Functional Importance of the DNA Binding Activity of Candida albicans Czf1p

The human opportunistic pathogen Candida albicans undergoes a reversible morphological transition between the yeast and hyphal states in response to a variety of signals. One such environmental trigger is growth within a semisolid matrix such as agar medium. This growth condition is of interest because it may mimic the growth of C. albicans in contact with host tissue during infection. During growth within a semisolid matrix, hyphal growth is positively regulated by the transcriptional regulator Czf1p and negatively by a second key transcriptional regulator, Efg1p. Genetic studies indicate that Czf1p, a member of the zinc-cluster family of transcriptional regulators, exerts its function by opposing the inhibitory influence of Efg1p on matrix-induced filamentous growth. We examined the importance of the two known activities of Czf1p, DNA-binding and interaction with Efg1p. We found that the two activities were separable by mutation allowing us to demonstrate that the DNA-binding activity of Czf1p was essential for its role as a positive regulator of morphogenesis. Surprisingly, however, interactions with Efg1p appeared to be largely dispensable. Our studies provide the first evidence of a key role for the DNA-binding activity of Czf1p in the morphological yeast-to-hyphal transition triggered by matrix-embedded growth

Estimating the NIH Efficient Frontier

Background: The National Institutes of Health (NIH) is among the world’s largest investors in biomedical research, with a mandate to: “…lengthen life, and reduce the burdens of illness and disability.” Its funding decisions have been criticized as insufficiently focused on disease burden. We hypothesize that modern portfolio theory can create a closer link between basic research and outcome, and offer insight into basic-science related improvements in public health. We propose portfolio theory as a systematic framework for making biomedical funding allocation decisions–one that is directly tied to the risk/reward trade-off of burden-of-disease outcomes. Methods and Findings: Using data from 1965 to 2007, we provide estimates of the NIH “efficient frontier”, the set of funding allocations across 7 groups of disease-oriented NIH institutes that yield the greatest expected return on investment for a given level of risk, where return on investment is measured by subsequent impact on U.S. years of life lost (YLL). The results suggest that NIH may be actively managing its research risk, given that the volatility of its current allocation is 17% less than that of an equal-allocation portfolio with similar expected returns. The estimated efficient frontier suggests that further improvements in expected return (89% to 119% vs. current) or reduction in risk (22% to 35% vs. current) are available holding risk or expected return, respectively, constant, and that 28% to 89% greater decrease in average years-of-life-lost per unit risk may be achievable. However, these results also reflect the imprecision of YLL as a measure of disease burden, the noisy statistical link between basic research and YLL, and other known limitations of portfolio theory itself. Conclusions: Our analysis is intended to serve as a proof-of-concept and starting point for applying quantitative methods to allocating biomedical research funding that are objective, systematic, transparent, repeatable, and expressly designed to reduce the burden of disease. By approaching funding decisions in a more analytical fashion, it may be possible to improve their ultimate outcomes while reducing unintended consequences

Categorial Compositionality III: F-(co)algebras and the Systematicity of Recursive Capacities in Human Cognition

Human cognitive capacity includes recursively definable concepts, which are prevalent in domains involving lists, numbers, and languages. Cognitive science currently lacks a satisfactory explanation for the systematic nature of such capacities (i.e., why the capacity for some recursive cognitive abilities–e.g., finding the smallest number in a list–implies the capacity for certain others–finding the largest number, given knowledge of number order). The category-theoretic constructs of initial F-algebra, catamorphism, and their duals, final coalgebra and anamorphism provide a formal, systematic treatment of recursion in computer science. Here, we use this formalism to explain the systematicity of recursive cognitive capacities without ad hoc assumptions (i.e., to the same explanatory standard used in our account of systematicity for non-recursive capacities). The presence of an initial algebra/final coalgebra explains systematicity because all recursive cognitive capacities, in the domain of interest, factor through (are composed of) the same component process. Moreover, this factorization is unique, hence no further (ad hoc) assumptions are required to establish the intrinsic connection between members of a group of systematically-related capacities. This formulation also provides a new perspective on the relationship between recursive cognitive capacities. In particular, the link between number and language does not depend on recursion, as such, but on the underlying functor on which the group of recursive capacities is based. Thus, many species (and infants) can employ recursive processes without having a full-blown capacity for number and language

DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway

Stabilization of mutant p53 (mutp53) in tumours greatly contributes to malignant progression. However, little is known about the underlying mechanisms and therapeutic approaches to destabilize mutp53. Here, through high-throughput screening we identify statins, cholesterol-lowering drugs, as degradation inducers for conformational or misfolded p53 mutants with minimal effects on wild-type p53 (wtp53) and DNA contact mutants. Statins preferentially suppress mutp53-expressing cancer cell growth. Specific reduction of mevalonate-5-phosphate by statins or mevalonate kinase knockdown induces CHIP ubiquitin ligase-mediated nuclear export, ubiquitylation, and degradation of mutp53 by impairing interaction of mutp53 with DNAJA1, a Hsp40 family member. Knockdown of DNAJA1 also induces CHIP-mediated mutp53 degradation, while its overexpression antagonizes statin-induced mutp53 degradation. Our study reveals that DNAJA1 controls the fate of misfolded mutp53, provides insights into potential strategies to deplete mutp53 through the mevalonate pathway–DNAJA1 axis, and highlights the significance of p53 status in impacting statins’ efficacy on cancer therapy

Categorial Compositionality: A Category Theory Explanation for the Systematicity of Human Cognition

Classical and Connectionist theories of cognitive architecture seek to explain systematicity (i.e., the property of human cognition whereby cognitive capacity comes in groups of related behaviours) as a consequence of syntactically and functionally compositional representations, respectively. However, both theories depend on ad hoc assumptions to exclude specific instances of these forms of compositionality (e.g. grammars, networks) that do not account for systematicity. By analogy with the Ptolemaic (i.e. geocentric) theory of planetary motion, although either theory can be made to be consistent with the data, both nonetheless fail to fully explain it. Category theory, a branch of mathematics, provides an alternative explanation based on the formal concept of adjunction, which relates a pair of structure-preserving maps, called functors. A functor generalizes the notion of a map between representational states to include a map between state transformations (or processes). In a formal sense, systematicity is a necessary consequence of a higher-order theory of cognitive architecture, in contrast to the first-order theories derived from Classicism or Connectionism. Category theory offers a re-conceptualization for cognitive science, analogous to the one that Copernicus provided for astronomy, where representational states are no longer the center of the cognitive universe—replaced by the relationships between the maps that transform them

Category Theoretic Analysis of Hierarchical Protein Materials and Social Networks

Materials in biology span all the scales from Angstroms to meters and typically consist of complex hierarchical assemblies of simple building blocks. Here we describe an application of category theory to describe structural and resulting functional properties of biological protein materials by developing so-called ologs. An olog is like a “concept web” or “semantic network” except that it follows a rigorous mathematical formulation based on category theory. This key difference ensures that an olog is unambiguous, highly adaptable to evolution and change, and suitable for sharing concepts with other olog. We consider simple cases of beta-helical and amyloid-like protein filaments subjected to axial extension and develop an olog representation of their structural and resulting mechanical properties. We also construct a representation of a social network in which people send text-messages to their nearest neighbors and act as a team to perform a task. We show that the olog for the protein and the olog for the social network feature identical category-theoretic representations, and we proceed to precisely explicate the analogy or isomorphism between them. The examples presented here demonstrate that the intrinsic nature of a complex system, which in particular includes a precise relationship between structure and function at different hierarchical levels, can be effectively represented by an olog. This, in turn, allows for comparative studies between disparate materials or fields of application, and results in novel approaches to derive functionality in the design of de novo hierarchical systems. We discuss opportunities and challenges associated with the description of complex biological materials by using ologs as a powerful tool for analysis and design in the context of materiomics, and we present the potential impact of this approach for engineering, life sciences, and medicine.Presidential Early Career Award for Scientists and Engineers (N000141010562)United States. Army Research Office. Multidisciplinary University Research Initiative (W911NF0910541)United States. Office of Naval Research (grant N000141010841)Massachusetts Institute of Technology. Dept. of MathematicsStudienstiftung des deutschen VolkesClark BarwickJacob Luri

Global mortality and readmission rates following COPD exacerbation-related hospitalisation: a meta-analysis of 65 945 individual patients

\ua9 2024, European Respiratory Society. All rights reserved.Background Exacerbations of COPD (ECOPD) have a major impact on patients and healthcare systems across the world. Precise estimates of the global burden of ECOPD on mortality and hospital readmission are needed to inform policy makers and aid preventive strategies to mitigate this burden. The aims of the present study were to explore global in-hospital mortality, post-discharge mortality and hospital readmission rates after ECOPD-related hospitalisation using an individual patient data meta-analysis (IPDMA) design. Methods A systematic review was performed identifying studies that reported in-hospital mortality, postdischarge mortality and hospital readmission rates following ECOPD-related hospitalisation. Data analyses were conducted using a one-stage random-effects meta-analysis model. This study was conducted and reported in accordance with the PRISMA-IPD statement. Results Data of 65 945 individual patients with COPD were analysed. The pooled in-hospital mortality rate was 6.2%, pooled 30-, 90- and 365-day post-discharge mortality rates were 1.8%, 5.5% and 10.9%, respectively, and pooled 30-, 90- and 365-day hospital readmission rates were 7.1%, 12.6% and 32.1%, respectively, with noticeable variability between studies and countries. Strongest predictors of mortality and hospital readmission included noninvasive mechanical ventilation and a history of two or more ECOPD-related hospitalisation

Risk Factors for Posttraumatic Stress Disorder Among Deployed US Male Marines

<p>Abstract</p> <p>Background</p> <p>Combat exposure has been reported as one of the strongest risk factors for postdeployment posttraumatic stress disorder (PTSD) among military service members. Determining the impact of specific deployment-related exposures on the risk of developing PTSD has not been fully explored. Our study objective was to explore the relationship between specific combat exposures and other life experiences with postdeployment PTSD.</p> <p>Methods</p> <p>This study consisted of male Marines who completed a Recruit Assessment Program (RAP) survey during recruit training at the Marine Corps Recruit Depot in San Diego, California as well as a follow-up survey several years after recruit training. Study participants included those Marines who deployed to the current operations in Iraq or Afghanistan between the baseline and follow-up surveys. Multivariable logistic regression was performed to determine which significant exposures and experiences were associated with postdeployment PTSD.</p> <p>Results</p> <p>Of the 706 study participants, 10.8% screened positive for postdeployment PTSD. Those who reported feeling in great danger of death (odds ratio [OR] = 4.63, 95% confidence interval [CI]: 2.46-8.73), were shot or seriously injured (OR = 3.51, 95% CI: 1.58-7.77), saw someone wounded or killed (OR = 2.47, 95% CI: 1.08-5.67), and baseline (before recruit training) prior violence exposures (OR = 2.99, 95% CI: 1.46-6.10) were at increased odds for reporting PTSD symptoms. Number of deployments, number of close friends or relatives reported at follow-up, and enlisted pay grade were also significantly associated with postdeployment PTSD.</p> <p>Conclusions</p> <p>Combat exposures, specifically the threat of death, serious injury, and witnessing injury or death are significant risk factors for screening positive for postdeployment PTSD among male Marines as well as violence exposures prior to entering the Marine Corps, which are independent of future combat exposures. A thorough history of lifetime violence exposures should be pursued when considering a clinical diagnosis of PTSD.</p

Establishment Failure in Biological Invasions: A Case History of Littorina littorea in California, USA

The early stages of biological invasions are rarely observed, but can provide significant insight into the invasion process as well as the influence vectors have on invasion success or failure.We characterized three newly discovered populations of an introduced gastropod, Littorina littorea (Linné, 1758), in California, USA, comparing them to potential source populations in native Europe and the North American East Coast, where the snail is also introduced. Demographic surveys were used to assess spatial distribution and sizes of the snail in San Francisco and Anaheim Bays, California. Mitochondrial DNA was sequenced and compared among these nascent populations, and various populations from the North American East Coast and Europe, to characterize the California populations and ascertain their likely source. Demographic and genetic data were considered together to deduce likely vectors for the California populations. We found that the three large California L. littorea populations contained only adult snails and had unexpectedly high genetic diversity rather than showing an extreme bottleneck as typically expected in recent introductions. Haplotype diversity in Californian populations was significantly reduced compared to European populations, but not compared to East Coast populations. Genetic analyses clearly suggested the East Coast as the source region for the California introductions.The California L. littorea populations were at an early, non-established phase of invasion with no evidence of recruitment. The live seafood trade is the most likely invasion vector for these populations, as it preferentially transports large numbers of adult L. littorea, matching the demographic structure of the introduced California L. littorea populations. Our results highlight continued operation of live seafood trade vectors and the influence of vectors on the demographic and genetic structure of the resulting populations, especially early stages of the invasion process