Multicomponent Synthesis of α-Branched Amines via a Zinc-Mediated Carbonyl Alkylative Amination Reaction.

Methods for the synthesis of α-branched alkylamines are important due to their ubiquity in biologically active molecules. Despite the development of many methods for amine preparation, C(sp3)-rich nitrogen-containing compounds continue to pose challenges for synthesis. While carbonyl reductive amination (CRA) between ketones and alkylamines is the cornerstone method for α-branched alkylamine synthesis, it is sometimes limited by the sterically demanding condensation step between dialkyl ketones and amines and the more restricted availability of ketones compared to aldehydes. We recently reported a "higher-order" variant of this transformation, carbonyl alkylative amination (CAA), which utilized a halogen atom transfer (XAT)-mediated radical mechanism, enabling the streamlined synthesis of complex α-branched alkylamines. Despite the efficacy of this visible-light-driven approach, it displayed scalability issues, and competitive reductive amination was a problem for certain substrate classes, limiting applicability. Here, we report a change in the reaction regime that expands the CAA platform through the realization of an extremely broad zinc-mediated CAA reaction. This new strategy enabled elimination of competitive CRA, simplified purification, and improved reaction scope. Furthermore, this new reaction harnessed carboxylic acid derivatives as alkyl donors and facilitated the synthesis of α-trialkyl tertiary amines, which cannot be accessed via CRA. This Zn-mediated CAA reaction can be carried out at a variety of scales, from a 10 µmol setup in microtiter plates enabling high-throughput experimentation, to the gram-scale synthesis of medicinally-relevant compounds. We believe that this transformation enables robust, efficient, and economical access to α-branched alkylamines and provides a viable alternative to the current benchmark methods.

Stories or Directives: A Cross Cultural Comparison of Governmental Messages to Their Constituents during COVID-19.

This cross-sectional investigation examines the message strategies employed by the CDC and the NHC regarding the COVID-19 pandemic and established that messages sent by the CDC via Twitter differed significantly from the messages posted by the NHC via Weibo. Within a random sample (n = 200) of CDC and NHC messaging, six common themes emerged. They were: offering general advice, offering advice for professionals, pandemic progress, organizational efforts, knowledge popularization, and event notification. Results suggest the CDC offered advice to the general public (n = 50) more often than the NHC (n = 19). Similarly, the CDC offered more advice oriented toward professionals (n = 20) than the NHC (n = 9). The NHC, was more likely to discuss the role of government in remedying the pandemic (n = 12) than the CDC (n = 0) and more likely to employ a narrative style in their messaging (n = 35) than the CDC (n = 1).

Patient accounts for nonadherence: A critical window into the patient experience.

OBJECTIVES: This paper explores patient use of excuses to better understand the patient experience during clinical interactions. METHODS: A content analysis of 32 residents treating 99 different patients was used to reveal accounts of nonadherence. Using grounded theory, these accounts were coded into types and then reduced using a Q-sort. RESULTS: Analysis revealed 163 accounts of nonadherence. When questioned about their adherence to treatment, 68% of patients offered at least one account for nonadherence during the visit. These accounts were coded into fourteen types and then the Q-sort identified four types of accounts: healthcare system failures, treatment failure, situational exigencies, and self-directed. Of the accounts offered, 7% of the patients provided 6 or more accounts and 25% provided between 3 and 5 accounts. CONCLUSIONS: The examination of excuses provides a unique way to gain insight into how patients communicate with their physicians. Patient accounts ranged from those where patients indicated adherence was within their control (self-directed) and accounts outside their control (healthcare system failure, treatment failure, and situational exigency). PRACTICE IMPLICATIONS: The types of accounts of nonadherence patients could provide doctors insight into the patient experience. Recognizing these types could allow opportunities for doctors to develop communication strategies for encouraging patient adherence.

Correction to: Human ovarian cancer intrinsic mechanisms regulate lymphocyte activation in response to immune checkpoint blockade.

The original version of this article unfortunately contained a mistake. Complete figure captions are missing.

Human ovarian cancer intrinsic mechanisms regulate lymphocyte activation in response to immune checkpoint blockade.

Immune checkpoint blocking antibodies are currently being tested in ovarian cancer (OC) patients and have shown some responses in early clinical trials. However, it remains unclear how human OC cancer cells regulate lymphocyte activation in response to therapy. In this study, we have established and optimised an in vitro tumour-immune co-culture system (TICS), which is specifically designed to quantify the activation of multiple primary human lymphocyte subsets and human cancer cell killing in response to PD-1/L1 blockade. Human OC cell lines and treatment naïve patient ascites show differential effects on lymphocyte activation and respond differently to PD-1 blocking antibody nivolumab in TICS. Using paired OC cell lines established prior to and after chemotherapy relapse, our data reveal that the resistant cells express low levels of HLA and respond poorly to nivolumab, relative to the treatment naïve cells. In accordance, knockdown of IFNγ receptor expression compromises response to nivolumab in the treatment naïve OC cell line, while enhanced HLA expression induced by a DNA methyltransferase inhibitor promotes lymphocyte activation in TICS. Altogether, our results suggest a 'cross resistance' model, where the acquired chemotherapy resistance in cancer cells may confer resistance to immune checkpoint blockade therapy through down-regulation of antigen presentation machinery. As such, agents that can restore HLA expression may be a suitable combination partner for immunotherapy in chemotherapy-relapsed human ovarian cancer patients.

The Relationship between Emotional and Esteem Social Support Messages and Health.

The purpose of this investigation is to determine the relative contribution of five types of social support to improved patient health. This analysis suggests that emotional and esteem social support messages are associated with improved patient health as measured by a decrease in average blood glucose levels among diabetic patients. In addition, when two system feature variables, two system use variables, two measures of learning, one measure of self-efficacy, and one measure of affect toward their HCP were added to the baseline model, a third significant factor emerged. Perceptions about learning about diabetes from reading the digital messages sent by their HCP also predicted improved patient health. Cognitive-Emotional Theory of Esteem Support Messages suggests a combination of esteem social support and emotional social support messages enhanced our ability to predict improved patient health by change in patient hemoglobin A1c (HbA1c) scores. While a nonrandomized prospective study, this investigation provides support for the notion that provider-patient interaction is related to improved patient health and that both emotional and esteem social support messages play a role in that process. Finally, the study suggests some types of social support are and other types are not associated with improved patient health; this is consistent with the optimal matching hypothesis.

Predictors of Cell Phone Use in Distracted Driving: Extending the Theory of Planned Behavior.

This study examines the predictors of six distracted driving behaviors, and the survey data partially support Ajzen's (1991) Theory of Planned Behavior (TPB). The data suggest that the attitude variable predicted intention to engage in all six distracted driving behaviors (reading and sending text messages, making and answering cell phone calls, reading/viewing social media, and posting on social media while driving). Extending the model to include past experience and the variable perceived safety of technology yielded an improvement in the prediction of the distraction variables. Specifically, past experience predicted all six distracted driving behaviors, and the variable perceived safety of technology predicted intentions to read/view social media and intention to post on social media while driving. The study provides evidence for the importance of incorporating expanded variables into the original TPB model to predict cell phone use behaviors while driving, and it suggests that it is essential to tailor campaign materials for each specific cell phone use behavior to reduce distracted driving.

What Residents Say About Communicating with Patients: A Preliminary Examination of Doctor-to-Doctor Interaction.

This article describes the implementation and initial assessment of a training blog created within a family medicine department and used as a feedback mechanism for residents. First-year residents (n = 7) at a large private East Coast university hospital had an interaction with a patient recorded and posted to a training blog. The residents then watched this, and posted a reaction to their interaction with the patient. Within this reaction the residents offered self-reflection on the experience and were provided an opportunity to solicit advice from their colleagues to improve their communicative strategies and style. Once the reaction was posted to the blog, other residents watched the videotaped interaction, read the self-assessment written by the resident, and responded as part of their communication training. Content analysis of the messages suggests that the residents are socially skilled. They offer each other advice, provide each other with emotional and esteem social support, and use techniques such as self-deprecation in what appears to be a strategic manner. Perhaps most interesting is that they tend to identify the problems and difficulties they experience during patient-physician interactions in an apparent effort to deflect responsibility from the practicing physician. Patient challenges raised by residents included talkativeness, noncompliance, health literacy, and situational constraints.

The orexin 1 receptor modulates kappa opioid receptor function via a JNK-dependent mechanism.

The orexin 1 receptor (OX1R) and the kappa opioid receptor (KOR) are two G protein-coupled receptors (GPCRs) previously demonstrated to play important roles in modulating the rewarding effects of drugs of abuse such as cocaine. Using cells heterologously expressing both receptors, we investigated whether OX1R can regulate the function of KOR and vice versa. Activation of OX1R was found to attenuate agonist-activated KOR-mediated inhibition of cAMP production. In contrast, agonist-activated KOR-mediated ß-arrestin recruitment and p38 activation were enhanced in the presence of activated OX1R. These effects are independent of OX1R internalization but are blocked in the presence of the JNK inhibitor SP-600125. OX1R signaling does not affect ligand binding by KOR. Taken together, these data suggest that OX1R signaling can modulate KOR function in a JNK-dependent manner, promoting preferential signaling of KOR via ß-arrestin/p38 rather than Gαi. Conversely, Gαq coupling of OX1R is unaffected by activation of KOR, suggesting that this crosstalk is unidirectional. Given that KOR Gαi-mediated signaling events and ß-arrestin-mediated signaling events are thought to promote distinct cellular responses and physiological outcomes downstream of KOR activation, this mechanism may have important implications on the behavioral effects of KOR activity.

Patient Perceptions of Acute Care Telemedicine: A Pilot Investigation.

This investigation focuses on the patient perceptions of the interaction that occurs during acute telemedical care in an emergency department and the effectiveness of this technology. Data indicate 95% of the patients were seen by a specialist within 15 minutes of arriving at the emergency room and fewer than 12% reported experiencing a technical problem (n = 150). Further, 80% of the patients indicated that they were satisfied with level of concern communicated to them by the specialist and 80% were satisfied with the explanation of their medical condition. Finally, 80% of the patients believed the use of telemedicine was a positive factor in the diagnostic process and 80% were reported being satisfied with their overall treatment.

Media complementarity and health information seeking in Puerto Rico.

This investigation incorporates the Orientation1-Stimulus-Orientation2-Response model on the antecedents and outcomes of individual-level complementarity of media use in health information seeking. A secondary analysis of the Health Information National Trends Survey Puerto Rico data suggests that education and gender were positively associated with individual-level media complementarity of health information seeking, which, in turn, was positively associated with awareness of health concepts and organizations, and this awareness was positively associated with a specific health behavior: fruit and vegetable consumption. This study extends the research in media complementarity and health information use; it provides an integrative social psychological model empirically supported by the Health Information National Trends Survey Puerto Rico data.

G protein-coupled receptor kinase 2 (GRK2) is a Rho-activated scaffold protein for the ERK MAP kinase cascade.

The G protein-coupled receptor kinases (GRKs) are best known for their role in phosphorylating and desensitising G protein-coupled receptors (GPCRs). The GRKs also regulate signalling downstream of other families of receptors and have a number of non-receptor substrates and binding partners. Here we identify RhoAGTP and Raf1 as novel binding partners of GRK2 and report a previously unsuspected function for this kinase. GRK2 is a RhoA effector that serves as a RhoA-activated scaffold protein for the ERK MAP kinase cascade. The ability of GRK2 to bind to Raf1, MEK1 and ERK2 is dependent on RhoAGTP binding to the catalytic domain of the kinase. Exogenous GRK2 has previously been shown to increase ERK activation downstream of the epidermal growth factor receptor (EGFR). Here we find that GRK2-mediated ERK activation downstream of the EGFR is Rho-dependent and that treatment with EGF promotes RhoAGTP binding and ERK scaffolding by GRK2. Depletion of GRK2 expression by RNAi reveals that GRK2 is required for EGF-induced, Rho- and ERK-dependent thymidine incorporation in vascular smooth muscle cells (VSMCs). We therefore hypothesise that Rho-dependent ERK MAPK scaffolding by GRK2 downstream of the EGFR may have an important role in the vasculature, where increased levels of both GRK2 and RhoA have been associated with hypertension.

Distinct structural features of G protein-coupled receptor kinase 5 (GRK5) regulate its nuclear localization and DNA-binding ability.

G protein-coupled receptor kinases (GRKs) act to desensitize G protein-coupled receptors (GPCRs). In addition to this role at the plasma membrane, a nuclear function for GRK5, a member of the GRK4 subfamily of GRKs, has been reported. GRK5 phosphorylates and promotes the nuclear export of the histone deacetylase, HDAC5. Here we demonstrate that the possession of a nuclear localization sequence (NLS) is a common feature of GRK4 subfamily members (GRKs 4, 5 and 6). However, the location of the NLS and the ability of these GRKs to bind DNA in vitro are different. The NLSs of GRK5 and 6 bind DNA in vitro, whilst the NLS of GRK4 does not. Using mutants of GRK5 we identify the regions of GRK5 required for DNA-binding in vitro and nuclear localization in cells. The DNA-binding ability of GRK5 requires both the NLS and an N-terminal calmodulin (CaM)-binding site. A functional nuclear export sequence (NES), required for CaM-dependent nuclear export of the kinase, is also identified. Based on our observations we propose a model to explain how nuclear localization of GRK5 may be regulated. Notably, the nuclear localization of GRK5 and 6 is differentially regulated. These results suggest subfamily specific nuclear functions for the GRK4 subfamily members. Identification of GRK specific small molecule inhibitors of nuclear localization and/or function for the GRK4 subfamily may thus be an achievable goal.

Expanding the walls of the health care encounter: support and outcomes for patients online.

This paper assesses the relationship between patient-health care provider (HCP) interaction and health behaviors. In total, 109 Native American patients diagnosed with diabetes mellitus were enrolled in a Web-based diabetes monitoring system. The system tracks patient-HCP interaction, and in total 924 personal messages were exchanged. These 924 messages contained 6,411 message units that were content analyzed using a nine-category scheme. Patient blood glucose monitoring was found to be related to the frequency of phatic communication, informational social support, and tangible social support messages, as well as messages containing references to personal contact. Finally, person-centered messages proved to be the single best predictor of patient involvement with the telemedicine system (as measured by the number of times the patient logged into the system).