Product and process: New York's Model Cities vest-pocket housing and rehabilitation programme.

In January 1966, US President Lyndon Johnson proposed the Model Cities programme to 'improve the quality of urban life' in the nation's poorest areas through comprehensive action and citizen participation. That same month, John Lindsay became mayor of New York with a platform to create a more equitable city. Toward this end, Lindsay's administration rejected earlier urban renewal approaches, prioritizing infill construction on vacant sites and reusing existing buildings, all while including local communities in the planning process. Eugenia Flatow spearheaded this 'vest-pocket and rehabilitation programme' as a 'head start' to future Model Cities funding. As she commissioned Raymond & May, Walter Thabit, Jonas Vizbaras, and Fisher/Jackson with housing plans for Brooklyn, the Bronx, and Harlem, she was acutely aware of the resulting tension between a desired democratic process and the timely delivery of the product. A close reading of archival materials reveals how these planners responded in very different ways to the prompt. The governmental programme had created a space of possibility for rethinking the relationship of product and process in planning through the specificity of housing design. The plans also highlighted the paradox in attempting to effect socio-economic change through housing supply, one that still resonates today.

Characterization of the nuclear import of the human CHD4-NuRD complex.

Chromatin remodeling enzymes form large multiprotein complexes that play central roles in regulating access to the genome. Here, we characterize the nuclear import of the human CHD4 protein. We show that CHD4 enters the nucleus by means of several importin-α proteins (1, 5, 6 and 7), but independently of importin ß1. Importin α1 directly interacts with a monopartite 'KRKR'-motif in the N-terminus of CHD4 (amino acids 304-307). However, alanine mutagenesis of this motif only leads to an ∼50% reduction in nuclear localization of CHD4, implying that there are additional import mechanisms. Interestingly, we could show that CHD4 was already associated with the nucleosome remodeling deacetylase (NuRD) core subunits, such as MTA2, HDAC1 and RbAp46 (also known as RBBP7), in the cytoplasm, suggesting an assembly of the NuRD core complex before nuclear import. We propose that, in addition to the importin-α-dependent nuclear localization signal, CHD4 is dragged into the nucleus by a 'piggyback' mechanism using the import signals of the associated NuRD subunits.

Disease outbreaks select for mate choice and coat color in wolves.

We know much about pathogen evolution and the emergence of new disease strains, but less about host resistance and how it is signaled to other individuals and subsequently maintained. The cline in frequency of black-coated wolves (Canis lupus) across North America is hypothesized to result from a relationship with canine distemper virus (CDV) outbreaks. We tested this hypothesis using cross-sectional data from wolf populations across North America that vary in the prevalence of CDV and the allele that makes coats black, longitudinal data from Yellowstone National Park, and modeling. We found that the frequency of CDV outbreaks generates fluctuating selection that results in heterozygote advantage that in turn affects the frequency of the black allele, optimal mating behavior, and black wolf cline across the continent.

Between-group attack and defence in an ecological setting: Insights from nonhuman animals.

Attempts to understand the fundamental forces shaping conflict between attacking and defending groups can be hampered by a narrow focus on humans and reductionist, oversimplified modelling. Further progress depends on recognising the striking parallels in between-group conflict across the animal kingdom, harnessing the power of experimental tests in nonhuman species and modelling the eco-evolutionary feedbacks that drive attack and defence.

Septin 9 isoform 1 (SEPT9_i1) specifically interacts with importin-α7 to drive hypoxia-inducible factor (HIF)-1α nuclear translocation.

We have shown previously that septin 9 isoform 1 (SEPT9_i1) protein associates with hypoxia-inducible factor (HIF)-1α to augment HIF-1 transcriptional activity by driving its importin-α-mediated nuclear translocation. Using in vitro and in vivo binding assays we identified that HIF-1α interacts with importin-α5 and importin-α7 in prostate cancer cells but only importin-α7 interacts with SEPT9_i1. The interaction with importin-α7 was dependent on the first 25 amino acids of SEPT9_i1 that are unique compared to other members of the mammalian septin family. Depletion of endogenous importin-α7 reduced HIF-1α levels in the nucleus. Our results provide evidence that there are importin-α specificities in the cytosolic/nuclear translocation process of HIF-1α protein, which may act differently under certain pathophysiological circumstances where SEPT9_i1 is overexpressed.

Factors influencing within-group conflict over defence against conspecific outsiders seeking breeding positions.

In social species, groups face a variety of threats from conspecific outsiders. Defensive actions are therefore common, but there is considerable variation in which individuals contribute and to what extent. There has been some theoretical exploration of this variation when the defence is of shared resources, but the relative contributions when a single intruder threatens a particular breeding position have received less attention. Defensive actions are costly, both for the individual and dependent young, and contributions are likely to differ depending on individual sex, rank and size, current breeding stage, infanticide risk and relatedness levels. Here, we model analytically the relative fitness benefits of different group members to engaging in defence against individual intruders and determine when within-group conflicts of interest might arise over these defensive contributions. Conflicts of interest between the challenged breeder and other group members depend on relatedness to the brood and the potential relatedness reduction if an intruder acquires breeding status. Conflicts are more likely to occur when there is a low chance of winning the contest, low infanticide rates, inefficient defence from helpers, a long remaining brood-dependency period and high external (non-contest-related) mortality. Our work can help explain variation in defensive actions against out-group threats.

Sex-Specific Heterogeneity in Fixed Morphological Traits Influences Individual Fitness in a Monogamous Bird Population.

Theoretical work has emphasized the important role of individual traits on population dynamics, but empirical models are often based on average or stage-dependent demographic rates. In this study on a monogamous bird, the Eurasian hoopoe (Upupa epops), we show how the interactions between male and female fixed and dynamic heterogeneity influence demographic rates and population dynamics. We built an integral projection model including individual sex, age, condition (reflecting dynamic heterogeneity), and fixed morphology (reflecting fixed heterogeneity). Fixed morphology was derived from a principal component analysis of six morphological traits. Our results revealed that reproductive success and survival were linked to fixed heterogeneity, whereas dynamic heterogeneity influenced mainly the timing of reproduction. Fixed heterogeneity had major consequences for the population growth rate, but interestingly, its effect on population dynamics differed between the sexes. Female fixed morphology was directly linked to annual reproductive success, whereas male fixed morphology also influenced annual survival, being twice higher in large than in small males. Even in a monogamous bird with shared parental care, large males can reach 10% higher fitness than females. Including the dynamics of male and female individual traits in population models refines our understanding of the individual mechanisms that influence demographic rates and population dynamics and can help in identifying differences in sex-specific strategies.

Modeling Adaptive and Nonadaptive Responses of Populations to Environmental Change.

Understanding how the natural world will be impacted by environmental change over the coming decades is one of the most pressing challenges facing humanity. Addressing this challenge is difficult because environmental change can generate both population-level plastic and evolutionary responses, with plastic responses being either adaptive or nonadaptive. We develop an approach that links quantitative genetic theory with data-driven structured models to allow prediction of population responses to environmental change via plasticity and adaptive evolution. After introducing general new theory, we construct a number of example models to demonstrate that evolutionary responses to environmental change over the short-term will be considerably slower than plastic responses and that the rate of adaptive evolution to a new environment depends on whether plastic responses are adaptive or nonadaptive. Parameterization of the models we develop requires information on genetic and phenotypic variation and demography that will not always be available, meaning that simpler models will often be required to predict responses to environmental change. We consequently develop a method to examine whether the full machinery of the evolutionarily explicit models we develop will be needed to predict responses to environmental change or whether simpler nonevolutionary models that are now widely constructed may be sufficient.

Sex-specific demography and generalization of the Trivers-Willard theory.

The Trivers-Willard theory proposes that the sex ratio of offspring should vary with maternal condition when it has sex-specific influences on offspring fitness. In particular, mothers in good condition in polygynous and dimorphic species are predicted to produce an excess of sons, whereas mothers in poor condition should do the opposite. Despite the elegance of the theory, support for it has been limited. Here we extend and generalize the Trivers-Willard theory to explain the disparity between predictions and observations of offspring sex ratio. In polygynous species, males typically have higher mortality rates, different age-specific reproductive schedules and more risk-prone life history tactics than females; however, these differences are not currently incorporated into the Trivers-Willard theory. Using two-sex models parameterized with data from free-living mammal populations with contrasting levels of sex differences in demography, we demonstrate how sex differences in life history traits over the entire lifespan can lead to a wide range of sex allocation tactics, and show that correlations between maternal condition and offspring sex ratio alone are insufficient to conclude that mothers adaptively adjust offspring sex ratio.

Demography, not inheritance, drives phenotypic change in hunted bighorn sheep.

Selective harvest, such as trophy hunting, can shift the distribution of a quantitative character such as body size. If the targeted character is heritable, then there will be an evolutionary response to selection, and where the trait is not, then any response will be plastic or demographic. Identifying the relative contributions of these different mechanisms is a major challenge in wildlife conservation. New mathematical approaches can provide insight not previously available. Here we develop a size- and age-based two-sex integral projection model based on individual-based data from a long-term study of hunted bighorn sheep (Ovis canadensis) at Ram Mountain, Canada. We simulate the effect of trophy hunting on body size and find that the inheritance of body mass is weak and that any perceived decline in body mass of the bighorn population is largely attributable to demographic change and environmental factors. To our knowledge, this work provides the first use of two-sex integral projection models to investigate the potential eco-evolutionary consequences of selective harvest.

The influence of nonrandom mating on population growth.

When nonrandom mating alters offspring numbers or the distribution of offspring phenotypes, it has the potential to impact the population growth rate. Similarly, sex-specific demographic parameters that influence the availability of mating partners can leave a signature on the population growth rate. We develop a general framework to explore how mating patterns and sex differences influence the population growth rate. We do this by constructing a two-sex integral projection model to explore ways in which altering the mating behavior from random to nonrandom mating (assortative, disassortative, or selection for size) and altering demographic parameters in one or both sexes (growth, survival, and parental contribution to offspring phenotype) affect the population growth rate. We demonstrate our framework using data from a population of Columbian ground squirrels. Our results suggest that the population growth rate is substantially affected when nonrandom mating is linked to sex differences in demographic parameters or parental contributions to offspring phenotype, but interestingly, the effect of the mating pattern alone is rather small. Our results also suggest that the population growth rate of Columbian ground squirrels would increase with the degree of disassortative mating and with the degree of the mating advantage of large individuals.

Preferring the fittest mates: an analytically tractable model.

We develop an analytically tractable model of female preference for fit mates. Our population-genetic model allows to trace the dynamics at both the individual and the population level. The preference for fit mates links ecological adaptation and mating success is individually advantageous and causes polymorphic subpopulations. This polymorphism is a strong and stable clustering in genotype and phenotype space. The alleles coding for the mating preference spread rapidly through the population, thereby increasing the selection pressure between different habitats. The resulting polymorphism exceeds the expected selection-migration equilibrium by several orders of magnitude. The evolution of preference for fit mates can, thus, act as the trigger for parapatric speciation because it initiates prezygotic isolation and divergence.

Linking the population growth rate and the age-at-death distribution.

The population growth rate is linked to the distribution of age at death. We demonstrate that this link arises because both the birth and death rates depend on the variance of age-at-death. This bears the prospect to separate the influences of the age patterns of fertility and mortality on population growth rate. Here, we show how the age pattern of death affects population growth. Using this insight we derive a new approximation of the population growth rate that uses the first and second moments of the age-at-death distribution. We apply our new approximation to 46 mammalian life tables (including humans) and show that it is on par with the most prominent other approximations.

SMAC-expression in denervated human skeletal muscle as a potential inhibitor of coexpressed inhibitor-of-apoptosis proteins.

In multinucleated skeletal muscle fibers, apoptotic muscle fiber loss is mediated by a consecutive disassembly of single fiber segments. During this period of time, proapoptotic and antiapoptotic factors compete for promotion or inhibition of apoptotic fiber degradation. In 16 patients with a neurogenic muscular atrophy, we studied the immunohistochemical expression of the inhibitor-of-apoptosis proteins (IAP) survivin, cIAP1, and XIAP and also of second mitochondria-derived activator of caspase (SMAC), which is released during apoptosis and binds to IAPs to prevent them from inhibiting caspases. Although normal control muscle fibers show no expression of SMAC and IAPs, there was a distinct sarcoplasmic expression of SMAC (12.0%+/-3.5%), survivin (10.2%+/-4.0%), cIAP1 (9.0%+/-3.1%), and XIAP (11.0%+/-4.6%) in varying numbers of muscle fibers in neurogenic muscular atrophy. Coexpression of SMAC and IAPs varied. Some denervated muscle fibers displayed up-regulation of either SMAC or IAPs. Other groups of atrophic muscle fibers showed coexpression of SMAC and IAPs. All factors were exclusively up-regulated in atrophic muscle fibers. These findings indicate that IAPs may inhibit apoptotic degradation of denervated muscle fibers. However, IAPs are finally insufficient to counterbalance and prevent muscle fiber apoptosis, as up-regulated expression of SMAC can antagonize this antiapoptotic potential and promote apoptotic muscle fiber disassembly and loss. The interplay between IAPs and SMAC may represent a threshold for muscle fiber-degrading caspase activities. If this bears a therapeutic potential in the prevention of loss of denervated muscle fibers, it remains highly speculative.

Expression of extracellular matrix-degrading proteins in classic, atypical, and anaplastic meningiomas.

Although the majority of meningiomas, commonly benign tumors (WHO I), are amenable to surgical resection, a percentage of up to 3% will recur as higher-grade meningiomas with potential brain invasion. Our study aims at the in situ identification of proteolytic, extracellular matrix-degrading enzymes in a broad spectrum of meningiomas. We examined 80 meningiomas (50 classic meningiomas WHO I, 19 meningiomas WHO II, including atypical, chordoid, and clear cell types, as well as 11 anaplastic meningiomas WHO III) for the immunohistochemical expression patterns of cathepsin D and metalloproteinases MMP-2 and MMP-9. Meningiomas of all types and grades revealed a distinct expression of MMP-9 and cathepsin D, while MMP-2 was found predominantly in WHO II and III meningiomas. There was a significant increase in positive tumor cells from WHO grade I to II and III for MMP-2 (p<0.001), but not for cathepsin D (p=0.099). MMP-9 displayed an increased number of positive tumor cells from WHO grade I to II, but a decrease in WHO III meningiomas (p<0.002). Routine screening for the expression of metalloproteinases and cathepsin D will not reveal any new diagnostically or prognostically relevant information. However, these factors may represent a potential target for pharmacological blocking as an anti-invasive therapy.

Expression patterns of initiator and effector caspases in denervated human skeletal muscle.

There is evidence that apoptotic cell death contributes to the loss of denervated muscle fibers. In 17 patients with neurogenic muscular atrophy, we studied the expression of the apoptosis mediators APAF-1/caspase-9 and degrading caspases-2, -3, and -7 by immunohistochemical and western blot analyses. Muscle with neurogenic atrophy showed distinct upregulation of caspase-9 and -7 and no expression for APAF-1 (apoptosis protease-activating factor-1) and caspase-2 and -3. Expression of caspase-7 was restricted to atrophic fibers, but caspase-9 was also found in normal-sized muscle fibers where its expression was often confined to single fiber segments. These findings indicate that upregulated expression of caspase-9 can initiate the proteolytic cascade involving the downstream executioner caspase-7, which mediates degradation of denervated muscle fibers. However, apoptotic events may be restricted to single muscle-fiber segments, where apoptotic cell degradation contributes to the long-term process of atrophy. Pharmacological inhibition of caspases may be a therapeutic strategy in diminishing muscle atrophy.

Role of biliary brush cytology in primary sclerosing cholangitis.

OBJECTIVE: To assess the role of brush cytology in the routine evaluation of patients with primary sclerosing cholangitis (PSC). STUDY DESIGN: From January 1995 to June 2000, 64 brush cytology specimens were obtained from 21 patients who had at least one cytologic sample obtained during endoscopic retrograde cholangiography. All patients had a diagnosis of primary sclerosing cholangitis. Cases were classified as benign, atypical or malignant according to major cytologic criteria (nuclear contour and chromatin irregularities) and minor cytologic criteria (polarity, cellularity, nuclear enlargement, mitosis, increased nuclear/cytoplasmic ratio) used by us to diagnose biliary brush cytology. Follow-up was available in all cases. RESULTS: Diagnoses were benign (13), atypical (5) and malignant (3) on cytology. Follow-up of the 13 benign cases showed bile duct stones (2), gallbladder adenocarcinoma at cholecystectomy (1), ascending cholangitis (1) and clinically/cytologically by benign follow-up (9). Five of 13 benign cases had subsequent liver transplantation for liver failure, with explants showing changes of primary sclerosing cholangitis. Of the 3 malignant cases, 1 had carcinoma in situ on biopsy, with the explanted liver showing high grade dysplasia; the second patient had cholangiocarcinoma on explant; and the third had hepatocellular carcinoma on liver five needle aspiration. The 5 patients with atypical cytology were reclassified on review as reactive (3) and atypical not otherwise specified (2). Follow-up showed benign disease in 3 of 3 atypical cases reclassified as reactive; 2 of 2 reclassified as atypical not otherwise specified showed low grade dysplasia in the explant. CONCLUSION: The overall incidence of malignancy was low (3 of 21) in patients with PSC. Bile duct brushing is a sensitive method of detecting neoplasia in the setting of PSC when well-defined cytologic criteria are applied.

Reclassification of "atypical" diagnoses in endoscopic retrograde cholangiopancreaticography-guided biliary brushings.

OBJECTIVE: To evaluate the usefulness of reclassifying "atypical" diagnoses in reporting biliary cytology using strict morphologic criteria. STUDY DESIGN: Cytologic specimens from 139 patients (direct, alcohol-fixed smears or cytocentrifuge preparations) were evaluated. Diagnoses were benign (70), atypical (36) and malignant (33). Using strict criteria--major (nuclear contour, chromatin pattern) and minor (polarity, cell types, nuclear size, nuclear grooves, nucleoli, mitosis, nuclear/cytoplasmic [N/C] ratio)--atypical cases were reevaluated and reclassified. Follow-up (F/U) was available on all cases. RESULTS: Atypical cases, (36) were reclassified as malignant (26), atypical favor benign (2)/reactive (3) and atypical, not otherwise specified (NOS) (5). Cases reclassified as malignant showed irregular nuclear contours, chromatin irregularities and rare mitosis. Nuclear enlargement, nucleoli and cellularity varied widely in all groups. N/C ratio was increased in most reclassified malignant cases. All 26 malignant reclassifications correlated with F/U of malignancy. Benign and reactive cases (5) were negative for malignancy on F/U (4), and in 1 case a metastatic carcinoma involving the biliary tree was found. In the 5 atypical (NOS) cases, F/U showed malignancy (3) and pancreatitis (2). Cytocentrifuge preparations made in our laboratory were of superior quality when compared to other methods of cell preparation. CONCLUSION: Irregularities in nuclear membrane and abnormal chromatin pattern were the most consistently useful features correlating with malignancy. The sensitivity and specificity of biliary brush cytology can be enhanced by using strict cytomorphologic criteria and proper collection and fixation, all of which decrease atypical diagnoses.

Expression of cytokeratin 20 in mucinous bronchioloalveolar carcinoma.

Mucinous bronchioloalveolar carcinomas (BACs) can closely mimic metastatic adenocarcinoma to the lung both clinically and morphologically. Several studies have demonstrated that the differential expression of cytokeratin 7 (CK7) and cytokeratin 20 (CK20) is a valuable diagnostic tool in differentiating primary pulmonary adenocarcinomas (PPAs) (usually CK7 positive/CK20 negative) from metastatic colonic adenocarcinoma (usually CK7 negative/CK20 positive). The present study is designed to correlate the histologic subtypes of PPA with expression of 7 and 20. A total of 113 cases of bonafide PPA were selected and classified according to the 1999 World Health Organization criteria as adenocarcinoma, NOS (n = 80), nonmucinous BAC (n = 14), and mucinous BAC (n = 19). Representive sections of all the tumors were immunohistochemically analyzed for CK7 and CK20 expression. To evaluate the diagnostic utility of CK7 and CK20 expression, 6 cases of colonic adenocarcinoma metastatic to the lung were tested with the same antibodies and compared with mucinous BAC. Results were expressed in a semiquantitative fashion based on the percentage of positive tumor cells: <10%, focal; 10% to 25%, 1+; 26% to 75%, 2+; > or =76%, 3+. All 113 PPAs exhibited strong, diffuse CK7 expression. With respect to CK20 expression, 17 of the 19 cases (89.4%) of mucinous BAC showed moderate to strong expression of this protein, whereas only 10 cases of conventional adenocarcinomas and 4 cases of nonmucinous BAC exhibited expression. All 6 examples of metastatic colonic adenocarcinomas were negative for CK7 and strongly positive for CK20. In summary, mucinous BAC is distinct from other PPAs by virtue of its CK20 expression. Although the CK7/CK20 immunoprofile is a valuable diagnostic marker for differentiating primary lung adenocarcinoma from metastatic colonic adenocarcinoma, caution should be exercised when dealing with mucinous BAC.