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Thieno[3,4-d]pyrimidin-4(3H)-thione: An Effective, Oxygenation Independent, Heavy-Atom-Free Photosensitizer for Cancer Cells
Get PDFAll-organic, heavy-atom-free photosensitizers based on thionation of nucleobases are receiving increased attention because they are easy to make, noncytotoxic, work both in the presence and absence of molecular oxygen, and can be readily incorporated into DNA and RNA. In this contribution, the DNA and RNA fluorescent probe, thieno[3,4-d]pyrimidin-4(1H)-one, has been thionated to develop thieno[3,4-d]pyrimidin-4(3H)-thione, which is nonfluorescent and absorbs near-visible radiation with about 60% higher efficiency. Steady-state absorption and emission spectra are combined with transient absorption spectroscopy and CASPT2 calculations to delineate the electronic relaxation mechanisms of both pyrimidine derivatives in aqueous and acetonitrile solutions. It is demonstrated that thieno[3,4-d]pyrimidin-4(3H)-thione efficiently populates the long-lived and reactive triplet state generating singlet oxygen with a quantum yield of about 80% independent of solvent. It is further shown that thieno[3,4-d]pyrimidin-4(3H)-thione exhibits high photodynamic efficacy against monolayer melanoma cells and cervical cancer cells both under normoxic and hypoxic conditions. Our combined spectroscopic, computational, and in vitro data demonstrate the excellent potential of thieno[3,4-d]pyrimidin-4(1H)-thione as a heavy-atom-free PDT agent and paves the way for further development of photosensitizers based on the thionation of thieno[3,4-d]pyrimidine derivatives. Collectively, the experimental and computational results demonstrate that thieno[3,4-d]pyrimidine-4(3H)-thione stands out as the most promising thiobase photosensitizer developed to this date
Facilitators and Barriers to Reunification among Housing Unstable Families
Get PDFHousing unstable families with child welfare system involvement face multiple challenges to successfully reunifying with their families. This explanatory qualitative study followed up on findings from a county-sponsored Pay for Success (PFS) RCT. The study focused on understanding the facilitators and barriers to reunification, bringing together the perspectives of a random sample of 16 housing-unstable caregivers whose children were in foster care, their PFS program workers, and their child welfare caseworkers. We conducted in-depth, in-person interviews with 52 participants. Major facilitators of reunification included strong client motivation, PFS program workers empowering and advocating for clients, the program\u27s ability to meet clients’ basic needs, and PFS program worker/child welfare worker collaboration. The barriers participants identified included the clients’ complex and continuing challenges and crises, limited and/or toxic social support systems, and systemic issues within the court and child welfare systems, including evaluations of worthiness and a failure to collaborate. We explore findings regarding their contribution to the literature on housing unstable families involved with child welfare and implications for practice, policy, and research
Fabrication Methods and Chronic In Vivo Validation of Mechanically Adaptive Microfluidic Intracortical Devices
Get PDFIntracortical neural probes are both a powerful tool in basic neuroscience studies of brain function and a critical component of brain computer interfaces (BCIs) designed to restore function to paralyzed patients. Intracortical neural probes can be used both to detect neural activity at single unit resolution and to stimulate small populations of neurons with high resolution. Unfortunately, intracortical neural probes tend to fail at chronic timepoints in large part due to the neuroinflammatory response that follows implantation and persistent dwelling in the cortex. Many promising approaches are under development to circumvent the inflammatory response, including the development of less inflammatory materials/device designs and the delivery of antioxidant or anti-inflammatory therapies. Here, we report on our recent efforts to integrate the neuroprotective effects of both a dynamically softening polymer substrate designed to minimize tissue strain and localized drug delivery at the intracortical neural probe/tissue interface through the incorporation of microfluidic channels within the probe. The fabrication process and device design were both optimized with respect to the resulting device mechanical properties, stability, and microfluidic functionality. The optimized devices were successfully able to deliver an antioxidant solution throughout a six-week in vivo rat study. Histological data indicated that a multi-outlet design was most effective at reducing markers of inflammation. The ability to reduce inflammation through a combined approach of drug delivery and soft materials as a platform technology allows future studies to explore additional therapeutics to further enhance intracortical neural probes performance and longevity for clinical applications
Validation of a New Species for Studying Postoperative Atrial Fibrillation: Swine Sterile Pericarditis Model
Get PDFBackground: The canine sterile pericarditis model associated with atrial inflammation is an experimental counterpart of postoperative atrial fibrillation (POAF). However, the use of canines for research is restricted by ethics committees in many countries, and social acceptance is declining. Objective: To validate the feasibility of the swine sterile pericarditis model as an experimental counterpart to study POAF. Methods: Seven domestic pigs (35–60 kg) underwent initial pericarditis surgery. On two or more postoperative days in the closed‐chest state, we performed electrophysiological measurements of pacing threshold and atrial effective refractory period (AERP) while pacing from the right atrial appendage (RAA) and the posterior left atrium (PLA). The inducibility of POAF (\u3e5 min) by burst pacing was determined in both the conscious and anesthetized closed‐chest state. These data were compared to previously published canine sterile pericarditis data for validation. Results: The pacing threshold increased from day 1 to day 3 (2 ± 0.1 to 3.3 ± 0.6 mA in the RAA, 2.5 ± 0.1 to 4.8 ± 0.2 mA in the PLA). Also, the AERP increased from day 1 to day 3 (118 ± 8 to 157 ± 16 ms in the RAA; 98 ± 4 to 124 ± 2 ms in the PLA, both p \u3c .05). Induction of sustained POAF occurred in 43% (POAF CL range 74–124 ms). All electrophysiologic data from the swine model were consistent with the canine model with respect to (1) the range of both pacing threshold and AERP; (2) the progressive increase in threshold and AERP over time; (3) a 40%–50% incidence of POAF. Conclusion: A newly developed swine sterile pericarditis model demonstrated electrophysiologic properties consistent with the canine model and patients after open heart surgery
Superfluid Dark Matter in Tension with Weak Gravitational Lensing Data
Get PDFSuperfluid dark matter (SFDM) is a model that promises to reproduce the successes of both particle dark matter on cosmological scales and those of Modified Newtonian Dynamics (MOND) on galactic scales. SFDM reproduces MOND only up to a certain distance from the galactic center, and only for kinematic observables: it does not affect trajectories of light. We test whether this is consistent with a recent analysis of weak gravitational lensing that has probed accelerations around galaxies to unprecedentedly large radii. This analysis found the data to be close to the prediction of MOND, suggesting they might be difficult to fit with SFDM. To investigate this matter, we solved the equations of motion of the model and compared the result to observational data. Our results show that the SFDM model is incompatible with the weak-lensing observations, at least in its current form
Can I Count on You? Social support, Depression and Suicide Risk
Get PDFObjectives: Interpersonal factors play an important role in the etiology and treatment of depression. Social support derives from compassionate words and helpful actions provided by family, friends or a significant other. The present study was designed to examine various sources of social support as they relate to the severity of depressive symptoms, hopelessness and suicide risk in adult psychiatric outpatients. Method: Participants were recruited through mental health clinics at a veteran\u27s affairs medical centre. A total of 96 depressed patients were assessed using a diagnostic interview and self-report measures of depression severity, hopelessness and social support. Among these depressed adults, 45.8% had attempted suicide at least once. Social support variables were compared between suicide attempters and non-attempters to better understand the relationship between social support and suicidal behaviour. Results: Depression severity and hopelessness were both significantly associated with lower levels of social support in multiple areas. Individuals with a history of suicide attempt reported lower levels of available support as compared to those who have never attempted suicide. Conclusion: Deficient social relationships increase the risk of suicide in depressed patients, exceeding the impact of depression alone on suicide risk. The lack of social support may play a vital role in feelings of hopelessness and isolation that contribute to a suicidal crisis. Psychosocial treatment should be considered to reduce the risk of suicide and severity of depression by strengthening social support and bolstering interpersonal relationships
Classical American Pragmatism as Antiscientism
Get PDFScientism has recently experienced a resurgence of interest in philosophy. One version of scientism often defended is ontological scientism—the view that any kind or property not mentioned in the theories of science has only a subordinate, secondary kind of reality. It is worth noting that a dominant tradition in the history of philosophy of science—classical American pragmatism—undertook decades of critical engagement with contemporaneous scientistic beliefs, many of which resemble those being debated at the present time. This antiscientistic philosophy has multiple points of relevance for contemporary debates and defenses of ontological scientism
Minimal Auxiliary Basis Set Approach for the Electronic Excitation Spectra of Organic Molecules
Get PDFWe report a minimal auxiliary basis model for time-dependent density functional theory (TDDFT) with hybrid density functionals that can accurately reproduce excitation energies and absorption spectra from TDDFT while reducing cost by about \change{two} orders of magnitude. Our method, dubbed TDDFT-ris, employs the resolution-of-the-identity technique with just one -type auxiliary basis function per atom for the linear response operator, where the Gaussian exponents are parametrized across the periodic table using %using tabulated atomic radii with a single global scaling factor. By tuning on a small test set, we determine a single functional-independent scale factor that balances errors in excitation energies and absorption spectra. Benchmarked on organic molecules and compared to standard TDDFT, TDDFT-ris has an average energy error of only 0.06 eV, and yields absorption spectra in close agreement with TDDFT. Thus, TDDFT-ris enables simulation of realistic absorption spectra in large molecules that would be inaccessible from standard TDDFT
The Self-Work of Planetary Justice
Get PDFA necessary part of planetary justice is self-work, restoring or forming our being truthful, consistent, dependable, and accountable people. Planetary justice – so far typically associated with vast, geological scales of space and time – involves an intimate dimension, too. We can work on it wherever we are. Moreover, self-work and planetary justice intertwine historically and conceptually. The historical context for self-work involves the histories of violence that led to the breakthrough of the planetary as a category of thought about justice. Facing this, the essay notes areas for further reflection, study, and action
Prediction of Kinase-Substrate Associations Using The Functional Landscape of Kinases and Phosphorylation Sites
Get PDFProtein phosphorylation is a key post-translational modification that plays a central role in many cellular processes. With recent advances in biotechnology, thousands of phosphorylated sites can be identified and quantified in a given sample, enabling proteome-wide screening of cellular signaling. However, for most (\u3e 90%) of the phosphorylation sites that are identified in these experiments, the kinase(s) that target these sites are unknown. To broadly utilize available structural, functional, evolutionary, and contextual information in predicting kinase-substrate associations (KSAs), we develop a network-based machine learning framework. Our framework integrates a multitude of data sources to characterize the landscape of functional relationships and associations among phosphosites and kinases. To construct a phosphosite-phosphosite association network, we use sequence similarity, shared biological pathways, co-evolution, co-occurrence, and co-phosphorylation of phosphosites across different biological states. To construct a kinase-kinase association network, we integrate protein-protein interactions, shared biological pathways, and membership in common kinase families. We use node embeddings computed from these heterogeneous networks to train machine learning models for predicting kinase-substrate associations. Our systematic computational experiments using the PhosphositePLUS database shows that the resulting algorithm, NetKSA, outperforms two state-of-the-art algorithms, including KinomeXplorer and LinkPhinder, in overall KSA prediction. By stratifying the ranking of kinases, NetKSA also enables annotation of phosphosites that are targeted by relatively less-studied kinases. Availability: The code and data are available at compbio.case.edu/NetKSA/
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