On the origin of the order Artiodactyla.

The first known members of the order Artiodactyla appeared suddenly throughout the Holarctic region at the beginning of the Eocene. They are characterized by distinctive cursorial skeletal specializations. Owing to their abrupt appearance and the lack of transitional forms, the origin of the order is problematic. Descent from a "condylarth," specifically the arctocyonid Chriacus, has been suggested based on dental resemblances, but until now postcranial anatomy seemed to preclude close relationship between Arctocyonidae and Artiodactyla. A middle Paleocene specimen of a small arctocyonid (?Chriacus) reported here is much more similar to the oldest artiodactyl, Diacodexis, in the derived condition of the hindlimb, reviving the possibility that Artiodactyla evolved from an arctocyonid.

Antimycobacterial activities of antisense oligodeoxynucleotide phosphorothioates in drug-resistant strains.

Strains of Mycobacterium smegmatis, a mycobacterium which shares genetic sequences, grows more rapidly, and is nonpathogenic in man as compared with Mycobacterium tuberculosis, were utilized for the initial development of new antimycobacterial therapy. Drug-resistant strains of M. smegmatis which are known to arise in a manner identical to the emergence of drug-resistant strains of M. tuberculosis were isolated and utilized as models for the antimycobacterial activities of modified and unmodified oligodeoxynucleotide phosphorothioates in broth cultures. Under normal conditions, oligodeoxynucleotide phosphorothioates do not enter mycobacteria, and several strategies were successfully utilized to afford entry of oligonucleotides into the mycobacterial cells. One involved the presence of very low levels of ethambutol, which enables the entry of oligonucleotides into mycobacteria because of its induced alterations in the cell wall, and another involved the utilization of oligonucleotides covalently attached to a D-cycloserine molecule, whereby entry into the mycobacterial cell is achieved by a receptor-mediated process. Another low molecular weight, covalently attached ligand that enabled the entry and subsequent antimycobacterial activities of oligodeoxynucleotide phosphorothioates in the absence of a cell wall modifying reagent was biotin. Significant sequence-specific growth inhibition of wild-type, as well as of drug-resistant, M. smegmatis was obtained by modified oligonucleotides complementary in sequence to a specific region of the mycobacterium aspartokinase (ask) gene when utilized in combinations with ethambutol (as compared to ethambutol alone) or as D-cycloserine or biotin covalent adducts without the presence of any other cytotoxic or cytostatic agent.

Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors.

Stimulation of muscarinic m1 or m3 receptors can, by generating diacylglycerol and activating protein kinase C, accelerate the breakdown of the amyloid precursor protein (APP) to form soluble, nonamyloidogenic derivatives (APPs), as previously shown. This relationship has been demonstrated in human glioma and neuroblastoma cells, as well as in transfected human embryonic kidney 293 cells and PC-12 cells. We now provide evidence that stimulation of metabotropic glutamate receptors (mGluRs), which also are coupled to phosphatidylinositol 4,5-bisphosphate hydrolysis, similarly accelerates processing of APP into nonamyloidogenic APPs. This process is demonstrated both in hippocampal neurons derived from fetal rats and in human embryonic kidney 293 cells transfected with cDNA expression constructs encoding the mGluR 1 alpha subtype. In hippocampal neurons, both an mGluR antagonist, L-(+)-2-amino-3-phosphonopropionic acid, and an inhibitor of protein kinase C, GF 109203X, blocked the APPs release evoked by glutamate receptor stimulation. Ionotropic glutamate agonists, N-methyl-D-aspartate or S(-)-5-fluorowillardiine, failed to affect APPs release. These data show that selective mGluR agonists that initiate signal-transduction events can regulate APP processing in bona fide primary neurons and transfected cells. As glutamatergic neurons in the cortex and hippocampus are damaged in Alzheimer disease, amyloid production in these regions may be enhanced by deficits in glutamatergic neurotransmission.

Oligonucleotide N3'-->P5' phosphoramidates.

Synthetic oligonucleotides and their analogs have attracted considerable interest recently. These compounds may lead to highly specific therapeutic agents, as well as to powerful diagnostic tools. Here, we present the synthesis of uniformly modified oligodeoxyribonucleotide N3'-->P5' phosphoramidates containing 3'-NHP(O)(O-)O-5' internucleoside linkages and the study of their hybridization properties. Thermal dissociation experiments show that these compounds form very stable duplexes with single-stranded DNA, RNA, and with themselves following Watson-Crick base pairing. The duplex thermal stability was enhanced by 2.2-2.6 degrees C per modified linkage compared with phosphodiesters. The structure of complexes formed by phosphoramidates closely resembles that of RNA oligomers and corresponds to an A form, as judged by CD spectroscopy. N3'-->P5' phosphoramidates also form stable triplexes with double-stranded DNA under near-physiological conditions when natural phosphodiesters fail to do so. Physicochemical characteristics of the amidates are similar to those of RNA oligomers, even though they are composed of 2'-deoxyfuranose-based nucleosides.

A role for ciliary neurotrophic factor as an inducer of reactive gliosis, the glial response to central nervous system injury.

Within the central nervous system (CNS) ciliary neurotrophic factor (CNTF) is expressed by astrocytes where it remains stored as an intracellular protein; its release and function as an extracellular ligand are thought to occur in the event of cellular injury. We find that overexpression of CNTF in transgenic mice recapitulates the glial response to CNS lesion, as does its injection into the uninjured brain. These results demonstrate that CNTF functions as an inducer of reactive gliosis, a condition associated with a number of neurological diseases of the CNS.

Stimulation of human monocytes with macrophage colony-stimulating factor induces a Grb2-mediated association of the focal adhesion kinase pp125FAK and dynamin.

Macrophage colony-stimulating factor (M-CSF) is required for the growth and differentiation of mononuclear phagocytes. In the present studies using human monocytes, we show that M-CSF induces interaction of the Grb2 adaptor protein with the focal adhesion kinase pp125FAK. The results demonstrate that tyrosine-phosphorylated pp125FAK directly interacts with the SH2 domain of Grb2. The findings indicate that a pYENV site at Tyr-925 in pp125FAK is responsible for this interaction. We also demonstrate that the Grb2-FAK complex associates with the GTPase dynamin. Dynamin interacts with the SH3 domains of Grb2 and exhibits M-CSF-dependent tyrosine phosphorylation in association with pp125FAK. These findings suggest that M-CSF-induced signaling involves independent Grb2-mediated pathways, one leading to Ras activation and another involving pp125FAK and a GTPase implicated in receptor internalization.

Eficacia de un programa de tratamiento cognitivo-conductal para trastornos por estrés traumático, depresivos y de ansiedad a largo plazo en víctimas de atentados terroristas

OBJETIVO Se analiza la eficacia de la terapia cognitivo-conductual centrada en el trauma en víctimas de atentados terroristas con trastorno por estrés postraumático (TEPT) o trastornos de ansiedad o depresivos a muy largo plazo (> 5 años después del atentado). Se pretende, así, engrosar el limitado conocimiento científico sobre la eficacia de los tratamientos en esta población concreta. MÉTODO Un grupo de 120 víctimas directas e indirectas de atentados terroristas cometidos en España una media de 18,43 años atrás, que presentaban aislada o concurrentemente trastorno por estrés postraumático (TEPT; 49,2%), trastorno depresivo mayor (TDM; 40,8%) y otros trastornos de ansiedad (75,8%), fueron aleatorizados en 16 sesiones de Terapia Cognitivo-Conductual (TCC) centrada en el trauma (grupo experimental) o 16 semanas de espera (grupo control). La TCC centrada en el trauma estaba basada en el protocolo de exposición prolongada de Foa y Rothbaum (1998) pero se le añadieron técnicas específicas para el manejo de los trastornos del estado de ánimo y trastornos de ansiedad, se hizo un mayor énfasis en la psicoeducación sobre las reacciones post traumáticas y en la reestructuración cognitiva y se añadieron estrategias de motivación, regulación emocional y terapia narrativa. De las 60 personas que fueron asignadas al grupo experimental, 25 (41,6%) rechazaron la terapia y 10 (28,6%) la abandonaron una vez iniciada. RESULTADOS Las personas del grupo experimental que completaron el tratamiento (n = 25) tenían puntuaciones medias en sintomatología postraumática (PCL), depresiva (BDIL-II) y de ansiedad (BAI) significativamente inferiores a las obtenidas en el pretratamiento. Ninguna de ellas presentó en el postratamiento TEPT ni TDM y se redujo significativamente el porcentaje de otros trastornos de ansiedad. Estos resultados fueron significativamente mejores que los del grupo de control. Se obtuvieron tamaños del efecto pre/post grandes (d PCL = 1,39; d BDI-II = 1,19; d BAI = 1,20) y grandes y medios entre grupos (d PCL = 0,84; d BDI-II = 0,69; d BAI = 0,88). Un 78,3%, 91,7% y 91,7% obtuvieron una puntuación media inferior a la puntuación C para la PCL, el BDI-II y el BAI, y un 56,5%, 45,8% y 54,2% mejoraron según el índice de cambio fiable. Los beneficios se mantuvieron a los 6 meses de seguimiento y el análisis de intención de tratar (n = 35) y el análisis de todas las personas que habían completado el tratamiento (incluyendo al grupo control; n = 40) confirmaron la significación de los datos. La terapia tenía efectos mejores sobre la comorbilidad triple (TEPT, trastornos depresivos y ansiosos), pero no se encontró un efecto positivo de la adición de psicofármacos, en todo caso, peores resultados (por ejemplo, en la puntuación del BAI y la muestra de intención de tratar). CONCLUSIONES Los resultados de este estudio, comparables a los de otros estudios específicos previos, sugieren que la TCC centrada en el trauma y adaptada a víctimas del terrorismo que sufren TEPT o trastornos de ansiedad o depresivos muchos años después de los atentados terroristas, es eficaz. Aunque se recomienda mejorar las técnicas de motivación, hacer nuevos estudios con tamaños muestrales más amplios, donde se realicen análisis de componentes, análisis de la fiabilidad y adherencia al protocolo y atendiendo a diferentes grupos de víctimas y factores de riesgo, los resultados de esta tesis doctoral sustentan firmemente la idea de que la terapia cognitivo-conductual centrada en el trauma debe ser el tratamiento de elección para víctimas del terrorismo con TEPT, TDM u otros trastornos de ansiedad, incluso cuando éstos se presentan de manera comórbida y crónica.

Hādhā Sharḥ al-Faqīh al-ʻallāmah ... al-fahhāmah Sayyid Muḥammad ibn al-Ḥasan Aqṣabī ʻalá Manẓūmat al-Shaykh al-Imām khātimat jahābidhat al-muḥaqqiqīn al-aʻlām Sayyid al-Ṭayyib Ibn Kīrān wa-bi-hāmishihi Sharḥ al-Shaykh al-ʻālim al-bāriʻ ... Sayyid al-Tihāmī al-Būrī ʻalá al-Manẓūmah al-madhkūrah ayḍan

Āqaṣbī's commentary of the Manẓūmah of Ibn Kīrān, with al-Tihāmī's commentary of the same Manẓūmah in the margin.

Sharḥ Qānūn Āmulī : manuscript, undated

Paper.

Fatḥ al-ʻazīz li-ahl al-tamyīz : manuscript, [ca. 1686]

Written in one column, 17 lines per page, in black rubricated in red, framed within triple red, golden and black lines.

Ḥāshiyat Qarah Kamāl ʻalá Ṣadr al-Sharīʻah : manuscript, undated

Written in one column, from 17 to 23 lines per page, in black rubricated in red.

al- Ḥāshiyah al-jad��dah ʻalá Fatḥ al-ʻazīz li-ahl al-tamyīz : manuscript, 1686

Copy completed in the hand of Jaʻfar Bīk ibn Farrukh Bīk on 18 Dhū al-Qaʻdah 1097 [October 6, 1686] in Akbarabad.

[ Risālah fī masḥ al-aqd��m fī al-wuḍūʼ] : manuscript, [ca. 1686]

A treatise on washing and wiping feet in ritual ablution.

Brief narrative of events touching various reforms /

Last page blank.

Chronicon Angliae Petriburgense /

Ascribed in MS. Cotton Claud. A. v. to a certain Johannes, Abbot of Peterborough, whom some have attempted to identify as Johannes de Caleto or John Deeping. The last part of the Chronicle is sometimes attributed to Robert of Boston.