Structure and mechanism of blood-brain-barrier lipid transporter MFSD2A.

MFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain1,2, which is crucial for the development and performance of the brain3. Mutations that affect MFSD2A cause microcephaly syndromes4,5. The ability of MFSD2A to transport lipid is also a key mechanism that underlies its function as an inhibitor of transcytosis to regulate the blood-brain barrier6,7. Thus, MFSD2A represents an attractive target for modulating the permeability of the blood-brain barrier for drug delivery. Here we report the cryo-electron microscopy structure of mouse MFSD2A. Our structure defines the architecture of this important transporter, reveals its unique extracellular domain and uncovers its substrate-binding cavity. The structure-together with our functional studies and molecular dynamics simulations-identifies a conserved sodium-binding site, reveals a potential lipid entry pathway and helps to rationalize MFSD2A mutations that underlie microcephaly syndromes. These results shed light on the critical lipid transport function of MFSD2A and provide a framework to aid in the design of specific modulators for therapeutic purposes.

Informing ocean color inversion products by seeding with ancillary observations.

Ocean reflectance inversion algorithms provide many products used in ecological and biogeochemical models. While a number of different inversion approaches exist, they all use only spectral remote-sensing reflectances (Rrs(λ)) as input to derive inherent optical properties (IOPs) in optically deep oceanic waters. However, information content in Rrs(λ) is limited, so spectral inversion algorithms may benefit from additional inputs. Here, we test the simplest possible case of ingesting optical data ('seeding') within an inversion scheme (the Generalized Inherent Optical Property algorithm framework default configuration (GIOP-DC)) with both simulated and satellite datasets of an independently known or estimated IOP, the particulate backscattering coefficient at 532 nm (bbp(532)). We find that the seeded-inversion absorption products are substantially different and more accurate than those generated by the standard implementation. On global scales, seasonal patterns in seeded-inversion absorption products vary by more than 50% compared to absorption from the GIOP-DC. This study proposes one framework in which to consider the next generation of ocean color inversion schemes by highlighting the possibility of adding information collected with an independent sensor.

Plankton Imagery Data Inform Satellite-Based Estimates of Diatom Carbon.

Estimating the biomass of phytoplankton communities via remote sensing is a key requirement for understanding global ocean ecosystems. Of particular interest is the carbon associated with diatoms given their unequivocal ecological and biogeochemical roles. Satellite-based algorithms often rely on accessory pigment proxies to define diatom biomass, despite a lack of validation against independent diatom biomass measurements. We used imaging-in-flow cytometry to quantify diatom carbon in the western North Atlantic, and compared results to those obtained from accessory pigment-based approximations. Based on this analysis, we offer a new empirical formula to estimate diatom carbon concentrations from chlorophyll a. Additionally, we developed a neural network model in which we integrated chlorophyll a and environmental information to estimate diatom carbon distributions in the western North Atlantic. The potential for improving satellite-based diatom carbon estimates by integrating environmental information into a model, compared to models that are based solely on chlorophyll a, is discussed.

A selective class of inhibitors for the CLC-Ka chloride ion channel.

CLC proteins are a ubiquitously expressed family of chloride-selective ion channels and transporters. A dearth of pharmacological tools for modulating CLC gating and ion conduction limits investigations aimed at understanding CLC structure/function and physiology. Herein, we describe the design, synthesis, and evaluation of a collection of N-arylated benzimidazole derivatives (BIMs), one of which (BIM1) shows unparalleled (>20-fold) selectivity for CLC-Ka over CLC-Kb, the two most closely related human CLC homologs. Computational docking to a CLC-Ka homology model has identified a BIM1 binding site on the extracellular face of the protein near the chloride permeation pathway in a region previously identified as a binding site for other less selective inhibitors. Results from site-directed mutagenesis experiments are consistent with predictions of this docking model. The residue at position 68 is 1 of only ∼20 extracellular residues that differ between CLC-Ka and CLC-Kb. Mutation of this residue in CLC-Ka and CLC-Kb (N68D and D68N, respectively) reverses the preference of BIM1 for CLC-Ka over CLC-Kb, thus showing the critical role of residue 68 in establishing BIM1 selectivity. Molecular docking studies together with results from structure-activity relationship studies with 19 BIM derivatives give insight into the increased selectivity of BIM1 compared with other inhibitors and identify strategies for further developing this class of compounds.

The biomechanical effectiveness of the Boston brace in the management of adolescent idiopathic scoliosis.

The present study assesses the biomechanical effectiveness of the Boston brace on a group of 14 patients with adolescent scoliosis. Interface pressure measurements were performed at the appropriate compression pads within the brace when it was first applied and on two further sessions within the 6-month period of brace treatment. A corresponding series of Cobb angle measurements also were performed. Mean values of total force exerted through the brace of 58 +/- 18 N were associated with an initial curve correction of 37 +/- 21%. This mean force level was maintained throughout the study, although the mean curve correction at 6 months had reduced to 15 +/- 14%. In addition to biomechanical parameters, factors relating to the nature of the individual curve were important in determining the overall effectiveness of the Boston brace system.

A new spinal brace for use in Duchenne muscular dystrophy.

Nine boys with Duchenne muscular dystrophy, chairbound but without scoliosis, were fitted with a recently developed brace of metal and moulded medium-density polyethylene, the modified Calot brace. Each was also fitted with a wrap-around, moulded leather jacket. Each brace held the relaxed lumbar spine in an angle of lordosis similar to that achieved by a brief active effort to sit erect without a brace. Over-all, they proved equally acceptable to patients and carers. The modified Calot brace caused substantially less restriction of pulmonary function and so may be preferable to the moulded leather jacket.

A comparative trial of two walking systems for paralysed people.

A trial has been performed to compare two designs of reciprocal walking orthosis for paralysed people--the hip guidance orthosis (HGO) from Oswestry, England, and the reciprocating gait orthosis (RGO) from New Orleans, USA. Eighteen male and 4 female paraplegic subjects used each orthosis for 4 months, in a crossover study. All aspects of the provision and use of the devices were monitored, and a variety of assessments were made. Fifteen subjects were able to use both orthoses, 5 were unable to use either and 2 succeeded with the HGO but not the RGO. At the end of the trial 12 subjects chose to keep the RGO, 4 the HGO, and 6 kept neither. Those choosing the RGO liked its appearance; those choosing the HGO liked the speed of donning and doffing. The RGO was about 50% more expensive to supply than the HGO.