Beginning with the discovery of penicillin by Alexander Fleming in the late 1920s, antibiotics have revolutionized the field of medicine. They have saved millions of lives each year, alleviated pain ...and suffering, and have even been used prophylactically for the prevention of infectious diseases. However, we have now reached a crisis where many antibiotics are no longer effective against even the simplest infections. Such infections often result in an increased number of hospitalizations, more treatment failures and the persistence of drug-resistant pathogens. Of particular concern are organisms such as methicillin-resistant Staphylococcus aureus, Clostridium difficile, multidrug and extensively drug-resistant Mycobacterium tuberculosis, Neisseria gonorrhoeae, carbapenem-resistant Enterobacteriaceae and bacteria that produce extended spectrum β-lactamases, such as Escherichia coli. To make matters worse, there has been a steady decline in the discovery of new and effective antibiotics for a number of reasons. These include increased costs, lack of adequate support from the government, poor returns on investment, regulatory hurdles and pharmaceutical companies that have simply abandoned the antibacterial arena. Instead, many have chosen to focus on developing drugs that will be used on a chronic basis, which will offer a greater profit and more return on investment. Therefore, there is now an urgent need to develop new and useful antibiotics to avoid returning to the 'pre-antibiotic era'. Some potential opportunities for antibiotic discovery include better economic incentives, genome mining, rational metabolic engineering, combinatorial biosynthesis and further exploration of the earth's biodiversity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Microbes are the leading producers of useful natural products. Natural products from microbes and plants make excellent drugs. Significant portions of the microbial genomes are devoted to production ...of these useful secondary metabolites. A single microbe can make a number of secondary metabolites, as high as 50 compounds. The most useful products include antibiotics, anticancer agents, immunosuppressants, but products for many other applications, e.g., antivirals, anthelmintics, enzyme inhibitors, nutraceuticals, polymers, surfactants, bioherbicides, and vaccines have been commercialized. Unfortunately, due to the decrease in natural product discovery efforts, drug discovery has decreased in the past 20 years. The reasons include excessive costs for clinical trials, too short a window before the products become generics, difficulty in discovery of antibiotics against resistant organisms, and short treatment times by patients for products such as antibiotics. Despite these difficulties, technology to discover new drugs has advanced, e.g., combinatorial chemistry of natural product scaffolds, discoveries in biodiversity, genome mining, and systems biology. Of great help would be government extension of the time before products become generic.
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CEKLJ, DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Microbes have made a phenomenal contribution to the health and well-being of people throughout the world. In addition to producing many primary metabolites, such as amino acids, vitamins and ...nucleotides, they are capable of making secondary metabolites, which constitute half of the pharmaceuticals on the market today and provide agriculture with many essential products. This review centers on these beneficial secondary metabolites, the discovery of which goes back 80 years to the time when penicillin was discovered by Alexander Fleming.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary
For over 40 years, natural products have served us well in combating cancer. The main sources of these successful compounds are microbes and plants from the terrestrial and marine ...environments. The microbes serve as a major source of natural products with anti‐tumour activity. A number of these products were first discovered as antibiotics. Another major contribution comes from plant alkaloids, taxoids and podophyllotoxins. A vast array of biological metabolites can be obtained from the marine world, which can be used for effective cancer treatment. The search for novel drugs is still a priority goal for cancer therapy, due to the rapid development of resistance to chemotherapeutic drugs. In addition, the high toxicity usually associated with some cancer chemotherapy drugs and their undesirable side‐effects increase the demand for novel anti‐tumour drugs active against untreatable tumours, with fewer side‐effects and/or with greater therapeutic efficiency. This review points out those technologies needed to produce the anti‐tumour compounds of the future.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective: The aim of this study was to synthesize published data regarding long-term effects of ADHD on information learned (measured via achievement tests) and success within the school environment ...(academic performance). Method: A systematic search identified 176 studies (1980-2012) of long-term (≥2 years) academic outcomes with ADHD. Results: Achievement test outcomes (79%) and academic performance outcomes (75%) were worse in individuals with untreated ADHD compared with non-ADHD controls, also when IQ difference was controlled (72% and 81%, respectively). Improvement in both outcome groups was associated with treatment, more often for achievement test scores (79%) than academic performance (42%), also when IQ was controlled (100% and 57%, respectively). More achievement test and academic performance outcomes improved with multimodal (100% and 67%, respectively) than pharmacological (75% and 33%) or non-pharmacological (75% and 50%) treatment alone. Conclusion: ADHD adversely affects long-term academic outcomes. A greater proportion of achievement test outcomes improved with treatment compared with academic performance. Both improved most consistently with multimodal treatment.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Genetic exchange between divergent evolutionary lineages, from introgressive hybridization between locally adapted populations to insertion of retroviral sequences into eukaryotic genomes, has now ...been documented. The detection of frequent divergence-with-gene-flow contrasts the neo-Darwinian paradigm of largely allopatric diversification. Nevertheless, of even greater significance is the growing wealth of data suggesting that the recipients of the transferred genomic material gain adaptive phenotypes from the donor lineages. This adaptive enrichment is reflected by changes in pathogenicity in viruses and bacteria, the transformation of ecological amplitude in eukaryotes, and adaptive radiations in extremely diverse lineages. Although genetic exchange may produce maladaptive consequences, most of the recently reported examples suggest increases in fitness, and many such adaptive trait transfers have been identified in our own species.
Although the exchange of genetic material between lineages as diverse as viruses and mammals has been recognized for decades, particularly through the analysis of genomic datasets, it has remained an active debate as to whether such exchanges can lead to adaptive evolution.
Recently, the growing wealth of examples of genetic transfer involving organisms from all domains of life has provided the means to test the hypothesis of adaptive genetic exchange. The repeated testing of this hypothesis has revealed not only adaptive effects among viral and prokaryotic lineages but also for plants, animals, and fungi. Indeed, the data now available indicate how profoundly important ancient and more recent gene exchange has been in the evolution of even humans.
Adaptive evolutionary diversification can now be seen as being often facilitated by the addition of standing genetic variation from one divergent lineage to another.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Microbial enzymes are of great importance in the development of industrial bioprocesses. Current applications are focused on many different markets including pulp and paper, leather, detergents and ...textiles, pharmaceuticals, chemical, food and beverages, biofuels, animal feed and personal care, among others. Today there is a need for new, improved or/and more versatile enzymes in order to develop more novel, sustainable and economically competitive production processes. Microbial diversity and modern molecular techniques, such as metagenomics and genomics, are being used to discover new microbial enzymes whose catalytic properties can be improved/modified by different strategies based on rational, semi-rational and random directed evolution. Most industrial enzymes are recombinant forms produced in bacteria and fungi.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
IMPORTANCE: Accumulation of disability in multiple sclerosis may occur as relapse-associated worsening (RAW) or steady progression independent of relapse activity (PIRA), with PIRA regarded as a ...feature of primary and secondary progressive multiple sclerosis. OBJECTIVE: To investigate the contributions of relapse-associated worsening vs relapse-independent progression to overall confirmed disability accumulation (CDA) and assess respective baseline prognostic factors and outcomes of 2 treatments. DESIGN, SETTING, AND PARTICIPANTS: Analyses occurred from July 2015 to February 2020 on pooled data from the intention-to-treat population of 2 identical, phase 3, multicenter, double-blind, double-dummy, parallel-group randomized clinical trials (OPERA I and II) conducted between August 2011 and April 2015. In the trials, patients with relapsing multiple sclerosis (RMS), diagnosed using the 2010 revised McDonald criteria, were randomized from 307 trial sites in 56 countries; resulting data were analyzed in the pooled data set. INTERVENTIONS: Participants were randomized 1:1 to receive 600 mg of ocrelizumab by intravenous infusion every 24 weeks or subcutaneous interferon β-1a 3 times a week at a dose of 44 μg throughout a 96-week treatment period. MAIN OUTCOMES AND MEASURES: Confirmed disability accumulation was defined by an increase in 1 or more of 3 measures (Expanded Disability Status Scale, timed 25-ft walk, or 9-hole peg test), confirmed after 3 or 6 months, and classified per temporal association with confirmed clinical relapses (PIRA or RAW). RESULTS: In the pooled OPERA I and II population (1656 of 2096 eligible participants), baseline demographics and disease characteristics were similar for patients randomized to interferon β-1a vs ocrelizumab (mean SD age, 37.2 9.2 vs 37.1 9.2 years; 552 66.6% vs 541 women 65.4%). After 96 weeks, 12-week composite CDA had occurred in 223 (29.6% by Kaplan-Meier estimate) randomized to interferon β-1a and 167 (21.1%) randomized to ocrelizumab; 24-week composite CDA had occurred in 170 (22.7%) taking interferon β-1a and 129 (16.2%) taking ocrelizumab. The PIRA events were the main contributors to 12-week and 24-week composite CDA after 96 weeks in patients treated with interferon β-1a (174 of 223 78.0% and 137 of 170 80.6%, respectively) and ocrelizumab (147 of 167 88.0% and 115 of 129 89.1%, respectively); a minority had CDA explained by RAW events (69 of 390 17.7% and 52 of 299 17.4%, respectively). Very few patients with composite CDA experienced both RAW and PIRA events (17 of 390 4.4% for 12-week and 15 of 299 5.0% for 24-week composite CDA). Ocrelizumab (vs interferon β-1a) was associated with reduced risk of composite CDA (hazard ratio HR, 0.67) and confirmed PIRA (HR, 0.78) and RAW (HR, 0.47) events. CONCLUSIONS AND RELEVANCE: Most disability accumulation in RMS is not associated with overt relapses. This indicates an underlying progression in this typical RMS population and challenges the current clinical distinction of relapsing and progressive forms of multiple sclerosis. Ocrelizumab was superior to interferon β-1a in preventing both RAW and PIRA. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: OPERA I (NCT01247324) and OPERA II (NCT01412333).
Even before the publication of Darwin's Origin of Species, the perception of evolutionary change has been a tree-like pattern of diversification — with divergent branches spreading further and ...further from the trunk. In the only illustration of Darwin's treatise, branches large and small never reconnect. However, it is now evident that this view does not adequately encompass the richness of evolutionary pattern and process. Instead, the evolution of species from microbes to mammals builds like a web that crosses and re-crosses through genetic exchange, even as it grows outward from a point of origin. Some of the avenues for genetic exchange, for example introgression through sexual recombination versus lateral gene transfer mediated by transposable elements, are based on definably different molecular mechanisms. However, even such widely different genetic processes may result in similar effects on adaptations (either new or transferred), genome evolution, population genetics, and the evolutionary/ecological trajectory of organisms. For example, the evolution of novel adaptations (resulting from lateral gene transfer) leading to the flea-borne, deadly, causative agent of plague from a rarely-fatal, orally-transmitted, bacterial species is quite similar to the adaptations accrued from natural hybridization between annual sunflower species resulting in the formation of several new species. Thus, more and more data indicate that evolution has resulted in lineages consisting of mosaics of genes derived from different ancestors. It is therefore becoming increasingly clear that the tree is an inadequate metaphor of evolutionary change. In this book, the author promotes the ‘web-of-life’ metaphor as a more appropriate representation of evolutionary change in all life-forms.
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