419 research outputs found
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 hypothalamus7 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 (g-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 hypothalamu
Molecular Characterization, Tissue Distribution, Subcellular Localization and Actin-Sequestering Function of a Thymosin Protein from Silkworm
We identified a novel gene encoding a Bombyx mori thymosin (BmTHY) protein from a cDNA library of silkworm pupae, which has an open reading frame (ORF) of 399 bp encoding 132 amino acids. It was found by bioinformatics that BmTHY gene consisted of three exons and two introns and BmTHY was highly homologous to thymosin betas (Tβ). BmTHY has a conserved motif LKHTET with only one amino acid difference from LKKTET, which is involved in Tβ binding to actin. A His-tagged BmTHY fusion protein (rBmTHY) with a molecular weight of approximately 18.4 kDa was expressed and purified to homogeneity. The purified fusion protein was used to produce anti-rBmTHY polyclonal antibodies in a New Zealand rabbit. Subcellular localization revealed that BmTHY can be found in both Bm5 cell (a silkworm ovary cell line) nucleus and cytoplasm but is primarily located in the nucleus. Western blotting and real-time RT-PCR showed that during silkworm developmental stages, BmTHY expression levels are highest in moth, followed by instar larvae, and are lowest in pupa and egg. BmTHY mRNA was universally distributed in most of fifth-instar larvae tissues (except testis). However, BmTHY was expressed in the head, ovary and epidermis during the larvae stage. BmTHY formed complexes with actin monomer, inhibited actin polymerization and cross-linked to actin. All the results indicated BmTHY might be an actin-sequestering protein and participate in silkworm development
Comments on Holographic Entanglement Entropy and RG Flows
Using holographic entanglement entropy for strip geometry, we construct a
candidate for a c-function in arbitrary dimensions. For holographic theories
dual to Einstein gravity, this c-function is shown to decrease monotonically
along RG flows. A sufficient condition required for this monotonic flow is that
the stress tensor of the matter fields driving the holographic RG flow must
satisfy the null energy condition over the holographic surface used to
calculate the entanglement entropy. In the case where the bulk theory is
described by Gauss-Bonnet gravity, the latter condition alone is not sufficient
to establish the monotonic flow of the c-function. We also observe that for
certain holographic RG flows, the entanglement entropy undergoes a 'phase
transition' as the size of the system grows and as a result, evolution of the
c-function may exhibit a discontinuous drop.Comment: References adde
Present status and upcoming prospects of hedgehog pathway inhibitors in small cell lung cancer therapy
Testing the role of predicted gene knockouts in human anthropometric trait variation
National Heart, Lung, and Blood Institute (NHLBI)
S.L. is funded by a Canadian Institutes of Health Research
Banting doctoral scholarship. G.L. is funded by Genome Canada
and Génome Québec; the Canada Research Chairs program; and
the Montreal Heart Institute Foundation. C.M.L. is supported by
Wellcome Trust (grant numbers 086596/Z/08/Z, 086596/Z/08/A);
and the Li Ka Shing Foundation. N.S. is funded by National Institutes
of Health (grant numbers HL088456, HL111089, HL116747).
The Mount Sinai BioMe Biobank Program is supported by the Andrea
and Charles Bronfman Philanthropies. GO ESP is supported
by NHLBI (RC2 HL-103010 to HeartGO, RC2 HL-102923 to LungGO,
RC2 HL-102924 to WHISP). The ESP exome sequencing was
performed through NHLBI (RC2 HL-102925 to BroadGO, RC2 HL-
102926 to SeattleGO). EGCUT work was supported through the
Estonian Genome Center of University of Tartu by the Targeted
Financing from the Estonian Ministry of Science and Education
(grant number SF0180142s08); the Development Fund of the University
of Tartu (grant number SP1GVARENG); the European Regional
Development Fund to the Centre of Excellence in
Genomics (EXCEGEN) [grant number 3.2.0304.11-0312]; and
through FP7 (grant number 313010). EGCUT were further supported
by the US National Institute of Health (grant number
R01DK075787). A.K.M. was supported by an American Diabetes
Association Mentor-Based Postdoctoral Fellowship (#7-12-MN-
02). The BioVU dataset used in the analyses described were obtained
from Vanderbilt University Medical Centers BioVU which
is supported by institutional funding and by the Vanderbilt CTSA
grant ULTR000445 from NCATS/NIH. Genome-wide genotyping
was funded by NIH grants RC2GM092618 from NIGMS/OD and
U01HG004603 from NHGRI/NIGMS. Funding to pay the Open Access
publication charges for this article was provided by a block
grant from Research Councils UK to the University of Cambridge
Testing the role of predicted gene knockouts in human anthropometric trait variation
National Heart, Lung, and Blood Institute (NHLBI)
S.L. is funded by a Canadian Institutes of Health Research
Banting doctoral scholarship. G.L. is funded by Genome Canada
and Génome Québec; the Canada Research Chairs program; and
the Montreal Heart Institute Foundation. C.M.L. is supported by
Wellcome Trust (grant numbers 086596/Z/08/Z, 086596/Z/08/A);
and the Li Ka Shing Foundation. N.S. is funded by National Institutes
of Health (grant numbers HL088456, HL111089, HL116747).
The Mount Sinai BioMe Biobank Program is supported by the Andrea
and Charles Bronfman Philanthropies. GO ESP is supported
by NHLBI (RC2 HL-103010 to HeartGO, RC2 HL-102923 to LungGO,
RC2 HL-102924 to WHISP). The ESP exome sequencing was
performed through NHLBI (RC2 HL-102925 to BroadGO, RC2 HL-
102926 to SeattleGO). EGCUT work was supported through the
Estonian Genome Center of University of Tartu by the Targeted
Financing from the Estonian Ministry of Science and Education
(grant number SF0180142s08); the Development Fund of the University
of Tartu (grant number SP1GVARENG); the European Regional
Development Fund to the Centre of Excellence in
Genomics (EXCEGEN) [grant number 3.2.0304.11-0312]; and
through FP7 (grant number 313010). EGCUT were further supported
by the US National Institute of Health (grant number
R01DK075787). A.K.M. was supported by an American Diabetes
Association Mentor-Based Postdoctoral Fellowship (#7-12-MN-
02). The BioVU dataset used in the analyses described were obtained
from Vanderbilt University Medical Centers BioVU which
is supported by institutional funding and by the Vanderbilt CTSA
grant ULTR000445 from NCATS/NIH. Genome-wide genotyping
was funded by NIH grants RC2GM092618 from NIGMS/OD and
U01HG004603 from NHGRI/NIGMS. Funding to pay the Open Access
publication charges for this article was provided by a block
grant from Research Councils UK to the University of Cambridge
Comparative Genomics of the Anopheline Glutathione S-Transferase Epsilon Cluster
Enzymes of the glutathione S-transferase (GST) family play critical roles in detoxification of xenobiotics across many taxa. While GSTs are ubiquitous both in animals and plants, the GST epsilon class (GSTE) is insect-specific and has been associated with resistance to chemical insecticides. While both Aedes aegypti and Anopheles gambiae GSTE clusters consist of eight members, only four putative orthologs are identifiable between the species, suggesting independent expansions of the class in each lineage. We used a primer walking approach, sequencing almost the entire cluster from three Anopheles species (An. stephensi, An. funestus (both Cellia subgenus) and An. plumbeus (Anopheles subgenus)) and compared the sequences to putative orthologs in An. gambiae (Cellia) in an attempt to trace the evolution of the cluster within the subfamily Anophelinae. Furthermore, we measured transcript levels from the identified GSTE loci by real time reverse transcription PCR to determine if all genes were similarly transcribed at different life stages. Among the species investigated, gene order and orientation were similar with three exceptions: (i) GSTE1 was absent in An. plumbeus; (ii) GSTE2 is duplicated in An. plumbeus and (iii) an additional transcriptionally active pseudogene (ψAsGSTE2) was found in An. stephensi. Further statistical analysis and protein modelling gave evidence for positive selection on codons of the catalytic site in GSTE5 albeit its origin seems to predate the introduction of chemical insecticides. Gene expression profiles revealed differences in expression pattern among genes at different life stages. With the exception of GSTE1, ψAsGSTE2 and GSTE2b, all Anopheles species studied share orthologs and hence we assume that GSTE expansion generally predates radiation into subgenera, though the presence of GSTE1 may also suggest a recent duplication event in the Old World Cellia subgenus, instead of a secondary loss. The modifications of the catalytic site within GSTE5 may represent adaptations to new habitats
Testing the role of predicted gene knockouts in human anthropometric trait variation
National Heart, Lung, and Blood Institute (NHLBI)
S.L. is funded by a Canadian Institutes of Health Research
Banting doctoral scholarship. G.L. is funded by Genome Canada
and Génome Québec; the Canada Research Chairs program; and
the Montreal Heart Institute Foundation. C.M.L. is supported by
Wellcome Trust (grant numbers 086596/Z/08/Z, 086596/Z/08/A);
and the Li Ka Shing Foundation. N.S. is funded by National Institutes
of Health (grant numbers HL088456, HL111089, HL116747).
The Mount Sinai BioMe Biobank Program is supported by the Andrea
and Charles Bronfman Philanthropies. GO ESP is supported
by NHLBI (RC2 HL-103010 to HeartGO, RC2 HL-102923 to LungGO,
RC2 HL-102924 to WHISP). The ESP exome sequencing was
performed through NHLBI (RC2 HL-102925 to BroadGO, RC2 HL-
102926 to SeattleGO). EGCUT work was supported through the
Estonian Genome Center of University of Tartu by the Targeted
Financing from the Estonian Ministry of Science and Education
(grant number SF0180142s08); the Development Fund of the University
of Tartu (grant number SP1GVARENG); the European Regional
Development Fund to the Centre of Excellence in
Genomics (EXCEGEN) [grant number 3.2.0304.11-0312]; and
through FP7 (grant number 313010). EGCUT were further supported
by the US National Institute of Health (grant number
R01DK075787). A.K.M. was supported by an American Diabetes
Association Mentor-Based Postdoctoral Fellowship (#7-12-MN-
02). The BioVU dataset used in the analyses described were obtained
from Vanderbilt University Medical Centers BioVU which
is supported by institutional funding and by the Vanderbilt CTSA
grant ULTR000445 from NCATS/NIH. Genome-wide genotyping
was funded by NIH grants RC2GM092618 from NIGMS/OD and
U01HG004603 from NHGRI/NIGMS. Funding to pay the Open Access
publication charges for this article was provided by a block
grant from Research Councils UK to the University of Cambridge
A Surprising Prevention Success: Why Did the HIV Epidemic Decline in Zimbabwe?
Daniel Halperin and colleagues examine reasons for the remarkable decline in HIV in Zimbabwe, in the context of severe social, political, and economic disruption
- …