Protein Kinase A Regulates ATP Hydrolysis and Dimerization by a CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) Domain

Gating of the CFTRCl− channel is associated with ATP hydrolysis at the nucleotide-binding domains (NBD1, NBD2) and requires PKA (protein kinase A) phosphorylation of the R domain. The manner in which the NBD1, NBD2 and R domains of CFTR (cystic fibrosis transmembrane conductance regulator) interact to achieve a properly regulated ion channel is largely unknown. In this study we used bacterially expressed recombinant proteins to examine interactions between these soluble domains of CFTR in vitro. PKA phosphorylated a fusion protein containing NBD1 and R (NBD1–R–GST) on CFTR residues Ser-660, Ser-700, Ser- 712, Ser-737, Ser-768, Ser-795 and Ser-813. Phosphorylation of these serine residues regulated ATP hydrolysis by NBD1–R–GST by increasing the apparent Km for ATP (from 70 to 250 μM) and the Hill coefficient (from 1 to 1.7) without changing the Vmax. When fusion proteins were photolabelled with 8-azido- [α-32P]ATP, PKA phosphorylation increased the apparent kd for nucleotide binding and it caused binding to become co-operative. PKA phosphorylation also resulted in dimerization of NBD1– R–GST but not of R–GST, a related fusion protein lacking the NBD1 domain. Finally, an MBP (maltose-binding protein) fusion protein containing the NBD2 domain (NBD2–MBP) associated with and regulated the ATPase activity of PKA-phosphorylated NBD1–R–GST. Thus when the R domain in NBD1–R–GST is phosphorylated by PKA,ATP binding and hydrolysis becomes cooperative and NBD dimerization occurs. These findings suggest that during the activation of native CFTR, phosphorylation of the R domain by PKA can control the ability of the NBD1 domain to hydrolyse ATP and to interact with other NBD domains

Implications of Epigenetic Drift in Colorectal Neoplasia

NIH grants U01CA182940 (G.E. Luebeck, W.D. Hazelton, W.M. Grady, S.K. Madden, K. Curtius), U01CA199336 (G.E. Luebeck, W.D. Hazelton); Barts Charity grant 472-2300, London (K. Curtius) and UK Medical Research Council Rutherford fellowship (K. Curtius); and NIH grants (P30CA15704, U01CA152756, R01CA194663, R01CA220004, U54CA143862, P01CA077852),R.A.C.E. Charities, Cottrell Family Fund, R03CA165153, Listwin Family Foundation, Seattle Translational Tumor Research program, Fred Hutchinson Cancer Research Center (S.K. Madden, M. Yu, K.T. Carter, and W.M. Grady), R01CA189184 (C. Lee, C.M. Ulrich, S.K.Madden, M. Yu, K.T. Carter, and W.M. Grady), R01CA112516, R01CA114467, R01CA120523 (C.M. Ulrich, S.K. Madden, M. Yu, K.T. Carter, and W.M. Grady), Huntsman Cancer Foundation, U01 CA206110, R01CA189184 R01CA 207371 and P30CACA042014 (C.M. Ulrich). U24CA074794 (P.A. Newcomb, S.K. Madden, M. Yu, K.T. Carter, and W.M. Grady). This material is the result of work supported in part by resources from the VA Puget Sound Health Care System and the ColoCare Study

The need for exercise sciences and an integrated response to COVID-19: A position statement from the international HL-PIVOT network

COVID-19 is one of the biggest health crises that the world has seen. Whilst measures to abate transmission and infection are ongoing, there continues to be growing numbers of patients requiring chronic support, which is already putting a strain on health care systems around the world and which may do so for years to come. A legacy of COVID-19 will be a long-term requirement to support patients with dedicated rehabilitation and support services. With many clinical settings characterized by a lack of funding and resources, the need to provide these additional services could overwhelm clinical capacity. This position statement from the Healthy Living for Pandemic Event Protection (HL-PIVOT) Network provides a collaborative blueprint focused on leading research and developing clinical guidelines, bringing together professionals with expertise in clinical services and the exercise sciences to develop the evidence base needed to improve outcomes for patients infected by COVID-19

Losing Our Minds? New Research Directions on Skilled Migration and Development

This paper critiques the last decade of research on the effects of high-skill emigration from developing countries, and proposes six new directions for fruitful research. The study singles out a core assumption underlying much of the recent literature, calling it the Lump of Learning model of human capital and development, and describes five ways that research has come to challenge that assumption. It assesses the usefulness of the Lump of Learning model in the face of accumulating evidence. The axioms of the Lump of Learning model have shaped research priorities in this literature, but many of those axioms do not have a clear empirical basis. Future research proceeding from established facts would set different priorities, and would devote more attention to measuring the effects of migration on skilled-migrant households, rigorously estimating human capital externalities, gathering microdata beyond censuses, and carefully considering optimal policy among others. The recent literature has pursued a series of extensions to the Lump of Learning model. This study urges discarding the Lump of Learning model, pointing toward a new paradigm for research on skilled migration and development

Baseline Features and Reasons for Nonparticipation in the Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) Study, a Colorectal Cancer Screening Trial.

IMPORTANCE: The Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) randomized clinical trial sought to recruit 50 000 adults into a study comparing colorectal cancer (CRC) mortality outcomes after randomization to either an annual fecal immunochemical test (FIT) or colonoscopy. OBJECTIVE: To (1) describe study participant characteristics and (2) examine who declined participation because of a preference for colonoscopy or stool testing (ie, fecal occult blood test [FOBT]/FIT) and assess that preference\u27s association with geographic and temporal factors. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study within CONFIRM, which completed enrollment through 46 Department of Veterans Affairs medical centers between May 22, 2012, and December 1, 2017, with follow-up planned through 2028, comprised veterans aged 50 to 75 years with an average CRC risk and due for screening. Data were analyzed between March 7 and December 5, 2022. EXPOSURE: Case report forms were used to capture enrolled participant data and reasons for declining participation among otherwise eligible individuals. MAIN OUTCOMES AND MEASURES: Descriptive statistics were used to characterize the cohort overall and by intervention. Among individuals declining participation, logistic regression was used to compare preference for FOBT/FIT or colonoscopy by recruitment region and year. RESULTS: A total of 50 126 participants were recruited (mean [SD] age, 59.1 [6.9] years; 46 618 [93.0%] male and 3508 [7.0%] female). The cohort was racially and ethnically diverse, with 748 (1.5%) identifying as Asian, 12 021 (24.0%) as Black, 415 (0.8%) as Native American or Alaska Native, 34 629 (69.1%) as White, and 1877 (3.7%) as other race, including multiracial; and 5734 (11.4%) as having Hispanic ethnicity. Of the 11 109 eligible individuals who declined participation (18.0%), 4824 (43.4%) declined due to a stated preference for a specific screening test, with FOBT/FIT being the most preferred method (2820 [58.5%]) vs colonoscopy (1958 [40.6%]; P \u3c .001) or other screening tests (46 [1.0%] P \u3c .001). Preference for FOBT/FIT was strongest in the West (963 of 1472 [65.4%]) and modest elsewhere, ranging from 199 of 371 (53.6%) in the Northeast to 884 of 1543 (57.3%) in the Midwest (P = .001). Adjusting for region, the preference for FOBT/FIT increased by 19% per recruitment year (odds ratio, 1.19; 95% CI, 1.14-1.25). CONCLUSIONS AND RELEVANCE: In this cross-sectional analysis of veterans choosing nonenrollment in the CONFIRM study, those who declined participation more often preferred FOBT or FIT over colonoscopy. This preference increased over time and was strongest in the western US and may provide insight into trends in CRC screening preferences

A Molecular Clock Infers Heterogeneous Tissue Age Among Patients with Barrett's Esophagus

National Institutes of Health (www.nih.gov) and the National Cancer Institute (www.cancer.gov) under grants U01CA182940 (BG-U01) (to EGL, CJW, WDH, WMG, and KC), 5P30CA015704 (to WMG and CJW), 5U01CA152756 (to WMG and CJW), 5U54CA163060 (to AC), and NIH1P50CA150964-01A1 (to JEW