Comparative Genomics and Mutational Analysis Reveals a Novel XoxF-Utilizing Methylotroph in the Roseobacter Group Isolated From the Marine Environment

The Roseobacter group comprises a significant group of marine bacteria which are involved in global carbon and sulfur cycles. Some members are methylotrophs, using one-carbon compounds as a carbon and energy source. It has recently been shown that methylotrophs generally require a rare earth element when using the methanol dehydrogenase enzyme XoxF for growth on methanol. Addition of lanthanum to methanol enrichments of coastal seawater facilitated the isolation of a novel methylotroph in the Roseobacter group: Marinibacterium anthonyi strain La 6. Mutation of xoxF5 revealed the essential nature of this gene during growth on methanol and ethanol. Physiological characterization demonstrated the metabolic versatility of this strain. Genome sequencing revealed that strain La 6 has the largest genome of all Roseobacter group members sequenced to date, at 7.18 Mbp. Multilocus sequence analysis (MLSA) showed that whilst it displays the highest core gene sequence similarity with subgroup 1 of the Roseobacter group, it shares very little of its pangenome, suggesting unique genetic adaptations. This research revealed that the addition of lanthanides to isolation procedures was key to cultivating novel XoxF-utilizing methylotrophs from the marine environment, whilst genome sequencing and MLSA provided insights into their potential genetic adaptations and relationship to the wider community

Author Correction: Scientific evidence on the political impact of the Sustainable Development Goals

Correction to: Nature Sustainability https://doi-org.proxy.library.uu.nl/10.1038/s41893-022-00909-5, published online 20 June 2022

Scientific evidence on the political impact of the Sustainable Development Goals

In 2015, the United Nations agreed on 17 Sustainable Development Goals as the central normative framework for sustainable development worldwide. The effectiveness of governing by such broad global goals, however, remains uncertain, and we lack comprehensive meta-studies that assess the political impact of the goals across countries and globally. We present here condensed evidence from an analysis of over 3,000 scientific studies on the Sustainable Development Goals published between 2016 and April 2021. Our findings suggests that the goals have had some political impact on institutions and policies, from local to global governance. This impact has been largely discursive, affecting the way actors understand and communicate about sustainable development. More profound normative and institutional impact, from legislative action to changing resource allocation, remains rare. We conclude that the scientific evidence suggests only limited transformative political impact of the Sustainable Development Goals thus far

Pimasertib Versus Dacarbazine in Patients With UnresectableNRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg/m2 ; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42–0.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00–4.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61–1.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade ≥3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068

Influence of Butorphanol, Buprenorphine and Levomethadone on Sedation Quality and Postoperative Analgesia in Horses Undergoing Cheek Tooth Extraction

The aim of this prospective clinical trial was to compare the influence of butorphanol, buprenorphine and levomethadone on sedation quality and postoperative analgesia in horses undergoing cheek tooth extraction. Fifty horses were assigned to three groups prior to oral cheek tooth extraction. Horses were treated with acepromazine, followed by a detomidine bolus, one of the three opioids and both a nerve block and gingival anaesthesia. During the surgery, sedation was maintained with a detomidine constant rate infusion. After surgery, the quality of sedation, surgical conditions and severity of the extraction were assessed with a numerical rating scale. To evaluate differences in the quality of analgesia between the three treatments, postoperative pain was estimated with the Equine Utrecht University Scale for Facial Assessment of Pain. Additionally, several parameters that are associated with dental pain were added to this validated pain score, and blood samples were taken to measure serum cortisol. Our analysis showed lower pain scores and a greater analgesic effect with levomethadone and buprenorphine compared with butorphanol, with increased locomotor activity induced by buprenorphine. While cortisol values demonstrated higher response in horses treated with levomethadone and buprenorphine compared to butorphanol, these values could be biased by unrelated stressors

Influence of Butorphanol, Buprenorphine and Levomethadone on Sedation Quality and Postoperative Analgesia in Horses Undergoing Cheek Tooth Extraction

The aim of this prospective clinical trial was to compare the influence of butorphanol, buprenorphine and levomethadone on sedation quality and postoperative analgesia in horses undergoing cheek tooth extraction. Fifty horses were assigned to three groups prior to oral cheek tooth extraction. Horses were treated with acepromazine, followed by a detomidine bolus, one of the three opioids and both a nerve block and gingival anaesthesia. During the surgery, sedation was maintained with a detomidine constant rate infusion. After surgery, the quality of sedation, surgical conditions and severity of the extraction were assessed with a numerical rating scale. To evaluate differences in the quality of analgesia between the three treatments, postoperative pain was estimated with the Equine Utrecht University Scale for Facial Assessment of Pain. Additionally, several parameters that are associated with dental pain were added to this validated pain score, and blood samples were taken to measure serum cortisol. Our analysis showed lower pain scores and a greater analgesic effect with levomethadone and buprenorphine compared with butorphanol, with increased locomotor activity induced by buprenorphine. While cortisol values demonstrated higher response in horses treated with levomethadone and buprenorphine compared to butorphanol, these values could be biased by unrelated stressors

NLRP12 is a neutrophil-specific, negative regulator of in vitro cell migration but does not modulate LPS- or infection-induced NF-κB or ERK signalling

NOD-like receptors (NLR) are a family of cytosolic pattern recognition receptors that include many key drivers of innate immune responses. NLRP12 is an emerging member of the NLR family that is closely related to the well-known inflammasome scaffold, NLRP3. Since its discovery, various functions have been proposed for NLRP12, including the positive regulation of dendritic cell (DC) and neutrophil migration and the inhibition of NF-kappa B and ERK signalling in DC and macrophages. We show here that NLRP12 is poorly expressed in murine macrophages and DC, but is strongly expressed in neutrophils. Using myeloid cells from WT and Nlrp12(-/-) mice, we show that, contrary to previous reports, NLRP12 does not suppress LPS- or infection-induced NF-kappa B or ERK activation in myeloid cells, and is not required for DC migration in vitro. Surprisingly, we found that Nlrp12 deficiency caused increased rather than decreased neutrophil migration towards the chemokine CXCL1 and the neutrophil parasite Leishmania major, revealing NLRP12 as a negative regulator of directed neutrophil migration under these conditions. (C) 2015 Elsevier GmbH. All rights reserved

Appraising patient preference methods for decision-making in the medical product lifecycle: an empirical comparison

BACKGROUND: Incorporating patient preference (PP) information into decision-making has become increasingly important to many stakeholders. However, there is little guidance on which patient preference assessment methods, including preference exploration (qualitative) and elicitation (quantitative) methods, are most suitable for decision-making at different stages in the medical product lifecycle (MPLC). This study aimed to use an empirical approach to assess which attributes of PP assessment methods are most important, and to identify which methods are most suitable, for decision-makers' needs during different stages in the MPLC. METHODS: A four-step cumulative approach was taken: 1) Identify important criteria to appraise methods through a Q-methodology exercise, 2) Determine numerical weights to ascertain the relative importance of each criterion through an analytical hierarchy process, 3) Assess the performance of 33 PP methods by applying these weights, consulting international health preference research experts and review of literature, and 4) Compare and rank the methods within taxonomy groups reflecting their similar techniques to identify the most promising methods. RESULTS: The Q-methodology exercise was completed by 54 stakeholders with PP study experience, and the analytical hierarchy process was completed by 85 stakeholders with PP study experience. Additionally, 17 health preference research experts were consulted to assess the performance of the PP methods. Thirteen promising preference exploration and elicitation methods were identified as likely to meet decision-makers' needs. Additionally, eight other methods that decisio

Identification of the p53 family-responsive element in the promoter region of the tumor suppressor gene hypermethylated in cancer 1

The tumor suppressor gene hypermethylated in cancer 1 (HIC1), located on human chromosome 17p13.3, is frequently silenced in cancer by epigenetic mechanisms. Hypermethylated in cancer 1 belongs to the bric à brac/poxviruses and zinc-finger family of transcription factors and acts by repressing target gene expression. It has been shown that enforced p53 expression leads to increased HIC1 mRNA, and recent data suggest that p53 and Hic1 cooperate in tumorigenesis. In order to elucidate the regulation of HIC1 expression, we have analysed the HIC1 promoter region for p53-dependent induction of gene expression. Using progressively truncated luciferase reporter gene constructs, we have identified a p53-responsive element (PRE) 500 bp upstream of the TATA-box containing promoter P0 of HIC1, which is sequence specifically bound by p53 in vitro as assessed by electrophoretic mobility shift assays. We demonstrate that this HIC1 p53-responsive element (HIC1.PRE) is necessary and sufficient to mediate induction of transcription by p53. This result is supported by the observation that abolishing endogenous wild-type p53 function prevents HIC1 mRNA induction in response to UV-induced DNA damage. Other members of the p53 family, notably TAp73beta and DeltaNp63alpha, can also act through this HIC1.PRE to induce transcription of HIC1, and finally, hypermethylation of the HIC1 promoter attenuates inducibility by p53