It should be mentioned that several neuropeptide systems in the brain are substantially affected by stress30 and, upon characterization of their distinct expression patterns in the selected paradigm, might eventually enrich the www.selleckchem.com/JNK.html palette of neurochemical indicators. Endocrine end points Activation of the limbic-hypothalamo-pituitary-adrenal (LHPA) neuroendocrine axis is not only a “constant companion” of the stress response, but also provides the most reliable neurohumoral substrate for the assessment of its

magnitude, dynamics and, ultimately, the capacity of the organism to overcome the present and meet sub-sequent challenges. As comprehensive Inhibitors,research,lifescience,medical work of reference has addressed the structural and functional organization and the regulation Inhibitors,research,lifescience,medical of the LHPA axis under stressful conditions,31 here we will focus on the conclusiveness of individual measures of its activity in

models of stress. Input from stress-responsive neural circuits onto the hypothalamic paraventricular nucleus (PVN) induces the release of neuropeptide Inhibitors,research,lifescience,medical secretagogues of adrenocorti-cotropin (ACTH). Although stress-related fluctuations in corticotropin-releasing hormone (CRH) blood levels have been reported, its measurement in the systemic circulation has not attained widespread appreciation in laboratory animals. Monitoring of CRH concentrations in hypophyseal portal blood and, especially, perfusates and dialysates Inhibitors,research,lifescience,medical from defined brain regions is considered more reliable, and enables the distinction of CRH release from individual neuronal populations.3 The most popular approach, however, is the direct assessment of CRH neurons by either the “output” of the hypophyseotropic population to the median eminence or the “steady state” of the CRH gene expression. The latter gained importance also in view of evidence for multiple

neurotropic effects of intracerebral projections of CRH neurons, beyond those involved in the neuroendocrine response to stress.32 CRH-coding transcripts in the parvocellular compartment Inhibitors,research,lifescience,medical of the PVN are a good descriptor of LHPA axis activity under basal and stress-related conditions. Measurements of circulating vasopressin (AVP) levels have been used for assessment of stress responses; however, caution applies to their interpretation, due to the heterogeneity of the neuronal populations that produce AVP found found in the circulation.33 Peripheral AVP originates mainly from the posterior pituitary terminals of magnocellular neurons of the supraoptic and the posterior lateral portion of the paraventricular nucleus, and the involvement of these neuronal populations in the control of the LHPA axis is ambivalent.34 Thus, quantification of AVP expression in anatomically defined neuronal clusters, which make up the adenohypophyseal projection of the PVN, appears to be the method of choice for assessement of the contribution of vasopressin to the endocrine response to stress.

In another case the patient received neoadjuvant temozolomide chemotherapy followed by a wedge resection

of the stomach (29). Three other cases of metastatic gastric melanoma were managed with chemotherapy alone, one reported controlled disease after one course of dacarbazine, nimustine, and cisplatin (30), and two other reports did not state which chemotherapy agents were used (19,31). Radiation therapy has been used to control BMS-345541 chemical structure bleeding in a variety of cancers. Studies have shown radiation therapy to be beneficial in controlling hemoptysis in lung cancer, hematuria in bladder cancer, and vaginal bleeding in cervical cancer (10-13), more recently studies on radiation therapy to treat Inhibitors,research,lifescience,medical gastric bleeding have been reported. One retrospective study demonstrated a 54% response to bleeding in patients with locally advanced or recurrent gastric cancer who were treated with radiation therapy alone (17). Another

retrospective study demonstrated a 70% response to bleeding in patients who received radiation therapy Inhibitors,research,lifescience,medical with or without concurrent chemotherapy (16). Subsequent studies have focused on the effects of radiation dose in symptomatic palliation. A 2009 retrospective study showed that patients with bleeding from primary gastric cancer who received a dose of greater than or equal to 40 Gy in 16 fractions have statistically significant Inhibitors,research,lifescience,medical improvement in control of bleeding compared to those who received less Inhibitors,research,lifescience,medical than 40 Gy in 16 fractions (15). Most recently a study on patients who received 30 Gy in 10 fractions showed a 73% hemostasis rate. Additionally this study demonstrated that those treated with chemotherapy and radiation had Inhibitors,research,lifescience,medical a significant longer time to rebleeding when compared to those who received radiation therapy alone (14). The case presented marks the first use of standalone radiation therapy as a palliative therapy for persistent upper GI bleeding secondary to primary gastric melanoma.

In the case presented, palliative radiation therapy of 16 Gy in four fractions provided four months of symptomatic relief. In addition, Rolziracetam the patient tolerated a second course of therapy of 9 Gy in three fractions for his rebleeding and is currently asymptomatic. In conclusion, malignant melanoma of the stomach with no identifiable extra-gastric primary is a rare occurrence with surgery being the current mainstay of therapy. In symptomatic patients who are poor surgical candidates, palliative radiation therapy can provide symptomatic relief and improve quality of life. Acknowledgements Disclosure: The authors declare no conflict of interest.
Red meat might be directly linked to the incidence of colorectal cancer or indirectly because diets high in meat may be deficient of other dietary components such as fibre and polyphenols from fruit and vegetables.

​(Fig.2424). Figure 24 Performance of WT and SOD1 mutant mice on the loaded grid test. Performance is based on the duration of time in seconds (sec) before the loaded grid was dropped. (A) Each mouse was tested twice with a 15 g weight and allowed unlimited time before dropping … Discussion Sporadic ALS and SOD1 mutant forms of FALS are clinically indistinguishable. Mice and rats expressing mutant forms of human SOD1 develop progressive MN degeneration and clinical signs that closely mimic sporadic and familial forms of human ALS (Gurney et al. 1994). Initial characterization

of the animal models understandably focused Inhibitors,research,lifescience,medical on pathological events associated with obvious behavioral symptoms (e.g., leg tremor) and MN degeneration. The onset of overt clinical symptoms in the SDO1G93A mouse is generally reported to occur at approximately P90, but see (Mancuso et al. 2011; Mead et al. 2011; Gerber et al. 2012). We find that signs of axonal Inhibitors,research,lifescience,medical degeneration are evident by Inhibitors,research,lifescience,medical P75, but the absolute number of ventral root axons is still comparable with WT. The MNs that will die can be identified by P60 even though their removal from the spinal cord does not occur until later ages. Consistent with previous reports, we confirm that muscle denervation long precedes activation of cell death pathways and the classical definition of clinical

pathology (Frey et al. 2000; Raff et al. 2002; Medana and Esiri 2003; Fischer et al. 2004; Gould et al. 2006; Palop et al. 2006; Pun et al. 2006; Conforti et al. 2007; Gould and Oppenheim 2007). However, our observations place

the onset of denervation Inhibitors,research,lifescience,medical at P25–30, 10–20 days earlier than previous reports. As demonstrated previously Inhibitors,research,lifescience,medical (Pun et al. 2006; Hegedus et al. 2007), denervation does not occur LY317615 clinical trial uniformly in all muscles but is dependent on fiber type with fast fibers being denervated before slow fibers. Here, we report that denervation of the TA muscle occurs between P14 and P30, while at the same time little denervation occurs in the soleus muscle that is composed primarily of slow fibers. Muscle denervation during the first postnatal Montelukast Sodium month calls into question previous characterization of the SOD1G93A mouse model in terms of disease onset. Traditionally, disease onset was considered to occur in the third postnatal month, a time coincident with detection of MN cell death; however, here we also provide evidence that motor function deficits begin coincident with initial muscle denervation. Muscle strength, as assessed by the loaded grid test and treadmill gait was impaired in mutant mice beginning around P30–40 and treadmill deficits only occurred in mice walking uphill at increased speeds when the TA muscle is increasingly engaged (Roy et al. 1991).

Residual enzyme activity is generally inversed correlated with disease severity, having infantile onset patients less than 1% of normal activity and late onset patients less than 40%; ABT-378 datasheet however patients with late onset and < 1% enzyme activity in skin fibroblasts are reported in the literature (12). Mutation analysis is used in the identification of heterozygotes when a familial mutation is known. Due to potential overlap of residual enzyme activity

in late onset Pompe patients with heterozygotes, in some cases molecular Inhibitors,research,lifescience,medical analysis may be required to confirm diagnosis. Apart from the above case, mutation analysis may be helpful to diagnosis only in specific populations (for example R850X mutation in African Americans and D 645E in Chinese population). For prenatal diagnosis molecular testing is the preferred method when both mutations are known; enzyme analysis in chorionic villus samples Inhibitors,research,lifescience,medical is preferred when molecular testing is not feasible or when enzyme analysis is an adjunct to molecular testing, though confirmation in amnyocytes may be considered if mutations are known (12). Conclusion With the advent of enzyme replacement Inhibitors,research,lifescience,medical treatment and other developing therapies, the recognition

of Pompe disease in its variable clinical presentations has assumed a new importance. As for other treatable lysosomal disorders a central database of patients will assist in obtaining a better understanding of the natural course of Pompe disease and in defining the standards of treatment.
This abnormal glycogen, made of long chains of glucose units infrequently branched, known as polyglucosans, is intensely positive Inhibitors,research,lifescience,medical to periodic acid-Schiff stain and partially resistant to diastase digestion. Ultrastructurally, it consists of filamentous and finely Inhibitors,research,lifescience,medical granular material. Polyglucosan accumulates in skin, liver, muscle, heart

and central nervous system, but to different degrees (1). Polyglucosan deposition is not peculiar of GSD-IV, but can be found in other disorders, such as phosphofructokinase (PFK) deficiency and Lafora disease. As previously discussed, the polyglucosan deposition in PFK deficiency is caused by the alteration of the normal ratio of glycogen synthase and branching enzyme (2). Clinical presentation The typical presentation of GSD-IV, originally whatever described by Andersen in 1956 (3), is characterized by failure to thrive, hepatosplenomegaly, and liver cirrhosis leading to death in early childhood. Non-progressive hepatic form is rarely reported (4). However, the neuromuscular system can be primarily involved, and three clinical variants based on age at onset can be identified: i) congenital, ii) juvenile, and iii) adult. The congenital phenotype can, in turn, be subdivided into two clinical subgroups.

Attention will be given to anesthesia and analgesia, blood conservation and transfusion. Particular attention will be paid to perioperative strategies designed to decrease the need for blood transfusion. Anesthesia, analgesia, and fluid administration Optimizing hemodynamics and fluid administration is crucial in patients undergoing major hepatic resection. As with all surgical patients, fluid administration is necessary during operation; however, the balance between providing adequate resuscitation to ensure proper end organ perfusion while maintaining a low patient central venous pressure (0-5 mm Hg) during the parenchymal transection

phase to minimize hepatic venous back bleeding is unique to liver surgery. Furthermore, Inhibitors,research,lifescience,medical following the acute reduction of hepatic function patients are thrown into some degree of liver failure and may Inhibitors,research,lifescience,medical develop substantial ascites and edema. This can precipitate other http://www.selleckchem.com/products/bix-01294.html complications, such as wound breakdown, liver failure and death. The follow section covers the use of invasive monitoring, fluid administration, and epidural anesthesia/analgesia and how to negotiate these techniques and concepts. Central venous pressure and fluid administration Communication regarding surgical manipulation and management of hemodynamics between the anesthesiology and surgical Inhibitors,research,lifescience,medical staff is a critical component of optimal outcomes. Unless there is

a preoperative expectation Inhibitors,research,lifescience,medical of extensive vascular involvement, plans for vascular occlusion, or underlying cardiac dysfunction, we do not monitor liver

resection patients with Swan Ganz catheters. In our practice, the majority of patients undergoing major hepatic resection are monitored with continuous central venous pressure (CVP). Invasive monitoring is sometimes forgone in the young, thin, healthy individual with tumors away from the major vessels. Proper CVP management is crucial to successful liver surgery, and requires open communication between surgeons, anesthesiologists, Inhibitors,research,lifescience,medical and physician extenders prior to, during and following surgery. Due to concern of substantial blood loss, some hepatic surgeons advocate for preoperative volume loading to establish a euvolemic or hypervolemic state in anticipation of ensuing intraoperative blood loss (23,24). Other groups, including ours, feel that this distends the central veins and increases the difficulty in controlling blood loss during resection from hepatic veins during parenchymal most transaction (24,25). As such, others have supported performing hepatectomies under low CVP (0-5 mm Hg) (see Table 1) (24,26,27). In one study, comparing low CVP strategies to the standard CVP cohort, there was a correlation between blood loss and transfusion with CVP; patients with low CVP had a median blood loss of 200 mL versus 1000 mL, and 2% versus 48% required transfusions (32). This target CVP should be discussed prior to surgery.

Patients in group C had a lower VAPS over time than those in groups A and B. Time to first analgesia was longer (429±197 minutes) in group

C than in group A (254±157 minutes). Fewer patients in group C required parenteral opioid postoperatively than in group A. The incidence of bradycardia was higher in the groups #Crenolanib mouse randurls[1|1|,|CHEM1|]# receiving meperidine. No symptoms of transient radicular irritation (TRI) were reported in Inhibitors,research,lifescience,medical the groups receiving meperidine. It was concluded that the addition of 0.3 mg/kg of meperidine to spinal lidocaine extended postoperative analgesia, and did not postpone the discharge from post anesthetic care unit. It also reduced the requirements for parenteral analgesics. Our findings agree these finding, except for bradycardia that did not occur in our study. Our findings receive support from those of Murto et al.18 in a number of aspects. First of all, their study was similar to ours; then, the sensory Inhibitors,research,lifescience,medical level in both studies was the same; and next, similar dosages of meperidine were administered in both studies. However, no measurement of blood loss was performed in that study. Our findings also agree with those of Nguyen et al.19 who found that adding

meperidine to intrathecal bupivacaine improved post-operative analgesia. Conway et al.20 studied the hemodynamic effects of intrathecal meperidine (0.8 mg/kg), meperidine (0.4 mg/kg) plus 1.5 ml of heavy bupivacaine Inhibitors,research,lifescience,medical 0.5% or 3 ml of heavy bupivacaine 0.5% in 42 Chinese patients (59-87 years) scheduled for transurethral bladder or prostate surgery. Non-invasive SAP and MAP, central venous pressure Inhibitors,research,lifescience,medical and cardiac index, stroke index and HR were measured. The onset of sensory and motor block was also evaluated. The onset of block was slower in the meperidine group. Decreases in SAP, MAP, and systemic vascular resistance index (SVRI) occurred within five minutes of drug administration in all three groups. Due to inadequate block, six patients receiving meperidine and two patients receiving the mixture required general anesthesia. The incidence of nausea and vomiting was higher in the patients receiving meperidine alone. They concluded that the administration Inhibitors,research,lifescience,medical of intrathecal meperidine,

Montelukast Sodium alone or mixed with bupivacaine, had no intra-operative advantage over heavy bupivacaine 0.5%. Unfortunately, the amount of blood loss was not reported for the three groups in that study. Kafle compared,21 intrathecal meperidine with heavy lidocaine in 50 full-term pregnant women, with ASA physical status I or II, who were candidates for elective caesarean under spinal anesthesia. He found that the sensory and motor blockades in all patients except two in each group, who required sedation at the time of skin incision, were adequate for surgery. None of the mothers suffered from any major side effects. The incidence of hypotension was higher in the lidocaine group compared to the meperidine group. In the meperidine group, pruritus and drowsiness were more common than in the lidocaine group.

” Structural MRI MRI scans were obtained on a 1.5-T Magnetom VISION system (SB216763 Siemens Inc., Iselin,

NJ) equipped with a standard quadrature head coil. A volumetric-magnetization-prepared, rapid-gradient echo MRI (MPRAGE, TR/TE/TI = 10/4/300 msec) was used to obtain T1-weighted images of the entire brain, 15° flip angle, coronal orientation perpendicular to the double-spin echo sequence, 1.0 × 1.0 mm2 in-plane Inhibitors,research,lifescience,medical resolution, and 1.5-mm slab thickness. Voxel-based morphometry VBM preprocessing and analyses were performed using the SPM5 software package (Welcome Department of Cognitive Neurology, London; http://www.fil.ion.ucl.ac.uk/spm) running on MATLAB 7.1.0 (Math Works, Natick, MA). In all preprocessing steps, SPM5 default parameters were kept, except for the morphological filtering step, in Inhibitors,research,lifescience,medical which the light cleanup procedure was used. More anatomically precise intersubject registration was then performed with the Diffeomorphic Anatomical Registration through Exponentiated Lie algebra (DARTEL) toolbox (Ashburner 2007) by warping each subject’s image to a template created from 50 additional older NC. Spatially normalized, segmented, and modulated gray matter images

were smoothed with a 12-mm FWHM isotropic Gaussian kernel. VBM analyses of socioemotional self-awareness Inhibitors,research,lifescience,medical Covariates-only (multiple regression design) statistical analyses were used to determine the relationship between discrepancy z-scores Inhibitors,research,lifescience,medical and smoothed gray matter volumes in the polisher/neutral sample (negative correlation) and in the tarnisher/neutral sample (positive correlation). Age, gender, MMSE (as a proxy for disease severity), and total intracranial volume (TIV) were entered as covariates into all designs. The resulting statistical parametric

(SPM) map was thresholded at voxel-wise P < 0.001, and then corrected for multiple comparisons Inhibitors,research,lifescience,medical at P < 0.05 based on cluster extent and a custom-fit error distribution determined by 1000 permutations of the data (Wilson et al. 2010). Resulting SPM T-maps were superimposed on the Montreal Neurological Institute (MNI) single subject brain using automated anatomical labeling (AAL) included in the MRIcron software package (http://www.sph.sc.edu/comd/rorden/mricro.html). The following two statistical analyses were performed Terminal deoxynucleotidyl transferase for identifying neural substrates of overestimation and underestimation of one’s empathic concern: Main effect analysis (voxel-wise regression of gray matter volume on empathic concern discrepancy score) To identify neural correlates across all diagnostic groups, the empathic concern discrepancy score was correlated with smoothed gray matter volume, using a one-tailed t-contrast, adjusting for age, gender, MMSE, and TIV.

In clinical practice it is still useful to follow a categorical approach at the first stage (diagnostic utility), but bearing in mind that bipolar depressions and nonbipolar depressions have a fluctuating course and also have mixed episodes of depression and VX-689 cell line superimposed manic/hypomanic symptoms. The impact on treatment of these findings may be important for bipolar disorders and depressive disorders. If, when, and how long to use antidepressants and moodstabilizing agents in Inhibitors,research,lifescience,medical the light of the spectrum concept of mood disorders have to be defined, setting the stage for a new series of studies. Notes I wish

to thank Professor Jules Angst for his support and for his suggestions.
Decades of basic and clinical neuroscience research have greatly improved our understanding of the neurobiology of depression. Clinical studies have helped establish which treatments Inhibitors,research,lifescience,medical are effective, and have led to evidence-based treatment algorithms that can be readily applied to the “real-world” situation.1 Basic research has yielded insights into the genetic, molecular, cellular, and neuroanatomical bases of depression. Based on these findings, there is a growing acceptance of depression, Inhibitors,research,lifescience,medical and other mood disorders, as diseases of the brain rather

than purely aberrations of “mind.” Despite these advances, depression remains a common and inadequately treated illness, with few strategies for prevention or cure. The lifetime prevalence of depression approaches 17% in the United States,2 and depression is recognized Inhibitors,research,lifescience,medical to be one of the leading causes of disability worldwide.3,4 Available treatments for depression – including pharmacotherapy, evidence-based psychotherapy, and electroconvulsive therapy (ECT) – are Inhibitors,research,lifescience,medical effective in reducing symptoms in the majority of patients with an acute depressive episode, and the combination of these treatments may be more efficacious than individual treatments alone.5 However,

up to 40% of patients continue to have clinically significant symptoms despite optimized treatment,6 and up to 20% of patients may show little to no response to the most aggressive management (including the use of ECT).7-9 Even for patients Sclareol who do respond to treatment, the illness tends to be highly recurrent, with up to 80% of patients experiencing at least one subsequent episode.10 Psychotherapy and/or maintenance antidepressant medications may substantially decrease the risk of relapse but do not eliminate it.11 In the face of these clear challenges, the continued neurobiological investigation of depression offers reason for optimism. Based on a solid foundation, basic and clinical neuroscience research is progressing rapidly, with many exciting developments on the horizon. Importantly, as the pathophysiology of depression becomes better understood, a number of novel treatment targets are being identified.

This point is nicely illustrated by several articles in this volume addressing memory changes in neurological and psychiatric conditions that can have a profound impact on an individual’s ability to function

in daily life. Memory research has also been applied extensively in legal settings, where such issues as how to construct effective lineups and how to deal with the inaccuracy of eyewitness testimony are of paramount importance.1,2 In this editorial, I discuss Inhibitors,research,lifescience,medical briefly some recent applications of memory research in educational and clinical settings that show promise for providing meaningful benefits in everyday life. Enhancing attention and memory in educational settings During the past several years, a rapidly expanding number of studies have attempted to apply principles and methods of cognitive psychology to educational settings. Inhibitors,research,lifescience,medical For example,

one basic question concerns whether memory research can be used to increase the effectiveness with which students study for exams. In a recent comprehensive review, Dunlosky and colleagues3 evaluated the effectiveness of ten different study methods, and characterized each one as being of either high, moderate, or low utility based on available research. Some of the popular methods commonly embraced by students—including rereading, summarizing, and highlighting—received Inhibitors,research,lifescience,medical low utility assessments. Only two techniques, both supported by data from numerous laboratory studies, received high Inhibitors,research,lifescience,medical utility assessments: distributed study, which involves spreading out study activities so that more time intervenes between repetitions of the to-be-learned information (as opposed to

mass study or “cramming”), and practice testing, where students are intermittently given brief quizzes about what they have learned prior to taking a formal test. The beneficial effects of practice testing for students Inhibitors,research,lifescience,medical are based mainly on studies demonstrating that the act of retrieving information can be a highly effective means of strengthening memory for the retrieved information.4 Recent work in my laboratory has used a variant of the practice testing technique in an attempt to enhance attention and memory Endonuclease during video recorded lectures.5 Students frequently experience lapses of attention both during classroom6 and video7 lectures. For example, when probed during either a classroom or online lecture regarding whether they are attending to the lecture or mind wandering to other topics, students indicated on approximately 40% of Cisplatin price probes that they were mind wandering; not surprisingly, the extent of mind wandering was negatively correlated with retention of lecture content.6-8 Our study5 focused on video recorded lectures because they are a key element in online education, which has exploded during recent years, partly as a result of the development of massive open online courses (MOOCs).

Especially the NMDA-sensitive glutamate receptor, when blocked with a noncompetitive antagonist, alters function primarily in click here limbic and frontal cortex (as measured by immediate early gene alterations in laboratory rodents in response to phencyclidine17 or by rCBF alterations in humans in response to ketamine).18 Thus, even if the initiation of this NMDA antagonist change is in

the limbic cortex, the extensive influence of the limbic system on related neocortical and subcortical structures is so potent, that it alters function in frontal cortex Inhibitors,research,lifescience,medical and even in the limbic striatum when hippocampal firing changes. Thus, a convergent projection area of both of these systems – the frontal neocortex and limbic cortex – is common to both dopaminergic Inhibitors,research,lifescience,medical and NMDA-sensitive glutamatergic transmission. Thus, while dopamine and glutamate system pharmacologies are similar, each has its preferential primary action systems and each delivers its “information” to diverse brain regions in a highly interactive/overlapping fashion,

through the welldescribed and existing neuronal circuits. Conclusion Schizophrenia is a disease of disordered mental productivity and organization, Inhibitors,research,lifescience,medical not of a single neurotoxic or neurodegenerative pathogen, and, can be formulated entirely as a neural systems disorder of the central nervous system (CNS).This suggests that, the function of Inhibitors,research,lifescience,medical the system overall, not of any single component, may be abnormal in the illness and could result, in the symptoms of the illness. Thus,

we have formulated our current antipsychotic treatment actions as a systems approach to treating, not necessarily the primary pathology of schizophrenia, but the disordered system “output.” Because dopamine and glutamate strongly modulate neural systems that have overlapping tertiary targets (ie, the frontal cortex and limbic striatum), the same kind of pharmacological action (ie, “antipsychotic”) could be delivered to regions regulating the behaviors of the CNS, be they motor, cognitive, Inhibitors,research,lifescience,medical or affective, through, for example, the frontal cortex. Thus, it is not only a drug action at a regional target within the brain, but also, its overall action on a related neural system in the brain that determines its overall actions and on neurally mediated behaviors and illnesses, like schizophrenia. Known antipsychotic drugs that block D2 receptors likely have their therapeutic action on functions of the frontal cortex, mediated through the BGTC neuronal circuit. Psychotomimetic agents like ketamine also appear to have their actions (antitherapeutic, in this case) within the limbic cortex, but. these actions also extend into the frontal cortical regions. It. would follow then that neither of these drug effects seems to be exerted primarily in the area of delivery, but as an indirect projection effect to frontal cortex from different, but overlapping, neuronal networks.