The relative abundance of dimethylsulfoniopropionate (DMSP) among other zwitterions in branching coral at Heron Island, southern Great Barrier Reef.

Dimethylsulfoniopropionate (DMSP) and eleven other target zwitterions were quantified in the branch tips of six Acropora species and Stylophora pistillata hard coral growing on the reef flat surrounding Heron Island in the southern Great Barrier Reef (GBR), Australia. Hydrophilic interaction liquid chromatography mass spectrometry (HILIC-MS) was used for sample analysis with isotope dilution MS applied to quantify DMSP. The concentration of DMSP was ten times greater in A. aspera than A. valida, with this difference being maintained throughout the spring, summer and winter seasons. In contrast, glycine betaine was present in significantly higher concentrations in these species during the summer than the winter. Exposure of branch tips of A. aspera to air and hypo-saline seawater for up to 1 h did not alter the concentrations of DMSP present in the coral when compared with control samples. DMSP was the most abundant target zwitterion in the six Acropora species examined, ranging from 44-78% of all target zwitterions in A. millepora and A. aspera, respectively. In contrast, DMSP only accounted for 7% in S. pistillata, with glycine betaine and stachydrine collectively accounting for 88% of all target zwitterions in this species. The abundance of DMSP in the six Acropora species examined points to Acropora coral being an important source for the biogeochemical cycling of sulfur throughout the GBR, since this reef-building branching coral dominates the coral cover of the GBR. Graphical Abstract HILIC-MS extracted ion chromatogram showing zwitterionic metabolites from the branching coral Acropora isopora.

Quantification of dimethylsulfoniopropionate (DMSP) in Acropora spp. of reef-building coral using mass spectrometry with deuterated internal standard.

Dimethylsulfoniopropionate (DMSP) in scleractinian coral is usually analysed indirectly as dimethylsulfide (DMS) using gas chromatography (GC) with a sulfur-specific detector. We developed a headspace GC method for mass spectral analysis of DMSP in branching coral where hexa-deuterated DMSP (d 6 -DMSP) was added to samples and standards to optimise the analytical precision and quantitative accuracy. Using this indirect HS-GC-MS method, we show that common coral sample handling techniques did not alter DMSP concentrations in Acropora aspera and that endogenous DMS was insignificant compared to the store of DMSP in A. aspera. Field application of the indirect HS-GC-MS method in all seasons over a 5-year period at Heron Island in the southern Great Barrier Reef indicated that healthy colonies of A. aspera ordinarily seasonally conserve their branch tip store of DMSP; however, this store increased to a higher concentration under extended thermal stress conditions driven by a strong El Niño Southern Oscillation event. A liquid chromatography mass spectral method (LC-MS) was subsequently developed for direct analysis of DMSP in branching coral, also utilising the d 6 -DMSP internal standard. The quantitative comparison of DMSP in four species of Acropora coral by indirect HS-GC-MS and direct LC-MS analyses gave equivalent concentrations in A. aspera only; in the other three species, HS-GC-MS gave consistently higher concentrations, indicating that indirect analysis of DMSP may lead to artificially high values for some coral species. Graphical Abstract Dimethylsulfoniopropionate (DMSP) was quantified in Acropora spp. of branching coral using deuterated stable isotope dilution mass spectrometry.

Radiosynthesis and preliminary PET evaluation of (18)F-labeled 2-(1-(3-fluorophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)benzonitrile for imaging AMPA receptors.

To prompt the development of (18)F-labeled positron emission tomography (PET) tracers for the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, we have prepared (18)F-labeled 2-(1-(3-fluorophenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)benzonitrile ([(18)F]8). The radiosynthesis was achieved by a one-pot two-step method that utilized a spirocyclic hypervalent iodine(III) mediated radiofluorination to prepare the (18)F-labeled 1-bromo-3-fluorobenzene ([(18)F]15) intermediate with K(18)F. A subsequent copper(I) iodide mediated coupling reaction was carried out with 2-(2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl)benzonitrile (10) to [(18)F]8 in 10±2% uncorrected radiochemical yield relative to starting (18)F-fluoride with >99% radiochemical purity and 29.6±7.4Gbq/µmol specific activity at the time of injection. PET imaging studies with the title radiotracer in normal mice demonstrated good brain uptake (peak standardized uptake value (SUV)=2.3±0.1) and warrants further in vivo validation.

How Digital Solutions Might Provide a World of New Opportunities for Holistic and Empathic Support of Patients with Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a complex chronic relapsing inflammatory condition anchored in the hair follicle wherein painful abscesses, nodules, and tunnels form under the skin with the potential for intermittent pus drainage and tissue scarring. Current estimates of incidence are 1-4% globally with the disease three times more prevalent in women and higher rates among Black populations. Patients with HS are also more likely to suffer from depression, anxiety, and loneliness underscoring the need for carefully approached strategies on disease awareness and interventions. Delays in formal diagnosis, which have been estimated at 7-10 years on average, impede timely provision of optimal care. Despite best intent, when patients present at a physician's office, stigmas relating to physical appearance can be exacerbated by negative interactions experienced by patients. In addition to long wait times and the dearth of available HS expert dermatology professionals, patients perceive heightened physician focus on two of the HS flare risk factors (smoking and body mass index [BMI]) as negatively impacting their care. Given the need for continual, personal, and sensitive patient support, herein we advocate for re-examination of approach to care and the leveraging of highly personalized digital support solutions. New medications which can directly or indirectly control elements of the disease and its comorbidities are also entering the marketplace. Collectively, we posit that these new developments provide opportunity for a holistic approach for patients with HS, leading to long-term engagement and improved outcomes.

Extending the versatility of the Hemetsberger-Knittel indole synthesis through microwave and flow chemistry.

Microwave, flow and combination methodologies have been applied to the synthesis of a number of substituted indoles. Based on the Hemetsberger-Knittel (HK) process, modifications allow formation of products rapidly and in high yield. Adapting the methodology allows formation of 2-unsubstituted indoles and derivatives, and a route to analogs of the antitumor agent PLX-4032 is demonstrated. The utility of the HK substrates is further demonstrated through bioconjugation and subsequent ring closure and via Huisgen type [3+2] cycloaddition chemistry, allowing formation of peptide adducts which can be subsequently labeled with fluorine tags.

Design and evaluation of xanthine based adenosine receptor antagonists: potential hypoxia targeted immunotherapies.

Molecular modeling techniques were applied to the design, synthesis and optimization of a new series of xanthine based adenosine A(2A) receptor antagonists. The optimized lead compound was converted to a PEG derivative and a functional in vitro bioassay used to confirm efficacy. Additionally, the PEGylated version showed enhanced aqueous solubility and was inert to photoisomerization, a known limitation of existing antagonists of this class.

Physician centricity in the deployment of digital solutions for neurological conditions.

The widespread deployment of telemedical approaches to managed care during the CoV2 pandemic has provided an opportunity for clinicians to engage in the development and refinement of this mode of delivery. This also represents a pivotal moment to help effect a paradigm shift in how new and more sophisticated digital health services are designed and delivered with the caregiver playing a guiding role. Building on momentum this way can allow the fuller potential of digital health to be realized by focusing on "end user pull" which balances the omnipresent "technology push" of the consumer product and medical device industries. Perhaps nowhere is this more critical than in the care of neurological illnesses where patient-provider interactions must be managed frequently and rely on a complex battery of data measures. The emergent role of the physician-entrepreneur can be envisioned, complimenting established physician-scientist career paths and represents a timely and opportune moment to refine medical education curricula.

The economic imperatives for technology enabled wellness centered healthcare.

A 2020 World Health Organization report underscored the impact of rising healthcare spending globally and questioned the long-term economic sustainability of current funding models. Increases in costs associated with care of late-stage irreversible diseases and the increasing prevalence of debilitating neurodegenerative disorders, coupled with increases in life expectancy are likely to overload the healthcare systems in many nations within the next decade if not addressed. One option for sustainability of the healthcare system is a change in emphasis from illness to wellness centered care. An attractive model is the P4 (Predictive, Preventative, Personalized and Participatory) medicine approach. Recent advances in connected health technology can help accelerate this transition; they offer prediction, diagnosis, and monitoring of health-related parameters. We explain how to integrate such technologies with conventional approaches and guide public health policy toward wellness-based care models and strategies to relieve the escalating economic burdens of managed care.

Democratizing Global Health Care Through Scalable Emergent (Beyond the Mobile) Wireless Technologies.

Advances in mobile phone technologies coupled with the availability of modern wireless networks are beginning to have a marked impact on digital health through the growing array of apps and connected devices. That said, limited deployment outside of developed nations will require additional approaches to collectively reach the 8 billion people on earth. Another consideration for development of digital health centered around mobile devices lies in the need for pairing steps, firmware updates, and a variety of user inputs, which can increase friction for the patient. An alternate, so-called Beyond the Mobile approach where medicaments, devices, and health services communicate directly to the cloud offers an attractive means to expand and fully realize our connected health utopia. In addition to offering highly personalized experiences, such approaches could address cost, security, and convenience concerns associated with smartphone-based systems, translating to improved engagement and adherence rates among patients. Furthermore, connecting these Internet of Medical Things instruments through next-generation networks offers the potential to reach patients with acute needs in nonurban regions of developing nations. Herein, we outline how deployment of Beyond the Mobile technologies through low-power wide-area networks could offer a scalable means to democratize digital health and contribute to improved patient outcomes globally.

Internalization of a C17α-alkynylestradiol-porphyrin conjugate into estrogen receptor positive MCF-7 breast cancer cells.

We hypothesized that expression of nuclear estrogen receptor (ER) in hormone-sensitive breast cancer cells could be harnessed synergistically with the tumor-accumulating effect of porphyrins to selectively deliver estrogen-porphyrin conjugates into breast tumor cells, and preferentially kill tumor cells upon exposure to visible light. In this study we synthesized a conjugate of C(17α)-alkynylestradiol and pyropheophorbide and demonstrated that this conjugate is internalized by ER-positive MCF-7 cells while pyropheophorbide did not, suggesting an ER-mediated uptake and internalization of the conjugate by incipient nuclear ER in MCF-7 cells. This study is a direct demonstration of our hypothesis about ER-mediated internalization of estrogen-porphyrin conjugates.

Envisioning Post-pandemic Digital Neurological, Psychiatric and Mental Health Care.

The SARS-Cov-2 pandemic placed a dramatic burden on managed healthcare and perhaps nowhere as evident as in neurological and psychiatric disease care. This said, the duration of the pandemic mandated adaptability of the entire care system and the oft-vaunted benefits of telehealth and telemedicine were subjected to deep scrutiny at scale. Positive experiences were reported by both patients and providers from routine check-ups, to use of cognitive behavioral therapy associated with mental disorders, and management of complex diseases such as multiple sclerosis and other neurological and psychiatric conditions. Integration into standard care looks likely in the post pandemic era with many healthcare systems moving to expand reimbursement categories and develop equitable incentive models for developers and providers. In this commentary we share perspective on how the future of care may evolve through hybrid delivery models, and the advent of new therapeutic approaches which can address pain points identified during the pandemic.

An efficient route to xanthine based A(2A) adenosine receptor antagonists and functional derivatives.

A one-pot route to 8-substituted xanthines has been developed from 5,6-diaminouracils and carboxaldehydes. Yields are good and the process applicable to a range of substrates including a family of A(2A) adenosine receptor antagonists. A new route to the KW-6002 family of antagonists is presented including a pro-drug variant, and application to related image contrast agents developed.

Moving the Dial on Heart Failure Patient Adherence Rates.

INTRODUCTION: Heart failure remains a substantive contributor to patient morbidity and mortality rates worldwide and represents a significant burden on the healthcare ecosystem. Faced with persistent physical symptoms and debilitating social consequences, patients follow complex treatment regimens and often have difficulty adhering to them. PURPOSE: In this manuscript, we review factors which contribute to low adherence rates and advance potential single- and multi-factor-based interventions. It is hoped that these observations can lead to improvements in managed care of this vulnerable population of patients. METHODS: A narrative review of the primary literature was performed on contributing factors with primary focus on the period 2015-2020 using available databases and search engines. Adherence pain points identified were mapped against a series of potential solutions which are presented. RESULTS: Enhancement of treatment adherence relies on two approaches viz. single-factor and multi-factor solutions. Single factors identified include electronic reminders, enhanced health education, financial incentives, gamification strategies, community drivers, persona-based modeling, and burden relief of poly pharmacy. Multi-factor solutions combine two or more of the seven approaches offering the potential for flexible interventions tailored to the individual. DISCUSSION AND CONCLUSION: Heart failure patients with poor adherence have increased mortality, hospitalization needs, and healthcare costs. This review highlights current single-factor and multi-factor adherence methods. Against a backdrop of diversity of approaches, multi-factor solutions cast the widest net for positively influencing adherent behaviors. A key enabler lies in the development and leveraging of patient personas in the synthesis of successful intervention methods. Deployable solutions can also be envisioned in clinical trials where adherence tracking represents an essential component.

Designed DNA probes from the neocarzinostatin family: impact of glycosyl linkage stereochemistry on bulge base binding.

Bulged sites in DNA and RNA have become targets for rational drug design due to their suspected involvement in a number of key biomolecular processes. A lead compound, derived from the enediyne natural product NCS-chrom has been used to inform chemical synthesis of a family of designed probes of DNA bulges, one of which shows 80 nM affinity for a two base bulged target. Key contributors to binding of these spirocyclic compounds have been studied in order to correlate affinity and specificity with structural features. Herein, we demonstrate that the glycosyl linkage stereochemistry of the pendant aminofucosyl group plays a pivotal role in binding, and coupled with insight obtained with various bulged targets, will allow rational design of second generation ligands.

Synthesis, functionalization and photo-Bergman chemistry of enediyne bioconjugates.

Methodology is outlined for the chemical synthesis of versatile photo-Bergman enediyne building blocks and their conjugates. Routes to both mono and bis conjugated enediyne templates are detailed together with representative examples of their bioconjugates, nanoconjugates, PEG derivatives and water soluble salts. The immunocompetence of antibody conjugates is retained, and application in the form of reagents for photodynamic therapy (PDT) advanced.

Surface flux and vertical profile of dimethyl sulfide in acid sulfate soils at Cudgen Lake, northern New South Wales, Australia.

A dimethyl sulfide (DMS) vertical concentration profile and DMS surface emission flux were quantified in undisturbed acid sulfate soils (ASS) at Cudgen Lake on the north coast of New South Wales, Australia. A deuterated internal standard was used to account for soil adsorption characteristics. The DMS vertical concentration profile increased exponentially from 0.6 m depth to the surface layer. This profile reflected the adsorption properties of the ASS horizons present and the experimentally determined octanol/water partition coefficient for DMS of 1.36, suggesting that DMS would be mobilised in the soil water medium for upward translocation in time due to surface evaporation. The organic material in the oxidised ASS crustal layer had a chemically strong adsorption affinity for DMS, which appeared to restrain its emission from surface soil particles to the atmosphere. The seasonally averaged DMS surface flux estimate from the Cudgen Lake ASS was 9 ng S m-2 min-1, which is relatively low by comparison to DMS fluxes reported from other wetland soils such as salt-marshes and acidic peat bogs. The worldwide annual average DMS emission from ASS was estimated to be 1.14 × 10-3 Tg S, which is globally insignificant by comparison to DMS emission from the world's oceans.

Digital biomarkers for Alzheimer's disease: the mobile/ wearable devices opportunity.

Alzheimer's Disease (AD) represents a major and rapidly growing burden to the healthcare ecosystem. A growing body of evidence indicates that cognitive, behavioral, sensory, and motor changes may precede clinical manifestations of AD by several years. Existing tests designed to diagnose neurodegenerative diseases, while well-validated, are often less effective in detecting deviations from normal cognitive decline trajectory in the earliest stages of the disease. In the quest for gold standards for AD assessment, there is a growing interest in the identification of readily accessible digital biomarkers, which harness advances in consumer grade mobile and wearable technologies. Topics examined include a review of existing early clinical manifestations of AD and a path to the respective sensor and mobile/wearable device usage to acquire domain-centric data towards objective, high frequency and passive digital phenotyping.

Photoactivated enediynes as targeted antitumoral agents: efficient routes to antibody and gold nanoparticle conjugates.

Efficient syntheses of a series of functionalized aryl enediynes have been developed. The building blocks were used to effect conjugation to carrier PEG templates which allowed subsequent coupling to a cardiac targeted monoclonal antibody. Immunocompetence of the enediyne-Mab conjugates was demonstrated by ELISA, and both parent enediynes and bioconjugates underwent successful photo-Bergman cyclization. Finally, surface modified (Au) nanoparticle conjugates were prepared and size confirmed by TEM analysis. Application as long-circulating photoactivated prodrugs is anticipated.

Harnessing the Digital Exhaust: Incorporating wellness into the pharma model.

The increasing availability of devices capable of tracking biomarkers presents major opportunities in contemporary healthcare. Herein we advocate a new role for the pharmaceutical industry to capitalize on these opportunities and in doing so incorporate wellness and patient engagement programs into their standard business models. Medical grade decision making using diagnostic, prognostic, and monitoring biomarkers will require coordinated approaches between the pharmaceutical and technology industries and the careful design of longitudinal clinical studies to validate their efficacy. These studies will also require data capture, archiving, curating and sharing on a previously unprecedented scale, and raise additional concerns with regard to data security and ownership. Concurrently, systems-based approaches to the capture and interpretation of a new class of digital biomarkers are emerging, and hold promise for heightened levels of patient engagement and remote sensing. Collectively, if these new opportunities are approached within the context of the patient-provider ecosystem, major repositioning of the pharmaceutical industry may be possible in the near term.