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High-power laser delivery with near-diffraction-limited beam quality is typically limited to tens of metres distances by nonlinearity-induced spectral broadening inside the glass core of delivery fibres. Anti-resonant hollow-core fibres offer not only orders-of-magnitude lower nonlinearity but also loss and modal purity comparable to conventional beam-delivery fibres. Using a single-mode hollow-core nested anti-resonant nodeless fibre with 0.74 dB km−1 loss, we demonstrate the delivery of 1 kW of near-diffraction-limited continuous-wave laser light over a 1 km distance, with a total throughput efficiency of ~80%. From simulations, a further improvement in transmitted power or length of more than one order of magnitude should be possible in such air-filled fibres, and considerably more if the core is evacuated. This paves the way to multi-kilometre, kilowatt-scale power delivery that is potentially useful not only for future manufacturing and subsurface drilling but also for new scientific possibilities in sensing, particle acceleration and gravitational wave detection.Microstructured optical fibre is shown to be able transmit high-power laser light over long distances with high throughput efficiency.

High-performance interferometers, gyroscopes, frequency combs, quantum information experiments and optical clocks rely on the transmission of light beams with the highest possible spatial and polarization purity. Free-space propagation in vacuum unlocks the ultimate performance but becomes impractical at even modest length scales. Glass optical fibres offer a more pragmatic alternative, but degrade polarization purity and suffer from detrimental nonlinear effects. Hollow-core fibres have been heralded for years as the ideal compromise between the two, but achieving high modal purity in both spatial and polarization domains has proved elusive thus far. Here, we show that carefully designed, low-nonlinearity hollow-core antiresonant fibres can transmit a single pair of orthogonal polarization modes with cross-coupling on the scale of 10–10 m–1; that is, orders of magnitude lower than any other solution. This free-space-like optical guidance can immediately provide a leap in performance for photonics-enabled sensors and instruments.Carefully designed hollow-core antiresonant fibres support a pair of orthogonal polarization modes with a level of purity and cross-coupling that is orders of magnitude lower than other fibre designs and beyond the fundamental Rayleigh scattering limit of glass core fibres.

Nephropathic cystinosis is a rare genetic disorder characterized by cystine accumulation in lysosomes that causes early renal dysfunction and progressive chronic kidney disease. Although several metabolic pathways, including oxidative stress and inflammation, have been implicated in the progression of renal parenchyma damage, the precise mechanisms driving its progression are not fully understood. Recent studies suggest that epigenetic modifications, particularly DNA methylation (DNAm), play a critical role in the development of chronic kidney disease. We hypothesized that epigenetic dysregulation may contribute to the progression of kidney disease in cystinosis. To investigate this, we conducted genome-wide DNAm analyses on kidneys harvested from 6-month-old wild type (WT) and mice, a well-established model of cystinosis. Our analysis revealed extensive DNAm alterations in cystinotic kidneys, characterized by a significant hypermethylation profile. Interestingly, the majority of differentially methylated CpG sites were located within gene bodies and to a lesser extent in promoter and enhancer regions. Methylation changes were primarily found in genes and pathways crucial for kidney function, particularly those related to the physiology of the proximal tubules. Importantly, DNAm changes correlated with changes in gene expression, as validated by qPCR analyses of key genes. Furthermore, treatment of human proximal tubular epithelial cells with the demethylating agent decitabine resulted in the upregulation of critical transporter genes, suggesting a potential therapeutic approach. These findings underscore the role of epigenetic regulation in the progression of kidney damage in cystinosis and suggest that DNAm could serve as a promising target for novel therapeutic strategies.

Background: Osteopetrosis, a genetic disease characterised by osteoclast failure, is classified into three forms: infantile malignant autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IRO), and autosomal dominant osteopetrosis (ADO). Methods: We studied 49 patients, 21 with ARO, one with IRO, and 27 with type II ADO (ADO II). Results: Most ARO patients bore known or novel (one case) ATP6i (TCIRG1) gene mutations. Six ADO II patients had no mutations in ClCN7, the only so far recognised gene implicated, suggesting involvement of yet unknown genes. Identical ClCN7 mutations produced differing phenotypes with variable degrees of severity. In ADO II, serum tartrate resistant acid phosphatase was always elevated. Bone alkaline phosphatase (BALP) was generally low, but osteocalcin was high, suggesting perturbed osteoblast differentiation or function. In contrast, BALP was high in ARO patients. Elevated osteoclast surface/bone surface was noted in biopsies from most ARO patients. Cases with high osteoclasts also showed increased osteoblast surface/bone surface. ARO osteoclasts were morphologically normal, with unaltered formation rates, intracellular pH handling, and response to acidification. Their resorption activity was greatly reduced, but not abolished. In control osteoclasts, all resorption activity was abolished by combined inhibition of proton pumping and sodium/proton antiport. Conclusions: These findings provide a rationale for novel therapies targeting pH handling mechanisms in osteoclasts and their microenvironment.

In recent years several reports have suggested involvement of interleukin 6 (IL-6) in beta-adrenergic effects on myocardium, particularly in enhancement of STAT3 phosphorylation (downstream signal transducer of IL-6). Here we present a study of isoproterenol effects on hearts of IL-6 deficient mice. Male 12 week old C57Bl6/J mice and age and sex matched mice from IL-6 knockout strain (C57B16/JIL6-/−) received a single intraperitoneal bolus of either isoproterenol (15 mg/kg) or placebo (0.9% NaCl) and were sacrificed after 1 or 24 hours (n=8 in each group). Another group of mice from both genotypes received a three-day isoproterenol treatment (20 mg/kg every 8h). Activation of STAT3 and MEK/ERK pathways were assessed after a single dose of isoproterenol by means of western blotting. After injection of placebo a significantly lower level of STAT3 phosphorylation was observed in IL-6 KO animals. This difference was abolished after isoproterenol both at 1 and 24-hour time points. Isoproterenol produced potent and rapid activation of both STAT3 and MEK/ERK pathways that returned to the levels of placebo treated controls after 24 hours. Lack of IL-6 did not affect phosphorylation of ERKs. Three-day treatment with isoproterenol caused significant increase of indices of RV and LV hypertrophy in both WT and IL-6 KO animals with no significant differences between genotypes. IL-6 is not necessary for isoproterenol induced STAT3 phosphorylation, but may affect activation of this pathway by mild non-specific stimuli. Lack of IL-6 does not affect activation of MEK/ERK pathway nor cardiac hypertrophy by beta-adrenergic agonists.

A 16-year-old male patient with type II autosomal dominant benign osteopetrosis (ADO) was genotyped and found to harbor a novel mutation in exon 25 of the gene encoding for the osteoclast-specific chloride channel, CLCN7, inherited from the father, who was asymptomatic. The patient had normal biochemical findings and acid-base balance, except for increased serum levels of creatine kinase, lactic dehydrogenase, and the bone formation markers bone alkaline phosphatase isoenzyme, osteocalcin and N-terminal type I collagen telopeptide/creatinine ratio. Unusual generalized osteosclerosis was observed together with a canonical increase in vertebral and pelvis bone mass. An affected first grade cousin presented with normal biochemical findings and a milder osteosclerotic pattern of the pelvis. At the cellular level, cultured osteoclasts from the patient showed increased motility, with lamellipodia, membrane ruffling and motile pattern of podosome distribution, all of which could have contributed to functional impairment of bone resorption. The present report documents a novel mutation of the CLCN7 gene causing osteopetrosis in a radiologically uncertain form of the diseases, with apparent incomplete penetrance.

Human malignant infantile osteopetrosis (arOP) is a genetically heterogeneous autosomal recessive disorder of bone metabolism. The TCIRG1 gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, is responsible for more than one‐half of the arOP patients. We performed genetic analysis of TCIRG1 in 55 arOP patients including 25 new cases and identified nine novel mutations. The two most frequent mutations, c.1674–1G>A (aberrant splicing: r.1674_1884del) and c.2005C>T (protein variation: p.Arg669X), found in 17 and 16 alleles, respectively, constituted 30% of all TCIRG1 abnormalities. They both originated in Northern Europe, p.Arg669X quite recently from West Flanders, Belgium. As substitutions in splicing regulatory sequences represented a large portion (40%; 44 alleles) of the TCIRG1 variations, we developed a functional splicing assay to distinguish between polymorphic variants and disease‐causing mutations. Three intronic nucleotide substitutions flanking the splice sites (c.117+4A>T; c.1673+5G>A; and c.504–8G>A) were studied using hybrid minigenes and an abnormal processing of the transcripts was demonstrated in all cases. Cotransfection experiments with complementary U1 snRNAs performed in c.117+4A>T and c.1673+5G>A mutations showed that only in the first case was the defect at the 5′ splice site corrected, indicating that mutations near the invariant GT donor sites are mechanistically different. These findings indicate the feasibility of the hybrid minigene approach to detect splicing defects, particularly in patients in whom the RNA is not available. In addition, the present results suggest that modified U1 snRNAs may represent a new therapeutic strategy for arOP patients with a U1 snRNP‐dependent splicing defect. Hum Mutat 24:225–235, 2004. © 2004 Wiley‐Liss, Inc.

We report a hollow core Nested Antiresonant Nodeless Fibre (NANF) with a loss of 0.65dB/km across the full C and L telecommunication bands. The fabricated fibre is 1.23km long, it is effectively single moded over sufficiently long lengths, and is able to transmit data.