Disruption of ergosterol biosynthesis,growth, and the morphological transition in <Emphasis Type="Italic">Candida albicans</Emphasis> by sterol methyltransferase inhibitors containing sulfur at C-25 in the sterol side chain

The sterol substrate analog 25-thialanosterol and its corresponding sulfonium salt were evaluated for their ability to serve as antifungal agents and to inhibit sterol methyltransferase (SMT) activity in Candida albicans. Both compounds inhibited cell proliferation, were fungistatic, interrupted the yeastlike-form to germ-tube-form transition, and resulted in the accumulation of zymosterol and related Δ²⁴-sterols concurrent with a decrease in ergosterol, as was expected for the specific inhibition of SMT activity. Feedback on sterol synthesis was evidenced by elevated levels of cellular sterols in treated vs. control cultures. However, neither farnesol nor squalene accumulated in significant amounts in treated cultures, suggesting that carbon flux is channeled from the isoprenoid pathway to the sterol pathway with minor interruption or redirection until blockage at the C-methylation step. Activity assays using solubilized C. albicans SMT confirmed the inhibitors impair SMT action. Kinetic analysis indicated that 25-thialanosterol inhibited SMT with the properties of a time-dependent mechanismbased inactivator K _i of 5 =gmM and apparent k _inact of 0.013 min⁻¹, whereas the corresponding sulfonium salt was a reversible-type transition state analog exhibiting a K _i of 20 nM. The results are interpreted to imply changes in ergosterol homeostasis as influenced by SMT activity can control growth and the morphological transition in C. albicans, possibly affecting disease development.     

Reports of the DAS02 working groups

This document is a collection of four working group reports in the areas of digital libraries, document image retrieval, layout analysis, and Web document analysis. These reports were the outcome of discussions by participants at the Fifth IAPR International Workshop on Document Analysis Systems held in Princeton, NJ on 19-21 August 2002.Published online: 16 March 2004     

Reproductive sequelae in female rats after in utero and neonatal exposure to the phytoestrogen genistein

OBJECTIVE: To determine reproductive sequelae in female rats after in utero and lactational dietary exposure to genistein. DESIGN: Experimental animal study. SETTING: University laboratory. ANIMAL(S): Sprague Dawley rats. INTERVENTION(S): Pregnant rats were fed control rat chow or rat chow incorporated with genistein (approximately 50 microg/d) beginning on day 17 of gestation and continuing until the end of lactation (postpartum day 21). Genistein-exposed female pups were divided into two groups on day 21. One group continued to receive a genistein-added diet (G70); the other group was changed to a control diet (Ex-G). At necropsy (days 21 and 70), blood and reproductive tissues were collected. MAIN OUTCOME MEASURE(S): Serum levels of gonadotropins and gonadal steroids and histopathologic examination of the ovaries. RESULT(S): The weight of the ovaries and uterus and serum levels of E2 and progesterone in genistein-exposed rats on day 21 (G21) were significantly reduced compared with control rats. On day 70, serum levels of E2, progesterone, LH, and FSH were similar in all groups. Atretic follicles and secondary interstitial glands were more common in G70 and Ex-G rats compared with control rats. Cystic rete ovarii was observed in some G70 and Ex-G rats. CONCLUSION(S): Our data indicate that in utero and lactational exposure to dietary genistein adversely affects reproductive processes in the adult female rat.     

5-GHz 32-bit integer execution core in 130-nm dual-V/sub T/ CMOS

A 32-bit integer execution core containing a Han-Carlson arithmetic-logic unit (ALU), an 8-entry /spl times/ 2 ALU instruction scheduler loop and a 32-entry /spl times/ 32-bit register file is described. In a 130 nm six-metal, dual-V/sub T/ CMOS technology, the 2.3 mm/sup 2/ prototype contains 160 K transistors. Measurements demonstrate capability for 5-GHz single-cycle integer execution at 25/spl deg/C. The single-ended, leakage-tolerant dynamic scheme used in the ALU and scheduler enables up to 9-wide ORs with 23% critical path speed improvement and 40% active leakage power reduction when compared to a conventional Kogge-Stone implementation. On-chip body-bias circuits provide additional performance improvement or leakage tolerance. Stack node preconditioning improves ALU performance by 10%. At 5 GHz, ALU power is 95 mW at 0.95 V and the register file consumes 172 mW at 1.37 V. The ALU performance is scalable to 6.5 GHz at 1.1 V and to 10 GHz at 1.7 V, 25/spl deg/C.     

Style context with second-order statistics

Patterns often occur as homogeneous groups or fields generated by the same source. In multisource recognition problems, such isogeny induces statistical dependencies between patterns (termed style context). We model these dependencies by second-order statistics and formulate the optimal classifier for normally distributed styles. We show that model parameters estimated only from pairs of classes suffice to train classifiers for any test field length. Although computationally expensive, the style-conscious classifier reduces the field error rate by up to 20 percent on quadruples of handwritten digits from standard NIST data sets.     

Feature extraction from optimization samples via ensemble based symbolic regression

We demonstrate a means of knowledge discovery through feature extraction that exploits the search history of a search-based optimization run. We regress a symbolic model ensemble from optimization run search points and their objective scores. The frequency of a variable in the models of the ensemble indicates to what the extent it is an influential feature. Our demonstration uses a genetic programming symbolic regression software package that is designed to be “off-the-shelf”. By default, the only parameter needed in order to evolve a suite of models is how long the user is willing to wait. Then the user can easily specify which models should go forward in terms of sufficient accuracy and complexity. For illustration purposes, we consider a sequencing heuristic used to chain remote sensors from one to the next: “place the most reliable sensor last”. The heuristic is derived based on the mathematical form of the optimization objective function which places emphasis on the decision variable pertaining to the last sensor. Feature extraction on optimized sensor sequences demonstrates that the heuristic is usually effective though it is not always trustworthy. This is consistent with knowledge in sensor processing.     

Carcinoma in situ and seminoma in equine testis

The presence of atypical germ cells resembling carcinoma in situ of human testis is reported for the first time in an unilaterally cryptorchid stallion. These cells were found in association with developing intratubular seminoma indicating they represented carcinoma in situ.     

Deficiency of fucosidase results in acrosomal dysgenesis and impaired sperm maturation

The goal of therapeutic vaccination is to elicit an antiviral immune response within persistently infected individuals and consequently eradicate the infection. CD8+ T cells are potent mediators of viral clearance; however, during chronic infections CD4+ T cell help is required to sustain antiviral CD8+ T cell activity. Therapeutic vaccination should be targeted towards enhancing both CD4+ and CD8+ T cell virus-specific responses.     

Cryptorchidism in common eutherian mammals

Cryptorchidism is failure of one or both testes to descend into the scrotum. Primary fault lies in the testis. We provide a unifying cross-species interpretation of testis descent and urge the use of precise terminology. After differentiation, a testis is relocated to the scrotum in three sequential phases: abdominal translocation, holding a testis near the internal inguinal ring as the abdominal cavity expands away, along with slight downward migration; transinguinal migration, moving a cauda epididymidis and testis through the abdominal wall; and inguinoscrotal migration, moving a s.c. cauda epididymidis and testis to the bottom of the scrotum. The gubernaculum enlarges under stimulation of insulin-like peptide 3, to anchor the testis in place during gradual abdominal translocation. Concurrently, testosterone masculinizes the genitofemoral nerve. Cylindrical downward growth of the peritoneal lining into the gubernaculum forms the vaginal process, cremaster muscle(s) develop within the gubernaculum, and the cranial suspensory ligament regresses (testosterone not obligatory for latter). Transinguinal migration of a testis is rapid, apparently mediated by intra-abdominal pressure. Testosterone is not obligatory for correct inguinoscrotal migration of testes. However, normally testosterone stimulates growth of the vaginal process, secretion of calcitonin gene-related peptide by the genitofemoral nerve to provide directional guidance to the gubernaculum, and then regression of the gubernaculum and constriction of the inguinal canal. Cryptorchidism is more common in companion animals, pigs, or humans (2-12%) than in cattle or sheep (< or =1%). Laboratory animals rarely are cryptorchid. In respect to non-scrotal locations, abdominal testes predominate in cats, dogs, and horses. Inguinal testes predominate in rabbits, are common in horses, and occasionally are found in cats and dogs. S.c. testes are found in cattle, cats and dogs, but are most common in humans.     

Micro Structural Investigation On Friction Stir Welded Al–4.5Cu–5TiB<Subscript>2</Subscript> Composite

Aluminium matrix composites are widely used in defence and aerospace applications. Welding them is very difficult and is an outstanding issue in a cost effective way. Friction stir welding is a solid state welding technique which is circumventing those barriers and is applied successfully to many such materials recently. In the present work, Al–4.5Cu alloy with TiB₂ reinforcement as in situ which was synthesized by stir casting method was welded by friction stir welding. Threaded pin was used as the friction stir tool profile. One of the joints was found to have tunnel defect in the stir zone due to improper material flow. The microstructural investigation through XRD and SEM revealed that the nugget zone had numerous small particles and refined fine grains which were distributed uniformly and hardness at the welded zone was found to be higher than that of the base material.