Editorial

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Multi-omics Analyses of Starvation Responses Reveal a Central Role for Lipoprotein Metabolism in Acute Starvation Survival in <i>C. elegans</i>

Starvationcauses comprehensivemetabolicchanges, which are still not fully understood. Here, we used quantitative proteomics and RNA sequencing to examine the temporal starvation responses in wildtype Caenorhabditis elegans and animals lacking the transcription factor HLH-30. Our findings show that starvation alters the abundance of hundreds of proteins and mRNAs in a temporal manner, many of which are involved in central metabolic pathways, including lipoprotein metabolism. We demonstrate that premature death of hlh-30 animals under starvation can be prevented by knockdown of either vit-1 or vit-5, encoding two different lipoproteins. We further showthat the size and number of intestinal lipid droplets under starvation are altered in hlh-30 animals, which can be rescued by knockdown of vit-1. Taken together, this indicates that survival of hlh-30 animals under starvation is closely linked to regulation of intestinal lipid stores. We provide the most detailed poly-omic analysis of starvation responses to date, which serves as a resource for further mechanistic studies of starvation

The placental RCAS1 expression during stillbirth

Background: Independently of the fetal death cause the beginning and course of stillbirth is closely related with the growing cytotoxic activity at the maternal-fetal interface. RCAS1 participates in the inhibition of maternal immune response during pregnancy. The alterations of RCAS1 protein expression in placental cells seem to determine the beginning of the labor and participate in the placental abruption. The aim of the present study was to investigate RCAS1 expression in placentas obtained following stillbirths or normal term births. Methods: RCAS1 expression was evaluated by Western blot method with the use of monoclonal anti-RCAS1 antibody in 67 placental tissue samples. Pregnant women were divided into four groups according to the mode of labor onset – spontaneous or induced, and the type of labor, stillbirth or labor at term. Placental beta-Actin expression was chosen as a control protein. Relative amounts of placental RCAS1 were compared with the use of Student's t-test, whereas beta-Actin control data were compared with the use of Mann-Whitney U test. Results: The average relative amount of RCAS1 was significantly lower in women with induced stillbirths than in women with induced labor at term. Similarly, significantly lower RCAS1 placental levels were observed in patients with spontaneous stillbirths than in women with spontaneous labor at term. Significant differences in RCAS1 expression were also observed with the respect to the beginning of the stillbirth: spontaneous and induced. Lowest RCAS1 placental levels were observed in women with spontaneous stillbirth. Conclusions: These preliminary results indicate that the alterations of RCAS1 expression in the human placenta may be involved in the changes of maternal immune system that take place during stillbirth

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

The nuclear lamina couples mechanical forces to cell fate in the preimplantation embryo via actin organization

During preimplantation development, contractile forces generated at the apical cortex segregate cells into inner and outer positions of the embryo, establishing the inner cell mass (ICM) and trophectoderm. To which extent these forces influence ICM-trophectoderm fate remains unresolved. Here, we found that the nuclear lamina is coupled to the cortex via an F-actin meshwork in mouse and human embryos. Actomyosin contractility increases during development, upregulating Lamin-A levels, but upon internalization cells lose their apical cortex and downregulate Lamin-A. Low Lamin-A shifts the localization of actin nucleators from nucleus to cytoplasm increasing cytoplasmic F-actin abundance. This results in stabilization of Amot, Yap phosphorylation and acquisition of ICM over trophectoderm fate. By contrast, in outer cells, Lamin-A levels increase with contractility. This prevents Yap phosphorylation enabling Cdx2 to specify the trophectoderm. Thus, forces transmitted to the nuclear lamina control actin organization to differentially regulate the factors specifying lineage identity

Thin channel β-Ga2O3 MOSFETs with self-aligned refractory metal gates

We report the first demonstration of self-aligned gate (SAG) β-Ga2O3 metal-oxide-semiconductor field-effect transistors (MOSFETs) as a path toward eliminating source access resistance for low-loss power applications. The SAG process is implemented with a subtractively defined and etched refractory metal, such as Tungsten, combined with ion-implantation. We report experimental and modeled DC performance of a representative SAG device that achieved a maximum transconductance of 35 mS mm-1 and an on-resistance of ∼30 Ω mm with a 2.5 μm gate length. These results highlight the advantage of implant technology for SAG β-Ga2O3 MOSFETs enabling future power switching and RF devices with low parasitic resistance. © Not subject to copyright in the USA. Contribution of Wright-Patterson AFB

Enhancement-mode Ga2O3 wrap-gate fin field-effect transistors on native (100) β-Ga2O3 substrate with high breakdown voltage

Sn-doped gallium oxide (Ga2O3) wrap-gate fin-array field-effect transistors (finFETs) were formed by top-down BCl3 plasma etching on a native semi-insulating Mg-doped (100) β-Ga2O3 substrate. The fin channels have a triangular cross-section and are approximately 300 nm wide and 200 nm tall. FinFETs, with 20 nm Al2O3 gate dielectric and ∼2 μm wrap-gate, demonstrate normally-off operation with a threshold voltage between 0 and +1 V during high-voltage operation. The ION/IOFF ratio is greater than 105 and is mainly limited by high on-resistance that can be significantly improved. At VG = 0, a finFET with 21 μm gate-drain spacing achieved a three-terminal breakdown voltage exceeding 600 V without a field-plate

Production of YP170 Vitellogenins Promotes Intestinal Senescence in Caenorhabditis elegans

During aging, etiologies of senescence cause multiple pathologies, leading to morbidity and death. To understand aging requires identification of these etiologies. For example, C. elegans hermaphrodites consume their own intestinal biomass to support yolk production, which in later life drives intestinal atrophy and ectopic yolk deposition. Yolk proteins (vitellogenins) exist as 3 abundant species: YP170, derived from vit-1 - vit-5, and YP115 and YP88, derived from vit-6. Here we show that inhibiting YP170 synthesis leads to a reciprocal increase in YP115/YP88 levels and vice versa, an effect involving post-transcriptional mechanisms. Inhibiting YP170 production alone, despite increasing YP115/YP88 synthesis, reduces intestinal atrophy as much as inhibition of all YP synthesis, which increases lifespan. By contrast, inhibiting YP115/YP88 production alone accelerates intestinal atrophy and reduces lifespan, an effect that is dependent upon increased YP170 production. Thus, despite copious abundance of both YP170 and YP115/YP88, only YP170 production is coupled to intestinal atrophy and shortened lifespan. In addition, increasing levels of YP115/YP88 but not of YP170 increases resistance to oxidative stress; thus, longevity resulting from reduced vitellogenin synthesis is not attributable to oxidative stress resistance

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362