Over half of breakpoints in gene pairs involved in cancer-specific recurrent translocations are mapped to human chromosomal fragile sites.

Gene rearrangements such as chromosomal translocations have been shown to contribute to cancer development. Human chromosomal fragile sites are regions of the genome especially prone to breakage, and have been implicated in various chromosome abnormalities found in cancer. However, there has been no comprehensive and quantitative examination of the location of fragile sites in relation to all chromosomal aberrations

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

Abstract OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10\u2009mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of 652 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation

DNA topoisomerases participate in fragility of the oncogene RET

Fragile site breakage was previously shown to result in rearrangement of the RET oncogene, resembling the rearrangements found in thyroid cancer. Common fragile sites are specific regions of the genome with a high susceptibility to DNA breakage under conditions that partially inhibit DNA replication, and often coincide with genes deleted, amplified, or rearranged in cancer. While a substantial amount of work has been performed investigating DNA repair and cell cycle checkpoint proteins vital for maintaining stability at fragile sites, little is known about the initial events leading to DNA breakage at these sites. The purpose of this study was to investigate these initial events through the detection of aphidicolin (APH)-induced DNA breakage within the RET oncogene, in which 144 APHinduced DNA breakpoints were mapped on the nucleotide level in human thyroid cells within intron 11 of RET, the breakpoint cluster region found in patients. These breakpoints were located at or near DNA topoisomerase I and/or II predicted cleavage sites, as well as at DNA secondary structural features recognized and preferentially cleaved by DNA topoisomerases I and II. Co-treatment of thyroid cells with APH and the topoisomerase catalytic inhibitors, betulinic acid and merbarone, significantly decreased APH-induced fragile site breakage within RET intron 11 and within the common fragile site FRA3B. These data demonstrate that DNA topoisomerases I and II are involved in initiating APH-induced common fragile site breakage at RET, and may engage the recognition of DNA secondary structures formed during perturbed DNA replication

X-ray absorption spectroscopy systematics at the tungsten L-edge

A series of mononuclear six-coordinate tungsten compounds spanning formal oxidation states from 0 to +VI, largely in a ligand environment of inert chloride and/or phosphine, has been interrogated by tungsten L-edge X-ray absorption spectroscopy. The L-edge spectra of this compound set, comprised of [W&lt;sup&gt;0&lt;/sup&gt;(PMe&lt;sub&gt;3&lt;/sub&gt;)&lt;sub&gt;6&lt;/sub&gt;], [W&lt;sup&gt;II&lt;/sup&gt;Cl&lt;sub&gt;2&lt;/sub&gt;(PMePh&lt;sub&gt;2&lt;/sub&gt;)&lt;sub&gt;4&lt;/sub&gt;], [W&lt;sup&gt;III&lt;/sup&gt;Cl&lt;sub&gt;2&lt;/sub&gt;(dppe)&lt;sub&gt;2&lt;/sub&gt;][PF&lt;sub&gt;6&lt;/sub&gt;] (dppe = 1,2-bis(diphenylphosphino)ethane), [W&lt;sup&gt;IV&lt;/sup&gt;Cl&lt;sub&gt;4&lt;/sub&gt;(PMePh&lt;sub&gt;2&lt;/sub&gt;)&lt;sub&gt;2&lt;/sub&gt;], [W&lt;sup&gt;V&lt;/sup&gt;(NPh)Cl&lt;sub&gt;3&lt;/sub&gt;(PMe&lt;sub&gt;3&lt;/sub&gt;)&lt;sub&gt;2&lt;/sub&gt;], and [W&lt;sup&gt;VI&lt;/sup&gt;Cl&lt;sub&gt;6&lt;/sub&gt;] correlate with formal oxidation state and have usefulness as references for the interpretation of the L-edge spectra of tungsten compounds with redox-active ligands and ambiguous electronic structure descriptions. The utility of these spectra arises from the combined correlation of the estimated branching ratio (EBR) of the L&lt;sub&gt;3,2&lt;/sub&gt;-edges and the L&lt;sub&gt;1&lt;/sub&gt; rising-edge energy with metal Z&lt;sub&gt;eff&lt;/sub&gt;, thereby permitting an assessment of effective metal oxidation state. An application of these reference spectra is illustrated by their use as backdrop for the L-edge X-ray absorption spectra of [W&lt;sup&gt;IV&lt;/sup&gt;(mdt)&lt;sub&gt;2&lt;/sub&gt;(CO)&lt;sub&gt;2&lt;/sub&gt;] and [W&lt;sup&gt;IV&lt;/sup&gt;(mdt)&lt;sub&gt;2&lt;/sub&gt;(CN)&lt;sub&gt;2&lt;/sub&gt;]&lt;sup&gt;2–&lt;/sup&gt; (mdt&lt;sup&gt;2–&lt;/sup&gt; = 1,2-dimethylethene-1,2-dithiolate), which shows that both compounds are effectively W&lt;sup&gt;IV&lt;/sup&gt; species. Use of metal L-edge XAS to assess a compound of uncertain formulation requires: 1) Placement of that data within the context of spectra offered by unambiguous calibrant compounds, preferably with the same coordination number and similar metal ligand distances. Such spectra assist in defining upper and/or lower limits for metal Z&lt;sub&gt;eff&lt;/sub&gt; in the species of interest; 2) Evaluation of that data in conjunction with information from other physical methods, especially ligand K-edge XAS; 3) Increased care in interpretation if strong π-acceptor ligands, particularly CO, or π-donor ligands are present. The electron-withdrawing/donating nature of these ligand types, combined with relatively short metal-ligand distances, exaggerate the difference between formal oxidation state and metal Z&lt;sub&gt;eff&lt;/sub&gt; or, as in the case of [W&lt;sup&gt;IV&lt;/sup&gt;(mdt)&lt;sub&gt;2&lt;/sub&gt;(CO)&lt;sub&gt;2&lt;/sub&gt;], add other subtlety by modulating the redox level of other ligands in the coordination sphere

TRH: Pathophysiologic and clinical implications

Thyrotropin releasing hormone is thought to be a tonic stimulator of the pituitary TSH secretion regulating the setpoint of the thyrotrophs to the suppressive effect of thyroid hormones. The peptide stimulates the release of normal and elevated prolactin. ACTH and GH may increase in response to exogenous TRH in pituitary ACTH and GH hypersecretion syndromes and in some extrapituitary diseases. The pathophysiological implications of extrahypothalamic TRH in humans are essentially unknown. The TSH response to TRH is nowadays widely used as a diganostic amplifier in thyroid diseases being suppressed in borderline and overt hyperthyroid states and increased in primary thyroid failure. In hypothyroid states of hypothalamic origin, TSH increases in response to exogenous TRH often with a delayed and/or exaggerated time course. But in patients with pituitary tumors and suprasellar extension TSH may also respond to TRH despite secondary hypothyroidism. This TSH increase may indicate a suprasellar cause for the secondary hypothyroidism, probably due to portal vessel occlusion. The TSH released in these cases is shown to be biologically inactive

Developments in the negative-U modelling of the cuprate HTSC systems

The paper deals with the many stands that go into creating the unique and complex nature of the HTSC cuprates above Tc as below. Like its predecessors it treats charge, not spin or lattice, as prime mover, but thus taken in the context of the chemical bonding relevant to these copper oxides. The crucial shell filling, negative-U, double-loading fluctuations possible there require accessing at high valent local environment as prevails within the mixed valent, inhomogeneous two sub-system circumstance of the HTSC materials. Close attention is paid to the recent results from Corson, Demsar, Li, Johnson, Norman, Varma, Gyorffy and colleagues.Comment: 44 pages:200+ references. Submitted to J.Phys.:Condensed Matter, Sept 7 200

The braincase and jaws of a Devonian 'acanthodian' and modern gnathostome origins.

Modern gnathostomes (jawed vertebrates) emerged in the early Palaeozoic era, but this event remains unclear owing to a scant early fossil record. The exclusively Palaeozoic acanthodians are possibly the earliest gnathostome group and exhibit a mosaic of shark- and bony fish-like characters that has long given them prominence in discussions of early gnathostome evolution. Their relationships with modern gnathostomes have remained mysterious, partly because their un-mineralized endoskeletons rarely fossilized. Here I present the first-known braincase of an Early Devonian (approximately 418-412 Myr bp) acanthodian, Ptomacanthus anglicus, and re-evaluate the interrelationships of basal gnathostomes. Acanthodian braincases have previously been represented by a single genus, Acanthodes, which occurs more than 100 million years later in the fossil record. The braincase of Ptomacanthus differs radically from the osteichthyan-like braincase of Acanthodes in exhibiting several plesiomorphic features shared with placoderms and some early chondrichthyans. Most striking is its extremely short sphenoid region and its jaw suspension, which displays features intermediate between some Palaeozoic chondrichthyans and osteichthyans. Phylogenetic analysis resolves Ptomacanthus as either the most basal chondrichthyan or as the sister group of all living gnathostomes. These new data alter earlier conceptions of basal gnathostome phylogeny and thus help to provide a more detailed picture of the acquisition of early gnathostome characters