Deprotection Research Articles

Chemotherapy effects on mitochondrial function in adipose tissue in oesophageal and gastroesophageal junction adenocarcinomas with or without associated cachexia: protocol for a prospective, comparative observational study (ChiFMeOE)

IntroductionCachexia is strongly associated with digestive cancers, particularly oesogastric cancer. Mitochondria in adipose tissue are involved in the regulation of metabolism and physiopathology of cancer cachexia in animal studies. Chemotherapeutic...

Enantiomerically Pure Indazole Bioisosteres of Ifenprodil and Ro 25-6981 as Negative Allosteric Modulators of NMDA Receptors with the GluN2B Subunit.

Administration of negative allosteric modulators of GluN2B subunit-containing NMDA receptors such as Ro 25-6981 (1) and ifenprodil (2) results in neuroprotective effects. In this study, the phenol of 1 and 2 was replaced bioisosterically by an indazole to inhibit glucuronidation. The γ- and β-aminoalcohols 10 and 11 were prepared without installing a protective group at the indazole ring using the ketone 6 as a common intermediate. All four stereoisomeric γ- and β-aminoalcohols 10 and 11 were obtained by diastereoselective reduction of ketones 7 and 9 followed by separation of enantiomers. The analogously structured γ-aminoalcohol (1S,2S)-10c (Ro 25-6981 bioisostere) and β-aminoalcohol (1R,2R)-11c (ifenprodil bioisostere) exhibited high GluN2B affinity (Ki = 50 and 66 nM, respectively) and high to moderate inhibitory activity in two-electrode voltage clamp experiments. The indazole bioisosteres 10 and 11 showed higher metabolic stability than 1. In the presence of uridinyldiphosphate activated glucuronic acid, glucuronidation of 10 and 11 was not observed.

Cerebral emboli detection and autonomous neuromonitoring using robotic transcranial Doppler with artificial intelligence for transcatheter aortic valve replacement with and without embolic protection devices: a pilot study

BackgroundPeriprocedural ischemic stroke remains a serious complication in patients undergoing transcatheter aortic valve replacement (TAVR). We used a novel robotic transcranial Doppler (TCD) system equipped with artificial intelligence (AI) for...

Enhancing fairness in AI-enabled medical systems with the attribute neutral framework

Questions of unfairness and inequity pose critical challenges to the successful deployment of artificial intelligence (AI) in healthcare settings. In AI models, unequal performance across protected groups may be partially attributable to the learning of spurious or otherwise undesirable correlations between sensitive attributes and disease-related information. Here, we introduce the Attribute Neutral Framework, designed to disentangle biased attributes from disease-relevant information and subsequently neutralize them to improve representation across diverse subgroups. Within the framework, we develop the Attribute Neutralizer (AttrNzr) to generate neutralized data, for which protected attributes can no longer be easily predicted by humans or by machine learning classifiers. We then utilize these data to train the disease diagnosis model (DDM). Comparative analysis with other unfairness mitigation algorithms demonstrates that AttrNzr outperforms in reducing the unfairness of the DDM while maintaining DDM’s overall disease diagnosis performance. Furthermore, AttrNzr supports the simultaneous neutralization of multiple attributes and demonstrates utility even when applied solely during the training phase, without being used in the test phase. Moreover, instead of introducing additional constraints to the DDM, the AttrNzr directly addresses a root cause of unfairness, providing a model-independent solution. Our results with AttrNzr highlight the potential of data-centered and model-independent solutions for fairness challenges in AI-enabled medical systems.

Meso-Hydroxylmethyl-1,3,5,7-tetramethylBODIPY: A Visible-Light Photoremovable Protective Group for Carboxyl Groups

AbstractA meso-BODIPY-type photoremovable protecting group for carboxyl group is developed. BODIPYs are well-known for brilliant color, favorable to reaction monitoring and purification. meso-BODIPY esters are achieved via esterification in 44–89% yields, while deprotection is fulfilled under irradiation of blue LED bulb in the presence of photocatalyst and organic hydrogen donor in 43–95% yields. This method is applicable to a variety of acids, such as aromatic, heteroaromatic, alkyl, α,β-unsaturated carboxylic acids, etc. Our BODIPY-deprotective condition is almost neutral that both methyl and tert-butyl esters are compatible.

Explaining contributions of features towards unfairness in classifiers: A novel threshold-dependent Shapley value-based approach

A number of approaches has been proposed to investigate and mitigate unfairness in machine learning algorithms. However, as the definition and understanding of fairness may vary in different situations, the study of ethical disparities remains an open area of research. Besides the importance of analyzing ethical disparities, explainability in machine learning is also a relevant issue in Trustworthy Artificial Intelligence. Usually, both fairness and explainability analysis are based on a fixed decision threshold, which differentiates the positive cases from the negative ones according to the predicted probabilities. In this paper, we investigate how changes in this threshold can impact the fairness of predictions between protected and other groups and how features contribute towards such a measure. We propose a novel Shapley value-based approach as a tool to investigate how changes in the threshold values change the contribution of each feature towards unfairness. This gives us an ability to evaluate how fairness measures vary for different threshold values and which features have the higher (or lower) impact on creating ethical disparities. We demonstrate this using three different case studies that are carefully chosen to highlight different unfairness scenarios and features contributions. We also applied our proposal as a feature selection strategy, which contributed to decrease unfair results substantially.

Pan-cancer characterization of cellular senescence reveals its inter-tumor heterogeneity associated with the tumor microenvironment and prognosis

Cellular senescence (CS) is characterized by the irreversible cell cycle arrest and plays a key role in aging and diseases, such as cancer. Recent years have witnessed the burgeoning exploration of the intricate relationship between CS and cancer, with CS recognized as either a suppressing or promoting factor and officially acknowledged as one of the 14 cancer hallmarks. However, a comprehensive characterization remains absent from elucidating the divergences of this relationship across different cancer types and its involvement in the multi-facets of tumor development. Here we systematically assessed the cellular senescence of over 10,000 tumor samples from 33 cancer types, starting by defining a set of cancer-associated CS signatures and deriving a quantitative metric representing the CS status, called CS score. We then investigated the CS heterogeneity and its intricate relationship with the prognosis, immune infiltration, and therapeutic responses across different cancers. As a result, cellular senescence demonstrated two distinct prognostic groups: the protective group with eleven cancers, such as LIHC, and the risky group with four cancers, including STAD. Subsequent in-depth investigations between these two groups unveiled the potential molecular and cellular mechanisms underlying the distinct effects of cellular senescence, involving the divergent activation of specific pathways and variances in immune cell infiltrations. These results were further supported by the disparate associations of CS status with the responses to immuno- and chemo-therapies observed between the two groups. Overall, our study offers a deeper understanding of inter-tumor heterogeneity of cellular senescence associated with the tumor microenvironment and cancer prognosis.

Effects of a sedentary behaviour intervention in emergency dispatch centre phone operators: a study protocol for the SECODIS randomised controlled cross-over trial

IntroductionSedentary behaviour is a public health problem. We mainly have sedentary behaviour at work, transforming them into occupational risk. To our knowledge, there is no intervention study on the reduction...

Fairness-enhancing classification methods for non-binary sensitive features—How to fairly detect leakages in water distribution systems

Especially if artificial intelligence (AI)-supported decisions affect the society, the fairness of such AI-based methodologies constitutes an important area of research. In this contribution, we investigate the applications of AI to the socioeconomically relevant infrastructure of water distribution systems (WDSs). We propose an appropriate definition of protected groups in WDSs and generalized definitions of group fairness, applicable even to multiple non-binary sensitive features, that provably coincide with existing definitions for a single binary sensitive feature. We demonstrate that typical methods for the detection of leakages in WDSs are unfair in this sense. Further, we thus propose a general fairness-enhancing framework as an extension of the specific leakage detection pipeline, but also for an arbitrary learning scheme, to increase the fairness of the AI-based algorithm. Finally, we evaluate and compare several specific instantiations of this framework on a toy and on a realistic WDS to show their utility.

Pushing at the Boundaries of Pterin Chemistry.

Pterins are molecules of substantial interest as they occur in nature in a number of forms with quite distinct and often indispensable roles. Chemically, the synthesis of the principle pterin scaffold is comparably simple, while the insolubility of the pterin building block renders synthetic derivatization extremely difficult. When aiming at modeling naturally occurring pterins of extended chemical structure, this is a considerable problem. A notable set of strategies was developed in the course of the present study, which are able to overcome the lack of reactivity of the pterin backbone. These include a strategic choice regarding protection groups, uncommon chemical transformation, ball milling and combinations thereof. Some novel pterins with quite distinct substitution motifs were successfully synthesized and characterized by spectroscopic and spectrometric analyses as well as single-crystal structural analyses for three of them.

Vienna road crashes: a multivariate approach to understanding driver-related risks

Road safety is worldwide researched field where crashes play a causal role and injuries are counted as outcomes. Approaches and techniques are diverse, but with same goal—contribute to safer road environment for everyone included. Drivers of personal vehicles are the most protected traffic group due to protection provided by vehicle and mandatory safety belt in comparison to pedestrians as the most venerable participants. Also, this group of drivers is characterized by the high presence of very young drivers whose psychological characteristics place them in a vulnerable risky subgroup. According to the original data of the traffic police on crashes of personal car drivers in the town of Vienna, since 2010 they have had the highest number of crashes in 2012 and after slow decrease is recorded. Still high in total number of crashes involving only drivers of personal vehicles from a traffic safety point of view this still represents an extremely worrying problem that has not received proper social attention. In response to knowledge gaps, this research is essential to address leading characterizations in crashes with aim to answer what is trend in crash occurrence during 2010–2020 inside Vienna municipality, and what is predicted trend. Is there significant and distinctive difference based on gender and age with conditions under which crashes are occurring influencing different injury degree. Multiple regression undoubtedly points fields for action in statistically based findings providing the most important answer to this research: why there are so many injuries and what is leading cause of them. Answering this question contributes toward higher safety environment for all participants.

Early intravenous high-dose vitamin C in postcardiac arrest shock (VICEPAC): study protocol for a randomised, single-blind, open-label, multicentre, controlled trial

IntroductionThe high incidence of morbidity and mortality associated with the post-cardiac arrest (CA) period highlights the need for novel therapeutic interventions to improve the outcome of out-of-hospital cardiac arrest (OHCA)...

Safety and efficacy of apixaban versus warfarin in peritoneal dialysis patients with non-valvular atrial fibrillation: protocol for a prospective, randomised, open-label, blinded endpoint trial (APIDP2)

IntroductionSeveral randomised controlled trials have demonstrated that novel oral anticoagulants are safer compared with vitamin K antagonists for the management of non-valvular atrial fibrillation (NVAF) to prevent thromboembolic events in...

Synthetic Approaches, Properties, and Applications of Acylals in Preparative and Medicinal Chemistry.

Diesters of geminal diols (R-CH(O-CO-R')2, RR'C(OCOR″)2, etc. with R = H, aryl or alkyl) are termed acylals according to IUPAC recommendations (Rule P-65.6.3.6 Acylals) if the acids involved are carboxylic acids. Similar condensation products can be obtained from various other acidic structures as well, but these related "non-classical acylals", as one might call them, differ in various aspects from classical acylals and will not be discussed in this article. Carboxylic acid diesters of geminal diols play a prominent role in organic chemistry, not only in their application as protective groups for aldehydes and ketones but also as precursors in the total synthesis of natural compounds and in a variety of organic reactions. What is more, acylals are useful as a key structural motif in clinically validated prodrug approaches. In this review, we summarise the syntheses and chemical properties of such classical acylals and show what potentially under-explored possibilities exist in the field of drug design, especially prodrugs, and classify this functional group in medicinal chemistry.

The pro-drug C13 activates AMPK by two distinct mechanisms.

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is expressed in almost all eukaryotic cells. In the canonical activation mechanism, it is activated by increases in AMP:ATP and ADP:ATP ratios that signify declining cellular energy status. Once activated, AMPK phosphorylates numerous targets that promote catabolic pathways generating ATP, while inhibiting anabolic and other processes that consume ATP, thus acting to restore energy homeostasis. Pharmacological agents that activate AMPK have been useful in identifying downstream targets and have potential as drugs for treatment of metabolic disorders such as Type 2 diabetes and non-alcoholic fatty liver disease. One such agent is C13, a pro-drug with a phosphonate bis(isobutyryloxymethyl) ester moiety, with the isobutyryloxymethyl groups increasing membrane permeability. Following cellular uptake, C13 is cleaved to release C2, an AMP analogue and potent AMPK activator that is specific for complexes containing the α1 (but not the α2) catalytic subunit isoform. This has previously been assumed to be the sole mechanism by which C13 activates AMPK, with potential roles for the isobutyryloxymethyl groups being ignored. We now report that, following cleavage from C13, these protective groups are metabolized to formaldehyde, an agent that inhibits mitochondrial function and increases cellular AMP:ATP ratios, thus providing additional AMPK activation by the canonical mechanism.

Metal-Free Wet Chemistry for the Fast Gram-Scale Synthesis of γ-Graphyne and its Derivatives.

γ-Graphyne (GY), an emerging carbon allotrope, is envisioned to offer various alluring properties and broad applicability. While significant progress has been made in the synthesis of GY over recent decades, its widespread application hinges on developing efficient, scalable, and accessible synthetic methods for the production of GY and its derivatives. Here we report a facile metal-free nucleophilic crosslinking method using wet chemistry for fast gram-scale production of GY and its derivatives. This synthesis method involves the aromatic nucleophilic substitution reactions between fluoro-(hetero)arenes and alkynyl silanes in the presence of a catalytic amount of tetrabutylammonium fluoride, where the fluoride plays a crucial role in removing protective groups from alkynyl silanes and generating reactive alkynylides. Our comprehensive analysis of the as-prepared GY reveals a layered structure, characterized by the presence of the C(sp)-C(sp2) bond. The synthetic strategy shows remarkable tolerance to various functional groups and enables the preparation of diverse F-/N-rich GY derivatives, using electron-deficient fluoro-substituted (hetero)arenes as precursors. The feasibility of producing GY and derivatives from fluorinated (hetero)arenes through the metal-free, scalable, and cost-effective approach paves the way for broad applications of GY and may inspire the development of new carbon materials.

PSLBI-15 Effects of heat shock protein 70 on cell viability and protective capacity of serum against histone cytotoxicity

Abstract Bovine respiratory disease (BRD) is the most significant health problem associated with newly received cattle in the beef industry. Serum concentrations of extracellular histones increase in a variety of diseases and histones are known to be cytotoxic to mammalian cells. Work in our lab indicated that failure to protect against cytotoxic effects of extracellular histones may be a component of severe cases of respiratory disease in cattle. The mechanisms or proteins that neutralize cytotoxic effects of extracellular histones are not fully elucidated, but C-reactive protein and complement activity have been associated with a reduced cytotoxic effect of extracellular histones. Work in the literature suggests that heat shock protein 70 (HSP70) concentrations in the serum is increased in disease and may directly activate complement. Unpublished observations in our lab indicated that HSP70 potentially interacts with histones to exacerbate cytotoxicity leading to our hypothesis that increased concentrations of HSP70 will decrease the protective capacity against histone cytotoxicity. Therefore, the objectives of the current study were to evaluate serum concentrations of HSP70 in weaned bulls entering the feedlot and the effects of increasing HSP70 concentrations on histone cytotoxicity in vitro. Weaned seedstock bulls (n = 130) composed of various breeds were fed using the GrowSafe System at the Tucumcari Bull Test for 122 d. At receiving, blood samples were obtained via coccygeal venipuncture, centrifuged, and serum immediately frozen on dry ice. Serum was analyzed for complement activity (CH50 assay) and protective capacity against extracellular histones using our novel histone toxicity assay. The ratio value of histone toxicity to CH50 was used to separate a subset of bulls as protective (n = 10) and non-protective (n = 10). Concentrations of HSP70 were quantified utilizing a commercially available ELISA kit. Data were analyzed using the GLM procedure of SAS. Serum concentrations of HSP70 were similar (P > 0.10) for protective and non-protective bulls. To test the responses to increased concentrations of HSP70 to mimic disease, protective and non-protective serum was tested against histones alone and in combination with 0.5 or 40 ng/mL recombinant bovine HSP70. Complement activity from protective and non-protective bulls was not influenced (P > 0.10) in the presence and absence of recombinant bovine HSP70. Exogenous HSP70 at 0.5 or 40 ng/mL did not influence protective capacity in non-protective animals (P = 0.95). However, HSP70 at 0.5 ng/mL did not (P = 0.18) reduce protective capacity and reduced protective capacity (P < 0.01) at 40 ng/mL in serum from bulls that were assigned to the protective group. Results indicate that weaned bulls entering the feedlot display varied capacity to protect against histone toxicity and increased concentrations of HSP70 can reduce the protective capacity indicating that circulating HSP70 may play a role in bovine respiratory disease pathogenesis.

Emotional exhaustion weakens the relationship between social media use and knowledge sharing behavior

PurposeKnowledge sharing behavior is crucial for ensuring organizational success, fueling innovation, solving problems, and informing decision-making. While social media platforms offer powerful tools for employees to share knowledge, the intricate relationship between social media use and knowledge sharing behavior remains unclear. Few studies have examined the influencing mechanisms of emotional exhaustion on the above relationships, especially through self-determination perspective. Design/methodology/approachAs knowledge is inherently private to the individual, grounded in self-determination theory, this study employed a moderated mediation analysis to explore the internal mechanisms of social media use on employee knowledge sharing behavior. The survey of 356 full-time employees was collected from a large environmental protection group in China. Hypotheses are tested using hierarchical regression analysis and bootstrap tests. FindingsThe results show that social media use positively affects employee knowledge sharing behavior; knowledge sharing intention partially positively mediates the influence of social media use on knowledge sharing behavior; emotional exhaustion negatively moderates the relationship between social media use and knowledge sharing intention. Contribution of researchThe study identifies how two styles of social media use - work-related purpose and social-related purpose – affect knowledge sharing behavior. It significantly advances the understanding of social media use on knowledge sharing behavior from self-determination perspective. Practical implicationsThis study has several important practical implications for organizations seeking to facilitate employee knowledge sharing behavior through social media use. Organizations should improve employees' knowledge sharing intention and avoid emotional exhaustion.

Rotation or change of biotherapy after TNF blocker treatment failure for axial spondyloarthritis: the ROC-SpA study, a randomised controlled study protocol

IntroductionAxial spondyloarthritis (axSpA) is a chronic inflammatory disease characterised by inflammatory low back pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as a first treatment in axSpA. In case of inadequate...

Early life child protection contacts and developmental risk at age five: a whole-of-population cohort study of 479,413 children in two Australian states.

IntroductionChildren who experience maltreatment have worse health and development outcomes than other children. Early prevention relies on opportunities to respond to system contacts that reliably indicate the population burden of children’s future developmental risk. Objectives and ApproachWe quantified the population burden of developmental vulnerability at age five by the type, timing, and frequency of child protection contacts before school, among children in two Australian states. We used linked whole-population births, child protection and Australian Early Development Census (AEDC) data (2009-2018 cycles) in New South Wales (NSW) and South Australia (SA). Results56,650/398,702 (14%) NSW and 12,617/80,731 (16%) SA children had ≥1 child protection contacts before school. The risk of developmental vulnerability on ≥1 domains was lowest in the no child protection group (NSW, 17-18%; SA, 19%), with higher risks in the child protection report (NSW, 28-29%; SA, 32-35%) through to the OOHC (NSW, 35-38%; SA, 39-50%) groups, with a similar pattern for the risk of medically diagnosed conditions. Children with only one child protection report before school had a higher developmental risk than the no child protection group (NSW, 34% versus 21%; SA, 42% versus 24%). Conclusions/ImplicationsEven a single child protection report in the first 2000 days of children’s lives was a robust indicator of developmental risk at age five, with higher developmental risks among children with more serious child protection contacts before school. Child protection reports represent an under-utilised asset to inform early universal and targeted support from health, human and early education services.