bluuebunny/crossref_metadata_2025 huggingface dataset:
A Death Due to Perirenal Hematoma Complicating Extracorporeal Shockwave Lithotripsy
Authors: Uemura Koichi , Takahashi Sayuri , Shintani‐Ishida Kaori , Nakajima Makoto , Saka Kanju , Yoshida Ken‐ichi
Published: March 2008

Abstract:  Perirenal hematoma is an occasional complication of extracorporeal shockwave lithotripsy (ESWL) which does not usually require treatment. A 79‐year‐old woman died 23 h after ESWL. Forensic autopsy was performed to determine whether medical treatment contributed to her death. The cause of death was hemorrhagic shock due to massive hematoma from a ruptured small vein in the perirenal adipose capsule. No injury to other organs was found and the patient had neither coagulation abnormality nor venous disease. Perirenal hematoma can easily be diagnosed with abdominal sonography, if pain or symptoms of anemia develop. Doctors must be aware of the possibilities of severe renal hematomas after ESWL.
The Impact of Māori Cultural Values on Forensic Science Practice in New Zealand
Authors: Hudson Maui L. , Allan Christine A. , Bedford Keith R. , Buckleton John S. , Stuart Keriata
Published: March 2008

Abstract:  Forensic science aims to serve society by advancing justice. It is accepted that some actions taken by the state in the interests of advancing justice, such as postmortem examinations, may impinge on values held by members of groups within society. Such actions have the potential to cause cultural offense. It is important that forensic scientists are aware of these issues and that as a profession we should take actions, where possible, to reduce any potential offense and consequently reduce unnecessary distress. This paper examines the impact of these issues on forensic practice in New Zealand, and, in particular, in relation to the cultural values of Māori, the indigenous people of New Zealand. Interviews and workshops were used to identify forensic practices involving a risk of cultural offense. Particular issues were identified in regard to crime scene attendance and examination, postmortem attendance and sample storage, disposal, and return. This paper describes the response developed by the Institute of Environmental Science and Research Limited (ESR) to address these issues, including a cultural awareness training package and reference brochure.
Sarcoidosis and Mechanisms of Unexpected Death
Authors: Byard Roger W. , Manton Nicholas , Tsokos Michael
Published: March 2008

Abstract:  Sarcoidosis is a multisystem disease of uncertain etiology characterized by multifocal areas of discrete and confluent granulomatous inflammation that may rarely be responsible for sudden and unexpected death. Two cases are reported to demonstrate disparate pathological features in fatal cases, one involving cardiac sarcoidosis, and the other neurosarcoidosis with hypothalamic infiltration. Sarcoidosis in individuals dying suddenly may be completely unrelated to the death, contributory or causal. Cardiovascular causes of sudden death in sarcoidosis include arrhythmias associated with cardiomyopathy and ischemia, ventricular rupture, and cor pulmonale due to pulmonary hypertension; respiratory causes include hemorrhage and upper airway obstruction; central nervous system causes include arrhythmias from infiltration of autonomic centers, epilepsy, and obstructive hydrocephalus from brainstem involvement; and gastrointestinal deaths may be due to hemorrhage from esophageal varices associated with portal hypertension. The diagnosis relies on the demonstration of typical noncaseating granulomas and the exclusion of other infective and environmental diseases with similar histopathological findings.
Cerebral Traumatism With a Playground Rocking Toy Mimicking Shaken Baby Syndrome
Authors: Sauvageau Anny , Bourgault André , Racette Stéphanie
Published: March 2008

Abstract:  Shaken baby syndrome (SBS), one of the most deadly and devastating forms of child abuse, is caused by violent shaking. The combination of subdural hematoma, retinal hemorrhage, brain swelling, and diffuse axonal injury is highly typical of this syndrome and faced with these autopsy findings, induced traumatic lesions are strongly considered. However, it is known that motor‐vehicle accidents and falls from great height can also produce this pattern of injury. Nevertheless, stories of arms fall, couch fall, or bumped head while the baby is being carried are generally considered incompatible with SBS. We here report a case of a 2‐year‐old boy presenting with all the classic autopsy findings of SBS from a playground rocking toy shaken by an older child.
Sequential Monitoring of Burials Containing Small Pig Cadavers Using Ground Penetrating Radar*
Authors: Schultz John J.
Published: March 2008

Abstract:  Ground‐penetrating radar (GPR) was used to monitor 12 pig burials in Florida, each of which contained a small pig cadaver. Six of the cadavers were buried in sand at a depth of 0.50–0.60 m, and the other six were buried in sand at a depth of 1.00–1.10 m to represent deep and shallow burials that are generally encountered in forensic scenarios. Four control excavations with no pig interment were also constructed as blank graves and monitored with GPR. The burials were monitored for durations of either 13 or 21 months, and were then excavated to correlate the decomposition state of the cadaver with the GPR imagery. Overall, this study demonstrated that it may be difficult to detect small cadavers buried in sand soon after they are skeletonized because the area surrounding the body, or the grave, may not provide a strong enough contrasting area to be detected by GPR when compared to that of the surrounding undisturbed soil. Also, depth of burial appears to influence grave detection because bodies that are buried at deeper depths may be detected for a longer period of time due to reduced decomposition rates.
Direct STR Amplification from Whole Blood and Blood‐ or Saliva‐Spotted FTA® without DNA Purification*
Authors: Park Su Jeong , Kim Jong Yeol , Yang Young Geun , Lee Seung Hwan
Published: March 2008

Abstract:  The DNA purification step has been thought to be essential for typing of STR DNA. However, this process is time‐consuming, and there is a risk of unexpected cross‐contamination during purification. We report a new method for direct short tandem repeat (STR) amplification using a newly developed direct PCR buffer, AnyDirect™, which can amplify STR loci from whole blood and blood‐ or saliva‐spotted FTA® cards without DNA purification. The autosomal and Y chromosomal STR loci were analyzed for whole blood and blood or saliva spots of random individuals, followed by comparison of the results with those of corresponding purified DNA. The results from whole blood and blood spots showed perfect concordance with those from purified DNA without allele or locus drop‐out. However, in the case of saliva spots, no amplification or locus drop‐out was observed in some of the samples, which offers a topic for further study. Additionally, some commercial hot‐start DNA polymerases other than AmpliTaq Gold® DNA polymerase were also found to be compatible with this buffer system. Therefore, this direct PCR buffer was demonstrated to be useful for fast forensic DNA analysis or criminal DNA databases for which there is no need to store DNA samples.
Dual Fingerprint Reagents with Enhanced Sensitivity: 5‐Methoxy‐ and 5‐Methylthioninhydrin
Authors: Almog Joseph , Klein Asne , Davidi Inbal , Cohen Yaron , Azoury Myriam , Levin‐Elad Michal
Published: March 2008

Abstract:  “Dual fingerprint reagents” are chemical formulations which produce with latent fingerprints in a single step, impressions that are both colored and fluorescent. Pre‐mixed solutions of the two commercially available ninhydrin analogues, 5‐methoxyninhydrin (MN) and 5‐methylthioninhydrin (MTN) with zinc or cadmium salts, are true dual reagents. They are much more sensitive than the parent dual reagent, ninhydrin/ZnCl2. The main advantage of the new formulations is that they can be used at room temperature, with no need to cool the sample to liquid nitrogen temperature. At 0.05% concentration, which is 10‐fold lower than the common ninhydrin working solution, MTN/ZnCl2 is as sensitive as DFO in the fluorescence mode and considerably more sensitive in the color mode. MTN is also slightly cheaper than DFO.
Y‐STR Profiling in Extended Interval (≥3 days) Postcoital Cervicovaginal Samples*
Authors: Mayntz‐Press Kathleen A. , Sims Lynn M. , Hall Ashley , Ballantyne Jack
Published: March 2008

Abstract:  Depending upon specific situations, some victims of sexual assault provide vaginal samples more than 36–48 h after the incident. We have tested the ability of commercial and in‐house Y‐STR systems to provide DNA profiles from extended interval (≥3 days) postcoital samples. The commercial Y‐STR systems tested included the AmpFℓSTR® Yfiler™ (Applied Biosystems), PowerPlex® Y (Promega) and Y‐PLEX™ 12 (Reliagene) products whereas the in‐house systems comprised Multiplex I (MPI) and Multiplex B (MPB). Three donor couples were recruited for the study. Postcoital cervicovaginal swabs (x2) were recovered by each of the three females at specified intervals after sexual intercourse (3–7 days). Each time point sample was collected after a separate act of sexual intercourse and was preceded by a 7‐day abstention period. As a negative control, a precoital swab was also recovered prior to coitus for each sampling and only data from postcoital samples that demonstrated a lack of male DNA in the associated precoital sample was used. A number of DNA profile enhancement strategies were employed including sampling by cervical brushing, nondifferential DNA extraction methodology, and post‐PCR purification. Full Y‐STR profiles from cervicovaginal samples recovered 3–4 days after intercourse were routinely obtained. Profiles were also obtainable 5–6 days postcoitus although by this stage partial profiles rather than full profiles were a more likely outcome. The DNA profiles from the sperm fraction of a differential lysis were superior to that obtained when a nondifferential method was employed in that the allelic signal intensities were generally higher and more balanced and exhibited less baseline noise. The incorporation of a simple post‐PCR purification process significantly increased the ability to obtain Y‐STR profiles, particularly from 5‐ to 6‐day postcoital samples. Remarkably an 8 locus Y‐STR profile was obtained from a 7‐day postcoital sample, which is approaching the reported time limit for sperm detection in the cervix.
Whole Body Postmortem Angiography with a High Viscosity Contrast Agent Solution Using Poly Ethylene Glycol as Contrast Agent Dissolver
Authors: Jackowski Christian , Persson Anders , Thali Michael J.
Published: March 2008

Abstract:  Postmortem minimal invasive angiography has already been implemented to support virtual autopsy examinations. An experimental approach in a porcine model to overcome an initially described artificial tissue edema artifact by using a poly ethylene glycol (PEG) containing contrast agent solution showed promising results. The present publication describes the first application of PEG in a whole corpse angiographic CT examination. A minimal invasive postmortem CT angiography was performed in a human corpse utilizing the high viscosity contrast agent solution containing 65% of PEG. Injection was carried out via the femoral artery into the aortic root in simulated cardiac output conditions. Subsequent CT scanning delivered the 3D volume data of the whole corpse. Visualization of the human arterial anatomy was excellent and the contrast agent distribution was generally limited to the arterial system as intended. As exceptions an enhancement of the brain, the left ventricular myocardium and the renal cortex became obvious. This most likely represented the stage of centralization of the blood circulation at the time of death with dilatation of the precapillary arterioles within these tissues. Especially for the brain this resulted in a distinctively improved visualization of the intracerebral structures by CT. However, the general tissue edema artifact of postmortem minimal invasive angiography examinations could be distinctively reduced.
Toxicology and Circumstances of Death of Homicide Victims in New South Wales, Australia 1996–2005
Authors: Darke Shane , Duflou Johan
Published: March 2008

Abstract:  To determine the prevalence and circumstances of psychoactive substances amongst homicide victims, 485 consecutive cases autopsied at the NSW Department of Forensic Medicine (1/1/1996–12/31/2005) were analyzed. Substances were detected in 62.6% of cases, and illicit drugs in 32.8%. Alcohol, cannabis, opioids, and psychostimulants were most commonly detected. Alcohol and cannabis were both more prevalent amongst males. Mean ages were significantly younger for decedents who tested positive for a substance and for an illicit drug. Cases where death resulted from a physical altercation were more likely to have had alcohol and cannabis present. Illicit drugs were prominent amongst firearms deaths. The proportion of alcohol positive cases increased from 25.0% on Monday to 49.4% for Saturdays/Sundays. Alcohol was more common in incidents in the 0001–0600 h and 1800–2400 h periods. Psychoactive substances appear to substantially increase the risk of homicide, although there are important differences between drug classes in the circumstances of such incidents.
Y‐Chromosome STR Haplotypes in Three Different Population Groups From Ecuador (South America)
Authors: González‐Andrade Fabricio , Sánchez Dora , Martínez‐Jarreta Begoña , Budowle Bruce
Published: March 2008

Populations:  Over 102 unrelated Mestizos, 102 Native Amerindian (Kichwas), and 102 African Americans who represent the three largest communities of the country Ecuador (South America).
Alzheimer’s Signals
Authors: Ray L. Bryan
Published: March 2008

Alzheimer’s disease is associated with excessive cleavage of the β-amyloid precursor protein (APP) to form the β-amyloid peptide (Aβ), which is thought to contribute to neuronal degeneration. APP can also be cleaved to form the APP intracellular domain (AICD) peptide, which may function analogously to the Notch intracellular domain, a portion of the receptor Notch that is cleaved upon receptor activation and migrates to the nucleus to control transcription. Knowing that a protein known as F3 appears to function as a ligand for Notch, Ma
et al
. tested whether it or another member of the F3 family of proteins might be a ligand for APP. They go on to show that TAG1 appears to fit the bill. TAG1 functions as a neural cell adhesion molecule with roles in neuronal development. When cultured Chinese hamster ovary cells were transfected with TAG1 from mouse or the homologous human protein, the cells adhered to spots on culture dishes that were coated with APP. Neuronal progenitor cells isolated from mice lacking APP or TAG1 and then differentiated in vitro showed increased expression of markers of differentiated neurons. Analysis of embryos lacking both TAG1 and APP also showed increased neuronal differentiation, indicating that the TAG1 and APP may function to restrain neurogenesis. Mouse embryo fibroblasts transfected with TAG1 produced increased amounts of AICD, consistent with the idea that TAG1 may function as an activating ligand for APP. Transfection of fetal neuronal progenitor cells from

TAG1
−/−

mice with TAG1 decreased the abnormal neurogenesis of the mutant cells but was not effective in cells from animals also lacking APP. Fe65 is a scaffold protein proposed to act with AICD to promote transcription. Experiments with a Fe65-Gal4 fusion protein were consistent with a role of Fe65 downstream of TAG1 and APP. TAG1 also failed to reverse abnormal neurogenesis in neuronal precursor cells from

Fe65
−/−

mice. The authors propose that TAG functions as a ligand for a signaling pathway that includes Fe65 and negatively controls neurogenesis. Commentary from Mattson and van Praag notes that the TAG1 is also present in the adult brain and points out that new results raise the possibility that increased TAG1-APP signaling could contribute in two ways to Alzheimer’s disease--increasing cleavage of APP to form more Aβ (which is formed after a second cleavage of AICD) and decreasing neurogenesis, which may contribute to memory formation in the adult hippocampus.

Q.-H. Ma, T. Futagawa, W.-L. Yang, X.-D. Jiang, L. Zeng, Y. Takeda, R.-X. Xu, D. Bagnard, M. Schachner, A. J. Furley, D. Karagogeos, K. Watanabe, G. S. Dawe, Z.-C. Xiao, A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis.
Nat. Cell Biol
.
10
, 283-294 (2008).
[PubMed]

M. P. Mattson, H. van Praag, TAGing APP constrains neurogenesis.
Nat. Cell Biol.
10
, 249-250 (2008).
[PubMed]
Predisposed to a Long Life?
Authors: Adler Elizabeth M.
Published: March 2008

Mutations that disrupt growth hormone production or sensitivity and thereby lead to decreased serum concentrations of insulin-like growth factor 1 (IGF-1) are associated with increased longevity in mice. Furthermore, decreased abundance of the IGF-1 receptor (IGF1R) is associated with increased life span in female mice, and mutations that decrease the activity of components of the insulin/IGF-1 system are associated with increased longevity in invertebrates. The role of IGF-1 signaling in human longevity, however, is less clear. Indeed, growth hormone secretion and serum concentrations of IGF-1 decline with age, and administration of growth hormone (which increases circulating IGF-1) may reverse some physiological correlates of aging. Suh
et al
. found that the daughters of centenarians had 35% higher serum IGF-1 concentrations than age-matched women of similar ethnic background (Ashkenazi Jews) from families that were not so long-lived. Additionally, the average maximum height attained by the centenarians’ daughters was 2.5 cm less than that of their control group. Sequence analysis revealed no variations in the
IGF1
genes of 79 female centenarians who were shorter than the mean height but showed 20
IGF1R
sequence variants. Two nonsynonymous heterozygous mutations of
IGF1R
coding regions were more common in centenarians than in controls and were associated with increased serum IGF1. Immortalized lymphocytes from three centenarians, each carrying a different
IGF1R
mutation, showed decreased IGF1R abundance compared with lymphocytes from centenarians without
IGF1R
mutations and decreased phosphorylation of Akt in response to IGF-1. Thus, the authors conclude that human IGF1R mutations that affect IGF signaling may be associated with a predisposition toward long life.

Y. Suh, G. Atzmon, M.-O. Cho, D. Hwang, B. Liu, D. J. Leahy, N. Barzilai, P. Cohen, Functionally significant insulin-like growth factor I receptor mutations in centenarians.
Proc. Natl. Acad. Sci.
U.S.A.
105
, 3438-3442 (2008).
[Abstract]
[Full Text]
Matrix Elasticity, Cytoskeletal Tension, and TGF-β: The Insoluble and Soluble Meet
Authors: Wells Rebecca G. , Discher Dennis E.
Published: March 2008

Soluble growth factors are potent regulators of normal and pathological processes. Mechanical factors are emerging as similarly important, but there has been no obvious mechanism linking the different factors. A recent report now demonstrates that cell-generated mechanical tension results in release of active transforming growth factor–β from stiff extracellular matrix, providing a mechanism for differentiation and maintenance of myofibroblasts in processes like fibrosis. More broadly, the work suggests that matrix stiffness could regulate the equilibrium between storage and release of a host of matrix-bound growth factors.
A Working Model of Working Memory
Authors: Stern Peter
Published: March 2008

Working memory, the system that enables us to hold information temporarily for processing purposes, is thought to be stored primarily in the form of elevated, persistent neuronal firing rates. Mongillo
et al
. (see the Perspective by Fusi) now suggest that working memory may instead be stored in the short-term facilitation caused by a temporary calcium increase in synapses from neurons that code for a particular memory. Short-term facilitation on the necessary time scale has recently been observed in prefrontal cortex, lending itself to memory maintenance on the scale of seconds. During the memory span, and also during recall, neuronal activity then shows population spikes. If memory is indeed stored in the form of synaptic facilitation, few spikes need to be expended in maintaining it, which would reduce the metabolic cost of working memory.

G. Mongillo, O. Barak, M. Tsodyks, Synaptic theory of working memory.
Science
319
, 1543-1546 (2008).
[Abstract]
[Full Text]

S. Fusi, A quiescent working memory.
Science
319
, 1495-1496 (2008).
[Summary]
[Full Text]
Notch and Integrin Affinity: A Sticky Situation
Authors: Karsan Aly
Published: March 2008

The Notch pathway is a conserved signal transduction system that mediates intercellular signaling to regulate cell fate decisions in various tissues. Dysregulation of Notch activity results in various disorders, including cardiovascular diseases and cancer. Notch regulates cell fate through a number of mechanisms that include control of cell proliferation, survival, migration, and differentiation. Notch activation increases vascular endothelial cell adhesion through the enhancement of β
1
integrin affinity for fibronectin, collagens I and IV, and vitronectin without altering the abundance of β
1
integrin at the cell surface. A study now suggests that this Notch-dependent increase in β
1
integrin affinity occurs through the activation of the small guanosine triphosphate (GTP)–binding protein, R-Ras. It is proposed that Notch-dependent activation of R-Ras reverses H-Ras–mediated suppression of integrin affinity. Activation of R-Ras by Notch may be triggered by a noncanonical CSL (CBF1 or RBP-Jκ in vertebrates, Suppressor of Hairless in
Drosophila
, Lag-1 in
Caenorhabditis elegans
)–independent pathway. Because R-Ras is selectively distributed in vascular cells, these findings are of particular importance in understanding the effector functions of Notch in the vascular system.
Cycling in Synchrony
Authors: Adler Elizabeth M.
Published: March 2008

Hair follicles cycle through growth, involution, and resting phases, with entry into the anagen (or growth) phase depending on activation of hair stem cells. Following anagen, there is a refractory period that has been postulated to depend on an inhibitory substance called "chalone." Whereas cycling in individual follicles depends on periodic activation of the Wnt effector β-catenin, hair regeneration in various mammalian species occurs in coordinated waves, and the mechanism whereby cycling in populations of follicles is coordinated has been unclear. Plikus
et al
. analyzed cycling of hair follicle domains (in which cycling is coordinated) and found that there was a minimum 28-day telogen (resting) phase, which they defined as "early telogen," followed by a "late telogen" phase of 0 to 60 days. Entry into anagen after hair plucking was faster for hairs in late telogen than for hairs in early telogen, indicating that early telogen correlated with the refractory period. Experiments with
lacZ
reporter mice revealed that interfollicular expression of bone morphogenetic protein 2 (
Bmp2
) and
Bmp4
fluctuated with hair cycles, such that BMP signaling was out of phase with Wnt signaling.
Bmp
expression, which was not apparent in early anagen, rose during anagen and remained active during early (refractory) telogen but disappeared in late telogen. Similarly, Smad 1/5/8 is active (phosphorylated) in refractory follicles but not during late telogen. Overexpression of the BMP antagonist noggin shortened the refractory phase, whereas administration of BMP4 ahead of an anagen wave caused local follicles to become refractory, and experiments involving skin grafts from
Nog
-overexpressing to wild-type mice revealed mutual effects of host and donor on follicle cycling. Thus the authors conclude that BMP signaling regulates and coordinates regional hair follicle cycling and may constitute the long-postulated inhibitory "chalone."

M. V. Plikus, J. A. Mayer, D. de la Cruz, R. E. Baker, P. K. Maini, R. Maxson, C.-M. Chuong, Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.
Nature
451
, 340-344 (2008).
[PubMed]
An Exception to the Trimer Paradigm
Authors: Gough Nancy R.
Published: March 2008

The tumor necrosis factor (TNF) superfamily is a large and diverse group of ligands involved in various biological processes. All previously characterized members of this family adopted a trimeric active structure that interacted in a 3:3 ligand:receptor stoichiometry with the cognate receptor. Two groups (Chattopadhyay
et al
. and Zhou
et al
.) report that mouse glucocorticoid-induced tumor necrosis factor receptor ligand (mGITRL) adopts a dimeric structure. Both groups crystallized the ectodomain of mGITRL (TNF ligands are synthesized as transmembrane proteins that either act on adjacent cells or are cleaved into soluble forms) and found that it formed a dimer with domain swap regions that formed intermolecular β sheets composed of the C terminus of one subunit and an inner β sheet of the other. Mutation and deletion analysis indicated that this C-terminal region was critical for formation of the dimer. The dimer was confirmed by sedimentation analysis. Exactly how this dimeric ligand interacts with the receptor GITR remains an open question. GITRL:GITR signaling is important in modulating immune responses, although mouse GITRL (dimeric) and human GITRL (trimeric) appear to play different roles and do not substitute for one another, suggesting species-specific evolution of structure and function.

K. Chattopadhyay, U. A. Ramagopal, M. Brenowitz, S. G. Nathenson, S. C. Almo, Evolution of GITRL immune function: Murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily.
Proc. Nat. Acad. Sci. U.S.A.
105
, 635-640 (2008).
[Abstract]
[Full Text]

Z. Zhou, Y. Tone, X. Song, K. Furuuchi, J. D. Lear, H. Waldmann, M . Tone, M. I. Greene, R. Murali, Structural basis for ligand-mediated mouse GITR activation.
Proc. Nat. Acad. Sci. U.S.A.
105
, 641-645 (2008).
[Abstract]
[Full Text]
The Endoplasmic Reticulum Takes Center Stage in Cell Cycle Regulation
Authors: Fearon Paula , Cohen-Fix Orna
Published: March 2008

Cell cycle progression is controlled by the action of cyclins and their partners, the cyclin-dependent kinases (CDKs). Although many of the cyclin/CDK targets are in the nucleus, some cyclins spend part of their time in the cytoplasm. Until recently, it was not clear what happens to these cyclins while they are in the cytoplasm; now, two different cyclins have been found to be associated with the endoplasmic reticulum. The question is why.
It’s the Kinase, Stupid!
Authors: Ray L. Bryan
Published: March 2008

Semaphorins function as axon guidance molecules in the nervous system and also have effects on other biological processes that depend on cell migration, such as immune responses, morphogenesis, and tumor progression. The semaphorin 4D protein (Sema4D) binds to a receptor known as plexin-B1, which signals through interaction with small guanosine triphosphatases (GTPases) and the tyrosine kinases Met and ErbB-2. In an attempt to explain why it is that activation of plexin-B1 is reported to either stimulate or inhibit cell migration in various cell types, Swiercz
et al
. took a closer look at the roles of Met and ErbB-2. Treatment of human breast cancer MCF-7 cells (which express ErbB-2 but not Met) with Sema4D caused an increase in migration, whereas similar stimulation of the MDA-MB-468 breast cancer cells (which express Met but not ErbB-2) inhibited migration. Sema4D-induced migration in the MCF-7 cells was blocked if ErbB-2 was depleted with siRNA, whereas siRNA to Met had no effect. In the MDA-MB-468 cells, depletion of Met prevented the inhibition of migration in response to Sema4D, and siRNA to ErB-2 had no effect. If the two kinases were swapped between the two cell lines (by depletion of the endogenous kinase with siRNA and replacement with exogenously expressed Met or Erb-B2), the biological effects of Sema4D were reversed (that is, MCF-7 cells expressing Met and depleted of ErbB2 now showed inhibition of migration in response to Sema4D, and MDA-MB-48 cells expressing ErbB-2 instead of Met showed a Sema4D-induced increase in migration). Thus, the coupling of plexin-B1 to distinct tyrosine kinases can account for the opposite effects of Sema4D in various cell types. The authors note that the differential effects on migration are correlated with opposite effects of Met and Erb-B2 on the activity of the small GTPase RhoA, but other differences in signaling by the two tyrosine kinases may also contribute their distinct biological effects.

J. M. Swiercz, T. Worzfeld, S. Offermanns, ErbB-2 and Met reciprocally regulate cellular signaling via plexin-B1.
J. Biol. Chem.
283
, 1893-1901 (2008).
[Abstract]
[Full Text]
Glucose Fattens Up Muscle
Authors: Gough Nancy R.
Published: March 2008

Both adipose tissue and muscle tissue contain stem cells that can differentiate into adipocytes. Because increased concentrations of circulating glucose are associated with increased adiposity, Aguiari
et al
. investigated whether glucose exposure was sufficient to drive stem cell differentiation. The authors exposed stem cells isolated from human adipose tissue or neonatal rat muscle to medium containing low (5.5 mM) or high (25 mM) concentrations of glucose and found that higher concentrations of glucose increased the proportion of cells adopting an adipocyte phenotype. High concentrations of glucose stimulated the production of reactive oxygen species and activation (translocation to the plasma membrane) of protein kinase Cβ (PKCβ). Addition of hydrogen peroxide to low glucose-containing medium stimulated differentiation of muscle-derived stem cells into adipocytes, whereas inhibition of PKCβ activity through RNAi techniques blocked differentiation of the muscle-derived stem cells into adipocytes. Overexpression of PKCβ increased the proportion of cells adopting the adipocyte phenotype. Adipose-derived stem cells differentiated on sponge supports in high-glucose-containing medium were successfully introduced into nude rats; the tissue became vascularized, and morphological characterization upon surgical removal revealed that this tissue contained adipocytes, preadipocytes, and capillaries. Thus, high circulating concentrations of glucose--a common cause of obesity and a condition associated with diabetes--may be a key factor causing not only the expansion of adipose tissue but also the differentiation of nonadipose tissue, such as muscle or (as has been previously reported) pancreatic β cells, into adipocytes.

P. Aguiari, S. Leo, B. Zavan, V. Vindigni, A. Rimessi, K. Bianchi, C. Franzin, R. Cortivo, M. Rossato, R. Vettor, G. Abatangelo, T. Pozzan, P. Pinton, R. Rizzuto, High glucose induces adipogenic differentiation of muscle-derived stem cells.
Proc. Natl. Acad. Sci. U.S.A
105
, 1226-1231 (2008).
[Abstract]
[Full Text]
MIFed About Metabolism
Authors: Adler Elizabeth M.
Published: March 2008

AMP (adenosine monophosphate)-activated protein kinase (AMPK), which modulates metabolic pathways in response to changes in cellular energy status, stimulates glucose uptake and glycolysis in the ischemic heart, limiting myocardial injury. Noting that macrophage migration inhibition factor (MIF, a cytokine implicated in the pathogenesis of various inflammatory conditions) stimulates glycolysis and is expressed in cardiomyocytes, Miller
et al
. investigated its role in cardiac AMPK activation. AMPK activation in hypoxic rat heart muscle was associated with increased MIF release, whereas antibodies directed against MIF inhibited hypoxia-stimulated activation of AMPK and glucose uptake. Ischemia triggered MIF release from isolated mouse heart, and phosphorylation and activation of AMPK in response to ischemia was decreased in mice lacking MIF (

Mif
–/–

mice), as was stimulation of glucose uptake during ischemia-reperfusion. Hearts from

Mif
–/–

mice showed decreased post-ischemic function compared with those from wild-type mice and larger infarcts after coronary occlusion-reperfusion. Short interfering RNA directed against CD74 (the ligand-binding component of the MIF receptor complex) decreased hypoxia-stimulated AMPK phosphorylation in fibroblasts, and the effects of MIF or hypoxia on AMPK phosphorylation in COS-7/M6 cells depended on expression of CD74 and CD44 (the signal-transducing component). Human fibroblasts with MIF promoter polymorphism that led to decreased expression and secretion showed decreased AMPK phosphorylation during hypoxia, which was restored by exogenous MIF. Thus, the authors conclude that MIF acts as a local factor to activate AMPK during cardiac ischemia, linking inflammation with cardiac metabolism, and suggest that MIF genotyping could help predict risk of ischemic injury in individuals with coronary artery disease.

E. J. Miller, J. Li, L. Leng, C. McDonald, T. Atsumi, R. Bucala, L. H. Young, Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart.
Nature
451
, 578-582 (2008).
[PubMed]
Regulating Ovulation
Authors: Purnell Beverly A.
Published: March 2008

In mammals, the ability of a female to remain fertile for an extended period depends on the continuous awakening of primordial follicles from their dormant state in the ovary. Menopause, or the natural end of female reproductive life, occurs when the pool of primordial follicles has been depleted. The mechanisms controlling follicular activation have remained a mystery. Reddy
et al.
now reveal that follicle activation is controlled by the oocyte PTEN (phosphatase and tensin homolog deleted on chromosome 10)-phosphatidylinositol 3-kinase pathway. In a mouse model where
Pten
is deleted specifically in oocytes, the entire pool of primordial follicles is prematurely activated and subsequently depleted in early adulthood, which results in premature ovarian failure.

P. Reddy, L. Liu, D. Adhikari, K. Jagarlamudi, S. Rajareddy, Y. Shen, C. Du, W. Tang, T. Hämäläinen, S. L. Peng, Z.-J. Lan, A. J. Cooney, I. Huhtaniemi, K. Liu, Oocyte-specific deletion of
Pten
causes premature activation of the primordial follicle pool.
Science
319
, 611-613 (2008).
[Abstract]
[Full Text]
T Cell Role for Cathepsin K
Authors: Simpson Stephen J.
Published: March 2008

Cathepsins are cysteine proteases that degrade proteins in the lysosome, and some cathepsins assist with the processing of antigens for the immune system. Asagiri
et al.
(see the Perspective by Krieg and Lipford) uncover a further but distinct immunological role for another cathepsin, cathepsin K, which is known to be involved in osteoclast function in the bone. Cathepsin K is expressed in immunological dendritic cells and is needed for the complete induction of the inflammatory T helper 17 cells. In animal models for two autoimmune conditions, pathology was ameliorated by cathepsin K deficiency because of its unexpected involvement in signaling through the innate immune receptor TLR9. Cathepsin K is already a target for some antirheumatic drugs, so its emergence as regulator of the immune response may further bolster efforts to target this pathway.

M. Asagiri, T. Hirai, T. Kunigami, S. Kamano, H.-J. Gober, K. Okamoto, K. Nishikawa, E. Latz, D. T. Golenbock, K. Aoki, K. Ohya, Y. Imai, Y. Morishita, K. Miyazono, S. Kato, P. Saftig, H. Takayanagi, Cathepsin K-dependent Toll-like receptor 9 signaling revealed in experimental arthritis.
Science
319
, 624-627 (2008).
[Abstract]
[Full Text]

A. M. Krieg, G. B. Lipford, The Toll of cathepsin K deficiency.
Science
319
, 576-577 (2008).
[Summary]
[Full Text]
Exosomes Secreted by Bacterially Infected Macrophages Are Proinflammatory
Authors: O’Neill Helen C. , Quah Ben J. C.
Published: March 2008

Exosomes are small vesicles that are secreted from cells. They are derived from multivesicular endosomes that fuse with the plasma membrane, thereby releasing their internal vesicles into the extracellular environment. Exosomes from antigen-presenting cells contain a range of immunostimulatory molecules that activate T cells, which suggests that they may have an important role in the propagation of immune responses. Of considerable interest is the finding that exosomes derived from bacterially infected macrophages carry bacterial coat components and use these to stimulate bystander macrophages and neutrophils to secrete proinflammatory mediators, including tumor necrosis factor-α, the chemokine regulated upon activation, normal T cell–expressed and –secreted (RANTES, also known as CCL5), and inducible nitric oxide synthase. Here, we address these studies in relation to other findings on dendritic cell–derived exosomes that are also powerful immunoregulators.
A Fungus Gets SNAREd
Authors: Foley John F.
Published: March 2008

The resistance of
Arabidopsis
to infection by the fungus
Blumeria
graminis
is partly mediated by preinvasion responses involving the syntaxin protein PEN1, a SNARE [soluble
N
-ethylmaleimide-sensitive factor (NSF) attachment protein receptor] component, but the mechanism involved is unclear. t-SNAREs, such as PEN1, are target membrane proteins that associate with vesicle (v)-SNAREs such as vesicle-associated membrane proteins (VAMPs) to mediate intracellular membrane fusion. Kwon
et al
. noticed that, whereas
pen1
-1 null mutant
Arabidopsis
showed poor resistance to
B
.
graminis
, plants with the
pen1
-3 allele, which contains a mutation that decreases the stability of SNARE-SNARE interactions, exhibited partial resistance to infection. Western blotting analyses showed the presence of a PEN1-containing complex in wild-type, but not
pen1
-3, leaves. Inoculation with
B
.
graminis
increased the abundance of this complex. Coimmunoprecipitation assays demonstrated that PEN1 formed a pathogen-dependent complex with the t-SNARE SNAP33 and with either VAMP721 or VAMP722. Transgenic plants that were inducibly deficient in both
vamp721
and
vamp722
showed increased susceptibility to fungal infection. Confocal microscopic analysis of
vamp721
- and
vamp722­
-deficient plants that expressed a fusion of VAMP722 and green fluorescent protein showed pathogen-dependent directed movement to and focal accumulation of VAMP722-containing complexes at the sites of
B
.
graminis
entry of leaf epidermal cells. This process resembled the formation of the synapse between a mammalian cytotoxic T cell and its target. Accumulation of the PEN1-SNAP32-VAMP722 complexes to sites of infection was associated with increased resistance to infection and improved repair of the plant cell wall. This study demonstrates that VAMP721 and VAMP722, which the authors showed were critical for plant development and growth, were coopted to mount a secretory response to fungal infection.

C. Kwon, C. Neu, S. Pajonk, H. S. Yun, U. Lipka, M. Humphry, S. Bau, M. Straus, M. Kwaaitaal, H. Rampelt, F. El Kasmi, G. Jürgens, J. Parker, R. Panstruga, V. Lipka, P. Schulze-Lefert, Co-option of a default secretory pathway for plant immune responses.
Nature
451
, 835-840 (2008).
[PubMed]
Quantitative Models of Mammalian Cell Signaling Pathways
Authors: Iyengar Ravi
Published: March 2008

This teaching resource provides lecture notes and slides for a class on mathematical modeling of mammalian signaling pathways. This lecture was part of the course "Cell Signaling Systems: A Course for Graduate Students" and focused on quantitative modeling. The lecture describes how different types of mathematical representations are applied to different signaling systems to provide insight into how a signaling system controls cell behavior. The development of an ordinary differential equation–based model for a bistable switch and the predictions that can be obtained from the model are described. The lecture concludes with a description of how models can be tested experimentally and modified when the details of the models and the resultant predictive behavior are not confirmed by experimentation.
Context-Dependent Activation or Inhibition of Wnt-β-Catenin Signaling by Kremen
Authors: Cselenyi Christopher S. , Lee Ethan
Published: March 2008

Wnt-β-catenin signaling controls critical events in metazoan development, and its dysregulation leads to cancers and developmental disorders. Binding of a Wnt ligand to its transmembrane co-receptors Frizzled (Fz) and low-density lipoprotein (LDL) receptor–related protein (LRP) 5 or LRP6 inhibits the degradation of the transcriptional coactivator β-catenin, which translocates to the nucleus to regulate gene expression. The secreted protein Dickkopf1 (Dkk1) inhibits Wnt signaling by binding to LRP5 and LRP6 and blocking their interaction with Wnt and Fz. Kremen 1 and 2 (Krm1 and 2, collectively termed Krms) are single-pass transmembrane Dkk1 receptors that synergize with Dkk1 to inhibit Wnt signaling by promoting the endocytosis of LRP5 and LRP6. A study now suggests that Krms, in the absence of Dkk1, potentiate Wnt signaling by maintaining LRP5 and LRP6 at the plasma membrane. It is proposed that the absence or presence of Dkk1 determines whether Krms will activate or inhibit Wnt-β-catenin signaling, respectively. Here, we speculate that the proposed context-dependent positive and negative roles for Krms could promote biphasic Wnt signaling in response to a shallow gradient of Dkk1, resulting in the generation of precise and robust borders between cells during development. Identification of a context-dependent role for Krms in Wnt-β-catenin signaling offers insight into the mechanism of Wnt signaling and has important developmental implications.
Channel Talk
Authors: Ray L. Bryan
Published: March 2008

Petroff
et al.
describe an interaction between two ion channels that confers sensitivity of K
+
channels to extracellular protons. The authors studied acid-sensing ion channels (ASICs), which are Na
+
-conducting neuronal channels whose conductance is increased by reduced extracellular pH. These channels are implicated in regulation of a range of physiologic and pathological processes. Their Na
+
conductance would tend to depolarize neurons, but some of their actions in mice are not easily explained by such a mechanism. In searching for another mechanism by which ASICs might function, the authors noted that the channels contain a conserved sequence similar to the portion of scorpion alpha-K-toxins that plugs the pore of K
+
channels, inhibiting their conductance. Indeed, when ASIC1a channels were expressed together with high-conductance Ca
2+
- and voltage-activated (BK) K
+
channels in human embryonic kidney (HEK) 293 cells, current flow through the BK channels was reduced. The proteins appeared to interact with one another as they promoted interaction of fluorescently tagged cells expressing one or the other of the channels. Addition of protons inhibited clustering and relieved the inhibition of the BK channel conductance. The function of the ASIC1a channels was also modified by the interaction, showing reduced current amplitude and an increased time for desensitization. Thus, interaction of two unrelated channels alters the activity of the channels and confers sensitivity to acidosis on BK channels. Acidosis occurs with neuronal activity in various pathological states and through this mechanism would modulate channel function and produce opposing effects on membrane voltage through the ASIC and BK channels.

E. Y. Petroff, M. P. Price, V. Snitsarev, H. Gong, V. Korovkina, F. M. Abboud, M. J. Welsh, Acid-sensing ion channels interact with and inhibit BK K
+
channels.
Proc. Natl. Acad. Sci. U.S.A.
105
, 3140-3144 (2008).

[Abstract]
[Full Text]
Targeted Effects
Authors: Foley John F.
Published: March 2008

Correct positioning of the presynaptic terminal of a motoneuron and the postsynaptic membrane of its target muscle are essential for the formation of an effective neuromuscular junction (NMJ). Compounds secreted from the presynaptic terminal such as agrin and acetylcholine (ACh) regulate clustering of ACh receptors (AChRs) in the muscle, and muscle-derived factors are thought to affect presynaptic terminal differentiation and function; however, the factors involved are unknown. Wnt proteins play a role in the development of the nervous system. In canonical Wnt signaling, β-catenin translocates to the nucleus to activate expression of Wnt-target genes, but β-catenin also anchors cadherin adhesion proteins to the cytoskeleton. Li
et al
. developed a mouse (
HSA–
β

-cat
−/−

) selectively deficient in β-catenin in skeletal muscle cells. Whole-mount staining of diaphragms showed that whereas primary nerve branches were properly positioned at muscle fibers in control mice, they were misaligned in
HSA–
β

-cat
−/−

mice.
HSA–
β

-cat
−/−

mice also had fewer and longer secondary branches than did control mice. AChR clusters in
HSA–
β

-cat
−/−

mice were larger and spread out over a wider area than those in control mice. Electrophysiological recordings revealed that
HSA–
β

-cat
−/−

mice had a defect in spontaneous and depolarization-induced release of ACh from the presynaptic terminal but did not have any defect in postsynaptic AChR responsiveness. When this study was repeated in mice with a motoneuron-specific deficiency in β-catenin, no defects in NMJ morphology or function were found, which ruled out defective β-catenin-cadherin interactions as being responsible for the
HSA–
β

-cat
−/−

phenotype. As Fu
et al
. speculate in commentary, one way that β-catenin in the muscle could regulate NMJ function is through driving the expression of genes that encode the retrograde signals needed for motoneuron differentiation.

X.-M. Li, X.-P. Dong, S.-W. Luo, B. Zhang, D.-H. Lee, A. K. L. Ting, H. Neiswender, C.-H. Kim, E. Carpenter-Hyland, T.-M. Gao, W.-C. Xiong, L. Mei, Retrograde regulation of motoneuron differentiation by muscle β-catenin.
Nat
.
Neurosci
.
11
, 262-268 (2008).
[PubMed]

A. K. Y. Fu, Z. H. Cheung, N. Y. Ip, β-catenin in reverse action.
Nat
.
Neurosci
.
11
, 244-246 (2008).
[PubMed]