A disinhibitory microcircuit for associative fear learning in the auditory cortex

Learning causes a change in how information is processed by neuronal circuits. Whereas synaptic plasticity, an important cellular mechanism, has been studied in great detail, we know much less about how learning is implemented at the level of neuronal circuits and, in particular, how interactions between distinct types of neurons within local networks contribute to the process of learning. Here we show that acquisition of associative fear memories depends on the recruitment of a disinhibitory microcircuit in the mouse auditory cortex. Fear-conditioning-associated disinhibition in auditory cortex is driven by foot-shock-mediated cholinergic activation of layer 1 interneurons, in turn generating inhibition of layer 2/3 parvalbumin-positive interneurons. Importantly, pharmacological or optogenetic block of pyramidal neuron disinhibition abolishes fear learning. Together, these data demonstrate that stimulus convergence in the auditory cortex is necessary for associative fear learning to complex tones, define the circuit elements mediating this convergence and suggest that layer-1-mediated disinhibition is an important mechanism underlying learning and information processing in neocortical circuits.     

The origin of spontaneous activity in the developing auditory system

Spontaneous activity in the developing auditory system is required for neuronal survival as well as the refinement and maintenance of tonotopic maps in the brain. However, the mechanisms responsible for initiating auditory nerve firing in the absence of sound have not been determined. Here we show that supporting cells in the developing rat cochlea spontaneously release ATP, which causes nearby inner hair cells to depolarize and release glutamate, triggering discrete bursts of action potentials in primary auditory neurons. This endogenous, ATP-mediated signalling synchronizes the output of neighbouring inner hair cells, which may help refine tonotopic maps in the brain. Spontaneous ATP-dependent signalling rapidly subsides after the onset of hearing, thereby preventing this experience-independent activity from interfering with accurate encoding of sound. These data indicate that supporting cells in the organ of Corti initiate electrical activity in auditory nerves before hearing, pointing to an essential role for peripheral, non-sensory cells in the development of central auditory pathways.     

Über die Zytologie der Parthenogenese und der Geschlechtsbestimmung bei der GallmückeOligarces paradoxus Mein

Summary InOligarces paradoxus, the chromosomal behaviour was compared during pedogenetic development of and . The -egg undergoes a single non-reductional maturation division, the -egg shows two divisions which result in reduced nuclei. After maturation in the -egg, the number of chromosomes is restored by endomitosis. The nuclei of germ-line cells contain a high number of chromosomes (: 74\2-82; : at least 58) in both sexes. In somatic nuclei, the number is diminished by elimination to 10 in , to 5 in .     

Synchrone Replikation aller Chromosomen beiXenopus laevis

Summary Autoradiographics showed synchronous replication of all chromosomes inXenopus laevis.     

The effect of anoxia and of muscle activity on the lymphatic and venous transport of lactate dehydrogenase

Zusammenfassung Nach 3 1/2 stündiger Muskelischämie wurde bei Hunden mit Ductus thoracicus-Fistel eine signifikante Zunahme der Milchsäuredehydrogenase-Aktivität im Blutserum und in der Lymphe der anoxischen Extremität bei gleichzeitiger signifikanter arterovenöser Aktivitätsdifferenz beobachtet. Auch Muskelarbeit verursachte eine Erhöhung der Enzymaktivität im Serum und in der Lymphe. Durch Unterbrechen der Verbindung zwischen Venen und Lymphsystem konnte das direkte Eindringen des Enzymproteins in die Blutkapillaren bewiesen werden.     

Suppression of immunization to tuberculosis and diphtheria by an extract of lymphoid tissue

Zusammenfassung Dank einer neuen Anwendung von Lymphknotenextrakten (statt Röntgenextrakten, Corticosteroiden, Antilymphozytenserum usw.) wird eine erhebliche Reduktion der immunologischen Reaktion erzielt, wenn die Tiere mit diesen Extrakten vorbehandelt und gleichzeitig mit Antigenen behandelt werden.

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This investigation was supported in part by U.S.P.H.S. Research Grant No. CA-02624 from National Cancer Institute; and in part by an institutional grant to Detroit Institute of Cancer Research from United Foundation of greater Detroit allocated through Michigan Cancer Foundation and the Detroit General Hospital Research Corporation, and Newaygo County Cancer Society.     

A histochemical study of immune destruction of the lymphopoietic system

Zusammenfassung Eine auffallende Zunahme von -Galactosidase kommt im lymphoetischen Säuger-Gewebe im Zusammenhang mit der immunologischen Auflösung dieses Systems vor. Die hernach auftretende Proliferation retikulärer Zellen steht im Zusammenhang mit der Regeneration dieses Organs. Diese Zellen enthalten eine reichliche Anzahl lysosomatischer Enzyme (z.B. -Galactosidase).

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This investigation was supported in part by Public Health Service Research Grants Nos. Ca 02624 and CA 02903 from the National Cancer Institute and in part by an institutional grant to the Detroit Institute of Cancer Research Division of the Michigan Cancer Foundation from the United Foundation of Greater Detroit, and Detroit General Hospital Research Corporation. Newaygo County Cancer Association. We wish to express our gratitude for stenographic assistance to Mrs.Connie Malucusky and MissPatricia Warzocha.     

Yersinia pestis genome sequencing identifies patterns of global phylogenetic diversity

Plague is a pandemic human invasive disease caused by the bacterial agent Yersinia pestis. We here report a comparison of 17 whole genomes of Y. pestis isolates from global sources. We also screened a global collection of 286 Y. pestis isolates for 933 SNPs using Sequenom MassArray SNP typing. We conducted phylogenetic analyses on this sequence variation dataset, assigned isolates to populations based on maximum parsimony and, from these results, made inferences regarding historical transmission routes. Our phylogenetic analysis suggests that Y. pestis evolved in or near China and spread through multiple radiations to Europe, South America, Africa and Southeast Asia, leading to country-specific lineages that can be traced by lineage-specific SNPs. All 626 current isolates from the United States reflect one radiation, and 82 isolates from Madagascar represent a second radiation. Subsequent local microevolution of Y. pestis is marked by sequential, geographically specific SNPs.     

Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia

The Abl kinase inhibitor imatinib mesylate is the preferred treatment for Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but is much less effective in CML blast crisis or Ph(+) B-cell acute lymphoblastic leukemia (B-ALL). Here, we show that Bcr-Abl activated the Src kinases Lyn, Hck and Fgr in B-lymphoid cells. BCR-ABL1 retrovirus-transduced marrow from mice lacking all three Src kinases efficiently induced CML but not B-ALL in recipients. The kinase inhibitor CGP76030 impaired the proliferation of B-lymphoid cells expressing Bcr-Abl in vitro and prolonged survival of mice with B-ALL but not CML. The combination of CGP76030 and imatinib was superior to imatinib alone in this regard. The biochemical target of CGP76030 in leukemia cells was Src kinases, not Bcr-Abl. These results implicate Src family kinases as therapeutic targets in Ph(+) B-ALL and suggest that simultaneous inhibition of Src and Bcr-Abl kinases may benefit individuals with Ph(+) acute leukemia.     

Direct evidence that the N-terminal extensions of the TAP complex act as autonomous interaction scaffolds for the assembly of the MHC I peptide-loading complex

The loading of antigenic peptides onto major histocompatibility complex class I (MHC I) molecules is an essential step in the adaptive immune response against virally or malignantly transformed cells. The ER-resident peptide-loading complex (PLC) consists of the transporter associated with antigen processing (TAP1 and TAP2), assembled with the auxiliary factors tapasin and MHC I. Here, we demonstrated that the N-terminal extension of each TAP subunit represents an autonomous domain, named TMD(0), which is correctly targeted to and inserted into the ER membrane. In the absence of coreTAP, each TMD(0) recruits tapasin in a 1:1 stoichiometry. Although the TMD(0)s lack known ER retention/retrieval signals, they are localized to the ER membrane even in tapasin-deficient cells. We conclude that the TMD(0)s of TAP form autonomous interaction hubs linking antigen translocation into the ER with peptide loading onto MHC I, hence ensuring a major function in the integrity of the antigen-processing machinery.