Thapsigargin and Dimethyl Sulfoxide Activate Medium P i ↔ HOH Oxygen Exchange Catalyzed by Sarcoplasmic Reticulum Ca 2+ -ATPase

Thapsigargin is a potent inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase. It binds the Ca(2+)-free E2 conformation in the picomolar range, supposedly resulting in a largely catalytically inactive species. We now find that thapsigargin has little effect on medium P(i) HOH oxygen exchange and that this activity is greatly stimulated (up to 30-fold) in the presence of 30% (v/v) Me(2)SO. Assuming a simple two-step mechanism, we have evaluated the effect of thapsigargin and Me(2)SO on the four rate constants governing the reaction of P(i) with Ca(2+)-ATPase. The principal effect of thapsigargin alone is to stimulate EP hydrolysis (k(-2)), whereas that of Me(2)SO is to greatly retard P(i) dissociation (k(-1)), accounting for its well known effect on increasing the apparent affinity for P(i). These effects persist when the agents are used in combination and substantially account for the activated oxygen exchange (v(exchange) = k(-2)[EP]). Kinetic simulations show that the overall rate constant for the formation of EP is very fast (approximately 300 s(-1)) when the exchange is maximal. Thapsigargin greatly stabilizes Ca(2+)-ATPase against denaturation in detergent in the absence of Ca(2+), as revealed by glutaraldehyde cross-linking, suggesting that the membrane helices lock together. It seems that the reactions at the phosphorylation site, associated with the activated exchange reaction, are occurring without much movement of the transport site helices, and we suggest that they may be associated solely with an occluded H+ state

Long term cognitive outcomes of early term (37-38 weeks) and late preterm (34-36 weeks) births: a systematic review

Background: There is a paucity of evidence regarding long-term outcomes of late preterm (34-36 weeks) and early term (37-38 weeks) delivery.  The objective of this systematic review was to assess long-term cognitive outcomes of children born at these gestations. Methods: Four electronic databases (Medline, Embase, clinicaltrials.gov and PsycINFO) were searched.  Last search was 5 th August 2016.  Studies were included if they reported gestational age, IQ measure and the ages assessed.  The protocol was registered with the International prospective register of systematic reviews (PROSPERO Record CRD42015015472).  Two independent reviewers assessed the studies.  Data were abstracted and critical appraisal performed of eligible papers. Results: Of 11,905 potential articles, seven studies reporting on 41,344 children were included.  For early term births, four studies (n = 35,711) consistently showed an increase in cognitive scores for infants born at full term (39-41 weeks) compared to those born at early term (37-38 weeks) with increases for each week of term (difference between 37 and 40 weeks of around 3 IQ points), despite differences in age of testing and method of IQ/cognitive testing.  Four studies (n = 5644) reporting childhood cognitive outcomes of late preterm births (34 - 36 weeks) also differed in study design (cohort and case control); age of testing; and method of IQ testing, and found no differences in outcomes between late preterm and term births, although risk of bias was high in included studies. Conclusion:  Children born at 39-41 weeks have higher cognitive outcome scores compared to those born at early term (37-38 weeks).  This should be considered when discussing timing of delivery.  For children born late preterm, the data is scarce and when compared to full term (37-42 weeks) did not show any difference in IQ scores

Using Nominal Group Technique to Identify Key Attributes of Oncology Treatments for a Discrete Choice Experiment.

Background. Responding to rising oncology therapy costs, multiple value frameworks are emerging. However, input from economists in their design and conceptualization has been limited, and no existing framework has been developed using preference weightings as legitimate indicators of value. This article outlines use of the nominal group technique to identify valued treatment attributes (such as treatment inconvenience) and contextual considerations (such as current life expectancy) to inform the design of a discrete choice experiment to develop a preference weighted value framework for future decision makers. Methods. Three focus groups were conducted in 2017 with cancer patients, oncology physicians, and nurses. Using the nominal group technique, participants identified and prioritized cancer therapy treatment and delivery attributes as well as contextual issues considered when choosing treatment options. Results. Focus groups with patients (n = 8), physicians (n = 6), and nurses (n = 10) identified 30 treatment attributes and contextual considerations. Therapy health gains was the first priority across all groups. Treatment burden/inconvenience to patients and their families and quality of evidence were prioritized treatment attributes alongside preferences for resource use and cost (to patients and society) attributes. The groups also demonstrated that contextual considerations when choosing treatment varied across the stakeholders. Patients prioritized existence of alternative treatments and oncologist/center reputation while nurses focused on administration harms, communication, and treatment innovation. The physicians did not prioritize any contextual issues in their top rankings. Conclusions. The study demonstrates that beyond health gains, there are treatment attributes and contextual considerations that are highly prioritized across stakeholder groups. These represent important candidates for inclusion in a discrete choice experiment seeking to provide weighted preferences for a value framework for oncology treatment that goes beyond health outcomes

Three-dimensional organization of basal bodies from wild-type and δ-tubulin deletion strains of Chlamydomonas reinhardtii

Improved methods of specimen preparation and dual-axis electron tomography have been used to study the structure and organization of basal bodies in the unicellular alga Chlamydomonas reinhardtii. Novel structures have been found in both wild type and strains with mutations that affect specific tubulin isoforms. Previous studies have shown that strains lacking δ-tubulin fail to assemble the C-tubule of the basal body. Tomographic reconstructions of basal bodies from the δ-tubulin deletion mutant uni3-1 have confirmed that basal bodies contain mostly doublet microtubules. Our methods now show that the stellate fibers, which are present only in the transition zone of wild-type cells, repeat within the core of uni3-1 basal bodies. The distal striated fiber is incomplete in this mutant, rootlet microtubules can be misplaced, and multiflagellate cells have been observed. A suppressor of uni3-1, designated tua2-6, contains a mutation in α-tubulin. tua2-6; uni3-1 cells build both flagella, yet they retain defects in basal body structure and in rootlet microtubule positioning. These data suggest that the presence of specific tubulin isoforms in Chlamydomonas directly affects the assembly and function of both basal bodies and basal body-associated structures

LGBT Trainee and Health Professional Perspectives on Academic Careers—Facilitators and Challenges

Purpose: Diversity efforts in the academic medicine workforce have often neglected the identification and inclusion of lesbian, gay, bisexual, and transgender (LGBT) health professionals. Many of these professionals have served as educators, researchers, administrators, and leaders at their academic institutions, but their perspectives on the barriers to and facilitators of pursuing academic careers, as well as the perspectives of trainees, have not been explored. Methods: We applied a purposeful convenience sampling strategy to collect quantitative and qualitative data among LGBT health care professionals (HCP) and trainees. The authors identified trends in data using bivariate analyses and consensual qualitative research methods. Results: We analyzed data from 252 surveys completed by HCPs and trainees and a subset of 41 individuals participated in 8 focus groups. Among survey participants, 100% identified as lesbian, gay, and bisexual (LGB) or queer; 4.5% identified along the trans-spectrum; 31.2% identified as a racial or ethnic minority; 34.1% identified as faculty; and 27.4% as trainees. Eighty-one percent of trainees were interested in academia and 47% of HCPs held faculty appointments. Overall, 79.4% were involved in LGBT-related educational, research, service, or clinical activities. Facilitators of academic careers included engagement in scholarly activities, mentorship, LGBT-specific networking opportunities, personal desire to be visible, campus opportunities for involvement in LGBT activities, and campus climate inclusive of LGBT people. Barriers included poor recognition of LGBT scholarship, a paucity of concordant mentors or LGBT networking opportunities, and hostile or non-inclusive institutional climates. Conclusion: LGBT trainees and HCPs contribute significantly to services, programs, and scholarship focused on LGBT communities. LGBT individuals report a desire for a workplace environment that encourages and supports diversity across sexual orientation and gender identities. Institutional policies and programming that facilitate LGBT inclusion and visibility in academia may lead to greater faculty work satisfaction and productivity, higher retention and supportive role modeling and mentoring for the health professions pipeline.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140160/1/lgbt.2015.0024.pd

Clumpy Galaxies in CANDELS. I. The Definition of UV Clumps and the Fraction of Clumpy Galaxies at 0.5<z<3

Although giant clumps of stars are crucial to galaxy formation and evolution, the most basic demographics of clumps are still uncertain, mainly because the definition of clumps has not been thoroughly discussed. In this paper, we study the basic demographics of clumps in star-forming galaxies (SFGs) at 0.5<z<3, using our proposed physical definition that UV-bright clumps are discrete star-forming regions that individually contribute more than 8% of the rest-frame UV light of their galaxies. Clumps defined this way are significantly brighter than the HII regions of nearby large spiral galaxies, either individually or blended, when physical spatial resolution and cosmological dimming are considered. Under this definition, we measure the fraction of SFGs that contain at least one off-center clump (Fclumpy) and the contributions of clumps to the rest-frame UV light and star formation rate of SFGs in the CANDELS/GOODS-S and UDS fields, where our mass-complete sample consists of 3239 galaxies with axial ratio q>0.5. The redshift evolution of Fclumpy changes with the stellar mass (M*) of the galaxies. Low-mass (log(M*/Msun)<9.8) galaxies keep an almost constant Fclumpy of about 60% from z~3.0 to z~0.5. Intermediate-mass and massive galaxies drop their Fclumpy from 55% at z~3.0 to 40% and 15%, respectively, at z~0.5. We find that (1) the trend of disk stabilization predicted by violent disk instability matches the Fclumpy trend of massive galaxies; (2) minor mergers are a viable explanation of the Fclumpy trend of intermediate-mass galaxies at z<1.5, given a realistic observability timescale; and (3) major mergers are unlikely responsible for the Fclumpy trend in all masses at z<1.5. The clump contribution to the rest-frame UV light of SFGs shows a broad peak around galaxies with log(M*/Msun)~10.5 at all redshifts, possibly linked to the molecular gas fraction of the galaxies. (Abridged)Comment: 22 pages, 15 figures. Appeared in ApJ (2015, 800, 39). A few typos correcte