This document summarizes a speech given by Michael L. Riordan about the development of oligonucleotide therapeutics. Riordan discusses two main avenues for increasing the potency of oligonucleotides: 1) enhancing cellular permeation through modifications that allow passive diffusion, and 2) targeting DNA instead of RNA to reduce the copy number of the target per cell. He also describes a new technique called aptamers, where oligonucleotides are selected and amplified based on their ability to bind target molecules, allowing novel therapeutics with high affinity and specificity to be developed.
Promise Seen in Antisense Medicine and Neutralizing Harmful GenesGatewayAvenue
By Marilyn Chase
Illustration by Michael Reingold
August 22, 1988
Article includes, in order mentioned:
Thomas Rogers, Monsanto scientist
Michael L Riordan, the founder and CEO of Gilead Sciences
Samuel Broder, National Cancer Institute associate director
Claude Helene, scientist at France’s National Institute for Health and Medical Research
Paul Miller, Johns Hopkins professor
Laure Aurelian, University of Maryland professor
Jack Cohen, National Cancer Institute scientist
Makoto Matsukura, National Cancer Institute scientist
Len Neckers, National Cancer Institute scientist
Peter Dervan, California Institute of Technology professor
Douglas Melton, Harvard professor
Hal Weintraub, Hutchinson Cancer Research Center principal scientist
The concept of transferring genes to tissues for clinical applications has been discussed for nearly half a century, but the ability to manipulate genetic material via recombinant DNA technology has brought this goal to reality. ‘Gene Therapy’ covers both the research and clinical applications of the new genetic therapy techniques currently being developed. The application of molecular biology has revolutionized researchers understanding of many diseases and has been readily applied for diagnostic purposes. Now-a-day this is originally conceived as a way to treat life-threatening disorders (inborn errors, cancers) refractory to conventional treatment, gene therapy now is considered for many non–life-threatening conditions, including those adversely affecting a patient’s quality of life. The lack of suitable treatment has become a rational basis for extending the scope of gene therapy. It is not very far, the justifiable optimism that with increased biotechnological improvement, gene therapy will become a standard part of clinical practice.
PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education" http://www.pharmacon2007.com
Abstract is available at http://www.pharmaconnectme.com
Promise Seen in Antisense Medicine and Neutralizing Harmful GenesGatewayAvenue
By Marilyn Chase
Illustration by Michael Reingold
August 22, 1988
Article includes, in order mentioned:
Thomas Rogers, Monsanto scientist
Michael L Riordan, the founder and CEO of Gilead Sciences
Samuel Broder, National Cancer Institute associate director
Claude Helene, scientist at France’s National Institute for Health and Medical Research
Paul Miller, Johns Hopkins professor
Laure Aurelian, University of Maryland professor
Jack Cohen, National Cancer Institute scientist
Makoto Matsukura, National Cancer Institute scientist
Len Neckers, National Cancer Institute scientist
Peter Dervan, California Institute of Technology professor
Douglas Melton, Harvard professor
Hal Weintraub, Hutchinson Cancer Research Center principal scientist
The concept of transferring genes to tissues for clinical applications has been discussed for nearly half a century, but the ability to manipulate genetic material via recombinant DNA technology has brought this goal to reality. ‘Gene Therapy’ covers both the research and clinical applications of the new genetic therapy techniques currently being developed. The application of molecular biology has revolutionized researchers understanding of many diseases and has been readily applied for diagnostic purposes. Now-a-day this is originally conceived as a way to treat life-threatening disorders (inborn errors, cancers) refractory to conventional treatment, gene therapy now is considered for many non–life-threatening conditions, including those adversely affecting a patient’s quality of life. The lack of suitable treatment has become a rational basis for extending the scope of gene therapy. It is not very far, the justifiable optimism that with increased biotechnological improvement, gene therapy will become a standard part of clinical practice.
PharmaCon2007 Congress, Dubrovnik, Croatia "New Technologies and Trends in Pharmacy, Pharmaceutical Industry and Education" http://www.pharmacon2007.com
Abstract is available at http://www.pharmaconnectme.com
In the past 10 years, there has been tremendous progress made in the field of gene therapy. Effective
treatments of Leber congenital amaurosis, hemophilia, and spinal muscular atrophy have been largely based on
the efficiency and safety of adeno-associated vectors. Myocardial gene therapy has been tested in patients with
heart failure using adeno-associated vectors with no safety concerns but lacking clinical improvements. Cardiac
gene therapy is adapting to the new developments in vectors, delivery systems, targets, and clinical end points and
is poised for success in the near future
Insilico Comprehension of Stop Codon Readthrough in Human Virusesijtsrd
Readthrough is an event in which stop codon is misread, resulting in elongation of polypeptides. Stop codon suppression or termination codon readthrough, is a mechanism of expression of many disorder proteins. Many important cellular functions are carried out by way of the Readthrough process. This could alter the gene function which thereon produces either destructive or constructive effects. Hence, this study aims to diagnose this recoding mechanism in certain selected humans infecting pathogenic viruses through insilico approach. For this target, the 3'UnTranslated Regions of the selected viruses were retrieved from the Genbank database. Each of these 3'UTRs were translated into all their reading frames. Motif search using Interproscan in each of the frames, followed by homology search using BLASTX, and were achieved to identify stop codon readthrough candidates in each of the selected viruses. Finally, the secondary structure of RNA was predicted using RNAFold web server to ensure the stability of the RNA. The 3'UTRs from Aichi Virus 1, Cosa Virus A, Dengue Virus 1, Duvenhage Lyssavirus, Enterovirus A, HepatitisGB Virus B, Human Cosavirus A, Human Pegivirus 2, Langat Virus, Parechovirus A, WestNile Virus and Zika Virus were retrieved. A total of 48 motifs were identified in different reading frames of 3'UTR of the selected viruses. BlastX search recognized 9 homologs in the reading frames of 3'UTR. The secondary structure analysis and search of motifs and homologs resulted in the confirmation of 5 candidates with strong evidence for the readthrough event. These candidates showed homology with proteins of prime importance such as Imidazole glycerol Phosphate synthase protein, 50S ribosomal protein L27, DNA replication, and repair protein, replication origin binding protein, and adenosine deaminase. Hence, we proved that the 3'untranslated regions would undergo translation. This strongly suggests that many such readthrough events are to be determined to exactly unravel the pathogenicity behind Viruses. To design anti viral drugs to impede this viral machinery, it is essential to analyse their 3'UTR regions. Arockiyajainmary M | Balaji S | Sivashankari Selvarajan "Insilico Comprehension of Stop Codon Readthrough in Human Viruses" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-4 | Issue-4 , June 2020, URL: https://www.ijtsrd.com/papers/ijtsrd31550.pdf Paper Url :https://www.ijtsrd.com/biological-science/biotechnology/31550/insilico-comprehension-of-stop-codon-readthrough-in-human-viruses/arockiyajainmary-m
This PPT includes the details about some cardiovascular diseases and how they are treated using Gene Therapy. It also discuss about the vectors that are used in the process.
Enhancing mRNA Stability - Effective commercialization of discoveries researc...UOTT UW
From a Discovery to Clinical Applications Worldwide.
A discovery gives new hope to millions of people suffering from cancers, inborn genetic defects and
to patients awaiting autotransplantation or regeneration of damaged or missing tissues. This is a
new chapter in the development of effective genetic vaccines which, in the near future, will make it
possible to fight malignancies, among others.
A team from the University of Warsaw discovered universal analogous endings for mRNA
molecules (so called 5’ caps) which guarantee higher mRNA stability in cell natural environment
and enhance the production of desired proteins.
Raj Lab Meeting presentation (05/01/19)
by Katia Lopes and Ricardo Vialle
Discussing the paper "The impact of rare variation on gene expression across tissues" - Li et al. Nature (2017)
In medicine, gene therapy (also called human gene transfer) is the therapeutic delivery of nucleic acid into a patient's cells as a drug to treat disease.[ The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989.[2] The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.
Summary of PROTAC And Other Targeted Protein Degradation Technologies.pdfDoriaFang
We summarize various targeted degradation strategies and their respective advantages and disadvantages, hoping to provide guidance value for the development of targeted protein degradation drugs.
In the past 10 years, there has been tremendous progress made in the field of gene therapy. Effective
treatments of Leber congenital amaurosis, hemophilia, and spinal muscular atrophy have been largely based on
the efficiency and safety of adeno-associated vectors. Myocardial gene therapy has been tested in patients with
heart failure using adeno-associated vectors with no safety concerns but lacking clinical improvements. Cardiac
gene therapy is adapting to the new developments in vectors, delivery systems, targets, and clinical end points and
is poised for success in the near future
Insilico Comprehension of Stop Codon Readthrough in Human Virusesijtsrd
Readthrough is an event in which stop codon is misread, resulting in elongation of polypeptides. Stop codon suppression or termination codon readthrough, is a mechanism of expression of many disorder proteins. Many important cellular functions are carried out by way of the Readthrough process. This could alter the gene function which thereon produces either destructive or constructive effects. Hence, this study aims to diagnose this recoding mechanism in certain selected humans infecting pathogenic viruses through insilico approach. For this target, the 3'UnTranslated Regions of the selected viruses were retrieved from the Genbank database. Each of these 3'UTRs were translated into all their reading frames. Motif search using Interproscan in each of the frames, followed by homology search using BLASTX, and were achieved to identify stop codon readthrough candidates in each of the selected viruses. Finally, the secondary structure of RNA was predicted using RNAFold web server to ensure the stability of the RNA. The 3'UTRs from Aichi Virus 1, Cosa Virus A, Dengue Virus 1, Duvenhage Lyssavirus, Enterovirus A, HepatitisGB Virus B, Human Cosavirus A, Human Pegivirus 2, Langat Virus, Parechovirus A, WestNile Virus and Zika Virus were retrieved. A total of 48 motifs were identified in different reading frames of 3'UTR of the selected viruses. BlastX search recognized 9 homologs in the reading frames of 3'UTR. The secondary structure analysis and search of motifs and homologs resulted in the confirmation of 5 candidates with strong evidence for the readthrough event. These candidates showed homology with proteins of prime importance such as Imidazole glycerol Phosphate synthase protein, 50S ribosomal protein L27, DNA replication, and repair protein, replication origin binding protein, and adenosine deaminase. Hence, we proved that the 3'untranslated regions would undergo translation. This strongly suggests that many such readthrough events are to be determined to exactly unravel the pathogenicity behind Viruses. To design anti viral drugs to impede this viral machinery, it is essential to analyse their 3'UTR regions. Arockiyajainmary M | Balaji S | Sivashankari Selvarajan "Insilico Comprehension of Stop Codon Readthrough in Human Viruses" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-4 | Issue-4 , June 2020, URL: https://www.ijtsrd.com/papers/ijtsrd31550.pdf Paper Url :https://www.ijtsrd.com/biological-science/biotechnology/31550/insilico-comprehension-of-stop-codon-readthrough-in-human-viruses/arockiyajainmary-m
This PPT includes the details about some cardiovascular diseases and how they are treated using Gene Therapy. It also discuss about the vectors that are used in the process.
Enhancing mRNA Stability - Effective commercialization of discoveries researc...UOTT UW
From a Discovery to Clinical Applications Worldwide.
A discovery gives new hope to millions of people suffering from cancers, inborn genetic defects and
to patients awaiting autotransplantation or regeneration of damaged or missing tissues. This is a
new chapter in the development of effective genetic vaccines which, in the near future, will make it
possible to fight malignancies, among others.
A team from the University of Warsaw discovered universal analogous endings for mRNA
molecules (so called 5’ caps) which guarantee higher mRNA stability in cell natural environment
and enhance the production of desired proteins.
Raj Lab Meeting presentation (05/01/19)
by Katia Lopes and Ricardo Vialle
Discussing the paper "The impact of rare variation on gene expression across tissues" - Li et al. Nature (2017)
In medicine, gene therapy (also called human gene transfer) is the therapeutic delivery of nucleic acid into a patient's cells as a drug to treat disease.[ The first attempt at modifying human DNA was performed in 1980 by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989.[2] The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990.
Summary of PROTAC And Other Targeted Protein Degradation Technologies.pdfDoriaFang
We summarize various targeted degradation strategies and their respective advantages and disadvantages, hoping to provide guidance value for the development of targeted protein degradation drugs.
PROTAC Technology: An Effective Targeted Protein Degrader.pdfDoriaFang
PROTACs are heterofunctional small molecules consisting of two ligands linked by an appropriate linker: one ligand recruits and binds the protein of interest (POI), while the other recruits and binds the E3 ubiquitin ligase.
Several Types of PROTACs Based On Nucleic AcidsDoriaFang
So far, more than 10 nucleic acid drugs have been approved for marketing worldwide, and many nucleic acid drugs are in the stage of clinical trials. Nucleic acid drugs are expected to become the third type of drugs after small molecule drugs and antibody drugs.
Summary of Targeted Protein Degradation in Clinical Trials.pdfDoriaFang
Summary of targeted protein degradation, such as PROTAC and molecular glues in clinical trials. PROTAC and molecular glues are the two main modes of TPD technology based on the UPS.
Exploring Molecular Targets for Repositioning of Hypertensive DrugsYogeshIJTSRD
Drug repositioning or drug repurposing or drug profiling is the discovery of new applications for approved or failed drug.. Drug repositioning is the development of new approved drug applications. The cost of bringing a medicine to the market is around one million which include clinical and preclinical trials. Repositioning of drugs help in cutting down costs as well as time involve in intial validation and authorization. The procedure involved in Drug repositioning is generally performed during the drug development phase to modify or extend an active molecules distribution line. On a fundamental level, repositioning opportunities exist because drugs perturb multiple biological entities and engage themselves in multiple biological processes. Therefore, a drug can play multiple roles or perform a various mode of actions that are responsible for its pharmacology. Hypertension, is a condition that causes increase in the risk of cardiovascular diseases. In this study an attempt has been made to reposition hypertensive drugs for different diseases by exploring molecular targets of hypertensive drugs. Consider that they often need to be administered for long periods of time, often over whole life time Side effects although present, have been found safe enough to be used for such long durations, hence repurposing these drugs for other diseases may be beneficial with limited side effects. Bhawna Singh | Asmita Das "Exploring Molecular Targets for Repositioning of Hypertensive Drugs" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-5 | Issue-3 , April 2021, URL: https://www.ijtsrd.com/papers/ijtsrd39910.pdf Paper URL: https://www.ijtsrd.com/biological-science/bioinformatics/39910/exploring-molecular-targets-for-repositioning-of-hypertensive-drugs/bhawna-singh
Polymer therapeutics: an smart drug delivary systemAlok kumar Soni
The development of polymer therapeutics has emerged as an exciting field of research for improving the therapeutic potential of low-molecular-weight drugs and proteins. this presentation depicted overview of nanomedicine in healthcare industry
Prota cs and targeted protein degradationDoriaFang
PROTACs (proteolysis targeting chimera) induced targeted protein degradation has emerged as a novel therapeutic strategy in drug development and attracted the favor of academic institutions, large pharmaceutical enterprises, and biotechnology companies. PROTACs opened a new chapter for novel drug development.
Antibody drug conjugates for cancer therapy - prospects and challenges htpDoriaFang
Antibody-drug conjugates (ADCs) are a rapidly evolving class of anticancer therapeutics consisting of antibodies attached to potent cytotoxic drugs via chemical linkers. What're the prospects and challenges of Antibody-Drug Conjugates for cancer therapy?
Exploiting Edinburgh's Guide to PHARMACOLOGY database as a source of protein ...Chris Southan
Presented by Jamie Davies at the SULSA Synthetic Biology Meeting, Edinburgh, 10 June 2014
http://www.eventbrite.co.uk/e/sulsa-synthetic-biology-meeting-registration-11251454403?aff=eorg
Abstract: Synthetic creation of new biological systems typically incorporates pathways and signaling modules from known protein building blocks. Testing the models underpinning the synthetic engineering thus needs the experimental manipulation of individual proteins, for example, ablating a specific enzyme activity via RNAi, SNP mutation, or knockout. However, the option of small-molecule inhibition as the system perturbation has the advantages of 1) rapid onset 2) dose-response 3) analog testing for structure-activity relationships, 4) exploring mixtures for combinatorial effects 5) pulsing and reversal by wash-out. 6) accurate measurements of added substances and 7) a vast precedent of published results in natural systems from medicinal chemistry, pharmacology, and chemical biology. For the synthetic biologists the GToPdb1 can thus be considered as compendium of the latter. It encompasses an interaction matrix between ~4000 small molecules and ~1000 human proteins with a focus on drugs, clinical candidates, research compounds and peptide ligands These not only have ~ 10,000 mapped binding constants but also the spectrum of documented modulation extends across enzymes, receptors, channels and transporters. It thus becomes an increasingly plausible option to choose a “Lego protein” from GToPdb as a synthetic system component that can have experimentally useable activity probes available from chemical vendors. Even if it does not currently have a suitable target-probe pair, as knowledge base (and expertise resource via the curation team who populate it) GToPdb is an ideal starting point from which to walk out to wider chemogenomic spaces. For example, while an approved drug and its target might seem a logical choice, analogs from the lead series or different chemotypes from which the drug was optimized, or even failed in development, can have superior probe-like properties for in vitro experiments (e.g. be more potent, specific and soluble). The GToPdb facilitates access to such compound data via curated papers and patents.
References
1. Pawson AJ, Sharman JL, Benson HE, Faccenda E, Alexander SP, Buneman OP, Davenport AP, McGrath JC, Peters JA, Southan C, Spedding M, Yu W, Harmar AJ; NC-IUPHAR. The IUPHAR/BPS Guide to PHARMACOLOGY: an expert-driven knowledgebase of drug targets and their ligands. Nucleic Acids Res. 2014 Jan 1;42(1)
Peptide Drug Conjugates (PDCs) Novel Targeted Therapeutics For Cancer.pdfDoriaFang
Peptide-drug conjugates (PDCs) are the next generation of targeted therapies after ADCs. PDCs has been developed as targeted therapeutic candidates for cancer, COVID-19, metabolic diseases, etc.
Environment inside even a small tumor is characterized by total (anoxia) or partial oxygen deprivation, hypoxia. It has been shown that radiotherapy and some conventional chemotherapies may be less effective in hypoxia, and therefore it is important to investigate how different drugs act in different microenvironments. In this study we perform a large screening of the effects of 19 clinically used or experimental chemotherapeutic drugs on four different cell lines in conditions of normoxia, hypoxia and anoxia.
We have 13 research and development projects within:
• Research
• Oncology
• Respiratory, Inflammation and Autoimmunity
• Cardiovascular and Metabolic Disease
• Antibody Discovery and Protein Engineering
• Pathology
• Biopharmaceutical Development
• Cell Culture and Fermentation Sciences
• Formulation Sciences
• Analytical Biotechnology Science
Could PDC Be A New Direction For Targeted Therapy After ADC.pdfDoriaFang
Peptide-drug conjugates (PDCs) are the next generation of targeted therapeutics after ADCs, and their core advantages are enhanced cell permeability and improved drug selectivity.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
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Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Adv. biopharm. APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMSAkankshaAshtankar
MIP 201T & MPH 202T
ADVANCED BIOPHARMACEUTICS & PHARMACOKINETICS : UNIT 5
APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMS By - AKANKSHA ASHTANKAR
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Antisense Oligonucleotides, Aptamers & Triple Helix: Speech by Michael L Riordan, the Founder of Gilead Sciences
1. OUGONUCLEOTIDE1HERAPEUTICS:11fE PLOTnDCKENS
Followingis a transcript of a speech deliveredon January 16, 1991, by Michael L~·Riordan,M.D.,
President and Chief Executive Officer of Gilead Sciences,Inc., at the International Conferenceon
Nucleic Acid Therapeutics sponsored by the International Union of Biochemistry and the U.S.
National CancerInstitute, held in ClearwaterBeach,Florida.
I would like to begin with these insightful words of Claude Bernard, the gifted 19th century French
physiologist: "Art is I; Scienceis we." Certainly his words are true for the sciences represented here:
the field of oligonucleotide chemistry and the emerging biology of sequence-specific gene inhibition.
Our company, Gilead Sciences, is a direct beneficiary of the scientific infrastructure in nucleic acids and
molecular biology that has been built over the past 15 to 20 years, constructed in part by many of the
participants at this conference. Our hats are off to you. Scienceis "we".
We are fortunate among pharmaceutical research organizations to know, in advance, approximately
what our final products will look like. This is .not true of ma~y other pharmaceutical discovery
programs, wherein lead structures are usually identified only after considerable investment has been
made in biological assays,protein crystal structures, inassive screening programs or basic research in
disease etiology.
The general specifications of our would-be products are outlined in Figure 1: a 15-mer oligonucleotide
having a molecular weight of approximately 5,000, containing backbone alterations to enhance
permeation and stabilizing moieties to inhibit nuclease degradation. Depending upon the nature of the
molecular target, the compound will also contain modified bases to augment recognition, enhance
~ffinity, or position a reactive group, such as the aziridinyl moiety Mark Matteucci of Gilead described
yesterday. As you are aware, other modifications can also be made to the intrinsic oligonucleotide
structure.
2. Figure 1
General specifications do not a drug make,
however. At some point along the ongoing
continuum of modifications that confer favor-
able pharmaceutical properties, one must stop
and select individual chemical entities for
costly preclinical and clinical studies. Making
the wrong choice, especially that of choosing a
specificcompound too early in the continuum of
improvements, can be disastrous for two reasons:
(a) Toxicity or poor efficacy may result in large
sums of money being poured down the drain for
fruitless preclinical and clinical evaluation;
and (b) presenting to the FDA a premature,
suboptimal compound with suboptimal support-
ing studies, either at the IND or NOA stages,
may result in a muddying of the waters for this
broad, new class of oligonucleotide therapeutics, and delay introduction of subsequent successful
therapies for desperate patients.
What are the chief objectives in further refining the compound specifications? In our opinion, the chief
objective _is to increase potency. By increasing the potency (i.e. reducing the required dose) of
oligonucleotides, we are assured of reducing toxicities, easing pharmacokinetic constraints, and reducing
the costs of treatment. This evening I would like to address what we believe are the two central
avenues toward radically increasing the potency of oligonucleotides. Then, at the end of my remarks, I
would like to describe a new, promising extension of oligonucleotide technology into the realm of
therapeutics. The two central avenues I refer to for radically increasing potency are, first, marked
enhancement of cellular permeation and, second, attacking a low-copy target, namely DNA.
-2-
3. The first objective, markedly enhanced cytosolic penetration, is best accomplished, we believe, by
altering the oligonucleotide structure so as to enable passive diffusion through the plasma membrane.
It is our opinion that oligonucleotide uptake via a putative membrane protein porting mechanism is
unlikely to be adequate for broad pharmaceutical purposes, because such porting mechanisms are
unlikely to accommodate the various structural modifications of the oligonucleotide that are necessary
to confer various pharmaceutical properties. Passive diffusion through a lipid membrane is known to be
roughly inversely related to size and polar character of the penetrating molecule, but the details of
this relationship between polarity, size and permeability are entirely unknown for molecules in the
molecular weight range of the oligonucleotides we are developing.
There are very few even theoretical touchstones for analyzing this problem or for predicting efficacious
structural alterations of molecules in the molecular weight range of relevance to us, namely the 3,000to
6,000 mw range. As sh own in Figure 2, oligonucleotides in the 5,000 mw range fa 11 i nt o large Iy
MW Spectrum for Human Therapeutics
25K
f f
Protein•
SOK
Penicillin Bleom7cin
(MW ...371) (MW ...1,5H)
75K 100K
f
15-mer
(MW ...5,ttt)
Figure2
-3-
125K 150K
Antibodies
175K
f
Monoclonals
(MW2!180,000)
lOK
4. unexplored territory for human therapeutics. At the top of Figure 2 is depicted the entire molecular
weight spectrum of therapeutics, including proteins like human growth hormone at 22 kilodaltons, TPA
at 59 kilodaltons, and antibodies at 180,000and above. The zero to 10,000molecular weight range is
expanded at the lower part of the figure, showing conventional small drugs like penicillin in the 300 to
500 range, and other larger, natural product-derived compounds like bleomycin in the 1500molecular
weight range. Notably, I should add, bleomycin and several other relatively large anti-tumor agents
have the nucleus as their site of action. In the 3,000 to 6,000 molecular weight range one can find very
few examples in today's pharmacopoeia, and even less information regarding membrane permeability
parameters in this size bracket.
The challenge is illustrated crudely in the following computer modeling rendition (Figure 3) of an
oligonucleotide 15-mer bearing 3' methoxyethylamine "endcaps" juxtaposed with a cross-sectional
segment of lipid bilayer membrane.
Figure3
-4-
5. By delineating the structural requirements for membrane permeation of oligonucleotides, I believe
entirely new horizons for medicinal chemistry will be opened up with regard to other classes of
molecules that lie in this unexplored territory - peptides, for example - and the insights garnered
will potentially be used to improve the intracellular disposition of smaller molecules as well.
Performing this rigorous structure-function evaluation of permeability requires cell biology methods
that are far more sophisticated than the techniques that historically have been part of standard
pharmaceutical sciences. High-resolution fluorescence microscopy is but one example of the
sophisticated cell biology tools that have been presented at this conference and are at work in our
laboratories.
At this meeting we have seen hints of the highly refined cellular biology that must be brought to bear
in a field that historically has been driven primarily by chemistry, not biology. The relative paucity
of biological muscle exerted heretofore in the antisense oligonucleotide arena has been unfortunate, and
has resulted in many studies which underestimate the complexity of the cellular response to exogenous
oligonucleotides.
The second major avenue toward markedly increasing potency is to use triple helix oligonucleotides to
inhibit gene expression at an earlier stage - at the level of transcription. Our own program in triple
helix gene inhibition, which began at Gilead's inception, has dramatically expanded in scope, driven
by rapid technical advances and the quest for high potency. An additional reason for our triple helix
emphasis is its attractiveness for attacking viruses whose life cycle includes a double stranded DNA
stage, such as in viral latency. The prospects for a very low dose agent, although speculative until
confirmed in actual pharmacokinetic studies, are outlined below in Figure 4.
On the right in Figure 4 are listed three classes of pharmaceutical candidates: triple helix agents,
antisense oligonucleotides, and conventional small molecules. Most conventional small molecules act
upon a protein, whose copy number per cell is generally in the range of 10,000to 1 million. Antisense
-5-
6. Protein
Triple Helix Drugs: Potentially Very Low Dose
Figure4
# Copies of
Target per Cell
10,000- 1,000,000
Type of
Drug
TripleHelix
Antisense
Conventional
oligonucleotides of course act upon RNA species which typically exist at a copy number of 100to 100,000
per cell, and are being regenerated over time, if the encoding gene is transcriptionally active.
At the DNA level, the copy number of the corresponding sequence is in the range of 1,2, or only a few per
cell, depending on the allelic status of the gene. Unlike RNA, DNA is not being regenerated, except of
course at the usually modest rate of cell division. These considerations, although they are paper
arguments, suggest that DNA-directed agents potentially could be effective at dose levels orders of
magnitudes lower than those of the corresponding antisense agent. Concerns that chromatin structure or
superhelicity might be formidable obstacles to effective triple helix formation have not held up. In
retrospect, one need only look at endogenous transcription factors, whose activity we wish to mimic, in
order to see why these early concerns are proving not to be salient. After all, transcription factors
generally are larger in molecular weight than our oligonucleotides, and in some cases much larger, and
-6-
7. yet they wend their way through complex chromatin structure and adherent histones to find their
appropriate DNA binding sites.
As has been well described previously in this conference, historically there have been constraints on
the types of DNA code that can be recognized by triple helix agents. The purine and pyrimidine motifs
both require homopurine tracts within the target DNA. If one does sequence searches of
therapeutically relevant genes, one finds that this homopurine requirement greatly limits the number
of targets that can be addressed. How can we circumvent this code restriction? Certainly a key
objectivemust be to devise novel heterocycles that can engage in hydrogen bonding schemes to recognize
the two base couplets that are currently not part of the triple helix repertoire.
Switchback Triple Helix
FigureS
-7-
Another partial yet highly employable
solution to "extending the code" for the triple
helix was presented by Brian Froehler of
Gilead this past August in Sweden. His idea
was to join two or more oligonucleotide segments
of reverse polarity in such a manner as to allow
one segment to recognize, or "read", one strand
of the double helix, and the second segment to
read the other strand. This construct, shown in
Figure 5, we term a "switchback". The task
remained, however, to shrewdly select,
synthesize and evaluate various linker
moieties, in this case joining the 3' ends of the
two segments, in such a manner that the
complete oligonucleotide molecule bound with
8. an affinity approximating that of a single-polarity oligonucleotide directed against a standard biple
helix target.
Guided in large part by his molecular modeling studies, Froehler tested a series of attractive linker
configurations which were successful in effecting high affinity binding to the completed switchback.
The resulting optimal class of linkers in the 3'-3' orientation is reflected in Figure 6, which shows a
xylene group linking the two deoxyribose termini of two 9-mer oligonucleotide segments directed
against the double-stranded DNA sequence shown in detail at the left and schematically at the right.
Ether-Linked Xylose Diiner
S' 3'
A-T
G-C
A-T
A-T
S' A - T
C+ G - C
T-A-T
T - A - T
T - A - T
T-A-T
T-A-T
C+ G - C
T - A - T
T - A - T
3•~3•
T - A - T
T - A - T
T - A - T
C - G+ C
T - A - T
T - A - T
C - G+ C
T - A - T
T - A - T
T - A S'
T-A
T - A
C-G
T-A
3' - S'
s·~sc:==z=~--5-,-3'
3'----====~-s·
Figure6
-8-
DNA footprinting analyses and thermal
melting studies have demonstrated that this
switchback construct and several variants
perform comparably to the full-length single
polarity oligonucleotide directed against a
standard biple helix site. We believe this is a
clear demonstration that molecular modeling
can be very successfulin the design of improved
triple helix agents, and in prioritizing our
chemical synthesis objectives. Most
importantly, sequence searches for feasible
switchback targets in clinically relevant genes
have revealed an abundance of attractive
targets for prospective triple helix
therapeutics. This further reinforces our
optimism for biple helix methodologies.
9. I would like to return now to the basic structure of the oligonucleotide, and my final topic this evening.
Oligonucleotides are turning out to be far more interesting and versatile than was understood even just a
year ago. Over the past few months, an entirely new pharmaceutical technology using oligonucleotides
has unfolded. This past fall, a handful of scientific reports appeared in Science and Nature. two of
them authored by members of Gilead's scientific advisory group, Harold Weintraub and Jack Szostak,
describing a powerful technique whereby oligonucleotide molecules can be selected and amplified to
yield specific entities that bind very tightly to proteins or small molecules. We refer to these selected
and amplified oligonucleotides as "aptamers", a term coined by Professor Szostak (aptus being the
Latin word for "to fit").
Aptamers are synthesized and identified through a process that can be described as "evolution in a test
tube". Randomly generated oligonucleotide sequences are synthesized, and then selected and replicated
according to their ability to bind to a biological target molecule. In this process, tight binders are
favored over loose binders and, after several rounds of selection and amplification, those
oligonucleotide variants, or aptamers, that bind most tightly can be identified and potentially
employed to interrupt disease processes mediated by the_target to which the aptamer binds. Gilead's
scientists have launched a promising new program in aptamer development, which complements, in
many ways, our efforts in antisense and triple helix oligonucleotides.
I would like to review the aptamer development process in more detail. We begin by generating a
random pool of oligonucleotides via chemical synthesis. Given the enormous number of combinations of
bases that are possible within an oligonucleotide strand of modest length, an extraordinary number of
different chemical entities can be generated, for example 1013
, as in Figure 7. This random pool of
oligonucleotides is then exposed to a biological target molecule whose activity we wish to inhibit.
Those molecules within the pool that bind only loosely to the target are separated from those that, by
chance, bind tightly, and only the tight-binders are subsequently replicated, or amplified, using PCR.
-9-
10. Aptamer Technology
Randomly generate oligos
(-1 x 1013 different molecules)
BiologicalTarget
Molecule
Figure 7
Selectivelyreplicate tight
binders (test tube evolution)
Novel therapeutics having
high affinity and high specificity
This step, wherein only the suitable high affinity molecules are allowed to be replicated to large
numbers, might be called "survival of the fittest".
The process of binding, selection and amplification depicted in Figure 8 is repeated several times, each
cycle resulting in an enrichment of high-affinity sequences within ·the pool of oligonucleotides. After
several cycles, a single oligonucleotide, or a small number of distinct oligonucleotides, can be isolated,
and their precise sequences determined. Subsequently the oligonucleotide, or aptamer, can be assessed
for biological activity, be chemically modified to improve certain pharmaceutical characteristics, and
be produced in larger amounts, via chemical synthesis, for further studies.
This "evolution in a test tube" can be regarded as a molecular screening technique having an
astonishingly high throughput. A rapid biological assay in the conventional pharmaceutical industry,
-10-
11. Aptamer Development
Synthesize random pool-----•~~
of oligonucleotides _.
(-10
13
distinct molecules) _/
Repeat Cycle
Evaluation&; Production "
Sequence
Assay biological activity ◄
Chemically modify , _____ ,:
Scale-up synthesis
Binding
Exposeoligo-
nucleotides to
biologicaltarget
molecule
Selection
Isolate high-affinity
binders from
low-affinity binders
Amplifi,ation/
Amplify selected
pool using PCR
Figure8
when operating at full capacity, might evaluate 10,000 different compounds per year. Using the
aptamer technique just outlined, in a period of weeks approximately 1013
different chemical entities,
all oligonucleotides, can be evaluated. Here, at last, in a screening system, the numbers are on our side.
To summarize, chemical synthesis allows us to generate in a single vessel an enormous diversity of
oligonucleotide molecules. Some small number of discrete chemical entities within this diverse pool
have three dimensional structures that enable them to bind with high affinity to a biological target
molecule. Through so-called evolution in a test tube, the high-affinity species are selectively
amplified. These "evolved" molecules, because of their high specificity and affinity to a particular
biological target molecule, are prospective drug candidates.
-11-
12. It must be stressed that aptamers are as yet at an early stage, and their ultimate pharmaceutical
utility is far from proven. However, they may lead to an array of novel therapeutics, and we are
optimistic about the rapid extension of our oligonucleotide technology into this new arena. The
expanding number of potential oligonucleotide applications - antisense, triple helix, aptamers, and
likely others in the future - provide a solid foundation for pharmaceutical development. As a
consequence of our scientific commitment to the chemistry and biology of this versatile class of
molecules called oligonucleotides, we now find ourselves in a richer, deeper mine than we had
anticipated.
-12-