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Despite their high clinical relevance, obtaining structural and biophysical data on transmembrane proteins has been hindered by challenges involved in their expression and extraction in a homogeneous, functionally-active form. The inherent enzymatic activity of receptor tyrosine kinases (RTKs) presents additional challenges. Oncogenic fusions of RTKs with heterologous partners represent a particularly difficult-to-express protein subtype due to their high flexibility, aggregation propensity and the lack of a known method for extraction within the native lipid environment. One such protein is the fibroblast growth factor receptor 3 fused with transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3), which has failed to express to sufficient quality or functionality in traditional expression systems. Cell-free protein expression (CFPE) is a burgeoning arm of synthetic biology, enabling the rapid and efficient generation of recombinant proteins. This platform is characterised by utilising an optimised solution of cellular machinery to facilitate protein synthesis in vitro. In doing so, CFPE can act as a surrogate system for a range of proteins that are otherwise difficult to express through traditional host cell-based approaches. Here, functional FGFR3-TACC3 was expressed through a novel cell-free expression system in under 48 h. The resultant protein was reconstituted using SMA copolymers with a specific yield of 300 µg/mL of lysate. Functionally, the protein demonstrated significant kinase domain phosphorylation ( t  <  0.0001 ). Currently, there is no published, high-resolution structure of any full-length RTK. These findings form a promising foundation for future research on oncogenic RTKs and the application of cell-free systems for synthesising functional membrane proteins.

The MscL channel gates in response to membrane tension changes to allow the exchange of molecules through its pore. Lipid removal from transmembrane pockets leads to a MscL response. However, it is unknown whether there is correlation between the tension mediated state and the state derived by pocket delipidation in the absence of tension. Transitions between MscL states may follow a similar pathway to cover the available conformational space but may not necessarily sample the same discrete intermediates. Here, we combined pulsed-EPR and HDX-MS measurements on MscL, coupled with molecular dynamics under membrane tension, to investigate the changes associated with the distinctively derived states. Whether it is tension or pocket delipidation, we find that MscL samples a similar expanded state, which is the final step of the delipidation pathway but only an intermediate stop of the tension mediated path. Our findings hint at synergistic modes of regulation in mechanosensitive channels. Competing Interest Statement The authors have declared no competing interest. Footnotes * http://archive.researchdata.leeds.ac.uk/777/

Despite their high clinical relevance, obtaining structural and biophysical data on transmembrane proteins has been bottlenecked by challenges involved in their expression. The inherent enzymatic activity of receptor tyrosine kinases (RTK) presents an additional hurdle to producing functional protein. The oncogenic fusion of proteins to such RTKs creates a particularly difficult-to-express protein subtype due to their high flexibility, lack of stability, and propensity for aggregation. One such protein is the fibroblast growth factor receptor 3 fused with transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3), which has failed to express to sufficient quality or functionality in traditional expression systems. Cell-free protein expression (CFPE) is a burgeoning arm of synthetic biology, enabling the rapid and efficient generation of recombinant proteins. This platform is characterised by utilising an optimised solution of cellular machinery to facilitate protein synthesis in vitro. In doing so, CFPE can act as a surrogate system for a range of proteins that are otherwise difficult to express through traditional host cell-based approaches. Here, functional FGFR3-TACC3 was expressed through a novel cell-free expression system in under 48 hours. The resultant protein can be reconstituted using SMA copolymers. Functionally, the protein demonstrated significant kinase domain phosphorylation (t<0.0001). Currently, there is no published, high-resolution structure of any full-length RTK. These findings form a promising foundation for future research on oncogenic RTKs and the application of cell-free systems for synthesising functional membrane proteins.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Updates to author affiliation, updates to all figures and manuscript.

There has recently been interest in understanding the differences between specific levels of global warming, especially the Paris Agreement limits of 1.5 °C and 2 °C above pre-industrial levels. However, different model experiments1–3 have been used in these analyses under varying rates of increase in global-average temperature. Here, we use climate model simulations to show that, for a given global temperature, most land is significantly warmer in a rapidly warming (transient) case than in a quasi-equilibrium climate. This results in more than 90% of the world’s population experiencing a warmer local climate under transient global warming than equilibrium global warming. Relative to differences between the 1.5 °C and 2 °C global warming limits, the differences between transient and quasi-equilibrium states are substantial. For many land regions, the probability of very warm seasons is at least two times greater in a transient climate than in a quasi-equilibrium equivalent. In developing regions, there are sizable differences between transient and quasi-equilibrium climates that underline the importance of explicitly framing projections. Our study highlights the need to better understand differences between future climates under rapid warming and quasi-equilibrium conditions for the development of climate change adaptation policies. Yet, current multi-model experiments1,4 are not designed for this purpose.

Telemedicine is an expanding and feasible approach to improve medical care for patients with long-term conditions. However, there is a poor understanding of patients' acceptability of this technology and their rate of uptake. The aim of this study was to systematically review the current evidence on telemonitoring in the management of patients with long-term conditions and evaluate the patients' uptake and acceptability of this technology. MEDLINE, Scopus, and CENTRAL (the Cochrane Central Register of Controlled Trials) were searched from the date of inception to February 5, 2021, with no language restrictions. Studies were eligible for inclusion if they reported any of the following outcomes: intervention uptake and adherence; study retention; patient acceptability, satisfaction, and experience using the intervention; changes in physiological values; all-cause and cardiovascular-related hospitalization; all-cause and disease-specific mortality; patient-reported outcome measures; and quality of life. In total, 2 reviewers independently assessed the articles for eligibility. A total of 96 studies were included, and 58 (60%) were pooled for the meta-analyses. Meta-analyses showed a reduction in mortality (risk ratio=0.71, 95% CI 0.56-0.89; P=.003; I =0%) and improvements in blood pressure (mean difference [MD]=-3.85 mm Hg, 95% CI -7.03 to -0.68; P=.02; I =100%) and glycated hemoglobin (MD=-0.33, 95% CI -0.57 to -0.09; P=.008; I =99%) but no significant improvements in quality of life (MD=1.45, 95% CI -0.10 to 3; P=.07; I =80%) and an increased risk of hospitalization (risk ratio=1.02, 95% CI 0.85-1.23; P=.81; I =79%) with telemonitoring compared with usual care. A total of 12% (12/96) of the studies reported adherence outcomes, and 9% (9/96) reported on satisfaction and acceptance outcomes; however, heterogeneity in the assessment methods meant that a meta-analysis could not be performed. Telemonitoring is a valid alternative to usual care, reducing mortality and improving self-management of the disease, with patients reporting good satisfaction and adherence. Further studies are required to address some potential concerns regarding higher hospitalization rates and a lack of positive impact on patients' quality of life. PROSPERO CRD42021236291; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=236291.

Background Telemonitoring for the remote patient self-management of chronic conditions can be a cost-effective method for delivering care in chronic disease; nonetheless, its implementation in clinical practice remains low. The aim of this meta-synthesis is to explore barriers and facilitators associated with the use of remote patient monitoring of chronic disease, drawing on qualitative research, and assessing participant interactions with this technology. Method A meta-synthesis of qualitative studies was performed. MEDLINE, SCOPUS and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from database date of inception to 5 February 2021. The Critical Appraisal Skills Programme (CASP) was used to critically appraise each study. Thematic synthesis was performed to identify user (patients, carers and healthcare professionals) perspectives and experiences of patient remote monitoring of chronic disease (Type 2 diabetes mellitus, chronic obstructive pulmonary disease, and cardiovascular disease). Results Searches returned 10,401 studies and following independent screening by two reviewers, nine studies were included in this meta-synthesis. Data were synthesised and categorised into four key themes: (1) Improved care ; (2) Communication ; (3) Technology feasibility & acceptability ; and (4) Intervention concerns . Most patients using patient remote devices felt motivated in managing their own lifestyles and felt reassured by the close monitoring and increased communication. Barriers identified involved generational differences and difficulties with the technology used. Conclusion Most studies showed a positive attitude to telemonitoring, with patients preferring the convenience of telemonitoring in comparison to attending regular clinics. Further research is required to assess the most effective technology for chronic disease management, how to maintain long-term patient adherence, and identify effective approaches to address generational variation in telemonitoring up-take.

We report key epidemiologic parameter estimates for coronavirus disease identified in peer-reviewed publications, preprint articles, and online reports. Range estimates for incubation period were 1.8-6.9 days, serial interval 4.0-7.5 days, and doubling time 2.3-7.4 days. The effective reproductive number varied widely, with reductions attributable to interventions. Case burden and infection fatality ratios increased with patient age. Implementation of combined interventions could reduce cases and delay epidemic peak up to 1 month. These parameters for transmission, disease severity, and intervention effectiveness are critical for guiding policy decisions. Estimates will likely change as new information becomes available.

The incidence of keratinocyte cancer (basal cell and squamous cell carcinomas of the skin) is 17-fold lower in Singapore than the UK 1 – 3 , despite Singapore receiving 2–3 times more ultraviolet (UV) radiation 4 , 5 . Aging skin contains somatic mutant clones from which such cancers develop 6 , 7 . We hypothesized that differences in keratinocyte cancer incidence may be reflected in the normal skin mutational landscape. Here we show that, compared to Singapore, aging facial skin from populations in the UK has a fourfold greater mutational burden, a predominant UV mutational signature, increased copy number aberrations and increased mutant TP53 selection. These features are shared by keratinocyte cancers from high-incidence and low-incidence populations 8 – 13 . In Singaporean skin, most mutations result from cell-intrinsic processes; mutant NOTCH1 and NOTCH2 are more strongly selected than in the UK. Aging skin in a high-incidence country has multiple features convergent with cancer that are not found in a low-risk country. These differences may reflect germline variation in UV-protective genes. A comparison of somatic mutations in skin from individuals from the UK and Singapore suggests that the difference in cancer incidence between the two countries is due to markedly different mutational spectra and patterns of selection.

Atrial fibrillation (AF) often remains undetected following stroke. Documenting AF is critical to initiate oral anticoagulation, which has proven benefit in reducing recurrent stroke and mortality in patients with AF. The accuracy and acceptability of using smart wearables to detect AF in patients following stroke is unknown. The aims of the Liverpool-Huawei Stroke Study are to determine the effectiveness, cost-effectiveness and patient and staff acceptability of using Huawei smart wearables to detect AF following ischemic stroke. The study plans to recruit 1,000 adults aged ≥18 years following ischemic stroke from participating hospitals over 12 months. All participants will be asked to wear a Huawei smart band for 4 weeks postdischarge. If participants do not have access to a compatible smartphone required for the study, they will be provided with a smartphone for the 4-week AF monitoring period. Participants with suspected AF detected by the smart wearables, without previous known AF, will be referred for further evaluation. To determine the effectiveness of the Huawei smart wearables to detect AF, the positive predictive value will be determined. Patient acceptability of using this technology will also be examined. Additional follow-up assessments will be conducted at 6 and 12 months, and clinical outcomes recorded in relation to prevalent and incident AF post-stroke. The study opened for recruitment on May 30, 2022, and is currently open at 4 participating hospitals; the first 106 participants have been recruited. One further hospital is preparing to open for recruitment. This prospective study will examine the effectiveness and acceptability of the use of smart wearables in patients following ischemic stroke. This could have important implications for detection of AF and therefore, earlier prophylaxis for recurrent stroke. The study is registered on https://www.isrctn.com/ (Identifier ISRCTN30693819).

Candida auris is an emerging global healthcare-associated pathogen. During July-December 2018, four patients with C. auris were identified in Victoria, Australia, all with previous overseas hospitalization. Phylogenetic analysis revealed putative transmission between 2 patients and suspected overseas acquisition in the others. Vigilant screening of at-risk patients is required.