The parallel projection operators of a nonlinear feedback system

The authors define and study a pair of nonlinear parallel projection operators associated with a nonlinear feedback system. The input-output L_2-stability of a feedback system is shown to be equivalent to a coordinating of the input and output spaces, which is also equivalent to the existence of a pair of nonlinear parallel projection operators onto the graph of the plant and the inverse graph of the controller. These projections have equal norms whenever one of the feedback elements is linear. A bound on this norm is given in the case of passive systems with unity negative feedback

Diagnosis and surgical approach of popliteal artery entrapment syndrome: a retrospective study

Stavros Gourgiotis1, John Aggelakas1, Nikolaos Salemis1, Charalabos Elias2, Charalabos Georgiou11Second Surgical Department, 401 General Army Hospital of Athens, Greece; 2Second Surgical Department, 417 NIMTS Veterans General Hospital of Athens, GreeceBackground: Popliteal artery entrapment syndrome (PAES) is a rare but potentially limb threatening peripheral vascular disease occurring predominantly in young adults. This study is a retrospective review of 49 limbs in 38 patients with PAES treated surgically over an 8-year period.Patients and methods: From 1995 to 2002, 38 patients with a mean age of 21 years (range, 18–29 years) underwent surgery for PAES at a single institution. The patients’ demographic data and clinical features are recorded. The preoperative diagnosis of PAES was made based on various combinations of investigations including positional stress test, duplex ultrasonography, computed tomography, computed tomographic angiography, and angiography. Results: Nine, 33, and 7 patients had Delaney’s type I, II, and III PAES respectively. The surgical procedures consisted of simple release of the popliteal artery in 33 limbs (67.3%), autogenous saphenous vein (ASV) patch angioplasty with or without thromboendarterectomy (TEA) in 5 limbs (10.2%) and ASV graft interposition or bypass in 11 limbs (22.5%). At a median follow up of 34 months (range, 8–42 months), there were no postoperative complications and all the patients were cured of their symptoms.Conclusions: PAES is an unusual but important cause of peripheral vascular insufficiency especially in young patients. Early diagnosis through a combined approach is necessary for exact diagnosis. Popliteal artery release alone or with vein bypass is the treatment of choice when intervention is indicated for good operative outcome and to prevent limb loss.Keywords: popliteal artery, entrapment syndrome, diagnosis, surgery, treatmen

Engineering and preclinical evaluation of a human enzyme immune checkpoint inhibitor for cancer therapy

The work presented here builds on the findings that the amino acid kynurenine (L-Kyn) synthesized via the enzymes indoleamine/tryptophan dioxygenase (IDO/TDO) mediates cancer immune suppression in a paracrine fashion and evaluates the hypothesis that systemic elimination of secreted Kyn in the extracellular space using an engineered human kynureninase enzyme (KYNase) to degrade it into inactive metabolites will have pronounced anti-tumor activity and overcome the limitations associated with IDO/TDO inhibitors. The significance of L-Kyn production in cancer is well recognized and has led to the development of inhibitors of IDO and TDO; with at least one IDO inhibitor currently undergoing Phase II/III clinical evaluation. However IDO or TDO inhibition is problematic for cancer therapy because: (1) there are two isoforms of IDO and together with TDO, the inhibition of all possible pathways for Kynurenine generation at present requires the generation of multiple small molecule inhibitors; (2) resistance to inhibition can arise, and (3) as a single agent IDO/TDO inhibitors show very little efficacy. Wild-type human KYNase has a strong preference for the degradation of 3’OH Kynurenine (OH-Kyn) with a kcat/KM = 105 M-1s-1, about 1,000 fold higher than that displayed for L-Kyn degradation (102 M-1s-1). In contrast some bacterial enzymes such as the KYNase from P.fluorescens displays a nearly equal and opposite substrate preference for Kyn over OH-Kyn. Although the P.fluorescens KYNase has ideal kinetics desired in an enzyme therapeutic targeting tumor L-Kyn, its high immunogenicity render it unsuitable as a clinical candidate, necessitating the engineering of a human KYNase with the requisite pharmacological properties. Therefore we undertook a directed evolution campaign coupled with high throughput competitive genetic selections and screening strategies to engineer the human KYNase enzyme, creating variants with \u3e 500 fold increases in catalytic activity towards L-Kyn. Engineered human KYNase enzymes were then PEGylated for long circulatory persistence and administered to mice bearing murine cancer allografts and evaluated for efficacy and PK/PD. We found that administration of PEGylated engineered human KYNase enzymes resulted in lowered systemic L-Kyn levels accompanied by significant tumor growth retardation, extended survival and even complete regressions in a manner similar to that observed with immune checkpoint inhibitors such as anti-PD. Flow cytometric analysis showed a significant increase in the proportion of TCRB+ T cells in the tumor-infiltrating lymphocytes (TILs) that is consistent with significant incorporation of BrdU in CD4+ and CD8+ T cells in the tumor-draining lymph nodes (dLNs) and TILs compared to control mice treated with deactivated enzyme. Additionally, marked elevation of CD8+ and CD4+ T cells expressing granzyme (Gzm)B and interferon (IFNG) was observed in the active-enzyme-treated mice, further highlighting the importance of L-Kyn in tumor evasion of immune surveillance. As a monotherapy, small molecule inhibitors of IDO1 display at most marginal anti-cancer activity in animal models as well as in clinical trials likely due to the redundancy of Kyn biosynthetic pathways; necessitating combinations of IDO1/TDO inhibitors. The therapeutic enzyme approach using engineered human KYNase represents an effective “first in class” drug for restoring T-cell immunity for cancer eradication, without the limitations of IDO1/TDO inhibition. This work further demonstrates the utility of “enzymes as drugs” in targeting aberrantly regulated metabolites in disease states

Administration of kynurenine depleting enzymes for tumor therapy

Methods and compositions related to the use of a protein with kynureninase activity are described. For example, in certain aspects there may be disclosed a modified kynureninase capable of degrading kynurenine. Furthermore, certain aspects of the invention provide compositions and methods for the treatment of cancer with kynurenine depletion using the disclosed proteins or nucleic acids.Board of Regents, University of Texas Syste

Population dynamics, delta vulnerability and environmental change: comparison of the Mekong, Ganges–Brahmaputra and Amazon delta regions

Tropical delta regions are at risk of multiple threats including relative sea level rise and human alterations, making them more and more vulnerable to extreme floods, storms, surges, salinity intrusion, and other hazards which could also increase in magnitude and frequency with a changing climate. Given the environmental vulnerability of tropical deltas, understanding the interlinkages between population dynamics and environmental change in these regions is crucial for ensuring efficient policy planning and progress toward social and ecological sustainability. Here, we provide an overview of population trends and dynamics in the Ganges–Brahmaputra, Mekong and Amazon deltas. Using multiple data sources, including census data and Demographic and Health Surveys, a discussion regarding the components of population change is undertaken in the context of environmental factors affecting the demographic landscape of the three delta regions. We find that the demographic trends in all cases are broadly reflective of national trends, although important differences exist within and across the study areas. Moreover, all three delta regions have been experiencing shifts in population structures resulting in aging populations, the latter being most rapid in the Mekong delta. The environmental impacts on the different components of population change are important, and more extensive research is required to effectively quantify the underlying relationships. The paper concludes by discussing selected policy implications in the context of sustainable development of delta regions and beyond

A Co-operative Regulation of Neuronal Excitability by UNC-7 Innexin and NCA/NALCN Leak Channel

Gap junctions mediate the electrical coupling and intercellular communication between neighboring cells. Some gap junction proteins, namely connexins and pannexins in vertebrates, and innexins in invertebrates, may also function as hemichannels. A conserved NCA/Dmα1U/NALCN family cation leak channel regulates the excitability and activity of vertebrate and invertebrate neurons. In the present study, we describe a genetic and functional interaction between the innexin UNC-7 and the cation leak channel NCA in Caenorhabditis elegans neurons. While the loss of the neuronal NCA channel function leads to a reduced evoked postsynaptic current at neuromuscular junctions, a simultaneous loss of the UNC-7 function restores the evoked response. The expression of UNC-7 in neurons reverts the effect of the unc-7 mutation; moreover, the expression of UNC-7 mutant proteins that are predicted to be unable to form gap junctions also reverts this effect, suggesting that UNC-7 innexin regulates neuronal activity, in part, through gap junction-independent functions. We propose that, in addition to gap junction-mediated functions, UNC-7 innexin may also form hemichannels to regulate C. elegans' neuronal activity cooperatively with the NCA family leak channels

800-5 Improving Accuracy of Ultrafast Computed Tomography in the Detection of Angiographically Significant Coronary Artery Disease

In differentiating coronary calcium from artifact by ultrafast computed tomography (UFCT), many different thresholds have been proposed. UFCT has demonstrated a high sensitivity and only modest specificity to detect coronary calcifications when compared to angiography. The Agatston method is most widely used today, utilizing a minimum CT number of 130 Hounsfield units (HU). In an attempt to improve specificity without markedly reducing sensitivity, we evaluated 272 coronary vessels from 68 patients with angiography and UFCT coronary scanning. All patients underwent coronary angiography for clinical indications, and had UFCT scanning done within three months of the angiogram. A blinded reader evaluated all the UFCT scans. We then varied the minimum CT number to assess whether 130 HU was truly the best threshold. Sensitivity, specificity and accuracy for different thresholds are listed.Threshold130 HU150 HU170 HU200 HUSensitivity95%92%89%87%Specificity65%72%75%78%Accuracy72%77%78%79%The results above indicate that 130 HU is too low a threshold to maximize accuracy of this test when compared with angiography. Sensitivity is reduced as the threshold is improved, however this result is not significant (p=0.61). The improved specificity from 130 to 150 represents a significant improvement (p<0.0001), although a larger study must be performed before widespread use of this new threshold is employed

Impact of External Cue Validity on Driving Performance in Parkinson's Disease

This study sought to investigate the impact of external cue validity on simulated driving performance in 19 Parkinson's disease (PD) patients and 19 healthy age-matched controls. Braking points and distance between deceleration point and braking point were analysed for red traffic signals preceded either by Valid Cues (correctly predicting signal), Invalid Cues (incorrectly predicting signal), and No Cues. Results showed that PD drivers braked significantly later and travelled significantly further between deceleration and braking points compared with controls for Invalid and No-Cue conditions. No significant group differences were observed for driving performance in response to Valid Cues. The benefit of Valid Cues relative to Invalid Cues and No Cues was significantly greater for PD drivers compared with controls. Trail Making Test (B-A) scores correlated with driving performance for PDs only. These results highlight the importance of external cues and higher cognitive functioning for driving performance in mild to moderate PD