Lessons From MAVERICK-HCM: The Need for Less Speed.
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ABSTRACT:
SUBMITTER: Wilcox JE
PROVIDER: S-EPMC7469939 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: Not available
| S-EPMC9873110 | biostudies-literature
Project description:The psychostimulant methamphetamine (MA) is a highly addictive drug that has surged in popularity over the last decade in North America. A burgeoning number of clandestine drug laboratories has led to dramatic increases in MA production, which have resulted in significant public health, legal and environmental problems. Current evidence indicates that exposure to MA is neurotoxic, and neuroimaging studies confirm that long-term use in humans may lead to extensive neural damage. These physiological changes are commonly associated with persistent forms of cognitive impairment, including deficits in attention, memory and executive function. In the present review, we provide a comprehensive description of the factors relating to MA use and the major health-related consequences, with an emphasis on MA-induced psychosis. It is hoped that increased knowledge of MA abuse will provide the basis for future treatment strategies.
| S-EPMC1557685 | biostudies-literature
Project description:Maverick isolated from Pond water. Durham UK.
| PRJEB40427 | ENA
Project description:The idea that chemotherapy can be used in combination with immunotherapy may seem somewhat counterproductive, as it can theoretically eliminate the immune cells needed for antitumour immunity. However, much preclinical work has now demonstrated that in addition to direct cytotoxic effects on cancer cells, a proportion of DNA damaging agents may actually promote immunogenic cell death, alter the inflammatory milieu of the tumour microenvironment and/or stimulate neoantigen production, thereby activating an antitumour immune response. Some notable combinations have now moved forward into the clinic, showing promise in phase I-III trials, whereas others have proven toxic, and challenging to deliver. In this review, we discuss the emerging data of how DNA damaging agents can enhance the immunogenic properties of malignant cells, focussing especially on immunogenic cell death, and the expansion of neoantigen repertoires. We discuss how best to strategically combine DNA damaging therapeutics with immunotherapy, and the challenges of successfully delivering these combination regimens to patients. With an overwhelming number of chemotherapy/immunotherapy combination trials in process, clear hypothesis-driven trials are needed to refine the choice of combinations, and determine the timing and sequencing of agents in order to stimulate antitumour immunological memory and improve maintained durable response rates, with minimal toxicity.
| S-EPMC5808021 | biostudies-literature
Project description:It is generally assumed that an investment into cognitive abilities and their associated cost is particularly beneficial for long-lived species, as a prolonged lifespan allows to recoup the initial investment. However, ephemeral organisms possess astonishing cognitive abilities too. Invertebrates, for example, are capable of simple associative learning, reversal learning, and planning. How can this discrepancy between theory and evidence be explained? Using a simulation, we show that short lives can actually select for an increase in learning abilities. The rationale behind this is that when learning is needed to exploit otherwise inaccessible resources, one needs to learn fast in order to utilize the resources when constrained by short lifespans. And thus, increased cognitive abilities may evolve, not despite short lifespan, but because of it.
| S-EPMC6811680 | biostudies-literature
Project description:ObjectiveTo determine whether fast driving, luxury car ownership, and leniency by police officers differ across medical specialties.DesignObservational study.SettingFlorida, USA.Participants5372 physicians and a sample of 19 639 non-physicians issued a ticket for speeding during 2004-17.Main outcome measuresObserved rates of extreme speeding (defined as driving >20 mph above the speed limit), luxury car ownership, and leniency of the speeding ticket by police officers, by physician specialty, after adjustment for age and sex.ResultsThe sample included 5372 physicians who received 14 560 speeding tickets. The proportion of drivers who were reported driving at speeds greater than 20 mph was similar between physicians and a sample of 19 639 non-physicians who received a ticket for speeding (26.4% v 26.8% of tickets, respectively). Among physicians who received a ticket, psychiatrists were most likely to be fined for extreme speeding (adjusted odds ratio of psychiatry compared with baseline specialty of anesthesia 1.51, 95% confidence interval 1.07 to 2.14). Among drivers who received a ticket, luxury car ownership was most common among cardiologists (adjusted proportion of ticketed cardiologists who owned a luxury car 40.9%, 95% confidence interval 35.9% to 45.9%) and least common among physicians in emergency medicine, family practice, pediatrics, general surgery, and psychiatry (eg, adjusted proportion of luxury car ownership among family practice physicians 20.6%, 95% confidence interval 18.2% to 23.0%). Speed discounting, a marker of leniency by police officers in which ticketed speed is recorded at just below the threshold at which a larger fine would otherwise be imposed, was common, but rates did not differ by specialty and did not differ between physicians and a sample of non-physicians.ConclusionsRates of extreme speeding were highest among psychiatrists who received a ticket, whereas cardiologists were the most likely to be driving a luxury car when ticketed. Leniency by police officers was similar across specialties and between physicians and non-physicians.
| S-EPMC7191945 | biostudies-literature
Project description:Although the "skunky" odor characteristic of cannabis has been widely referenced, its cause has been historically misassigned to unspecified "skunky terpenes". Recent reports from two independent research groups, the Koziel team (March and April 2021) and Oswald team (August and November 2021), have corrected this misassignment by linking the "skunky" character of industrial hemp and cannabis to 3-methyl-2-butene-1-thiol (321MBT). A recent USPTO patent application review clearly indicated that the Oswald team should take full credit for the discovery of this link with respect to cannabis. However, the August 19, 2021 publication of their patent application appears to be their formal public disclosure of 321MBT as the primary source odorant which is responsible for the targeted "skunky" odor. This date is well after the March and April 2021 public disclosures by the Koziel team for the 321MBT/"skunky" odor link relative to both cannabis and industrial hemp. This Viewpoint summarizes the investigative strategy leading to the public disclosure of this historically elusive link. It is presented from the perspective of the rapid multidimensional-gas chromatography-mass spectrometry-olfactometry (i.e., MDGC-MS-O) based odorant-prioritization "screening" approach, as applied by the Koziel team.
| S-EPMC9201892 | biostudies-literature
Project description:Here, we investigate an unusual antiviral mechanism developed in the bacterium Streptomyces griseus SgrAI is a type II restriction endonuclease that forms run-on oligomer filaments when activated and possesses both accelerated DNA cleavage activity and expanded DNA sequence specificity. Mutations disrupting the run-on oligomer filament eliminate the robust antiphage activity of wild-type SgrAI, and the observation that even relatively modest disruptions completely abolish this anti-viral activity shows that the greater speed imparted by the run-on oligomer filament mechanism is critical to its biological function. Simulations of DNA cleavage by SgrAI uncover the origins of the kinetic advantage of this newly described mechanism of enzyme regulation over more conventional mechanisms, as well as the origin of the sequestering effect responsible for the protection of the host genome against damaging DNA cleavage activity of activated SgrAI.IMPORTANCE This work is motivated by an interest in understanding the characteristics and advantages of a relatively newly discovered enzyme mechanism involving filament formation. SgrAI is an enzyme responsible for protecting against viral infections in its host bacterium and was one of the first such enzymes shown to utilize such a mechanism. In this work, filament formation by SgrAI is disrupted, and the effects on the speed of the purified enzyme as well as its function in cells are measured. It was found that even small disruptions, which weaken but do not destroy filament formation, eliminate the ability of SgrAI to protect cells from viral infection, its normal biological function. Simulations of enzyme activity were also performed and show how filament formation can greatly speed up an enzyme's activation compared to that of other known mechanisms, as well as to better localize its action to molecules of interest, such as invading phage DNA.
| S-EPMC6384071 | biostudies-literature
Project description:Cellular immunotherapies promise to transform cancer care. However, they must overcome serious challenges, including: (1) the need to identify and characterize novel cancer antigens to expand the range of therapeutic targets; (2) the need to develop strategies to minimize serious adverse events, such as cytokine release syndrome and treatment-related toxicities; and (3) the need to develop efficient production/manufacturing processes to reduce costs. Here, we discuss whether these challenges might better be addressed through forms of public-private research collaborations, including public-private partnerships (PPPs), or whether these challenges are best addressed by way of standard market transactions. We reviewed 14 public-private relationships and 25 underlying agreements for the clinical development of cancer cellular immunotherapies in the US. Most were based on bilateral research agreements and pure market transactions in the form of service contracts and technology licenses, which is representative of the commercialization focus of the field. We make the strategic case that multiparty PPPs may better advance cancer antigen discovery and characterization and improved cell processing/manufacturing and related activities. In the rush toward the competitive end of the translational continuum for cancer cellular immunotherapy and the attendant focus on commercialization, many gaps have appeared in our understanding of cellular biology, immunology, and bioengineering. We conclude that the model of bilateral agreements between leading research institutions and the private sector may be inadequate to efficiently harness the interdisciplinary skills and knowledge of the public and private sectors to bring these promising therapies to the clinic for the benefit of cancer patients.
| S-EPMC5561330 | biostudies-literature
Project description:ObjectiveHuman skeletal muscle consists of a mixture of slow- and fast-twitch fibers with distinct capacities for contraction mechanics, fermentation, and oxidative phosphorylation. While the divergence in mitochondrial volume favoring slow-twitch fibers is well established, data on the fiber type-specific intrinsic mitochondrial function and morphology are highly limited with existing data mainly being generated in animal models. This highlights the need for more human data on the topic.MethodsHere, we utilized THRIFTY, a rapid fiber type identification protocol to detect, sort, and pool fast- and slow-twitch fibers within 6 h of muscle biopsy sampling. Respiration of permeabilized fast- and slow-twitch fiber pools was then analyzed with high-resolution respirometry. Using standardized western blot procedures, muscle fiber pools were subsequently analyzed for control proteins and key proteins related to respiratory capacity.ResultsMaximal complex I+II respiration was 25% higher in human slow-twitch fibers compared to fast-twitch fibers. However, per mitochondrial volume, the respiratory rate of mitochondria in fast-twitch fibers was approximately 50% higher for complex I+II, which was primarily mediated through elevated complex II respiration. Furthermore, the abundance of complex II protein and proteins regulating cristae structure were disproportionally elevated in mitochondria of the fast-twitch fibers. The difference in intrinsic respiratory rate was not reflected in fatty acid-or complex I respiration.ConclusionMitochondria of human fast-twitch muscle fibers compensate for their lack of volume by substantially elevating intrinsic respiratory rate through increased reliance on complex II.
| S-EPMC10788296 | biostudies-literature