BACKGROUNDSpinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODSWe conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTSIn the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P = 0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P = 0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONSAmong infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074.)

Plants use receptor kinases, such as FLS2 and EFR, to perceive bacterial pathogens and initiate innate immunity. This immunity is often suppressed by bacterial effectors, allowing pathogen propagation. To counteract, plants have evolved disease resistance genes that detect the bacterial effectors and reinstate resistance. The Pseudomonas syringae effector AvrPto promotes infection in susceptible plants but triggers resistance in plants carrying the protein kinase Pto and the associated resistance protein Prf. Here we show that AvrPto binds receptor kinases, including Arabidopsis FLS2 and EFR and tomato LeFLS2, to block plant immune responses in the plant cell. The ability to target receptor kinases is required for the virulence function of AvrPto in plants. The FLS2-AvrPto interaction and Pto-AvrPto interaction appear to share similar sequence requirements, and Pto competes with FLS2 for AvrPto binding. The results suggest that the mechanism by which AvrPto recognizes virulence targets is linked to the evolution of Pto, which, in association with Prf, recognizes the bacterium and triggers strong resistance.

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We report on highly efficient, bioresponsive, controlled-release antibacterial coatings constructed by direct assembly of tannic acid (TA) with one of several cationic antibiotics (tobromycin, gentamicin, and polymyxin B) using the layer-by-layer (LbL) technique. These films exhibit a distinct “self-defense” behavior triggered by acidification of the immediate environment by pathogenic bacteria, such as Staphylococcus epidermidis (S. epidermidis) or Escherichia coli (E. coli). Films assembled using spin-assisted and dip-assisted techniques show drastically different morphology, thickness and pH-/bacteria-triggered antibiotic release characteristics. While dip-deposited films have rough surfaces with island-like, granular structures regardless of the film thickness, spin-assisted LbL assemblies demonstrate a transition from linear deposition of uniform 2D films to a highly developed 3D morphology for films thicker than ∼45 nm. Ellipsometry, UV–vis and mass spectrometry confirm that all coatings do not release antibiotics in phosphate buffered saline at pH 7.4 for as long as one month in the absence of bacteria and therefore do not contribute to the development of antibiotic resistance. These films do, however, release antibiotics upon pH lowering. The rate of triggered release can be controlled through the choice of assembled antibiotic and the assembly technique (spin- vs dip-deposition) and by the spinning rate used during deposition, which all affect the strength of TA–antibiotic binding. TA/antibiotic coatings as thin as 40 nm strongly inhibit S. epidermidis and E. coli bacterial growth both at surfaces and in surrounding medium, but support adhesion and proliferation of murine osteoblast cells. These coatings thus present a promising way to incorporate antibacterial agents at surfaces to prevent bacterial colonization of implanted biomedical devices.

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