Regulation of cell signaling dynamics by the protein kinase-scaffold Ste5.

Cell differentiation requires the ability to detect and respond appropriately to a variety of extracellular signals. Here we investigate a differentiation switch induced by changes in the concentration of a single stimulus. Yeast cells exposed to high doses of mating pheromone undergo cell division arrest. Cells at intermediate doses become elongated and divide in the direction of a pheromone gradient (chemotropic growth). Either of the pheromone-responsive MAP kinases, Fus3 and Kss1, promotes cell elongation, but only Fus3 promotes chemotropic growth. Whereas Kss1 is activated rapidly and with a graded dose-response profile, Fus3 is activated slowly and exhibits a steeper dose-response relationship (ultrasensitivity). Fus3 activity requires the scaffold protein Ste5; when binding to Ste5 is abrogated, Fus3 behaves like Kss1, and the cells no longer respond to a gradient or mate efficiently with distant partners. We propose that scaffold proteins serve to modulate the temporal and dose-response behavior of the MAP kinase.

Metabolic gene regulation in a dynamically changing environment.

Natural selection dictates that cells constantly adapt to dynamically changing environments in a context-dependent manner. Gene-regulatory networks often mediate the cellular response to perturbation, and an understanding of cellular adaptation will require experimental approaches aimed at subjecting cells to a dynamic environment that mimics their natural habitat. Here we monitor the response of Saccharomyces cerevisiae metabolic gene regulation to periodic changes in the external carbon source by using a microfluidic platform that allows precise, dynamic control over environmental conditions. We show that the metabolic system acts as a low-pass filter that reliably responds to a slowly changing environment, while effectively ignoring fast fluctuations. The sensitive low-frequency response was significantly faster than in predictions arising from our computational modelling, and this discrepancy was resolved by the discovery that two key galactose transcripts possess half-lives that depend on the carbon source. Finally, to explore how induction characteristics affect frequency response, we compare two S. cerevisiae strains and show that they have the same frequency response despite having markedly different induction properties. This suggests that although certain characteristics of the complex networks may differ when probed in a static environment, the system has been optimized for a robust response to a dynamically changing environment.

A non-invasive method for concurrent detection of early-stage women-specific cancers.

We integrated untargeted serum metabolomics using high-resolution mass spectrometry with data analysis using machine learning algorithms to accurately detect early stages of the women specific cancers of breast, endometrium, cervix, and ovary across diverse age-groups and ethnicities. A two-step approach was employed wherein cancer-positive samples were first identified as a group. A second multi-class algorithm then helped to distinguish between the individual cancers of the group. The approach yielded high detection sensitivity and specificity, highlighting its utility for the development of multi-cancer detection tests especially for early-stage cancers.

An epidemiological study of blood pressure and lipid levels among Marwaris of Calcutta, India.

This population based study was conducted among the Marwaris of Calcutta, India. A total of 1,096 individuals from 151 randomly selected families were studied. Mean blood pressures were high. About 17% of the population was hypertensive, i.e., systolic blood pressure > 160 mm Hg and/or diastolic blood pressure > 95 mm Hg. The mean value of the ratio of total cholesterol to HDL cholesterol was 4.75. Comparison with a rural agricultural population showed that unadjusted blood pressure profiles differed significantly, but not when the profiles were adjusted for variation in concomitants (e.g., age, weight, fatness, etc.). It is hypothesized that the "intrinsic" blood pressure profiles of both populations are similar and that genes influencing physical variables (e.g., fatness) do not directly influence blood pressure. © 1994 Wiley-Liss, Inc.

Fine-needle aspiration cytology in tuberculous lymphadenitis of patients with and without HIV infection.

A study of the cytologic features and role of fine-needle aspiration cytology (FNAC) in tuberculous lymphadenitis (TBL) of 21 patients with HIV (group 1) and 21 patients without HIV (group 2) infection was undertaken. Four cytologic patterns were observed, of which necrotizing lymphadenitis (42.9%) and necrotizing suppurative lymphadenitis (28.6%) were predominant in group 1 while necrotizing granulomatous lymphadenitis (47.7%) and granulomatous lymphadenitis (23.8%) were more common in group 2. No pattern was found specific for either group. Zeihl-Neelsen-stained cytology smears of group 1 showed a much higher percentage of positively (61.9%) and a higher density of acid-fast bacilli than group 2. Definitive diagnoses of TBL on FNAC could be provided in 61.9% of group 1 as against 9.5% of group 2. The need for culture or biopsy for definitive diagnosis was higher in group 2. In suspected TBL, diagnostic efficacy can be improved and the need for surgical biopsy reduced if material collected on FNA is also used for culture.

Fine-needle aspiration cytology in lymphadenopathy of HIV-positive patients.

Fine-needle aspiration cytology (FNAC) of 32 HIV-positive cases presenting with lymphadenopathy was performed to evaluate its role in this group of patients. For each case air-dried smears were stained with Leishman, hematoxylin and eosin, and Zeihl-Neelsen stains for acid fast bacilli (AFB). The results were tuberculous (TB) lymphadenopathy (15), reactive lymphadenopathy (10), acute lymphadenitis/abscess (5), and suspected malignancy (2). In seven cases of TB lymphadenitis findings were suggestive of TB since no AFB was demonstrable on the cytology smears. In TB lymphadenitis, two additional patterns besides necrotising granulomatous (4) and granulomatous (2) were observed. These were necrotising (6) and necrotising suppurative (3) patterns. FNAC is a simple, inexpensive, rapid investigative procedure which can reduce surgical excisions and provide definite guidelines about further management.

Primary squamous cell carcinoma of the ovary in a young patient. A case report.

A case report of a squamous cell carcinoma arising in a dermoid cyst of the ovary in a 29 year old patient is presented. Such an occurrence in young patients is unusual.

Unusual mesenchymal tumour of uterus--a case report with immunohistochemical findings.

This is a case report of a mesenchymal tumor of uterus in a 60 year female initially interpreted as myxoid leiomyosarcoma. Immunohistochemical studies were negative for smooth muscle actin, desmin and p53 but positive for S-100 protein. The tumor was therefore reclassified as a low grade malignant mesenchymal tumor of neural origin.

Yeast dynamically modify their environment to achieve better mating efficiency.

The maintenance and detection of signaling gradients are critical for proper development and cell migration. In single-cell organisms, gradient detection allows cells to orient toward a distant mating partner or nutrient source. Budding yeast expand their growth toward mating pheromone gradients through a process known as chemotropic growth. MATα cells secrete α-factor pheromone that stimulates chemotropism and mating differentiation in MATa cells and vice versa. Paradoxically, MATa cells secrete Bar1, a protease that degrades α-factor and that attenuates the mating response, yet is also required for efficient mating. We observed that MATa cells avoid each other during chemotropic growth. To explore this behavior, we developed a computational platform to simulate chemotropic growth. Our simulations indicated that the release of Bar1 enabled individual MATa cells to act as α-factor sinks. The simulations suggested that the resultant local reshaping of pheromone concentration created gradients that were directed away from neighboring MATa cells (self-avoidance) and that were increasingly amplified toward partners of the opposite sex during elongation. The behavior of Bar1-deficient cells in gradient chambers and mating assays supported these predictions from the simulations. Thus, budding yeast dynamically remodel their environment to ensure productive responses to an external stimulus and avoid nonproductive cell-cell interactions.

Unusual mesenchymal tumour of uterus--a case report with immunohistochemical findings.

This is a case report of a mesenchymal tumor of uterus in a 60 year female initially interpreted as myxoid leiomyosarcoma. Immunohistochemical studies were negative for smooth muscle actin, desmin and p53 but positive for S-100 protein. The tumor was therefore reclassified as a low grade malignant mesenchymal tumor of neural origin.

Primary squamous cell carcinoma of the ovary in a young patient. A case report.

A case report of a squamous cell carcinoma arising in a dermoid cyst of the ovary in a 29 year old patient is presented. Such an occurrence in young patients is unusual.