Subsumed complexity: abiogenesis as a by-product of complex energy transduction.

The origins of life bring into stark relief the inadequacy of our current synthesis of thermodynamic, chemical, physical and information theory to predict the conditions under which complex, living states of organic matter can arise. Origins research has traditionally proceeded under an array of implicit or explicit guiding principles in lieu of a universal formalism for abiogenesis. Within the framework of a new guiding principle for prebiotic chemistry called subsumed complexity, organic compounds are viewed as by-products of energy transduction phenomena at different scales (subatomic, atomic, molecular and polymeric) that retain energy in the form of bonds that inhibit energy from reaching the ground state. There is evidence for an emergent level of complexity that is overlooked in most conceptualizations of abiogenesis that arises from populations of compounds formed from atomic energy input. We posit that different forms of energy input can exhibit different degrees of dissipation complexity within an identical chemical medium. By extension, the maximum capacity for organic chemical complexification across molecular and macromolecular scales subsumes, rather than emerges from, the underlying complexity of energy transduction processes that drive their production and modification.This article is part of the themed issue 'Reconceptualizing the origins of life'.

Amoeba-inspired nanoarchitectonic computing implemented using electrical Brownian ratchets.

In this study, we extracted the essential spatiotemporal dynamics that allow an amoeboid organism to solve a computationally demanding problem and adapt to its environment, thereby proposing a nature-inspired nanoarchitectonic computing system, which we implemented using a network of nanowire devices called 'electrical Brownian ratchets (EBRs)'. By utilizing the fluctuations generated from thermal energy in nanowire devices, we used our system to solve the satisfiability problem, which is a highly complex combinatorial problem related to a wide variety of practical applications. We evaluated the dependency of the solution search speed on its exploration parameter, which characterizes the fluctuation intensity of EBRs, using a simulation model of our system called 'AmoebaSAT-Brownian'. We found that AmoebaSAT-Brownian enhanced the solution searching speed dramatically when we imposed some constraints on the fluctuations in its time series and it outperformed a well-known stochastic local search method. These results suggest a new computing paradigm, which may allow high-speed problem solving to be implemented by interacting nanoscale devices with low power consumption.

Atomic switch networks-nanoarchitectonic design of a complex system for natural computing.

Self-organized complex systems are ubiquitous in nature, and the structural complexity of these natural systems can be used as a model to design new classes of functional nanotechnology based on highly interconnected networks of interacting units. Conventional fabrication methods for electronic computing devices are subject to known scaling limits, confining the diversity of possible architectures. This work explores methods of fabricating a self-organized complex device known as an atomic switch network and discusses its potential utility in computing. Through a merger of top-down and bottom-up techniques guided by mathematical and nanoarchitectonic design principles, we have produced functional devices comprising nanoscale elements whose intrinsic nonlinear dynamics and memorization capabilities produce robust patterns of distributed activity and a capacity for nonlinear transformation of input signals when configured in the appropriate network architecture. Their operational characteristics represent a unique potential for hardware implementation of natural computation, specifically in the area of reservoir computing-a burgeoning field that investigates the computational aptitude of complex biologically inspired systems.

Association between skin toxicity and efficacy of necitumumab in squamous non-small-cell lung cancer: a pooled analysis of two randomized clinical trials-SQUIRE and JFCM.

BACKGROUND: Efficacy of necitumumab [recombinant human monoclonal antibody that blocks the ligand binding epidermal growth factor receptor (EGFR)] in patients with squamous (SQ) non-small-cell lung cancer (NSCLC) has been confirmed in two randomized clinical trials (SQUIRE and JFCM). This study evaluated the association between efficacy and initial skin toxicity with necitumumab treatment by analyzing pooled data from two clinical trials (SQUIRE and JFCM). MATERIALS AND METHODS: Data of 635 patients with SQ-NSCLC (intent-to-treat population) treated with necitumumab plus gemcitabine and cisplatin (N + GC) were pooled from two clinical trials (SQUIRE and JFCM). The relationship between skin toxicities developed by the end of the second cycle and efficacy was evaluated. Efficacy endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Univariate and multivariate analyses were carried out for these endpoints. RESULTS: OS and ORR were associated with skin toxicity, whereas PFS was not. Patients with grade ≥2 or grade 1 skin toxicity had significantly longer OS compared to patients without skin toxicity (grade 0) in the N + GC group [median = 15.0 (grade ≥2); 12.7 (grade 1); 9.4 (grade 0) months; hazard ratio (HR) = 0.51 (grade ≥2 to grade 0); 95% confidence interval (CI) 0.40-0.64, P < 0.001 and HR = 0.64 (grade 1 to grade 0); 95% CI 0.52-0.80, P < 0.001]. In multivariate analysis, OS was significantly associated with skin toxicity. CONCLUSIONS: A significant association was found between necitumumab-induced skin toxicity and efficacy. These results are consistent with the previously reported association between other EGFR inhibitors-induced skin toxicity and efficacy.

Efficacy and safety of switching from basal insulin to sitagliptin in Japanese type 2 diabetes patients.

Basal-supported oral therapy (BOT) is often used to treat poorly controlled type 2 diabetes. However, patients sometimes experience nocturnal and early morning hypoglycemia. Thus, maintaining targeted glycemic control by BOT is limited in some patients. We assessed the efficacy and safety of replacing basal insulin by sitagliptin therapy in Japanese type 2 diabetes patients on BOT. Forty-nine subjects were sequentially recruited for the 52-week, prospective, single arm study. Patients on BOT therapy were switched from basal insulin to sitagliptin. The primary endpoint was change in HbA1c in 52 weeks. The secondary endpoints were dropout rate, changes in body weight, frequency of hypoglycemia, and relationship between change in HbA1c and insulin secretion capacity evaluated by glucagon loading test. The average dose of basal insulin was 15.0±8.4 units. Sixteen subjects (31.3%) were dropped because replacement by sitagliptin was less effective for glycemic control. In these subjects, diabetes duration was longer, FPG and HbA1c at baseline were higher, and insulin secretion capacity was lower. Change in HbA1c in 52 weeks was - 4 mmol/mol (95% CI - 5 to - 4 mmol/mol) (p<0.05). Change in body weight was - 0.71 kg (95% CI - 1.42 to - 0.004 kg) (p<0.05). Frequency of hypoglycemia was decreased from 1.21±1.05 to 0.06±0.24 times/month. HbA1c level was improved if C-peptide index (CPI) was over 1.19. In conclusion, basal insulin in BOT can be replaced by sitagliptin with a decrease in HbA1c level and frequency of hypoglycemia in cases where insulin secretion capacity was sufficiently preserved.

Volatile and nonvolatile selective switching of a photo-assisted initialized atomic switch.

A photo-assisted atomic switch, which has a photoconductive molecular layer in a gap of about 20 nm between an Ag2S electrode and a Pt electrode, is set to a conventional gap-type atomic switch operation mode by light irradiation with the application of a small bias that precipitates Ag atoms from an Ag2S electrode. After this initialization, the switch operates only with application of a bias. In this study, we also found that after the set-operation a photo-assisted initialized atomic switch shows different switching modes depending on the bias range, i.e., volatile switching when the applied bias is smaller than the threshold bias, and nonvolatile switching when the applied bias is larger than the threshold bias. These characteristics can be useful in reconfiguring a circuit such as in neural computing systems.

The effects of age on maintenance of intense neuromuscular block with rocuronium.

BACKGROUND: Increasing age is associated with a longer duration of action of neuromuscular block. The aim of this study was to determine the influence of ageing on the recovery of the post-tetanic count (PTC) from rocuronium-induced neuromuscular block. METHODS: Twenty-two younger (20-60 years) and 22 older (> 70 years) patients were enrolled in this study. After induction of anaesthesia with fentanyl and propofol, all patients initially received 1 mg/kg rocuronium and neuromuscular block were evaluated by contractions of the adductor pollicis muscle to ulnar nerve train-of-four stimulation using an acceleromyograph. Subsequently, intense rocuronium-induced block was determined every 6 min using the PTC during 1.0-1.5% sevoflurane and remifentanil anaesthesia. When the first response to the PTC stimulus was detected, 0.2 mg/kg rocuronium was additionally administered, and again, spontaneous recovery of neuromuscular function was monitored until the first response to the PTC reappeared. RESULTS: Median values (range) of the times from the administration of 1 mg/kg and 0.2 mg/kg rocuronium until recovery of the first detectable PTC were significantly longer in the older [51.0 (27-100) min, P < 0.0001 and 30.0 (12-66) min, P = 0.0036, respectively] than the younger patients [31.5 (21-45) min and 18.0 (12-36) min, respectively]. CONCLUSION: The times from rocuronium injection to reappearance of the first response to PTC stimulation are approximately twofold longer and more variable in older than younger patients. Hence, the dosing interval of rocuronium should be adjusted using neuromuscular monitoring when maintaining intense neuromuscular block, especially in older patients.

Sitagliptin add-on to low dosage sulphonylureas: efficacy and safety of combination therapy on glycaemic control and insulin secretion capacity in type 2 diabetes.

AIMS: To assess the efficacy and safety of combination therapy with sitagliptin and low dosage sulphonylureas on glycaemic control and insulin secretion capacity in Japanese type 2 diabetes. METHODS: Eighty-two subjects were sequentially recruited for the 52-week, prospective, single arm study. Sitagliptin was added on to sulphonylureas (glimepride or gliclazide) with or without metformin. The primary endpoint was a change in A1C. The secondary endpoints were changes in BMI, insulin secretion capacity, blood pressure and urinary albumin excretion, unresponsive rate, and hypoglycaemia. Insulin secretion capacity was evaluated by glucagon loading test. RESULTS: Change in A1C was -0.80% (95% CI -0.90 to -0.68) (p < 0.001). Change in BMI, systemic and diastolic blood pressure, and urinary albumin excretion were -0.38 kg/m(2) (95% CI -0.72 to -0.04) (p < 0.05), -6.7/-3.6 mmHg (95% CI -10.0 to -3.4/-4.8 to -2.4) (p < 0.001), and -43.2 mg/gCr (95% CI -65.7 to -20.8) (p < 0.001) respectively. Mild hypoglycaemia was observed in three cases. The unresponsive rate was 6.1%. Glucagon loading test showed that 0-min and 6-min CPR at baseline and 52-week were not significantly changed: 0-min CPR, 1.58 ± 0.58-1.71 ± 0.73 ng/ml; 6-min CPR, 3.48 ± 1.47-3.58 ± 1.21 ng/ml. Insulin secretion capacity, CPI and SUIT index at baseline did not predict the efficacy of the combination therapy. The final dosages of glimepiride and gliclazide were 1.44 ± 0.90 mg and 34.5 ± 15.3 mg respectively. The dosage of sitagliptin was increased from 50 mg to 69.0 ± 24.5 mg in 52-week. CONCLUSIONS: The combination therapy with sitagliptin and low dosage sulphonylureas was safe and effective for glycaemic control. Glucagon loading test indicated that 1 year administration of sitagliptin and sulphonylureas preserved insulin secretion capacity.

Quantized conductance atomic switch.

A large variety of nanometre-scale devices have been investigated in recent years that could overcome the physical and economic limitations of current semiconductor devices. To be of technological interest, the energy consumption and fabrication cost of these 'nanodevices' need to be low. Here we report a new type of nanodevice, a quantized conductance atomic switch (QCAS), which satisfies these requirements. The QCAS works by controlling the formation and annihilation of an atomic bridge at the crossing point between two electrodes. The wires are spaced approximately 1 nm apart, and one of the two is a solid electrolyte wire from which the atomic bridges are formed. We demonstrate that such a QCAS can switch between 'on' and 'off' states at room temperature and in air at a frequency of 1 MHz and at a small operating voltage (600 mV). Basic logic circuits are also easily fabricated by crossing solid electrolyte wires with metal electrodes.

Forming and switching mechanisms of a cation-migration-based oxide resistive memory.

We report detailed current-voltage and current-time measurements to reveal the forming and switching behaviors of Cu/Ta(2)O(5)/Pt nonvolatile resistive memory devices. The devices can be initially SET (from the OFF state to the ON state) when a low positive bias voltage is applied to the Cu electrode. This first SET operation corresponds to the first formation of a metal filament by inhomogeneous nucleation and subsequent growth of Cu on the Pt electrode, based on the migration of Cu ions in the stable Ta(2)O(5) matrix. After the forming, the device exhibits bipolar switching behavior (SET at positive bias and RESET (from the ON state to the OFF state) at negative bias) with increasing the ON resistance from a few hundred Ω to a few kΩ. From the measurements of the temperature stability of the ON states, we concluded that the RESET process consists of the Joule-heating-assisted oxidation of Cu atoms at the thinnest part of the metal filament followed by diffusion and drift of the Cu ions under their own concentration gradient and the applied electric field, disconnecting the metal filament. With ON resistances of the order of a few kΩ, the SET and RESET operations are repeated by the inhomogeneous nucleation and the Joule-heating-assisted dissolution of a small filament on a remaining filament. This switching model is applicable to the operation of cation-migration-based resistive memories using other oxide materials.

Formation and electrical transport properties of pentacene nanorod crystal.

The monophasic formation of an uncharted pentacene crystal, the pentacene nanorod, has been investigated. The restricted formation of the pentacene nanorod on a bare mica surface reveals a peculiar surface catalytic crystal growth mode of the pentacene. We demonstrated the charge transport measurements through a single pentacene nanorod and analyzed the data using a periodic hopping conduction model. The results revealed that the pentacene nanorod has a periodic conductive node within their one-dimensional crystal.

Toward sub-20 nm hybrid nanofabrication by combining the molecular ruler method and electron beam lithography.

It is of great interest and importance to develop new nanofabrication processes to fabricate sub-20 nm structures with sub-2 nm resolution for next-generation nanoelectronic devices. A combination of electron beam lithography (EBL) and a molecular ruler is one of the promising methods to make these fine structures. Here we successfully develop a hybrid method to fabricate sub-20 nm nanogap devices at the desired positions with a complex structure by developing a post-EBL process, which enabled us to avoid damaging the molecular ruler with the high-energy electron beam, and to fully utilize the EBL resolution. It was found that slight etching of the Ti adhesion layer of the parent metal (Pt) by ACT935J solution assisted the removal of molecular rulers, resulting in improved enhancement in the product yield (over 70%) of nanogap devices.

Formation of nanometer-scale grooves in silicon with a scanning tunneling microscope.

Grooves a few nanometers wide can be formed on a Si(111) surface with a scanning tunneling microscope when the tip is above a critical voltage. This may provide a promising approach to nanodevice fabrication. The dependence of the critical voltage on tunneling current, tip polarity, and tip material was studied with silver, gold, platinum, and tungsten tips. The results are consistent with field emission of positive and negative silicon ions. The variation of critical voltage with current is explained quantitatively by a simple tunneling equation that includes the effect of the contact potential between tip and sample.

Electrical properties of individual ZnO nanowires.

The electrical properties of individual ZnO nanowires were investigated for two methods of fabricating nanowire-electrode junctions. The number of carriers in the nanowires was increased by electrostatically doping them by applying a gate voltage. The nanowires were chemically doped by introducing impurities during growth. The Ga-doped nanowires had a linear current-voltage relationship over a wide voltage region. The nanowire-electrode junctions were formed either by using lithography to form electrodes on the nanowire or by using an AFM probe to move a nanowire onto prepared electrodes. With both methods, electrodes made of Ga-doped ZnO were found to make better electrical contact with the nanowire than those made of Ti/Au.

Lipid composition of tracheobronchial secretions from normal individuals and patients with cystic fibrosis.

The lipid composition of tracheobronchial secretions from normal individuals and patients with cystic fibrosis was investigated. Lipids were extracted from he dialyzed and lyophilized samples, and fractionated on silicic acid columns into neutral lipids, glycolipids and phospholipids. The lipids contained each fraction were separated into individual components by thin-layer chromatography and quantified. The secretions of patients with cystic fibrosis and were found to contain about 30% more lipids than that of normal individuals and exhibited elevated levels of cholesterol, phospholipids and glycosphingolipids. The level of free fatty acids and glyceroglucolipids was higher in the normal secretions. The phospholipids of cystic fibrosis secretions exhibited higher content of sphingomyelin and phosphatidylserine, while the normal samples contained more lysophosphatidylcholine. The glycosphingolipids of both types of samples consisted mainly of glucosyl- and lactosylceramides. The major glyceroglucolipid of the normal tracheobronchial secretions was tetraglucosyl glyceroglucolipid, whereas hexa-and octaglucosyl glyceroglucolipids were the predominant compounds of the cystic fibrosis secretions.

Decrease in Activity of Glutathione Reductase Enhances Paraquat Sensitivity in Transgenic Nicotiana tabacum.

Transgenic tobacco (Nicotiana tabacum L. cv SR1) with decreased activity of glutathione reductase exhibited enhanced sensitivity to paraquat in the light as evaluated by chlorophyll destruction and electrolyte leakage from leaf discs. This result indicates the involvement of glutathione reductase in the tolerance of plants to photooxidative stress caused by the herbicide.

Effects of polymyxin B on superoxide anion release and priming in human polymorphonuclear leukocytes.

We studied the effect of a potent inhibitor of protein kinase C, polymyxin B (PMXB), on superoxide anion (O2-) release by human polymorphonuclear leukocytes (PMNL). PMXB was compared with another inhibitor of protein kinase C, 1-(5-isoquinoline-sulfonyl)-2-methyl piperazine (H-7). Both PMXB and H-7 inhibited phorbol myristate acetate (PMA)-stimulated O2- release. Formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated O2- release by cytochalasin B-treated PMNL was not inhibited significantly by either PMXB or H-7. 1-Oleoyl-2-acetyl-glycerol (OAG,25-100 microM) stimulated PMNL to release O2- with a long lag-time (8-10 min). Although H-7 inhibited OAG-stimulated O2- release, PMXB augmented the OAG-stimulated response by increasing rate and reducing lag time. The augmenting effect of PMXB was evident only when added after stimulation by OAG, with maximum effect observed at 3 min after addition of OAG. The augmenting effect was also seen with PMXB immobilized on agarose beads. PMXB did not affect the respiratory burst response to 1,2-dioctanoylglycerol. PMXB-augmented, OAG-stimulated O2- release was inhibited by the addition of H-7 before OAG. In contrast to the effect on O2- release, OAG-stimulated protein phosphorylation was inhibited similarly by either PMXB or H-7, when these agents were added 3 min after stimulation by OAG. These results suggested that initial activation of protein kinase C by OAG is essential for O2- release, but that PMXB acts in a manner independent from protein kinase C to augment OAG-stimulated O2- release. When priming by OAG for enhanced O2- release (as opposed to direct stimulation of O2- release) in FMLP-stimulated PMNL was examined, PMXB inhibited O2- release in OAG-primed PMNL, suggesting that protein kinase C is involved in priming of PMNL by OAG.

Protective effect of apolipoprotein E-mimetic peptides on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cell cultures.

Apolipoprotein E (apoE) is a 34-kD protein with multiple biological properties. Recent clinical and preclinical observations implicate a role for apoE in modifying the response of the brain to focal and global ischemia. One mechanism by which apoE might exert these effects is by reducing glutamate-induced excitotoxic neuronal injury associated with ischemic insults. We demonstrate that human recombinant apoE confers a mild neuroprotective effect in primary neuronal-glial cultures exposed to 100 microM N-methyl-D-aspartate. Furthermore, a peptide derived from the receptor-binding region of apoE (residues 133-149) maintained a significant helical population as assessed by circular dichroism, and completely suppressed the neuronal cell death and calcium influx associated with N-methyl-D-aspartate exposure. Neuroprotection was greatest when the peptide was added concurrently with N-methyl-D-aspartate; however, a significant protection was observed when peptide was preincubated and washed off prior to N-methyl-D-aspartate exposure. These results suggest that one mechanism by which apoE may modify the CNS response to ischemia is by partially blocking glutamate excitotoxicity. Moreover, small peptide fragments derived from the receptor-binding region of apoE have enhanced bioactivity compared with the intact holoprotein, and may represent a novel therapeutic strategy for the treatment of brain ischemia.

Enhancement of the lipid content and physical properties of gastric mucus by geranylgeranylacetone.

The effects of intragastric administration of geranylgeranylacetone (GGA) on the content, composition and physical properties of the mucus component of the gastric mucosal barrier were investigated. One group of rats received twice daily for 3 consecutive days a dose of 100 mg/kg body weight of GGA, while the control group was subjected to daily doses of the vehicle. Sixteen hours following the last dose, the animals were killed, and their stomach was cut open and subjected to measurements of the adherent mucus gel content, analysis of its lipids and molecular forms of elaborated mucin, and evaluation of the viscosity and H+ retardation capacity. The results revealed that GGA elicited a 62% increase in the adherent mucus gel and caused a marked decrease in the proportion of the lower molecular weight mucin. Furthermore, the mucus of the GGA group exhibited a 67% higher content of covalently bound fatty acids and contained 46% more total lipids which were greatly (143%) enriched in phospholipids. The physical measurements demonstrated that mucus elaborated in the presence of GGA also exhibited 2.3 times higher viscosity and had a 32% greater ability to retard the diffusion of H+ than the mucus of the control group. The results suggest that GGA exerts a profound effect on the lipid content and the properties of gastric mucus associated with the maintenance of the mucosal integrity.

Extracellular superoxide dismutase overexpression improves behavioral outcome from closed head injury in the mouse.

Oxidative stress is known to play an important role in the response of brain to traumatic insults. We tested the hypothesis that increased extracellular superoxide dismutase (EC-SOD) expression can reduce injury in a mouse model of closed head injury. Neurologic, cognitive, and histologic outcomes were compared between transgenic mice exhibiting a fivefold increase in EC-SOD activity and wild-type littermate controls. Severe or moderate transcranial impact was induced in anesthetized and physiologically controlled animals. After severe impact, transgenic mice had better neurological outcome at 24 hr postinjury (p = 0.038). Brain water content was increased, but there was no difference between groups. Moderate impact resulted in predominantly mild neurologic deficits in both groups at both 24 hr and 14 days postinjury. Morris water maze performance, testing cognitive function at 14-17 days after trauma, was better in EC-SOD overexpressors (p = 0.018). No differences were observed between groups for histologic damage in hippocampal CA1 and CA3. We conclude that EC-SOD has a beneficial effect on behavioral outcome after both severe and moderate closed head injury in mice. Because EC-SOD is believed to be predominantly located in the extracellular space, these data implicate an adverse effect of extracellular superoxide anion on outcome from closed head injury.