IN SILICO METHODS FOR DRUG DESIGN AND DISCOVERY

Computer-aided drug design (CADD) methodologies are playing an ever-increasing role in drug discovery that are critical in the cost-effective identification of promising drug candidates. These computational methods are relevant in limiting the use of animal models in pharmacological research, for aiding the rational design of novel and safe drug candidates, and for repositioning marketed drugs, supporting medicinal chemists and pharmacologists during the drug discovery trajectory.Within this field of research, we launched a Research Topic in Frontiers in Chemistry in March 2019 entitled “In silico Methods for Drug Design and Discovery,” which involved two sections of the journal: Medicinal and Pharmaceutical Chemistry and Theoretical and Computational Chemistry. For the reasons mentioned, this Research Topic attracted the attention of scientists and received a large number of submitted manuscripts. Among them 27 Original Research articles, five Review articles, and two Perspective articles have been published within the Research Topic. The Original Research articles cover most of the topics in CADD, reporting advanced in silico methods in drug discovery, while the Review articles offer a point of view of some computer-driven techniques applied to drug research. Finally, the Perspective articles provide a vision of specific computational approaches with an outlook in the modern era of CADD

Human retroviruses and AIDS 1996. A compilation and analysis of nucleic acid and amino acid sequences

This compendium and the accompanying floppy diskettes are the result of an effort to compile and rapidly publish all relevant molecular data concerning the human immunodeficiency viruses (HIV) and related retroviruses. The scope of the compendium and database is best summarized by the five parts that it comprises: (1) Nuclear Acid Alignments and Sequences; (2) Amino Acid Alignments; (3) Analysis; (4) Related Sequences; and (5) Database Communications. Information within all the parts is updated throughout the year on the Web site, http://hiv-web.lanl.gov. While this publication could take the form of a review or sequence monograph, it is not so conceived. Instead, the literature from which the database is derived has simply been summarized and some elementary computational analyses have been performed upon the data. Interpretation and commentary have been avoided insofar as possible so that the reader can form his or her own judgments concerning the complex information. In addition to the general descriptions of the parts of the compendium, the user should read the individual introductions for each part

Mobile Diagnosis 2.0

Mobile sensing and diagnostic capabilities are becoming extremely important for a wide range of emerging applications and fields spanning mobile health, telemedicine, point-of-care diagnostics, global health, field medicine, democratization of sensing and diagnostic tools, environmental monitoring, and citizen science, among many others. The importance of low-cost mobile technologies has been underlined during this current COVID-19 pandemic, particularly for applications such as the detection of pathogens, including bacteria and viruses, as well as for prediction and management of different diseases and disorders. This book focuses on some of these application areas and provides a timely summary of cutting-edge results and emerging technologies in these interdisciplinary fields

Analyses of observational studies and randomised trials to increase understanding of the occurrence and role of drug resistance in HIV infection.

This thesis explores the relationship between the use of antiretroviral therapy (ARVs) and drug resistance emergence in HIV-1 infected individuals. It also describes the combined impact of treatment use and resistance mutations on virological and immunological response in individuals who are under follow-up in one of four trials: MaxCminl, MaxCmin2, COLATE or SMART and three observational studies: EuroSIDA, the UK CHIC study and the UK drug resistance database. The emergence of resistance to an ARV that an individual is receiving may influence viral replication rates, which could increase the risk of CD4+T cell count deterioration, clinical progression and death, unless changes are made to the treatment regimen. Individuals may exhaust all treatment options if large amounts of resistance mutations are detected in their viral sub-populations. In the current era, new ARVs are still arriving on the market, but resistance to these ARVs is only partially understood. Understanding what mutations emerge in individuals who are failing treatment and the impact of specific mutations and combinations of mutations on the likelihood of responding to future regimens is still essential for being able to administer long-term therapy successfully. Research for this thesis started just after the introduction of ritonavir boosted protease inhibitors (Pl/rs). Drug resistance emergence among individuals who experienced virological failure on a Pl/r containing regimen is described in detail, and the relationship between resistance at baseline and virological response is also quantified. Other aspects of drug resistance are investigated, including: the potential benefit of harbouring the M184IA/ mutation, the impact of resistance on immunological response and the relationship between resistance and viral re-suppression rates amongst patients who interrupt an NNRTI containing regimen. This thesis outlines the benefits of resistance testing and highlights some of the key issues with interpreting resistance data. Resistance tests are generally performed on a selective group of individuals so caution needs to be used when extending the results to all HIV-1 infected individuals. Further, consensus sequences are useful for indicating resistance that is present in the predominant virus however, more minor, archived, species are not usually identified through this method and these may also be an important determinant of therapy response

Towards a Learning Health System: a SOA based platform for data re-use in chronic infectious diseases

Abstract Information and Communication Technology (ICT) tools can efficiently support clinical research by providing means to collect automatically huge amount of data useful for the management of clinical trials conduction. Clinical trials are indispensable tools for Evidence-Based Medicine and represent the most prevalent clinical research activity. Clinical trials cover only a restricted part of the population that respond to particular and strictly controlled requirements, offering a partial view of the overall patients\u2019 status. For instance, it is not feasible to consider patients with comorbidities employing only one kind of clinical trial. Instead, a system that have a comprehensive access to all the clinical data of a patient would have a global view of all the variables involved, reflecting real-world patients\u2019 experience. The Learning Health System is a system with a broader vision, in which data from various sources are assembled, analyzed by various means and then interpreted. The Institute of Medicine (IOM) provides this definition: \u201cIn a Learning Health System, progress in science, informatics, and care culture align to generate new knowledge as an ongoing, natural by-product of the care experience, and seamlessly refine and deliver best practices for continuous improvement in health and health care\u201d. The final goal of my project is the realization of a platform inspired by the idea of Learning Health System, which will be able to re-use data of different nature coming from widespread health facilities, providing systematic means to learn from clinicians\u2019 experience to improve both the efficiency and the quality of healthcare delivery. The first approach is the development of a SOA-based architecture to enable data collection from sparse facilities into a single repository, to allow medical institutions to share information without an increase in costs and without the direct involvement of users. Through this architecture, every single institution would potentially be able to participate and contribute to the realization of a Learning Health System, that can be seen as a closed cycle constituted by a sequential process of transforming patient-care data into knowledge and then applying this knowledge to clinical practice. Knowledge, that can be inferred by re-using the collected data to perform multi-site, practice-based clinical trials, could be concretely applied to clinical practice through Clinical Decision Support Systems (CDSS), which are instruments that aim to help physicians in making more informed decisions. With 4 this objective, the platform developed not only supports clinical trials execution, but also enables data sharing with external research databases to participate in wider clinical trials also at a national level without effort. The results of these studies, integrated with existing guidelines, can be seen as the knowledge base of a decision support system. Once designed and developed, the adoption of this system for chronical infective diseases management at a regional level helped in unifying data all over the Ligurian territory and actively monitor the situation of specific diseases (like HIV, HCV and HBV) for which the concept of retention in care assumes great importance. The use of dedicated standards is essential to grant the necessary level of interoperability among the structures involved and to allow future extensions to other fields. A sample scenario was created to support antiretroviral drugs prescription in the Ligurian HIV Network setting. It was thoroughly tested by physicians and its positive impact on clinical care was measured in terms of improvements in patients\u2019 quality of life, prescription appropriateness and therapy adherence. The benefits expected from the employment of the system developed were verified. Student\u2019s T test was used to establish if significant differences were registered between data collected before and after the introduction of the system developed. The results were really acceptable with the minimum p value in the order of 10 125 and the maximum in the order of 10 123. It is reasonable to assess that the improvements registered in the three analysis considered are ascribable to this system introduction and not to other factors, because no significant differences were found in the period before its release. Speed is a focal point in a system that provides decision support and it is highly recognized the importance of velocity optimization. Therefore, timings were monitored to evaluate the responsiveness of the system developed. Extremely acceptable results were obtained, with the waiting times of the order of 10 121 seconds. The importance of the network developed has been widely recognized by the medical staff involved, as it is also assessed by a questionnaire they compiled to evaluate their level of satisfaction

Topics on Cervical Cancer With an Advocacy for Prevention

Cervical Cancer is one of the leading cancers among women, especially in developing countries. Prevention and control are the most important public health strategies. Empowerment of women, education, "earlier" screening by affordable technologies like visual inspection, and treatment of precancers by cryotherapy/ LEEP are the most promising interventions to reduce the burden of cervical cancer.Dr Rajamanickam Rajkumar had the privilege of establishing a rural population based cancer registry in South India in 1996, as well as planning and implementing a large scale screening program for cervical cancer in 2000. The program was able to show a reduction in the incidence rate of cervical cancer by 25%, and reduction in mortality rate by 35%. This was the greatest inspiration for him to work on cerrvical cancer prevention, and he edited this book to inspire others to initiate such programs in developing countries. InTech - Open Access Publisher plays a major role in this crusade against cancer, and the authors have contributed to it very well

Book of Abstracts of MICROBIOTEC09

Sítio da conferência: http://www.deb.uminho.pt/microbiotec09/This book contains the abstracts presented at the 3rd joint meeting of the Portuguese Society of Microbiology and The Portuguese Society of Biotechnology - MicroBiotec09, held in Vilamoura, Portugal, over 3 days, from the 28th to the 30th of November, 2009. MicroBiotec09 comes in the sequence of previous conferences organized by each society, since 1982, date of the I Encontro Nacional de Biotecnologia (Lisbon), till 2005, date of the first joint meeting - MICRO'05 + BIOTEC'05 (Póvoa de Varzim). Following this joint meeting, another - MICRO 07 + BIOTEC 07 + XXIII JPG took place in Lisbon (2007). MicroBiotec09 is a joint organization of “Sociedade Portuguesa de Biotecnologia”, “Sociedade Portuguesa de Microbiologia”, Institute for Biotechnology and Bioengineering (Universidade do Minho – Departamento de Engenharia Biológica) and Centro de Recursos Microbiológicos (Universidade Nova de Lisboa, Faculdade de Ciências e Tecnologia – Departamento de Ciências da Vida). MicroBiotec09 brings together both young and established researchers and end users to discuss recent developments in different areas of Biotechnology and Microbiology. The conference program has thus been divided in 8 major sessions: Microbial Physiology, Molecular Biology and Functional Genomics; Cell and Tissue Engineering, Biomaterials and Nanobiotechnologies; Clinical Microbiology and Epidemiology; Environmental Microbiology and Biotechnology; Health and Pharmaceutical Biotechnology; Cellular Microbiology and Pathogenesis; Industrial and Food Microbiology and Biotechnology; Bioinformatics, Comparative Genomics and Evolution. A special session to celebrate the 200th anniversary of Charles Darwin's birth and the 150th anniversary of the publication of his landmark work “On the Origin of Species by Means of Natural Selection” will also take place. A total of 295 abstracts are included in the book, consisting of 6 invited lecturers, 10 oral presentations and 44 short oral presentations given in 3 parallel sessions, along with 4 slots for viewing poster presentations. All abstracts have been reviewed and we are grateful to the members of scientific and organizing committees for their evaluations. It was an intensive task since 328 submitted abstracts were received. It has been an honor for us to contribute to setting up MicroBiotec09 during an intensive period of 6 months. We wish to thank the authors who have contributed to yield a high scientific standard to the program. We are thankful to the sponsors who have contributed decisively to this event. We also extend our gratefulness to all those who, through their dedicated efforts, have assisted us in this task. On behalf of the Scientific and Organizing Committees we wish you that together with an interesting reading, the scientific program and the social moments organized will be memorable for all.Fundação para a Ciência e a Tecnologia (FCT

Influence of non-synonymous sequence mutations on the architecture of HIV-1 clade C protease receptor site : docking and molecular dynamics studies

Despite the current interventions to avert contagions and AIDS-related deaths, sub-Saharan Africa is still the region most severely affected by the HIV/AIDS pandemic, where clade C is the dominant circulating HIV-1 strain. The pol-encoded HIV-1 protease enzyme has been extensively exploited as a drug target. Protease inhibitors have been engineered within the framework of clade B, the commonest in America, Europe and Australia. Recent studies have attested the existence of sequence and catalytic disparities between clades B and C proteases that could upset drug susceptibilities. Emergence of drug-resistant associated mutations and combinatorial explosions due to recombination thwarts the attempt to stabilize the current highly active antiretroviral therapy (HAART) baseline. The project aimed at identifying the structural and molecular mechanisms hired by mutants to affect the efficacies of both FDA approved and Rhodes University (RU)-synthesized inhibitors, in order to define how current and or future drugs ought to be modified or synthesized with the intent of combating drug resistance. The rationale involved the generation of homology models of the HIV-1 sequences from the South African infants failing treatment with two protease inhibitors: lopinavir and ritonavir (as monitored by alterations in surrogate markers: CD4 cell count decline and viral load upsurge). Consistent with previous studies, we established nine polymorphisms: 12S, 15V, 19I, 36I, 41K, 63P, 69K, 89M, and 93L, linked to subtype C wild-type; some of which are associated with protease treatment in clade B. Even though we predicted two occurrence patterns of M46I, I54V and V82A mutations as V82A→I54V→M46I and I54V→V82A→M46V, other possibilities might exist. Mutations either caused a protracted or contracted active site cleft, which enforced differential drug responses. The in silico docking indicated susceptibility discordances between clades B and C in certain polymorphisms and non-polymorphisms. The RU-synthesized ligands displayed varied efficacies that were below those of the FDA approved protease inhibitors. The flaps underwent a wide range of structural motions to accommodate and stabilize the ligands. Computational analyses unravelled the need for these potential drugs to be restructured by (de novo) drug engineers to improve their binding fits, affinities, energies and interactions with multiple key protease residues in order to target resilient HIV-1 assemblages. Accumulating evidences on contrasting drug-choice interpretations from the Stanford HIVdb should act as an impetus for the customization of a HIVdb for the sub-Saharan subcontinent

Biotechnology to Combat COVID-19

This book provides an inclusive and comprehensive discussion of the transmission, science, biology, genome sequencing, diagnostics, and therapeutics of COVID-19. It also discusses public and government health measures and the roles of media as well as the impact of society on the ongoing efforts to combat the global pandemic. It addresses almost every topic that has been studied so far in the research on SARS-CoV-2 to gain insights into the fundamentals of the disease and mitigation strategies. This volume is a useful resource for virologists, epidemiologists, biologists, medical professionals, public health and government professionals, and all global citizens who have endured and battled against the pandemic