Enthesis tissue engineering: biological requirements meet at the interface

Tendon-to-bone interface (enthesis) exhibits a complex multiscale architectural and compositional organization maintained by a heterogeneous cellular environment. Orthopedic surgeons have been facing several challenges when treating tendon pullout or tear from the bony insertion due to unsatisfactory surgical outcomes and high retear rates. The limited understanding of enthesis hinders the development of new treatment options toward enhancing regeneration. Mimicking the natural tissue structure and composition is still a major challenge to be overcome. In this review, we critically assess current tendon-to-bone interface tissue engineering strategies through the use of biological, biochemical, or biophysical cues, which must be ultimately combined into sophisticated gradient systems. Cellular strategies are described, focusing on cell sources and cocultures to emulate a physiological heterotypic niche, as well as hypoxic environments, alongside with growth factor delivery and the use of platelet-rich hemoderivatives. Biomaterial design considerations are revisited, highlighting recent progresses in tendon-to-bone scaffolds. Mechanical loading is addressed to uncover prospective engineering advances. Finally, research challenges and translational aspects are considered. In summary, we highlight the importance of deeply investigating enthesis biology toward establishing foundational expertise and integrate cues from the native niche into novel biomaterial engineering, aiming at moving today's research advances into tomorrow's regenerative therapies.Authors thank the support from the European Union Framework Programme for Research and Innovation HORIZON2020 [TEAMING Grant agreement No 739572 - The Discoveries CTR]; FCT–Fundação para a Ciência e a Tecnologia for the PhD grant of IC [PD/BD/128088/2016]; the Project NORTE-01-0145-FEDER-000021:“Accelerating tissue engineering and personalized medicine discoveries by the integration of key enabling nanotechnologies, marine-derived biomaterials and stem cells”, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) and the ERC Consolidator grant of ME [ERC-2017-CoG-772817]

Search for Gravitational Waves Associated with Gamma-Ray Bursts Detected by Fermi and Swift during the LIGO-Virgo Run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC-2020 March 27 17:00 UTC). We conduct two independent searches: A generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate. © 2022. The Author(s). Published by the American Astronomical Society

Narrowband Searches for Continuous and Long-duration Transient Gravitational Waves from Known Pulsars in the LIGO-Virgo Third Observing Run

Isolated neutron stars that are asymmetric with respect to their spin axis are possible sources of detectable continuous gravitational waves. This paper presents a fully coherent search for such signals from eighteen pulsars in data from LIGO and Virgo's third observing run (O3). For known pulsars, efficient and sensitive matched-filter searches can be carried out if one assumes the gravitational radiation is phase-locked to the electromagnetic emission. In the search presented here, we relax this assumption and allow both the frequency and the time derivative of the frequency of the gravitational waves to vary in a small range around those inferred from electromagnetic observations. We find no evidence for continuous gravitational waves, and set upper limits on the strain amplitude for each target. These limits are more constraining for seven of the targets than the spin-down limit defined by ascribing all rotational energy loss to gravitational radiation. In an additional search, we look in O3 data for long-duration (hours-months) transient gravitational waves in the aftermath of pulsar glitches for six targets with a total of nine glitches. We report two marginal outliers from this search, but find no clear evidence for such emission either. The resulting duration-dependent strain upper limits do not surpass indirect energy constraints for any of these targets. © 2022. The Author(s). Published by the American Astronomical Society

Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux

Cystic fibrosis is a disease caused by defective function of a chloride channel coupled to a blockade of autophagic flux. It has been proposed to use synthetic chloride transporters as pharmacological agents to compensate insufficient chloride fluxes. Here, we report that such chloride anionophores block autophagic flux in spite of the fact that they activate the pro-autophagic transcription factor EB (TFEB) coupled to the inhibition of the autophagy-suppressive mTORC1 kinase activity. Two synthetic chloride transporters (SQ1 and SQ2) caused a partially TFEB-dependent relocation of the autophagic marker LC3 to the Golgi apparatus. Inhibition of TFEB activation using a calcium chelator or calcineurin inhibitors reduced the formation of LC3 puncta in cells, yet did not affect the cytotoxic action of SQ1 and SQ2 that could be observed after prolonged incubation. In conclusion, the squaramide-based synthetic chloride transporters studied in this work (which can also dissipate pH gradients) are probably not appropriate for the treatment of cystic fibrosis yet might be used for other indications such as cancer.</p

Effectiveness of an integrated phonological awareness approach for children with childhood apraxia of speech (CAS)

This study investigated the effectiveness of an integrated phonological awareness approach for children with childhood apraxia of speech (CAS). Change in speech, phonological awareness, letter knowledge, word decoding, and spelling skills were examined. A controlled multiple single-subject design was employed. Twelve children aged 4—7 years with CAS participated in two 6-week intervention blocks (2 sessions per week), separated by a 6-week withdrawal block. Nine children with CAS made significant gains in their production of target speech sounds and these demonstrated transfer of skills to connected speech for at least one speech target. Eight children showed significant gains in at least one target phoneme awareness skill, and these children demonstrated transfer of skills to novel phoneme awareness tasks. As a group the children with CAS demonstrated improvement in phonological awareness, letter knowledge, word decoding, and spelling ability. An integrated phonological awareness programme was an effective method of simultaneously improving speech, phoneme awareness, word decoding, and spelling ability for some children with CAS