- Concise Review: Induced Pluripotent Stem Cell-Based Drug Discovery for Mitochondrial Disease. [Review]
- SCStem Cells 2017 May 22
- High attrition rates and loss of capital plague the drug discovery process. This is particularly evident for mitochondrial disease that typically involves neurological manifestations and is caused by...
High attrition rates and loss of capital plague the drug discovery process. This is particularly evident for mitochondrial disease that typically involves neurological manifestations and is caused by nuclear or mitochondrial DNA defects. This group of heterogeneous disorders is difficult to target because of the variability of the symptoms among individual patients and the lack of viable modeling systems. The use of induced pluripotent stem cells (iPSCs) might significantly improve the search for effective therapies for mitochondrial disease. iPSCs can be used to generate patient-specific neural cell models in which innovative compounds can be identified or validated. Here we discuss the promises and challenges of iPSC-based drug discovery for mitochondrial disease with a specific focus on neurological conditions. We anticipate that a proper use of the potent iPSC technology will provide critical support for the development of innovative therapies against these untreatable and detrimental disorders. Stem Cells 2017.
- Zinc transporters YbtX and ZnuABC are required for the virulence of Yersinia pestis in bubonic and pneumonic plague in mice. [Journal Article]
- MMetallomics 2017 May 25
- A number of bacterial pathogens require the ZnuABC Zinc (Zn(2+)) transporter and/or a second Zn(2+) transport system to overcome Zn(2+) sequestration by mammalian hosts. Previously we have shown that...
A number of bacterial pathogens require the ZnuABC Zinc (Zn(2+)) transporter and/or a second Zn(2+) transport system to overcome Zn(2+) sequestration by mammalian hosts. Previously we have shown that in addition to ZnuABC, Yersinia pestis possesses a second Zn(2+) transporter that involves components of the yersiniabactin (Ybt), siderophore-dependent iron transport system. Synthesis of the Ybt siderophore and YbtX, a member of the major facilitator superfamily, are both critical components of the second Zn(2+) transport system. Here we demonstrate that a ybtX znu double mutant is essentially avirulent in mouse models of bubonic and pneumonic plague while a ybtX mutant retains high virulence in both plague models. While sequestration of host Zn is a key nutritional immunity factor, excess Zn appears to have a significant antimicrobial role in controlling intracellular bacterial survival. Here, we demonstrate that ZntA, a Zn(2+) exporter, plays a role in resistance to Zn toxicity in vitro, but that a zntA zur double mutant retains high virulence in both pneumonic and bubonic plague models and survival in macrophages. We also confirm that Ybt does not directly bind Zn(2+)in vitro under the conditions tested. However, we detect a significant increase in Zn(2+)-binding ability of filtered supernatants from a Ybt(+) strain compared to those from a strain unable to produce the siderophore, supporting our previously published data that Ybt biosynthetic genes are involved in the production of a secreted Zn-binding molecule (zincophore). Our data suggest that Ybt or a modified Ybt participate in or promote Zn-binding activity in culture supernatants and is involved in Zn acquisition in Y. pestis.
- Anti-microbial peptide SR-0379 stimulates human endothelial progenitor cell-mediated repair of peripheral artery diseases. [News]
- BRBMB Rep 2017 May 25
- Ischemia is a major plague of modern life. In the search of peptide drug candidates for curing ischemic disease, we evaluated the effects of an anti-microbial peptide SR-0379 on stem cell-mediated th...
Ischemia is a major plague of modern life. In the search of peptide drug candidates for curing ischemic disease, we evaluated the effects of an anti-microbial peptide SR-0379 on stem cell-mediated therapy of ischemic diseases. Migration and tube-forming ability of human endothelial progenitor cells (EPCs) were enhanced by SR-0379 treatment in vitro. Intramuscular administration of SR-0379 into murine ischemic hindlimb significantly enhanced blood perfusion and decreased tissue necrosis, and increased the number of blood vessels in ischemic muscle. Moreover, co-administration of SR-0379 together with EPCs more potently stimulated blood perfusion in ischemic hindlimb than intramuscular injection with either SR-0379 or EPCs alone. The enhanced blood perfusion was accompanied by a significant increase in the number of CD31- and α-SMA-positive blood vessels in ischemic hindlimb. These results suggest that SR-0379 is a potential drug candidate for potentiating EPC-mediated therapy of ischemic diseases.
- The Tip of The Iceberg: Non-Calcified Coronary Plague and Epicardial Adipose TissueReplyRelationship between calcium score and myocardial scintigraphy in the diagnosis of coronary diseaseA 15-year warranty period for asymptomatic individuals without coronary artery calcium: a prospective follow-up of 9,715 individualsLong-term prognosis after coronary artery calcification testing in asymptomatic patients: a cohort study10-year coronary heart disease risk prediction using coronary artery calcium and traditional risk factors: derivation in the MESA (Multi-Ethnic Study of Atherosclerosis) with validation in the HNR (Heinz Nixdorf Recall) Study and the DHS (Dallas Heart Study)Role of coronary artery calcium score of zero and other negative risk markers for cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA)Increased discordance between HeartScore and coronary artery calcification score after introduction of the new ESC prevention guidelinesCoronary artery calcium predicts cardiovascular events in participants with a low lifetime risk of cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA)Guideline-based statin eligibility, coronary artery calcification, and cardiovascular eventsImplications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association Cholesterol Management Guidelines: MESA (Multi-Ethnic Study of Atherosclerosis)Assessing Level of Agreement for Atherosclerotic Cardiovascular Disease Risk Categorization Between Coronary Artery Calcium Score and the American College of Cardiology/American Heart Association Cardiovascular Prevention Guidelines and the Potential ImpaCollective impact of conventional cardiovascular risk factors and coronary calcium score on clinical outcomes with or without statin therapy: The St Francis Heart StudyDyslipidemia, coronary artery calcium, and incident atherosclerotic cardiovascular disease: implications for statin therapy from the multi-ethnic study of atherosclerosisCoronary artery calcium to guide a personalized risk-based approach to initiation and intensification of antihypertensive therapyUse of coronary artery calcium testing to guide aspirin utilization for primary prevention: estimates from the multi-ethnic study of atherosclerosisCAC score as a possible criterion for administration of angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers the MultiEthnic Study of AtherosclerosisII Guidelines on Cardiovascular Magnetic Resonance and Computed Tomography of the Brazilian Society of Cardiology and the Brazilian College of Radiology2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR)CAC score improves coronary and CV risk assessment above statin indication by ESC and AHA/ACC Primary Prevention Guidelines2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice GuidelinesACCF/AHA/ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2013 multi- modality appropriate use criteria for the detection and risk assessment of stable ischemic heart disease: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. [Letter]
- ABArq Bras Cardiol 2017; 108(4):383-385
- Yersinia pestis YopK inhibits bacterial adhesion to host cells by binding to the extracellular matrix adaptor protein matrilin-2. [Journal Article]
- IIInfect Immun 2017 May 22
- Pathogenic yersiniae harbor a type III secretion system (T3SS) that injects Yersinia outer protein (Yop) into host cells. YopK has been shown to control Yop translocation and prevent inflammasome rec...
Pathogenic yersiniae harbor a type III secretion system (T3SS) that injects Yersinia outer protein (Yop) into host cells. YopK has been shown to control Yop translocation and prevent inflammasome recognition of T3SS by the innate immune system. Here, we demonstrate that YopK inhibits bacterial adherence to host cells by binding to the extracellular matrix adaptor protein matrilin-2 (MATN2). YopK binds to MATN2 and deleting the amino acids 91--124 disrupts binding of YopK to MATN2. A yopK null mutant exhibits hyper-adhesive phenotype, which could be responsible for the established Yop hyper-translocation phenotype of yopK mutant. Expression of YopK, but not YopKΔ91-124, in a yopK mutant restored the wild-type phenotypes of adhesion and Yop translocation, suggesting that binding to MATN2 might be essential for YopK to inhibit bacterial adhesion and negatively regulate Yop translocation. A green fluorescent protein (GFP)-YopK fusion specifically binds to the endogenous MATN2 on the surface of HeLa cells, whereas GFP-YopKΔ91-124 cannot. Addition of purified YopK protein during infection decreased adhesion of Y. pestis to HeLa cells, while YopKΔ91-124 protein showed no effect. Taken together, we proposed a model that the T3SS-secreted YopK hinders bacterial adhesion to HeLa cells by binding to MATN2 that is ubiquitously exposed on eukaryotic cells.
- A Comprehensive Method to Quantify Adaptations by Male and Female Mice with Hot Flashes Induced by the Neurokinin B Receptor Agonist, Senktide. [Journal Article]
- EEndocrinology 2017 May 22
- Vasomotor symptoms (VMS, or hot flashes) plague millions of reproductive age men and women who have natural or iatrogenic loss of sex steroid production. Many affected individuals are left without tr...
Vasomotor symptoms (VMS, or hot flashes) plague millions of reproductive age men and women who have natural or iatrogenic loss of sex steroid production. Many affected individuals are left without treatment options because of contraindications to hormone replacement therapy and the lack of equally effective non-hormonal alternatives. Moreover, development of safer, more effective therapies has been stymied by the lack of an animal model that recapitulates the hot flash phenomenon and enables direct testing of hypotheses regarding the pathophysiology underlying hot flashes. To address these problems, we developed a murine model for hot flashes and a comprehensive method for measuring autonomic and behavioral thermoregulation in mice. We designed and constructed an instrument called a thermocline, that produces a thermal gradient along which mice behaviorally adapt to a thermal challenge to their core body temperature set point while their thermal preference over time is tracked and recorded. We tested and validated this murine model for VMS by administration of a TRPV1 agonist and a NK3R agonist, capsaicin and senktide respectively, to unrestrained mice and observed their autonomic and behavioral responses. Following both treatments, the mice exhibited a VMS-like response characterized by a drop in core body temperature and cold-seeking behavior on the thermocline. Senktide also caused a rise in tail skin temperature and increased Fos expression in the median preoptic area, a hypothalamic temperature control center. This dynamic model may be used to fully explore the cellular and molecular basis for VMS and to develop and test new therapeutic options.
- Alternative Medicine: Contagion and Cure in Karel Čapek's <i>The White Plague</i>. [Journal Article]
- LMLit Med 2017; 35(1):167-182
- Though written amid an atmosphere of unprecedented medical advance in both diagnosis and therapeutics, Karel Čapek's The White Plague takes a starkly critical stance against overconfidence in medical...
Though written amid an atmosphere of unprecedented medical advance in both diagnosis and therapeutics, Karel Čapek's The White Plague takes a starkly critical stance against overconfidence in medical science and its dubious ethical orbit. This article explores Čapek's censure of those who would privilege scientific interest in disease over the holistic plight of the sufferer. Provocatively, Čapek achieves this not only via the play's content, but also-prefiguring aspects of contemporary live art practice by several decades-by placing audience members in worrying proximity to abject ill bodies. Čapek proposes a sort of theatrical homeopathy, suggesting that limited exposure to the threat of disease might spur spectators toward empathy for those who suffer and promote a healthier, more compassionate society.
- Flea and Small Mammal Species Composition in Mixed-Grass Prairies: Implications for the Maintenance of Yersinia pestis. [Journal Article]
- VBVector Borne Zoonotic Dis 2017 May 18
- Maintenance of sylvatic plague in prairie dogs (Cynomis spp.) was once thought unlikely due to high mortality rates; yet more recent findings indicate that low-level enzootic plague may be maintained...
Maintenance of sylvatic plague in prairie dogs (Cynomis spp.) was once thought unlikely due to high mortality rates; yet more recent findings indicate that low-level enzootic plague may be maintained in susceptible prairie dog populations. Another hypothesis for the maintenance of sylvatic plague involves small mammals, other than prairie dogs, as an alternative reservoir in the sylvatic plague system. These hypotheses, however, are not mutually exclusive, as both prairie dogs and small mammals could together be driving sylvatic cycles of plague. The concept of a bridging vector has been used to explain the transmission of pathogens from one host species to another. In the case of sylvatic plague, this would require overlap in fleas between small mammals and prairie dogs, and potentially other species such as carnivores. Our goal was to evaluate the level of flea sharing between black-tailed prairie dogs (Cynomis ludovicianus) and other small mammals in a mixed-grass prairie in South Dakota. We investigated the species richness of small mammals and small-mammal fleas in a mixed-grass prairie system and compared findings with previous studies from a short-grass ecosystem in Colorado. Over the summer field seasons 2014-2016 we live-trapped small mammals, collected fleas, and showed differences between both the flea and small mammal composition of the two systems. We also recorded higher densities of deer mice and lower densities of northern grasshopper mice in mixed versus shortgrass prairies. We confirmed, as is the case in shortgrass prairies, a lack of substantial flea species overlap on small mammal hosts and fleas from prairie dogs and their burrows. Moreover this study demonstrates that although small mammals may not play a large part in interepizootic plague cycling in shortgrass prairie ecosystems, their role in mixed-grass prairies requires further evaluation.
- Overview of the impact of Typhoid and Paratyphoid fever. Utility of Ty21a vaccine (Vivotif®). [Review]
- JPJ Prev Med Hyg 2017; 58(1):E1-E8
- Cases of diarrhoeal disease number from 1.7 to 5 billion per year worldwide. One of the main causes of diarrhoeal disease is typhoid fever, which is a potentially life-threatening multi-systemic illn...
Cases of diarrhoeal disease number from 1.7 to 5 billion per year worldwide. One of the main causes of diarrhoeal disease is typhoid fever, which is a potentially life-threatening multi-systemic illness. According to the most recent estimates, a total of 26.9 million typhoid fever episodes occurred in 2010. The geographical distribution of the disease differs widely; in developed countries, the incidence rate per 100,000 per year varies from < 0.1 to 0.3, and the disease mainly affects people who travel to endemic areas located in low- and middle-income countries. Low- and middle-income countries are mainly affected owing to the lack of clean water and proper sanitation. In the fight against this plague, prevention is fundamental, and vaccination against typhoid is an effective measure. Vivotif(®) is an oral live attenuated vaccine which contains a mutated strain of Salmonella (Ty21a) and reproduces the natural infection. The vaccine was first licensed in Europe in 1983 and in the US in 1989, and over the years it has proved efficacious and safe. It is indicated for adults and children from 5 years of age upwards. Specifically, in the most developed countries, vaccination is suggested for highrisk population groups and particularly for international travellers to destinations where the risk of contracting typhoid fever is high. It must also be borne in mind that international travel is increasing. Indeed, international tourist arrivals totalled 1,184 million in 2015 and, on the basis of current trends, international travel is expected to grow by 3-4% in 2017. Vivotif(®) appears to be a powerful means of disease prevention, the importance of which is highlighted by the spread of antibiotic-resistant strains of Salmonella typhy (S. typhi).
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- Accept or Decline? An Analytics-Based Decision Tool for Kidney Offer Evaluation. [Journal Article]
- TTransplantation 2017 May 17
- CONCLUSIONS: The development of a data-driven analytics-based model may assist transplant practitioners and candidates during the complex decision of whether to accept or forgo a current kidney offer in anticipation of a future high-quality offer. The latter holds promise to facilitate timely transplantation and optimize the efficiency of allocation.