The design of peptides that assemble in membranes to form functional ion channels is challenging. Specifically, hydrophobic interactions must be designed between the peptides and at the peptide-lipid ...interfaces simultaneously. Here, we take a multi-step approach towards this problem. First, we use rational de novo design to generate water-soluble α-helical barrels with polar interiors, and confirm their structures using high-resolution X-ray crystallography. These α-helical barrels have water-filled lumens like those of transmembrane channels. Next, we modify the sequences to facilitate their insertion into lipid bilayers. Single-channel electrical recordings and fluorescent imaging of the peptides in membranes show monodisperse, cation-selective channels of unitary conductance. Surprisingly, however, an X-ray structure solved from the lipidic cubic phase for one peptide reveals an alternative state with tightly packed helices and a constricted channel. To reconcile these observations, we perform computational analyses to compare the properties of possible different states of the peptide.
We studied a critically-endangered hydrobiid snail, Pyrgulopsis bernardina, in Snail Spring, Cochise County, Arizona. We determined the relationships between its abundance and a suite of habitat ...variables and document formerly-occupied sites. Using Akaike's Information Criterion for model selection and averaging, 14 models were defined a priori using eight habitat variables to explain its abundance. All biologically supported predictors, in the first order, provided the most parsimonious explanation of P. bernardina densities. Structural variables received stronger support than physicochemical variables. P. bernardina densities were positively associated with sand and cobble substrates, vegetation density, water velocity, and dissolved oxygen, as well as water temperatures of 14-22°C and pH values between 7.6 and 8.0. Snail densities were negatively associated with silt and organic substrates, deep water, and high conductance. The current and all former localities for P. bernardina are associated with a shallow aquifer that is distinct from an adjacent deep aquifer.
To determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease.
One thousand six hundred fifty-eight elderly ambulatory ...adults free from dementia, cardiovascular disease, and stroke who participated in the US population-based Cardiovascular Health Study between 1992-1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992-1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria.
During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95% confidence interval CI) for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25 to <50 nmol/L) were 2.25 (95% CI: 1.23-4.13) and 1.53 (95% CI: 1.06-2.21) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 (95% CI: 1.02-4.83) and 1.69 (95% CI: 1.06-2.69). In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L.
Our results confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease. This adds to the ongoing debate about the role of vitamin D in nonskeletal conditions.
The purpose of this study was to obtain validity and reliability indexes for scores on a 12-item scale measuring family perspectives on extended school year (ESY) programs for students in special ...education. Responses from 128 families with a child potentially eligible for ESY programs indicated that a two-component model was both valid and interpretable. (SLD)
De novo protein design is advancing rapidly. However, most designs are for single states. Here we report a de novo designed peptide that forms multiple α-helical-bundle states that are accessible and ...interconvertible under the same conditions. Usually in such designs amphipathic α helices associate to form compact structures with consolidated hydrophobic cores. However, recent rational and computational designs have delivered open α-helical barrels with functionalisable cavities. By placing glycine judiciously in the helical interfaces of an α-helical barrel, we obtain both open and compact states in a single protein crystal. Molecular dynamics simulations indicate a free-energy landscape with multiple and interconverting states. Together, these findings suggest a frustrated system in which steric interactions that maintain the open barrel and the hydrophobic effect that drives complete collapse are traded-off. Indeed, addition of a hydrophobic co-solvent that can bind within the barrel affects the switch between the states both in silico and experimentally.
A database consisting of approximately 4000 storm observations has been objectively analyzed to determine environmental characteristics that produce high radar reflectivities above the freezing ...level, large total lightning flash rates on the order of 10 flashes per minute, and anomalous vertical charge structures (most notably, dominant midlevel positive charge). The storm database is drawn from four regions of the United States featuring distinct environments, each with coinciding Lightning Mapping Array (LMA) network data. LMAs are able to infer total lightning flash rates using flash clustering algorithms, such as the one implemented in this study. Results show that anomalous charge structures inferred from LMA data, significant lightning flash rates, and increased radar reflectivities above the freezing level tend to be associated with environments that have high cloud base heights (approximately 3 km above ground level) and large atmospheric instability, quantified by normalized convective available potential energy (NCAPE) near 0.2 m s−2. Additionally, we infer that aerosols may affect storm intensity. Maximum flash rates were observed in storms with attributed aerosol concentrations near 1000 cm−3, while total flash rates decrease when aerosol concentrations exceed 1500 cm−3, consistent with previous studies. However, this effect is more pronounced in regions where the NCAPE and cloud base height are low. The dearth of storms with estimated aerosol concentrations less than 700 cm−3 (approximately 1% of total sample) does not provide a complete depiction of aerosol invigoration.
Key Points
Lightning flash rates computed from LMA data with novel clustering algorithm
Aerosol impacts on storm intensity dependent on thermodynamics
Unique charge structures observed for large NCAPE and high CBH
The growing use of health information technology in operational settings, along with the maturation of the discipline of biomedical informatics, requires reorganization of educational programs in the ...field. The objective of this paper is to provide a context and description of the biomedical informatics education program at Oregon Health & Science University.
The details of the program are provided.
The paper describes the overall program and its component curricula.
OHSU has developed a program that caters to the full spectrum of those who will work in the field, allowing education tailored to their career goals and needs. The maturation of Internet technologies also allow most aspects of the program to be delivered on-line. The informatics field must step up to the challenge of educating the best workforce to achieve our goals for the optimal use of HIT.
Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib ...therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy.
In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282.
Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled from 15 sites across the USA. 91 patients had received ibrutinib as the last BCR inhibitor therapy before enrolment, 43 of whom were enrolled in the main cohort and 48 in the expansion cohort recruited later after a protocol amendment. At the time of analysis, the median follow-up was 14 months (IQR 8–18) for all 91 patients, 19 months (9–27) for the main cohort, and 12 months (8–15) for the expansion cohort. 59 (65%, 95% CI 53–74) of 91 patients had an overall response, including 30 (70%, 54–83) of 43 patients in the main cohort and 29 (60%, 43–72) of 48 patients in the expansion cohort. The most common treatment-emergent grade 3 or 4 adverse events were neutropenia (46 51% of 91 patients), thrombocytopenia (26 29%), anaemia (26 29%), decreased white blood cell count (17 19%), and decreased lymphocyte count (14 15%). 17 (19%) of 91 patients died, including seven because of disease progression. No treatment-related deaths occurred.
The results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019.
AbbVie, Genentech.
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