bluuebunny/crossref_metadata_2025 huggingface dataset:
Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens
Authors: Lee Ko-Woon , Kim Yong , Kim Amie M. , Helmin Kathryn , Nairn Angus C. , Greengard Paul
Published: February 2006

Psychostimulant-induced alteration of dendritic spines on dopaminoceptive neurons in nucleus accumbens (NAcc) has been hypothesized as an adaptive neuronal response that is linked to long-lasting addictive behaviors. NAcc is largely composed of two distinct subpopulations of medium-sized spiny neurons expressing high levels of either dopamine D1 or D2 receptors. In the present study, we analyzed dendritic spine density after chronic cocaine treatment in distinct D1 or D2 receptor-containing medium-sized spiny neurons in NAcc. These studies made use of transgenic mice that expressed EGFP under the control of either the D1 or D2 receptor promoter (Drd1-EGFP or Drd2-EGFP). After 28 days of cocaine treatment and 2 days of withdrawal, spine density increased in both Drd1-EGFP- and Drd2-EGFP-positive neurons. However, the increase in spine density was maintained only in Drd1-EGFP-positive neurons 30 days after drug withdrawal. Notably, increased ΔFosB expression also was observed in Drd1-EGFP- and Drd2-EGFP-positive neurons after 2 days of drug withdrawal but only in Drd1-EGFP-positive neurons after 30 days of drug withdrawal. These results suggest that the increased spine density observed after chronic cocaine treatment is stable only in D1-receptor-containing neurons and that ΔFosB expression is associated with the formation and/or the maintenance of dendritic spines in D1 as well as D2 receptor-containing neurons in NAcc.
PPARδ regulates glucose metabolism and insulin sensitivity
Authors: Lee Chih-Hao , Olson Peter , Hevener Andrea , Mehl Isaac , Chong Ling-Wa , Olefsky Jerrold M. , Gonzalez Frank J. , Ham Jungyeob , Kang Heonjoong , Peters Jeffrey M. , Evans Ronald M.
Published: February 2006

The metabolic syndrome is a collection of obesity-related disorders. The peroxisome proliferator-activated receptors (PPARs) regulate transcription in response to fatty acids and, as such, are potential therapeutic targets for these diseases. We show that PPARδ (NR1C2) knockout mice are metabolically less active and glucose-intolerant, whereas receptor activation in
db/db
mice improves insulin sensitivity. Euglycemic–hyperinsulinemic-clamp experiments further demonstrate that a PPARδ-specific agonist suppresses hepatic glucose output, increases glucose disposal, and inhibits free fatty acid release from adipocytes. Unexpectedly, gene array and functional analyses suggest that PPARδ ameliorates hyperglycemia by increasing glucose flux through the pentose phosphate pathway and enhancing fatty acid synthesis. Coupling increased hepatic carbohydrate catabolism with its ability to promote β-oxidation in muscle allows PPARδ to regulate metabolic homeostasis and enhance insulin action by complementary effects in distinct tissues. The combined hepatic and peripheral actions of PPARδ suggest new therapeutic approaches to treat type II diabetes.
Prion protein (PrP
c
) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis
Authors: Steele Andrew D. , Emsley Jason G. , Özdinler P. Hande , Lindquist Susan , Macklis Jeffrey D.
Published: February 2006

The misfolding of the prion protein (PrP
c
) is a central event in prion diseases, yet the normal function of PrP
c
remains unknown. PrP
c
has putative roles in many cellular processes including signaling, survival, adhesion, and differentiation. Given the abundance of PrP
c
in the developing and mature mammalian CNS, we investigated the role of PrP
c
in neural development and in adult neurogenesis, which occurs constitutively in the dentate gyrus (DG) of the hippocampus and in the olfactory bulb from precursors in the subventricular zone (SVZ)/rostral migratory stream.
In vivo
, we find that PrP
c
is expressed immediately adjacent to the proliferative region of the SVZ but not in mitotic cells.
In vivo
and
in vitro
studies further find that PrP
c
is expressed in multipotent neural precursors and mature neurons but is not detectable in glia. Loss- and gain-of-function experiments demonstrate that PrP
c
levels correlate with differentiation of multipotent neural precursors into mature neurons
in vitro
and that PrP
c
levels positively influence neuronal differentiation in a dose-dependent manner. PrP
c
also increases cellular proliferation
in vivo
; in the SVZ, PrP
c
overexpresser (OE) mice have more proliferating cells compared with wild-type (WT) or knockout (KO) mice; in the DG, PrP
c
OE and WT mice have more proliferating cells compared with KO mice. Our results demonstrate that PrP
c
plays an important role in neurogenesis and differentiation. Because the final number of neurons produced in the DG is unchanged by PrP
c
expression, other factors must control the ultimate fate of new neurons.
Synapsins regulate use-dependent synaptic plasticity in the calyx of Held by a Ca
2+
/calmodulin-dependent pathway
Authors: Sun Jianyuan , Bronk Peter , Liu Xinran , Han Weiping , Südhof Thomas C.
Published: February 2006

Synapsins are abundant synaptic-vesicle phosphoproteins that are known to regulate neurotransmitter release but whose precise function has been difficult to pinpoint. Here, we use knockout mice to analyze the role of synapsins 1 and 2 in the calyx of Held synapse, allowing precise measurements of neurotransmitter release. We find that deletion of synapsins did not induce significant changes in spontaneous release or release evoked by isolated action potentials (APs) and did not alter the size of the readily releasable vesicle pool (RRP), the kinetics of RRP depletion, or the rate of recovery of the RRP after depletion. Deletion of synapsins, however, did increase use-dependent synaptic depression induced by a high-frequency stimulus train (≥50 Hz). The increased depression was due to a decrease in the fraction of the RRP, whose release was evoked by APs late in the stimulus train. The effect of synapsin deletions was occluded by intracellular application of the Ca
2+
-chelator EGTA or of a calmodulin inhibitor. Our results show that synapsins boost the release probability during high-frequency stimulation and suggest that this effect involves Ca
2+
/calmodulin-dependent phosphorylation of synapsins.
Vital functions of corticotropin-releasing factor (CRF) pathways in maintenance and regulation of energy homeostasis
Authors: Carlin Kendall M. , Vale Wylie W. , Bale Tracy L.
Published: February 2006

Regulation of energy homeostasis is a vital function of the CNS requiring adaptive responses to maintain and support life after stress perturbations. The mechanisms whereby these processes occur are, however, only partially understood. A major determinate of these responses is corticotropin-releasing factor (CRF). Receptors for CRF, CRFR1 and CRFR2, have been hypothesized to play distinct roles in the alterations necessary for homeostatic maintenance. The function of CRFR2, in particular, has remained elusive despite its presence in both the CNS and periphery. In this work, we have used complimentary gene deletion and pharmacological approaches to elucidate the crucial role CRFR2 plays in the regulation of regional tissue thermogenesis and adaptive physiology. Analyses of interscapular brown adipose tissue (IBAT) thermogenesis by thermal signature analysis and the concordant biochemical changes in key sympathetic components in mice deficient for CRFR2 revealed significantly elevated basal IBAT thermogenesis and prolonged adrenergic responsivity of IBAT in older mice. Measurement of metabolic rates by indirect calorimetry after chronic high-fat diet challenge and treatment with the CRFR1 antagonist NBI-27914 revealed a decreased respiratory exchange ratio of these mice that was normalized with NBI-27914. Further, as a definitive measure for physiological pathology, mice examined in a behavioral model of differential temperature selection showed a predilection for warmer external temperatures, supporting a loss of body heat in these mice. These studies provide physiological, biochemical, and behavioral evidence for the critical participation of CRF pathways in the maintenance and adaptive responses necessary for regulation of energy homeostasis.
RNA polymerase II subunit Rpb9 is important for transcriptional fidelity
in vivo
Authors: Nesser Nicole K. , Peterson David O. , Hawley Diane K.
Published: February 2006

The fidelity of yeast RNA polymerase II (Pol II) was assessed
in vivo
with an assay in which errors in transcription of
can1–100
, a nonsense allele of
CAN1
, result in enhanced sensitivity to the toxic arginine analog canavanine. The Pol II accessory factor TFIIS has been proposed to play a role in transcript editing by stimulating the intrinsic nuclease activity of the RNA polymerase. However, deletion of
DST1
, the gene encoding the yeast homolog of TFIIS, had only a small effect on transcriptional fidelity, as determined by this assay. In contrast, strains containing a deletion of
RPB9
, which encodes a small core subunit of Pol II, were found to engage in error-prone transcription.
rpb9
Δ strains also had increased steady-state levels of
can1–100
mRNA, consistent with transcriptional errors that decrease the normal sensitivity of the
can1–100
transcript to nonsense-mediated decay, a pathway that degrades mRNAs with premature stop codons. Sequences of cDNAs from
rpb9
Δ strains confirmed a significantly increased occurrence of transcriptional substitutions and insertions. These results suggest that Rpb9 plays an important role in maintaining transcriptional fidelity, whereas TFIIS may serve a different primary purpose.
Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson–Gilford progeria syndrome
Authors: Varga Renee , Eriksson Maria , Erdos Michael R. , Olive Michelle , Harten Ingrid , Kolodgie Frank , Capell Brian C. , Cheng Jun , Faddah Dina , Perkins Stacie , Avallone Hedwig , San Hong , Qu Xuan , Ganesh Santhi , Gordon Leslie B. , Virmani Renu , Wight Thomas N. , Nabel Elizabeth G. , Collins Francis S.
Published: February 2006

Children with Hutchinson–Gilford progeria syndrome (HGPS) suffer from dramatic acceleration of some symptoms associated with normal aging, most notably cardiovascular disease that eventually leads to death from myocardial infarction and/or stroke usually in their second decade of life. For the vast majority of cases, ade novopoint mutation in the lamin A (LMNA) gene is the cause of HGPS. This missense mutation creates a cryptic splice donor site that produces a mutant lamin A protein, termed “progerin,” which carries a 50-aa deletion near its C terminus. We have created a mouse model for progeria by generating transgenics carrying a human bacterial artificial chromosome that harbors the common HGPS mutation. These mice develop progressive loss of vascular smooth muscle cells in the medial layer of large arteries, in a pattern very similar to that seen in children with HGPS. This mouse model should prove valuable for testing experimental therapies for this devastating disorder and for exploring cardiovascular disease in general.
The effect of climate variation on agro-pastoral production in Africa
Authors: Stige Leif Christian , Stave Jørn , Chan Kung-Sik , Ciannelli Lorenzo , Pettorelli Nathalie , Glantz Michael , Herren Hans R. , Stenseth Nils Chr.
Published: February 2006

Using national crop and livestock production records from 1961–2003 and satellite-derived data on pasture greenness from 1982–2003 we show that the productivity of crops, livestock, and pastures in Africa is predictably associated with the El Niño Southern Oscillation and the North Atlantic Oscillation. The causal relations of these results are partly understandable through the associations between the atmospheric fluctuations and African rainfall. The range of the explained among-year variation in crop production in Africa as a whole corresponds to the nutritional requirements for ≈20 million people. Results suggest reduced African food production if the global climate changes toward more El Niño-like conditions, as most climate models predict. Maize production in southern Africa is most strongly affected by El Niño events. Management measures include annual changes in crop selection and storage strategies in response to El Niño Southern Oscillation-based and North Atlantic Oscillation-based predictions for the next growing season.
Individual and contextual determinants of exclusive breast-feeding in São Paulo, Brazil: a multilevel analysis
Authors: Venancio Sonia Isoyama , Monteiro Carlos Augusto
Published: February 2006

Objective

To identify individual and contextual factors associated with the practice of exclusive breast-feeding (EBF).

Methodology

We analysed 34 435 children under 6 months of age living in 111 municipalities in the state of São Paulo, south-eastern Brazil, who participated in a survey investigating feeding practices during the first year of life, carried out during the 1999 national vaccination campaign. The questionnaire employed included questions on the consumption, in the last 24 h, of breast milk, water, tea, other types of milk and other foods, in addition to mother and child characteristics. Information on the pro-breast-feeding measures implemented in the municipalities was also collected. The effects of individual and contextual characteristics on EBF were analysed using multilevel models.

Results

The final model showed a greater chance of EBF in women with tertiary education (odds ratio (OR) = 1.91; 95% confidence interval (CI) 1.75–2.06); women aged between 25 and 29 years (OR = 1.52; 95% CI 1.41–1.63); multiparae (OR = 1.42; 95% CI 1.33–1.49); female babies (OR = 1.12; 95% CI 1.05–1.18); birth weight ≥3000 g (OR = 1.73; 95% CI 1.49–1.97); child follow-up in the private health-care network (OR = 1.10; 95% CI 1.02–1.18); and municipalities with four or five pro-breast-feeding measures (OR = 2.4; 95% CI 2.19–2.88). An analysis of the interactions between individual and contextual variables showed that the presence of at least four pro-breast-feeding measures in the municipality attenuated the risk of early termination of EBF associated with low maternal schooling and low birth weight, and transformed child follow-up in the public network into a protective factor against the early termination of breast-feeding.

Conclusions

The presence of measures aimed at protecting, promoting and supporting breast-feeding in the municipality had a positive influence on EBF and attenuated the impact of risk factors for the termination of breast-feeding.
Malnutrition and high childhood mortality among the Onge tribe of the Andaman and Nicobar Islands
Authors: Rao VG , Sugunan AP , Murhekar MV , Sehgal SC
Published: February 2006

Objectives

A study was conducted among the Onge tribe of the Andaman and Nicobar Islands with the objectives of identifying demographic factors responsible for the decline in their population and assessing their nutritional status, which is an important determinant of child survival.

Study design and subjects

The study included estimation of indices of fertility and child mortality, and assessment of nutritional status. All individuals of the Onge community settled on Little Andaman Island were included.

Results

The mean total marital fertility rate was estimated to be 5.15 live births per woman and the general fertility rate was 200 live births per 1000 married-woman-years. Although the gross reproduction rate was estimated to be 2.2 female children per married woman, the net reproduction rate was only 0.9 surviving female child per married woman. The mean infant mortality rate during the past 30 years was 192.7 per 1000 live births, and the child survival rate was found to be only 53.2%. A mild to moderate degree of malnutrition was found in 85% of children of pre-school age and severe malnutrition in 10%. The Onges had low intakes of iron, vitamin A and vitamin C. All the screened Onges were found to be infested with one or more intestinal parasites.

Conclusions

High childhood mortality appears to be the predominant demographic factor responsible for the decline in the Onge population. The high prevalence of undernutrition and micronutrient deficiency disorders could be important factors contributing to the high childhood mortality.
Anaemia, iron status and vitamin A deficiency among adolescent refugees in Kenya and Nepal
Authors: Woodruff Bradley A , Blanck Heidi Michels , Slutsker Laurence , Cookson Susan T , Larson Mary Kay , Duffield Arabella , Bhatia Rita
Published: February 2006

Objective

To investigate the prevalence of anaemia (haemoglobin < 11.0 to 13.0 g dl−1depending on age and sex group), iron deficiency (transferrin receptor concentration > 8.3 μg ml−1) and vitamin A deficiency (serum retinol < 0.7 μmoll−1) in adolescent refugees.

Design

Cross-sectional surveys.

Setting

Kakuma refugee camp in Kenya and seven refugee camps in Nepal.

Subjects

Adolescent refugee residents in these camps.

Results

Anaemia was present in 46% (95% confidence interval (CI): 42–51) of adolescents in Kenya and in 24% (95% CI: 20–28) of adolescents in Nepal. The sensitivity of palmar pallor in detecting anaemia was 21%. In addition, 43% (95% CI: 36–50) and 53% (95% CI: 46–61) of adolescents in Kenya and Nepal, respectively, had iron deficiency. In both surveys, anaemia occurred more commonly among adolescents with iron deficiency. Vitamin A deficiency was found in 15% (95% CI: 10–20) of adolescents in Kenya and 30% (95% CI: 24–37) of adolescents in Nepal. Night blindness was not more common in adolescents with vitamin A deficiency than in those without vitamin A deficiency. In Kenya, one of the seven adolescents with Bitot's spots had vitamin A deficiency.

Conclusions

Anaemia, iron deficiency and vitamin A deficiency are common among adolescents in refugee populations. Such adolescents need to increase intakes of these nutrients; however, the lack of routine access makes programmes targeting adolescents difficult. Adolescent refugees should be considered for assessment along with other at-risk groups in displaced populations.
Serum ferritin, cardiovascular risk factors and ischaemic heart diseases: a prospective analysis in the SU.VI.MAX (SUpplementation en VItamines et Minéraux AntioXydants) cohort
Authors: Galan Pilar , Noisette Nathalie , Estaquio Carla , Czernichow Sebastien , Mennen Louise , Renversez Jean-Charles , Briançon Serge , Favier Alain , Hercberg Serge
Published: February 2006

Background

Iron has been suggested to play a role in the development of cardiovascular disease (CVD) through its pro-oxidant properties. However, epidemiological studies on iron status and the risk of CVD have yielded conflicting results. We therefore carried out a prospective study to evaluate the relationship between iron status and CVD in a middle-aged French population.

Methods

In total, 9917 subjects (3223 men aged 45–60 years and 6694 women aged 35–60 years) included in the SU.VI.MAX (SUpplementation en VItamines et Minéraux AntioXydants) cohort were followed prospectively for 7.5 years. All cases of ischaemic heart disease (IHD) were identified and validated. CVD risk factors, haemoglobin and serum ferritin concentrations were measured at baseline.

Findings

Of men 4.3%, and of women 37.8%, presented at baseline a serum ferritin concentration <30 μg l−1. During the follow-up, 187 subjects (148 men, 39 women) developed IHD. Serum ferritin was positively associated with total cholesterol, serum triglycerides, systolic and diastolic blood pressure, body mass index and haemoglobin. No linear association was found between serum ferritin and IHD risk in men or in women.

Conclusion

Our data do not support a major role of iron status in the development of IHD in a healthy general population.
Comparative evaluation of anthropometric measures to predict cardiovascular risk factors in Tehranian adult women
Authors: Esmaillzadeh Ahmad , Mirmiran Parvin , Azizi Fereidoun
Published: February 2006

Objective

To compare the ability of waist circumference (WC), body mass index (BMI), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) to predict cardiovascular risk factors in an urban adult population of Tehranian women.

Design

Population-based cross-sectional study.

Setting

Tehran, the capital of Iran.

Subjects

This study was conducted on 5073 women aged 18–74 years, participants of the Tehran Lipid and Glucose Study. Demographic data were collected. Anthropometric indices were measured according to standard protocols. Cut-off points of BMI, WC, WHR and WHtR were considered as 25 kg m−2, 80 cm, 0.8 and 0.5, respectively. Blood pressure was measured and hypertension was defined based on the sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Biochemical analyses were conducted on fasting blood samples. Diabetes was defined as fasting plasma glucose ≥126 mg dl−1or 2-hour plasma glucose ≥200 mg dl−1and dyslipidaemia based on the third report of the National Cholesterol Education Program Expert Panel. The presence of ‘at least one risk factor’ from the three major cardiovascular risk factors (hypertension, dyslipidaemia and diabetes) was also evaluated.

Results

Mean (±standard deviation) age of women was 39.9 ± 14.6 years; mean BMI, WC, WHR and WHtR were 27.1 ± 1.5 kg m−2, 86.5 ± 13.5 cm and 0.83 ± 0.08 and 0.55 ± 0.08, respectively. Of the four anthropometric measures, WC had the highest sensitivity and specificity to identify subjects with risk factors in both the 18–39 year and the 40–74 year age categories. WC was seen to have a higher percentage of correct prediction than BMI, WHR and WHtR.

Conclusion

It is concluded that WC is the best screening measure for cardiovascular risk factors, compared with BMI, WHR and WHtR, in Tehranian adult women.
A +TIP for a smooth trip
Authors: Xiang Xin
Published: February 2006

Is there a cellular mechanism for preventing a depolymerizing microtubule track from “slipping out from under” its cargo? A recent study in budding yeast indicates that when a chromosome is transported to the minus end of a spindle microtubule, its kinetochore-bound microtubule plus end–tracking protein (+TIP) Stu2 may move to the plus end to promote rescue; i.e., to switch the depolymerizing end to a polymerizing end. The possibility that other +TIPs may play a similar role in sustaining a microtubule track during vesicular transport deserves investigation.
The Vac14p–Fig4p complex acts independently of Vac7p and couples PI3,5P2 synthesis and turnover
Authors: Duex Jason E. , Tang Fusheng , Weisman Lois S.
Published: February 2006

Phosphoinositide-signaling lipids function in diverse cellular pathways. Dynamic changes in the levels of these signaling lipids regulate multiple processes. In particular, when Saccharomyces cerevisiae cells are exposed to hyperosmotic shock, PI3,5P2 (phosphatidylinositol [PI] 3,5-bisphosphate) levels transiently increase 20-fold. This causes the vacuole to undergo multiple acute changes. Control of PI3,5P2 levels occurs through regulation of both its synthesis and turnover. Synthesis is catalyzed by the PI3P 5-kinase Fab1p, and turnover is catalyzed by the PI3,5P2 5-phosphatase Fig4p. In this study, we show that two putative Fab1p activators, Vac7p and Vac14p, independently regulate Fab1p activity. Although Vac7p only regulates Fab1p, surprisingly, we find that Vac14 regulates both Fab1p and Fig4p. Moreover, Fig4p itself functions in both PI3,5P2 synthesis and turnover. In both the absence and presence of Vac7p, the Vac14p–Fig4p complex controls the hyperosmotic shock–induced increase in PI3,5P2 levels. These findings suggest that the dynamic changes in PI3,5P2 are controlled through a tight coupling of synthesis and turnover.
Cortistatin, a new antiinflammatory peptide with therapeutic effect on lethal endotoxemia
Authors: Gonzalez-Rey Elena , Chorny Alejo , Robledo Gema , Delgado Mario
Published: February 2006

Cortistatin is a recently discovered cyclic neuropeptide related to somatostatin that has emerged as a potential endogenous antiinflammatory factor based on its production by and binding to immune cells. Because human septic shock involves excessive inflammatory cytokine production, we investigated the effect of cortistatin on the production of inflammatory mediators and its therapeutic action in various murine models of endotoxemia. Cortistatin down-regulated the production of inflammatory mediators by endotoxin-activated macrophages. The administration of cortistatin protected against lethality after cecal ligation and puncture, or injection of bacterial endotoxin or Escherichia coli, and prevented the septic shock-associated histopathology, such as infiltration of inflammatory cells and intravascular disseminated coagulation in various target organs. The therapeutic effect of cortistatin was mediated by decreasing the local and systemic levels of a wide spectrum of inflammatory mediators, including cytokines, chemokines, and acute phase proteins. The combined use of cortistatin and other antiinflammatory peptides was very efficient treating murine septic shock. This work provides the first evidence of cortistatin as a new immunomodulatory factor with the capacity to deactivate the inflammatory response. Cortistatin represents a potential multistep therapeutic agent for human septic shock, to be used in combination with other immunomodulatory agents or as a complement to other therapies.
Immature monocytes acquire antigens from other cells in the bone marrow and present them to T cells after maturing in the periphery
Authors: Tacke Frank , Ginhoux Florent , Jakubzick Claudia , van Rooijen Nico , Merad Miriam , Randolph Gwendalyn J.
Published: February 2006

Monocytes are circulating precursors for tissue macrophages and dendritic cells (DCs) but are not recognized to directly participate in antigen presentation. We developed techniques to label mouse monocyte subsets with particulate tracers in vivo. Gr-1lo but not Gr-1hi monocytes were stably labeled by intravenous injection of 0.5-μm microspheres. Gr-1hi monocytes could be labeled when the microspheres were injected after systemic depletion of blood monocytes and spleen macrophages. In this condition, the phagocytic tracer was transferred to immature bone marrow monocytes by neutrophils and B cells that first carried the particles to the bone marrow. Moreover, antigens from B cells or proteins conjugated to the tracer particles were processed for presentation by monocytes and could induce T cell responses in the periphery. Cell-associated antigen taken up by bone marrow monocytes was retained intracellularly for presentation of the antigen days later when monocyte-derived DCs migrated to lymph nodes or in vitro after differentiation with granulocyte/macrophage colony-stimulating factor. These data reveal that immature monocytes unexpectedly sample antigen from the bone marrow environment and that they can present these antigens after they leave the bone marrow.
Factors Controlling Fibroblast Growth Factor Receptor-1's Cytoplasmic Trafficking and Its Regulation as Revealed by FRAP Analysis
Authors: Dunham-Ems Star M. , Pudavar Haridas E. , Myers Jason M. , Maher Pamela A. , Prasad Paras N. , Stachowiak Michal K.
Published: February 2006

Biochemical and microscopic studies have indicated that FGFR1 is a transmembrane and soluble protein present in the cytosol and nucleus. How FGFR1 enters the cytosol and subsequently the nucleus to control cell development and associated gene activities has become a compelling question. Analyses of protein synthesis, cytoplasmic subcompartmental distribution and movement of FGFR1-EGFP and FGFR1 mutants showed that FGFR1 exists as three separate populations (a) a newly synthesized, highly mobile, nonglycosylated, cytosolic receptor that is depleted by brefeldin A and resides outside the ER-Golgi lumen, (b) a slowly diffusing membrane receptor population, and (c) an immobile membrane pool increased by brefeldin A. RSK1 increases the highly mobile cytosolic FGFR1 population and its overall diffusion rate leading to increased FGFR1 nuclear accumulation, which coaccumulates with RSK1. A model is proposed in which newly synthesized FGFR1 can enter the (a) “nuclear pathway,” where the nonglycosylated receptor is extruded from the pre-Golgi producing highly mobile cytosolic receptor molecules that rapidly accumulate in the nucleus or (b) “membrane pathway,” in which FGFR1 is processed through the Golgi, where its movement is spatially restricted to trans-Golgi membranes with limited lateral mobility. Entrance into the nuclear pathway is favored by FGFR1's interaction with kinase active RSK1.
UNC-83 Is a KASH Protein Required for Nuclear Migration and Is Recruited to the Outer Nuclear Membrane by a Physical Interaction with the SUN Protein UNC-84
Authors: McGee Matthew D. , Rillo Regina , Anderson Amy S. , Starr Daniel A.
Published: February 2006

UNC-84 is required to localize UNC-83 to the nuclear envelope where it functions during nuclear migration. A KASH domain in UNC-83 was identified. KASH domains are conserved in the nuclear envelope proteins Syne/nesprins, Klarsicht, MSP-300, and ANC-1. Caenorhabditis elegans UNC-83 was shown to localize to the outer nuclear membrane and UNC-84 to the inner nuclear membrane in transfected mammalian cells, suggesting the KASH and SUN protein targeting mechanisms are conserved. Deletion of the KASH domain of UNC-83 blocked nuclear migration and localization to the C. elegans nuclear envelope. Some point mutations in the UNC-83 KASH domain disrupted nuclear migration, even if they localized normally. At least two separable portions of the C-terminal half of UNC-84 were found to interact with the UNC-83 KASH domain in a membrane-bound, split-ubiquitin yeast two-hybrid system. However, the SUN domain was essential for UNC-84 function and UNC-83 localization in vivo. These data support the model that KASH and SUN proteins bridge the nuclear envelope, connecting the nuclear lamina to cytoskeletal components. This mechanism seems conserved across eukaryotes and is the first proposed mechanism to target proteins specifically to the outer nuclear membrane.
The Slp4-a Linker Domain Controls Exocytosis through Interaction with Munc18-1·Syntaxin-1a Complex
Authors: Tsuboi Takashi , Fukuda Mitsunori
Published: February 2006

Synaptotagmin-like protein 4-a (Slp4-a)/granuphilin-a is specifically localized on dense-core vesicles in certain neuroendocrine cells and negatively controls dense-core vesicle exocytosis through specific interaction with Rab27A. However, the precise molecular mechanism of its inhibitory effect on exocytosis has never been elucidated and is still a matter of controversy. Here we show by deletion and chimeric analyses that the linker domain of Slp4-a interacts with the Munc18-1·syntaxin-1a complex by directly binding to Munc18-1 and that this interaction promotes docking of dense-core vesicles to the plasma membrane in PC12 cells. Despite increasing the number of plasma membrane docked vesicles, expression of Slp4-a strongly inhibited high-KCl–induced dense-core vesicle exocytosis. The inhibitory effect by Slp4-a is absolutely dependent on the linker domain of Slp4-a, because substitution of the linker domain of Slp4-a by that of Slp5 (the closest isoform of Slp4-a that cannot bind the Munc18-1·syntaxin-1a complex) completely abrogated the inhibitory effect. Our findings reveal a novel docking machinery for dense-core vesicle exocytosis: Slp4-a simultaneously interacts with Rab27A and Munc18-1 on the dense-core vesicle and with syntaxin-1a in the plasma membrane.
A “Holistic” Kinesin Phylogeny Reveals New Kinesin Families and Predicts Protein Functions
Authors: Wickstead Bill , Gull Keith
Published: February 2006

Kinesin superfamily proteins are ubiquitous to all eukaryotes and essential for several key cellular processes. With the establishment of genome sequence data for a substantial number of eukaryotes, it is now possible for the first time to analyze the complete kinesin repertoires of a diversity of organisms from most eukaryotic kingdoms. Such a “holistic” approach using 486 kinesin-like sequences from 19 eukaryotes and analyzed by Bayesian techniques, identifies three new kinesin families, two new phylum-specific groups, and unites two previously identified families. The paralogue distribution suggests that the eukaryotic cenancestor possessed nearly all kinesin families. However, multiple losses in individual lineages mean that no family is ubiquitous to all organisms and that the present day distribution reflects common biology more than it does common ancestry. In particular, the distribution of four families—Kinesin-2, -9, and the proposed new families Kinesin-16 and -17—correlates with the possession of cilia/flagella, and this can be used to predict a flagellar function for two new kinesin families. Finally, we present a set of hidden Markov models that can reliably place most new kinesin sequences into families, even when from an organism at a great evolutionary distance from those in the analysis.
Logic and Language
Authors: Stern David G.
Published: February 2006

An analysis of the sources of Wittgenstein’s picture theory — which include not only his moment of insight on reading a magazine story about the use of models in a traffic court, but also the work of Russell, Hertz, and Boltzmann — provides the basis for an exploration of Wittgenstein’s articulation of a pictorial conception of representation in his wartime notebooks and its crystallization in the Tractatus. A discussion of Wittgenstein’s later criticism of the picture theory and his notion of a “philosophical picture” illustrates the fundamental reversal in his transition to his later conception of philosophy: instead of taking literal pictures as a guide to the nature of meaning, he came to regard philosophical theories as akin to expressing an aesthetic preference for a certain style of representation. Wittgenstein’s treatment of factual language in the picture theory is related to his Tractarian approach to logical form, and the role of the show/say distinction in his early conception of logic and language. Particular attention is given to the difficulties generated by the idea that the conditions for the possibility of a given domain of discourse cannot be described in language, but must be shown by the form of words in question.
Diverse Tests on an Independent World
Authors: Trout J. D.
Published: February 2006

This chapter shows how the central epistemological notion of this book, population-guided estimation, makes contact with traditional epistemological categories. The persistent empiricist and others skeptical of theoretical progress in the social sciences and psychology deny the independence of diverse, converging tests. It is argued that different and relatively independent methods introduce errors into the data that are, roughly speaking, randomly distributed. In fact, those critical of the long-term reliability of diverse testing are committed to at least one of two implausible doctrines: (1) that the world conspires to keep information from us (and changes systematically to do so), or (2) that an adequate scientific methodology must empower the scientist to predict the future history of science. These two principles are incompatible with, respectively, the realist metaphysics and the naturalistic epistemology independently advanced in this book.
Personal Identity in African Metaphysics
Authors: Adeofe Leke
Published: February 2006

This essay explores the issues involved in determining what it means to be a person within the Yoruba metaphysical context. Yoruba thought is characterized as having tripartite conceptions of persons, and does not fall prey to criticisms that have plagued Western conceptions of persons. Variants of the continuity and persistence theories associated with Kant, Descartes, and Hume are discussed in light of Yoruba conceptions of persons. It is argued that Yoruba conceptual language provides an accurate conception of human existence that is sufficient for clarifying personal identity concerns within Western culture.
The Concept of the Person in Luo Modes of Thought
Authors: Masolo D. A.
Published: February 2006

This essay examines the concept of juok, found among the Southern (Kenya) and Central (Uganda) Luo. The implications of the concept for understanding what constitutes personhood, grounding the principles of moral discourse and judgement, and determining the principles of social geography in the Luo world are discussed. It is argued that the nature of personhood results from the interplay between the culturally objectified perceptions of persons and the subjectively apprehended aspects of social life through which individuals express their subjectivity in opposition or resistance to conventionally defined roles, rules, and regulations of the habitus.
An Engineer Dissects Two Case StudiesHayles on Fluid Mechanics and MacKenzie on Statistics Philip A. Sullivan
Authors: Sullivan Philip A.
Published: February 2006

Building on a discussion of the nature of scientific knowledge, it is argued that a convincing demonstration of the presence of social values in the content of such knowledge requires showing that it occurs in disciplines where the knowledge has become stable, or has a record of accurate prediction. Two studies of this type are reviewed: a feminist critique of fluid mechanics, and an analysis by an Edinburgh sociologist of a dispute in the early 20th-century development of statistics. Both studies are shown to be fatally flawed. The first is riddled with elementary technical errors, making its subsequent case for male bias meaningless. The second ignores fundamental mathematical questions at issue in the dispute, leading its author to cast about for implausible sociological explanations.
Evidence‐Free Forensics and Enemies of Objectivity Paul R. Gross
Authors: Gross Paul A.
Published: February 2006

Feminist philosopher Elizabeth A. Lloyd has contributed to the so-called science wars a lengthy book chapter attacking scientist-authors who have recently defended natural science from various indictments (e.g., sexism, racism, masculinism, militarism, imperialism) lodged against it in the field of “science studies”. Her main charge is that the named scientists, not those against whose charges they defend science, are the real enemies of objectivity. It is argued that her methods are old and well-known devices of propaganda; her conclusions are therefore nugatory.
Avoiding the Experimenters' Regress Allan Franklin
Authors: Franklin Allan
Published: February 2006

Harry Collins claims that there are no internal methods for evaluating the validity of scientific techniques. Experimental results are accepted only after a process of negotiation between parties with different non-epistemic interests. His account of Weber’s attempts to detect gravity waves is criticized.
Latour's Relativity John Huth
Authors: Huth John
Published: February 2006

Bruno Latour’s article on Einstein attempts to show that even physics is “social through and through”. This essay criticizes his relativistic account of Einstein’s theory of relativity, showing that Latour misunderstood the role of the observer in that theory.
Nativist Rebellions
Authors: Graziano Frank
Published: February 2006

This chapter analyzes how millennial, messianic, apocalyptic, and utopian ideas contributed to indigenous peoples’ response to conquest. The case material is diverse — from the preconquest Maya to current movements — with particular emphasis on the War of Mixtón, the Taqui Onqoy movement, the Pueblo Revolt, the Caste War of the Yucatan, and the eighteenth-century Andean rebellions (including those of Túpac Amaru II and Túpac Catari).
Monism in Spinoza
Authors: Carriero John
Published: February 2006

This essay explores Spinoza’s attitude towards the ontological status of finite corporeal things, i.e., finite bodies or, in the Cartesian context in which he is working, finite regions of res extensa. It argues that Spinoza’s monism, especially as it bears on the ontological status of finite bodies, should be understood as a response to revisions in the concept of matter wrought by Descartes’s science. The early exchange of letters between Henry Oldenburg and Spinoza is examined to defend this argument.
The Middle Spinoza
Authors: Huenemann Charles
Published: February 2006

This essay explores Spinoza’s early work, Metaphysical Thoughts, which was published as an appendix to his commentary on Descartes’s Principles of Philosophy. It discusses four topics that illustrate the difference between Metaphysical Thoughts and both Descartes’s philosophy and Spinoza’s later philosophy: (1) the identity of the will and intellect in God, (2) the necessity of all things, (3) God’s moral character, and (4) the relation of creatures to God. These topics shed light on some aspects of Spinoza’s mature philosophy.
Thought Experiments
Authors: Sorensen Roy A.
Published: February 2006

Can merely thinking about an imaginary situation provide evidence for how the world actually is — or how it ought to be? This book addresses this question with an analysis of a wide variety of thought experiments ranging from aesthetics to zoology. Presenting the first general theory of thought experiment, the book sets it within an evolutionary framework and integrates recent advances in experimental psychology and the history of science, with special emphasis on Ernst Mach and Thomas Kuhn. The book explores what thought experiments are, how they work, and what their virtues and vices are. In this view, philosophy differs from science in degree, but not in kind. For this reason, the book claims, it is possible to understand philosophical thought experiments by concentrating on their resemblance to scientific relatives. The book assesses the hazards of thought experiments and grants that there are interesting ways in which the method leads us astray, but attacks most scepticism about thought experiments as arbitrary. It maintains that they should be used — as they generally are — as part of a diversified portfolio of techniques, creating a network of cross-checks that make for impressive reliability.
Mach and Inner Cognitive Africa
Authors: Sorensen Roy A.
Published: February 2006

This chapter focuses on the views of Australian philosopher-physicist Ernst Mach, the earliest and most systematic writer on thought experiments (and, not coincidentally, mentor of the young Albert Einstein). It discusses Mach's response to the problem of informativeness. It then details the book's disagreements with Mach. It is argued that Mach's mistakes can be traced to his sensationalism and a one-sided diet of examples. His sensationalism led him to overemphasize the mentalistic aspects of thought experiment and to throw away tools needed to explain its genuinely a priori features. Perhaps because of this, Mach's attention gravitated toward thought experiments he could explain (natural science cases) and away from the recalcitrant normative examples (in aesthetics, ethics, logic, and mathematics). To get a complete account of thought experiments, we should reject sensationalism and consider how armchair inquiry works in general.
Kuhntradictions
Authors: Sorensen Roy A.
Published: February 2006

This chapter focuses on Thomas Kuhn's account of thought experiments. It begins with what Kuhn takes to be the smart talk about thought experiments. It then details Kuhn's amendments to this view and raises objections, most of which are directed against the notion of local incoherence. Finally, Kuhn's error is reconstructed in order to salvage the considerable insight that it contains.
Matter and Motion in the Metaphysical Foundations and the First Critique
Authors: Friedman Michael
Published: February 2006

This paper focuses on the relationship between the general metaphysics of the Critique of Pure Reason and the special metaphysics of the Metaphysical Foundations of Natural Science. Kant claims that what distinguishes the latter from the former is that the latter presupposes an empirical concept, namely the concept of matter, whereas the former does not. It is argued that the concept of matter is empirical not in any ordinary sense, but in the sense that it requires actual perceptible objects to be given. Only the system of contingently given, empirical objects of the solar system as described by Newtonian physics, satisfies this requirement. This interpretation suggests that “experience”, whose possibility Kant is exploring in the first Critique, is exclusively “scientific experience”, and that the task of theoretical philosophy thus lies primarily in understanding the conceptual presuppositions of scientific experience.
Kant's Dynamics
Authors: Warren Daniel
Published: February 2006

Kant contrasts dynamical and mechanistic approaches to physics, and rejects the latter. This paper attempts to connect this rejection to Kant’s views about a fundamental shift in the conception of matter’s basic properties, and in the explanatory projects in which they figure. It argues that for Kant, the mechanistic conception of impenetrability involves an attempt to characterize matter through its inner (nonrelational) properties. In this way, Kant’s rejection of the mechanistic conception is tied to considerations from the first Critique, namely, the critical doctrine that we cannot know things as they are in themselves.
Kant on Empirical Psychology
Authors: Sturm Thomas
Published: February 2006

This paper explains Kant’s views on the theory of matter as developed in the Dynamics chapter of his Metaphysical Foundations, and elaborates their background in the chemistry of the period. Kant’s general approach to matter theory unites Newtonian and Leibnizian motifs, and entails an intricate internal structure for matter involving a multiple overlap of material shells of different density. Kant’s chemical views derive from Stahlian chemistry and involve a noncorpuscularian account of chemical combination and a nonoperational conception of chemical elements.
We Children of the Enlightenment
Authors: Abbey Ruth
Published: February 2006

The works of the middle period are sometimes labeled positivist, and one of their distinguishing features is the praise they contain for science. In these works, Friedrich Nietzsche repeatedly expresses his admiration for science’s methods and procedures, and for the values and characteristics of its practitioners. As part of his vision of an enlightened future, Nietzsche looks forward to the generation of a new aristocracy. This chapter explores the tension in these writings between his ideas of an aristocracy of spirit and an aristocracy of birth. The significance of embodiment in each of these models of aristocracy is discussed, and a Nietzschean ethic of care of the self is adduced.
One Cannot Be Too Kind about Women
Authors: Abbey Ruth
Published: February 2006

Contrary to the common classification of Friedrich Nietzsche as a misogynist, the works of the middle period do not entirely denigrate or dismiss women. Nietzsche’s views on women at this time were more nuanced and less vitriolic than they became. The works of the middle period repeatedly measure women by the values constitutive of free-spirithood such as autonomy, intellectual strength, desire and ability to pursue the sort of scientific knowledge Nietzsche prizes, capacity for cruelty, and the skills of dialogue. This suggests that women can be considered as candidates for free spirithood, even if Nietzsche assumes that most females, like most males, will fail to meet its requirements. Rather than focus on the shaping power of biology, these writings point to the social and cultural forces that shape gender identity, allowing Nietzsche to adumbrate a non-essentialist approach to women and their potential.
The Political Critique
Authors: Alcoff Linda Martín
Published: February 2006

This chapter argues that there is yet a case to be made about the nature of identity and its political and epistemic implications. It is certainly not the case that the work we need to do is finished; there are numerous “authentic” problems of identity that need attending to, but we do not need to overcome identity as much as tounderstand it more deeply. An alternative account of identity is developed which will be used to show the inadequacy of the assumptions behind the critique of identity.