The three-dimensional positions of atoms in protein molecules define their structure and their roles in biological processes. The more precisely atomic coordinates are determined, the more chemical ...information can be derived and the more mechanistic insights into protein function may be inferred. Electron cryo-microscopy (cryo-EM) single-particle analysis has yielded protein structures with increasing levels of detail in recent years
. However, it has proved difficult to obtain cryo-EM reconstructions with sufficient resolution to visualize individual atoms in proteins. Here we use a new electron source, energy filter and camera to obtain a 1.7 Å resolution cryo-EM reconstruction for a human membrane protein, the β3 GABA
receptor homopentamer
. Such maps allow a detailed understanding of small-molecule coordination, visualization of solvent molecules and alternative conformations for multiple amino acids, and unambiguous building of ordered acidic side chains and glycans. Applied to mouse apoferritin, our strategy led to a 1.22 Å resolution reconstruction that offers a genuine atomic-resolution view of a protein molecule using single-particle cryo-EM. Moreover, the scattering potential from many hydrogen atoms can be visualized in difference maps, allowing a direct analysis of hydrogen-bonding networks. Our technological advances, combined with further approaches to accelerate data acquisition and improve sample quality, provide a route towards routine application of cryo-EM in high-throughput screening of small molecule modulators and structure-based drug discovery.
Provision of high quality transitional care is a challenge for health care providers in many western countries. This systematic review was conducted to (1) identify and synthesise research, using ...randomised control trial designs, on the quality of transitional care interventions compared with standard hospital discharge for older people with chronic illnesses, and (2) make recommendations for research and practice.
Eight databases were searched; CINAHL, Psychinfo, Medline, Proquest, Academic Search Complete, Masterfile Premier, SocIndex, Humanities and Social Sciences Collection, in addition to the Cochrane Collaboration, Joanna Briggs Institute and Google Scholar. Results were screened to identify peer reviewed journal articles reporting analysis of quality indicator outcomes in relation to a transitional care intervention involving discharge care in hospital and follow-up support in the home. Studies were limited to those published between January 1990 and May 2013. Study participants included people 60 years of age or older living in their own homes who were undergoing care transitions from hospital to home. Data relating to study characteristics and research findings were extracted from the included articles. Two reviewers independently assessed studies for risk of bias.
Twelve articles met the inclusion criteria. Transitional care interventions reported in most studies reduced re-hospitalizations, with the exception of general practitioner and primary care nurse models. All 12 studies included outcome measures of re-hospitalization and length of stay indicating a quality focus on effectiveness, efficiency, and safety/risk. Patient satisfaction was assessed in six of the 12 studies and was mostly found to be high. Other outcomes reflecting person and family centred care were limited including those pertaining to the patient and carer experience, carer burden and support, and emotional support for older people and their carers. Limited outcome measures were reported reflecting timeliness, equity, efficiencies for community providers, and symptom management.
Gaps in the evidence base were apparent in the quality domains of timeliness, equity, efficiencies for community providers, effectiveness/symptom management, and domains of person and family centred care. Further research that involves the person and their family/caregiver in transitional care interventions is needed.
Alternative splicing of AMPA-type glutamate receptors (AMPARs) and allosteric modulation by auxiliary subunits, such as transmembrane AMPAR regulatory proteins (TARPs), are two important mechanisms ...that regulate the time course of glutamatergic neurotransmission. Prior work has shown that alternative splicing of the flip/flop cassette profoundly regulates TARP γ2 modulation, where flip receptor gating exhibits robust sensitivity to TARPs while flop isoforms are relatively insensitive to TARP modulation. Whether this splice variant-specific regulation extends to other auxiliary subunit families, such as cornichons (CNIHs), GSG1L, or CKAMPs, remains unknown. Here, we demonstrate that CNIH-3 modulation is unaffected by AMPAR alternative splicing due to inherent differences in how CNIH-3 and TARP γ2 modify channel gating. CNIH-3 slows receptor deactivation from the outset of current decay, consistent with structural evidence showing its point of contact at the level of the pore. In contrast, TARP γ2 acts via the KGK site of the ligand-binding domain (LBD) to slow the onset of desensitization. Although GSG1L and CKAMP44 primarily slow recovery from desensitization, their effects on channel gating are unaffected by alternative splicing, further underlining that structural events leading to the onset and recovery from desensitization are separable. Together, this work establishes that alternative splicing and TARP auxiliary subunits form a unique partnership that governs fast glutamatergic signaling at central synapses. Since proteomic studies suggest that all native AMPARs co-assemble with at least two TARPs, allosteric coupling between the flip/flop cassette and TARPs may represent a common design element in all AMPAR complexes of the mammalian brain.
All fast excitatory neurotransmission in the mammalian brain is mediated by AMPA-type glutamate receptors (AMPARs). The time course of AMPAR gating can be regulated by two distinct mechanisms: alternative splicing of the flip/flop cassette and association with auxiliary subunits. Although these regulatory mechanisms have been well studied individually, it is not clear whether alternative splicing impacts auxiliary protein modulation of AMPARs. Here, we compare the four main families of AMPAR auxiliary subunits, transmembrane AMPAR regulatory proteins (TARPs; γ2), cornichons (CNIH-3), GSG1L and CKAMPs (CKAMP44), and find a privileged relationship between TARPs and the flip/flop cassette that is not shared by others. The flop cassette acts as a master switch to override TARP action, and this coupling represents a way to fine-tune AMPAR signaling.
Salmonella enterica serotype Dublin is a cattle-adapted bacterium that typically causes bloodstream infections in humans. To summarize demographic, clinical, and antimicrobial drug resistance ...characteristics of human infections with this organism in the United States, we analyzed data for 1968-2013 from 5 US surveillance systems. During this period, the incidence rate for infection with Salmonella Dublin increased more than that for infection with other Salmonella. Data from 1 system (FoodNet) showed that a higher percentage of persons with Salmonella Dublin infection were hospitalized and died during 2005-2013 (78% hospitalized, 4.2% died) than during 1996-2004 (68% hospitalized, 2.7% died). Susceptibility data showed that a higher percentage of isolates were resistant to >7 classes of antimicrobial drugs during 2005-2013 (50.8%) than during 1996-2004 (2.4%).
Patients with cancer often endure substantial symptoms and treatment toxicities leading to high healthcare utilization, including hospitalizations and emergency department visits, throughout the ...continuum of their illness. Innovative oncology care models are needed to improve patient outcomes and reduce their healthcare utilization. Using a novel hospital at home care platform, we developed a Supportive Oncology Care at Home intervention to address the needs of patients with cancer.
We are conducting three trials to delineate the role of Supportive Oncology Care at Home for patients with cancer. The Supportive Oncology Care at Home intervention includes: (1) a hospital at home care model for symptom assessment and management; (2) remote monitoring of daily patient-reported symptoms, vital signs, and body weight; and (3) structured communication with the oncology team. Our first study is a randomized controlled trial to test the efficacy of Supportive Oncology Care at Home versus standard oncology care for improving healthcare utilization, cancer treatment interruptions, and patient-reported outcomes in patients with cancer receiving definitive treatment of their cancer. Participants include adult patients with gastrointestinal and head and neck cancer, as well as lymphoma, receiving definitive treatment (e.g., treatment with curative intent). The second study is a single-arm trial assessing the feasibility and acceptability of the Supportive Oncology Care at Home intervention for hospitalized patients with advanced cancer. Eligible participants include adult patients with incurable cancer who are admitted with an unplanned hospitalization. The third study is a single-arm trial assessing the feasibility and acceptability of the Supportive Oncology Care at Home intervention to enhance the end-of-life care for patients with advanced hematologic malignancies. Eligible participants include adult patients with relapsed or refractory hematologic malignancy receiving palliative therapy or supportive care alone.
These studies are approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board and are being conducted in accordance with the Consolidated Standards of Reporting Trials statement for non-pharmacological trials. This work has the potential to transform the paradigm of care for patients with cancer by providing them with the necessary support at home to improve their health outcomes and care delivery.
NCT04544046, NCT04637035, NCT04690205.
This meta-synthesis aimed to improve understanding of user experience of older people, carers, and health providers; and care integration in the care of older people transitioning from hospital to ...home. Following our systematic search, we identified and synthesized 20 studies, and constructed a comprehensive framework. We derived four themes: (1) ‘Who is taking care of what? Trying to work together”; (2) ‘Falling short of the mark’; (3) ‘A proper discharge’; and (4) ‘You adjust somehow.’ The themes that emerged from the studies reflected users’ experience of discharge and transitional care as a social process of ‘negotiation and navigation of independence (older people/carers), or dependence (health providers).’ Users engaged in negotiation and navigation through the interrogative strategies of questioning, discussion, information provision, information seeking, assessment, and translation. The derived themes reflected care integration that facilitated, or a lack of care integration that constrained, users’ experiences of negotiation and navigation of independence/dependence.
Background
Transitioning from hospital to home is challenging for many older people living with chronic health conditions. Transitional care facilitates safe and timely transfer of patients between ...levels of care and across care settings and includes communication between practitioners, assessment and planning, preparation, medication reconciliation, follow‐up care and self‐management education. To date, there is limited understanding of how to actively involve care recipient service users in transitional care.
Objective
This study was part of a larger research project. The objective of this article was to report the first study phase, in which we aimed to describe user experience pertaining to patients and carers.
Design, setting and participants
The study design was qualitative descriptive using interviews. Patients (n = 19) and carers (n = 7) participated in semi‐structured interviews about their experience of transition from hospital to home in an urban Australian health‐care setting. Interview data were analysed using thematic analysis.
Findings
All participants reported that they needed to become independent in transition. Participants perceived a range of social processes supported their independence at home: supportive relationships with carers, caring relationships with health‐care practitioners, seeking information, discussing and negotiating the transitional care plan and learning to self‐care.
Discussion
Findings contribute to our understanding that quality transitional care should focus on patients’ need to regain independence. Social processes supporting the capacities of patients and carers should be emphasized in future initiatives.
Conclusion
Future transitional care interventions should emphasize strategies to enable negotiation for suitable supports and assist care recipients to overcome barriers identified in this study.
•Interaction among self-regulation, habit, and mindfulness on texting while driving.•Low self-regulation was associated with greater texting while driving.•Habitual texting mediated the relationship ...between low self-regulation and texting while driving.•Trait mindfulness moderated the relationship between habitual texting and texting while driving.
The saturation of mobile phones throughout Australia has led to some individuals being unable to regulate their use within situations that are inappropriate or risky. One of the most prevalent risky mobile phone use behaviours is texting while driving. Attempts to explain texting while driving suggest cognitive variables and personality characteristics are key factors. This study explored relationships between trait self-regulation, habitual text messaging, trait mindfulness, and texting while driving. One hundred and seventy participants comprising Australian undergraduate psychology students and members of the public completed an online survey measuring trait self-regulation, habitual text messaging behaviour, trait mindfulness, and frequency of texting while driving. It was found that habitual texting behaviour mediated the relationship between trait self-regulation and frequency of texting while driving. Additionally, trait mindfulness moderated the relationship between habit and texting while driving, such that habitual texting was significantly, positively related to texting while driving, but only for individuals with low to moderate trait mindfulness. These results suggest personality constructs related to attention, awareness, and control of behaviour play a significant role in counteracting the association that habitual texting behaviour has with the frequency of texting while driving. As these traits are considered malleable, this association may be applicable in future development of intervention programs aimed at increasing control over mobile phone use and reducing the frequency with which people text while driving.
Most ligand- and voltage-gated ion channels assemble as signaling complexes consisting of pore-forming and auxiliary subunits. In the mammalian brain, AMPA-type ionotropic glutamate receptors ...(AMPARs) coassemble with several families of auxiliary subunits that regulate channel gating as well as ion channel block and permeation. Previous work has shown that auxiliary proteins stargazin (or γ2) and cornichon-3 (CNIH-3) attenuate the cytoplasmic polyamine channel block of AMPARs, although the underlying mechanism has yet to be established. Here, we show that γ2 and CNIH-3 relieve channel block by enhancing the rate of blocker permeation. Surprisingly, the relative permeability of the polyamine spermine (Spm) through the pore of the AMPAR-γ2 or -CNIH-3 complexes is considerably more than AMPARs expressed alone. Spm permeability is comparable to that of Na
for the GluA2-γ2 complex and four times greater than Na
with GluA2 + CNIH-3. A modified model of permeant channel block fully accounts for both the voltage- and time-dependent nature of Spm block. Estimates of block rate constants reveal that auxiliary subunits do not attenuate block by shifting the location of the block site within the membrane electric field, and they do not affect the blocker's ability to reach it. Instead, γ2 and CNIH-3 relieve channel block by facilitating the blocker's exit rates from the open channel. From a physiological perspective, the relief of channel block exerted by γ2 and CNIH-3 ensures that there is unfettered signaling by AMPARs at glutamatergic synapses. Moreover, the pronounced ability of AMPARs to transport polyamines may have an unexpected role in regulating cellular polyamine levels.
COVID‐19 and the resulting stay‐at‐home orders issued to reduce the spread of the virus created a novel social situation in which people could not spend in‐person time with their family and friends. ...Thus, emerging technologies like video calling and other forms of mediated communication like voice calling and text messaging became important resources for people to stay in touch. The purpose of this study was threefold. First, we wanted to test whether people would use more mediated communication (video calls, voice calls, text messaging) to stay in touch during the stay‐at‐home order. Second, we wanted to see if increased mediated communication would be positively associated with well‐being. Finally, we explored whether mediated communication was related to age. To answer these questions, we surveyed 2092 participants who answered questions online about how their use of video calls, voice calls, and text messaging and their well‐being had changed since the stay‐at‐home order. Our results show that people increased their use of mediated communication, particularly video calling; and increases in mediated communication with close others, particularly friends, was related to higher levels of well‐being. Finally, we found that age was related only to the use of video calling; younger people tended to use more video calling. These findings support the compensatory theory of technology use, that people use technologically mediated communication to maintain contact with their close friends and family when in‐person contact is not possible, and that this form of contact, when in‐person interaction is unavailable, is associated with positive outcomes.
PDF
