Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus

The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.     

The Collaborative Cross, a community resource for the genetic analysis of complex traits

The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.     

Detachment fronts and the onset of dynamic friction

The dynamics of friction have been studied for hundreds of years, yet many aspects of these everyday processes are not understood. One such aspect is the onset of frictional motion (slip). First described more than 200 years ago as the transition from static to dynamic friction, the onset of slip is central to fields as diverse as physics, tribology, mechanics of earthquakes and fracture. Here we show that the onset of frictional slip is governed by three different types of coherent crack-like fronts: these are observed by real-time visualization of the net contact area that forms the interface separating two blocks of like material. Two of these fronts, which propagate at subsonic and intersonic velocities, have been the subject of intensive recent interest. We show that a third type of front, which propagates an order of magnitude more slowly, is the dominant mechanism for the rupture of the interface. No overall motion (sliding) of the blocks occurs until either of the slower two fronts traverses the entire interface.     

Hypotensive and Ganglion blocking action of methyl substituted 3-amino-norcamphanes

Zusammenfassung 5 Methyl-substituierte 3-Amino-norcamphane wurden im Vergleich zu 3-Methylamino-isocamphan in bezug auf Blockierung der Synapsen der autonomen Nervensysteme und blutdrucksenkenden Wirkung im narkotisierten Tier untersucht.Die Ergebnisse deuten auf eine ganz spezifische Konstitutions-und Konfigurationsabhängigkeit der Wirkung sowie auf einen komplexen pharmakodynamischen Mechanismus, in dem die zentrale Blutdrucksenkung eine nicht unwesentliche Rolle spielt.Erfahrungen aus kurzzeitigen klinischen Versuchen werden mitgeteilt.     

Cerebrovascular reactivity to CO2: modulation by arterial pressure

Cerebrovascular reactivity to CO2 (CO2R), measured in halothane-anesthetized rabbits, decreased as arterial pressure was increased either pharmacologically or mechanically. On the other hand, hypotension, induced by bleeding, led to an increase in CO2R. These responses were unaffected by denervation of baroreceptors.     

Aggregation of equivalence relations

Each ofn attributes partitions a set of items into equivalence classes. Aconsistent aggregator of then partitions is defined as an aggregate partition that satisfies an independence condition and a unanimity condition. It is shown that the class of consistent aggregators is precisely the class ofconjunctive aggregators. That is, for each consistent aggregator there is a nonempty subsetN of the attributes such that two items are equivalent in the aggregate partition if and only if they are equivalent with respect to each attribute inN.     

Identification of loci associated with schizophrenia by genome-wide association and follow-up

We carried out a genome-wide association study of schizophrenia (479 cases, 2,937 controls) and tested loci with P < 10(-5) in up to 16,726 additional subjects. Of 12 loci followed up, 3 had strong independent support (P < 5 x 10(-4)), and the overall pattern of replication was unlikely to occur by chance (P = 9 x 10(-8)). Meta-analysis provided strongest evidence for association around ZNF804A (P = 1.61 x 10(-7)) and this strengthened when the affected phenotype included bipolar disorder (P = 9.96 x 10(-9)).     

Subnanometre-resolution structure of the intact Thermus thermophilus H+-driven ATP synthase

Ion-translocating rotary ATPases serve either as ATP synthases, using energy from a transmembrane ion motive force to create the cell's supply of ATP, or as transmembrane ion pumps that are powered by ATP hydrolysis. The members of this family of enzymes each contain two rotary motors: one that couples ion translocation to rotation and one that couples rotation to ATP synthesis or hydrolysis. During ATP synthesis, ion translocation through the membrane-bound region of the complex causes rotation of a central rotor that drives conformational changes and ATP synthesis in the catalytic region of the complex. There are no structural models available for the intact membrane region of any ion-translocating rotary ATPase. Here we present a 9.7?? resolution map of the H(+)-driven ATP synthase from Thermus thermophilus obtained by electron cryomicroscopy of single particles in ice. The 600-kilodalton complex has an overall subunit composition of A(3)B(3)CDE(2)FG(2)IL(12). The membrane-bound motor consists of a ring of L subunits and the carboxy-terminal region of subunit I, which are equivalent to the c and a subunits of most other rotary ATPases, respectively. The map shows that the ring contains 12 L subunits and that the I subunit has eight transmembrane helices. The L(12) ring and I subunit have a surprisingly small contact area in the middle of the membrane, with helices from the I subunit making contacts with two different L subunits. The transmembrane helices of subunit I form bundles that could serve as half-channels across the membrane, with the first half-channel conducting protons from the periplasm to the L(12) ring and the second half-channel conducting protons from the L(12) ring to the cytoplasm. This structure therefore suggests the mechanism by which a transmembrane proton motive force is converted to rotation in rotary ATPases.     

Ultra-violet laser probe measurement of ^40Ar／^39Ar age profile in phlogopite

Ultra-Violet Laser Ablation Microprobe (UVLAMP) extraction technique enables the direct investigation of Ar-Ar age prorde in crystals, and yields more information on rates and durations of geological process than conventional single time snapshots. Phlogopite flakes from lamprophyre at Pishan dyke in western Kunlun were dated by using an UV laser (λ= 213 nm) microprobe with spot analyses. The results show good agreement with those from the conventional ^40Ar/^39Ar step heating experiments. This indicates that the Ar isotopes are distributed homogenously in the phlogopite and the UVLAMP can be a powerful tool in the study of thermal history.