Neuromotor prostheses (NMPs) aim to replace or restore lost motor functions in paralysed humans by routeing movement-related signals from the brain, around damaged parts of the nervous system, to external effectors. To translate preclinical results from intact animals to a clinically useful NMP, movement signals must persist in cortex after spinal cord injury and be engaged by movement intent when sensory inputs and limb movement are long absent. Furthermore, NMPs would require that intention-driven neuronal activity be converted into a control signal that enables useful tasks. Here we show initial results for a tetraplegic human (MN) using a pilot NMP. Neuronal ensemble activity recorded through a 96-microelectrode array implanted in primary motor cortex demonstrated that intended hand motion modulates cortical spiking patterns three years after spinal cord injury. Decoders were created, providing a 'neural cursor' with which MN opened simulated e-mail and operated devices such as a television, even while conversing. Furthermore, MN used neural control to open and close a prosthetic hand, and perform rudimentary actions with a multi-jointed robotic arm. These early results suggest that NMPs based upon intracortical neuronal ensemble spiking activity could provide a valuable new neurotechnology to restore independence for humans with paralysis.

PrefaceGenome maintenance is a constant problem in all cells and a coordinated response to DNA damage is required to maintain cellular viability and prevent disease. The ATR and ATM protein kinases are master regulators of the DNA damage response, signaling to control cell cycle transitions, DNA replication, DNA repair, and apoptosis. Recent studies have provided insights into the mechanisms controlling ATR activation, helped to explain the overlapping but non-redundant activities of ATR and ATM in DNA damage signaling, and clarified the critical functions of ATR in maintaining genome integrity. IntroductionAll cells have elaborate mechanisms to maintain their genomes. DNA can be damaged during replication, by reactive metabolic byproducts as well as environmental mutagens. Responding to and repairing DNA damage is critical for cell viability and disease prevention.The DNA damage response (DDR) is a signal transduction pathway that coordinates cell cycle transitions, DNA replication, DNA repair and apoptosis. The major regulators of the DDR are the phosphoinositide 3-kinase related protein kinases (PIKKs), including ataxia-telangiectasia mutated (ATM) and ATM and Rad3 related (ATR). ATM and ATR share many biochemical and functional similarities. Both are large kinases with significant sequence homology and a strong preference to phosphorylate serine or threonine residues that are followed by glutamine. Both target an overlapping set of substrates that promote cell cycle arrest and DNA repair. However, ATR is essential for the viability of replicating human and mouse cells, whereas ATM is not 1-3 . ATM functions in response to rare occurrences of double strand breaks. By contrast, ATR is activated during every S-phase to regulate the firing of replication origins, the repair of damaged replication forks and to prevent the premature onset of mitosis 4, 5 (Fig. 1).Mutations in ATM predispose carriers to cancer and are found in approximately 0.5-1% of the population 6, 7 . People with mutations in both alleles of ATM suffer from the neurodegenerative and cancer predisposition disorder ataxia-telangiectasia 8 . Mutations in ATR are rare and probably only compatible with viability when heterozygous or hypomorphic. While the only clear link between ATR gene mutation and disease is in a few patients with the rare Seckel syndrome (characterized by growth retardation and microcephaly) 9 , disruptions in the ATR pathway do cause genomic instability, and ATR is activated by most cancer chemotherapies. Furthermore, ATR signaling is a promising target for cancer drug development 10, 11 . This review will focus on ATR signaling in the DNA damage response, and compare and contrast it with the more specialized role of ATM. NIH Public Access Mechanisms of ATR ActivationThe broad functions and physiological importance of ATR derive in large part from recognizing the signals that lead to its activation versus that of ATM. Thus, we will address the mechanism of activation in some detail. Recognizing DNA damageAlthough ATR is activ...

Seventy percent of breast cancers express estrogen receptor (ER) and most of these are sensitive to ER inhibition. However, many such tumors become refractory to inhibition of estrogen action in the metastatic setting for unknown reasons. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER+ breast tumors and identified mutations in the ligand binding domain (LBD) of ESR1 in 14/80 cases. These included highly recurrent mutations p.Tyr537Ser/Asn and p.Asp538Gly. Molecular dynamics simulations suggest the Tyr537Ser and Asp538Gly structures lead to hydrogen bonding of the mutant amino acid with Asp351, thus favoring the receptor’s agonist conformation. Consistent with this model, mutant receptors drive ER-dependent transcription and proliferation in the absence of hormone and reduce the efficacy of ER antagonists. These data implicate LBD mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may have significant therapeutic benefit.

Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.