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BACKGROUND: The Gompertz-Makeham law describes a characteristic pattern of mortality in human populations where death rate is near constant between age 18 and 30 years (Makeham's Law) and rises exponentially thereafter (Gompertz Law). This pattern has not been described in surgical populations, but if true, would have important implications for understanding surgical risk and design and interpretation of surgical risk models. The aim of this study was to determine if the Gompertz-Makeham law applies to perioperative mortality risk and the conditions under which it may apply. METHODS: We examined the relationship between age and 1-month postoperative all-cause mortality risk in a 10-year New Zealand administrative dataset comprising of 5,615,100 surgical procedures from 2007 to 2016. The dataset includes patient and surgical factors including procedures, American Society of Anesthesiologist's physical status score (ASA-PS), diagnoses and other relevant details. Semi-logarithmic graphs of mortality risk and age were plotted. Linear regression models were fitted, with regression line slope and Pearson's correlation coefficient calculated. RESULTS: The primary outcome occurred in 114,782 (2.0%) of 5,615,100 included participants. The Gompertz-Makeham law seems to apply to the national surgical population as a whole (slope = 0.0241, R2 = 0.971). The law applies in all subgroups studied including sex, ASA-PS, surgical acuity, surgical severity category, cancer status and ethnicity (slopes 0.0066 to 0.0307, R2 0.771 to 0.990). Important interactions were found between age, mortality risk and three high risk groups (cancer diagnosis, ASA-PS 4-5 and high surgical severity). CONCLUSIONS: The Gompertz-Makeham law seems to apply in a national cohort of surgical patients. The inflection point for increased 1-month risk is apparent at age 30 years. A strict exponential rise in mortality risk occurs thereafter. This finding improves our understanding of surgical risk and suggests a concept-driven approach to improve modelling of age and important interactions in future surgical risk models.

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Neurosteroids such as progesterone and allopregnanolone have been shown to exert neuroprotective effects under a variety of pathological or insult conditions, and there is evidence that the neurosteroid system is perturbed in Multiple Sclerosis (MS) patients. Neurosteroids are synthesized in the central nervous system (CNS) through a series of metabolic transformations, beginning with a rate-limiting step of cholesterol transport through the outer mitochondrial membrane via the transporter translocator protein (TSPO). We examined the effects of etifoxine and XBD-173, two different brain penetrant TSPO agonists, for their ability to ameliorate clinical signs in two different experimental autoimmune encephalitis (EAE) models. Etifoxine, as previously reported, was efficacious in EAE, while XBD-173 was not. Surprisingly, XBD-173, but not etifoxine elevated relevant neurosteroids in brain of female rats and differed in its ability to exert anti-inflammatory and direct neuroprotective effects in vitro as compared to etifoxine. We conclude that the neurosteroid elevations produced in brain by XBD-173 are not sufficient to ameliorate EAE and suggest that etifoxine may have additional mechanisms of action that provide therapeutic benefit in this model system.

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The matrix (MA) domain of the HIV-1 structural precursor Gag (PrGag) protein targets PrGag proteins to membrane assembly sites, and facilitates incorporation of envelope proteins into virions. To evaluate the specific requirements for the MA membrane-binding domain (MBD) in HIV-1 assembly and replication, we examined viruses in which MA was replaced by alternative MBDs. Results demonstrated that the pleckstrin homology domains of AKT protein kinase and phospholipase C delta1 efficiently directed the assembly and release of virus-like particles (VLPs) from cells expressing chimeric proteins. VLP assembly and release also were mediated in a phorbol ester-dependent fashion by the cysteine-rich binding domain of phosphokinase Cgamma. Although alternative MBDs promoted VLP assembly and release, the viruses were not infectious. Notably, PrGag processing was reduced, while cleavage of GagPol precursors resulted in the accumulation of Pol-derived intermediates within virions. Our results indicate that the HIV-1 assembly machinery is flexible with regard to its means of membrane association, but that alternative MBDs can interfere with the elaboration of infectious virus cores.

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In structural studies, the retrovirus capsid interdomain linker region has been shown as a flexible connector between the CA N-terminal domain and its C-terminal domain. To analyze the function of the linker region, we have examined the effects of three Moloney murine leukemia virus (M-MuLV) capsid linker mutations/variations in vivo, in the context of the full-length M-MuLV structural precursor protein (PrGag). Two mutations, A1SP and A5SP, respectively, inserted three and seven additional codons within the linker region to test the effects of increased linker lengths. The third variant, HIV/Mo, represented a chimeric HIV-1/M-MuLV PrGag protein, fused at the linker region. When expressed in cells, the three variants reduced the efficiency of virus particle assembly, with PrGag proteins and particles accumulating at the cellular plasma membranes. Although PrGag recognition of viral RNA was not impaired, the capsid linker variant particles were abnormal, with decreased stabilities, anomalous densities, and aberrant multiple lobed and tubular morphologies. Additionally, rather than crosslinking as PrGag dimers, particle-associated A1SP, A5SP, and HIV/Mo proteins showed an increased propensity to crosslink as trimers. Our results suggest that a wild-type retrovirus capsid linker region is required for the proper alignment of capsid protein domains.

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