IMPORTANCE: Effective and well-tolerated, interferon-free regimens are needed for treatment of patients with chronic hepatitis C virus (HCV) infection and cirrhosis. OBJECTIVE: All-oral therapy with ...daclatasvir (nonstructural protein 5A NS5A inhibitor), asunaprevir (NS3 protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor), with or without ribavirin, was evaluated in patients with HCV genotype 1 infection and compensated cirrhosis. DESIGN, SETTING, AND PARTICIPANTS: The UNITY-2 study was conducted between December 2013 and October 2014 at 49 outpatient sites in the United States, Canada, France, and Australia. Patients were treated for 12 weeks, with 24 weeks of follow-up after completion of treatment. Adult patients with cirrhosis were enrolled in 2 cohorts: HCV treatment-naive or HCV treatment-experienced. Statistical analyses were based on historical controls; there were no internal controls. INTERVENTIONS: All patients received twice-daily treatment with the fixed-dose combination of daclatasvir (30 mg), asunaprevir (200 mg), and beclabuvir (75 mg). In addition, patients within each cohort were stratified according to HCV genotype 1 subtype (1a or 1b) and randomly assigned (1:1) to receive double-blinded weight-based ribavirin (1000-1200 mg/d) or matching placebo. MAIN OUTCOMES AND MEASURES: Sustained virologic response at posttreatment week 12 (SVR12). RESULTS: One hundred twelve patients in the treatment-naive group and 90 patients in the treatment-experienced group were treated and included in the analysis. Enrolled patients were 88% white with a median age of 58 years (treatment-naive group) or 60 years (treatment-experienced group); 74% had genotype 1a infection. SVR12 rates were 98% (97.5% CI, 88.9%-100%) for patients in the treatment-naive group and 93% (97.5% CI, 85.0%-100.0%) for those in the treatment-experienced group when ribavirin was included in the regimen. With the fixed-dose combination alone, response rates were 93% (97.5% CI, 85.4%-100.0%) for patients in the treatment-naive group and 87% (97.5% CI, 75.3%-98.0%) for those in the treatment-experienced group. Three serious adverse events were considered to be treatment related and there were 4 adverse event–related discontinuations. Treatment-emergent grade 3 or 4 alanine aminotransferase elevations were observed in 4 patients, of which 1 had concomitant total bilirubin elevation. CONCLUSIONS AND RELEVANCE: In this open-label uncontrolled study, patients with chronic HCV genotype 1 infection and cirrhosis who received a 12-week oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir, with or without ribavirin, achieved high rates of SVR12.
The continuing expansion of seaweed cultivation could assist in ensuring future global food security. The Laminariales species
Alaria esculenta
and
Saccharina latissima
are each cultivated for food ...across their European ranges. The predominant method for cultivating European kelps involves growing juveniles on twine within a hatchery which is then deployed at a farm site. The associated hatchery and deployment cost of this approach are relatively high. A new and innovative methodology—called binder-seeding—can reduce these costs, but, has yet to be validated. We compare the biomass yield and morphology of
A. esculenta
and
S. latissima
cultured using either the traditional twine-longline method or binder-seeding onto AlgaeRope and AlgaeRibbon, specially designed textiles. In a controlled growth experiment,
A. esculenta
had a similar biomass yield on all materials, but fronds were shorter (23 ± 7%) and thinner on the AlgaeRibbon (42 ± 4%) due to a 3–4-fold higher density of developing sporophytes compared to the twine-longline. In contrast,
S. latissima
gave a 4-fold higher biomass yield on the AlgaeRibbon in June (4.0 kg m
−1
), but frond morphology was not different between materials, despite a 4-fold higher sporophyte density on the AlgaeRibbon. The stipe length of both species also increased at the higher sporophyte density on the AlgaeRibbon. The AlgaeRope gave an intermediate response or was similar to the twine-longline. These results show that binder-seeding onto the AlgaeRibbon significantly increases the achieved biomass yield in
S. latissima.
These results can assist cultivators to select the most appropriate method of kelp cultivation depending on morphological/yield requirements of the end use. Further study is needed on the optimisation of the binder-seeding density and its impact on thallus morphology.
ABSTRACT
A synthesis of new publically available borehole and bathymetric data, combined with a wealth of other existing disparate data sources, reveals new insights into the Quaternary history of ...the Bristol Channel area. Sediment boreholes throughout the Bristol Channel confirm the area was glaciated in the Pleistocene. Till is present below marine deposits and, in some areas, is visible morphologically as submerged moraines. In the central and eastern Bristol Channel the submerged valley course of the palaeo‐Severn is very clear in new high‐resolution bathymetric surveys. This former river course and associated tributaries cross‐cut through glacial sediments in the Bristol Channel. At least three phases of glaciation are recorded in the Bristol Channel, one related to the southern limits of a Late Devensian Substage (∼Marine Isotope Stage (MIS) 2) Welsh Ice Cap which reached into Swansea Bay, an earlier Devensian (MIS 4–3) glaciation associated with Irish Sea ice, and another older glaciation that is associated with ice that filled the entire outer and central Bristol Channel. The age of the older Bristol Channel glaciation is still open, although it pre‐dates the Devensian (Late Pleistocene) and must date to the Middle Pleistocene. It is therefore evident that Pleistocene glacial and fluvial activity, combined with subsequent post‐glacial sea transgression, directly account for current morphometries of the Bristol Channel and Severn Estuary, and the current geography of the SW British Isles.
The macroalga Saccharina latissima holds promise as a widespread crop in northern Europe. Currently, seeded lines are cultured for 1–2 months within a hatchery until they become ≥1 mm sporophytes, ...which are then outplanted to a farm. Textiles are being developed as a cultivation substrate for macroalgae, however due to their large surface area, these need either direct in-situ seeding at the farm or a very short, high turnover hatchery period. Two materials, Kuralon twine and non-woven textile, were seeded using three S. latissima developmental stages: meiospore, gametophyte or juvenile sporophyte. The gametophyte and sporophyte stages were applied using a binder solution to adhere them to the materials. These were outplanted at a seaweed farm in the Sound of Kerrera, UK. After 5 weeks, fronds were significantly larger (45 ± 25 mm) and more abundant (20 ± 8·20 cm−1) when seeded with sporophytes over gametophytes or meiospores (8 ± 10 mm and 2 ± 2·20 cm−1). This reflects the growth advantage of outplanting juvenile sporophytes, since they are larger and more developed when outplanted. Higher fouling of filamentous algae was seen on the non-woven textile but this did not appear to affect growth. After four months, sporophyte seeded materials had the largest fronds and the greatest fresh mass of 2.1 ± 0.8 kg·20 cm−1, equivalent to simultaneously deployed hatchery reared twine (2.0 ± 0.1 kg·20 cm−1). Gametophyte seeding achieved 0.8 ± 0.6 kg·20 cm−1 while meiospore seeding achieved only 0.1 ± 0.1 kg·20 cm−1. No difference was found between growth on Kuralon twine or non-woven textile (p > 0.05), showing that both are suitable growth substrates. Seeding of juvenile sporophytes onto textile using the binder is demonstrated to be a successful method for the cultivation of S. latissima, and may require only 1% of the hatchery tankage, once optimised. It is expected that this method is transferable to the cultivation of other kelp species.
•Seeding of Saccharina latissima using sporophytes, gametophytes or meiospores•Sporophyte seeding resulted in higher fresh weight and larger thalli after four month.•Both Kuralon twine and a non-woven textile gave the same results.•Fouling was greater on the non-woven textile than Kuralon twine.•Sporophyte seeding, can reduce the space needed for kelp hatcheries.
Capillary malformation-arteriovenous malformation (CM-AVM) is a blood vascular anomaly caused by inherited loss-of-function mutations in RASA1 or EPHB4 genes, which encode p120 Ras GTPase-activating ...protein (p120 RasGAP/RASA1) and Ephrin receptor B4 (EPHB4). However, whether RASA1 and EPHB4 function in the same molecular signaling pathway to regulate the blood vasculature is uncertain. Here, we show that induced endothelial cell-specific (EC-specific) disruption of Ephb4 in mice resulted in accumulation of collagen IV in the EC ER, leading to EC apoptotic death and defective developmental, neonatal, and pathological angiogenesis, as reported previously in induced EC-specific RASA1-deficient mice. Moreover, defects in angiogenic responses in EPHB4-deficient mice could be rescued by drugs that inhibit signaling through the Ras pathway and drugs that promote collagen IV export from the ER. However, EPHB4-mutant mice that expressed a form of EPHB4 that is unable to physically engage RASA1 but retains protein tyrosine kinase activity showed normal angiogenic responses. These findings provide strong evidence that RASA1 and EPHB4 function in the same signaling pathway to protect against the development of CM-AVM independent of physical interaction and have important implications for possible means of treatment of this disease.
The phaeophyte macroalgae
Sargassum muticum
is under investigation as a cultivation crop within its native range in SE Asia, alongside other members of the
Sargassum
genus. During the critical ...hatchery phase, germlings are grown to ≥ several millimeters ready for outplanting. By optimising the growth medium and twine substrate used for the germling attachment, hatcheries can become more efficient and cost-effective. An 8-week replicated laboratory experiment investigated these factors. It found that adding 0.125 mL L
−1
of saturated germanium dioxide during the first week increased mean germling size by 23% (
p
< 0.005), whereas additional nutrients in the form of F/2 medium made no difference (
p
> 0.05). Six twine substrates were also tested: jute, cotton, polyamide/cotton, polyester, polyvinyl alcohol and polypropylene.
Sargassum muticum
grew similarly well on all, although attachment success during the first week was highest on the rougher natural fibres, particularly jute. A negative density-dependent effect of germling density on growth was seen across all materials, with the highest growth seen on the materials with the lowest germling density. Jute is recommended as a highly suitable substrate for hatchery cultivation in this species, although the initial density should be carefully controlled to prevent intraspecific competition.
Only a few small glaciers survive today in the Mountains of the Mediterranean. Notable examples are found in the Pyrenees, Maritime Alps, Italian Apennines, the Dinaric and Albanian Alps and the ...mountains of Turkey. Many glaciers disappeared during the 20th Century. Glaciers were much larger and more numerous during the Little Ice Age. Small glaciers even existed as far south as the High Atlas of Morocco and the Sierra Nevada of southern Spain. In more northerly areas, such as the western Balkans, glaciers and permanent snow fields occupied hundreds of cirques on relatively low-lying mountains. In the High Atlas and the Sierra Nevada no glaciers exist today, whilst in the Balkans only a few modern glaciers have been reported (<10). A similar situation is apparent throughout the mountains of the Mediterranean region. This paper presents new evidence for glacier change since the Little Ice Age and reviews the extent, timing and climatic significance of Little Ice Age glaciation in all the main mountain areas.
Past human mountain settlement patterns and resource and high-altitude landscape exploitation are underexplored research fields in archaeology. This study presents data gathered during more than 20 ...years of fieldwork in the Pindus range of Western Macedonia (Greece), focusing in particular on Holocene land use. The investigated territory is located around the Vlach town of Samarina. The area is partly bounded by Mounts Vasilitsa, Gurguliu, Bogdani and Anitsa, and their interconnecting watersheds between ca. 1400 and 2000 m a.s.l. This research led to the discovery of many sites and findspots of lithic and ceramic artefacts attributed to the Middle and Upper Palaeolithic, Mesolithic, Late Neolithic, Chalcolithic, Bronze Age, and several Historical periods. The radiocarbon results show an unexpected longue durée of Holocene human landscape use. The number of sites, their distribution, location, and subsistence strategies exhibit shifts between the Middle Palaeolithic and different periods of the Holocene, which are closely related to the exploitation of the mountain environment and its resources. Moreover, typical knapped stone artefacts have been used as a proxy for dating the glacial landforms which characterise the Samarina highland zone; we correlate them to the better-known moraine systems of Mount Tymphi in Epirus and contribute to the reconstruction of the Pleistocene glacial landscapes of the Pindus Range.
The ice age Ehlers, Jürgen; Hughes, Philip; Gibbard, Philip L
2016/01/01, 2015, 2016, 2015-10-19, 2015-10-09
eBook
This book provides a new look at the climatic history of the last 2.6 million years during the ice age, a time of extreme climatic fluctuations that have not yet ended. This period also coincides ...with important phases of human development from Neanderthals to modern humans, both of whom existed side by side during the last cold stage of the ice age. The ice age has seen dramatic expansions of glaciers and ice sheets, although this has been interspersed with relatively short warmer intervals like the one we live in today. The book focuses on the changing state of these glaciers and the effects of associated climate changes on a wide variety of environments (including mountains, rivers, deserts, oceans and seas) and also plants and animals. For example, at times the Sahara was green and colonized by humans, and Lake Chad covered 350, 000 km2 – larger than the United Kingdom. What happened during the ice age can only be reconstructed from the traces that are left in the ground. The work of the geoscientist is similar to that of a detective who has to reconstruct the sequence of events from circumstantial evidence. The book draws on the specialisms and experience of the authors who are experts on the glacial history of the Earth. Readership: Undergraduate and postgraduate students studying the Quaternary, researchers, and anyone interested in climate change, environmental change and geology. The book provides a rich collection of illustrations and photographs to help the readers at all levels visualise the dramatic consequences of glacier expansions during the Ice Age.
Despite much progress with remote sensing, on-site measurements of glacier mass balance (with stakes and snow pits) still have advantages for resolution of interannual and seasonal changes of mass ...balance. Understanding these changes may help to identify the types of glaciers most sensitive to climate change. The standard deviation of mass balance data series for a few years describes the interannual variability, and balance amplitude, defined as half the difference between winter and summer balances, describes the seasonal variability. Interannual variability increases with seasonal variability, and seasonal variability increases with annual precipitation and summer temperature available from a half-degree gridded climatology. Measured glaciers have higher mean and median precipitation than average for all glaciers in the Randolph Glacier Inventory (version 6). High balance amplitudes are associated with warm/wet (maritime) environments and low amplitudes with cold/dry (continental) environments, as shown in previous studies of climate at the equilibrium line altitude. Balance amplitude can be modelled for half-degree grid squares in the glacier inventory using multiple regression of measured balance amplitude on the climate data. The resulting modelled balance amplitude is relatively low for Arctic Islands and Central Asia, but high for Western North America, Iceland, Scandinavia, Alps, and Caucasus.
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