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The clinical use of the chemotherapeutic doxorubicin (Dox) is limited by cardiotoxic side-effects. One of the early Dox effects is induction of a sarcoplasmic reticulum (SR) Ca2+ leak. The chaperone Glucose regulated protein 78 (GRP78) is important for Ca2+ homeostasis in the endoplasmic reticulum (ER)-the organelle corresponding to the SR in non-cardiomyocytes-and has been shown to convey resistance to Dox in certain tumors. Our aim was to investigate the effect of cardiac GRP78 gene transfer on Ca2+ dependent signaling, cell death, cardiac function and survival in clinically relevant in vitro and in vivo models for Dox cardiotoxicity.By using neonatal cardiomyocytes we could demonstrate that Dox induced Ca2+ dependent Ca2+ /calmodulin-dependent protein kinase II (CaMKII) activation is one of the factors involved in Dox cardiotoxicity by promoting apoptosis. Furthermore, we found that adeno-associated virus (AAV) mediated GRP78 overexpression partly protects neonatal cardiomyocytes from Dox induced cell death by modulating Ca2+ dependent pathways like the activation of CaMKII, phospholamban (PLN) and p53 accumulation. Most importantly, cardiac GRP78 gene therapy in mice treated with Dox revealed improved diastolic function (dP/dtmin) and survival after Dox treatment. In conclusion, our results demonstrate for the first time that Ca2+ dependent CaMKII activation fosters Dox cardiomyopathy and provide additional insight into possible mechanisms by which GRP78 overexpression protects cardiomyocytes from Doxorubicin toxicity.

The increase in protein activity and upregulation of G-protein coupled receptor kinase 2 (GRK2) is a hallmark of cardiac stress and heart failure. Inhibition of GRK2 improved cardiac function and survival and diminished cardiac remodeling in various animal heart failure models. The aim of the present study was to investigate the effects of GRK2 on cardiac hypertrophy and dissect potential molecular mechanisms. In mice we observed increased GRK2 mRNA and protein levels following transverse aortic constriction (TAC). Conditional GRK2 knockout mice showed attenuated hypertrophic response with preserved ventricular geometry 6 weeks after TAC operation compared to wild-type animals. In isolated neonatal rat ventricular cardiac myocytes stimulation with angiotensin II and phenylephrine enhanced GRK2 expression leading to enhanced signaling via protein kinase B (PKB or Akt), consecutively inhibiting glycogen synthase kinase 3 beta (GSK3β), such promoting nuclear accumulation and activation of nuclear factor of activated T-cells (NFAT). Cardiac myocyte hypertrophy induced by in vitro GRK2 overexpression increased the cytosolic interaction of GRK2 and phosphoinositide 3-kinase γ (PI3Kγ). Moreover, inhibition of PI3Kγ as well as GRK2 knock down prevented Akt activation resulting in halted NFAT activity and reduced cardiac myocyte hypertrophy. Our data show that enhanced GRK2 expression triggers cardiac hypertrophy by GRK2-PI3Kγ mediated Akt phosphorylation and subsequent inactivation of GSK3β, resulting in enhanced NFAT activity.

Systems glycobiology aims to provide models and analysis tools that account for the biosynthesis, regulation, and interactions with glycoconjugates. To facilitate these methods, there is a need for a clear glycan representation accessible to both computers and humans. Linear Code, a linearized and readily parsable glycan structure representation, is such a language. For this reason, Linear Code was adapted to represent reaction rules, but the syntax has drifted from its original description to accommodate new and originally unforeseen challenges. Here, we delineate the consensuses and inconsistencies that have arisen through this adaptation. We recommend options for a consensus-based extension of Linear Code that can be used for reaction rule specification going forward. Through this extension and specification of Linear Code to reaction rules, we aim to minimize inconsistent symbology thereby making glycan database queries easier. With a clear guide for generating reaction rule descriptions, glycan synthesis models will be more interoperable and reproducible thereby moving glycoinformatics closer to compliance with FAIR standards. Here, we present Linear Code for Reaction Rules (LiCoRR), version 1.0, an unambiguous representation for describing glycosylation reactions in both literature and code.Systems glycobiology aims to provide models and analysis tools that account for the biosynthesis, regulation, and interactions with glycoconjugates. To facilitate these methods, there is a need for a clear glycan representation accessible to both computers and humans. Linear Code, a linearized and readily parsable glycan structure representation, is such a language. For this reason, Linear Code was adapted to represent reaction rules, but the syntax has drifted from its original description to accommodate new and originally unforeseen challenges. Here, we delineate the consensuses and inconsistencies that have arisen through this adaptation. We recommend options for a consensus-based extension of Linear Code that can be used for reaction rule specification going forward. Through this extension and specification of Linear Code to reaction rules, we aim to minimize inconsistent symbology thereby making glycan database queries easier. With a clear guide for generating reaction rule descriptions, glycan synthesis models will be more interoperable and reproducible thereby moving glycoinformatics closer to compliance with FAIR standards. Here, we present Linear Code for Reaction Rules (LiCoRR), version 1.0, an unambiguous representation for describing glycosylation reactions in both literature and code.

Recent work has claimed that (non-tonal) phonological patterns are subregular (Heinz 2011a,b, 2018; Heinz and Idsardi 2013), occupying a delimited proper subregion of the regular functions—the weakly deterministic (WD) functions (Heinz and Lai 2013; Jardine 2016). Whether or not it is correct (McCollum et al. 2020a), this claim can only be properly assessed given a complete and accurate definition of WD functions. We propose such a definition in this article, patching unintended holes in Heinz and Lai’s (2013) original definition that we argue have led to the incorrect classification of some phonological patterns as WD. We start from the observation that WD patterns share a property that we call unbounded semiambience, modeled after the analogous observation by Jardine (2016) about non-deterministic (ND) patterns and their unbounded circumambience. Both ND and WD functions can be broken down into compositions of deterministic (subsequential) functions (Elgot and Mezei 1965; Heinz and Lai 2013) that read an input string from opposite directions; we show that WD functions are those for which these deterministic composands do not interact in a way that is familiar from the theoretical phonology literature. To underscore how this concept of interaction neatly separates the WD class of functions from the strictly more expressive ND class, we provide analyses of the vowel harmony patterns of two Eastern Nilotic languages, Maasai and Turkana, using bimachines, an automaton type that represents unbounded bidirectional dependencies explicitly. These analyses make clear that there is interaction between deterministic composands when (and only when) the output of a given input element of a string is simultaneously dependent on information from both the left and the right: ND functions are those that involve interaction, while WD functions are those that do not.

The explanation of linguistic variation and change is one of the central questions in the language sciences. Functional explanations focus on how the needs and abilities of language users shape the distribution of linguistic structures that typically conventionalize -- e.g. structures that are harder to perceive or learn accurately are less likely to conventionalize accurately. Perceptibility effects are common sound patterns that seem closely related to the relative confusability of different speech sound sequences. One class of explanations -- purely phonological accounts --have assumed speakers (implicitly) know how confusability varies as a function of immediately adjacent sounds, and that this is a rich enough description of confusability to explain perceptibility effects. Chapter 2 shows that the perceptibility of tokens of any given sound in American English systematically varies based on a listener's incrementally-adjusted expectations about what the speaker intends to say, and shows that this variation is significantly greater than variation due to immediately adjacent sounds. To derive this result, I present a computational psycholinguistic model of word recognition and apply it to experimental confusability data and a transcribed lexicon of 104 words. I conclude that purely phonological accounts of perceptibility effects need to be more complicated and less modular than currently appreciated. Chapter 3 applies the same word recognition model and novel information-theoretic measures of confusability to two conversational corpora and shows that words that are more contextually confusable are lengthened in contexts where they are more confusable, and shortened where they are less so. This is a crucial step towards a linking hypothesis between the realtime perceptibility of different speech sound sequences and conventionalized perceptibility effects. Chapter 4 considers morphology. Prior research has observed an inverse relation between morphological complexity and demographic variables like speech community size and proportion of adult learners. Recent work has hypothesized that higher complexity may be helpful to child learners, and that populations with differing demographics constitute environments with different 'selection pressures' for language variants to 'evolve' in. I argue that mathematical formulations of Darwinian evolution suggest a more likely explanation: 'neutral' change caused by random fluctuations in variant frequency ('drift') is much more powerful in small populations and can easily overwhelm selection relative to large populations.

We present an empirical challenge to Jardine's (2016) assertion that only tonal spreading patterns can be unbounded circumambient, meaning that the determination of a phonological value may depend on information that is an unbounded distance away on both sides. We focus on a demonstration that the ATR harmony pattern found in Tutrugbu is unbounded circumambient, and we also cite several other segmental spreading processes with the same general character. We discuss implications for the complexity of phonology and for the relationship between the explanation of typology and the evaluation of phonological theories.

Systems glycobiology aims to provide models and analysis tools that account for the biosynthesis, regulation, and interactions with glycoconjugates. To facilitate these methods, there is a need for a clear glycan representation accessible to both computers and humans. Linear Code, a linearized and readily parsable glycan structure representation, is such a language. For this reason, Linear Code was adapted to represent reaction rules, but the syntax has drifted from its original description to accommodate new and originally unforeseen challenges. Here, we delineate the consensuses and inconsistencies that have arisen through this adaptation. We recommend options for a consensus-based extension of Linear Code that can be used for reaction rule specification going forward. Through this extension and specification of Linear Code to reaction rules, we aim to minimize inconsistent symbology thereby making glycan database queries easier. With a clear guide for generating reaction rule descriptions, glycan synthesis models will be more interoperable and reproducible thereby moving glycoinformatics closer to compliance with FAIR standards. Here, we present Linear Code for Reaction Rules (LiCoRR), version 1.0, an unambiguous representation for describing glycosylation reactions in both literature and code.

The ‘soak and smear’ regimen is a highly effective method for localised topical therapy employed by dermatologists for widespread inflammatory skin conditions. The regimen involves application of topical medication under occlusion after soaking in water. Complications from this treatment method are rare. We present a case of multiple, generalised methicillin-resistant Staphylococcus aureus (MRSA)-positive furuncles arising in a patient as an unexpected consequence of therapy. The case highlights an unanticipated risk of a commonly employed treatment amid an epidemic of MRSA in the community.

Jardine (2016) asserts a computational distinction between segmental and tonal phonology, arguing that certain tonal patterns require the strictly more expressive computational power of non-deterministic regular functions while segmental patterns require at most the power of weakly deterministic regular functions. We advance two claims bearing on this assertion. Empirically, we show that non-deterministic segmental patterns are in fact attested, focusing on the vowel harmony pattern found in Tutrugbu (McCollum and Essegbey 2018) and citing several others. We submit that these patterns are non-deterministic in exactly the same essential way as the tonal patterns discussed by Jardine (2016). Formally, we show that the definition of weakly deterministic regular functions offered by Heinz and Lai (2013) is incapable of distinguishing between non-deterministic patterns and the less complex weakly deterministic patterns it is intended to delimit. We offer a revised definition of weakly deterministic functions that makes the correct distinctions, subsuming the conditions imposed by Heinz and Lai (2013) under a proposed definition of ‘interaction’ between composed functions. We also conjecture that the inverse relationship between complexity and observed frequency is explainable by domain-general principles of learnability rather than a categorical cap on the complexity of a phonology-specific learning mechanism, contra Heinz and Idsardi (2011, 2013).

Abstract Systems glycobiology aims to provide models and analysis tools that account for the biosynthesis, regulation, and interactions with glycoconjugates. To facilitate these methods, there is a need for a clear glycan representation accessible to both computers and humans. Linear Code, a linearized and readily parsable glycan structure representation, is such a language. For this reason, Linear Code was adapted to represent reaction rules, but the syntax has drifted from its original description to accommodate new and originally unforeseen challenges. Here, we delineate the consensuses and inconsistencies that have arisen through this adaptation. We recommend options for a consensus-based extension of Linear Code that can be used for reaction rule specification going forward. Through this extension and specification of Linear Code to reaction rules, we aim to minimize inconsistent symbology thereby making glycan database queries easier. With a clear guide for generating reaction rule descriptions, glycan synthesis models will be more interoperable and reproducible thereby moving glycoinformatics closer to compliance with FAIR standards. Reaction rule-extended Linear Code is an unambiguous representation for describing glycosylation reactions in both literature and code. Competing Interest Statement The authors have declared no competing interest.