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"Fine, Michael"
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Structural basis for PtdInsP2-mediated human TRPML1 regulation
Transient receptor potential mucolipin 1 (TRPML1), a lysosomal channel, maintains the low pH and calcium levels for lysosomal function. Several small molecules modulate TRPML1 activity. ML-SA1, a synthetic agonist, binds to the pore region and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P
2
), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P
2
, another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P
2
and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P
2
, PtdIns(4,5)P
2
, or ML-SA1 and PtdIns(3,5)P
2
, revealing a unique lipid-binding site. PtdIns(3,5)P
2
and PtdIns(4,5)P
2
bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P
2
induces Y355 to form a π-cation interaction with R403, moving the S4–S5 linker, thus allosterically activating the channel. Our structures and electrophysiological characterizations reveal an allosteric site and provide molecular insight into how lipids regulate TRP channels.
Transient receptor potential mucolipin 1 (TRPML1) is a lysosomal channel which maintains the low pH and calcium levels for lysosomal function. Here authors use structural biology and electrophysiology to show how lipids bind and allosterically activate TRPML1.
Journal Article
Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial
Although practice guidelines recommend outpatient care for selected, haemodynamically stable patients with pulmonary embolism, most treatment is presently inpatient based. We aimed to assess non-inferiority of outpatient care compared with inpatient care.
We undertook an open-label, randomised non-inferiority trial at 19 emergency departments in Switzerland, France, Belgium, and the USA. We randomly assigned patients with acute, symptomatic pulmonary embolism and a low risk of death (pulmonary embolism severity index risk classes I or II) with a computer-generated randomisation sequence (blocks of 2–4) in a 1:1 ratio to initial outpatient (ie, discharged from hospital ≤24 h after randomisation) or inpatient treatment with subcutaneous enoxaparin (≥5 days) followed by oral anticoagulation (≥90 days). The primary outcome was symptomatic, recurrent venous thromboembolism within 90 days; safety outcomes included major bleeding within 14 or 90 days and mortality within 90 days. We used a non-inferiority margin of 4% for a difference between inpatient and outpatient groups. We included all enrolled patients in the primary analysis, excluding those lost to follow-up. This trial is registered with
ClinicalTrials.gov, number
NCT00425542.
Between February, 2007, and June, 2010, we enrolled 344 eligible patients. In the primary analysis, one (0·6%) of 171 outpatients developed recurrent venous thromboembolism within 90 days compared with none of 168 inpatients (95% upper confidence limit [UCL] 2·7%; p=0·011). Only one (0·6%) patient in each treatment group died within 90 days (95% UCL 2·1%; p=0·005), and two (1·2%) of 171 outpatients and no inpatients had major bleeding within 14 days (95% UCL 3·6%; p=0·031). By 90 days, three (1·8%) outpatients but no inpatients had developed major bleeding (95% UCL 4·5%; p=0·086). Mean length of stay was 0·5 days (SD 1·0) for outpatients and 3·9 days (SD 3·1) for inpatients.
In selected low-risk patients with pulmonary embolism, outpatient care can safely and effectively be used in place of inpatient care.
Swiss National Science Foundation, Programme Hospitalier de Recherche Clinique, and the US National Heart, Lung, and Blood Institute. Sanofi-Aventis provided free drug supply in the participating European centres.
Journal Article
An investigation of bubble resonance and its implications for sound production by deep-water fishes
Although the continental slope and abyss comprise the largest habitat on earth, the absence of documented fish sounds from deep waters is striking. Fishes with sexually dimorphic muscles attached to their swim bladders suggests that sounds are likely used in male courtship on the upper, mid and lower continental slope. To investigate the effects of environmental extremes on fish sound production, the acoustic behavior of a driven bubble is examined. This study is also relevant to target strength of sonar returns from fish and hearing in auditory specialist fishes. A bubble is a classic, if imperfect, model for swim bladder behavior since the swim-bladder wall is an anisotropic viscoelastic structure responsible for rapid damping. Acoustic properties of bubbles–including far-field resonant frequency, damping factor, and quality factor–are calculated in warm and cold surface conditions and in cold deep-water (depths 1000 m, 2000 m, and 3500 m) conditions using parameters for oxygen and nitrogen, the dominant gases in swim bladders. The far-field resonant frequency and damping factor of a bubble increase with depth, and the scattering cross-section and quality factor decrease with depth. These acoustic properties scale with undamped oscillation frequency of the bubble and do not vary significantly due to gas type or temperature. Bubbles in the deep-water environments are much less efficient radiators of sound than bubbles near the surface because the far-field radiated power for the same excitation decreases with depth. A bubble at depth 3500 m has a 25 dB loss in radiated sound power compared to the same-radius bubble at the surface. This reduction of radiation efficiency in deep water likely contributes to the absence of fish sound recordings in those environments.
Journal Article
James Turrell : a retrospective
\"Published in conjunction with a major retrospective, this comprehensive volume illuminates the origins and motivations of James Turrell's incredibly diverse and exciting body of work--from his Mendota studio days to his monumental work-in-progress Roden Crater. Whether he's projecting shapes on a flat wall or into the corner of a gallery space, James Turrell is perpetually asking us to \"go inside and greet the light\"--evoking his Quaker upbringing. In fact, all of Turrell's work has been influenced by his life experiences with aviation, science, and psychology, and as a key player in Los Angeles's exploding art scene of the 1960s. Enhanced by thoughtful essays and an illuminating interview with the artist, this monograph explores every aspect of Turrell's career to date--from his early geometric light projections, prints, and drawings, through his installations exploring sensory deprivation and seemingly unmodulated fields of colored light, to recent two-dimensional experiments with holograms. It also features an in-depth look at Roden Crater, a site-specific intervention into the landscape near Flagstaff, Arizona, which will be presented through models, plans, photographs, and drawings. Fans of this highly influential artist will find much to savor in this wide-ranging and beautiful book, featuring specially commissioned new photography by Florian Holzherr.\"--Publisher's website.
Book
Characterizing dual-pulse calls in five Sciaenid species
Many fish species use acoustic signals for various purposes, with sciaenids being among the best-known vocal teleosts. Although advertisement and disturbance calls have been well studied, the dual-pulse call (or dual-knock) has been reported infrequently. Here, we recorded dual-pulse sounds in five South Atlantic sciaenid species and analyzed their acoustic features from four species in captivity and one in the wild. These stereotyped calls are emitted by both free-swimming and stationary individuals, often without apparent social interactions, although they are routinely elicited by a human feeder. The occurrence of this call type across geographically distant species in South America, North America, and Asia suggests it may represent a basal trait within the family, potentially serving important but yet undetermined functions.
Journal Article
The Pneumonia Severity Index: A Decade after the Initial Derivation and Validation
The prognosis of community-acquired pneumonia ranges from rapid resolution of symptoms and full recovery of functional status to the development of severe medical complications and death. The pneumonia severity index is a rigorously studied prediction rule for prognosis that objectively stratifies patients into quintiles of risk for short-term mortality on the basis of 20 demographic and clinical variables routinely available at presentation. The pneumonia severity index was derived and validated with data on >50,000 patients with community-acquired pneumonia by use of well-accepted methodological standards and is the only pneumonia decision aid that has been empirically shown to safely increase the proportion of patients given treatment in the outpatient setting. Because of its prognostic accuracy, methodological rigor, and effectiveness and safety as a decision aid, the pneumonia severity index has become the reference standard for risk stratification of community-acquired pneumonia.
Journal Article
Health Care Reform and Primary Care — The Growing Importance of the Community Health Center
The Patient Protection and Affordable Care Act enables community health centers to serve nearly 20 million new patients while adding an estimated 15,000 providers to their staffs by 2015. Dr. Eli Adashi and colleagues describe the “new” community health centers.
During the debate over U.S. health care reform, relatively little attention was paid to the long-established network of community health centers (CHCs) in the United States. And yet this unique national asset constitutes a critical element of any reform intent on expanding access to health care through a primary care portal. With an eye toward meeting the primary care needs of an estimated 32 million newly insured Americans, the recently passed Patient Protection and Affordable Care Act underwrites the CHCs and enables them to serve nearly 20 million new patients while adding an estimated 15,000 providers to their staffs by . . .
Journal Article