Rapamycin attenuates hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in mice

BACKGROUND: Chronic hypoxia induces pulmonary arterial hypertension (PAH). Smooth muscle cell (SMC) proliferation and hypertrophy are important contributors to the remodeling that occurs in chronic hypoxic pulmonary vasculature. We hypothesized that rapamycin (RAPA), a potent cell cycle inhibitor, prevents pulmonary hypertension in chronic hypoxic mice. METHODS: Mice were held either at normoxia (N; 21% O(2)) or at hypobaric hypoxia (H; 0.5 atm; ~10% O(2)). RAPA-treated animals (3 mg/kg*d, i.p.) were compared to animals injected with vehicle alone. Proliferative activity within the pulmonary arteries was quantified by staining for Ki67 (positive nuclei/vessel) and media area was quantified by computer-aided planimetry after immune-labeling for α-smooth muscle actin (pixel/vessel). The ratio of right ventricle to left ventricle plus septum (RV/[LV+S]) was used to determine right ventricular hypertrophy. RESULTS: Proliferative activity increased by 34% at day 4 in mice held under H (median: 0.38) compared to N (median: 0.28, p = 0.028) which was completely blocked by RAPA (median HO+RAPA: 0.23, p = 0.003). H-induced proliferation had leveled off within 3 weeks. At this time point media area had, however, increased by 53% from 91 (N) to 139 (H, p < 0.001) which was prevented by RAPA (H+RAPA: 102; p < 0.001). RV/[LV+S] ratio which had risen from 0.17 (N) to 0.26 (H, p < 0.001) was attenuated in the H+RAPA group (0.22, p = 0.041). For a therapeutic approach animals were exposed to H for 21 days followed by 21 days in H ± RAPA. Forty two days of H resulted in a media area of 129 (N: 83) which was significantly attenuated in RAPA-treated mice (H+RAPA: 92). RV/[LV+S] ratios supported prevention of PH (N 0.13; H 0.27; H+RAPA 0.17). RAPA treatment of N mice did not influence any parameter examined. CONCLUSION: Therapy with rapamycin may represent a new strategy for the treatment of pulmonary hypertension

The regulatory and transcriptional landscape associated with carbon utilization in a filamentous fungus.

Filamentous fungi, such as Neurospora crassa, are very efficient in deconstructing plant biomass by the secretion of an arsenal of plant cell wall-degrading enzymes, by remodeling metabolism to accommodate production of secreted enzymes, and by enabling transport and intracellular utilization of plant biomass components. Although a number of enzymes and transcriptional regulators involved in plant biomass utilization have been identified, how filamentous fungi sense and integrate nutritional information encoded in the plant cell wall into a regulatory hierarchy for optimal utilization of complex carbon sources is not understood. Here, we performed transcriptional profiling of N. crassa on 40 different carbon sources, including plant biomass, to provide data on how fungi sense simple to complex carbohydrates. From these data, we identified regulatory factors in N. crassa and characterized one (PDR-2) associated with pectin utilization and one with pectin/hemicellulose utilization (ARA-1). Using in vitro DNA affinity purification sequencing (DAP-seq), we identified direct targets of transcription factors involved in regulating genes encoding plant cell wall-degrading enzymes. In particular, our data clarified the role of the transcription factor VIB-1 in the regulation of genes encoding plant cell wall-degrading enzymes and nutrient scavenging and revealed a major role of the carbon catabolite repressor CRE-1 in regulating the expression of major facilitator transporter genes. These data contribute to a more complete understanding of cross talk between transcription factors and their target genes, which are involved in regulating nutrient sensing and plant biomass utilization on a global level

An instrument to measure psychosocial determinants of health care professionals’ vaccination behavior:Validation of the Pro-VC-Be questionnaire

International audienc

De novo formation of an aggregation pheromone precursor by an isoprenyl diphosphate synthase-related terpene synthase in the harlequin bug.

Insects use a diverse array of specialized terpene metabolites as pheromones in intraspecific interactions. In contrast to plants and microbes, which employ enzymes called terpene synthases (TPSs) to synthesize terpene metabolites, limited information from few species is available about the enzymatic mechanisms underlying terpene pheromone biosynthesis in insects. Several stink bugs (Hemiptera: Pentatomidae), among them severe agricultural pests, release 15-carbon sesquiterpenes with a bisabolene skeleton as sex or aggregation pheromones. The harlequin bug, Murgantia histrionica, a specialist pest of crucifers, uses two stereoisomers of 10,11-epoxy-1-bisabolen-3-ol as a male-released aggregation pheromone called murgantiol. We show that MhTPS (MhIDS-1), an enzyme unrelated to plant and microbial TPSs but with similarity to trans-isoprenyl diphosphate synthases (IDS) of the core terpene biosynthetic pathway, catalyzes the formation of (1S,6S,7R)-1,10-bisaboladien-1-ol (sesquipiperitol) as a terpene intermediate in murgantiol biosynthesis. Sesquipiperitol, a so-far-unknown compound in animals, also occurs in plants, indicating convergent evolution in the biosynthesis of this sesquiterpene. RNAi-mediated knockdown of MhTPS mRNA confirmed the role of MhTPS in murgantiol biosynthesis. MhTPS expression is highly specific to tissues lining the cuticle of the abdominal sternites of mature males. Phylogenetic analysis suggests that MhTPS is derived from a trans-IDS progenitor and diverged from bona fide trans-IDS proteins including MhIDS-2, which functions as an (E,E)-farnesyl diphosphate (FPP) synthase. Structure-guided mutagenesis revealed several residues critical to MhTPS and MhFPPS activity. The emergence of an IDS-like protein with TPS activity in M. histrionica demonstrates that de novo terpene biosynthesis evolved in the Hemiptera in an adaptation for intraspecific communication

Protocolised early de-resuscitation in septic shock (REDUCE): protocol for a randomised controlled multicentre feasibility trial.

BACKGROUND Fluid overload is associated with excess mortality in septic shock. Current approaches to reduce fluid overload include restrictive administration of fluid or active removal of accumulated fluid. However, evidence on active fluid removal is scarce. The aim of this study is to assess the efficacy and feasibility of an early de-resuscitation protocol in patients with septic shock. METHODS All patients admitted to the intensive care unit (ICU) with a septic shock are screened, and eligible patients will be randomised in a 1:1 ratio to intervention or standard of care. INTERVENTION Fluid management will be performed according to the REDUCE protocol, where resuscitation fluid will be restricted to patients showing signs of poor tissue perfusion. After the lactate has peaked, the patient is deemed stable and assessed for active de-resuscitation (signs of fluid overload). The primary objective of this study is the proportion of patients with a negative cumulative fluid balance at day 3 after ICU. Secondary objectives are cumulative fluid balances throughout the ICU stay, number of patients with fluid overload, feasibility and safety outcomes and patient-centred outcomes. The primary outcome will be assessed by a logistic regression model adjusting for the stratification variables (trial site and chronic renal failure) in the intention-to-treat population. ETHICS AND DISSEMINATION The study was approved by the respective ethical committees (No 2020-02197). The results of the REDUCE trial will be published in an international peer-reviewed medical journal regardless of the results. TRIAL REGISTRATION NUMBER ClinicalTrials.gov, NCT04931485

ESPEN guideline on nutritional support for polymorbid medical inpatients.

BACKGROUND Disease-related malnutrition in polymorbid medical inpatients is a highly prevalent syndrome associated with significantly increased morbidity, disability, short- and long-term mortality, impaired recovery from illness, and cost of care. AIM As there are uncertainties in applying disease-specific guidelines to patients with multiple conditions, our aim was to provide evidence-based recommendations on nutritional support for the polymorbid patient population hospitalized in medical wards. METHODS This update adheres to the standard operating procedures for ESPEN guidelines. We did a systematic literature search for 15 clinical questions in three different databases (Medline, Embase and the Cochrane Library), as well as in secondary sources (e.g. published guidelines), until July 12th. Retrieved abstracts were screened to identify relevant studies that were used to develop recommendations (incl. SIGN grading), which was followed by submission to Delphi voting. RESULTS From a total of 3527 retrieved abstracts, 60 new relevant studies were analyzed and used to generate a guideline draft that proposed 32 recommendations (7x A, 11x B, 10x O and 4x GPP), which encompass different aspects of nutritional support including indication, route of feeding, energy and protein requirements, micronutrient requirements, disease-specific nutrients, timing, monitoring and procedure of intervention. The results of the first online voting showed a strong consensus (agreement of >90%) on 100% of the recommendations. Therefore, no final consensus conference was needed. CONCLUSIONS Recent high-quality trials have provided increasing evidence that nutritional support can reduce morbidity and other complications associated with malnutrition in polymorbid patients. The timely screening of patients for risk of malnutrition at hospital admission followed by individualized nutritional support interventions for at-risk patients should be part of routine clinical care and multimodal treatment in hospitals worldwide. Use of this updated guideline offers an evidence-based nutritional approach to the polymorbid medical inpatients and may improve their outcomes

In vitro interaction network of a synthetic gut bacterial community

A key challenge in microbiome research is to predict the functionality of microbial communities based on community membership and (meta)-genomic data. As central microbiota functions are determined by bacterial community networks, it is important to gain insight into the principles that govern bacteria-bacteria interactions. Here, we focused on the growth and metabolic interactions of the Oligo-Mouse-Microbiota (OMM12) synthetic bacterial community, which is increasingly used as a model system in gut microbiome research. Using a bottom-up approach, we uncovered the directionality of strain-strain interactions in mono- and pairwise co-culture experiments as well as in community batch culture. Metabolic network reconstruction in combination with metabolomics analysis of bacterial culture supernatants provided insights into the metabolic potential and activity of the individual community members. Thereby, we could show that the OMM12 interaction network is shaped by both exploitative and interference competition in vitro in nutrient-rich culture media and demonstrate how community structure can be shifted by changing the nutritional environment. In particular, Enterococcus faecalis KB1 was identified as an important driver of community composition by affecting the abundance of several other consortium members in vitro. As a result, this study gives fundamental insight into key drivers and mechanistic basis of the OMM12 interaction network in vitro, which serves as a knowledge base for future mechanistic in vivo studies

New species longevity record for the northern quahog (=hard clam), Mercenaria mercenaria

Author Posting. © National Shellfisheries Association, 2011. This article is posted here by permission of National Shellfisheries Association for personal use, not for redistribution. The definitive version was published in Journal of Shellfish Research 30 (2011): 35-38, doi:10.2983/035.030.0106.Twenty-two large shells (>90 mm shell height) from a sample of live collected hard shell clams, Mercenaria mercenaria, from Buzzards Bay, Woods Hole, Cape Cod, MA, were subjected to sclerochronological analysis. Annually resolved growth lines in the hinge region and margin of the shell were identified and counted; the age of the oldest clam shell was determined to be at least 106 y. This age represents a considerable increase in the known maximum life span for M. mercenaria, more than doubling the maximum recorded life span of the species (46 y). More than 85% of the clam shells aged had more than 46 annual increments, the previous known maximum life span for the species. In this article we present growth rate and growth performance indicators (the overall growth performance and phi prime) for this record-breaking population of M. mercenaria. Recently discovered models of aging require accurate age records and growth parameters for bivalve populations if they are to be utilized to their full potential.This work was supported by grants from the American Diabetes Association (to Z. U.), American Federation for Aging Research (to A. C.), the University of Oklahoma College of Medicine Alumni Association (to A. C.), the BBSRC (to C. A. R.),the National Institutes of Health (AT006526 and HL077256 to Z. U.; AG022873 and AG025063 to S. N. A.), and the DFG Cluster of Excellence ‘‘Future Ocean’’ (to E. P.)