Bacteria-to-Human Protein Networks Reveal Origins of Endogenous DNA Damage.

DNA damage provokes mutations and cancer and results from external carcinogens or endogenous cellular processes. However, the intrinsic instigators of endogenous DNA damage are poorly understood. Here, we identify proteins that promote endogenous DNA damage when overproduced: the DNA "damage-up" proteins (DDPs). We discover a large network of DDPs in Escherichia coli and deconvolute them into six function clusters, demonstrating DDP mechanisms in three: reactive oxygen increase by transmembrane transporters, chromosome loss by replisome binding, and replication stalling by transcription factors. Their 284 human homologs are over-represented among known cancer drivers, and their RNAs in tumors predict heavy mutagenesis and a poor prognosis. Half of the tested human homologs promote DNA damage and mutation when overproduced in human cells, with DNA damage-elevating mechanisms like those in E. coli. Our work identifies networks of DDPs that provoke endogenous DNA damage and may reveal DNA damage-associated functions of many human known and newly implicated cancer-promoting proteins.

Leveraging Lymphatic System Targeting in Systemic Lupus Erythematosus for Improved Clinical Outcomes.

The role of advanced drug delivery strategies in drug repositioning and minimizing drug attrition rates, when applied early in drug discovery, is poised to increase the translational impact of various therapeutic strategies in disease prevention and treatment. In this context, drug delivery to the lymphatic system is gaining prominence not only to improve the systemic bioavailability of various pharmaceutical drugs but also to target certain specific diseases associated with the lymphatic system. Although the role of the lymphatic system in lupus is known, very little is done to target drugs to yield improved clinical benefits. In this review, we discuss recent advances in drug delivery strategies to treat lupus, the various routes of drug administration leading to improved lymph node bioavailability, and the available technologies applied in other areas that can be adapted to lupus treatment. Moreover, this review also presents some recent findings that demonstrate the promise of lymphatic targeting in a preclinical setting, offering renewed hope for certain pharmaceutical drugs that are limited by efficacy in their conventional dosage forms. These findings underscore the potential and feasibility of such lymphatic drug-targeting approaches to enhance therapeutic efficacy in lupus and minimize off-target effects of the pharmaceutical drugs. SIGNIFICANCE STATEMENT: The World Health Organization estimates that there are currently 5 million humans living with some form of lupus. With limited success in lupus drug discovery, turning to effective delivery strategies with existing drug molecules, as well as those in the early stage of discovery, could lead to better clinical outcomes. After all, effective delivery strategies have been proven to improve treatment outcomes.

Dual production of human mesenchymal stromal cells and derived extracellular vesicles in a dissolvable microcarrier-based stirred culture system.

BACKGROUND & AIMS: Cell therapies based on mesenchymal stromal cells (MSCs) have gained an increasing therapeutic interest in the context of multiple disorders. Nonetheless, this field still faces important challenges, particularly concerning suitable manufacturing platforms. Here, we aimed at establishing a scalable culture system to expand umbilical cord-derived Wharton's jelly MSC (MSC(WJ)) and their derived extracellular vesicles (EVs) by using dissolvable microcarriers combined with xeno(geneic)-free culture medium. METHODS: MSC(WJ) isolated from three donors were cultured at a starting density of 1 × 106 cells per spinner flask, i.e., 2.8 × 103 cells per cm2 of dissolvable microcarrier surface area. After a 6-day expansion period of MSC(WJ), extracellular vesicles (EVs) were produced for 24 h. RESULTS: Taking advantage of an intermittent agitation regimen, we observed high adhesion rates to the microcarriers (over 90% at 24 h) and achieved 15.8 ± 0.7-fold expansion after 6 days of culture. Notably, dissolution of the microcarriers was achieved through a pectinase-based solution to recover the cell product, reducing the hurdles of downstream processing. MSC identity was validated by detecting the characteristic MSC immunophenotype and by multilineage differentiation assays. Considering the growing interest in MSC-derived EVs, which are known to be mediators of the therapeutic features of MSC, this platform also was evaluated for EV production. Upon a 24-h period of conditioning, secreted EVs were isolated by ultrafiltration followed by anion-exchange chromatography and exhibited the typical cup-shaped morphology, small size distribution (162.6 ± 30.2 nm) and expressed EV markers (CD63, CD9 and syntenin-1). CONCLUSIONS: Taken together, we established a time-effective and robust scalable platform that complies with clinical-grade standards for the dual production of MSC(WJ) and their derived EV.

Scope and challenges of seaweed utilization in food and nutraceutical industry in India: a review.

Seaweeds are an excellent source of unique antioxidant phytochemicals, dietary fibres, essential amino acids, vitamins, polyunsaturated fatty acids and minerals. The presence of such structurally diverse and high value bioactive compounds has led to popularization of seaweed as functional food ingredient in global health supplement market. India, with a long coastline of 8100 km and exclusive economic zone of 2.17 million km2, is rich in diverse seaweed resources belonging to almost 700 species. However, food and nutraceutical application of Indian seaweed is highly constrained. Apart from Kappaphycus alvarezii, there is no systematic commercial cultivation of seaweed in India. The regulatory framework for use of seaweed as food is still developing and consumer acceptance is still low. However, there is a timely and renewed interest from different government agencies and research organisations to develop a thriving food and nutraceutical industry using India's vast seaweed resources. The review briefly describes the nutritional and functional food potential of the seaweed and goes on to discuss the scope of seaweed utilization in food and nutraceutical industry in India. Further, the review has identified the regulatory challenges and quality control requirements for use of seaweeds in food and nutraceuticals.

Natural killer cells suppress human cutaneous squamous cell carcinoma cancer cell survival and tumor growth.

Cutaneous squamous cell carcinoma (CSCC), which develops in response to ultraviolet irradiation exposure, is among the most common cancers. CSCC lesions can be removed by surgical excision, but 4.5% of these cancers reappear as aggressive and therapy-resistant tumors. CSCC tumors display a high mutation burden, and tumor frequency is dramatically increased in immune-suppressed patients, indicating a vital role for the immune system in controlling cancer development. Natural killer cells (NK cells) play a key role in cancer immune surveillance, and recent studies suggest that NK cells from healthy donors can be expanded from peripheral blood for use in therapy. In the present study, we test the ability of ex vivo expanded human NK cells to suppress the CSCC cell cancer phenotype and reduce tumor growth. We expanded human NK cells from multiple healthy donors, in the presence of IL-2, and tested their ability to suppress the CSCC cell cancer phenotype. NK cell treatment produced a dose-dependent reduction in SCC-13 and HaCaT cell spheroid growth and matrigel invasion and induced SCC-13 and HaCaT cell apoptosis as evidenced by increased procaspase 9, procaspase 3, and PARP cleavage. Moreover, two important CSCC cell pro-cancer signaling pathways, YAP1/TAZ/TEAD and MEK1/2-ERK1/2, were markedly reduced. Furthermore, tail-vein injection of NK cells markedly suppressed the growth of SCC-13 xenograft tumors in NSG mice, which was also associated with a reduction in YAP1 and MEK1/2-P levels and enhanced apoptosis. These findings show that NK cell treatment suppresses CSCC cell spheroid formation, invasion, viability, and tumor growth, suggesting NK cell treatment may be a candidate therapy for CSCC.

Probing the origins of programmed death ligand-1 inhibition by implementing machine learning-assisted sequential virtual screening techniques.

PD-L1 is a key immunotarget involved in binding to its receptor PD-1. PD-L1/PD-1 interface blocking using antibodies (or small molecules) is the central area of interest for tumor suppression in various cancers. Blocking the PD-L1/PD-1 pathway in the tumor cells results in its immune activation and destruction, and thereby restoring the T-cell proliferation and cytokine production. The active binding site interface residues of PD-L1/PD-1 were experimentally known and proven by structural biology and site-directed mutagenesis studies. Structure-based molecular design technique was employed to identify the inhibitors for blocking the PD-L1/PD-1 interface. Nine hits to leads were identified from the SPECS small molecule database by machine learning, molecular docking, and molecular dynamics simulation techniques. Following this, a machine learning-assisted QSAR modeling approach was implemented using ChEMBL database to gain insights into the inhibitory potential of PD-L1 inhibitors and predict the activity of our previously screened nine hit molecules. The best leads identified in the present study bind strongly with the active sites of PD-L1/PD-1 interface residues, which include A121, M115, I116, S117, I54, Y56, D122, and Y123. These computational leads are considered promising molecules for further in vitro and in vivo analysis to be developed as potential PD-L1 checkpoint inhibitors to cure different types of cancers.

Comparison of the Aotearoa New Zealand Early Warning Score and National Early Warning Score to predict adverse inpatient events in a vital sign dataset.

Aotearoa New Zealand uses a single early warning score (EWS) across all public and private hospitals to detect adult inpatient physiological deterioration. This combines the aggregate weighted scoring of the UK National Early Warning Score with single parameter activation from Australian medical emergency team systems. We conducted a retrospective analysis of a large vital sign dataset to validate the predictive performance of the New Zealand EWS in discriminating between patients at risk of serious adverse events and compared this with the UK EWS. We also compared predictive performance for patients admitted under medical vs. surgical specialties. A total of 1,738,787 aggregate scores (13,910,296 individual vital signs) were obtained from 102,394 hospital admissions to six hospitals within the Canterbury District Health Board of New Zealand's South Island. Predictive performance of each scoring system was determined using area under the receiver operating characteristic curve. Analysis showed that the New Zealand EWS is equivalent to the UK EWS in predicting patients at risk of serious adverse events (cardiac arrest, death and/or unanticipated ICU admission). Area under the receiver operating characteristic curve for both EWSs for any adverse outcome was 0.874 (95%CI 0.871-0.878) and 0.874 (95%CI 0.870-0.877), respectively. Both EWSs showed superior predictive value for cardiac arrest and/or death in patients admitted under surgical rather than medical specialties. Our study is the first validation of the New Zealand EWS in predicting serious adverse events in a broad dataset and supports previous work showing the UK EWS has superior predictive performance in surgical rather than medical patients.

Recent Advances in mmWave-Radar-Based Sensing, Its Applications, and Machine Learning Techniques: A Review.

Human gesture detection, obstacle detection, collision avoidance, parking aids, automotive driving, medical, meteorological, industrial, agriculture, defense, space, and other relevant fields have all benefited from recent advancements in mmWave radar sensor technology. A mmWave radar has several advantages that set it apart from other types of sensors. A mmWave radar can operate in bright, dazzling, or no-light conditions. A mmWave radar has better antenna miniaturization than other traditional radars, and it has better range resolution. However, as more data sets have been made available, there has been a significant increase in the potential for incorporating radar data into different machine learning methods for various applications. This review focuses on key performance metrics in mmWave-radar-based sensing, detailed applications, and machine learning techniques used with mmWave radar for a variety of tasks. This article starts out with a discussion of the various working bands of mmWave radars, then moves on to various types of mmWave radars and their key specifications, mmWave radar data interpretation, vast applications in various domains, and, in the end, a discussion of machine learning algorithms applied with radar data for various applications. Our review serves as a practical reference for beginners developing mmWave-radar-based applications by utilizing machine learning techniques.

A biosurfactant-producing novel bacterial strain isolated from vermicompost having multiple plant growth-promoting traits.

The nutrient-rich vermicompost which is used as manure for the growth and development of plants is rich in microbial flora. These microbes protect the plants against several infectious pathogenic microbes. As certain microbes are known to produce biosurfactants as metabolites, an investigation was carried out to isolate biosurfactant-producing bacterial strains from vermicompost with the efficient antifungal property. From the study, it was revealed that biosurfactant-producing bacterial strains are present in the vermicompost. A total of nine bacterial strains were isolated from the vermicompost. Among them, one most efficient biosurfactant-producing bacterial strains with antifungal properties have been screened. After molecular characterization of the isolated strain, it was revealed that the bacterial strain is Bacillus licheniformis strain SCV1. The strain produces 3.4 ± 0.1 g/L of crude biosurfactant, which when column purified yields 3.1 ± 0.1 g/L of biosurfactant. The biosurfactant exhibited excellent emulsifying activity (E24 ) of 96.56% against crude oil. The produced biosurfactant was identified as a lipopeptide consisting of a mixer of surfactin and iturin. Furthermore, the biosurfactant exhibited significant antifungal activity against a wide range of phytopathogens, showing 76.3% inhibition against Sclerotinia sclerotiorum, 53% inhibition against Colletotrichum gloeosporioides, 51% against Fusarium verticillioides, and 36% against Corynespora cassicolla. Along with antifungal activities, the stain was found to exhibit multiple plant growth-promoting traits. This study, thus indicates that vermicompost might contain biosurfactant-producing microbes which can render protection to the plant against various phytopathogens by the production of biosurfactants and can also stimulate plant growth.

Discovery of Anticancer Hybrid Molecules by Supervised Machine Learning Models and in Vitro Validation in Drug Resistant Chronic Myeloid Leukemia Cells.

The concept of hybrid drugs for targeting multiple aberrant pathways of cancer, by combining the key pharmacophores of clinically approved single-targeted drugs, has emerged as a promising approach for overcoming drug-resistance. Here, we report the design of unique hybrid molecules by combining the two pharmacophores of clinically approved BCR-ABL inhibitor (ponatinib) and HDAC inhibitor (vorinostat) and results of in vitro studies in drug-resistant CML cells. Robust 2D-QSAR and 3D-pharmacophore machine learning supervised models were developed for virtual screening of the hybrid molecules based on their predicted BCR-ABL and HDAC inhibitory activity. The developed 2D-QSAR model showed five information rich molecular descriptors while the 3D-pharmacophore model of BCR-ABL showed five different chemical features (hydrogen bond acceptor, donor, hydrophobic group, positive ion group, and aromatic rings) and the HDAC model showed four different chemical features (hydrogen bond acceptor, donor, positive ion group, and aromatic rings) for potent BCR-ABL and HDAC inhibition. Virtual screening of the 16 designed hybrid molecules identified FP7 and FP10 with better potential of inhibitory activity. FP7 was the most effective molecule with predicted IC50 using the BCR-ABL based 2D-QSAR model of 0.005 µM and that of the HDAC model of 0.153 µM, and that using the BCR-ABL based 3D-pharmacophore model was 0.02 µM and that with HDAC model was 0.014 µM. In vitro study (dose-response relationship) of FP7 in wild type and imatinib-resistant CML cell lines harboring Thr315Ile or Tyr253His mutations showed growth inhibitory IC50 values of 0.000 16, 0.0039, and 0.01 µM, respectively. This molecule also showed better biocompatibility when tested in whole blood and in PBMCs as compared to ponatinib or vorinostat.

Machine learning models for predicting the activity of AChE and BACE1 dual inhibitors for the treatment of Alzheimer's disease.

Multi-target directed ligand-based 2D-QSAR models were developed using different N-benzyl piperidine derivatives showing inhibitory activity toward acetylcholinesterase (AChE) and ß-Site amyloid precursor protein cleaving enzyme (BACE1). Five different classes of molecular descriptors belonging to spatial, structural, thermodynamics, electro-topological and E-state indices were used for machine learning by linear method, genetic function approximation (GFA) and nonlinear method, support vector machine (SVM) and artificial neural network (ANN). Dataset used for QSAR model development includes 57 AChE and 53 BACE1 inhibitors. Statistically significant models were developed for AChE (R2 = 0.8688, q2 = 0.8600) and BACE1 (R2 = 0.8177, q2 = 0.7888) enzyme inhibitors. Each model was generated with an optimum five significant molecular descriptors such as electro-topological (ES_Count_aaCH and ES_Count_dssC), structural (QED_HBD, Num_TerminalRotomers), spatial (JURS_FNSA_1) for AChE and structural (Cl_Count, Num_Terminal Rotomers), electro-topological (ES_Count_dO), electronic (Dipole_Z) and spatial (Shadow_nu) for BACE1 enzyme, determining the key role in its enzyme inhibitory activity. The predictive ability of the generated machine learning models was validated using the leave-one-out, Fischer (F) statistics and predictions based on the test set of 11 AChE (r2 = 0.8469, r2pred = 0.8138) and BACE1 (r2 = 0.7805, r2pred = 0.7128) inhibitors. Further, nonlinear machine learning methods such as ANN and SVM predicted better than the linear method GFA. These molecular descriptors are very important in describing the inhibitory activity of AChE and BACE1 enzymes and should be used further for the rational design of multi-targeted anti-Alzheimer's lead molecules.

Enhanced inhibition of Pseudomonas aeruginosa virulence factor production and biofilm development by sublethal concentrations of eugenol and phenyllactic acid.

Biofilm development in Pseudomonas aeruginosa is regulated by its quorum sensing (QS) systems. It has three major QS systems: LasI/R, RhlI/R and PQS/MvfR. Previous studies showed that phenyllactic acid (PLA) binds to RhlR and PqsR and inhibits the Rhl and PQS QS; and eugenol at sublethal concentration inhibits Las and PQS QS systems. Here, we have demonstrated that a combination of sublethal doses of eugenol and PLA enhanced the inhibition of the QS mediated production of the virulence factors and biofilm development of this pathogen. A combination of 50 µmol l-1 eugenol and 0·3 mmol l-1 PLA significantly inhibited the pyocyanin production, protease activity, swarming motility and cytotoxic activities of P. aeruginosa strain PAO1, whereas eugenol and PLA when added individually to PAO1 cultures were less effective in inhibiting its virulence factor expression. Biofilm formation of PAO1 was reduced by 32, 19 and 87% on glass surfaces; and 54, 49 and 93% on catheter surfaces when treated using 50 µmol l-1 eugenol or 0·3 mmol l-1 PLA and their combinations, respectively. The in vitro finding in the reduction of biofilm development was further validated in vivo using a catheter associated medaka fish biofilm model. Our results indicate that a combination of QS inhibitors targeting different QS pathways should be selected while designing therapeutic molecules to achieve maximum QS mediated biofilm inhibition and clinical outcome against P. aeruginosa.

Characteristics and seal ability of blend films based on chicken protein isolate and fish skin gelatin.

Blend films from chicken protein isolate (CPI) and fish skin gelatin (FSG) at various CPI/FSG ratios (100:0, 80:20, 70:30, 60:40, 0:100), prepared at pH 3 or 11 were characterized. At the same pH, tensile strength (TS) of CPI/FSG films was higher than CPI and FSG films, and CPI/FSG film (60:40) had highest TS. Moreover, elongation at break (EAB) of blend films increased as FSG content augmented. EAB of CPI film and CPI/FSG (80:20) film was similar for both pHs. CPI films generally possessed higher water vapor permeability (WVP), light barrier property and b*-value than FSG counterpart. CPI films prepared at both pHs were not sealable. Nevertheless, addition of FSG improved sealing ability of blend films. At the same CPI/FSG ratio, seal strength and seal efficiency were lower for films prepared at pH 11. Moreover, higher TS and b*-value were gained, compared to those of films prepared at pH 3. Less cracks on surface and cross-section appeared for CPI/FSG films as revealed by scanning electron microscopy images, compared to CPI and FSG films. Therefore, incorporation of FSG up to 40% into blend film was able to improve mechanical properties, WVP, and sealing ability of blend films.

Influence of corn starch based bio-active edible coating containing fumaric acid on the lipid quality and microbial shelf life of silver pomfret fish steaks stored at 4 °C.

The present study aimed at assessing the impact of addition of fumaric acid (0.5%), as an active agent, in a corn starch (2%) based edible coating, on the lipid quality and microbial shelf life of silver pomfret (Pampus argenteus) fish steaks stored at 4 °C. Treating fish steaks with FA resulted in a bacteriostatic effect leading to reduced counts of total mesophilic and psychrotrophic bacteria, H2S producing bacteria and Pseudomonas spp. The total mesophilic bacterial count of uncoated control sample exceeded the permissible limit of 7 log cfu g-1 on 6th day and had the lowest microbial shelf life. FA incorporation in the CS coating improved the microbial stability of fish steaks resulting in a shelf life of 15 days. The outcomes of the study suggest that CS based coating is beneficial in delaying lipid oxidation as displayed by the lower TBA and PV values while FA is an effective agent for further increasing the preservative action of CS coating by significantly inhibiting microbial growth as well as lipid quality deterioration, which could be exploited by the seafood industry as an active packaging component.

A novel transcript variant of human G-protein coupled estrogen receptor.

The G-protein coupled estrogen receptor (GPER) mediates short-term non-genomic effects of estrogen in diverse cell types and tissues. According to the NCBI nucleotide database, three variants of GPER are known. They are NM_001505.2 (GPER-v2), NM_001039966.1 (GPER-v3), and NM_001098201.1 (GPER-v4). Investigations on GPER expression are key to understand its physiological and pathological roles. However, most studies on GPER mRNA expression have considered total GPER mRNA expression regardless of the individual variants. The present study is motivated by a novel transcript observed in the UCSC Genome Browser (uc010ksd.1), which is annotated as GPER. The novel variant is similar to the known transcript variants of GPER in terms of the protein-coding sequence and the 3'UTR. However, it has a unique 5'UTR, which distinguishes it from other GPER variants. Using primers specific for uc010ksd.1, we have performed RT-PCR to show that the novel GPER transcript (hereafter referred to as GPER-v5) is expressed in human cancer cell lines, such as MCF-7, SW-620, COLO-205, and HT-29. Preliminary evidences indicate that GPER-v5 is a novel GPER mRNA variant. The expression of GPER-v5 in primary cells and tissues should be investigated before probing into its role and relevance in physiological and pathological conditions.

Caenorhabditis elegans: a model to understand host-microbe interactions.

Host-microbe interactions within the gut are fundamental to all higher organisms. Caenorhabditis elegans has been in use as a surrogate model to understand the conserved mechanisms in host-microbe interactions. Morphological and functional similarities of C. elegans gut with the human have allowed the mechanistic investigation of gut microbes and their effects on metabolism, development, reproduction, behavior, pathogenesis, immune responses and lifespan. Recent reports suggest their suitability for functional investigations of human gut bacteria, such as gut microbiota of healthy and diseased individuals. Our knowledge on the gut microbial diversity of C. elegans in their natural environment and the effect of host genetics on their core gut microbiota is important. Caenorhabditis elegans, as a model, is continuously bridging the gap in our understanding the role of genetics, environment, and dietary factors on physiology of the host.

Synthesis, Molecular Docking and Preliminary Antileukemic Activity of 4-Methoxybenzyl Derivatives Bearing Imidazo[2,1-b][1,3,4]thiadiazole.

In this study, we synthesized 22 compounds in a series with various substitution on imidazo[2,1-b][1,3,4]thiadiazole. The potential cytotoxic activity of these compounds investigated in leukemia cell lines by Differential Nuclear Staining (DNS). Our results identified two compounds, 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate and 6-(4-chlorophenyl)-2-(4-methoxybenzyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde, exhibited the most cytotoxic effect against murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa) with IC50 values ranging between 0.79 and 1.6 µM. The results indicate that 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate is inducing phosphatidylserine externalization and caspase-3 activation which are both a hallmark of apoptosis. Docking studies showed that 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate binds within the active sites of transforming growth factor beta (TGF-ß) type I receptor kinase domain by strong hydrogen binding and hydrophobic interactions.

Tumor-Targeted, Cytoplasmic Delivery of Large, Polar Molecules Using a pH-Low Insertion Peptide.

Tumor-targeted drug delivery systems offer not only the advantage of an enhanced therapeutic index, but also the possibility of overcoming the limitations that have largely restricted drug design to small, hydrophobic, "drug-like" molecules. Here, we explore the ability of a tumor-targeted delivery system centered on the use of a pH-low insertion peptide (pHLIP) to directly deliver moderately polar, multi-kDa molecules into tumor cells. A pHLIP is a short, pH-responsive peptide capable of inserting across a cell membrane to form a transmembrane helix at acidic pH. pHLIPs target the acidic tumor microenvironment with high specificity, and a drug attached to the inserting end of a pHLIP can be translocated across the cell membrane during the insertion process. We investigate the ability of wildtype pHLIP to deliver peptide nucleic acid (PNA) cargoes of varying sizes across lipid membranes. We find that pHLIP effectively delivers PNAs up to ∼7 kDa into cells in a pH-dependent manner. In addition, pHLIP retains its tumor-targeting capabilities when linked to cargoes of this size, although the amount delivered is reduced for PNA cargoes greater than ∼6 kDa. As drug-like molecules are traditionally restricted to sizes of ∼500 Da, this constitutes an order-of-magnitude expansion in the size range of deliverable drug candidates.

Impacts of epizootic ulcerative syndrome on subsistence fisheries and wildlife.

Epizootic ulcerative syndrome (EUS), caused by the water mould (Oomycota) Aphanomyces invadans, has spread throughout the world's major continents over the last 50 years, with the apparent exception of South and Central America. With over 160 susceptible fish species representing 54 families and 16 orders recorded to date, EUS is of international concern and infection with A. invadans is a World Organisation for Animal Health (OIE) listed disease. This paper examines what little has been reported on the impacts of EUS on subsistence fisheries and wildlife, or what can be deduced about those impacts, and concludes that there is a need for systematic data collection on the size and socio-economic importance of subsistence fisheries. Such fisheries are often relied upon by the poorest communities, thus food and nutrition security impacts can be significant. Similarly, impacts on wildlife are poorly documented, emphasising the lack of, and the need for, research on and modelling of the ecosystem-level impacts of EUS and other aquatic animal diseases. The history of EUS and several other aquatic animal diseases also brings into question the effectiveness of current measures for controlling the international spread of aquatic animal diseases and calls for a re-think on how best to meet this ongoing challenge.

En l'espace d'un demi-siècle, le syndrome ulcératif épizootique dû à l'oomycète Aphanomyces invadans s'est propagé dans toutes les régions du monde, à l'exception, semble-t-il, de l'Amérique du Sud et Centrale. Avec plus de 160 espèces de poissons répertoriées comme sensibles, réparties en 54 familles et 16 ordres, le syndrome ulcératif épizootique est une maladie préoccupante à l'échelle internationale et figure parmi les maladies listées par l'Organisation mondiale de la santé animale (OIE) sous le nom d'infection à A. invadans. Les auteurs font état des très rares signalements concernant l'impact du syndrome ulcératif épizootique sur la pêche de subsistance et sur la faune sauvage et tentent d'en tirer quelques conclusions, en insistant sur la nécessité de procéder à une collecte systématique de données afin de déterminer l'envergure et l'importance socioéconomique de la pêche de subsistance. Les communautés les plus pauvres étant souvent celles qui dépendent le plus de cette activité, la maladie a sans doute un impact majeur sur la sécurité alimentaire et nutritionnelle de ces populations. De même, l'impact sur la faune sauvage n'a pas vraiment été étudié jusqu'à présent, d'où la nécessité de conduire des travaux de recherche et de modélisation sur l'impact du syndrome ulcératif épizootique (et d'autres maladies des animaux aquatiques) à l'échelle des écosystèmes. L'histoire du syndrome ulcératif épizootique et d'autres maladies des animaux aquatiques pose également la question de l'efficacité des mesures appliquées actuellement pour maîtriser la propagation internationale de ces maladies et invite à repenser la réponse à apporter à ce défi toujours présent.

En los últimos 50 años, el síndrome ulcerante epizoótico, causado por el hongo acuático (oomiceto) Aphanomyces invadans, se ha diseminado por casi todos los continentes del planeta, con la aparente salvedad de Sudamérica y Centroamérica. Se trata de una enfermedad de importancia internacional que, hasta donde consta a día de hoy, afecta a más de 160 especies piscícolas de 54 familias y 16 órdenes. De ahí que la infección por A. invadans sea una patología inscrita en la lista de la Organización Mundial de Sanidad Animal (OIE). Los autores, tras exponer lo poco que hasta ahora se ha descrito de los efectos de la enfermedad sobre la pesca de subsistencia y la fauna silvestre o lo que es posible inferir acerca de esos efectos, llegan a la conclusión de que se requiere una labor sistemática de obtención de datos sobre la magnitud e importancia socioeconómica de la actividad pesquera de subsistencia, de la que dependen a menudo las comunidades más pobres, por lo que las consecuencias para la seguridad nutricional y alimentaria pueden ser de calado. Tampoco están bien descritas las repercusiones de la enfermedad en los animales silvestres, lo que pone de relieve la ausencia, y por ende la necesidad, de investigaciones y de modelos sobre los efectos ecosistémicos del síndrome ulcerante epizoótico y otras varias enfermedades de los animales acuáticos. La historia de estas patologías también arroja dudas sobre la eficacia de las medidas aplicadas actualmente para controlar la propagación internacional de las enfermedades de los animales acuáticos y exige replantearse cuál es la respuesta idónea a este problema que no cesa.

Vulnerabilities in aquatic animal production.

The role of aquatic animals in global food and nutrition security is increasingly recognised. The global demand for fish is increasing, leading to a need to significantly increase its supply. Securing future fish supplies through sustainable production is a challenge as major resources such as fresh water and land are becoming limited worldwide. Aquaculture and capture fisheries face various threats from both human-mediated and natural environmental change, including climate change. Aquaculture systems and practices are vulnerable to such changes. Moreover, aquatic animal diseases are currently considered one of the most important constraints to sustainable global fish production. The need to increase global production, combined with climate change, may increase losses due to diseases. This paper examines key vulnerabilities, their impacts and management to achieve increased and sustainable global fish production. The authors focus on the need to apply international standards, and to develop biosecurity and capacity in aquatic animal health to improve global fish health. Research needed to underpin the development of improved detection and control of fish diseases is also discussed.

L'importance des animaux aquatiques pour la sécurité alimentaire et nutritionnelle mondiale est désormais reconnue. La demande mondiale en aliments issus d'animaux aquatiques ne cessant d'augmenter, il est devenu impératif de renforcer significativement l'offre du secteur. La sécurisation future de cette offre grâce à la mise en place d'une production durable constitue un défi de taille en raison de la raréfaction de certaines ressources cruciales, dont l'eau douce et les terres. L'aquaculture et la pêche de capture font face à plusieurs menaces induites par les transformations tant naturelles qu'anthropiques subies par l'environnement, y compris le changement climatique. Les systèmes et les pratiques de l'aquaculture présentent des vulnérabilités à ces changements. De plus, on considère aujourd'hui que les maladies des animaux aquatiques constituent l'une des principales entraves à une production aquacole durable au niveau mondial. Les pertes dues aux maladies vont probablement augmenter par l'effet conjoint du changement climatique et de la nécessité d'accroître les quantités produites dans le monde. Les auteurs examinent les principales vulnérabilités à l'œuvre ainsi que leur impact et les manières d'y faire face en vue d'une production aquacole mondiale accrue et durable. Ils mettent l'accent sur la nécessité de se conformer aux normes internationales et de renforcer la biosécurité et les capacités du secteur de la santé des animaux aquatiques afin d'améliorer le statut sanitaire de ces animaux à l'échelle mondiale. Ils font également le point sur les travaux de recherche qu'il convient de mener afin de mettre au point de meilleures méthodes de détection et de contrôle des maladies des animaux aquatiques.

Cada vez está más clara la función de los animales acuáticos en relación con la seguridad alimentaria y nutricional del mundo. La demanda planetaria de alimentos derivados de animales acuáticos va en aumento, lo que obliga a incrementar sustancialmente el suministro. El objetivo de asegurar el abastecimiento de animales acuáticos en el futuro gracias a una producción sostenible plantea no pocas dificultades, en la medida en que recursos importantes, como el agua dulce o las tierras, empiezan a escasear en todo el mundo. La acuicultura y la pesca de captura afrontan una serie de amenazas derivadas de los cambios ambientales, ya sean de origen natural o antrópico, en particular el cambio climático. Las praxis y los sistemas acuícolas son vulnerables a esos cambios. Están además las enfermedades de los animales acuáticos, consideradas actualmente uno de los principales frenos a la producción sostenible del sector en el mundo. La necesidad de elevar la producción mundial, combinada con el cambio climático, puede acrecentar el volumen de pérdidas debidas a enfermedades. Los autores examinan las principales fragilidades del sistema, sus consecuencias y la forma de gestionarlas para lograr una producción acuícola mundial más cuantiosa y sostenible, centrándose en la necesidad de aplicar normas internacionales y de desarrollar tanto la seguridad biológica como la capacidad en materia de sanidad de los animales acuáticos para mejorar el estado de salud de estos animales a escala mundial. También se refieren a las investigaciones necesarias para fundamentar sistemas más eficaces de detección y control de las enfermedades de los animales acuáticos.