Project description:Antimicrobial resistance (AMR) is a growing threat with severe health and economic consequences. The available antibiotics are losing efficacy, and the hunt for alternative strategies is a priority. Quorum sensing (QS) controls biofilm and virulence factors production. Thus, the quenching of QS to prevent pathogenicity and to increase bacterial susceptibility to antibiotics is an appealing therapeutic strategy. The phosphorylation of autoinducer-2 (a mediator in QS) by LsrK is a crucial step in triggering the QS cascade. Thus, LsrK represents a valuable target in fighting AMR. Few LsrK inhibitors have been reported so far, allowing ample room for further exploration. This perspective aims to provide a comprehensive analysis of the current knowledge about the structural and biological properties of LsrK and the state-of-the-art technology for LsrK inhibitor design. We elaborate on the challenges in developing novel LsrK inhibitors and point out promising avenues for further research.
Project description:Endobronchial Ultrasound (EBUS) has been widely used to stage lung tumors and to diagnose mediastinal diseases. In the last decade, this procedure has evolved in several technical aspects, with new tools available to optimize tissue sampling and to increase its diagnostic yield, like elastography, different types of needles and, most recently, miniforceps and cryobiopsy. Accordingly, the indications for the use of the EBUS scope into the airways to perform the Endobronchial Ultrasound-TransBronchial Needle Aspiration (EBUS-TBNA) has also extended beyond the endobronchial and thoracic boundaries to sample lesions from the liver, left adrenal gland and retroperitoneal lymph nodes via the gastroesophageal tract, performing the Endoscopic UltraSound with Bronchoscope-guided Fine Needle Aspiration (EUS-B-FNA). In this review, we summarize and critically discuss the main indication for the use of the EBUS scope, even the more uncommon, to underline its utility and versatility in clinical practice.
Project description:BackgroundmRNA polyadenylation, the addition of a poly(A) tail to the 3'-end of pre-mRNA, is a process critical to gene expression and regulation in eukaryotes. To understand the molecular mechanisms governing polyadenylation and other relevant biological processes, it is important to identify these poly(A) tails accurately in transcriptome sequencing data and differentiate them from artificial adapter sequences added in the sequencing process. But the annotation of these tails is complicated by the presence of sequencing errors and post-transcriptional modifications. While determining that a tail is present in a given transcript fragment is straight-forward, these obfuscations make the problem of boundary identification a challenge; conventional seed-and-extend algorithms struggle to accurately identify these poly(A) tail end-points. Further, all existing tools that we are aware of focus exclusively on the trimming of poly(A) tails, failing to provide the detailed information needed for studying the polyadenylation process.ResultsWe have created SCOPE++, an open-source tool for finding the precise border of poly(A) tails and other homopolymers in raw mRNA sequence reads. Based on a Hidden Markov Model (HMM) approach, SCOPE++ accurately identifies specific homopolymer sequences in error-prone EST/cDNA data or RNA-Seq data at a speed appropriate for large sequence sets.ConclusionsWe demonstrate that our tool can precisely identify poly(A) tails with near perfect accuracy at the speed required for high-throughput applications, providing a valuable resource for polyadenylation research.
Project description:Despite the relative prosperity of Scandinavian countries, contamination of the drinking water supply with parasites has occurred on various occasions in the last few decades. These events have resulted in outbreaks of disease involving several thousand cases and/or the necessity for implementation of boil-water advisories. Against this background, in 2008, and again in 2019, the Norwegian Food Safety Authority requested a risk assessment from an independent scientific body regarding parasites in Norwegian drinking water. On each occasion, it was requested that specific questions were addressed. For the first assessment, data, both of general relevance and specific for Norway, were collected from appropriate sources, as available. Based on some of this information, a quantitative probability model was established and run to estimate the number of cases of waterborne cryptosporidiosis and giardiasis that may be expected in Norway, both in the general public and the immunocompromised, and under conditions where water treatment should be optimal, and also when water treatment efficacy may be compromised by weather conditions. For the second assessment, approximately a decade after the first, an update on the previous assessment was requested. Differences in information availability and other changes between the two assessments were described; although more data were available at the second assessment, considerable gaps still remained. For both assessments, data on the occurrence of these parasites in the Norwegian population, particularly those infected in Norway, were considered a challenge. However, due to changes in reporting requirements in 2020, the situation was improved for the second assessment. In addition, data were lacking for both assessments on whether animals or humans are most likely to contaminate water sources, and the species and genotypes of these parasites in Norwegian animals. It was also noted that some of the newer data on parasite numbers detected in water samples should be treated with caution. Due to this, further modelling was not conducted. The relevance of risk-based sampling rather than ad hoc sampling of water sources was also addressed. Despite the data gaps, this article provides an overview of the opportunities provided by conducting such assessments. In addition, some of the challenges encountered in attempting to estimate the risk posed from parasite contamination of water sources in Norway, particularly under predicted conditions of climate change, are described.
Project description:Embodied emissions from the production of building materials account for 17% of China's carbon dioxide (CO2) emissions and are important to focus on as China aims to achieve its carbon neutrality goals. However, there is a lack of systematic assessments on embodied emissions reduction potential of building materials that consider both the heterogeneous industrial characteristics as well as the Chinese buildings sector context. Here, we developed an integrated model that combines future demand of building materials in China with the strategies to reduce CO2 emissions associated with their production, using, and recycling. We found that measures to improve material efficiency in the value-chain has the largest CO2 mitigation potential before 2030 in both Low Carbon and Carbon Neutrality Scenarios, and continues to be significant through 2060. Policies to accelerate material efficiency practices, such as incorporating embodied emissions in building codes and conducting robust research, development, and demonstration (RD&D) in carbon removal are critical.
Project description:Residents and their pets may experience aesthetic or health concerns resulting from elevated copper in their drinking water. The United States Environmental Protection Agency Lead and Copper Rule focuses on addressing systemwide corrosion issues, but gaps in the rule leave some municipal water consumers and residents with private well water vulnerable to high cuprosolvency. We developed guidance to aid residents in understanding, detecting, and addressing cuprosolvency issues in their drinking water. Three types of at-home test kits for copper and one for pH were determined to be accurate enough (R 2 > 0.9 (lab, based on average values from n = 5 replicates each) and >0.7 (field)) to detect concerns related to high cuprosolvency and inform selection of intervention options. Case study results indicate that, although water treatments such as increasing pH on-site may be effective, long-term treatment (>36 weeks or permanently) may be needed to maintain reductions in cuprosolvency. A decision tree is provided to help residents and citizen scientists navigate these concerns for both public water systems and private wells.
Project description:The development of immunotherapies has revolutionized intervention strategies for a variety of primary cancers. Despite this promising progress, treatment options for primary brain cancer and brain metastasis remain limited and still largely depend on surgical resection, radio- and/or chemotherapy. The paucity in the successful development of immunotherapies for brain cancers can in part be attributed to the traditional view of the brain as an immunologically privileged site. The presence of the blood-brain barrier and the absence of lymphatic drainage were believed to restrict the entry of blood-borne immune and inflammatory cells into the central nervous system (CNS), leading to an exclusion of the brain from systemic immune surveillance. However, recent insight from pre-clinical and clinical studies on the immune landscape of brain cancers challenged this dogma. Recruitment of blood-borne immune cells into the CNS provides unprecedented opportunities for the development of tumor microenvironment (TME)-targeted or immunotherapies against primary and metastatic cancers. Moreover, it is increasingly recognized that in addition to genotoxic effects, ionizing radiation represents a critical modulator of tumor-associated inflammation and synergizes with immunotherapies in adjuvant settings. This review summarizes current knowledge on the cellular and molecular identity of tumor-associated immune cells in primary and metastatic brain cancers and discusses underlying mechanisms by which ionizing radiation modulates the immune response. Detailed mechanistic insight into the effects of radiation on the unique immune landscape of brain cancers is essential for the development of multimodality intervention strategies in which immune-modulatory effects of radiotherapy are exploited to sensitize brain cancers to immunotherapies by converting immunologically "cold" into "hot" environments.
Project description:Despite advances in post-transplant management, the long-term survival rate of kidney grafts and patients has not improved as approximately forty percent of transplants fails within ten years after transplantation. Both immunologic and non-immunologic factors contribute to late allograft loss. Chronic kidney transplant rejection (CKTR) is often clinically silent yet progressive allogeneic immune process that leads to cumulative graft injury, deterioration of graft function. Chronic active T cell mediated rejection (TCMR) and chronic active antibody-mediated rejection (ABMR) are classified as two principal subtypes of CKTR. While significant improvements have been made towards a better understanding of cellular and molecular mechanisms and diagnostic classifications of CKTR, lack of early detection, differential diagnosis and effective therapies continue to pose major challenges for long-term management. Recent development of high throughput cellular and molecular biotechnologies has allowed rapid development of new biomarkers associated with chronic renal injury, which not only provide insight into pathogenesis of chronic rejection but also allow for early detection. In parallel, several novel therapeutic strategies have emerged which may hold great promise for improvement of long-term graft and patient survival. With a brief overview of current understanding of pathogenesis, standard diagnosis and challenges in the context of CKTR, this mini-review aims to provide updates and insights into the latest development of promising novel biomarkers for diagnosis and novel therapeutic interventions to prevent and treat CKTR.
Project description:PurposeThis review provides an overview of the proceedings of the symposium "Tackling the Challenges of Nanomedicines: Are We Ready?" organized by the International Pharmaceutical Federation (FIP) Hospital Pharmacy Section and Non-Biological Complex Drugs (NBCDs) Working Group at the 2019 FIP World Congress of Pharmacy and Pharmaceutical Sciences. Debate centered on reasons underlying the current complex regulatory landscape for nanomedicines and their follow-on products (referred to as nanosimilars) and the pivotal role of hospital pharmacists in selecting, handling, and guiding usage of nanomedicines and nanosimilars.SummaryThe evaluation and use of nanomedicines are recognized among scientific, pharmaceutical, and regulatory bodies as complex. Interchangeability and substitutability of nanomedicines and nanosimilars are confounded by a lack of pharmaceutical and pharmacological equivalence, reflecting the inherent complex nature of these drug products and manufacturing processes. Consequences include implications for clinical safety and efficacy and, ultimately, comparability. Local regulatory approvals of some nanomedicines have occurred, but there is no standard to ensure streamlined evaluation and use of consistent measures of therapeutic equivalence of reference products and their nanosimilars. Hospital pharmacists are expected to be experts in the selection, handling, and substitution of nanomedicines and familiarize themselves with the limitations of current methods of assessing pharmaceutical and clinical equivalence of nanosimilars in order to ensure informed formulary decision-making and eventual patient benefit.ConclusionSupportive guidance for pharmacists focusing on the substitutability and/or interchangeability of nanomedicines and their nanosimilars is needed. Current FIP guidance for pharmacists on therapeutic interchange and substitution should be extended to include nanomedicines and nanosimilars.
Project description:The metathetical modification of biomolecules in aqueous environments holds great promise for advances at the interface of chemistry, biology, and medicine. However, rapid degradation of the metathesis catalysts necessitates their use in large stoichiometric excess, resulting in undesired side-reactions promoted by the ruthenium products. Although water is now known to play a central role in catalyst decomposition, the elusive nature of the intermediates has hampered insight into the pathways involved. We describe the detailed speciation in water of AquaMet (AM), the dominant ruthenium catalyst used for aqueous metathesis, and implications for catalysis. Potentiometric and spectroscopic speciation studies reveal that only trace AM is present under the pH-neutral, salt-free conditions routinely employed in synthetic applications of aqueous metathesis. Instead, metathesis-inactive hydroxide species dominate. Even at pH 3, Ru-H2O complexes dominate in 0.01 M NaCl(aq), and the water ligands are readily deprotonated as the pH is increased. Raising NaCl(aq) concentrations to 1 M suppresses deprotonation events below pH 8, stabilizing AM as the dominant solution species at neutral pH, and significantly expanding the metathesis-compatible regime. Hitherto unrecognized catalyst solubility issues are also revealed, pointing toward avenues for advance. More broadly, the capacity to directly link catalyst environment to structure and performance opens new opportunities for olefin metathesis in complex, water-rich settings.