Our results demonstrate how the advantage of learning is maximise

Our results demonstrate how the advantage of learning is maximised when within-generation variability is minimised (the local environment

consists mainly of a single host plant species) and between-generation variability is maximised (different host plant species are the most common in different generations). We discuss how our results: (a) can be applied to recent empirical work in different lepidopteran species and (b) predict an important role of learning in lepidopteran agricultural pests. (C) 2007 Elsevier Ltd. All rights reserved.”
“Gaboxadol or 4,5,6,7-tetrahydroisoxazolo-[5,4-c] pyridine-3-ol (THIP) is a selective agonist for the delta-subunit containing extrasynaptic GABA(A) receptors that will soon enter the U.S. market as a sleep aid [Winsky-Sommerer R, Vyazovskiy VV, Homanics GE, Tobler 1 (2007) The EEG Dinaciclib in vivo effects of THIP (gaboxadol) on sleep and waking are mediated by the GABA(A)delta-subunit-containing receptors. Eur J Neurosci 25:1893-1899]. Numerous studies have shown that systemic administration of THIP reduces wakefulness and increases sleep both in humans and rats [Lancel M, Langebartels A (2000) Gamma-aminobutyric acid(A) (GABA(A)) agonist 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol

persistently increases sleep maintenance and intensity during chronic administration to rats. J Pharmacol Exp Ther 293:1084-1090; Walsh JK, Deacon S, Dijk DJ, Lundahl J (2007) The selective extrasynaptic GABAA agonist, gaboxadol, improves traditional hypnotic SNS-032 efficacy measures and enhances slow wave activity in a model of transient insomnia. Sleep 30:593-602].

SP600125 cost However, it is yet unclear where in the brain THIP acts to promote sleep. Since the perifornical lateral hypothalamus (PFH) contains orexin neurons and orexin neurons are critical for maintenance of arousal [McCarley RW (2007) Neurobiology of rapid eye movement (REM) and NREM sleep. Sleep Med 8:302-330], we hypothesized that THIP may act on PFH neurons to promote sleep. To test our hypothesis, we used reverse microdialysis to perfuse THIP unilaterally into the PFH and studied its effects on sleep-wakefulness during the light period in freely behaving rats.

Microdialysis perfusion of THIP (100 mu M) into the PFH produced a significant reduction in wakefulness with a concomitant increase in non-rapid eye movement or slow wave sleep as compared with artificial cerebrospinal fluid perfusion. REM sleep was unaffected.

This is the first study implicating the delta-subunit containing extrasynaptic GABAA receptors in PFH in control of sleep-wakefulness in freely behaving rats. Published by Elsevier Ltd on behalf of IBRO.”
“1. The changes of the macromolecular osmotic pressure associated with F-actin solutions are related to the changes of the free energy of the free actin monomers.

2. By making use of the model of Biron et al. [2006. Inter-filament attractions narrow the length distribution of actin filaments. Europhys. Lett.

“Oncogenic mutations inactivate the tumor suppressor p53 b

“Oncogenic mutations inactivate the tumor suppressor p53 by lowering

its stability or by weakening its binding to DNA Alkylating agents that reactivate OSI-027 ic50 mutant p53 are currently being explored for cancer therapy We have discovered ligands containing an alpha,beta-unsaturated double bond, characteristic of Michael acceptors, that bind covalently to generic cysteine sites in the p53 core domain They raised the melting temperature of the core domain of wild-type p53 and the hotspot mutants R175H, Y220C, G245S, R249S, and R282 by up to 3 degrees C Analysis of the relative reactivity of the cysteines in p53 by mass spectrometry found that C124 and C141 react first, followed by C135, https://www.selleckchem.com/products/CAL-101.html C182, and C277, and eventually C176 and C275 Post-translational modifications of cysteines are known to be involved in regulation of other transcription factors Modification of C277, which sits on the DNA-binding surface, may, for example, play

a role in regulating p53 activity in cells in response to environmental cues We found that the modifications progressively reduced DNA-binding activity of full-length p53 In light of these results, it is likely that the anticancer activity of the alkylating drugs works via a nontranscriptional activity of p53″
“Developmental exposure to endocrine disrupting drugs and environmental toxicants has been shown to alter a variety of physiological processes in mature offspring. Body (core) temperature (T-c) is a tightly regulated homeostatic system but is susceptible to disruptors of the hypothalamic pituitary thyroid (HPT) axis. We hypothesized that thermoregulation would be disrupted in adult offspring exposed perinatally to an HPT disruptor. Propylythiouracil (PTU) was used as a prototypical compound because of its well known antithyroidal properties. FLU was added to the drinking water of pregnant rats in concentrations of 0, 1, 2, 3, and 10 ppm from gestational day (GD) 6 through postnatal

day (PND) 21. Adult male offspring were implanted with radiotransmitters to monitor T-c and motor activity (MA) and were observed undisturbed at an Fedratinib chemical structure ambient temperature of 22 degrees C for 12 consecutive days. Data were averaged into a single 24 hour period to minimize impact of ultradian changes in T-c and MA. All treatment groups showed a distinct circadian temperature rhythm. Rats exposed to 10 ppm FLU exhibited a marked deviation in their regulated T-c with a reduction of approximately 0.4 degrees C below that of controls throughout the daytime period and a smaller reduction at night. Rats exposed to 1 or 2 ppm also had smaller but significant reductions in T-c. MA was unaffected by PTU. Overall, developmental exposure to moderate doses of an antithyroidal drug led to an apparent permanent reduction in T-c of adult offspring that was independent of changes in MA Published by Elsevier Inc.

Our results also show that part of the A9 permissiveness to MVMp

Our results also show that part of the A9 permissiveness to MVMp relies on the inability to produce type I IFNs upon parvovirus infection, a feature related either to an A9 intrinsic deficiency of this process or to an MVMp-triggered inhibitory mechanism, since stimulation of these cells by exogenous IFN-beta strongly inhibits the parvovirus life cycle. Taken together, our results demonstrate for the first time that

parvovirus infection triggers an innate antiviral response in normal cells and suggest that the MVMp oncotropism depends at least in part on the failure of infected transformed cells to mount such a response.”
“Two and a half million Americans with atrial fibrillation are at an elevated risk for embolic stroke. Warfarin therapy is standard treatment for high-risk patients, yet 40-65% of elderly patients do https://www.selleckchem.com/products/kpt-330.html not receive anticoagulation therapy due to bleeding complications. To address this clinical need, we are evaluating a minimally invasive stent-based stroke prevention device to divert emboli from entering the arterial

supply of the brain.

The feasibility of a J-shaped stroke prevention device was tested in a mock circulatory loop. Sixteen sets of 100 simulated emboli (1-5 mm(3)) were injected into the left atrium with and without learn more J stents protecting the aortic arch vessels. To determine efficacy, emboli were trapped in filters in the aortic SGC-CBP30 research buy arch vessels and distal aorta for manual counting.

J stents decreased the number of emboli that entered the brachiocephalic trunk by 93.7% (p < 0.0001), left common carotid artery by 79.8% (p < 0.0001), and left subclavian

artery by 89.7% (p < 0.0001).

In a mock circulation, J stents positioned in the aortic arch vessels and oriented downstream of aortic flow significantly decreased the number of emboli that entered the aortic arch vessels. These results warrant further investigation to determine the safety and efficacy of this prophylactic intervention to reduce embolic events, and chronic large animal studies are underway.”
“Paramecium bursaria chlorella virus 1 (PBCV-1), a member of the family Phycodnaviridae, is a large double-stranded DNA, plaque-forming virus that infects the unicellular green alga Chlorella sp. strain NC64A. The 330-kb PBCV-1 genome is predicted to encode 365 proteins and 11 tRNAs. To monitor global transcription during PBCV-1 replication, a microarray containing 50-mer probes to the PBCV-1 365 protein-encoding genes (CDSs) was constructed. Competitive hybridization experiments were conducted by using cDNAs from poly(A)containing RNAs obtained from cells at seven time points after virus infection.

These findings are consistent with previously published genetic s

These findings are consistent with previously published genetic studies implicating GABA(B), and NMDA transporter and receptor genes in OCD. It is posited that dysregulation of such mechanisms may lead to the generation and persistence of intrusive thoughts that form

the basis for this disorder. Neuropsychopharmacology (2012) 37, 1144-1151; doi:10.1038/npp.2011.300; published online 14 December 2011″
“Recent data indicate that the synchronisation of oscillatory activity is relevant for check details the development of cortical circuits as demonstrated by the involvement of neural synchrony in synaptic plasticity and changes in the frequency and synchronisation of neural oscillations during development. Analyses Sapitinib solubility dmso of resting-state and task-related neural synchrony indicate that gamma-oscillations emerge during early childhood and precise temporal coordination through neural synchrony continues

to mature until early adulthood. The late maturation of neural synchrony is compatible with changes in the myelination of cortico-cortical connections and with late development of GABAergic neurotransmission. These findings highlight the role of neural synchrony for normal brain development as well as its potential importance for understanding neurodevelopmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia.”
“Our previous study on immune-related changes in the aged liver described immune cell infiltration and elevation of inflammation with age. Levels of interferon (IFN)-gamma, a known cell cycle inhibitor, were elevated in the aging liver. Here, we determine the role played by IFN-gamma in the delayed regenerative response observed in the aged livers. We observed elevated IFN signaling in both aged hepatocytes and regenerating livers post-partial hepatectomy. ARS-1620 In vivo deletion of the major IFN-gamma producers-the macrophages and the

natural killer cells, leads to a reduction in the IFN-gamma levels accompanied with the restoration of the DNA synthesis kinetics in the aged livers. Eighteen-month-old IFN-gamma-/- mice livers, upon resection, exhibited an earlier entry into the cell cycle compared with age-matched controls. Thus, our study strongly suggests that an age-related elevation in inflammatory conditions in the liver often dubbed as “”inflammaging”" has a detrimental effect on the regenerative response.”
“Lung fibroblast plays a pivotal role in lung repair and remodeling, and also contributes to lung inflammation. The present study investigated differential protein profiling of normal human lung fibroblasts stimulated with tumor necrosis factor (TNF)-alpha. Total proteins from lung fibroblasts were separated by 2-DE, and differentially expressed proteins were identified by MALDI-TOF MS.

Median age was 73 years old (range, 22-91 years) Median aneurysm

Median age was 73 years old (range, 22-91 years). Median aneurysm diameter was 62 mm (range, 30-100 mm). Indications for CG were an anatomic condition precluding FBE in four patients (including three CBL0137 mouse with iliac occlusion), emergent repair of painful or ruptured aneurysm in four, a large-diameter aneurysm whose treatment could not wait for the manufacturing delay of an FBE in three, type Ia endoleak in three patients previously treated by infrarenal EVAR, and elective in two. Treatment involved 26 target vessels (6 superior mesenteric arteries, 20 renal arteries). Intraoperative technical success was 94% (1 type Ia endoleak). Postoperatively,

one patient died of a retroperitoneal hemorrhage and one patient died of mesenteric ischemia after leaving the hospital against medical learn more advice. One patient had a stroke, and four presented with local vascular complications (iliac dissection,

hematoma). The postoperative computed tomography scan showed two patients (12.5%) had a type Ia endoleak. With a median follow-up of 10.5 months (range, 2-19 months), two more patients died (not aneurysm-related). No rupture occurred. All target vessels were patent (primary patency rate, 96%), and one type Ia endoleak persisted.

Conclusion: CG is feasible and efficient to treat JAA in patients unsuitable for FBE. However, in this preliminary experience, complications of devices insertion and type I endoleaks were not rare. Until the anatomic applicability of FBE is extended and off-the-shelf FBE devices are available, click here CG remains a feasible endovascular

option for high-risk JAA patients. (J Vase Surg 2011;53:1520-7.)”
“A long-standing controversy in cognitive psychology concerns the need to assume short- and long-term memory stores. A new formal model of scale-invariant memory and perceptual identification, SIMPLE, accounts for a wide range of data over short and long time scales using the same basic retrieval principles. SIMPLE assumes a single store in which the distinctiveness of each memory item is calculated relative to other items presented across the same scale.”
“In the present study, we aimed to confirm the previous finding of an association between GRIK4 and GNB3 variants (rs195478 and rs5443) and remission and treatment resistance in major depression, using a multicenter sample of 223 patients. We did not find any supporting evidence for such associations. These conflicting data may result from difficulties in the replication of candidate gene association studies. Copyright (C) 2012 S. Karger AG, Basel”
“Rationale Anticipatory nausea (AN) experienced by chemotherapy patients is resistant to current anti-nausea treatments. In this study, the effect of manipulation of the endocannabinoid (EC) system on a rat model of nausea (conditioned gaping) was determined.

None of the RVFV-exposed mosquitoes tested by Vero cell plaque as

None of the RVFV-exposed mosquitoes tested by Vero cell plaque assay contained infectious selleck chemical RVFV after fixation. Furthermore, incubation of mosquito sections with trypsin prior to antibody staining is recommended for optimal visualization of RVFV antigen in infected mosquito

tissues by IFA. Published by Elsevier B.V.”
“Although the cardinal manifestations of Parkinson’s disease (PD) are attributed to a decline in dopamine levels in the striatum, a breadth of non-motor features and treatment-related complications in which the serotonergic system plays a pivotal role are increasingly recognised. Serotonin (5-HT)-mediated neurotransmission is altered in PD and the roles of the different 5-HT receptor subtypes in disease manifestations have been investigated. The aims of this article are to summarise and discuss all published preclinical and clinical studies that have investigated the serotonergic system in PD and related animal models, in order to recapitulate the state of the current knowledge and to identify areas that need further research and understanding. (C) 2011 Published by Elsevier Ltd.”
“In the context of eradication of poliomyelitis the World Health Organization stimulates the development of inactivated polio vaccines based on attenuated virus strains. In addition to vaccine development, tests have to be designed to assess the vaccine quality.

An important test is the identification test for poliovirus strains that are used for the vaccine production. A rapid and accurate PCR method with fluorescent probes has find more been developed to identify unequivocally the vaccine-specific poliovirus strains, such as Mahoney, MEF-1, Saukett H, Sabin type 1, Sabin type 2 and Sabin type 3. (C) 2013 Elsevier B.V. All rights reserved.”

laboratory studies have implicated the mobilization of bone marrow (BM)-derived stem cells in brain plasticity and stroke therapy. This mobilization of bone cells to the brain is an essential concept in regenerative medicine. Over the past ten years, mounting data have shown the ability of bone marrow-derived stem cells to mobilize from BM to the peripheral blood (PB) and eventually enter the injured brain. This homing action is exemplified in BM stem cell mobilization following ischemic brain injury. selleckchem Various BM-derived cells, such as hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and very small embryonic-like cells (VSELs) have been demonstrated to exert therapeutic benefits in stroke. Here, we discuss the current status of these BM-derived stem cells in stroke therapy, with emphasis on possible cellular and molecular mechanisms of action that mediate the cells’ beneficial effects in the ischemic brain. When possible, we also discuss the relevance of this therapeutic regimen in other central nervous system (CNS) disorders. (C) 2011 Elsevier Ltd. All rights reserved.

This component has previously been interpreted as reflecting conf

This component has previously been interpreted as reflecting conflict. These results indicate that taboo utterances can indeed be detected and corrected internally.”
“To investigate the development of advance check details task-set updating and reconfiguration, behavioral and event-related potential (ERP) data were recorded

in children (9-10 years), adolescents (13-14 years), and young adults (20-27 years) in a cued task-switching paradigm. In pure blocks, the same task was repeated. In mixed blocks, comprised of stay and switch trials, two tasks were intermixed. Age differences were found for stay-pure performance (mixing costs) in the 600-ms but not in the 1200-ms cue-target interval (CTI). Children showed larger reaction time mixing costs than adults. The ERPs suggested that the larger costs were due to delayed anticipatory task-set updating in children. Switch-stay performance decrements (switch costs) were age-invariant in both CTIs. However, ERP data suggested that children reconfigured the task-set on some

stay trials, rather than only on switch trials, suggesting the continued maturation of task-set reconfiguration processes.”
“Numerous studies have shown that the N1 event-related potential (ERP) response is attenuated when it is elicited by self-initiated sounds. This N1 suppression JNJ-64619178 nmr effect is generally interpreted to reflect an internal prediction mechanism, which enables the discrimination of the sensory consequences of our own actions and those of others. The blocked design used in the forerunner studies (i.e., self- and externally initiated sounds presented in different blocks) seriously limits the relevance of these findings, because the N1 effect find more can simply be explained by contextual task differences. In the present study, self-and externally initiated sounds were mixed within blocks. N1 suppression was found, and its magnitude

was even larger than that observed in a traditional blocked condition. This result supports the involvement of an internal prediction mechanism in the discrimination of the sensory consequences of one’s own actions and those of others.”
“This study determined which peripheral variables would better predict the rating of perceived exertion (RPE) and time to exhaustion (TE) during exercise at different intensities. Ten men performed exercises at first lactate threshold (LT1), second lactate threshold (LT2), 50% of the distance from LT1 to LT2 (TT50%), and 25% of the distance from LT2 to maximal power output (TW25%). Lactate, catecholamines, potassium, pH, glucose, (V) over dotO(2), VE, HR, respiratory rate (RR) and RPE were measured and plotted against the exercise duration for the slope calculation. Glucose, dopamine, and noradrenaline predicted RPE in TT50% (88%), LT2 (64%), and TW25% (77%), but no variable predicted RPE in LT1.

“This study compared the effectiveness of a family psychoe

“This study compared the effectiveness of a family psychoeducational intervention (FPEI) and a therapeutic alliance focused intervention (TAFI) for parents of daughters and sons with severe mental illness (SMI). A process-outcome model was used to compare the effectiveness of the two interventions and to evaluate how they achieved their outcomes. Extent of effectiveness was assessed in terms of the family burden (FB) of the parents and the this website quality of life (QoL) and psychiatric symptoms of the daughters and sons. This study did not uncover a difference in effectiveness between

the two interventions. However, at post-treatment, the participants in both interventions reported statistically significant less FB and attributed more QoL and less psychiatric symptoms to their daughters and sons than at pre-treatment. In addition, these pre- and post-treatment differences were mediated by specific mediating variables. These results are discussed in terms of the great psychotherapy

debate (Wampold, 2001) as to the relative effectiveness of technique oriented interventions as compared to context oriented interventions. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“Enviroxime is an antipicornavirus compound that targets host phosphatidylinositol selleck 4-kinase III beta (PI4KB) activity for its antipicornavirus activity. To date, several antipoliovirus (PV) compounds similar to enviroxime that are associated with a common resistance mutation in viral protein 3A (a G5318A [3A-Ala70Thr] mutation in PV) have been identified. Most of these compounds have a direct inhibitory effect on PI4KB activity, as well as enviroxime (designated major enviroxime-like compounds). However, one of the compounds, AN-12-H5, showed no inhibitory effect on PI4KB and was considered to belong to another group of enviroxime-like

compounds (designated minor enviroxime-like compounds). In the present study, we performed a small interfering RNA (siRNA) sensitization assay targeting PI4KB-related genes and identified oxysterol-binding protein (OSBP) as a target of minor enviroxime-like compounds. Knockdown of OSBP and OSBP2 increased the anti-PV activities of only AN-12-H5 and a newly identified minor enviroxime-like compound, T-00127-HEV2, and also to T-00127-HEV1 to a minor extent, in the cells. A ligand of OSBP, 25-hydroxycholesterol (25-HC), acted as a minor enviroxime-like compound. Minor enviroxime-like compounds induced relocalization of OSBP to the Golgi apparatus in cells. Treatment of the cells with major or minor enviroxime-like compounds suppressed the expression of genes (HMGCS1 and SQLE) in the SREBP/SCAP regulatory pathway and diminished endogenous phosphatidylinositol 4-phosphate (PI4P) at the Golgi apparatus.

63-4 40), and the frequency of TT genotypes was 19 2


63-4.40), and the frequency of TT genotypes was 19.2

versus 5.6%, p = 0.02 (OR = 4.0; 95% CI: 1.26-12.69); no difference was observed between the boys’ groups. Conclusion: The higher incidence of the C677T MTHFR gene polymorphism in girls with UTA could point to a developmental difference between the sexes that might be related to sexual dimorphism in methylation due to the lower activity of MTHFR in the system with the highest sexual dimorphism: the urogenital system. Naturally, this assumption should be further tested. Copyright (C) 2011 S. Karger AG, Basel”
“We examined the electrophysiological correlates https://www.selleckchem.com/products/elafibranor.html of the processing of social exclusion and inclusion by using a modified version of the Cyberball paradigm. Exclusion was found to be associated with a significant increase in the P3 complex. The frontal-central P3a was primarily related to the affective processing of rejection, whereas the late parietal P3b was associated with its perceived intensity. The expression of

P3a and negative mood did also depend on the earlier experience; earlier inclusion affected the processing of exclusion, and vice versa. In conclusion, our data indicate that the complex process of social rejection can be tracked by using event-related brain potentials. NeuroReport 22:453-458 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.”
“Cognitive impairment, including dementia, is WZB117 cost a common but poorly recognized problem among patients with end-stage renal disease (ESRD), affecting 16-38% of patients. Dementia is associated with high risks of death,

dialysis withdrawal, hospitalization, and disability among patients with ESRD; thus, recognizing and effectively managing cognitive impairment may improve clinical care. Dementia screening strategies should take into account patient factors, the time available, the timing of assessments Tideglusib relative to dialysis treatments, and the implications of a positive screen for subsequent management (for example, transplantation). Additional diagnostic testing in patients with cognitive impairment, including neuroimaging, is largely based on the clinical evaluation. There is limited data on the efficacy and safety of pharmacotherapy for dementia in the setting of ESRD; therefore, decisions about the use of these medications should be individualized. Management of behavioral symptoms, evaluation of patient safety, and advance care planning are important components of dementia management. Prevention strategies targeting vascular risk factor modification, and physical and cognitive activity have shown promise in the general population and may be reasonably extrapolated to the ESRD population. Modification of ESRD-associated factors such as anemia and dialysis dose or frequency require further study before they can be recommended for treatment or prevention of cognitive impairment. Kidney International (2011) 79, 14-22; doi: 10.1038/ki.2010.

Why should a polyglutamine stretch in the TATA-binding protein (t

Why should a polyglutamine stretch in the TATA-binding protein (that is important in all cells) particularly disrupt cerebellar coordination? We propose that advances in the genetics of cerebellar ataxias suggest a rational hypothesis for how so many different genes lead to predominantly cerebellar defects. We argue that the unifying feature of many genes involved in cerebellar ataxias is their impact on the signaling protein ITPR1 (inositiol

1,4,5-triphosphate receptor type 1), that underlies coincidence detection in Purkinje cells”
“Objective: Age, preoperative creatinine value, and ejection fraction 5-Fluoracil nmr are easily arranged in the age, creatinine, ejection fraction score to predict operative mortality in elective cardiac operations, as recently shown. We validate the age, creatinine, ejection fraction score in a large multicentric study.

Methods: We analyzed 29,659 consecutive patients who underwent elective cardiac

operations in 14 Italian institutions during the period from 2004 to 2009. The operative (30-day) mortality rate was recorded for the entire population and for subgroups of patients based on the risk distribution. The predicted mortality was assessed using the additive and logistic European System for Cardiac Operative Risk Evaluations, and the age, creatinine, ejection fraction score. Accuracy and clinical performance of the different models were tested.

Results: The observed mortality rate was 2.77%(95% confidence interval, 2.59-2.96). The predicted mortality rate ��-Nicotinamide was 2.84%(95% confidence interval, 2.79-2.88) for the age, creatinine,

ejection fraction score (not significantly different from the observed rate), 6.26% for the additive European System for Cardiac Operative Risk Evaluation, and 9.67% for the logistic European System for Cardiac Forskolin solubility dmso Operative Risk Evaluation (both significantly overestimated). For all deciles of risk distribution, the European System for Cardiac Operative Risk Evaluation significantly overestimated mortality risk; the age, creatinine, ejection fraction score slightly overestimated the mortality risk in very low-risk patients and significantly underestimated the mortality risk in very high-risk patients, correctly estimating the risk in 7 of 10 deciles. The accuracy of the age, creatinine, ejection fraction score was acceptable (area under the curve of 0.702). In a separate analysis, this value increased to 0.74 by excluding centers that reported no operative mortality. These values were similar or worse for the European System for Cardiac Operative Risk Evaluation.

Conclusions: The age, creatinine, ejection fraction score provides an accuracy level comparable to that of the European System for Cardiac Operative Risk Evaluation, with far superior clinical performance.