A supernumerary tooth is that which is present additionally to the normal series and can be found in any region of the dental arch. An impacted tooth is defined as the one which is embedded in the alveolus, so that its eruption is prevented, or the tooth is locked in position by bone or the adjacent teeth. The occurrence of multiple supernumerary teeth in only one patient in the absence of an associated systemic condition or syndrome is considered as a rare phenomenon. The occurrence of supernumerary teeth in the lower molar region is rare. A prevalence of less than 2% of cases occurring in this region has been estimated. Their occurrence presents a clinical problem for orthodontists and oral surgeons. The cause, frequency, complications, and surgical operation of impacted teeth are always interesting subjects for study and research. An impacted tooth can result in caries, pulp disease, periapical and periodontal disease, temporomandibular joint disorder, infection of the fascial space, root resorption of the adjacent tooth, and even oral and maxillofacial tumours. The management of impacted wisdom teeth has changed over the past 20 years from removal of nonsymptomatic third molars to simple observation. The aim of this paper is to present a rare case of bilateral multiple impacted supernumerary mandibular third molars.
Giant cell granuloma (GCG) is an uncommon bony lesion in the head and neck region, most commonly affecting the maxilla and mandible and has a female predilection. The clinical behavior of central GCG ranges from a slowly growing asymptomatic swelling to an aggressive lesion. The clinical, radiological, histological features and management of an aggressive GCG of maxilla in an 18-year-old female patient are described and discussed. It is emphasized that surgery is the traditional and still the most accepted treatment for GCG. Le Fort I osteotomy has been advocated as one of the access osteotomy for the surgical management of aggressive and extensive GCG involving the maxilla. The postoperative morbidity and recurrence have been discussed.
Giant cell granuloma; Le Fort I access osteotomy; maxillary sinus tumor
Age-related cataract (ARC) is a multifactorial disease and the leading cause of visual impairment and blindness worldwide. Genetic predisposition in association with other etiological factors may contribute to ARC. Although, there is some evidence for genetic influence for development of ARC, reports on gene mutations associated with ARC are scanty. In the present work, we identified a genetic variation (F71L) in the exon-2 of CRYAA gene in three unrelated female sporadic cases among 450 ARC patients but not in 144 normal non-cataractous controls. By comparing human recombinant wild-type and F71L-αA-crystallin, further we characterized the functional significance of this missense mutation. Size exclusion chromatography studies revealed that F71L mutation had no significant effect on the apparent molecular mass of αA-crystallin oligomeric complex. Intrinsic tryptophan fluorescence and far- and near-UV CD spectra indicated that F71L missense mutation did not significantly affect the secondary and tertiary structures of αA-crystallin. The ANS fluorescence emission spectra suggested no changes in surface hydrophobicity due to the F71L substitution. While the mutant αA-crystallin displayed almost complete loss (90%) of chaperone-like activity (CLA), in thermal aggregation of carbonic anhydrase, it showed 35-50% less protection in heat-induced aggregation of βL- and γ-crystallins. This is the first report of an αA-F71L mutation being associated with ARC. The results are consistent with the hypothesis that the mechanism of ARC in individuals carrying this mutation (F71L) might be due to the overall loss of in vivo chaperone activity due to interaction with other environmental factors.
Age-related cataract; αA-crystallin; F71L-mutation; chaperone-like activity; CD-spectra; oligomeric complex
Background: Proper gingival retraction improves the prognosis of crowns and bridges with sub gingival finishlines.Use of lasers assists the operator to achieve proper retraction with good clinical results.
Aims: The present study was intended to assess the amount of lateral gingival retraction achieved quantitatively by using diode lasers.
Settings and Design: Study was carried on 20 patients attended to a dental institution that underwent root canal treatment and indicated for fabrication of crowns.
Material and Methods: Gingival retraction was carried out on 20 teeth and elastomeric impressions were obtained. Models retrieved from the impressions were sectioned and the lateral distance between finish line and the marginal gingival was measured using tool makers microscope. Retraction was measured in mid buccal, mesio buccal and disto buccal regions.
Statistical Analysis: The values obtained were used to calculate the mean lateral retraction in microns.
Results: Mean retraction values of 399.5 μm, 445.5 μm and 422.5μm were obtained in mid buccal, mesio buccal and disto buccal regions respectively.
Conclusions: Gingival Retraction achieved was closer to the thickness of sulcular epithelium and greater than the minimum required retraction of 200um.
Lasers; Gingival Retraction; Finish Line
Epidemiological studies have shown that a diet rich in fruits and cruciferous vegetables is associated with a lower risk of prostate cancer. Indole-3-carbinol (I3C) and its dimeric product 3,3′-diindolylmethane (DIM) have been shown to exhibit anti-tumor activity both in vitro and in vivo. Recently, we have reported that a formulated DIM (B-DIM) induced apoptosis and inhibited growth, angiogenesis, and invasion of prostate cancer cells by regulating Akt, NF-κB, VEGF and the androgen receptor (AR) signaling pathway. However, the precise molecular mechanism(s) by which B-DIM inhibits prostate cancer cell growth and induces apoptosis have not been fully elucidated. Most importantly, it is not known how B-DIM affects cell cycle regulators and proteasome activity, which are critically involved in cell growth and apoptosis. In this study, we investigated the effects of B-DIM on proteasome activity and AR transactivation with respect to B-DIM-mediated cell cycle regulation and induction of apoptosis in both androgen-sensitive LNCaP and androgen-insensitive C4-2B prostate cancer cells. We believe that our results show for the first time the cell cycle-dependent effects of B-DIM on proliferation and apoptosis of synchronized prostate cancer cells progressing from G1 to S phase. B-DIM inhibited this progression by induction of p27Kip1 and down-regulation of AR. We also show for the first time that B-DIM inhibits proteasome activity in S phase, leading to the inactivation of NF-κB signaling and induction of apoptosis in LNCaP and C4-2B cells. These results suggest that B-DIM could be a potent agent for the prevention and/or treatment of both hormone sensitive as well as hormone-refractory prostate cancer.
The need for quantification of cell growth patterns in a multilayer, multi-cellular tissue necessitates the development of a 3D reconstruction technique that can estimate 3D shapes and sizes of individual cells from Confocal Microscopy (CLSM) image slices. However, the current methods of 3D reconstruction using CLSM imaging require large number of image slices per cell. But, in case of Live Cell Imaging of an actively developing tissue, large depth resolution is not feasible in order to avoid damage to cells from prolonged exposure to laser radiation. In the present work, we have proposed an anisotropic Voronoi tessellation based 3D reconstruction framework for a tightly packed multilayer tissue with extreme z-sparsity (2–4 slices/cell) and wide range of cell shapes and sizes. The proposed method, named as the ‘Adaptive Quadratic Voronoi Tessellation’ (AQVT), is capable of handling both the sparsity problem and the non-uniformity in cell shapes by estimating the tessellation parameters for each cell from the sparse data-points on its boundaries. We have tested the proposed 3D reconstruction method on time-lapse CLSM image stacks of the Arabidopsis Shoot Apical Meristem (SAM) and have shown that the AQVT based reconstruction method can correctly estimate the 3D shapes of a large number of SAM cells.
Impression making is not only important but is also the most significant step in the fabrication of any fixed or removable prosthesis. Proper impression making may be hindered by certain pathologic conditions. Reduced mouth opening is one of the common mechanical obstructions for proper orientation of the impression tray in the patient's mouth. In patients with trismus induced by submucous fibrosis, the procedure may be even more difficult to carry out because of reduced tissue resiliency and obliteration of vestibular spaces. Use of sectional trays offers one of the alternatives to overcome the problem of restricted mouth opening. Fabrication of customized impression trays according to the patient dentition improves the accuracy of impression making. The present case reports describe the fabrication of sectional custom trays designed for dentulous patients with chronic tobacco-induced submucous fibrosis.
The measles virus (MeV), a member of the paramyxovirus family, is an important cause of pediatric morbidity and mortality worldwide. In an effort to provide therapeutic treatments for improved measles management, we previously identified a small, non-nucleoside organic inhibitor of the viral RNA-dependent RNA polymerase (RdRp) by means of high-throughput screening (HTS). Subsequent structure-activity relationship (SAR) studies around the corresponding pyrazole carboxamide scaffold led to the discovery of 2 (AS-136a), a first generation lead with low nanomolar potency against life MeV and attractive physical properties suitable for development. However, its poor water solubility and low oral bioavailability (F) in the rat suggested that the lead could benefit from further SAR studies to improve the biophysical characteristics of the compound. Optimization of in vitro potency and aqueous solubility led to the discovery of 2o (ERDRP-00519), a potent inhibitor of MeV (EC50 = 60 nM) with aqueous solubility of approximately 60 μg/ml. The agent shows a 10-fold exposure (AUC/Cmax) increase in the rat model relative to 2, displays near dose proportionality in the range of 10 mg/kg to 50 mg/kg, and exhibits good oral bioavailability (F = 39%) in the rat. The significant solubility increase appears linked to the improved oral bioavailability.
measles virus; RNA-dependent RNA polymerase activity inhibitor; AS-136a; ERDRP-00519; pharmacokinetics
Background & objectives:
Pre-clinical toxicology evaluation of biotechnology products is a challenge to the toxicologist. The present investigation is an attempt to evaluate the safety profile of the first indigenously developed recombinant DNA anti-rabies vaccine [DRV (100 μg)] and combination rabies vaccine [CRV (100 μg DRV and 1.25 IU of cell culture-derived inactivated rabies virus vaccine)], which are intended for clinical use by intramuscular route in Rhesus monkeys.
As per the regulatory requirements, the study was designed for acute (single dose - 14 days), sub-chronic (repeat dose - 28 days) and chronic (intended clinical dose - 120 days) toxicity tests using three dose levels, viz. therapeutic, average (2x therapeutic dose) and highest dose (10 x therapeutic dose) exposure in monkeys. The selection of the model i.e. monkey was based on affinity and rapid higher antibody response during the efficacy studies. An attempt was made to evaluate all parameters which included physical, physiological, clinical, haematological and histopathological profiles of all target organs, as well as Tiers I, II, III immunotoxicity parameters.
In acute toxicity there was no mortality in spite of exposing the monkeys to 10XDRV. In sub chronic and chronic toxicity studies there were no abnormalities in physical, physiological, neurological, clinical parameters, after administration of test compound in intended and 10 times of clinical dosage schedule of DRV and CRV under the experimental conditions. Clinical chemistry, haematology, organ weights and histopathology studies were essentially unremarkable except the presence of residual DNA in femtogram level at site of injection in animal which received 10X DRV in chronic toxicity study. No Observational Adverse Effects Level (NOAEL) of DRV is 1000 ug/dose (10 times of therapeutic dose) if administered on 0, 4, 7, 14, 28th day.
Interpretation & conclusions:
The information generated by this study not only draws attention to the need for national and international regulatory agencies in formulating guidelines for pre-clinical safety evaluation of biotech products but also facilitates the development of biopharmaceuticals as safe potential therapeutic agents.
Biotech products; combination rabies vaccine (CRV); DNA rabies vaccine (DRV); pre-clinical toxicology; PVRV; purified vero cell-derived inactivated rabies virus vaccine; safety evaluation; toxicology
The plant stem cell regulator WUSCHEL is shown to repress differentiation-promoting transcription factors. This regulatory network is analyzed with a computational model of the three-dimensional shoot stem cell niche and a combination of genetic perturbation and live imaging.
We find that the transcription factor (TF) WUSCHEL (WUS) directly binds to the promoters and represses a group of genes including key TFs involved in differentiation thus keeping them repressed in the stem cells of the plant shoot, a mechanistic logic that is similar to animal stem cell regulation.We use a three-dimensional computational model of the plant shoot stem cell niche to show that the WUS-mediated repression of the differentiation program along with the previously reported activation of its own negative regulator leads to a robust stem cell homeostasis in a dynamic growth environment.Live imaging of target genes upon transient manipulation of WUS levels is combined with model perturbations to validate the proposed network and to connect it with a large body of previous experimental work.
In animal systems, master regulatory transcription factors (TFs) mediate stem cell maintenance through a direct transcriptional repression of differentiation promoting TFs. Whether similar mechanisms operate in plants is not known. In plants, shoot apical meristems serve as reservoirs of stem cells that provide cells for all above ground organs. WUSCHEL, a homeodomain TF produced in cells of the niche, migrates into adjacent cells where it specifies stem cells. Through high-resolution genomic analysis, we show that WUSCHEL represses a large number of genes that are expressed in differentiating cells including a group of differentiation promoting TFs involved in leaf development. We show that WUS directly binds to the regulatory regions of differentiation promoting TFs; KANADI1, KANADI2, ASYMMETRICLEAVES2 and YABBY3 to repress their expression. Predictions from a computational model, supported by live imaging, reveal that WUS-mediated repression prevents premature differentiation of stem cell progenitors, being part of a minimal regulatory network for meristem maintenance. Our work shows that direct transcriptional repression of differentiation promoting TFs is an evolutionarily conserved logic for stem cell regulation.
central zone; CLAVATA3; shoot apical meristem; stem cell niche; WUSCHEL
Fibromyxoma is a rare odontogenic tumour which is benign, but locally aggressive. The etiology of these tumours is unknown, but because of its limitation to the teeth bearing areas and occasional presence of odontogenic epithelial fragments within the tumour which suggest that it is of odontogenic origin. It is a slow growing painless tumour that frequently occurs in second and third decades of life. Females are more commonly affected than males. The tumour can cause gradual expansion of the cortical plates and cause loosening and displacement of teeth, although root resorption may be rare. The surgical treatment of these tumours consists of complete enucleation or radical excision. The aim of this paper is to present the rarity of a fibromyxoma of the maxilla.
The androgen receptor (AR) plays a critical role in the proliferation of prostate cancer cells. However, its mechanism of action in proliferation remains unknown. An understanding of the mechanism of AR action in proliferation may lead to the development of effective strategies for the treatment of prostate cancer.
In this study we report that pulse treatment of synchronized LNCaP cells with Casodex, an AR-antagonist, for 4 hours in mid-G1 phase was sufficient to prevent cells from entering S phase. Since the assembly of pre-replication complex (pre-RC) in G1 is required for the progression of cells from G1 to S phase, the effect of Casodex during mid-G1 suggested that the role of AR in proliferation might be to regulate the assembly of pre-RC. To test this possibility, we investigated the interaction between AR and Cdc6, an essential component of pre-RC in LNCaP cells. AR co-localized and co-immunoprecipitated with Cdc6, and Casodex treatment disrupted this interaction. AR-immunoprecipitate (AR-IP) also contained cyclin E and cyclin A, which play a critical role in pre-RC assembly and cell cycle entry into S phase, and DNA polymerase-α, PCNA, and ribonucleotide reductase, which are essential for the initiation of DNA synthesis. In addition, in cells in S phase, AR co-sedimented with components of the DNA replication machinery of cells that entered S phase.
Together, these observations suggest a novel role of AR as a component of the pre-RC to exert control over progression of LNCaP cells from G1 to S phase through a mechanism that is independent of its role as a transcription factor.
Cataract is a key factor in the morbidity associated with diabetes. While the pathogenesis of diabetic cataract formation is poorly understood, previous research has identified aldose reductase (ALR2) as a key player. To elucidate a potential role for this enzyme in diabetic cataract formation, we created a series of transgenic mice designed for expression of human ALR2 (AKR1B1) in epithelial and outer cortical fiber cells of the lens. One of the founder lines, designated PAR39, developed an early onset cataract that involved formation of a plaque of cells at the anterior aspect of the lens. These cells appear to separate from the anterior epithelium and undergo a dramatic change that is reminiscent of the epithelial to mesenchymal transition (EMT). We characterized this phenotype in the PAR39 strain by examining rates of cell proliferation and by immunostaining for markers of EMT. Incorporation of the thymidine analog bromodeoxyuridine (BrdU) was used to estimate cell proliferation in two functional areas of the lens epithelium: the mitotically active germinative zone (GZ) and the less proliferative center zone (CZ). Staining cell nuclei with diamido 4',6-diamidino-2-phenylindole (DAPI) was used to establish a total cell count in the demarcated areas. Lens epithelium in PAR39 transgenic mice demonstrated a decrease in the percentage of BrdU/DAPI staining within the GZ as compared to nontransgenic littermate controls (8.1% vs. 10.9%). A similar decrease in BrdU/DAPI was observed in the CZ (0.6% compared to 3.3%). However, cell density was greater within the GZ of PAR39 mice as compared with nontransgenic controls, while it was not significantly different in the CZ among the two groups. Furthermore, cells associated with the epithelial plaque did not stain positive for BrdU, but were strongly positive for alpha-smooth muscle actin, a classical marker for EMT. These findings suggest that ALR2 over-expression is associated with an alteration in the balance between proliferation and apoptosis of epithelial cells in the mouse lens, and that cells associated with epithelial plaques in the PAR39 lens have features in common with cells undergoing EMT.
cataract; EMT; epithelial-to-mesenchymal transition; aldo-keto reductase; diabetes
A transformation system which is free of in vitro plant regeneration following Agrobacterium infection is established for the forage legume, Sunnhemp (Crotalaria juncea L.) where in the entire embryo axis of the germinating seed was used as the target tissue for transformation. After standardization of transformation conditions, the cotyledonary node of the embryo axis was infected with Agrobacterium host LBA 4404 harboring the recombinant vector pCAMBIA 2301. The bivalent 1D gene of the two major foot and mouth disease virus (FMDV) serotypes ‘O’ and ‘A22’ and the neomycin phosphotransferase (nptII) gene were used as the markers for optimization of the protocol. The embryo axes were pricked randomly on the cotyledonary node and co-cultivated with Agrobacterium. The germlings were then allowed to grow under standard growth room conditions in to mature fertile plants. 60 T0 plants were established from 3 separate experiments. Three hundred seeds from the 60 T0 plants were sown to raise the T1 generation of which 180 were analyzed for integration of bivalent FMDV gene 1D “O” and “A22” and the nptII gene. Eighteen out of these 180 plants amplified both the marker genes. Two independent transgenic lines 24 and 37, showed elevated levels of expression of 12 μg and 8 μg (per gm of fresh leaf) of the bivalent ID antigen “O” and “A22” . The results showed that the transformation efficiency was 3 %. To the best of our knowledge, this is the first successful attempt of Agrobacterium tumefaciens mediated transformation of Sunnhemp. The protocol can generate whole plant transformants with relative ease and should be compatible to all genotypes of Sunnhemp.
Sunnhemp; Agrobacterium tumefaciens; FMDV -1D gene; nptII gene markers; in planta transformation
Telomeres protect the ends of linear chromosomes from being recognized as damaged DNA, and telomere stability is required for genome stability. Here we demonstrate that telomere stability in androgen receptor (AR)-positive LNCaP human prostate cancer cells is dependent on AR and androgen, as AR inactivation by AR antagonist bicalutamide (Casodex), AR-knockdown, or androgen-depletion caused telomere dysfunction, and the effect of androgen-depletion or Casodex was blocked by the addition of androgen. Notably, neither actinomycin D nor cycloheximide blocked the DNA damage response to Casodex, indicating that the role of AR in telomere stability is independent of its role in transcription. We also demonstrate that AR is a component of telomeres, as AR-bound chromatin contains telomeric DNA, and telomeric chromatin contains AR. Importantly, AR inactivation by Casodex caused telomere aberrations, including multiple abnormal telomere signals, remindful of a fragile telomere phenotype that has been described previously to result from defective telomere DNA replication. We suggest that AR plays an important role in telomere stability and replication of telomere DNA in prostate cancer cells, and that AR inactivation-mediated telomere dysfunction may contribute to genomic instability and progression of prostate cancer cells.
Androgen receptor; telomeres; fragile telomeres; Casodex; DNA damage; genomic instability; prostate cancer
Firefly luciferase-catalyzed light emission from D-luciferin is widely used as a reporter of gene expression and enzymatic activity both in vitro and in vivo. Despite the power of bioluminescence for imaging and drug discovery, light emission from firefly luciferase is fundamentally limited by the physical properties of the D-luciferin substrate. We and others have synthesized aminoluciferin analogs that exhibit light emission at longer wavelengths than D-luciferin and have increased affinity for luciferase. However, although these substrates can emit an intense initial burst of light that approaches that of D-luciferin, this is followed by much lower levels of sustained light output. We have previously postulated that this behavior is due to product inhibition. Here we describe the creation of mutant luciferases that yield improved sustained light emission with aminoluciferins in both lysed and live mammalian cells, allowing the use of aminoluciferins for cell-based bioluminescence experiments.
A report, prepared by WHO and the World Economic Forum says that India will incur an accumulated loss of $236.6 billion by 2015 on account of unhealthy lifestyles and faulty diet. The WHO and International Obesity Task Force have declared the obesity epidemic on a global scale. Though genetic factors contribute to human obesity, the nature of diet plays a key role in Medoroga. Ayurveda has given top priority to food under the three supporters of life. Among them, Yava (Hordeum vulgare) is a supplementary diet for which wide references were found in classics as preventive and curative aspects of medoroga. Keeping this in view the present study has been taken up to evaluate the efficacy of yava in medoroga.
30 clinically diagnosed cases of Medoroga were selected from O.P.D of S.V. Ayurvedic hospital, Tirupati following specific exclusion and inclusion criteria. Diagnostic criteria including laboratory investigations along with subjective and objective parameters were considered for the study. Dose Yava churna 10 gm BD with hot water. Duration 90 days.
Statistical data revealed highly significant reduction in serum cholesterol, Body weight, MI, serum triglycerides, VLDL and significant improvement in HDL levels.
Administration of yava churna has given better results. It was evident by the significant changes in the subjective and objective parameters.
Retinitis Pigmentosa (RP) is a common form of retinal degeneration characterized by photoreceptor degeneration and retinal pigment epithelium (RPE) atrophy causing loss of visual field and acuities. Exome sequencing identified a novel homozygous splice site variant (c.111+1G>A) in the gene encoding retinol binding protein 4 (RBP4). This change segregated with early onset, progressive, and severe autosomal recessive retinitis pigmentosa (arRP) in an eight member consanguineous pedigree of European ancestry. Additionally, one patient exhibited developmental abnormalities including patent ductus arteriosus and chorioretinal and iris colobomas. The second patient developed acne from young age and extending into the 5th decade. Both patients had undetectable levels of RBP4 in the serum suggesting that this mutation led to either mRNA or protein instability resulting in a null phenotype. In addition, the patients exhibited severe vitamin A deficiency, and diminished serum retinol levels. Circulating transthyretin levels were normal. This study identifies the RBP4 splice site change as the cause of RP in this pedigree. The presence of developmental abnormalities and severe acne in patients with retinal degeneration may indicate the involvement of genes that regulate vitamin A absorption, transport and metabolism.
Sam68 (Src-associated protein in mitosis 68 kDa) is a multifunctional protein, known to govern cellular signal transduction, transcription, RNA metabolism, proliferation, apoptosis and HIV-1 replication. Although intrinsic mechanisms that modulate Sam68 function are beginning to emerge, the regulatory events contributing to its expression remain elusive. We previously reported that heat shock protein-22 (Hsp22) antagonizes Sam68 function in rev-response element (RRE)-mediated gene expression. We now demonstrate that Sam68 levels correlate inversely with Hsp22 in a variety of cells, including U87, Jurkat, 293T and U-937. In U87 glioblastoma cells, which contained high levels of Hsp22 than other cell lines tested, Hsp22 knockdown dramatically increased both Sam68 mRNA and protein, altered cellular morphology and enhanced cell proliferation. This heightened proliferation was associated with a sharp decrease in G0/G1 and a corresponding increase in S and G2/M phases in exponentially growing cultures. The increased S phase population in turn correlated with enhanced expression of cell cycle regulatory proteins such as cyclin E, cyclin A, ribonucleotide reductase (RNR) and proliferating cell nuclear antigen (PCNA), which are required for the transition of cells from G1 to S phase. Collectively, our results demonstrate for the first time that Hsp22 regulates Sam68 expression and the ratio of Sam68 to Hsp22 may determine the proliferative potential of glioblastoma cells.
Hsp22 knockdown; Sam68; Cell morphology; Proliferation; Cell cycle analysis
Stem cell maintenance is essential for growth and development of plants and animals. Similar to animal studies, transcription factors play a critical role in plant stem cell maintenance, however the regulatory logic is not well understood. Shoot apical meristems (SAMs) harbor a pool of pluoripotent stem cells and they provide cells for the development of all above-ground organs. Molecular genetic studies spanning more than a decade have revealed cell-cell communication logic underlying stem cell homeostasis. WUSCHEL (WUS), a homeodomain transcription factor expressed in cells of the organizing center specifies stem cells in overlying cells of the central zone (CZ) and also activates a negative regulator-CLAVATA3 (CLV3). CLV3, a small secreted peptide, binds to CLAVATA1 (CLV1) and also possibly to CLV1-related receptors to activate signaling which restricts WUS transcription. Though the CLV-WUS feedback network explains the cell-cell communication logic of stem cell maintenance, how WUS communicates with adjacent cells had remained elusive. In October 15 2011 issue of Genes and Development, we report that WUS protein synthesized in cells of organizing center migrates into adjacent cells via cell-cell movement and activates CLV3 transcription by directly binding to promoter elements.
shoot apical meristem; CLAVATA3; CLAVATA1; central zone and peripheral zone
The acquisition of drug-resistance mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the best binders, from Ki of 30–50 nM in round one to below 100 pM in round two. Crystal structures of a subset of complexes revealed a binding mode similar to each design that respected the substrate envelope in nearly all cases. All four best binders from round one exhibited broad specificity against a clinically relevant panel of drug-resistant HIV-1 protease variants, losing no more than 6–13 fold affinity relative to wild type. Testing a subset of second-round compounds against the panel of resistant variants revealed three classes of inhibitors — robust binders (maximum affinity loss of 14–16 fold), moderate binders (35–80 fold), and susceptible binders (greater than 100 fold). Although for especially high-affinity inhibitors additional factors may also be important, overall, these results suggest that designing inhibitors using the substrate envelope may be a useful strategy in the development of therapeutics with low susceptibility to resistance.
computational drug design; protease inhibitors; drug resistance; substrate envelope hypothesis; binding specificity; inverse design
Gingival fibromatosis is a benign oral condition characterized by enlargement of gingival tissues. It usually develops as an isolated disorder but can be one of the features of a syndrome. This case report is of a 5-year-old male with severe gingival hyperplasia and mild mental retardation which was complicated by open bite, abnormal occlusion, open lip posture, and disabilities associated with mastication and speech. Full mouth gingivectomy in single sitting under general anesthesia was done with electrocautery.
Electrocautery; idiopathic gingival fibromatosis; mental retardation; SOS-1 gene
The aim was to evaluate the quantitative changes in nuclear diameter (ND), cytoplasmic diameter (CD) and nuclear/cytoplasmic ratio (N/C) in cytological buccal smears of iron deficiency anemic patients by comparing with normal healthy individuals.
Materials and Methods:
The study group consisted of 40 healthy individuals and 40 iron deficiency anemic patients who were selected on clinical history, hematological investigations, and confirmed by serum ferritin levels. Exfoliative buccal smears stained with PAP stain were evaluated for cytoplasimic, nuclear diameters, and nuclear/cytoplasmic ratios (N/C) using Image Proexpress Version 6.0 image analysis system. All the parameters were statistically analyzed by using unpaired ‘t’ test.
A significant increase is seen in the average nuclear diameter (ND) and N/C ratio of the anemic group when compared to the control group. The average cytoplasmic diameter (CD) did not show any statistical difference among the two groups.
Oral exfoliative cytological techniques could possibly be a noninvasive alternative diagnostic tool for iron deficiency anemia.
Cytomorphometry; iron deficiency anemia; oral exfoliative cytology
Cutaneous disorders can precede or follow the initiation of hemodialysis treatment. We evaluated the prevalence of various dermatological manifestations in patients undergoing hemodialysis at least twice a week for minimum of three months at our center. Patients were excluded if they were undergoing hemodialysis less than twice a week or on hemodialysis secondary to ESRD following graft dysfunction. One hundred and forty-three patients were evaluated. Among them, there were 113 male and 30 females. Among the skin changes, pruritus accounted for 56%, Xerosis was observed in 52%, Diffuse blackish hyper pigmentation was seen in 40%. Skin infections was seen in 53% of patients, of these fungal, bacterial and viral infections were 27.2%, 14.6%, and 11.2%, respectively. Kyrle's disease was observed only in 6.9%. Other skin manifestations include eczema 4.8%, psoriasis 2.7%, and drug rash 2.1%. Nail changes were observed in 46 patients of whom 27 patients had onychomycosis. Other changes include discoloration, onycholysis, and splinter hemorrhages. Hair changes were observed in 21.7%. Mucosal changes were seen in 27.3%. In our study, pruritus, xerosis, and pigmentation were higher among skin changes. Recognition and management of some of these dermatological manifestations vastly reduce the morbidity and improve the quality of life.