Genetic evaluation of suspected osteogenesis imperfecta (OI)

Osteogenesis imperfecta (OI) is probably the most common genetic form of fracture predisposition. The term OI encompasses a broad range of clinical presentations that may be first apparent from early in pregnancies to late in life, reflecting the extent of bone deformity and fracture predisposition at different stages of development or postnatal ages. Depending on the age of presentation, OI can be difficult to distinguish from some other genetic and nongenetic causes of fractures, including nonaccidental injury (abuse). The strategies for evaluation and the testing discussed here provide guidelines for evaluation that should help to distinguish among causes for fracture and bone deformity

Preservation of microvascular barrier function requires CD31 receptor-induced metabolic reprogramming

Endothelial barrier (EB) breaching is a frequent event during inflammation, and it is followed by the rapid recovery of microvascular integrity. The molecular mechanisms of EB recovery are poorly understood. Triggering of MHC molecules by migrating T-cells is a minimal signal capable of inducing endothelial contraction and transient microvascular leakage. Using this model, we show that EB recovery requires a CD31 receptor-induced, robust glycolytic response sustaining junction re-annealing. Mechanistically, this response involves src-homology phosphatase activation leading to Akt-mediated nuclear exclusion of FoxO1 and concomitant \u3b2-catenin translocation to the nucleus, collectively leading to cMyc transcription. CD31 signals also sustain mitochondrial respiration, however this pathway does not contribute to junction remodeling. We further show that pathologic microvascular leakage in CD31-deficient mice can be corrected by enhancing the glycolytic flux via pharmacological Akt or AMPK activation, thus providing a molecular platform for the therapeutic control of EB response

Radiolucent lines below the tibial component of a total knee replacement (TKR) – a comparison between single-and two-stage cementation techniques

Early non-progressive horizontal radiolucent lines (RLLs) (<2 mm) under the tibial component following cemented total knee replacement (TKR) are considered to result from poor cement injection into cancellous bone. These RLLs may facilitate the entry of joint fluid and wear debris into the interface, which may proceed to ballooning osteolysis. There is currently no consensus on the preferred cementing technique (single- versus two-stage cementation) in TKR. We have prospectively analysed postoperative radiographs in 50 consecutive TKRs to compare the RLLs following single- (25 TKRs) and two-stage (25 TKRs) cementation techniques. Of the TKR radiographs studied, 26 (52%) had RLLs; nine (36%) of these were single-stage TKRs, and 17 (68%) were two-stage TKRs. This study demonstrates that single-stage cementing may be superior to the two-stage technique in terms of avoiding RLLs in immediate postoperative TKRs

Pre-fusion structure of a human coronavirus spike protein

HKU1 is a human betacoronavirus that causes mild yet prevalent respiratory disease1, and is related to the zoonotic SARS2 and MERS3 betacoronaviruses, which have high fatality rates and pandemic potential. Cell tropism and host range is determined in part by the coronavirus spike (S) protein4, which binds cellular receptors and mediates membrane fusion. As the largest known class I fusion protein, its size and extensive glycosylation have hindered structural studies of the full ectodomain, thus preventing a molecular understanding of its function and limiting development of effective interventions. Here we present the 4.0 Å resolution structure of the trimeric HKU1 S protein determined using singleparticle cryo-electron microscopy. In the pre-fusion conformation, the receptor-binding subunits, S1, rest above the fusion-mediating subunits, S2, preventing their conformational rearrangement. Surprisingly, the S1 C-terminal domains are interdigitated and form extensive quaternary interactions that occlude surfaces known in other coronaviruses to bind protein receptors. These features, along with the location of the two protease sites known to be important for coronavirus entry, provide a structural basis to support a model of membrane fusion mediated by progressive S protein destabilization through receptor binding and proteolytic cleavage. These studies should also serve as a foundation for the structure-based design of betacoronavirus vaccine immunogens.NI