As a supplement to Gondan and Minakata’s (
2015
) tutorial on methods for testing the race model inequality, this theoretical note attempts to clarify further (a) the types of models that obey and ...violate the inequality and (b) the conclusions that can be drawn when the inequality is violated. In particular, the idea that individual racers proceed at the same speed in the single and redundant conditions (also known as “context independence”) is shown to be better understood as an inherent part of Raab’s (
1962
) original race model than as a separate, additional assumption. Thus, evidence that individual racers proceeded at different speeds in the single and redundant conditions, if available, should be viewed as supporting one type of coactivation model rather than an alternative model. In addition, it is shown that a class of race-like models without the assumption of context independence is so broad that it can never be falsified.
Researchers who analyze data within the framework of null hypothesis significance testing must choose a critical "alpha" level, α, to use as a cutoff for deciding whether a given set of data ...demonstrates the presence of a particular effect. In most fields, α = 0.05 has traditionally been used as the standard cutoff. Many researchers have recently argued for a change to a more stringent evidence cutoff such as α = 0.01, 0.005, or 0.001, noting that this change would tend to reduce the rate of false positives, which are of growing concern in many research areas. Other researchers oppose this proposed change, however, because it would correspondingly tend to increase the rate of false negatives. We show how a simple statistical model can be used to explore the quantitative tradeoff between reducing false positives and increasing false negatives. In particular, the model shows how the optimal α level depends on numerous characteristics of the research area, and it reveals that although α = 0.05 would indeed be approximately the optimal value in some realistic situations, the optimal α could actually be substantially larger or smaller in other situations. The importance of the model lies in making it clear what characteristics of the research area have to be specified to make a principled argument for using one α level rather than another, and the model thereby provides a blueprint for researchers seeking to justify a particular α level.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The storming of the US Capitol building in January 2021 focused attention on the multiple threats facing contemporary liberal democracies. Beyond the immediate problem of Covid-19, the past two ...decades saw political polarization, a dramatic rise in inequality, global warming and other environmental threats, as well as the growth of dangerous cultural and political divisions. Western liberal democracies find themselves in the midst of what political theorists call a legitimation crisis: major portions of the population lack confidence in the ability of governments to address our most pressing problems. This distrust in government and traditional political parties opened the door to populist leaders and a rising tide of authoritarianism.Liberal democracies face major structural and normative challenges in the near future that require us to look beyond the traditional set of solutions available. Democracy in Crisis points back to the world's first democratic government, Ancient Athen.
R-type pyocins are representatives of contractile ejection systems, a class of biological nanomachines that includes, among others, the bacterial type VI secretion system (T6SS) and contractile ...bacteriophage tails. We report atomic models of the Pseudomonas aeruginosa precontraction pyocin sheath and tube, and the postcontraction sheath, obtained by cryo-EM at 3.5-Å and 3.9-Å resolutions, respectively. The central channel of the tube is negatively charged, in contrast to the neutral and positive counterparts in T6SSs and phage tails. The sheath is interwoven by long N- and C-terminal extension arms emanating from each subunit, which create an extensive two-dimensional mesh that has the same connectivity in the extended and contracted state of the sheath. We propose that the contraction process draws energy from electrostatic and shape complementarities to insert the inner tube through bacterial cell membranes to eventually kill the bacteria.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Natural killer (NK) cells can provide effective immunotherapy for ovarian cancer. Here, we evaluated the ability of NK cells isolated from peripheral blood (PB) and NK cells derived from induced ...pluripotent stem cell (iPSC) to mediate killing of ovarian cancer cells in a mouse xenograft model. A mouse xenograft model was used to evaluate the intraperitoneal delivery of three different NK cell populations: iPSC‐derived NK cells, PB‐NK cells that had been activated and expanded in long‐term culture, and overnight activated PB‐NK cells that were isolated through CD3/CD19 depletion of PB B and T cells. Bioluminescent imaging was used to monitor tumor burden of luciferase expressing tumor lines. Tumors were allowed to establish prior to administering NK cells via intraperitoneal injection. These studies demonstrate a single dose of any of the three NK cell populations significantly reduced tumor burden. When mice were given three doses of either iPSC‐NK cells or expanded PB‐NK cells, the median survival improved from 73 days in mice untreated to 98 and 97 days for treated mice, respectively. From these studies, we conclude iPSC‐derived NK cells mediate antiovarian cancer killing at least as well as PB‐NK cells, making these cells a viable resource for immunotherapy for ovarian cancer. Due to their ability to be easily differentiated into NK cells and their long‐term expansion potential, iPSCs can be used to produce large numbers of well‐defined NK cells that can be banked and used to treat a large number of patients including treatment with multiple doses if necessary. Stem Cells 2016;34:93–101
At the time of preparing this Perspective, large-scale vaccination for COVID-19 is in progress, aiming to bring the pandemic under control through vaccine-induced herd immunity. Not only does this ...vaccination effort represent an unprecedented scientific and technological breakthrough, moving us from the rapid analysis of viral genomes to design, manufacture, clinical trial testing, and use authorization within the time frame of less than a year, but it also highlights rapid progress in the implementation of nanotechnology to assist vaccine development. These advances enable us to deliver nucleic acid and conformation-stabilized subunit vaccines to regional lymph nodes, with the ability to trigger effective humoral and cellular immunity that prevents viral infection or controls disease severity. In addition to a brief description of the design features of unique cationic lipid and virus-mimicking nanoparticles for accomplishing spike protein delivery and presentation by the cognate immune system, we also discuss the importance of adjuvancy and design features to promote cooperative B- and T-cell interactions in lymph node germinal centers, including the use of epitope-based vaccines. Although current vaccine efforts have demonstrated short-term efficacy and vaccine safety, key issues are now vaccine durability and adaptability against viral variants. We present a forward-looking perspective of how vaccine design can be adapted to improve durability of the immune response and vaccine adaptation to overcome immune escape by viral variants. Finally, we consider the impact of nano-enabled approaches in the development of COVID-19 vaccines for improved vaccine design against other infectious agents, including pathogens that may lead to future pandemics.
While the antibacterial properties of graphene oxide (GO) have been demonstrated across a spectrum of bacteria, the critical role of functional groups is unclear. To address this important issue, we ...utilized reduction and hydration methods to establish a GO library with different oxidation, hydroxyl, and carbon radical (•C) levels that can be used to study the impact on antibacterial activity. Using antibiotic-resistant bacteria as a test platform, we found that the •C density is most proximately associated with bacterial killing. Accordingly, hydrated GO (hGO), with the highest •C density, had the strongest antibacterial effects through membrane binding and induction of lipid peroxidation. To explore its potential applications, we demonstrated that coating of catheter and glass surfaces with hGO is capable of killing drug-resistant bacteria. In summary, •C is the principle surface moiety that can be utilized for clinical applications of GO-based antibacterial coatings.
Pertussis, also known as whooping cough, has recently re-emerged as a major public health threat despite high levels of vaccination against the aetiological agent Bordetella pertussis. In this ...Review, we describe the pathogenesis of this disease, with a focus on recent mechanistic insights into B. pertussis virulence-factor function. We also discuss the changing epidemiology of pertussis and the challenges facing vaccine development. Despite decades of research, many aspects of B. pertussis physiology and pathogenesis remain poorly understood. We highlight knowledge gaps that must be addressed to develop improved vaccines and therapeutic strategies.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This article examines why many studies fail to replicate statistically significant published results. We address this issue within a general statistical framework that also allows us to include ...various questionable research practices (QRPs) that are thought to reduce replicability. The analyses indicate that the base rate of true effects is the major factor that determines the replication rate of scientific results. Specifically, for purely statistical reasons, replicability is low in research domains where true effects are rare (e.g., search for effective drugs in pharmacology). This point is under-appreciated in current scientific and media discussions of replicability, which often attribute poor replicability mainly to QRPs.
Due to envelope differences between Gram-positive and Gram-negative bacteria, engineering precision bactericidal contractile nanomachines requires atomic-level understanding of their structures; ...however, only those killing Gram-negative bacteria are currently known. Here, we report the atomic structures of an engineered diffocin, a contractile syringe-like molecular machine that kills the Gram-positive bacterium Clostridioides difficile. Captured in one pre-contraction and two post-contraction states, each structure fashions six proteins in the bacteria-targeting baseplate, two proteins in the energy-storing trunk, and a collar linking the sheath with the membrane-penetrating tube. Compared to contractile machines targeting Gram-negative bacteria, major differences reside in the baseplate and contraction magnitude, consistent with target envelope differences. The multifunctional hub-hydrolase protein connects the tube and baseplate and is positioned to degrade peptidoglycan during penetration. The full-length tape measure protein forms a coiled-coil helix bundle homotrimer spanning the entire diffocin. Our study offers mechanical insights and principles for designing potent protein-based precision antibiotics.R-type contractile bacteriocins are natural-occurring nanomachines that kill bacteria. Here the authors report the atomic structures of a bacteriocin, called diffocin, that has been engineered to kill Gram-positive bacterium Clostridioides difficile.
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