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"Collins, T."
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Twists in the fibrodysplasia ossificans progressiva story challenge and expand our understanding of BMP biology
Fibrodysplasia ossificans progressiva (FOP) is an ultrarare, debilitating disease in which heterotopic bone is formed in certain soft tissues. A gain-of-function variant in the cytoplasmic domain of the activin A receptor type I (ACVR1) exists in all patients with FOP. Strikingly, these FOP-causing variants imbue a neofunction to ACVR1 - the ability to recognize activin A as an agonist with bone morphogenic protein-like signaling that leads to heterotopic ossification (HO). These findings are supported by the efficacy of anti-activin A antibodies in preventing HO in FOP mice. This surprising story continues in companion papers in this issue of the JCI. Aykul et al. and Lees-Shepard et al. independently found that antibodies against ACVR1, which were being developed as potential therapeutics for FOP, instead caused HO in FOP mice. While this unexpected finding may be the clinical final act for such antibodies, it provides another twist in the unique and evolving FOP story.
Journal Article
Consequences of using chronological age versus corrected age when testing cognitive and motor development in infancy and intelligence quotient at school age for children born preterm
Children born preterm (<37 weeks' gestation) have an increased risk of poor neurodevelopment, including lower intelligence quotient (IQ) scores compared with their term-born counterparts. To explore the differences in psychometric scores for cognition and motor skills when they are age-standardized according to chronological age instead of corrected age for children born preterm. We assessed = 554 children born <33 weeks' gestation with the Bayley Scales of Infant Development, 2.sup.nd edition (mental and motor scores) at 18 months and the Weschler Abbreviated Scale of Intelligence (IQ score) at seven years of age. Scores were standardized according to chronological age and corrected age and differences between mean chronological and corrected scores were compared, along with the proportion of children whose scores could be classified as impaired. When scores were standardized according to chronological age instead of corrected age there was a large significant difference of 17.3 points on the mental scale (79.5 vs. 96.8, respectively) and 11.8 points on the motor scale (84.8 vs. 96.6, respectively) at 18 months. By seven years, the difference in IQ scores remained, although of a smaller magnitude at 1.9 points between mean chronological and corrected age scoring (97.2 vs. 99.1, respectively). Consistent with previous literature, outcome assessments for preterm infants consistently differed according to use of chronological or corrected age to standardized scores. Cognitive scores were impacted more severely than motor scores, and differences were more substantial in early childhood than later in childhood. For clinical purposes, correction for preterm birth is only likely to have an impact during early childhood, however assessments for research purposes should continue to correct into childhood to account for the persistent bias due to preterm birth.
Journal Article
Tripled yield in direct-drive laser fusion through statistical modelling
Focusing laser light onto a very small target can produce the conditions for laboratory-scale nuclear fusion of hydrogen isotopes. The lack of accurate predictive models, which are essential for the design of high-performance laser-fusion experiments, is a major obstacle to achieving thermonuclear ignition. Here we report a statistical approach that was used to design and quantitatively predict the results of implosions of solid deuterium–tritium targets carried out with the 30-kilojoule OMEGA laser system, leading to tripling of the fusion yield to its highest value so far for direct-drive laser fusion. When scaled to the laser energies of the National Ignition Facility (1.9 megajoules), these targets are predicted to produce a fusion energy output of about 500 kilojoules—several times larger than the fusion yields currently achieved at that facility. This approach could guide the exploration of the vast parameter space of thermonuclear ignition conditions and enhance our understanding of laser-fusion physics.
A statistical approach to designing and predicting the fusion yield of cryogenic deuterium–tritium implosions leads to tripled yield in direct-drive laser fusion of deuterium–tritium layered targets.
Journal Article
A Systematic Review and Meta-Analysis of Human Milk Feeding and Morbidity in Very Low Birth Weight Infants
This systematic review and meta-analysis synthesised the post-1990 literature examining the effect of human milk on morbidity, specifically necrotising enterocolitis (NEC), late onset sepsis (LOS), retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD) and neurodevelopment in infants born ≤28 weeks’ gestation and/or publications with reported infant mean birth weight of ≤1500 g. Online databases including Medline, PubMed, CINAHL, Scopus, and the Cochrane Central Register of Controlled Trials were searched, and comparisons were grouped as follows: exclusive human milk (EHM) versus exclusive preterm formula (EPTF), any human milk (HM) versus EPTF, higher versus lower dose HM, and unpasteurised versus pasteurised HM. Experimental and observational studies were pooled separately in meta-analyses. Risk of bias was assessed for each individual study and the GRADE system used to judge the certainty of the findings. Forty-nine studies (with 56 reports) were included, of which 44 could be included in meta-analyses. HM provided a clear protective effect against NEC, with an approximate 4% reduction in incidence. HM also provided a possible reduction in LOS, severe ROP and severe NEC. Particularly for NEC, any volume of HM is better than EPTF, and the higher the dose the greater the protection. Evidence regarding pasteurisation is inconclusive, but it appears to have no effect on some outcomes. Improving the intake of mother’s own milk (MOM) and/or donor HM results in small improvements in morbidity in this population.
Journal Article
Fibrous Dysplasia of Bone and McCune–Albright Syndrome: A Bench to Bedside Review
Fibrous dysplasia is an uncommon mosaic disorder in which bone is replaced by structurally unsound fibro-osseous tissue. It is caused by the sporadic post-zygotic activating mutations in GNAS, resulting in dysregulated GαS-protein signaling in affected tissues. This manifests on a broad clinical spectrum ranging from insignificant solitary lesions to severe disease with deformities, fractures, functional impairment, and pain. Fibrous dysplasia may present in isolation or in association with hyperfunctioning endocrinopathies and café-au-lait macules, known as McCune–Albright Syndrome. This review summarizes the current understanding of pathophysiology in fibrous dysplasia, describes key pre-clinical and clinical investigations, and details the current approach to diagnosis and management.
Journal Article
Xylanases, xylanase families and extremophilic xylanases
Xylanases are hydrolytic enzymes which randomly cleave the β 1,4 backbone of the complex plant cell wall polysaccharide xylan. Diverse forms of these enzymes exist, displaying varying folds, mechanisms of action, substrate specificities, hydrolytic activities (yields, rates and products) and physicochemical characteristics. Research has mainly focused on only two of the xylanase containing glycoside hydrolase families, namely families 10 and 11, yet enzymes with xylanase activity belonging to families 5, 7, 8 and 43 have also been identified and studied, albeit to a lesser extent. Driven by industrial demands for enzymes that can operate under process conditions, a number of extremophilic xylanases have been isolated, in particular those from thermophiles, alkaliphiles and acidiphiles, while little attention has been paid to cold-adapted xylanases. Here, the diverse physicochemical and functional characteristics, as well as the folds and mechanisms of action of all six xylanase containing families will be discussed. The adaptation strategies of the extremophilic xylanases isolated to date and the potential industrial applications of these enzymes will also be presented.
Journal Article
McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia
Fibrous dysplasia (FD) is sometimes accompanied by extraskeletal manifestations that can include any combination of café-au-lait macules, hyperfunctioning endocrinopathies, such as gonadotropin-independent precocious puberty, hyperthyroidism, growth hormone excess, FGF23-mediated renal phosphate wasting, and/or Cushing syndrome, as well as other less common features. The combination of any of these findings, with or without FD, is known as McCune-Albright syndrome (MAS). The broad spectrum of involved tissues and the unpredictable combination of findings owe to the fact that molecular defect is due to dominant activating mutations in the widely expressed signaling protein, G
s
α, and the fact these mutations arises sporadically, often times early in development, prior to gastrulation, and can distribute across many or few tissues.
The complexity can be mastered by a systematic screening of potentially involved tissues and cognizance that the pattern of involved tissues is established, to some degree, in utero. Thorough testing allows the clinician to establish, often times at presentation, the full extent of the disease, and importantly as well what tissues are unaffected. Treatment and follow-up can then be focused on affected systems and a meaningful prognosis can be offered to the patient and family. The authors outline screening and treatment strategies that allow for effective management of the extraskeletal manifestations of FD.
Journal Article
Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting
Notch and vascular endothelial growth factor receptor (VEGFR) coordinates endothelial cells behaviour during angiogenesis sprouting although exactly how is uncertain. Endothelial cells dynamically compete for the leading position in a sprout through relative levels of Vegfr1 and Vegfr2 in a Notch dependent manner.
Sprouting angiogenesis requires the coordinated behaviour of endothelial cells, regulated by Notch and vascular endothelial growth factor receptor (VEGFR) signalling. Here, we use computational modelling and genetic mosaic sprouting assays
in vitro
and
in vivo
to investigate the regulation and dynamics of endothelial cells during tip cell selection. We find that endothelial cells compete for the tip cell position through relative levels of
Vegfr1
and
Vegfr2
, demonstrating a biological role for differential
Vegfr
regulation in individual endothelial cells. Differential
Vegfr
levels affect tip selection only in the presence of a functional Notch system by modulating the expression of the ligand Dll4. Time-lapse microscopy imaging of mosaic sprouts identifies dynamic position shuffling of tip and stalk cells
in vitro
and
in vivo
, indicating that the VEGFR–Dll4–Notch signalling circuit is constantly re-evaluated as cells meet new neighbours. The regular exchange of the leading tip cell raises novel implications for the concept of guided angiogenic sprouting.
Journal Article