Project description:BackgroundUse of artificial pancreas (AP) requires seamless interaction of device components, such as continuous glucose monitor (CGM), insulin pump, and control algorithm. Mobile AP configurations also include a smartphone as computational hub and gateway to cloud applications (e.g., remote monitoring and data review and analysis). This International Diabetes Closed-Loop study was designed to demonstrate and evaluate the operation of the inControl AP using different CGMs and pump modalities without changes to the user interface, user experience, and underlying controller.MethodsForty-three patients with type 1 diabetes (T1D) were enrolled at 10 clinical centers (7 United States, 3 Europe) and 41 were included in the analyses (39% female, >95% non-Hispanic white, median T1D duration 16 years, median HbA1c 7.4%). Two CGMs and two insulin pumps were tested by different study participants/sites using the same system hub (a smartphone) during 2 weeks of in-home use.ResultsThe major difference between the system components was the stability of their wireless connections with the smartphone. The two sensors achieved similar rates of connectivity as measured by percentage time in closed loop (75% and 75%); however, the two pumps had markedly different closed-loop adherence (66% vs. 87%). When connected, all system configurations achieved similar glycemic outcomes on AP control (73% [mean] time in range: 70-180 mg/dL, and 1.7% [median] time <70 mg/dL).ConclusionsCGMs and insulin pumps can be interchangeable in the same Mobile AP system, as long as these devices achieve certain levels of reliability and wireless connection stability.
Project description:Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonism-amyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 5' splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the 'missing' +15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPT and performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915+15A>C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915+15A>C variant caused a shift in tau splicing pattern to a predominantly exon 10+ pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915+15A>C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to +4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the 'stem' when the stem-loop model was first proposed and no mutations have been found within the 'loop' region as expected. Therefore we 'close the tau loop' having 'opened the loop' 21 years ago.
Project description:One of the agro-industry's side streams that is widely met is the-keratin rich fibrous material that is becoming a waste product without valorization. Its management as a waste is costly, as the incineration of this type of waste constitutes high environmental concern. Considering these facts, the keratin-rich waste can be considered as a treasure for the producers interested in the valorization of such slowly-biodegradable by-products. As keratin is a protein that needs harsh conditions for its degradation, and that in most of the cases its constitutive amino acids are destroyed, we review new extraction methods that are eco-friendly and cost-effective. The chemical and enzymatic extractions of keratin are compared and the optimization of the extraction conditions at the lab scale is considered. In this study, there are also considered the potential applications of the extracted keratin as well as the reuse of the by-products obtained during the extraction processes.
Project description:The RNA polymerase (RNAP) trigger loop (TL) is a mobile structural element of the RNAP active center that, based on crystal structures, has been proposed to cycle between an "unfolded"/"open" state that allows an NTP substrate to enter the active center and a "folded"/"closed" state that holds the NTP substrate in the active center. Here, by quantifying single-molecule fluorescence resonance energy transfer between a first fluorescent probe in the TL and a second fluorescent probe elsewhere in RNAP or in DNA, we detect and characterize TL closing and opening in solution. We show that the TL closes and opens on the millisecond timescale; we show that TL closing and opening provides a checkpoint for NTP complementarity, NTP ribo/deoxyribo identity, and NTP tri/di/monophosphate identity, and serves as a target for inhibitors; and we show that one cycle of TL closing and opening typically occurs in each nucleotide addition cycle in transcription elongation.
Project description:The first ribozymes are thought to have emerged at a time when RNA replication proceeded via nonenzymatic template copying processes. However, functional RNAs have stable folded structures, and such structures are much more difficult to copy than short unstructured RNAs. How can these conflicting requirements be reconciled? Also, how can the inhibition of ribozyme function by complementary template strands be avoided or minimized? Here, we show that short RNA duplexes with single-stranded overhangs can be converted into RNA stem loops by nonenzymatic cross-strand ligation. We then show that loop-closing ligation reactions enable the assembly of full-length functional ribozymes without any external template. Thus, one can envisage a potential pathway whereby structurally complex functional RNAs could have formed at an early stage of evolution when protocell genomes might have consisted only of collections of short replicating oligonucleotides.
Project description:Protein loop dynamics have recently been recognized as central to enzymatic activity, specificity and stability. However, the factors controlling loop opening and closing kinetics have remained elusive. Here, we combine molecular dynamics simulations with string-method determination of complex reaction coordinates to elucidate the molecular mechanism and rate-limiting step for WPD-loop dynamics in the PTP1B enzyme. While protein conformational dynamics is often represented as diffusive motion hindered by solvent viscosity and internal friction, we demonstrate that loop opening and closing is activated. It is governed by torsional rearrangement around a single loop peptide group and by significant friction caused by backbone adjustments, which can dynamically trap the loop. Considering both torsional barrier and time-dependent friction, our calculated rate constants exhibit very good agreement with experimental measurements, reproducing the change in loop opening kinetics between proteins. Furthermore, we demonstrate the applicability of our results to other enzymatic loops, including the M20 DHFR loop, thereby offering prospects for loop engineering potentially leading to enhanced designs.
Project description:Major depressive episodes are the largest cause of psychiatric disability, and can often resist treatment with medication and psychotherapy. Advances in the understanding of the neural circuit basis of depression, combined with the success of deep brain stimulation (DBS) in movement disorders, spurred several groups to test DBS for treatment-resistant depression. Multiple brain sites have now been stimulated in open-label and blinded studies. Initial open-label results were dramatic, but follow-on controlled/blinded clinical trials produced inconsistent results, with both successes and failures to meet endpoints. Data from follow-on studies suggest that this is because DBS in these trials was not targeted to achieve physiologic responses. We review these results within a technology-lifecycle framework, in which these early trial "failures" are a natural consequence of over-enthusiasm for an immature technology. That framework predicts that from this "valley of disillusionment," DBS may be nearing a "slope of enlightenment." Specifically, by combining recent mechanistic insights and the maturing technology of brain-computer interfaces (BCI), the next generation of trials will be better able to target pathophysiology. Key to that will be the development of closed-loop systems that semi-autonomously alter stimulation strategies based on a patient's individual phenotype. Such next-generation DBS approaches hold great promise for improving psychiatric care.
Project description:ObjectivesScanned documents (SDs), while common in electronic health records and potentially rich in clinically relevant information, rarely fit well with clinician workflow. Here, we identify scanned imaging reports requiring follow-up with high recall and practically useful precision.Materials and methodsWe focused on identifying imaging findings for 3 common causes of malpractice claims: (1) potentially malignant breast (mammography) and (2) lung (chest computed tomography [CT]) lesions and (3) long-bone fracture (X-ray) reports. We train our ClinicalBERT-based pipeline on existing typed/dictated reports classified manually or using ICD-10 codes, evaluate using a test set of manually classified SDs, and compare against string-matching (baseline approach).ResultsA total of 393 mammograms, 305 chest CT, and 683 bone X-ray reports were manually reviewed. The string-matching approach had an F1 of 0.667. For mammograms, chest CTs, and bone X-rays, respectively: models trained on manually classified training data and optimized for F1 reached an F1 of 0.900, 0.905, and 0.817, while separate models optimized for recall achieved a recall of 1.000 with precisions of 0.727, 0.518, and 0.275. Models trained on ICD-10-labelled data and optimized for F1 achieved F1 scores of 0.647, 0.830, and 0.643, while those optimized for recall achieved a recall of 1.0 with precisions of 0.407, 0.683, and 0.358.DiscussionOur pipeline can identify abnormal reports with potentially useful performance and so decrease the manual effort required to screen for abnormal findings that require follow-up.ConclusionIt is possible to automatically identify clinically significant abnormalities in SDs with high recall and practically useful precision in a generalizable and minimally laborious way.
Project description:BackgroundIn Australia, an estimated 57% of the population do not meet physical activity recommendations for health. The built environment is important for active living, and recreational trails provide safe and pleasant settings for this purpose. However, evidence for positive impacts on physical activity from real world natural experiments is sparse. We describe the impact of transforming a recreational trail into a loop on usage by cyclists and pedestrians and users' physical activity levels.MethodWe conducted time series analyses of pre and post-completion (November 2013-July 2015) counts taken from infrared electronic counters of pedestrians and cyclists on two established sections of the trail adjusted for underlying trend, trend change, weather, holidays and trail closures. Chi-square analyses of pre and post-completion visual counts examined change in the distribution of pedestrian/cyclist, adult/child, and male/female users. Descriptive and bivariate analyses of post-completion intercept survey data of 249 trail users were conducted to examine user characteristics and impact on physical activity.ResultsPedestrian and cyclist counts on established trail sections increased by between 200 and 340% from pre to post-completion. Visual count data showed a significant 7% increase in children (vs adults) using the trail at one site pre to post (p = 0.008). Of previous users, 48% reported doing more physical activity at the trail and this was additional to (not replacing) physical activity done elsewhere. Those users not meeting physical activity recommendations were more likely to report increased total physical activity since the loop was created (55.5% vs 39.2%, p = 0.031). The connected loop nature of the trail and its length was perceived to encourage more and different forms of physical activity.ConclusionCreating an accessible loop trail away from motorised traffic can lead to increased trail use and potentially total physical activity. The modification to the trail encouraged proportionate and real increases in usage among vulnerable populations such as children and perhaps greater total physical activity especially for people not meeting physical activity recommendations. The findings suggest that the benefits of environmental changes such as these can accrue to those most in need of support for being physically active.