Beyond Open Big Data: Addressing Unreliable Research

The National Institute of Health invests US $30.9 billion annually in medical research. However, the subsequent impact of this research output on society and the economy is amplified dramatically as a result of the actual medical treatments, biomedical innovations, and various commercial enterprises that emanate from and depend on these findings. It is therefore a great concern to discover that much of published research is unreliable. We propose extending the open data concept to the culture of the scientific research community. By dialing down unproductive features of secrecy and competition, while ramping up cooperation and transparency, we make a case that what is published would then be less susceptible to the sometimes corrupting and confounding pressures to be first or journalistically attractive, which can compromise the more fundamental need to be robustly correct.     

Relationship between sarcopenia,six‐minute walk distance and health‐related quality of life in liver transplant candidates

Sarcopenia, or loss of skeletal muscle mass, is associated with increased mortality and morbidity in liver transplant (LT) candidates. Six‐minute walk distance (6MWD) and health‐related quality of life (HRQOL) as assessed by short form 36 scores (SF‐36) also impact clinical outcomes in these patients. This study explored the relationship between the sarcopenia, 6MWD, and HRQOL in LT candidates. Sarcopenia was evaluated based on skeletal muscle mass index (SMI) quantified from abdominal computed tomography. Patients were followed until death, removal from the wait list or the end of the study period. Two hundred and thirteen patients listed for LT were included. The mean SMI, 6MWD and mean gait speed were 54.3 ± 9.7, 370.5 m and 1 m/s, respectively. Sarcopenia was noted in 22.2% of LT candidates. There was no correlation between sarcopenia, 6MWD, and SF‐36 scores. The 6MWD, but not sarcopenia, was an independent predictor of mortality (hazard ratio = 2.1 [0.9–4.7]). In summary, sarcopenia did not emerge as a significant predictor of waitlist mortality and also failed to correlate with either functional capacity or HRQOL in LT candidates. In patients with ESLD awaiting LT, 6MWD appears to be a more useful prognostic indicator than the presence of sarcopenia.     

HSV targeting of the host phosphatase PP1α is required for disseminated disease in the neonate and contributes to pathogenesis in the brain

Newborns are significantly more susceptible to severe disease after infection with herpes simplex virus (HSV) compared with adults, with differences in the host response implicated as a major factor. To understand host response differences between these age groups, we investigated the shutoff of protein synthesis by the host and the retargeting of host phosphatase PP1α by the HSV-1 protein γ34.5 for reversal of translational arrest. In a murine newborn model of viral dissemination, infection with the HSV-1 mutant for PP1α binding resulted in complete absence of disease. PP1α-binding mutant HSV-1 replicated in visceral organs early after inoculation, demonstrating that HSV-1 replication requires PP1α-targeting only later in infection. Newborn mice deficient in type I IFN signaling partially rescued the virulence of the PP1α-binding mutant virus, suggesting an IFN-independent role for eIF2α kinases during infection. When we investigated the contribution of PP1α targeting to pathogenesis in the brain, we found that the inability of HSV-1 to bind PP1α increased survival time in both newborn and adult mice. Unlike disseminated disease, type I IFN signaling in the brain was required to attenuate disease following PP1α-mutant virus infection. Furthermore, pharmacologic inhibition of eIF2α dephosphorylation reduced HSV-1 replication in a brain slice culture model of encephalitis. Our findings reveal age-dependent differences in γ34.5 function and tissue-specific reliance on the type I IFN response for protection from HSV disease. These results define an important role for γ34.5 in neonatal infections in contrast to other studies indicating that the autophagy-inhibiting function of γ34.5 is dispensable for pathogenesis in the newborn brain.Herpes simplex virus (HSV) infections cause a wide spectrum of outcomes, ranging from asymptomatic acquisition to lethal dissemination and central nervous system (CNS) disease (1). Newborns are particularly susceptible to HSV disease with over 50% of infected newborns progressing to disseminated disease or encephalitis. Of those who survive the initial encephalitis, 2/3 of newborns will go on to have long-term neurologic morbidity (2). This is in contrast to the adult population, where occurrence of HSV encephalitis and disseminated disease are rare and infection with HSV is often subclinical (3). Either serotype of HSV (HSV-1 or HSV-2) may cause disease in newborns, but recent data suggest a rising incidence of HSV-1 genital infection, paralleled by a predominance of HSV-1 as a cause of newborn disease (4, 5). The striking difference in outcomes between adults and neonates infected with HSV suggests an age-dependent difference in susceptibility to disease based on host factors.It is likely that differences in the immune response in the neonate compared with the adult result in the disparate outcomes following HSV infection, and this was investigated in our current studies.One of the earliest responses to infection is the type I IFN response and the innate pathways modulated by the IFN-inducible double-stranded RNA-dependent protein kinase R (PKR) system. HSV-1 counters the PKR response in part through production of the viral protein γ34.5 for successful replication in cell culture (6, 7). Mutant viruses deleted for the entire γ34.5 gene are significantly attenuated in vivo, and virulence of γ34.5-null HSV-1 is restored in adult PKR^−/− mice in models of ocular and CNS disease (8). Within γ34.5 are domains that specifically target host cell-mediated translational arrest (7, 9), type I IFN response induction through TANK-binding kinase 1 (TBK1) (10), and initiation of autophagy through beclin 1 binding (11, 12). The different functions of HSV-1 γ34.5 have been shown to contribute to replication in cell culture and in some models of HSV disease in the adult; however, evidence suggests that γ34.5 may interact with the host differently in the newborn. We recently demonstrated that the autophagy-inhibiting function of γ34.5 through beclin 1 binding, although important for disease in the adult murine CNS, is completely dispensable for pathogenesis in the neonatal murine brain (13). However, deletion of the entire γ34.5 gene still results in attenuation of HSV in the newborn brain (13), suggesting that there are other functions of γ34.5 that are important for pathogenesis in the neonate.The shutoff of protein synthesis resulting from eIF2α phosphorylation is an important host response to viral replication and ER stress during infection. There are four serine–threonine eIF2α kinases in mammalian cells (PKR, GCN2, HRI, PERK), two of which have been established to control eIF2α phosphorylation during HSV-1 infection, namely PKR and the endoplasmic reticulum (ER) resident kinase PERK (14). In cells infected with a γ34.5-mutant HSV-1, activation of PKR and subsequent eIF2α phosphorylation is responsible for the cessation of protein synthesis. However, wild-type HSV-1 has evolved an effective strategy through γ34.5 to reverse the translational arrest following eIF2α phosphorylation for successful viral replication. The carboxyl terminus of HSV-1 γ34.5 is homologous to the host protein GADD34 (15) and serves as an adaptor molecule to bind both the host phosphatase PP1α and eIF2α, thus targeting eIF2α for dephosphorylation and reversing translational arrest (7, 9, 16, 17). Evidence suggests that PP1α binding by HSV-1 γ34.5 contributes to pathogenesis in an ocular model of HSV disease (18); however, the role of PP1α targeting by HSV in CNS disease or in the unique immune environment of the developing newborn remain unknown.We demonstrate that the PP1α-targeting function of HSV-1 γ34.5 is required for pathogenesis in a model of neonatal disseminated disease. Investigation of early viral replication in visceral organs demonstrate that PP1α binding by HSV-1 is not required for early replication on the first day after infection, but is required for further replication after day 1 postinfection. Ablation of the type I IFN response only partially restored the virulence of a PP1α-binding–deficient virus, suggesting an IFN-independent contribution of PP1α targeting by HSV-1 to disease in the periphery. When inoculated directly intracranially, the PP1α-binding mutant virus was attenuated in both the neonatal and adult brain, suggesting that translational arrest is important for protection from HSV disease in both age groups. Unlike in the periphery, we show that the attenuation of a PP1α-binding mutant virus is dependent on the type I IFN response in the brain. Additionally, inhibiting inducible eIF2α dephosphorylation during HSV infection of organotypic brain slice cultures reduced viral replication in both age groups. Our findings suggest that viral targeting of PP1α mediated by HSV-1 γ34.5 significantly contributes to disease in both the neonate and the adult and that the host responses that result in translational arrest during infection are tissue-dependent.