Comparable reduction in Zif268 levels and cytochrome oxidase activity in the retrosplenial cortex following mammillothalamic tract lesions

Damage to the mammillothalamic tract (MTT) pro- duces memory impairments in both humans and rats, yet it is still not clear why this diencephalic pathway is vital for memory. One suggestion is that it is an important route for midbrain inputs to reach a wider cortical and subcortical net- work that supports memory. Consistent with this idea, MTT lesions produce widespread hypoactivity in distal brain regions as measured by the immediate-early gene, c-fos. To determine whether these findings were selective to c-fos or reflected more general changes in neuronal function, we assessed the effects of MTT lesions on the expression of the immediate-early gene protein, Zif268 and the metabolic marker, cytochrome oxidase, in the retrosplenial cortex and hippocampus. The lesions decreased levels of both activity markers in the superficial and deep layers of the retrosplenial cortex in both its granular and dysgranular subregions. In contrast, no significant changes were observed in the hip- pocampus, despite the MTT-lesioned animals showing marked impairments on T-maze alternation. These findings are consistent with MTT lesions providing important, indirect inputs for normal retrosplenial cortex functioning. These dis- tal functional changes may contribute to the memory impair- ments observed after MTT lesions

1-methylnicotinamide and its structural analog 1,4-dimethylpyridine for the prevention of cancer metastasis

Background: 1-methylnicotinamide (1-MNA), an endogenous metabolite of nicotinamide, has recently gained interest due to its anti-inflammatory and anti-thrombotic activities linked to the COX-2/PGI2 pathway. Given the previously reported anti-metastatic activity of prostacyclin (PGI2), we aimed to assess the effects of 1-MNA and its structurally related analog, 1,4-dimethylpyridine (1,4-DMP), in the prevention of cancer metastasis. Methods: All the studies on the anti-tumor and anti-metastatic activity of 1-MNA and 1,4-DMP were conducted using the model of murine mammary gland cancer (4T1) transplanted either orthotopically or intravenously into female BALB/c mouse. Additionally, the effect of the investigated molecules on cancer cell-induced angiogenesis was estimated using the matrigel plug assay utilizing 4T1 cells as a source of pro-angiogenic factors. Results: Neither 1-MNA nor 1,4-DMP, when given in a monotherapy of metastatic cancer, influenced the growth of 4T1 primary tumors transplanted orthotopically; however, both compounds tended to inhibit 4T1 metastases formation in lungs of mice that were orthotopically or intravenously inoculated with 4T1 or 4T1-luc2-tdTomato cells, respectively. Additionally, while 1-MNA enhanced tumor vasculature formation and markedly increased PGI2 generation, 1,4-DMP did not have such an effect. The anti-metastatic activity of 1-MNA and 1,4-DMP was further confirmed when both agents were applied with a cytostatic drug in a combined treatment of 4T1 murine mammary gland cancer what resulted in up to 80 % diminution of lung metastases formation. Conclusions: The results of the studies presented below indicate that 1-MNA and its structural analog 1,4-DMP prevent metastasis and might be beneficially implemented into the treatment of metastatic breast cancer to ensure a comprehensive strategy of metastasis control

p53 Regulates Cell Cycle and MicroRNAs to Promote Differentiation of Human Embryonic Stem Cells

Multiple studies show that tumor suppressor p53 is a barrier to dedifferentiation; whether this is strictly due to repression of proliferation remains a subject of debate. Here, we show that p53 plays an active role in promoting differentiation of human embryonic stem cells (hESCs) and opposing self-renewal by regulation of specific target genes and microRNAs. In contrast to mouse embryonic stem cells, p53 in hESCs is maintained at low levels in the nucleus, albeit in a deacetylated, inactive state. In response to retinoic acid, CBP/p300 acetylates p53 at lysine 373, which leads to dissociation from E3-ubiquitin ligases HDM2 and TRIM24. Stabilized p53 binds CDKN1A to establish a G1 phase of cell cycle without activation of cell death pathways. In parallel, p53 activates expression of miR-34a and miR-145, which in turn repress stem cell factors OCT4, KLF4, LIN28A, and SOX2 and prevent backsliding to pluripotency. Induction of p53 levels is a key step: RNA-interference-mediated knockdown of p53 delays differentiation, whereas depletion of negative regulators of p53 or ectopic expression of p53 yields spontaneous differentiation of hESCs, independently of retinoic acid. Ectopic expression of p53R175H, a mutated form of p53 that does not bind DNA or regulate transcription, failed to induce differentiation. These studies underscore the importance of a p53-regulated network in determining the human stem cell state

A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (me/cfs) and sickness behavior

It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions

Nuclear Interactions Of Super High Energy Cosmic-rays Observed In Mountain Emulsion Chambers

Here we present a summary of joint discussions on the results of three mountain experiments with large-scale emulsion chambers, at Pamir, Mt. Fuji and Chacaltaya. Observations cover gamma quanta, hadrons and their clusters (called "families"). The following topics are covered, concerning the characteristics of nuclear interactions the energy region 1014-1016 eV: (i) rapid dissipation seen in atmospheric diffusion of high-energy cosmic-rays; (ii) multiplicity and Pt increase in produced pi-mesons in the fragmentation region; (iii) existence of large-Pt jets, (iv) extremely hadron-rich family of the Centauro type; (v) exotic phenomena in the extremely high energy region beyond 1016 eV. © 1981.1911125(1977) Acta Univ. Lodz ser. II, (60)(1973) 13th Int. Cosmic-ray Conf., 3, p. 2228(1975) 14th Int. Cosmic-Ray Conf., 7, p. 2365(1979) AIP Conf. Proc. no. 49, p. 334(1979) 16th Int. Cosmic-ray Conf., 6, p. 344(1979) 16th Int. Cosmic-ray Conf., 7, p. 6816th Int. Cosmic-ray Conf. (1979) 16th Int. Cosmic-ray Conf., 7, p. 284(1979) 16th Int. Cosmic-ray Conf., 7, p. 294(1979) 16th Int. Cosmic-ray Conf., 13, p. 87(1979) 16th Int. Cosmic-ray Conf., 13, p. 92(1979) 16th Int. Cosmic-ray Conf., 13, p. 98(1979) AIP Conf. Proc. no. 49, p. 94(1979) AIP Conf. Proc. no. 49, p. 145(1979) AIP Conf. Proc. no. 49, p. 317(1979) 16th Int. Cosmic-ray Conf., 6, p. 350(1979) 16th Int. Cosmic-ray Conf., 6, p. 356(1979) 16th Int. Cosmic-ray Conf., 6, p. 362Nikolsky, Proc. 9th Int. High-energy Symp. (1978) CSSR, 21. , ToborMiyake, (1978) Proc. 19th Int. Conf. on High-energy physics, p. 433Vernov, (1977) Physica, 3, p. 1601Khristiansen, (1978) JETP Lett., 28, p. 124(1973) 13th Int. Cosmic-ray Conf., 3, p. 2219Izv. Acad. Nauk USSR, ser Phys. (1974) Izv. Acad. Nauk USSR, ser Phys., 38, p. 918(1975) 14th Int. Cosmic-ray Conf., 7, p. 2365(1979) 16th Int. Cosmic-ray Conf., 7, p. 68Dunaevsky, Urysson, Emelyanov, Shorin, Tashimov, (1975) FIAN preprint no. 150Dunaevsky, Urysson, Emelyanov, Shorin, Tashinov, (1979) Acta Univ. Lodz ser. II, (60), p. 199Ivanenko, Kanevskya, Roganova, (1978) JETP Lett., 40, p. 704Ivanenko, Kanevsky, Roganova, (1979) 16th Int. Cosmic-ray Conf., 7, p. 101Ivanenko, Kanevsky, Roganova, (1979) 16th Int. Cosmic-ray Conf., 7, p. 198Wrotniak, (1977) Acta Univ. Lodz ser. II, (60), p. 165Krys, Tomaszevski, Wrotniak, (1979) 16th Int. Cosmic-ray Conf., 7, p. 182Krys, Tomaszevski, Wrotniak, (1979) 16th Int. Cosmic-ray Conf., 7, p. 186Fomin, Kempa, Khristiansen, Levina, Piotrowska, Wdowczyk, (1977) 15th Int. Cosmic-ray Conf., 7, p. 248Fomin, Kempa, Khristiansen, Levina, Piotrowska, Wdowczyk, (1979) 16th Int. Cosmic-ray Conf., 13, p. 82Azimov, Mullazhanov, Yuldashbayev, (1979) 16th Int. Cosmic-ray Conf., 7, p. 262Azimov, Mullazhanov, Yuldashbayev, (1977) Acta Univ. Lodz ser. II, (60), p. 275Kasahara, Torri, Yuda, (1979) 16th Int. Cosmic-ray Conf., 13, p. 70Kasahara, Torii, Yuda, (1979) 16th Int. Cosmic-ray Conf., 13, p. 79Shibata, (1979) 16th Int. Cosmic-ray Conf., 7, p. 176H. Semba, T. Shibata and T. Tabuki, Suppl. Prog. Theor. Phys., to be publishedZhdanov, Roinishvilli, Smorodin, Tomaszevski, (1975) FIAN preprint no. 163Lattes, Fujimoto, Hasegawa, Hadronic interactions of high energy cosmic-ray observed by emulsion chambers (1980) Physics Reports, 65, p. 152Ellsworth, Gaisser, Yodh, (1981) Phys. Rev., 23 D, p. 764Baradzei, Smorodin, (1974) FIAN preprint nos. 103, 104Baradzei, Smorodin, (1977) Acta Univ. Lodz ser. II, (60), p. 51Zhdanov, (1980) FIAN preprint no. 140H. Semba, T. Shibata and T. Tabuki, Suppl. Prog. Theor. Phys., to be publishedShibata, (1980) Phys. Rev., 22 D, p. 100Slavatinsky, (1980) Proc. 7th European Symp. on Cosmic rays, , Leningrad, to be published(1979) AIP Conference Proc. no. 49, p. 145Azimov, Abduzhamilov, Chudakov, (1963) JETP (Sov. Phys.), 45, p. 40713th Int. Cosmic-ray Conf. (1973) 13th Int. Cosmic-ray Conf., 5, p. 326Acharya, Rao, Sivaprasad, Rao, (1979) 16th Int. Cosmic-ray Conf., 6, p. 289Ellsworth, Goodman, Yodh, Gaisser, Stanev, (1981) Phys. Rev., 23 D, p. 771Bariburina, Guseva, Denisova, (1980) Acta Univ. Lodz, 1, p. 9415th Int. Cosmic-ray Conf. (1977) 15th Int. Cosmic-ray Conf., 7, p. 184(1979) AIP Conf. Proc. no. 49, p. 33

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Keratins extracted from Merino wool and Brown Alpaca fibres as potential fillers for PLLA-based biocomposites

This paper reports on the promising perspectives of using keratins extracted by sulphitolysis reaction from Merino wool (KM) and Brown Alpaca fibres (KA) in poly (l-lactide) (PLLA)-based biomaterials. Both types of keratin were dispersed in chloroform (CHCl3) and tetrahydrofuran (THF), and optimisation of dispersion methods and parameters using the two selected solvents was considered. The extraction yield, as well as supermolecular structures, morphology and thermal behaviour of the two proteins before and after the regeneration in CHCl3 was investigated. The results indicated that the supermolecular structures and thermal behaviour of the two proteins were affected by the interaction with CHCl3, producing decrease of the amount of α-helix structures in KM and an increase for KA, a slight decrease of β-sheet structures and a reduced thermal stability of α-crystallites for both keratins. Biocomposite films based on PLLA polymer matrix and two different contents of Merino wool and Brown Alpaca keratins (1 % and 5 % wt) were successfully developed by solvent casting in chloroform and the resulting morphologies after incorporation of different keratins (as a function of content and source) give evidence of different surface topographies, with a random distribution of keratin in flask-like structure. PLLA/5KA and PLLA/5KM samples with 1 % and 5 % wt of keratins show a specific pore-like surface microstructure, induced by solvent evaporation.Peer Reviewe