An exact mathematical description of computation with transient spatiotemporal dynamics in a complex-valued neural network

We study a complex-valued neural network (cv-NN) with linear, time-delayed interactions. We report the cv-NN displays sophisticated spatiotemporal dynamics, including partially synchronized ``chimera'' states. We then use these spatiotemporal dynamics, in combination with a nonlinear readout, for computation. The cv-NN can instantiate dynamics-based logic gates, encode short-term memories, and mediate secure message passing through a combination of interactions and time delays. The computations in this system can be fully described in an exact, closed-form mathematical expression. Finally, using direct intracellular recordings of neurons in slices from neocortex, we demonstrate that computations in the cv-NN are decodable by living biological neurons. These results demonstrate that complex-valued linear systems can perform sophisticated computations, while also being exactly solvable. Taken together, these results open future avenues for design of highly adaptable, bio-hybrid computing systems that can interface seamlessly with other neural networks

Crystal structures of the NO sensor NsrR reveal how its iron-sulfur cluster modulates DNA binding

NsrR from Streptomyces coelicolor (Sc) regulates the expression of three genes through the progressive degradation of its [4Fe–4S] cluster on nitric oxide (NO) exposure. We report the 1.95 Å resolution crystal structure of dimeric holo-ScNsrR and show that the cluster is coordinated by the three invariant Cys residues from one monomer and, unexpectedly, Asp8 from the other. A cavity map suggests that NO displaces Asp8 as a cluster ligand and, while D8A and D8C variants remain NO sensitive, DNA binding is affected. A structural comparison of holo-ScNsrR with an apo-IscR-DNA complex shows that the [4Fe–4S] cluster stabilizes a turn between ScNsrR Cys93 and Cys99 properly oriented to interact with the DNA backbone. In addition, an apo ScNsrR structure suggests that Asn97 from this turn, along with Arg12, which forms a salt-bridge with Asp8, are instrumental in modulating the position of the DNA recognition helix region relative to its major groove

Ecological commonalities among pelagic fishes: comparison of freshwater ciscoes and marine herring and sprat

Systematic comparisons of the ecology between functionally similar fish species from freshwater and marine aquatic systems are surprisingly rare. Here, we discuss commonalities and differences in evolutionary history, population genetics, reproduction and life history, ecological interactions, behavioural ecology and physiological ecology of temperate and Arctic freshwater coregonids (vendace and ciscoes, Coregonus spp.) and marine clupeids (herring, Clupea harengus, and sprat, Sprattus sprattus). We further elucidate potential effects of climate warming on these groups of fish based on the ecological features of coregonids and clupeids documented in the previous parts of the review. These freshwater and marine fishes share a surprisingly high number of similarities. Both groups are relatively short-lived, pelagic planktivorous fishes. The genetic differentiation of local populations is weak and seems to be in part correlated to an astonishing variability of spawning times. The discrete thermal window of each species influences habitat use, diel vertical migrations and supposedly also life history variations. Complex life cycles and preference for cool or cold water make all species vulnerable to the effects of global warming. It is suggested that future research on the functional interdependence between spawning time, life history characteristics, thermal windows and genetic differentiation may profit from a systematic comparison of the patterns found in either coregonids or clupeids

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Seeding Science, Courting Conclusions: Reexamining the Intersection of Science, Corporate Cash, and the Law

Social scientists have expressed strong views on corporate influences over science, but most attention has been devoted to broad, Black/White arguments, rather than to actual mechanisms of influence. This paper summarizes an experience where involvement in a lawsuit led to the discovery of an unexpected mechanism: A large corporation facing a multibillion-dollar court judgment quietly provided generous funding to well-known scientists (including at least one Nobel prize winner) who would submit articles to "open," peer-reviewed journals, so that their "unbiased science" could be cited in an appeal to the Supreme Court. On balance, the corporation's most effective techniques of influence may have been provided not by overt pressure, but by encouraging scientists to continue thinking of themselves as independent and impartial

Microfluidics: reframing biological enquiry

The underlying physical properties of microfluidic tools have led to new biological insights through the development of microsystems that can manipulate, mimic and measure biology at a resolution that has not been possible with macroscale tools. Microsystems readily handle sub-microlitre volumes, precisely route predictable laminar fluid flows and match both perturbations and measurements to the length scales and timescales of biological systems. The advent of fabrication techniques that do not require highly specialized engineering facilities is fuelling the broad dissemination of microfluidic systems and their adaptation to specific biological questions. We describe how our understanding of molecular and cell biology is being and will continue to be advanced by precision microfluidic approaches and posit that microfluidic tools - in conjunction with advanced imaging, bioinformatics and molecular biology approaches - will transform biology into a precision science

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10‾⁴⁹), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.This work was funded by a Medical Research Council (MRC) strategic award to M.D.T., I.P.H., D.S. and L.V.W. (MC_PC_12010). This research has been conducted using the UK Biobank Resource under application 648. This article presents independent research funded partially by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the UK Department of Health. This research used the ALICE and SPECTRE High-Performance Computing Facilities at the University of Leicester. Additional acknowledgments and funding details can be found in the Supplementary Note

Protective intraoperative ventilation with higher versus lower levels of positive end-expiratory pressure in obese patients (PROBESE): study protocol for a randomized controlled trial

Background: Postoperative pulmonary complications (PPCs) increase the morbidity and mortality of surgery in obese patients. High levels of positive end-expiratory pressure (PEEP) with lung recruitment maneuvers may improve intraoperative respiratory function, but they can also compromise hemodynamics, and the effects on PPCs are uncertain. We hypothesized that intraoperative mechanical ventilation using high PEEP with periodic recruitment maneuvers, as compared with low PEEP without recruitment maneuvers, prevents PPCs in obese patients. Methods/design The PRotective Ventilation with Higher versus Lower PEEP during General Anesthesia for Surgery in OBESE Patients (PROBESE) study is a multicenter, two-arm, international randomized controlled trial. In total, 2013 obese patients with body mass index ≥35 kg/m2 scheduled for at least 2 h of surgery under general anesthesia and at intermediate to high risk for PPCs will be included. Patients are ventilated intraoperatively with a low tidal volume of 7 ml/kg (predicted body weight) and randomly assigned to PEEP of 12 cmH2O with lung recruitment maneuvers (high PEEP) or PEEP of 4 cmH2O without recruitment maneuvers (low PEEP). The occurrence of PPCs will be recorded as collapsed composite of single adverse pulmonary events and represents the primary endpoint. Discussion To our knowledge, the PROBESE trial is the first multicenter, international randomized controlled trial to compare the effects of two different levels of intraoperative PEEP during protective low tidal volume ventilation on PPCs in obese patients. The results of the PROBESE trial will support anesthesiologists in their decision to choose a certain PEEP level during general anesthesia for surgery in obese patients in an attempt to prevent PPCs. Trial registration ClinicalTrials.gov identifier: NCT02148692. Registered on 23 May 2014; last updated 7 June 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1929-0) contains supplementary material, which is available to authorized users

Legal Issues and Students with Learning Disabilities

The Individuals with Disabilities Education Act (IDEA), formerly the Education of All Handicapped Children Act, has exerted a profound influence on the education of students with disabilities. In 2004 major changes were made to the IDEA when it was amended in the Individuals with Disabilities Education Improvement Act. The category of disabilities that was most profoundly affected by these changes may have been the category of learning disabilities. In this chapter we (a) review the development and major components of the IDEA, (b) explain the important changes in the 2004 amendments for the education of students with learning disabilities, focusing on two specific requirements, and (c) reflect on possible changes in future amendments to the IDEA