Design, in silico evaluation, and in vitro verification of new bivalent Smac mimetics with pro-apoptotic activity.

Bivalent Smac mimetics have been shown to possess binding affinity and pro-apoptotic activity similar to or more potent than that of native Smac, a protein dimer able to neutralize the anti-apoptotic activity of an inhibitor of caspase enzymes, XIAP, which endows cancer cells with resistance to anticancer drugs. We design five new bivalent Smac mimetics, which are formed by various linkers tethering two diazabicyclic cores being the IAP binding motifs. We built in silico models of the five mimetics by the TwistDock workflow and evaluated their conformational tendency, which suggests that compound 3, whose linker is n-hexylene, possess the highest binding potency among the five. After synthesis of these compounds, their ability in tumour cell growth inhibition and apoptosis induction displayed in experiments with SK-OV-3 and MDA-MB-231 cancer cell lines confirms our prediction. Among the five mimetics, compound 3 displays promising pro-apoptotic activity and deserves further optimization.

High-throughput computational materials screening of transition metal peroxides.

Semiconductor materials of abnormal stoichiometric ratio often exhibit unique properties, yet it is still a challenge to determine the structures of such materials in an efficient way. Herein, we propose a method for structurally biased screening according to the coordination numbers and the numbers of Wyckoff positions, balancing the atom local environment and the global symmetry of structures. Based on first-principles calculations, we have predicted two metastable peroxides P21/c-ScO2 and Pmmn-TiO3 with more than six coordination points. For these two structures, the most stable intrinsic defect is the oxygen vacancy (VO) at the peroxide anion (O2-2), which induces the absence of antibonding orbital formed by O2-2 near the valence band maximum. With the introduction of VO, the decrease of coordination numbers leads to charge recombination, and results in the appearance of an ordered phase TiO2.5 with stronger Ti-O orbital hybridization. The proposed method presents a promising and feasible approach for the screening of novel compounds.

Management of floating hip injury: a review of the literature.

Aim: The aim of this study was to provide a comprehensive overview of floating hip injury and attempt to provide a management algorithm. Methods: PubMed was searched using the terms 'Floating hip' or 'acetabular fracture' and 'Ipsilateral femoral fracture' or 'pelvic fracture' and 'Ipsilateral femoral fracture'. One author performed a preliminary review of the abstracts and references of the retrieved articles. Results: The mean injury severe score reported was higher than 20. Chest and abdominal injuries, as well as fractures at other sites, were the most common associated injuries. Despite the high disability rate, surgery remained the preferred option for managing these injuries. The surgical timing varied from a few hours to several days and was subjected to the principles of damage control orthopedics. Although, in most cases, fixation of femoral fractures took precedence over pelvic or acetabular fractures, there was still a need to consider the impact of damage control orthopedics, associated injuries, and surgeon's considerations and preferences. Posttraumatic arthritis, neurological deficits, heterotopic ossification, femoral head necrosis, femoral nonunion, and limb inequality were common complications of the floating hip injury. Conclusions: The severity of such injuries often exceeds that of an isolated injury and often requires specialized multidisciplinary treatment. In the management of these complex cases, the complexity and severity of the injury should be fully assessed, and an appropriate surgical plan should be developed to perform definitive surgery as early as possible, with attention to prevention of complications during the perioperative period.

Clinical effect of full endoscopic lumbar annulus fibrosus suture.

PURPOSE: The aim of this study was to investigate the clinical efficacy of full endoscopic lumbar annulus fibrosus suture in the treatment of single-segment lumbar disc herniation (LDH). METHODS: The clinical data of patients with single-segment LDH who underwent full endoscopic lumbar discectomy from January 2017 to January 2019 in our hospital were retrospectively analysed. Patients with full endoscopic lumbar discectomy combined with annulus fibrosus suture were divided into group A, and those with simple full endoscopic lumbar discectomy were divided into group B. The general information, surgery-related data, visual analog scale (VAS), Oswestry disability index (ODI), modified MacNab score at the last follow-up, reoperation rate and recurrence were compared between the two groups. RESULTS: All patients were followed up for 12 to 24 months, and the surgical time was 133.6 ± 9.6 min in group A and 129.0 ± 11.7 min in group B. The difference was not statistically significant (p > 0.05). The blood loss of group A was higher than that of group B, and the difference was statistically significant when comparing the groups (p < 0.05). The postoperative symptoms of patients in both groups were significantly relieved, and the VAS score of low back pain and ODI index were significantly lower than the preoperative ones at all postoperative time points (1 month after surgery, 3 months after surgery, and at the last follow-up) (p < 0.05), but there was no significant difference between the groups (p > 0.05). The excellent rate of MacNab at the last follow-up in the two groups were 93.55% and 87.80%, respectively, with no statistically significant difference (p > 0.05). At the last follow-up, the recurrence rate of group A was significantly lower than that of group B, and the difference was statistically significant (p < 0.05), while the difference between the reoperation rate of the two groups was not statistically significant (p > 0.05). CONCLUSIONS: Full endoscopic lumbar discectomy combined with annulus fibrosus repair reduces the postoperative recurrence rate and achieves satisfactory clinical outcomes.

Genetic surveillance reveals low, sustained malaria transmission with clonal replacement in Sao Tome and Principe.

Despite efforts to eliminate malaria in Sao Tome and Principe (STP), cases have recently increased. Understanding residual transmission structure is crucial for developing effective elimination strategies. This study collected surveillance data and generated amplicon sequencing data from 980 samples between 2010 and 2016 to examine the genetic structure of the parasite population. The mean multiplicity of infection (MOI) was 1.3, with 11% polyclonal infections, indicating low transmission intensity. Temporal trends of these genetic metrics did not align with incidence rates, suggesting that changes in genetic metrics may not straightforwardly reflect changes in transmission intensity, particularly in low transmission settings where genetic drift and importation have a substantial impact. While 88% of samples were genetically linked, continuous turnover in genetic clusters and changes in drug-resistance haplotypes were observed. Principal component analysis revealed some STP samples were genetically similar to those from Central and West Africa, indicating possible importation. These findings highlight the need to prioritize several interventions such as targeted interventions against transmission hotspots, reactive case detection, and strategies to reduce the introduction of new parasites into this island nation as it approaches elimination. This study also serves as a case study for implementing genetic surveillance in a low transmission setting.