TRD stages are the following: stage I: failure of at least one adequate trial of a major class of antidepressants; stage II: stage I resistance plus failure of an adequate trial of an antidepressant (or combination) in a distinctly different class from that used in stage I [Thase and Rush, 1997]. The following medications failed to provide benefit: paroxetine (dose unknown), venlafaxine

262.5 mg, duloxetine 60 mg daily, gabapentin 600 mg at bedtime, propranolol 10 mg three times a day, trazodone (dose unknown), prazosin 3 mg (which was discontinued because the patient was not able to tolerate it due to side Inhibitors,research,lifescience,medical effects), chlorpromazine 100 mg at bedtime, dextroamphetamine extended release 5 mg, risperidone 2 mg, aripiprazole 15 mg and lithium 900 mg. The patient came to us on clonazepam 2 mg twice a day, Inhibitors,research,lifescience,medical mirtazapine 45 mg at bedtime and zolpidem 20 mg at bedtime, all taken orally. The patient scored 27 on PHQ-9, which is suggestive of severe depression. The patient’s 1-year-old son had died and she was still grieving after 24 years. The patient’s PTSD was from adult physical and sexual abuse, including rape. PTSD symptoms were flashbacks, hypervigilance, reliving the experience, avoidance, nightmares, insomnia and concentration difficulties. PTSD symptoms were chronic and active for Inhibitors,research,lifescience,medical many years. Prazosin was started at 1 mg orally at bedtime and was gradually titrated over 4

weeks to 15 mg in the morning, 5 mg at noon and 10 mg at bedtime based on response. Morning and noon doses were specifically to target daytime symptoms and the bedtime dose to target nightmares. Each time prazosin was increased by 2 mg daily to target a specific daytime

Inhibitors,research,lifescience,medical or nighttime symptom. In this patient, daytime symptoms were more pronounced than the nightmares and hence required 20 mg during Inhibitors,research,lifescience,medical the daytime and 10 mg at bedtime. The patient tolerated prazosin without reporting any side effects. Her baseline sitting BP was 133/106 and standing BP was 132/104, sitting HR was 75 and standing HR was 78. On prazosin 30 mg, sitting BP was 124/85, standing BP was 121/95, sitting HR was 83 and standing HR was 86. For the management of comorbid TRD, mirtazapine, zolpidem and clonazepam were tapered and discontinued. The patient was started on clomipramine because of TRD stage II. The patient was asked to continue psychotherapy and was referred for bereavement counseling. The patient was asked to start walking for 5 min daily for behavioral these activation and gradually to increase the duration. The patient also attended the weekly depression/bipolar/psychosis group. Two months later, the patient’s PHQ-9 was 0 and her PTSD was asymptomatic on clomipramine 300 mg orally daily and prazosin 15 mg in the morning, 5 mg at noon and 10 mg at bedtime. It is unclear what specific side effects the patient had on prazosin 3 mg when it was tried for the first time. It is also ZD1839 ic50 unknown what the starting dose was then and how quickly it was titrated.

1% BSA. Immunoreactive signals were detected using the enhanced chemiluminescence system (Millipore, Bedford, MA). To quantify the relative amount of ChAT protein, the blots were stripped and reprobed with an antibody against glyceraldehyde-3-phosphate dehydrogenase (GAPDH) [1:2000] (Biodesign, Saco, ME) for 1 h, followed by a horseradish peroxidase Inhibitors,research,lifescience,medical conjugated antibody [1:2000]. The ChAT and GAPDH

bands were quantified using the Genetools Analysis Software (Syngene, Cambridge, UK). ChAT immunoreactivity was normalized to GAPDH and the relative amount of ChAT protein in L1-deficient mice was expressed as a percent of ChAT present in wild-type littermates. ChAT activity ChAT activity was measured as previously described (Burgess and Aubert 2006; Burgess

et al. 2009), using the method of Fonnum (1969), modified by Tucek (1978). Briefly, each sample dissected from septal and striatal regions was homogenized, diluted, and TSA HDAC incubated with [14C] acetyl CoA at 37°C for 30 min. Homogenates prepared from septal Inhibitors,research,lifescience,medical cells in vitro were incubated for 50 min. The reaction was then stopped, and the newly formed [14C]acetylcholine was extracted, counted, and expressed as nanomoles of acetylcholine produced per milligram of protein per hour (nmol ACh/mg prot/h). The final Inhibitors,research,lifescience,medical value for each sample represents an average of duplicates. Immunostaining Coronal brain sections were cut at 50 μm on a freezing microtome, collected serially Inhibitors,research,lifescience,medical in 96-well plates filled with cryoprotectant, and stored at −20°C. Sections from L1-deficient mice and their wild-type littermates were processed simultaneously using standard immunostaining procedures for fluorescence microscopy (Aubert et al. 1998) and stereology (Ypsilanti et al. 2008). For immunofluorescence staining, sections were rinsed in 0.1 M Tris-buffered saline

(TBS, pH 7.4) and incubated in TBS with 5% normal donkey serum and 0.25% Triton X-100 for 1 h at room Inhibitors,research,lifescience,medical temperature. For the combined detection of ChAT and L1, the goat anti-ChAT antibody [1:100] (AB144P, Chemicon) and the rabbit anti-L1 antibody [1:1000] (a generous gift from Dr. Stallcup et al. 1985) were used overnight at 4°C. Sections were rinsed and incubated with donkey anti-goat and donkey anti-rabbit secondary antibodies [1:200] (Jackson ImmunoResearch) coupled to biotin Non-specific serine/threonine protein kinase and indocarbocyanine (Cy3), respectively, for 2 h at room temperature in the dark. Sections were rinsed and incubated for 2 h in the dark with streptavidin-Alexa 488 and the nucleic acid staining cyanine dye monomer TO-PRO-3 iodide (2 μM). Sections were rinsed and mounted on presubbed slides, allowed to dry briefly, and coverslipped with a 10% solution of polyvinyl alcohol containing 2.5% 1,4-diazabicyclo-2,2,2-octane (PVA/DABCO, both from Sigma, St. Louis, MO).

In contrast to the classic so-called “hypnotic drugs” (eg, benzodiazepines, barbiturates, zopiclone, and Zolpidem), melatonin does not have direct, hypnotic properties related to its chemical structure. Its hypnotic effects depend on the activity of NAT in the CNS. Melatonin: a bioprecursor of hypnotic metabolites During the development of the GC-MS method for the assay of melatonin in plasma,2 our attention was focussed on the chemical reactivity of melatonin at position 3, which allows cyciization of the side chain after acylation. Inhibitors,research,lifescience,medical This proceeds by nucleophilic attack

and leads to a fluoroacyl-β-carboline (Figure 4). Figure 4. Perfluoroacylation of melatonin. Chemical structure of the fluoroacyl derivative obtained during the derivatization

of melatonin using PFPA (pentafluoropropionic anhydride), according the gas chromatography-mass spectrometry (GC-MS) analysis. Acetyl CoA, … Considering our previous observations, we assumed that Inhibitors,research,lifescience,medical melatonin undergoes enzymatic acetylation during the night, under the control of NAT, and that this leads to an N-acetyl-β-carboline, which we call carbo2. We conclude that melatonin Inhibitors,research,lifescience,medical is a bioprecursor of hypnotic acetyl metabolites, such as carbo2. We have validated this assumption in several ways. Acetylation of melatonin in chick pineal Selleckchem Kinase Inhibitor Library glands Chick pineal glands were observed during an alternate light-dark program at 37°C for 7 Inhibitors,research,lifescience,medical days. In the middle of dark phase, they were treated with pHJacetyl coenzyme A and melatonin (or 2-oxomelatonin) for 30 min. Figure 5 and Figure 6 show that melatonin (or 2-oxomelatonin) undergoes an aeetylation that is significantly higher (P<0.002, in the middle of dark phase; P<0.0005, 1 h before end of dark phase [or P<0.00005 for 2oxomelatonin over the whole dark phase]) than that observed in Inhibitors,research,lifescience,medical controls (nonsignificant when melatonin was replaced by phosphate buffer).

Figure 5. Acetylation capacity of various substrates in chick pineal glands in an alternate light-dark program Isotretinoin (light 6. 00 am to 6. 00 pm; dark 6. 00 pm to 6. 00 am) and collected in the middle of dark phase (midnight). NAS, N-acetylserotonin; 5-MT, 5-methoxytryptamine; … Figure 6. Acetylation capacity of various substrates in chick pineal glands in an alternate light-dark program (light 8. 00 am to 8. 00 pm; dark 8. 00 pm to 8. 00 am) and collected 1 h before the light phase (7. 00 am). 5-MT, 5-methoxytryptamine; MEL, melatonin; … GC-MS indicated the biosynthesis of [3H]carbo2 for five chick pineal glands collected in the middle of dark phase (Table II). Table II. Amount of [3H]carbo2 collected from five chick pineal glands the middle of the dark phase of an alternate light-dark (12 h: 12 h) program.

Insulin glargine (0.1mM) was dissolved in phosphate buffer (pH 9.5) in the presence and absence of β-CyDs (10mM), and then isoelectric precipitation

of insulin glargine was obtained after pH shift from 9.5 to 7.4. Then, the release rate of insulin glargine was determined in phosphate buffer (pH 7.4) in the absence of selected anionic β-CyDs. SBE7-β-CyD significantly increased the dissolution rate of insulin glargine after 24h, compared to insulin glargine alone. This enhancing effect of SBE7-β-CyD on the dissolution rate is consistent with its solubilizing Inhibitors,research,lifescience,medical effect as shown in Figure 3. On the other hand, Sul-β-CyD appeared to decrease the dissolution rate of insulin glargine after 24h; however, no statistical significance was found. The inhibitory effect of Sul-β-CyD on the dissolution rate of insulin glargine from its precipitate may be ascribed to the enhancement of the association of insulin glargine Inhibitors,research,lifescience,medical molecules that is dominant over Inhibitors,research,lifescience,medical the solubilizing effect of Sul-β-CyD on insulin glargine. To reiterate, SBE7-β-CyD, and not Sul-β-CyD, increases dissolution of insulin glargine from its precipitate. Figure 5 Effects of Sul-β-CyD and SBE7-β-CyD (10mM) on dissolution from isoelectric precipitation of insulin glargine in phosphate buffer (pH 9.5, I = 0.2) at 25°C. The initial concentration

of insulin glargine was 0.1mM … 3.6. Stability of Insulin Glargine against Tryptic Cleavage Insulin and its analogues are digested by proteases such as trypsin, which cleaves insulin at

the carboxyl side of residues B22-arginine and B29-lysine, at an injection site and systemic circulation Inhibitors,research,lifescience,medical [28]. Therefore, a resistance towards enzymatic degradation is required for a formulation of insulin or its analogues to demonstrate improvement Inhibitors,research,lifescience,medical in bioavailability. Next, the effects of Sul-β-CyD and SBE7-β-CyD on stability of insulin glargine against trypsin digestion were investigated. In this study, insulin glargine was digested by trypsin at 2IU at pH 9.5 at 37°C with CT99021 chemical structure different degradation rates in the absence and presence of β-CyDs. As shown in Figure 6(a), the apparent degradation rate constant of insulin glargine alone (k0) was 0.357 ± 0.004h−1. Meanwhile, the apparent rate constants (kobs) Thymidine kinase in the presence of Sul-β-CyD and SBE7-β-CyD decreased with the increase in the concentration of these β-CyDs. The decline in the kobs value in the SBE7-β-CyD system was more than that in the Sul-β-CyD system. The rate constants (kc) and stability constants (Kc) of the 1:1 complex calculated with the regression lines shown in the Figure 6(b) were 0.129 ± 0.009h−1 and 244 ± 24M−1 in the Sul-β-CyD system and 0.137 ± 0.014h−1 and 182 ± 22M−1 in the SBE7-β-CyD system, respectively.

Such improvements represent the means to greatly increase the relevance of this model to investigate skeletal muscle disease states

since it allows observations made in vitro to be scaled, producing accurate predictions of in vivo responses. Furthermore, an ability to scale up observed in vitro responses based on physical parameters facilitates the tailoring of drug treatment dosages to an individual’s muscle mass and may have significant applications Inhibitors,research,lifescience,medical in the development of personalized treatment regimes. Finally, LY294002 in vitro improved predictions of in vivo responses from in vitro data are likely to accelerate future drug development and toxicology studies since greater power can be obtained in early pre-clinical screens. Acknowledgments This work was supported by NIH Grant Nos. R01NS050452 and R01EB009429. Special thanks to Mandy Esch

for aiding microfabrication.
In the United States alone nearly 18,000 new esophageal cancers are diagnosed and more than 15,000 deaths Inhibitors,research,lifescience,medical occur each year, illustrating the high mortality of this disease and the ongoing need for improved treatment strategies (1). Randomized controlled trials comparing neoadjuvant chemoradiotherapy (NAC) Inhibitors,research,lifescience,medical with surgery alone have demonstrated statistically significant improvements in overall survival (OS) (2-5). More recently, the CROSS trial modified traditional chemotherapy protocols, introducing weekly administration of carboplatin and paclitaxel with concomitant radiotherapy. This resulted in a clear OS benefit for NAC versus surgery alone, with a median OS of 49.3 versus 24 months, respectively (5). These studies are consistent with several meta-analyses, which demonstrate that NAC significantly increases OS compared to Inhibitors,research,lifescience,medical surgery alone (6-9). Taken together, these studies highlight the utility of NAC in the treatment of esophageal cancer. In addition to providing a clear survival benefit, NAC increases the likelihood of an R0 resection (6), which is associated with Inhibitors,research,lifescience,medical significantly improved OS in patients

with esophageal cancer (10). Importantly, the pathologic stage following esophagectomy in patients treated with NAC is a strong predictor of OS, and in particular, downstaging by NAC is associated with improved disease-free survival (DFS) and OS (11). Additional studies have demonstrated that patients with a pathologic complete response (pCR) following NAC and esophagectomy have high long-term OS rates (12,13). Based on these and other data, multimodality Phosphoprotein phosphatase treatment including NAC followed by esophagectomy has been established as standard of care for early stage (II-III), resectable esophageal cancer and that patients treated with NAC are more likely to have an R0 resection and pCR, more likely to be downstaged, and have improved DFS and OS. Therefore, the specific aim of the current study was to analyze OS outcomes of NAC at a single, tertiary care academic medical center.

54 Though some negative results were also reported in patients with coronary artery disease and previous myocardial infarction, there is now a consensus that, at least in man, the -174C allele is associated with increased plasma CRP and IL-6 concentrations,55 with higher systolic blood pressure,56 especially above a body mass index of 25,

and with an increased risk of coronary heart disease.57 Smoking appears to have an NU7441 nmr additive effect on these associations, as both an increase in blood pressure and a detrimental effect on endothelial function was observed in -174CC carriers.58 Obesity (an expansion of the adipose tissue closely related to insulin resistance) Inhibitors,research,lifescience,medical was also shown to be related to the IL-6 -174C allele, as the GG genotype is more common among lean male subjects with low concentrations of either Inhibitors,research,lifescience,medical insulin or glucose.59 A relationship was shown between alcohol consumption and clinical cardiovascular events and carotid atherosclerosis, as in subjects with a daily alcohol consumption of >30 g and with the CC genotype, there were

significantly higher plasma IL-6 levels and carotid artery intima-media thickness.60 The data with TNF-α gene polymorphisms are less abundant. TNF-α is involved in the inflammation process of atherosclerosis and lipid metabolism. A common polymorphism in the promoter region (-308 Inhibitors,research,lifescience,medical G/A) regulates the TNF-α production and was shown to be a candidate gene for the development of both obesity and insulin resistance.61 In an Australian population, it was shown that subjects who were homozygous for the -308 A allele had higher fasting insulin

levels, higher systolic blood pressure, and lower high-density-lipoprotein (HDL) levels than subjects homozygous for the -308G allele. Thus, this variant conveys Inhibitors,research,lifescience,medical an increased risk for the development of insulin resistance in obese subjects, and low HDL levels further increase the risks associated with insulin resistance in A allele carriers.62 Unfortunately, Inhibitors,research,lifescience,medical to date only a few inflammation genes related to CVD have also been examined in depression. For the IL-1BC to T substitution at position -511 (C-511T), there is literature suggesting that the -511C allele is more prevalent among patients with dysthymia,63 and might be associated with the severity of depressive symptoms,64 even in patients with Alzheimer’s Bumetanide disease.65 For the TNF-α gene polymorphism, the -308A allele, which was associated with enhanced inflammatory response after cardiac surgery66 was proposed to influence depressive symptoms.67 The genes of other inflammatory markers have not yet been examined in depression. Angiotensin-converting enzyme gene Angiotensin-converting-enzyme (ACE) is a membrane-bound endopeptidase which is involved in the metabolism of many small peptides, such as the generation of angiotensin II or bradykinin, both being important for the regulation of vascular tone and cardiac functions.

83, P = 0.082). The proportion of correct responses was 77% (SD = 6%) for stay trials and 77% (SD = 7%) for switch trials, showing no statistical difference (see Fig. ​Fig.1).1). Additional analyses were computed to evaluate whether the accuracy and time to respond to an item at study were related to later memory performance. In both the stay and switch conditions, responses were more accurate for subsequently remembered than for

forgotten words (t(20) = 7.40, P < 0.001 and t(20) = 7.34, P < 0.001 for stay and switch trials, respectively) but RTs were not different between conditions (t(20) = −1.58, P = 0.129 and t(20) = −1.68, P = 0.109 for stay and switch trials, respectively) Inhibitors,research,lifescience,medical (see Fig. ​Fig.1).1). Inhibitors,research,lifescience,medical The apparent difference between conditions of later remembered items did not reach significance (t(20) = −0.97, P = 0.342) and no RT differences were found. Figure 1 selleck kinase inhibitor Behavioral measures at study. T-test differences: **: P < 0.01 and ***: P < 0.001. (A) Reaction times (RTs) averaged across subjects. (B) Proportions of responses averaged across subjects. (C) RTs averaged across subjects, related to later ... At test, the proportion of remembered responses was 68% in the stay condition and 71% in the switch condition, and did not differ between conditions (t(20) = −0.93, P = 0.364) as well as mean RTs for correct answers (t(20) = 0.29, P = 0.799). Recognition memory Inhibitors,research,lifescience,medical performance results at test are shown in Table ​Table11 and Figure

​Figure22. Table 1 Recognition memory performance Inhibitors,research,lifescience,medical Figure 2 Behavioral measures at test. T-test differences: ***: P < 0.001. Only confident hits were considered remembered items, whereas forgotten values include nonconfident hits and wrong answers. (A) Reaction times (RTs) averaged across subjects. (B) ... Accuracy of confident and not confident recognition was assessed Inhibitors,research,lifescience,medical by the discrimination index Pr (Phit−Pfalse alarm). For confident hits, the discrimination index Pr was 0.43 in the stay condition and 0.49 in the switch condition, which was different from zero

(stay condition: t(20) = 20.60, switch condition: t(20) = 21.66, both Ps < 0.001). There was no difference between the two discrimination indices (t(20) = −1.59, P = 0.128). For nonconfident hits, the discrimination index was not different from zero in both conditions (stay condition: t(20) = 0.13, switch condition: t(20) = −0.49, both Ps > 0.620). On the basis of these findings, only confident hits were considered as “remembered” items in the ERP analyses, as they were the only ones that reliably MTMR9 discriminated between old and new words. The reason for this procedure was to maximize the signal-to-noise ratio for SMEs by comparing the ERPs of items yielding confident hits versus those yielding non confident hits or misses (Padovani et al. 2011). The differences in mean RTs and proportion of responses between subsequently remembered and subsequently forgotten items were always significant in the stay (RTs: t(20) = −5.05, P < 0.

TREC measurement is expected to provide much-needed clinical and research information on T cell immune dysfunction and can be used in clinical settings where T cell immunity is involved, including T cell immunodeficiencies, HIV infection, the aging process, autoimmune diseases, and immune reconstitution after BMT. Acknowledgments The Jeffrey Modell Foundation (JMF), the Inhibitors,research,lifescience,medical Israeli Science Foundation, and the Israel Ministry of Health are gratefully acknowledged for their support of Dr Somech. Abbreviations: ALC absolute lymphocyte count

BMT bone marrow transplantation DBS dried blood spot HSCT hematopoietic stem cell transplantation KRECs kappa-deleting recombination excision circles NBS newborn screening NK natural killer PCR polymerase chain Inhibitors,research,lifescience,medical reaction PKU phenylketonuria RTqPCR real-time quantitative polymerase chain reaction SCID severe combined immunodeficiency TCR T cell receptor

TRECs T cell receptor (TCR) excision circles.
Identifying active inflammatory pathology may be critical for adequate treatment. Further, precise measurement Inhibitors,research,lifescience,medical of inflammation may allow assessment of disease activity and assess the effect of therapeutic measures. Structural imaging methods such as computerized tomography (CT), magnetic resonance imaging (MRI), and ultrasound may detect large anatomical lesions and subtle swelling, but differentiating active disease from anatomical changes in healed tissue and/or normal variations is difficult. Two non-invasive imaging techniques, corneal confocal microscopy

(CCM) and positron emission tomography (PET), may, however, provide insights into peripheral nerve function. Inhibitors,research,lifescience,medical Corneal Confocal Microscopy The cornea is a window into free nerve fiber Inhibitors,research,lifescience,medical endings.2 Burning neuropathic pain and small fiber sensory loss involving the limbs, trunk, and face is characterized by abnormal skin biopsies as non-length-dependent small fiber neuropathy. A novel non-invasive technique to quantify small fiber pathology is corneal confocal microscopy (CCM). As the cornea contains C and A delta sensory fibers arising from branches of the trigeminal nerve, it offers a window for evaluating neuropathy in diabetic peripheral neuropathy,3 Crohn’s disease,4 Sjögren’s syndrome,4 idiopathic neuropathy,4 and Fabry’s disease.5 Future studies relating CCM findings to individual variations in pain and disability and central nervous system (CNS) function are Casein kinase 1 Apoptosis Compound Library purchase warranted. Peripheral Positron Emission Tomography Although it is not currently possible to image nociceptors in vivo with PET ligands directly, the technique may still inform us on the functional state of the inflammatory milieu and levels of receptor expression/occupancy. Due to changes in blood flow, vascular permeability, metabolism, white blood cell influx, and changes in the local chemical environment, many PET ligands accumulate at sites of peripheral inflammation.

5 and 1 mmol/gDW/h (Experiment C). The most significant changes were observed in the enolase (R49) and pyruvate kinase (R50) reactions where a 100% increase in flux is observed when glycerol consumption was increased from 0 to 0.5 mmol/gDW/h and from 0.5 to 1 mmol/gDW/h. Figure 3 NVP-BGJ398 order Relative changes in flux with changes in glycerol consumption rate. The response of selected reactions when the glycerol uptake rate is at 0 and 0.5 mmol/gDW/h is compared

in Experiment A, between 0 and 1 mmol/gDW/h in Experiment B, and between 0.5 and … 3.4. Parameter Variability Analysis To determine the degree of redundancy in the values of our estimated kinetic parameters, we performed PVA by repeating Inhibitors,research,lifescience,medical our estimation algorithm 100 times for Model 2. It is well known that different sets of parameters values can fit to experimental time-series Inhibitors,research,lifescience,medical data resulting in mathematical redundancy [28,29]. This means that running the parameter estimation 100 times may produce 100 different sets of parameter values that are able to fit the input data set equally well. In Inhibitors,research,lifescience,medical order to facilitate their interpretation, the results of PVA were split into five different categories based on the stoichiometry

of the reaction (uni-uni, uni-bi, bi-uni, bi-bi and reactions of more than two substrates or products). The results of PVA show that many parameters are not strongly constrained (Figure 4). Separate graphs of average values and standard Inhibitors,research,lifescience,medical deviations for parameters under each reaction category are shown in Supplementary File 5. These results show that overall Vf, the velocity of the forward reaction, is the most constrained parameter having the smallest standard deviation (Table 1). Since Vf is directly related to the amount of enzyme and the expression level of the corresponding gene(s), it is expected to be more tightly linked to a particular condition, thus more constrained by a given flux distribution. Figure 4 Average parameter values and standard deviations of estimated kinetic parameters after repeating the genetic algorithm 100 times. The parameters

were Inhibitors,research,lifescience,medical classified into five reaction types: uni-uni (black), uni-bi (red), bi-uni (blue), bi-bi (purple) and … Table 1 Average parameter values and standard Ketanserin deviation (Stdev) for the most constrained parameters in logarithmic scale over 100 iterations of parameter variability analysis (PVA). Reactions are of type uni-uni, uni-bi, bi-uni, bi-bi, or convenience kinetics … The high degree of redundancy in the parameter values as indicated by PVA comes in support of our underlying assumption that accurate rate equations and kinetic parameters are not necessarily crucial in constraining the behaviour of the biological system. Nevertheless, the integration of genomic and proteomic data, together with metabolic and flux data, is expected to reduce mathematical redundancy as shown by previous studies [14,29].