33356 A multinational chart review to examine gastrointestinal symptoms and their management in patients treated with apremilast for plaque psoriasis

Background: Diarrhea and nausea are the most common adverse events observed in phase 3 clinical trials and real-world studies of apremilast, an oral phosphodiesterase-4 inhibitor indicated for moderate-to-severe plaque psoriasis. Methods: A retrospective chart review was conducted between June and November 2020 in the United States (US) and France among patients with moderate psoriasis experiencing gastrointestinal (GI) symptoms within 3 months of initiating apremilast. Results: Dermatologists in US (200) and in France (52) abstracted patient charts (US: 494, France: 128). The following GI symptoms were reported: ‒diarrhea (US: 67% [331/494]; France: 76% [97/128]) with median time from onset to resolution/improvement of 26 days (US) and 21 days (France) ‒nausea (US: 52% [255/494]; France: 34% [44/128]) with median time from onset to resolution/improvement of 21 days (US) and 24 days (France). Management strategies for diarrhea included pharmacologic (loperamide/bismuth subsalicylate/racecadotril) with or without nonpharmacologic (dietary modifications, taking with food)/fiber (US: 30% [99/331], France: 41% [40/97]) and nonpharmacologic only (US: 32% [105/331], France: 27% [26/97]). Management strategies for nausea included pharmacologic (diphenhydramine/metoclopramide/metopimazine) with or without nonpharmacologic (dietary modifications, taking with food, avoidance of vigorous activity) (US: 5% [14/255], France: 30% [13/44]) and nonpharmacologic only (US: 58% [147/255], France: 36% [16/44]). Resolution/improvement of GI symptoms was observed in patients who used pharmacologic strategies and nonpharmacologic strategies. Conclusions: Recommendations to manage diarrhea and nausea after apremilast initiation with pharmacologic or non-pharmacologic strategies were effective and symptoms usually resolved within 3-4 weeks of onset

Temporal transcriptome and metabolite analyses provide insights into the biochemical and physiological processes underlying endodormancy release in pistachio (Pistacia vera L.) flower buds

Pistachio (Pistacia vera L.), an economically and nutritionally important tree crop, relies on winter chill for bud endodormancy break and subsequent blooming and nut production. However, insufficient winter chill poses an increasing challenge in pistachio growing regions. To gain a better understanding of the physiological and biochemical responses of endodormant pistachio buds to chilling accumulation, we investigated the global gene expression changes in flower buds of pistachio cv. Kerman that were cultivated at three different orchard locations and exposed to increasing durations of winter chill. The expression of genes encoding β-1,3-glucanase and β-amylase, enzymes responsible for breaking down callose (β-1,3-glucan) and starch (α-1,4-glucan), respectively, increased during the endodormancy break of pistachio buds. This result suggested that the breakdown of callose obstructing stomata as well as the release of glucose from starch enables symplasmic trafficking and provides energy for bud endodormancy break and growth. Interestingly, as chilling accumulation increased, there was a decrease in the expression of nine-cis-epoxycarotenoid dioxygenase (NCED), encoding an enzyme that uses carotenoids as substrates and catalyzes the rate-limiting step in abscisic acid (ABA) biosynthesis. The decrease in NCED expression suggests ABA biosynthesis is suppressed, thus reducing inhibition of endodormancy break. The higher levels of carotenoid precursors and a decrease in ABA content in buds undergoing endodormancy break supports this suggestion. Collectively, the temporal transcriptome and biochemical analyses revealed that the degradation of structural (callose) and non-structural (starch) carbohydrates, along with the attenuation of ABA biosynthesis, are critical processes driving endodormancy break in pistachio buds

Nuclear receptor binding protein 1 regulates intestinal progenitor cell homeostasis and tumour formation.

Genetic screens in simple model organisms have identified many of the key components of the conserved signal transduction pathways that are oncogenic when misregulated. Here, we identify H37N21.1 as a gene that regulates vulval induction in let-60(n1046gf), a strain with a gain-of-function mutation in the Caenorhabditis elegans Ras orthologue, and show that somatic deletion of Nrbp1, the mouse orthologue of this gene, results in an intestinal progenitor cell phenotype that leads to profound changes in the proliferation and differentiation of all intestinal cell lineages. We show that Nrbp1 interacts with key components of the ubiquitination machinery and that loss of Nrbp1 in the intestine results in the accumulation of Sall4, a key mediator of stem cell fate, and of Tsc22d2. We also reveal that somatic loss of Nrbp1 results in tumourigenesis, with haematological and intestinal tumours predominating, and that nuclear receptor binding protein 1 (NRBP1) is downregulated in a range of human tumours, where low expression correlates with a poor prognosis. Thus NRBP1 is a conserved regulator of cell fate, that plays an important role in tumour suppression

Characterization of Endothelial Progenitor Cell Interactions with Human Tropoelastin.

The deployment of endovascular implants such as stents in the treatment of cardiovascular disease damages the vascular endothelium, increasing the risk of thrombosis and promoting neointimal hyperplasia. The rapid restoration of a functional endothelium is known to reduce these complications. Circulating endothelial progenitor cells (EPCs) are increasingly recognized as important contributors to device re-endothelialization. Extracellular matrix proteins prominent in the vessel wall may enhance EPC-directed re-endothelialization. We examined attachment, spreading and proliferation on recombinant human tropoelastin (rhTE) and investigated the mechanism and site of interaction. EPCs attached and spread on rhTE in a dose dependent manner, reaching a maximal level of 56±3% and 54±3%, respectively. EPC proliferation on rhTE was comparable to vitronectin, fibronectin and collagen. EDTA, but not heparan sulfate or lactose, reduced EPC attachment by 81±3%, while full attachment was recovered after add-back of manganese, inferring a classical integrin-mediated interaction. Integrin αVβ3 blocking antibodies decreased EPC adhesion and spreading on rhTE by 39±3% and 56±10% respectively, demonstrating a large contribution from this specific integrin. Attachment of EPCs on N-terminal rhTE constructs N25 and N18 accounted for most of this interaction, accompanied by comparable spreading. In contrast, attachment and spreading on N10 was negligible. αVβ3 blocking antibodies reduced EPC spreading on both N25 and N18 by 45±4% and 42±14%, respectively. In conclusion, rhTE supports EPC binding via an integrin mechanism involving αVβ3. N25 and N18, but not N10 constructs of rhTE contribute to EPC binding. The regulation of EPC activity by rhTE may have implications for modulation of the vascular biocompatibility of endovascular implants

Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions

During meiosis, Structural Maintenance of Chromosome (SMC) complexes underpin two fundamental features of meiosis: homologous recombination and chromosome segregation. While meiotic functions of the cohesin and condensin complexes have been delineated, the role of the third SMC complex, Smc5/6, remains enigmatic. Here we identify specific, essential meiotic functions for the Smc5/6 complex in homologous recombination and the regulation of cohesin. We show that Smc5/6 is enriched at centromeres and cohesin-association sites where it regulates sister-chromatid cohesion and the timely removal of cohesin from chromosomal arms, respectively. Smc5/6 also localizes to recombination hotspots, where it promotes normal formation and resolution of a subset of joint-molecule intermediates. In this regard, Smc5/6 functions independently of the major crossover pathway defined by the MutLγ complex. Furthermore, we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4Eme1. Our data suggest that the Smc5/6 complex is required for specific recombination and chromosomal processes throughout meiosis and that in its absence, attempts at cell division with unresolved joint molecules and residual cohesin lead to severe recombination-induced meiotic catastroph

Scientists' warning on extreme wildfire risks to water supply

2020 is the year of wildfire records. California experienced its three largest fires early in its fire season. The Pantanal, the largest wetland on the planet, burned over 20% of its surface. More than 18 million hectares of forest and bushland burned during the 2019–2020 fire season in Australia, killing 33 people, destroying nearly 2500 homes, and endangering many endemic species. The direct cost of damages is being counted in dozens of billion dollars, but the indirect costs on water‐related ecosystem services and benefits could be equally expensive, with impacts lasting for decades. In Australia, the extreme precipitation (“200 mm day −1 in several location”) that interrupted the catastrophic wildfire season triggered a series of watershed effects from headwaters to areas downstream. The increased runoff and erosion from burned areas disrupted water supplies in several locations. These post‐fire watershed hazards via source water contamination, flash floods, and mudslides can represent substantial, systemic long‐term risks to drinking water production, aquatic life, and socio‐economic activity. Scenarios similar to the recent event in Australia are now predicted to unfold in the Western USA. This is a new reality that societies will have to live with as uncharted fire activity, water crises, and widespread human footprint collide all‐around of the world. Therefore, we advocate for a more proactive approach to wildfire‐watershed risk governance in an effort to advance and protect water security. We also argue that there is no easy solution to reducing this risk and that investments in both green (i.e., natural) and grey (i.e., built) infrastructure will be necessary. Further, we propose strategies to combine modern data analytics with existing tools for use by water and land managers worldwide to leverage several decades worth of data and knowledge on post‐fire hydrology

Connecting Earth Observation to High-Throughput Biodiversity Data

There is much interest in using Earth Observation (EO) technology to track biodiversity, ecosystem functions, and ecosystem services, understandable given the fast pace of biodiversity loss. However, because most biodiversity is invisible to EO, EO-based indicators could be misleading, which can reduce the effectiveness of nature conservation and even unintentionally decrease conservation effort. We describe an approach that combines automated recording devices, high-throughput DNA sequencing, and modern ecological modelling to extract much more of the information available in EO data. This approach is achievable now, 62 offering efficient and near-real time monitoring of management impacts on biodiversity and its functions and services

Connecting Earth observation to high-throughput biodiversity data

Understandably, given the fast pace of biodiversity loss, there is much interest in using Earth observation technology to track biodiversity, ecosystem functions and ecosystem services. However, because most biodiversity is invisible to Earth observation, indicators based on Earth observation could be misleading and reduce the effectiveness of nature conservation and even unintentionally decrease conservation effort. We describe an approach that combines automated recording devices, high-throughput DNA sequencing and modern ecological modelling to extract much more of the information available in Earth observation data. This approach is achievable now, offering efficient and near-real-time monitoring of management impacts on biodiversity and its functions and services