Antimicrobial Peptides Pom-1 and Pom-2 from Pomacea poeyana Are Active against Candida auris, C. parapsilosis and C. albicans Biofilms

Recently two peptides isolated from the Cuban freshwater snail Pomacea poeyana (Pilsbry, 1927) were described to have antimicrobial activity against bacterial pathogens. Here we show considerable activities of Pom-1 and Pom-2 to reduce the viability of C. albicans, C. parapsilosis and the less common species C. auris measured as the decrease of metabolic activity in the resazurin reduction assay for planktonic cells. Although these activities were low, Pom-1 and Pom-2 turned out to be highly potent inhibitors of biofilm formation for the three Candida species tested. Whereas Pom-1 was slightly more active against C. albicans and C. parapsilosis as representatives of the more common Candida species Pom-2 showed no preference and was fully active also against biofilms of the more uncommon species C. auris. Pom-1 and Pom-2 may represent promising lead structures for the development of a classical peptide optimization strategy with the realistic aim to further increase antibiofilm properties and other pharmacologic parameters and to generate finally the first antifungal drug with a pronounced dedication against Candida biofilms

Exploring the Pharmacological Potential of Promiscuous Host-Defense Peptides: From Natural Screenings to Biotechnological Applications

In the last few years, the number of bacteria with enhanced resistance to conventional antibiotics has dramatically increased. Most of such bacteria belong to regular microbial flora, becoming a real challenge, especially for immune-depressed patients. Since the treatment is sometimes extremely expensive, and in some circumstances completely inefficient for the most severe cases, researchers are still determined to discover novel compounds. Among them, host-defense peptides (HDPs) have been found as the first natural barrier against microorganisms in nearly all living groups. This molecular class has been gaining attention every day for multiple reasons. For decades, it was believed that these defense peptides had been involved only with the permeation of the lipid bilayer in pathogen membranes, their main target. Currently, it is known that these peptides can bind to numerous targets, as well as lipids including proteins and carbohydrates, from the surface to deep within the cell. Moreover, by using in vivo models, it was shown that HDPs could act both in pathogens and cognate hosts, improving immunological functions as well as acting through multiple pathways to control infections. This review focuses on structural and functional properties of HDP peptides and the additional strategies used to select them. Furthermore, strategies to avoid problems in large-scale manufacture by using molecular and biochemical techniques will also be explored. In summary, this review intends to construct a bridge between academic research and pharmaceutical industry, providing novel insights into the utilization of HDPs against resistant bacterial strains that cause infections in humans

Increased Activities against Biofilms of the Pathogenic Yeast Candida albicans of Optimized Pom-1 Derivatives

Antimicrobial peptides (AMPs) are an alternative group for the therapy of infectious diseases, with activity against a wide range of diverse pathogens. However, classical AMPs have significant side effects in human cells due to their unspecific pore formation in biomembranes. Nevertheless, AMPs are promising therapeutics and can be isolated from natural sources, which include sea and freshwater molluscs. The AMPs identified in these organisms show promising antimicrobial activities, as pathogens are mainly fought by innate defence mechanisms. An auspicious candidate among molluscs is the Cuban freshwater snail Pomacea poeyana, from which the peptides Pom-1 and Pom-2 have been isolated and studied. These studies revealed significant antimicrobial activities for both AMPs. Based on the activities determined, Pom-1 was used for further optimization. In order to meet the emerging requirements of improved anti-biofilm activity against naturally occurring Candida species, the six derivatives Pom-1A to F were developed and investigated. Analysis of the derivatives acting on the most abundant naturally occurring Candida yeast Candida albicans (C. albicans) revealed a strong anti-biofilm activity, especially induced by Pom-1 B, C, and D. Furthermore, a moderate decrease in the metabolic activity of planktonic yeast cells was observed

Artificial Intelligence and Intellectual Property Law - Position Statement of the Max Planck Institute for Innovation and Competition of 9 April 2021 on the Current Debate

This Position Statement presents a broad overview of issues arising at the intersection of AI and IP law based on the work of the Max Planck Institute for Innovation and Competition research group on Regulation of the Digital Economy. While the analysis is approached mainly from a perspective de lege lata, it also identifies questions which require further reflection de lege ferenda supported by in-depth interdisciplinary research. The scope is confined to substantive European IP law, in particular, as regards copyright, patents, designs, databases and trade secrets. Specific AI-related issues are mapped out around the core questions of IP law, namely, the eligibility for protection under the respective IP regimes, allocation of rights and the scope of protection. The structure of the analysis reflects three key components of AI: inputs required for the development of AI systems, AI as a process and the output of AI applications. Overall, it is emphasised that, while recent legal and policy discussions have mostly focused on AI-aided and AI-generated output, a more holistic view that accounts for the role of IP law across the AI innovation cycle is indispensable

Combination of Six Individual Derivatives of the Pom-1 Antibiofilm Peptide Doubles Their Efficacy against Invasive and Multi-Resistant Clinical Isolates of the Pathogenic Yeast Candida albicans

In previous studies, derivatives of the peptide Pom-1, which was originally extracted from the freshwater mollusk Pomacea poeyana, showed an exceptional ability to specifically inhibit biofilm formation of the laboratory strain ATCC 90028 as a model strain of the pathogenic yeast Candida albicans. In follow-up, here, we demonstrate that the derivatives Pom-1A to Pom-1F are also active against biofilms of invasive clinical C. albicans isolates, including strains resistant against fluconazole and/or amphotericin B. However, efficacy varied strongly between the isolates, as indicated by large deviations in the experiments. This lack of robustness could be efficiently bypassed by using mixtures of all peptides. These mixed peptide preparations were active against biofilm formation of all the isolates with uniform efficacies, and the total peptide concentration could be halved compared to the original MIC of the individual peptides (2.5 µg/mL). Moreover, mixing the individual peptides restored the antifungal effect of fluconazole against fluconazole-resistant isolates even at 50% of the standard therapeutic concentration. Without having elucidated the reason for these synergistic effects of the peptides yet, both the gain of efficacy and the considerable increase in efficiency by combining the peptides indicate that Pom-1 and its derivatives in suitable formulations may play an important role as new antibiofilm antimycotics in the fight against invasive clinical infections with (multi-) resistant C. albicans

The Layer 0 Inner Silicon Detector of the D0 Experiment

This paper describes the design, fabrication, installation and performance of the new inner layer called Layer 0 (L0) that was inserted in the existing Run IIa Silicon Micro-Strip Tracker (SMT) of the D0 experiment at the Fermilab Tevatron collider. L0 provides tracking information from two layers of sensors, which are mounted with center lines at a radial distance of 16.1 mm and 17.6 mm respectively from the beam axis. The sensors and readout electronics are mounted on a specially designed and fabricated carbon fiber structure that includes cooling for sensor and readout electronics. The structure has a thin polyimide circuit bonded to it so that the circuit couples electrically to the carbon fiber allowing the support structure to be used both for detector grounding and a low impedance connection between the remotely mounted hybrids and the sensors.Comment: 28 pages, 9 figure

Results of an Early Access Treatment Protocol of Daratumumab Monotherapy in Spanish Patients With Relapsed or Refractory Multiple Myeloma

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16 mg/kg) was administered to 73 patients who had >= 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03-13.17) months, with a median number of 12 (range: 1-25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatmentemergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma

Relationship Between Quorum Sensing and Secretion Systems

Quorum sensing (QS) is a communication mechanism between bacteria that allows specific processes to be controlled, such as biofilm formation, virulence factor expression, production of secondary metabolites and stress adaptation mechanisms such as bacterial competition systems including secretion systems (SS). These SS have an important role in bacterial communication. SS are ubiquitous; they are present in both Gram-negative and Gram-positive bacteria and in Mycobacterium sp. To date, 8 types of SS have been described (T1SS, T2SS, T3SS, T4SS, T5SS, T6SS, T7SS, and T9SS). They have global functions such as the transport of proteases, lipases, adhesins, heme-binding proteins, and amidases, and specific functions such as the synthesis of proteins in host cells, adaptation to the environment, the secretion of effectors to establish an infectious niche, transfer, absorption and release of DNA, translocation of effector proteins or DNA and autotransporter secretion. All of these functions can contribute to virulence and pathogenesis. In this review, we describe the known types of SS and discuss the ones that have been shown to be regulated by QS. Due to the large amount of information about this topic in some pathogens, we focus mainly on Pseudomonas aeruginosa and Vibrio spp

Anisotropy studies around the galactic centre at EeV energies with the Auger Observatory

Data from the Pierre Auger Observatory are analyzed to search for anisotropies near the direction of the Galactic Centre at EeV energies. The exposure of the surface array in this part of the sky is already significantly larger than that of the fore-runner experiments. Our results do not support previous findings of localized excesses in the AGASA and SUGAR data. We set an upper bound on a point-like flux of cosmic rays arriving from the Galactic Centre which excludes several scenarios predicting sources of EeV neutrons from Sagittarius $A$. Also the events detected simultaneously by the surface and fluorescence detectors (the `hybrid' data set), which have better pointing accuracy but are less numerous than those of the surface array alone, do not show any significant localized excess from this direction.Comment: Matches published versio