Fibroblast growth factor (FGF) signaling in development and skeletal diseases

AbstractFibroblast growth factors (FGF) and their receptors serve many functions in both the developing and adult organism. Humans contain 18 FGF ligands and four FGF receptors (FGFR). FGF ligands are polypeptide growth factors that regulate several developmental processes including cellular proliferation, differentiation, and migration, morphogenesis, and patterning. FGF-FGFR signaling is also critical to the developing axial and craniofacial skeleton. In particular, the signaling cascade has been implicated in intramembranous ossification of cranial bones as well as cranial suture homeostasis. In the adult, FGFs and FGFRs are crucial for tissue repair. FGF signaling generally follows one of three transduction pathways: RAS/MAP kinase, PI3/AKT, or PLCγ. Each pathway likely regulates specific cellular behaviors. Inappropriate expression of FGF and improper activation of FGFRs are associated with various pathologic conditions, unregulated cell growth, and tumorigenesis. Additionally, aberrant signaling has been implicated in many skeletal abnormalities including achondroplasia and craniosynostosis. The biology and mechanisms of the FGF family have been the subject of significant research over the past 30 years. Recently, work has focused on the therapeutic targeting and potential of FGF ligands and their associated receptors. The majority of FGF-related therapy is aimed at age-related disorders. Increased understanding of FGF signaling and biology may reveal additional therapeutic roles, both in utero and postnatally. This review discusses the role of FGF signaling in general physiologic and pathologic embryogenesis and further explores it within the context of skeletal development

Listening to ecosystems: data-rich acoustic monitoring through landscape-scale sensor networks

Ecologists have many ways to measure and monitor ecosystems, each of which can reveal details about the processes unfolding therein. Acoustic recording combined with machine learning methods for species detection can provide remote, automated monitoring of species richness and relative abundance. Such recordings also open a window into how species behave and compete for niche space in the sensory environment. These opportunities are associated with new challenges: the volume and velocity of such data require new approaches to species identification and visualization. Here we introduce a newly-initiated acoustic monitoring network across the subtropical island of Okinawa, Japan, as part of the broader OKEON (Okinawa Environmental Observation Network) project. Our aim is to monitor the acoustic environment of Okinawa’s ecosystems and use these space–time data to better understand ecosystem dynamics. We present a pilot study based on recordings from five field sites conducted over a one-month period in the summer. Our results provide a proof of concept for automated species identification on Okinawa, and reveal patterns of biogenic vs. anthropogenic noise across the landscape. In particular, we found correlations between forest land cover and detection rates of two culturally important species in the island soundscape: the Okinawa Rail and Ruddy Kingfisher. Among the soundscape indices we examined, NDSI, Acoustic Diversity and the Bioacoustic Index showed both diurnal patterns and differences among sites. Our results highlight the potential utility of remote acoustic monitoring practices that, in combination with other methods can provide a holistic picture of biodiversity. We intend this project as an open resource, and wish to extend an invitation to researchers interested in scientific collaboration

Measurement of the nuclear modification factor for muons from charm and bottom hadrons in Pb+Pb collisions at 5.02 TeV with the ATLAS detector

Heavy-flavour hadron production provides information about the transport properties and microscopic structure of the quark-gluon plasma created in ultra-relativistic heavy-ion collisions. A measurement of the muons from semileptonic decays of charm and bottom hadrons produced in Pb+Pb and pp collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV with the ATLAS detector at the Large Hadron Collider is presented. The Pb+Pb data were collected in 2015 and 2018 with sampled integrated luminosities of 208 mu b(-1) and 38 mu b(-1), respectively, and pp data with a sampled integrated luminosity of 1.17 pb(-1) were collected in 2017. Muons from heavy-flavour semileptonic decays are separated from the light-flavour hadronic background using the momentum imbalance between the inner detector and muon spectrometer measurements, and muons originating from charm and bottom decays are further separated via the muon track's transverse impact parameter. Differential yields in Pb+Pb collisions and differential cross sections in pp collisions for such muons are measured as a function of muon transverse momentum from 4 GeV to 30 GeV in the absolute pseudorapidity interval vertical bar eta vertical bar < 2. Nuclear modification factors for charm and bottom muons are presented as a function of muon transverse momentum in intervals of Pb+Pb collision centrality. The bottom muon results are the most precise measurement of b quark nuclear modification at low transverse momentum where reconstruction of B hadrons is challenging. The measured nuclear modification factors quantify a significant suppression of the yields of muons from decays of charm and bottom hadrons, with stronger effects for muons from charm hadron decays

A search for an unexpected asymmetry in the production of e+μ− and e−μ+ pairs in proton-proton collisions recorded by the ATLAS detector at root s = 13 TeV

This search, a type not previously performed at ATLAS, uses a comparison of the production cross sections for e(+)mu(-) and e(-)mu(+) pairs to constrain physics processes beyond the Standard Model. It uses 139 fb(-1) of proton-proton collision data recorded at root s = 13 TeV at the LHC. Targeting sources of new physics which prefer final states containing e(+)mu(-) and e(-)mu(+), the search contains two broad signal regions which are used to provide model-independent constraints on the ratio of cross sections at the 2% level. The search also has two special selections targeting supersymmetric models and leptoquark signatures. Observations using one of these selections are able to exclude, at 95% confidence level, singly produced smuons with masses up to 640 GeV in a model in which the only other light sparticle is a neutralino when the R-parity-violating coupling lambda(23)(1)' is close to unity. Observations using the other selection exclude scalar leptoquarks with masses below 1880 GeV when g(1R)(eu) = g(1R)(mu c) = 1, at 95% confidence level. The limit on the coupling reduces to g(1R)(eu) = g(1R)(mu c) = 0.46 for a mass of 1420 GeV

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Measurements of photo-nuclear jet production in Pb plus Pb collisions with ATLAS

Ultra-peripheral heavy ion collisions provide a unique opportunity to study the parton distributions in the colliding nuclei via the measurement of photo-nuclear jet production. An analysis of jet production in ultra-peripheral Pb+Pb collisions at √sNN = 5.02 TeV performed using data collected with the ATLAS detector in 2015 is described. The data set corresponds to a total Pb+Pb integrated luminosity of 0.38 nb−1. The ultra-peripheral collisions are selected using a combination of forward neutron and rapidity gap requirements. The cross-sections, not unfolded for detector response, are compared to results from Pythia Monte Carlo simulations re-weighted to match a photon spectrum obtained from the STARlight model. Qualitative agreement between data and these simulations is observed over a broad kinematic range suggesting that using these collisions to measure nuclear parton distributions is experimentally realisable

Measurements of photo-nuclear jet production in Pb + Pb collisions with ATLAS

Ultra-peripheral heavy ion collisions provide a unique opportunity to study the parton distributions in the colliding nuclei via the measurement of photo-nuclear jet production. An analysis of jet production in ultra-peripheral Pb+Pb collisions at √sNN = 5.02 TeV performed using data collected with the ATLAS detector in 2015 is described. The data set corresponds to a total Pb+Pb integrated luminosity of 0.38 nb⁻¹. The ultra-peripheral collisions are selected using a combination of forward neutron and rapidity gap requirements. The cross-sections, not unfolded for detector response, are compared to results from Pythia Monte Carlo simulations re-weighted to match a photon spectrum obtained from the STARlight model. Qualitative agreement between data and these simulations is observed over a broad kinematic range suggesting that using these collisions to measure nuclear parton distributions is experimentally realisable

Association of Sex Mismatch Between Donor and Recipient With Graft Survivorship at 5 Years After Osteochondral Allograft Transplantation

BACKGROUND Sex mismatch between donor and recipient has been considered a potential contributor to adverse outcomes after solid organ transplantation. However, the influence of sex mismatching in osteochondral allograft (OCA) transplantation has yet to be determined. PURPOSE To evaluate whether donor-recipient sex mismatching affects graft survival after OCA transplantation. STUDY DESIGN Cohort study; Level of evidence, 3. METHODS In this review of prospectively collected data, patients who underwent OCA transplantation between November 2013 and November 2017 by a single surgeon were analyzed. Cumulative survival was assessed via the Kaplan-Meier method using log-rank tests to compare patients with similar donor groups. Multivariable Cox regression analysis adjusted for patient age, graft size, and body mass index was used to evaluate the influence of donor-recipient sex on graft survival. RESULTS A total of 154 patients were included: 102 (66.2%) who received OCAs from a same-sex donor and 52 (33.8%) who received OCAs from a different-sex donor. At 5-year follow-up, a significantly lower graft survival rate was observed for different-sex donor transplantation in comparison with same-sex donorship (63% vs 92%; P = .01). When correcting for age, graft size, and body mass index, donor-recipient sex-mismatch transplantation demonstrated a 2.9-times greater likelihood to fail at 5 years compared with donor-recipient same-sex transplantation (95% CI, 1.11-7.44; P = .03). A subgroup analysis showed no significant difference in graft survival between the female-to-female and female-to-male groups (91% and 84%, respectively). Conversely, male-to-male transplantation demonstrated a significantly higher cumulative 5-year survival (94%; P = .04), whereas lower survival was found with male-to-female donorship (64%; P = .04). Multivariable Cox regression indicated a 2.6-times higher likelihood of failure for the male-to-female group in comparison with the other groups (95% CI, 1.03-6.69; P = .04). Male-to-male transplantation had a tendency toward decreased likelihood of OCA failure (hazard ratio, 0.33), although without statistical significance (95% CI, 0.11-1.01; P = .052). CONCLUSION Mismatch between donor and recipient sex had a negative effect on OCA survival after transplantation, particularly in those cases when male donor tissue was transplanted into a female recipient

Adenovirus-mediated gene delivery: Potential applications for gene and cell-based therapies in the new era of personalized medicine

With rapid advances in understanding molecular pathogenesis of human diseases in the era of genome sciences and systems biology, it is anticipated that increasing numbers of therapeutic genes or targets will become available for targeted therapies. Despite numerous setbacks, efficacious gene and/or cell-based therapies still hold the great promise to revolutionize the clinical management of human diseases. It is wildly recognized that poor gene delivery is the limiting factor for most in vivo gene therapies. There has been a long-lasting interest in using viral vectors, especially adenoviral vectors, to deliver therapeutic genes for the past two decades. Among all currently available viral vectors, adenovirus is the most efficient gene delivery system in a broad range of cell and tissue types. The applications of adenoviral vectors in gene delivery have greatly increased in number and efficiency since their initial development. In fact, among over 2000 gene therapy clinical trials approved worldwide since 1989, a significant portion of the trials have utilized adenoviral vectors. This review aims to provide a comprehensive overview on the characteristics of adenoviral vectors, including adenoviral biology, approaches to engineering adenoviral vectors, and their applications in clinical and preclinical studies with an emphasis in the areas of cancer treatment, vaccination and regenerative medicine. Current challenges and future directions regarding the use of adenoviral vectors are also discussed. It is expected that the continued improvements in adenoviral vectors should provide great opportunities for cell and gene therapies to live up to its enormous potential in personalized medicine