PEROXIREDOXIN Q stimulates the activity of the chloroplast 16:1Δ3trans FATTY ACID DESATURASE4.

Thylakoid membrane lipids, comprised of glycolipids and the phospholipid phosphatidylglycerol (PG), are essential for normal plant growth and development. Unlike other lipid classes, chloroplast PG in nearly all plants contains a substantial fraction of the unusual trans fatty acid 16:1Δ3trans or 16:1t. We determined that, in Arabidopsis thaliana, 16:1t biosynthesis requires both FATTY ACID DESATURASE4 (FAD4) and a thylakoid-associated redox protein, PEROXIREDOXIN Q (PRXQ), to produce wild-type levels of 16:1t. The FAD4-PRXQ biochemical relationship appears to be very specific in planta, as other fatty acids (FA) desaturases do not require peroxiredoxins for their activity, nor does FAD4 require other chloroplast peroxiredoxins under standard growth conditions. Although most of chloroplast PG assembly occurs at the inner envelope membrane, FAD4 was primarily associated with the thylakoid membranes facing the stroma. Furthermore, co-production of PRXQ with FAD4 was required to produce Δ3-desaturated FAs in yeast. Alteration of the redox state of FAD4 or PRXQ through site-directed mutagenesis of conserved cysteine residues impaired Δ3 FA production. However, these mutations did not appear to directly alter disulfide status of FAD4. These results collectively demonstrate that the production of 16:1t is linked to the redox status of the chloroplast through PRXQ associated with the thylakoids.

Erratum: Measurement of Preheat Due to Nonlocal Electron Transport in Warm Dense Matter [Phys. Rev. Lett. 120, 025002 (2018)].

This corrects the article DOI: 10.1103/PhysRevLett.120.025002.

Assessment of the effects of immunogenicity on the pharmacokinetics, efficacy and safety of tildrakizumab.

BACKGROUND: We evaluated antidrug antibody (ADA) development in patients with chronic plaque psoriasis from three clinical trials of tildrakizumab, a humanized anti-interleukin-23p19 monoclonal antibody (P05495, reSURFACE 1 and reSURFACE 2). OBJECTIVES: To determine the effects of immunogenicity on the pharmacokinetics, efficacy and safety of tildrakizumab. METHODS: In 1400 (weeks 12-16) and 780 (weeks 52-64) evaluable patients randomized to tildrakizumab 100 or 200 mg, treatment-emergent ADA-positive (TE-POS) patients were identified and characterized for neutralizing antibodies (NAbs). Pharmacokinetics, safety and efficacy were evaluated by ADA status. RESULTS: In patients treated with tildrakizumab 100 or 200 mg continuously, < 7% were inconclusive at 52-64 weeks. In long-term data through 52-64 weeks, the incidence of TE-POS was 6·5% (100 mg) and 8·2% (200 mg) and the incidence of TE-POS NAb-POS was 2·5% (100 mg) and 3·2% (200 mg). TE-POS NAb-POS patients had modestly increased median tildrakizumab clearance (36·5%) compared with ADA-NEG patients. Percentage Psoriasis Area and Severity Index improvements in TE-POS NAb-POS vs. ADA-NEG patients on continuous treatment through week 52 were 76% (n = 10) vs. 91% (n = 342) for 100 mg and 77% (n = 12) vs. 87% (n = 299) for 200 mg. The incidence of potential immunogenicity-related adverse events did not indicate a clear trend in any positive ADA patient category compared with ADA-NEG patients through weeks 52-64. The effects of ADA on pharmacokinetics, efficacy and safety at 12-16 weeks were also summarized. CONCLUSIONS: ADA development with tildrakizumab treatment for 52-64 weeks was low; around 3% of patients developed TE-POS NAb-POS ADAs and showed lower serum concentrations and corresponding reduced efficacy. No relationship between ADAs and safety was observed. What's already known about this topic? Unwanted immune responses - for example immunogenicity and antidrug antibodies (ADAs) - have been observed with therapeutic monoclonal antibodies and can affect efficacy and safety. Tildrakizumab is a humanized monoclonal antibody targeting interleukin-23 and is currently approved for patients with plaque psoriasis. What does this study add? ADA development in tildrakizumab-treated patients with psoriasis over 52 weeks was low. The small proportion of patients who had treatment-emergent ADAs and had neutralizing antibodies experienced lower serum tildrakizumab concentrations and reduced efficacy. No relationship between ADAs and safety events was observed.

Results of a pilot study of isoniazid in patients with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP), the most common porphyria of childhood and the third most common porphyria of adulthood, is characterized clinically by painful, non-blistering cutaneous photosensitivity. Two distinct inheritance patterns involving mutations affecting genes that encode enzymes of the heme biosynthetic pathway underlie the clinical phenotype. Aminolevulinic acid synthase 2 (ALAS2), the rate limiting enzyme of the heme pathway in the erythron, is a therapeutic target in EPP because inhibiting enzyme function would reduce downstream production of protoporphyrin IX (PPIX), preventing accumulation of the toxic molecule and thereby ameliorating symptoms. Isoniazid (INH) is widely used for treatment of latent and active M. tuberculosis (TB). Sideroblastic anemia is observed in some patients taking INH, and studies have shown that this process is a consequence of inhibition of ALAS2 by INH. Based on these observations, we postulated that INH might have therapeutic activity in patients with EPP. We challenged this hypothesis in a murine model of EPP and showed that, after 4 weeks of treatment with INH, both plasma PPIX and hepatic PPIX were significantly reduced. Next, we tested the effect of INH on patients with EPP. After eight weeks, no significant difference in plasma or red cell PPIX was observed among the 15 patients enrolled in the study. These results demonstrate that while INH can lower PPIX in an animal model of EPP, the standard dose used to treat TB is insufficient to affect levels in humans.

Measurement of Preheat Due to Nonlocal Electron Transport in Warm Dense Matter.

This Letter presents a novel approach to study electron transport in warm dense matter. It also includes the first x-ray Thomson scattering (XRTS) measurement from low-density CH foams compressed by a strong laser-driven shock at the OMEGA laser facility. The XRTS measurement is combined with velocity interferometry (VISAR) and optical pyrometry (SOP) providing a robust measurement of thermodynamic conditions in the shock. Evidence of significant preheat contributing to elevated temperatures reaching 17.5-35 eV in shocked CH foam is measured by XRTS. These measurements are complemented by abnormally high shock velocities observed by VISAR and early emission seen by SOP. These results are compared to radiation hydrodynamics simulations that include first-principles treatment of nonlocal electron transport in warm dense matter with excellent agreement. Additional simulations confirm that the x-ray contribution to this preheat is negligible.

Fishes in a changing world: learning from the past to promote sustainability of fish populations.

Populations of fishes provide valuable services for billions of people, but face diverse and interacting threats that jeopardize their sustainability. Human population growth and intensifying resource use for food, water, energy and goods are compromising fish populations through a variety of mechanisms, including overfishing, habitat degradation and declines in water quality. The important challenges raised by these issues have been recognized and have led to considerable advances over past decades in managing and mitigating threats to fishes worldwide. In this review, we identify the major threats faced by fish populations alongside recent advances that are helping to address these issues. There are very significant efforts worldwide directed towards ensuring a sustainable future for the world's fishes and fisheries and those who rely on them. Although considerable challenges remain, by drawing attention to successful mitigation of threats to fish and fisheries we hope to provide the encouragement and direction that will allow these challenges to be overcome in the future.

Free Energy Based Equation of State for Pentaerythritol Tetranitrate.

An equation of state for the energetic molecular crystal pentaerythritol tetranitrate (PETN) has been developed from a parametrized model for its Helmholtz free energy. The ion motion contribution to the free energy is represented by a sum of Debye models for the vibrational modes of mainly lattice phonon and intramolecular character. The dependence of the frequencies of the normal modes on density is captured using the quasi-harmonic approximation whereby the Debye temperatures for both populations of modes depend explicitly on specific volume. The dependence of the Debye temperatures on specific volume was parametrized to normal-mode frequencies computed from solid state dispersion-corrected density functional theory. The model provides a good description of the thermophysical properties of PETN. The equation of state has been applied to the calculation of thermodynamic states along the principal Hugoniot of single crystal PETN.

Equation of state measurements of warm dense carbon using laser-driven shock and release technique.

We present a new approach to equation of state experiments that utilizes a laser-driven shock and release technique combined with spatially resolved x-ray Thomson scattering, radiography, velocity interferometry, and optical pyrometry to obtain independent measurements of pressure, density, and temperature for carbon at warm dense matter conditions. The uniqueness of this approach relies on using a laser to create very high initial pressures to enable a very deep release when the shock moves into a low-density pressure standard. This results in material at near normal solid density and temperatures around 10 eV. The spatially resolved Thomson scattering measurements facilitate a temperature determination of the released material by isolating the scattering signal from a specific region in the target. Our results are consistent with quantum molecular dynamics calculations for carbon at these conditions and are compared to several equation of state models.

Evaluation of in vitro storage properties of apheresis platelets suspended in a bicarbonate-containing additive solution with low levels of plasma and stored with a 24-hour interruption of agitation.

BACKGROUND AND OBJECTIVES: PLT additive solutions (PAS) are useful for reducing the frequency and/or severity of plasma-associated transfusion reactions. A new PAS solution, PAS-5, containing 5% plasma, maintains in vitro PLT properties during 7-day storage. Periods with interruption of agitation (IA) ≤24 h routinely occur during PLT shipment and do not usually compromise platelet quality. The aim of the study was to evaluate the properties of PLTs stored for 7 days in 95% PAS-5/5% plasma subjected to a 24-h IA. MATERIALS AND METHODS: Double apheresis Amicus units (n = 12) were collected using a manual PAS-5 addition to hyperconcentrated PLTs. PLT units were equally divided in two containers. Control and test PLTs were stored with continuous agitation at 20-24°C except for 24-h IA period for test units between days 2-3. RESULTS: During storage, levels of glucose, lactate, mitochondrial membrane potential and aggregation significantly differed in test units compared to those of control. The pH levels of test PLTs were less than those of control units with 7/12 test units having pHs <6·2 on Day 7 compared to 1/12 control units. Morphology score, GP1bα expression, ESC values, superoxide production were also less, and activation was greater in test PLTs than those of control. All other parameters were similar between test and control units. CONCLUSION: PLTs stored in PAS-5 solution containing 5% plasma with a 24-h IA results in marked decrements in many in vitro PLT quality parameters during 7-day storage.

Addition of sialidase or p38 MAPK inhibitors does not ameliorate decrements in platelet in vitro storage properties caused by 4 °C storage.

BACKGROUND AND OBJECTIVES: Bacterial proliferation is inhibited in platelets (PLTs) stored at refrigerated temperatures, but also dramatically decreases PLT in vivo survival. Recent studies have demonstrated that cold temperature (CT) stored PLTs secrete sialidases upon re-warming, removing sialic acid from the PLT surface, which may be responsible for clustering of GPIbα and PLT clearance from circulation. In this study, the influence of a sialidase inhibitor or a p38 MAP kinase inhibitor was evaluated in units stored at 4 °C. MATERIALS AND METHODS: After collection of a single Trima apheresis unit (n = 12), PLTs were aliquoted into four 60-ml CLX storage bags. One bag was stored at 20-24 °C (RT) with continuous agitation; a second bag was stored at 4 °C without agitation; a third bag was held at 4 °C without agitation with sialidase inhibitor, a fourth bag was incubated at 4 °C with a p38 MAPK inhibitor without agitation. RESULTS: Beginning from Day 1, all in vitro PLT parameters were adversely affected by CT compared to those of RT. Similar in vitro storage properties were observed in CT PLT in the presence or absence of sialidase or p38 MAPK inhibitors. P38 MAPK phosphorylation inhibition was not observed at CT. Decrease of sialidase activity was observed for 2 days in PLTs stored in additive solution but not in plasma. CONCLUSION: Addition of either sialidase or p38 MAPK inhibitors do not improve any in vitro parameters of PLTs stored at 4 °C in 100% plasma.

Monte Carlo N-Particle forward modeling for density reconstruction of double shell capsule radiographs.

In the Double Shell Inertial Confinement Fusion concept, characterizing the shape asymmetry of imploding metal shells is vital for understanding energy-efficient compression and radiative losses of the thermonuclear fuel. The Monte Carlo N-Particle MCNP® code forward models radiography of Double Shell capsule implosions using the Advanced Radiographic Capability at the National Ignition Facility. A procedure is developed for using MCNP to reconstruct density profiles from the radiograph image intensity. For a given Double Shell imploding target geometry, MCNP radiographs predict image contrast, which can help guide experimental design. In future work, the calculated MCNP synthetic radiographs will be compared with experimental radiographs to determine the radial and azimuthal density profiles of the Double Shell capsules.

Preclinical efficacy of a prototype DNA vaccine: enhanced protection against antigenic drift in influenza virus.

Vaccination with plasmid DNA expression vectors encoding foreign proteins elicits antibodies and cell-mediated immunity and protects against disease in animal models. We report a comparison of DNA vaccines, using contemporary human strains of virus, and clinically licensed (inactivated virus or subvirion) vaccines in preclinical animal models, to better predict their efficacy in humans. Influenza DNA vaccines elicited antibodies in both non-human primates and ferrets and protected ferrets against challenge with an antigenically distinct epidemic human influenza virus more effectively than the contemporary clinically licensed vaccine. These studies demonstrate that DNA vaccines may be more effective, particularly against different strains of virus, than inactivated virus or subvirion vaccines.

Immunogenicity and protective efficacy of a tuberculosis DNA vaccine.

Tuberculosis is the most widespread and lethal infectious disease affecting humans. Immunization of mice with plasmid DNA constructs encoding one of the secreted components of Mycobacterium tuberculosis, antigen 85 (Ag85), induced substantial humoral and cell-mediated immune responses and conferred significant protection against challenge with live M. tuberculosis and M. bovis bacille Calmette-Guérin (BCG). These results indicate that immunization with DNA encoding a mycobacterial antigen provides an efficient and simple method for generating protective immunity and that this technique may be useful for defining the protective antigens of M. tuberculosis, leading to the development of a more effective vaccine.

Similarity decay of enstrophy in an electron fluid.

A similarity decay law is proposed for enstrophy of a one-signed-vorticity fluid in a circular free-slip domain. It excludes the metastable equilibrium enstrophy which cannot drive turbulence, and approaches Batchelor's t(-2) law for strong turbulence. Measurements of the decay of a turbulent electron fluid agree well with the predictions of the decay law for a variety of initial conditions.

Rainfall triggers more deep-seated landslides than Cascadia earthquakes in the Oregon Coast Range, USA.

The coastal Pacific Northwest USA hosts thousands of deep-seated landslides. Historic landslides have primarily been triggered by rainfall, but the region is also prone to large earthquakes on the 1100-km-long Cascadia Subduction Zone megathrust. Little is known about the number of landslides triggered by these earthquakes because the last magnitude 9 rupture occurred in 1700 CE. Here, we map 9938 deep-seated bedrock landslides in the Oregon Coast Range and use surface roughness dating to estimate that past earthquakes triggered fewer than half of the landslides in the past 1000 years. We find landslide frequency increases with mean annual precipitation but not with modeled peak ground acceleration or proximity to the megathrust. Our results agree with findings about other recent subduction zone earthquakes where relatively few deep-seated landslides were mapped and suggest that despite proximity to the megathrust, most deep-seated landslides in the Oregon Coast Range were triggered by rainfall.

Channel initiation and the problem of landscape scale.

Since the 1940s it has been proposed that landscape dissection into distinct valleys is limited by a threshold of channelization that sets a finite scale to the landscape. This threshold is equal to the hillslope length that is just shorter than that necessary to support a channel head. A field study supports this hypothesis by showing that an empirically defined topographic threshold associated with channel head locations also defines the border between essentially smooth, undissected hillslopes and the valley bottoms to which they drain. This finding contradicts assertions that landscapes are scale-independent and suggests that landscape response to changes in climate or land use depends on the corresponding changes in the threshold of channelization.

Squalene in petroleum asphaltenes.

Squalene, 2,6,10,15,19,23-hexamethyl-2,6,10,14,18,22-tetracosahexaene, a new biological marker, has been detected in various petroleum asphaltenes and their pyrolysis products. Since squalene is the most common triterpenoid in nature and the biological precursor of the important tetra- and pentacyclic triterpane markers, its detection in asphaltene suggests new ways for marker correlations.

Vascular pathology in male Lewis rats following short-term, low-dose rotenone administration.

The long-term administration of low doses of rotenone has been used to produce a model of Parkinson disease (PD) in rats. However, only about 50% of similarly treated rats develop the PD-like syndrome, with many dying during the first few days of treatment. The lesions in male Lewis rats that became moribund or died after short-term, low-dose rotenone administration are described. Dosed rats had fibrinoid change and acute hemorrhage involving small arteries and arterioles of the brain and lungs. The thalamus, hypothalamus, and medulla oblongata were most frequently and severely affected. Blood vessels in the brain of some male Lewis rats appeared acutely susceptible to the effects of rotenone. Understanding the selective nature of the fibrinoid change and hemorrhage might explain how rotenone produces PD-like signs and lesions in rats, and it might also provide the basis for a model of intraparenchymal hemorrhagic cerebrovascular disease (i.e., hemorrhagic strokes) in humans.

Direct-drive double-shell implosion: A platform for burning-plasma physics studies.

Double-shell ignition designs have been studied with the indirect-drive inertial confinement fusion (ICF) scheme in both simulations and experiments in which the inner-shell kinetic energy was limited to ∼10-15 kJ, even driven by megajoule-class lasers such as the National Ignition Facility. Since direct-drive ICF can couple more energy to the imploding shells, we have performed a detailed study on direct-drive double-shell (D^{3}S) implosions with state-of-the-art physics models implemented in radiation-hydrodynamic codes (lilac and draco), including nonlocal thermal transport, cross-beam energy transfer (CBET), and first-principles-based material properties. To mitigate classical unstable interfaces, we have proposed the use of a tungsten-beryllium-mixed inner shell with gradient-density layers that can be made by magnetron sputtering. In our D^{3}S designs, a 70-µm-thick beryllium outer shell is driven symmetrically by a high-adiabat (α≥10), 1.9-MJ laser pulse to a peak velocity of ∼240 km/s. Upon spherical impact, the outer shell transfers ∼30-40 kJ of kinetic energy to the inner shell filled with deuterium-tritium gas or liquid, giving neutron-yield energies of ∼6 MJ in one-dimensional simulations. Two-dimensional high-mode draco simulations indicated that such high-adiabat D^{3}S implosions are not susceptible to laser imprint, but the long-wavelength perturbations from the laser port configuration along with CBET can be detrimental to the target performance. Nevertheless, neutron yields of ∼0.3-1.0-MJ energies can still be obtained from our high-mode draco simulations. The robust α-particle bootstrap is readily reached, which could provide a viable platform for burning-plasma physics studies. Once CBET mitigation and/or more laser energy becomes available, we anticipate that break-even or moderate energy gain might be feasible with the proposed D^{3}S scheme.

Automated telephone follow-up after breast cancer: an acceptability and feasibility pilot study.

Traditional clinical follow-up after breast cancer is inefficient at detecting relapse and is poorly suited to detecting and ameliorating psychological problems. There is interest in developing more effective and efficient methods of follow-up. We report a prospective cohort study of the acceptability and feasibility of remote, automated telephone follow-up after breast cancer. Women with a history of breast cancer were approached at their annual follow-up visit. For participants, the follow-up questionnaire was administered on paper at baseline. In place of a clinic visit following year, the women completed the same questionnaire using an automated telephone system. All patients were given mammograms. A semi-structured interview was then conducted to assess the acceptability. The potential impact on clinic usage was assessed. In all, 110 of 121 women (91%) agreed to participate. Seventy-five patients (71%) completed follow-up using the new automated system 1 year later. Seventy-one of the 75 patients found the system easy to use. Forty-nine of the 75 (65.33%) liked the system and were happy to use it as their sole method of follow-up. A further 12% were happy to use it as part of their follow-up. In only 10.66% of participants were concerns raised which led to clinic attendance. Automated questionnaire-based telephone follow-up is acceptable to women and has the potential to reduce attendance at clinic. Further studies to validate this method further are planned.