Sirtuins rank among class III histone deacetylases which deacetylate N?-acetyllysine residues in an unusual chemical reaction that consumes NAD+ and releases nicotinamide, the deacetylated substrate and a novel product, 2’-O-acetyladenosine diphosphoribose. Sirtuins influence a wide range of biological functions and are required for gene silencing. They are also responsible for lifespan extension by calorie restriction. Their mechanism of action, means of modulating their activity and enzymatic targets, with the focus on age-related diseases, are discussed.
Arterial occlusion due to thrombosis caused by ruptured atherosclerotic plaques (Baba et al., 1975) has been recognized as a major cause of morbidity and mortality in western populations. Thrombosis may occur in various sections of arterial circulation, peripheral arteries of the limbs, coronary arteries, brain arteries, or both major and minor vessels within the abdominal cavity. The ultimate consequence is varying degrees of organ failure, mostly of ischemic origin. Arterial thrombosis represents a continuous problem, debilitating patients and decreasing their quality of life. Moreover, along with chronic heart failure, it can significantly decrease patient life expectancy. Arterial thrombosis results in ischemia, with serious systemic consequences, such as metabolic breakdown. The major goal of treatment remains fast and efficient recanalization - surgical, interventional or thrombolytic. To be able to prevent acute reocclusion with severe consequences (rhabdomyolysis, compartment syndrome, excessive tissue necrosis leading to limb amputation, etc.), several adjunctive treatment regimens have been advocated. Among others, thrombin inhibitors and platelet inhibitors have been widely used for both prophylaxis and adjunctive treatment. Direct thrombin inhibitors and antithrombin stimulators have been recognized as typical antithrombotic drugs. Direct (antithrombin-independent) thrombin inhibitors can be divided into two main categories: monovalent, active site inhibitors (argatroban, efegatran, inovastan, melagatran) and bivalent (hirudin, hirugen, hirulog, bivalirudin), while antithrombin stimulators represent standard (unfractionated) heparin (UFH) and its depolymerizing products - low molecular weight heparins (LMWH's). Recently, a clear change in the main use of heparin, as well as low-molecular weight heparins has been advocated representing a shift from treatment and prophylaxis of deep vein thrombosis to prophylaxis of thromboembolic disease following vascular, cardiovascular or orthopedic surgery, treatment of unstable angina and prevention of acute myocardial infarction. The main effect of heparins lies in their anticoagulant activity. Heparins are involved in different pathways of the coagulation cascade with anticoagulant, antithrombotic, profibrinolytic, anti-aggregative, as well as anti-inflammatory effects. Moreover, there is a little doubt about their anti-proliferative and anti-ischemic activity (Penka and Bulikova, 2006). Unlike standard heparin, low-molecular weight heparins do not affect the patient's general coagulation profile. Obviously, the difference in molecular weight results in different pharmacokinetic and pharmacodynamic properties of the agents.
The oncoprotein v-Myb induces myeloid leukemia and its cellular counterpart c-Myb is involved in the regulation of hematopoiesis. Although intensively studied, their precise subcellular localization is not known. In order to expand our knowledge in this respect, we used an artificial system overexpressing these proteins. We investigated the subcellular localization of Myb proteins in cultured non-synchronized insect cells transfected with recombinant baculoviruses overexpressing either v-myb oncogene or c-myb proto-oncogene. The cell expressing Myb proteins underwent extensive nuclear changes and exhibited distinct nuclear structures resembling nucleoli. The bulk of v-Myb and c-Myb proteins accumulated in such nucleolus-like structures which, according to the nucleolar nomenclature, we classified to three types: compact of enlarged size (type I), large ring-shaped (type II) and with nucleolonemas (type III). We investigated these structures for the presence of important nucleolar macromolecules in order to establish whether they were compatible with the function in the production of ribosomes. Strikingly, our results indicated that the different forms of these structures did not represent genuine nucleoli. They rather reflected progressive changes, induced by the virus infection and high expression of v-myb genes, accompanied by the formation of these prominent nucleolus-like structures highly enriched in Myb protein. Gradual changes in number of individual nucleolus-like forms during infection, increasing amount of Myb protein and DNA localized in them together with decreasing amount of RNA and their different interaction with viral particles indicate that the nucleolus-like structure of type I is a precursor of the type II and finally of the type III.
Humans tune in to the native language prosody before they are even born. Prior findings with newborns reported language-specific processing of forward versus backward speech and intonational contours and also indicated language-specific processing of iambic versus trochaic patterns in non-linguistic tone stimuli. The present experiment tested newborns’ processing of temporal rhythm patterns in naturalistic native-language speech. Czech-learning newborns were played naturally recorded well-formed Czech utterances with native Czech rhythm (virtually lacking cues to word-level stress) and with non-native rhythm (prolonged foot-initial syllables), while their hemodynamic activity was recorded. The results showed larger hemodynamic responses to the non-native than to the native rhythm in a late analysis window, attributable to a double-peak response shape in the non-native condition. This finding is discussed in terms of suprisal-induced resonating activity after hearing familiar native speech paired with an unfamiliar rhythm pattern. Further, there was an overall attenuated response to the native rhythm localized in the right frontal region (comprising the Broca's area), evidencing right-lateralized processing of speech rhythm. Traditional language development theories claimed that only coarse between-class rhythm differences between languages are processed at birth. Having demonstrated that newborns differentially process non-native vs. native rhythmic patterns within natural native-langugae speech, even in a language outside of the traditional rhythm classes, the present findings disprove some of the early theories and substantially deepen our understanding of early speech development.
Humans tune in to the native language prosody before they are even born. Prior findings with newborns reported language-specific processing of forward versus backward speech and intonational contours and also indicated language-specific processing of iambic versus trochaic patterns in non-linguistic tone stimuli. The present experiment tested newborns’ processing of temporal rhythm patterns in naturalistic native-language speech. Czech-learning newborns were played naturally recorded well-formed Czech utterances with native Czech rhythm (virtually lacking cues to word-level stress) and with non-native rhythm (prolonged foot-initial syllables), while their hemodynamic activity was recorded. The results showed larger hemodynamic responses to the non-native than to the native rhythm in a late analysis window, attributable to a double-peak response shape in the non-native condition. This finding is discussed in terms of suprisal-induced resonating activity after hearing familiar native speech paired with an unfamiliar rhythm pattern. Further, there was an overall attenuated response to the native rhythm localized in the right frontal region (comprising the Broca's area), evidencing right-lateralized processing of speech rhythm. Traditional language development theories claimed that only coarse between-class rhythm differences between languages are processed at birth. Having demonstrated that newborns differentially process non-native vs. native rhythmic patterns within natural native-langugae speech, even in a language outside of the traditional rhythm classes, the present findings disprove some of the early theories and substantially deepen our understanding of early speech development.
Structural changes of insect cells Spodoptera frugiperda in the baculovirus expression system after expression of v-myb oncogene and c-myb protooncogene inserts were studied by means of electron microscopy. Expression of v-myb gene insert was accompanied by extensive changes in cell structure, when compared with those of the noninfected and wild-type virus-infected cells. Enormous increase in nuclear content was apparent within 48 hrs after infection, along with changes in nucleolus appearance. Large ring-shaped nucleoli, compact nucleoli and nucleoli with nucleolonemas were detected together with dense nucleolus of normal appearance and small nucleolar structures localized in the nuclear periphery. The cytoplasm practically disappeared 72 hrs after infection. Morphological changes of insect cells expressing the c-myb gene were significantly less distinct, but more frequent unraveling of nucleoli was observed. Both v-Myb and c-Myb proteins were localized in the nucleus of infected cells as was revealed by fluorescence microscopy and electron microscopy. c-Myb marker decorated distinctly the ring-shaped area of nucleolus with some less intensive labelling of the inner part of nucleolus and proximal area on nuclear membrane. v-Myb protein revealed predominantly more compact and homogeneous distribution inside the nucleolus but a small proportion of it was also detected outside the nucleolus in the nuclear compartment. The data obtained on insect cells suggest that Myb proteins may participate also in the processes in which the nucleolus plays a role.
Lipoblastoma is a very rare benign tumour that is caused by embryonal fat. The present five cases of lipoblastoma operated on during the years 1996-2005. The localization of the lipoblastomas in our series were very unusual. A six-monthold girl with giant mediastinal lipoblastoma; a two-year old boy with very rare lipoblastoma of the kidney; a three-year old boy with mesenterial lipoblastoma; a seven-year old boy with mesenterial lipoblastoma; and an eight-week old girl with perineal localization. Histological diagnosis can be difficult. The basic differential diagnosis is to be made between lipoblastoma, myxoid, and round cell liposarcoma. In our sample group of patients all lipoblastomas were successfully and completely removed and we did not see any recurrence of the tumours. In only one case was more radical surgery needed. One patient with mesenterial lipoblastoma had to undergo a 30 cm long resection of the small intestine.
Abstract A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1 Cre strategies. In the absence of Isl1 , spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central compensatory plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.
