Current management of peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are an uncommon group of lymphoproliferative disorders accounting for approximately 10-15 % of all non-Hodgkin lymphomas (NHL) in Western countries. Although PTCLs are associated with poor prognosis, outcomes vary with disease subtype. The standard of care has been anthracycline-based induction combination chemotherapy, however, with the exception of low-risk ALK-positive anaplastic large cell lymphoma, relapse rates are high. Therefore, consolidation with autologous stem cell transplantation is usually recommended for patients deemed candidates, and with aggressive subtypes. In recent years, a number of novel agents including pralatrexate, histone deacetylase inhibitors, immunotoxins, proteasome inhibitors, aurora kinase inhibitors and the CD30 antibody-drug conjugate brentuximab vedotin, have shown promise in the treatment of PTCLs. Studies are underway to explore the activity of these newer agents used in the frontline setting.

Directional selectivity in hamster superior colliculus is modified by strobe-rearing but not by dark-rearing.

Visual response properties of superior collicular neurons of normal hamsters were compared with those of animals reared from birth to adulthood in either total darkness or with stroboscopic illumination. Directional selectivity was markedly reduced only in the strobe-reared animals, thus demonstrating visual plasticity in a system that develops apparently normally without visual experience.

The formation of a cortical somatotopic map.

The primary somatosensory cortex of small rodents is an isomorphic representation of the body surface. Similar representations are characteristic of the subcortical pathways, leading from the periphery to the cortex, and these representations develop in a sequence that begins at the periphery, and that ends in the cortex. Furthermore, central representations at all levels of the neural axis are altered by perinatal perturbations of the peripheral surface. This has led to the hypothesis that the periphery plays an instructional role in the formation of central neuronal structures. The morphology of this discrete organization has been examined thoroughly during the development of the thalamocortical projections. The mechanism(s) that underlies the formation of these representations remains unclear although some recent evidence suggests the involvement of activity-dependent processes that are modulated by 5-HT.

Lipid characteristics of subcutaneous adipose tissue and M. longissimus thoracis of Angus and Wagyu steers fed to US and Japanese endpoints.

We hypothesized that the concentrations of monounsaturated fatty acids (MUFA) and cholesterol of adipose tissue and M. longissimus thoracis would not differ between Angus and American Wagyu steers when fed to a typical US live weight, but would diverge when fed to a Japanese live weight. To test this, 8 steers of each breed type were assigned to a high-energy, corn-based diet, and another 8 steers of each breed type were fed coastal bermuda grass hay diet, supplemented with the corn-based diet to achieve a daily gain of 0.9kg/d. Targeted final body weights were 525kg for steers fed for 8 or 12mo the corn- or hay-based diets, respectively, and were 650kg for steers fed for 16 or 20mo the corn- or hay-based diets. Digesta concentrations of stearic (18:0) and trans-vaccenic acid decreased, whereas linoleic acid (18:2n-6) increased between the US and Japanese endpoints (all P⩽0.03). α-Linolenic acid (18:3n-3) increased in digesta only in the hay-fed steers during this time. Plasma concentrations of palmitic (16:0) and palmitoleic acid (16:1n-7), and the 16:1:18:0 ratio, were higher in Angus steers than in Wagyu steers. Also, the plasma 16:1:18:0 ratio was decreased by hay feeding in Angus steers, but increased in Wagyu steers, when fed to the Japanese endpoint. Concentrations of oleic (18:1n-9), linoleic, α-linolenic, and 18:2trans-10,cis-12 conjugated linoleic acid all were higher in Wagyu than in Angus subcutaneous (s.c.) adipose tissue, whereas myristic (14:0) and palmitic acid were higher in Angus s.c. adipose tissue (P⩽0.05). All MUFA increased, and saturated fatty acids decreased, between the US and Japanese endpoints. Slip points of lipids in s.c. adipose tissue were over 10°C lower (P=0.01) in Japanese-endpoint steers than in US endpoint steers, consistent with the overall increase in MUFA with time on feed. The concentration of cholesterol in the M. longissimus thoracis increased with time, which may have been related to the increase in oleic acid. Because the breed×endpoint interaction was not significant for cholesterol or any of the adipose tissue fatty acids, we conclude that our original hypothesis was incorrect. Of the three factors tested (breed type, diet, and slaughter age endpoint), endpoint had the greatest effect on adipose tissue lipid composition.

De novo fatty acid synthesis in the perfused rat lung. Incorporation of palmitate into phospholipids.

1. The incorporation of exogenously derived [14C]palmitate and endogenously synthesized [3H]palmitate (from 3H2O) was measured in the isolated perfused lung. 2. Over 40% of the fatty acid esterified into lung disaturated phosphatidylcholine was derived from de novo synthesis. 3. A major portion of the palmitate synthesized de novo was incorporated in the 2 position of disaturated phosphatidylcholine. 4. Streptozotocin-induced diabetes and the compound 5-(tetradecyloxy)-2-furoic acid markedly inhibited de novo fatty acid synthesis while the incorporation of exogenously supplied palmitate increased into disaturated phosphatidylcholine, primarily in the 2 position. 5. Treatment with insulin resulted in an increase in [14C]glucose incorporation into lung phospholipid, with the largest increase appearing in the glyceride-glycerol fraction of the phosphatidylcholine species. 6. Insulin neither stimulated de novo fatty acid synthesis nor increased exogenous palmitate incorporation. 7. These data show: (1) that de novo fatty acid synthesis in the perfused rat lung is involved in the remodeling reactions in the synthesis of phosphatidylcholine, and (2) that diabetes affects the relative contribution of de novo synthesized and exogenously supplied palmitate available for the esterification of lung phospholipid.

Fetal lung metabolism. Response to maternal fasting.

1. Fetal lung metabolic response to maternal fasting late in gestation was investigated. 2. Maternal fasting 4 days before term was associated with low fetal plasma glucose and insulin levels but increased levels of fetal plasma glucagon, glycerol, lactate and fatty acids. 3. Fetuses from fasted mothers showed a significant decrease in body weight (30%) and lung glycogen (46%), but no change in lung protein, phospholipid or total lung DNA, suggesting that lung size is affected more than maturation. 4. Fetal lung slices incubated in vitro showed that lactate oxidation to CO2 equalled that of glucose in control fetal lungs and was unaffected by maternal fasting, while glucose oxidation was depressed (23%). 5. Maternal fasting significantly decreased in vitro incorporation of [U-14C]-glucose, [U-14C]lactate and [1-14C]palmitate into lung phospholipids. 6. Fetal lungs from fasted mothers showed increased conversion of lactate to glucose, indicating gluconeogenic potential by fetal lung. 7. These studies show that plasma lactate serves as an important energy fuel and substrate for lipid synthesis for the fetal lung, and maternal fasting markedly alters fetal lung metabolism.

Regulation of fetal lung disaturated phosphatidylcholine synthesis by de novo palmitate supply.

Lung surfactant disaturated phosphatidylcholine (PC) is highly dependent on the supply of palmitate as a source of fatty acid. The purpose of this study was to investigate the importance of de novo fatty acid synthesis in the regulation of disaturated PC production during late prenatal lung development. Choline incorporation into disaturated PC and the rate of de novo fatty acid synthesis was determined by the relative incorporation of [14C]choline and 3H2O, respectively, in 20-day-old fetal rat lung explants and in 18-day-old explants which were cultured 2 days. Addition of exogenous palmitate (0.15 mM) increased (26%) choline incorporation into disaturated PC but did not inhibit de novo fatty acid synthesis, as classically seen in other lipogenic tissue. Even in the presence of exogenous palmitate, de novo synthesis accounted for 87% of the acyl groups for disaturated PC. Inhibition of fatty acid synthesis by agaric acid or levo-hydroxycitrate decreased the rate of choline incorporation into disaturated PC. When explants were subjected to both exogenous palmitate and 60% inhibition of de novo synthesis, disaturated PC synthesis was below control values and 75% of disaturated PC acyl moieties were still provided by de novo synthesis. These data show that surfactant disaturated PC synthesis is highly dependent on the supply of palmitate from de novo fatty acid synthesis.

Fatty acid synthesis in the fetal lung: relationship to surfactant lipids.

The aims of this study were to investigate the control of fatty acid synthesis and its relationship to surfactant production in the fetal lung during alteration of hormonal and substrate conditions. Lung explants from 18 day fetuses (term = 22 days) which were cultured 2 days in the presence of 10 mM lactate showed parallel acceleration of de novo fatty acid synthesis (3H2O incorporation) and [14C]choline incorporation into disaturated phosphatidylcholine (DSPC) compared to culture of explants in glucose. Both the cultured and fresh explants were resistant to the classical short term (4 h) cAMP inhibition of fatty acid synthesis with 3 mM dibutyryl cAMP or 0.5 mM aminophylline. In the cultured explants short term cAMP elevation increased DSPC production, and long term (2 day) cAMP elevation caused a further increase in DSPC synthesis and also stimulated fatty acid synthesis. In cultured explants from 17 day fetuses, dexamethasone (0.1 microM) caused a synergistic increase with aminophylline in both fatty acid synthesis and DSPC production whereas, in explants from 18 day fetuses, dexamethasone inhibited both processes and reduced the level of stimulation of DSPC and fatty acid synthesis seen with aminophylline alone. Dexamethasone also reduced the stimulation of both DSPC and fatty acid synthesis produced in the culture of 18 day explants with bacitracin (0.5 mg/ml), whereas the combination of bacitracin and aminophylline resulted in a synergistic increase in DSPC production. Culture with glucagon (0.1 microM) also stimulated DSPC synthesis but at physiological levels insulin had no effect on either DSPC or fatty acid synthesis. These data show that lung fatty acid synthesis exhibits unique features of fatty acid synthesis regulation compared to other lipogenic tissues and also suggest a link between de novo fatty acid synthesis and surfactant production during the critical period of accelerated lung maturation.

Variability of indirect methods used to determine blood pressure. Office vs mean 24-hour automated blood pressures.

Blood pressure is a cardiovascular measurement with dynamic characteristics that can be influenced by a number of internal and external factors. The preferred blood pressure determination method would be one that reduces variability between measurements and that reflects the true blood pressure level. In this article, we present the variability of, and agreement between, the blood pressures collected by two indirect methods on the same patients during a hypertensive research project. Data obtained on patients in a typical clinical setting are also provided. Twenty-four-hour diastolic pressures obtained by the automated method demonstrated no regression to a lower mean, while blood pressures obtained casually in the office exhibited such regression. The 95% confidence interval of repeated measures for casual office blood pressure on a patient in a research setting (35/17 mm Hg) or in typical clinic practice (26/19 mm Hg) were similar, while the range of the mean 24-hour automated blood pressure monitoring (21/11 mm Hg) was smaller and demonstrated less variability. The magnitudes of the differences in blood pressures obtained on separate occasions in the same subjects were significantly lower with automated vs casual blood pressure determination methods (7.9/4.6 vs 13.7/7.4 mm Hg for both systolic and diastolic pressures). The agreement (95% confidence interval) between blood pressures obtained by the two methods (19/12 mm Hg) was found to be similar to the repeatability of automated blood pressure monitoring alone, and superior to that for data recorded casually in the office (35/17 mm Hg). Thus, the variability in mean 24-hour automated blood pressures is less than that for casual office blood pressures. The clinician should understand that the variability of blood pressures measured on an individual may be much greater than that reported for populations of hypertensive patients, and must be considered when applying epidemiologic group data to a specific patient. Moreover, any methodology of indirect blood pressure measurement that may reduce the variability and improve repeatability of casual office blood pressures deserves further consideration.

H(2)O(2)-induced egr-1, fra-1, and c-jun gene expression is mediated by tyrosine kinase in aortic smooth muscle cells.

Hydrogen peroxide (H(2)O(2)) has recently been shown to have a dual effect on cell growth by stimulating proliferation and triggering apoptosis. Apoptosis induced by H(2)O(2) is a direct consequence of oxidant injury, while the proliferative response to H(2)O(2) is thought to be a protective mechanism against oxidant injury. Signaling of the H(2)O(2)-induced proliferative effect has been proposed to occur via the activation of mitogen-activated protein kinase (MAPK) and increase in expression of transcription factors. In the present study, H(2)O(2)-induced mitogenic signaling in aortic smooth muscle cells (ASMC) was investigated with a specific focus on the roles of tyrosine kinase and tyrosine phosphatase in the regulation of the H(2)O(2)-stimulated egr-1, fra-1, and c-jun transcription. The results show that H(2)O(2)-induced increases in egr-1, fra-1, and c-jun mRNA levels, as measured by Northern blot analysis, are time and dose dependent with the peak of the response within 2 h. Tyrosine kinase inhibitors (genistein, amino-genistein, and tyrphostin 51) significantly attenuated H(2)O(2)-induced expression of these genes and a tyrosine phosphatase inhibitor (perox-vanadate) stimulated their expression. H(2)O(2) stimulated tyrosine kinase activities and caused protein tyrosine phosphorylation, which was blocked by tyrphostin 51. H(2)O(2) also caused tyrosine phosphorylation of platelet derived growth factor (PDGF) receptor. These data show that H(2)O(2) increases egr-1, fra-1, and c-jun mRNA levels in vascular smooth muscle cells, and the increase in expression of these genes is mediated by activation of tyrosine kinase. Our data also provide evidence that the H(2)O(2)-induced mitogenic response is, in part, mediated through the receptor tyrosine kinase, PDGF receptor.

Expansion of the ipsilateral visual corticotectal projection in hamster subjected to partial lesions of the visual cortex during infancy: electrophysiological experiments.

Single unit recording from cells in the superior colliculus ipsilateral to the damaged hemisphere in hamsters subjected to unilateral removal of a part of the posterior neocortex during infancy was combined with electrical stimulation of the cortical remnant and the visual cortex in the undamaged hemisphere. Cells activated by stimulation of the cortical remnant were recorded in all portions of the colliculus. No differences in percentages of driven cells or threshold current intensities were noted between electrode penetrations in which collicular neurons having receptive fields within the remaining visual cortical representation were recorded and tracks where units with receptive fields outside this region were isolated. In the medical part of the tectum ipsilateral to the damaged hemisphere cells driven by stimulation of either cortex were encountered. It was also demonstrated that stimulation of the ipsilateral cortical remnant and/or the contralateral cortex was capable of suppressing discharges normally elicited by optic chiasm or visual stimulation in a manner qualitatively similar to that observed for collicular cells in normal hamsters. The response properties of cells functionally influenced by the ipsilateral and/or contralateral corticles were not different from those of neurons which received no demonstrable cortical input. The receptive field characteristics of the sample of neurons recorded were, on the whole, quite similar to those of collicular neurons in hamsters subjected to lesions of the visual cortex as adults.

Cortical and spinal somatosensory input to the superior colliculus in the golden hamster: an anatomical and electrophysiological study.

The horseradish peroxidase technique was used to identify the sources of somatosensory afferent fibers to the hamster superior colliculus. These experiments demonstrated that the tectum receives axons from pyramidal cells in layer V of the ipsilateral sensorimotor cortex, contralateral lamina IV of all levels of the spinal cord, the contralateral dorsal column nuclei, lateral cervical nucleus, internal basilar nucleus, and nucleus of the spinal trigeminal tract. Electrical stimulation of the spinal cord coupled with extracellular single unit recordings concentrated, for the most part, in the posterior portion of the tectum revealed that such stimuli activated approximately 40% of the cells tested. Almost all of these units were isolated ventral to the stratum opticum and 86% were responsive only to somatosensory stimulation. Analysis of the latencies of collicular responses obtained with two point spinal stimulation in intact hamsters and in animals subjected to somatosensory cortical and/or spinal damage indicated that the initial impulse elicited from most collicular cells was mediated by a polysynaptic pathway(s) which probably synapses in the dorsal column, lateral cervical, and/or internal basilar nuclei. Damage to the dorsal spinal cord and/or somatosensory cortex altered neither the incidence nor the response characteristics of spinally driven collicular neurons. This indicated that most somatosensory collicular cells also received input from the spinotectal fibers which travel in the ventrolateral quadrant. Electrical stimulation of somatosensory cortex activated about 20% of the cells tested in the ipsilateral superior colliculus. If cortical and spinal stimulation were delivered with an interstimulus interval ranging between 50 and 80 msec the response of the tectal neuron to the latter stimulus was suppressed in most cases. This was true regardless of the order of the stimulus pairing. Concurrent somatosensory cortical shocks also suppressed responses to tactile stimuli for 21% of the cells tested.

Expansion of the ipsilateral visual corticotectal projection in hamsters subjected to partial lesions of the visual cortex during infancy: anatomical experiments.

Electrophysiological methods were employed to determine whether or not partial visual cortical lesions in neonatal (7--11-day) hamster produced large scotomas in the cortical visual representation. In cases where such scotomas were present electrophoretic deposits of radioactive amino acids in the visually responsive "cortical remnant" of the damaged hemisphere resulted in labelling throughout the lower portion of the stratum griseum superficiale and the stratum opticum of the ipsilateral superior colliculus. No differential labeling of the part of the colliculus which was topographically matched with the remaining visual representation in the cortical remnant was observed. In normal hamsters relatively localized, visual cortical deposits of radioactive amino acids resulted in superficial layer labeling only in portions of the colliculus which corresponded to the locus of the cortical deposit. In a similar fashion, small lesions at physiologically defined loci in the cortical remnant produced degeneration throughout most of the superficial tectal laminae, but a more restricted "focus" of denser degeneration was also visible in these cases. The position of this focus in the colliculus for a given cortical lesion varied with the nature of the visual map in the cortical remnant. In several additional neonatally brain-damaged hamsters large lesions of the visual cortex in the intact hemisphere were combined with radioactive amino acid deposits in the cortical remnant to determine whether or not axons from the crossed corticocollicular pathway previously demonstrated in such hamsters were intermingled with fibers from the ipsilateral corticotectal projection. In alternate sections processed for autoradiography or by the Fink-Heimer ('67) method autoradiographic label and degeneration argyrophilia were both observed in the medical part of the colliculus ipsilateral to the neonatal cortical lesion.

An autoradiographic study of the retinotectal projection in the golden hamster.

Intraocular injections of tritiated leucine and proline were used to examine the retinotectal projection of the golden hamster. In the contralateral superior colliculus intense and complete label was seen in the stratum zonale, stratum griseum superficiale and the upper portion of the stratum opticum, with relatively less dense label in the lower part of the optic layer. On the ipsilateral side no label was found in the most rostral portion of the tectum. This area comprised about 10% of the rostro-caudal extent of the colliculus, and most likely, it receives a crossed input from the temporal retina (as demonstrated in the cat by Harting and Guillery, '76). Very sparse label was observed in an anterior segment of the ipsilateral colliculus. In coronal sections it appeared as discrete clumps or patches which were confined to the stratum opticum. Within this layer there was a tendency for the clumps to be located more dorsally with increasing laterality. There was considerable variability between and within animals in the size of the clumps as well as the distance between clumps. Reconstruction of coronal sections showed that the ipsilateral label forms discontinuous ribbons which extend up to 180 microns in the rostro-caudal dimension. No label was seen on the ipsilateral side in the remaining tectum (caudal 60%).

Receptive field characteristics of superior colliculus neurons and visually guided behavior in dark-reared hamsters.

Visual response properties of single neurons in the superior colliculus of golden hamsters reared from birth to adulthood in total darkness were compared to those of normal hamsters. Directional selectivity, speed preferences, and receptive field organization in dark-reared hamsters were essentially the same as those found in normally reared animals. Subtle neurophysiological effects of visual deprivation were indicated by the longer latencies of "on" responses to flashed spots of light in the dark-reared animals. Also, in the visually deprived animals three cells were encountered which changed their responses from phasic to tonic as the size of the visual stimulus was increased. In normally reared animals all cells responding to stationary stimuli showed only phasic responses regardless of spot size. Behaviorally, dark-reared animals could not be distinguished from normal animals on the basis of visual orienting and following tests. It was concluded that in the golden hamster visual experience during development has a minimal role in the induction or maintenance of the normal functional development of the superior colliculus.

Functional properties of the corticotectal projection in the golden hamster.

Approximately 31% of the cells recorded in the hamster's superior colliculus could be activated by stimulation of the ipsilateral primary visual cortex. While cortically activated cells were encountered in all laminae of the colliculus where visual cells were isolated, the highest probability of driving visual cells was observed in the deeper laminae, that is, those ventral to the stratum opticum. Response latency, jitter (latency variability), latency shifts as a function of shock intensity, thresholds, and spike numbers did not vary as a function of depth in the colliculus. There was a clear correspondence between the visual fields of the best cortical stimulus points and the receptive fields of cortically activated cells recorded in the superficial laminae of the colliculus. However, there was considerably less retinotopic fidelity for the cortical areas from which cells isolated in the deeper laminae could be driven. This suggests a greater degree of convergence from relatively widespread cortical regions upon visual cells of the deeper laminae. The visal organization) of the cortically activated cells did not differ appreciably from the overall sample of visual cells recorded in the colliculus. Only 3 of the 159 cells tested were driven by stimulation of the contralateral visual cortex and two of these were responsive only at very long latencies.

Representation of whisker follicle intrinsic musculature in the facial motor nucleus of the rat.

Retrograde transport of wheatgerm-agglutinin horseradish peroxidase (WGA-HRP) and fluorescent tracers (true blue-TB, nuclear yellow-NY, and diamidino yellow-DY) from isolated whisker follicles was used to define the somatotopic organization of the facial (VII) motoneurons which innervate the intrinsic follicle muscles. Motoneurons supplying these muscles were restricted almost completely to the lateral (Martin and Lodge, '77) facial subnucleus and the motoneurons which innervated a given follicle were distributed over the entire length of this subnucleus. Cells projecting to dorsal (A-row) follicles were located in the most lateral part of the lateral subnucleus, while those supplying ventral (E-row) follicles were restricted to the medial part of the subnucleus. Injections of different tracers into rostral and caudal follicles within a given row revealed no somatotopic representation of the rostrocaudal axis of the whiskerpad. Additional control experiments demonstrated that some of the labelling obtained with WGA-HRP resulted from spread of this tracer to extrinsic muscles. This was not the case with the fluorescent tracers. The results of the control experiments suggested further that a significant percentage of the motoneurons in the lateral facial subnucleus innervate only intrinsic follicle muscles.

Effects of neonatal infraorbital lesions upon central trigeminal primary afferent projections in rat and hamster.

Transganglionic and anterograde horseradish peroxidase transport was used to evaluate the central projections of undamaged trigeminal (V) nerve branches in adult rats and hamsters subjected to transection of the infraorbital nerve and to cauterization of the vibrissae follicles at birth. In rats, deafferented regions of the V brainstem nuclear complex did not receive abnormal projections from undamaged mandibular sensory afferents. Undamaged ophthalmic-maxillary fibers also failed to terminate heavily in the region deafferented by the neonatal infraorbital lesions. In the hamster, on the other hand, neonatal infraorbital nerve lesions were associated with statistically significant increases in mandibular terminal fields in the principalis, subnucleus interpolaris, and subnucleus caudalis. Tracing experiments were also carried out in neonatal rats and hamsters to determine whether the above-described differences in the response to infraorbital nerve damage reflected a difference in the maturity of the V primary afferent projections to the brainstem at the time of our neonatal lesions. In neonatal rats, the infraorbital and mandibular projections to the V brainstem nuclear complex were quite adultlike, both in their pattern and in the extent of their overlap, which was minimal. Overlap between mandibular and infraorbital terminal fields was also minimal in the newborn hamsters.

Conduction velocity distribution of the retinal input to the hamster's superior colliculus and a correlation with receptive field characteristics.

Cells driven reliably by shocks delivered to the optic nerve or optic chiasm were encountered throughout the depth of the colliculus. The incidence of such cells, however, decreased markedly in the laminae ventral to the stratum opticum. The distribution of conduction velocities for the retinal afferents to the tectum was quite broad (range: 1.7-25.5 m/sec) and clearly biomodal with peaks at about 6 and 12 m/sec. A small number of cells were innervated by rapidly (greater than 15 m/sec) conducting axons. No evidence of an indirect-fast pathway from the retina to the colliculus via the lateral geniculate nucleus and visual cortex was obtained. Afferent conduction velocity was not correlated with retinal eccentricity, collicular depth or speed selectivity. It was, however, clearly related to directional selectivity. Ninety percent of the tectal neurons receiving inputs from axons having conduction velocities of less than 5 m/sec were directionally selective while only 41% of those neurons innervated by more rapidly conducting fibers (greater than 5 m/sec) exhibited selectivity. One hundred and sixteen cells in the anterior portion of the colliculus were tested with shocks delivered to the ipsilateral optic nerve and photic stimulation of the ipsilateral eye. Of these, 11% exhibited some degree of binocularity and only 6% were responsive to optic nerve shocks. These electrophysiological findings were correalted with the limited nature of the retinal input to the ipsilateral superior colliculus.