottingham, University Park, Nottingham, UK.

Brillouin light scattering (BLS) is an emerging method for cell imaging and characterisation. It allows elasticity-related contrast, optical resolution and label-free operation. Phonon microscopy detects BLS from laser generated coherent phonon fields to offer an attractive route for imaging since, at GHz frequencies, the phonon wavelength is sub-optical. Using phonon fields to image single cells is challenging as the signal to noise ratio and acquisition time are often poor. However, recent advances in the instrumentation have enabled imaging of fixed and living cells. This work presents the first experimental characterisation of phonon-based axial resolution provided by the response to a sharp edge. The obtained axial resolution is up to 10 times higher than that of the optical system used to take the measurements. Validation of the results are obtained with various polymer objects, which are in good agreement with those obtained using atomic force microscopy. Edge localisation, and hence profilometry, of a phantom boundary is measured with accuracy and precision of approximately 60 nm and 100 nm respectively. Finally, 3D imaging of fixed cells in culture medium is demonstrated.
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http://dx.doi.org/10.1038/s41598-021-82639-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870650PMC
February 2021

A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans.

Hum Genet 2021 Jun 26;140(6):915-931. Epub 2021 Jan 26.

Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.

Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.
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http://dx.doi.org/10.1007/s00439-020-02254-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099798PMC
June 2021
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