132 research outputs found
Inhibitor Mediated Protein Degradation
SummaryThe discovery of drugs that cause the degradation of their target proteins has been largely serendipitous. Here we report that the tert-butyl carbamate-protected arginine (Boc3Arg) moiety provides a general strategy for the design of degradation-inducing inhibitors. The covalent inactivators ethacrynic acid and thiobenzofurazan cause the specific degradation of glutathione-S-transferase when linked to Boc3Arg. Similarly, the degradation of dihydrofolate reductase is induced when cells are treated with the noncovalent inhibitor trimethoprim linked to Boc3Arg. Degradation is rapid and robust, with 30%–80% of these abundant target proteins consumed within 1.3–5 hr. The proteasome is required for Boc3Arg-mediated degradation, but ATP is not necessary and the ubiquitin pathways do not appear to be involved. These results suggest that the Boc3Arg moiety may provide a general strategy to construct inhibitors that induce targeted protein degradation
Persistent recalcitrant hypocalcemia following total thyroidectomy : a management challenge
Hypocalcemia is the most common complication following total thyroidectomy and could be due to direct injury or ischemic damage to parathyroid glands during surgery. Hypocalcemia adds significantly to hospital stay and cost of hospitalisation. While there are numerous proposed treatment algorithms for post-thyroidectomy hypocalcemia, there are no universally accepted standard guidelines or treatment algorithms available. We present a case of prolonged recalcitrant hypocalcemia post-total thyroidectomy, requiring hospitalisation for more than a month, to illustrate the practical problems we faced during management of this patient.peer-reviewe
Multiscale dynamics in honeybee societies
In this dissertation, I examine the social organization of a model organism, the honeybee, at multiple scales. I begin in Part I at the microbial scale, by studying the relationship between the social caste of individuals and the microbes they harbour in their gastrointestinal tracts. Using 16S rRNA sequence data, I reconstruct the gut microbiomes of honeybees of different castes. I find that the microbiomes of two previously-uncharacterized social castes -- drones and queens -- contain the same bacteria as those in the guts of worker bees. However, despite this similarity, I show that the compositions of these bacteria in drones and queens are sufficiently different that their microbiomes can be distinguished from those of workers.
In Part II, I study the honeybee society at the level of its individual constituents, in particular, the set of foragers. I characterize the distribution of foraging activity across these individuals in the society, and find that this is highly skewed, with some individuals contributing much more to the activity of the colony than others. I establish these results in the framework used to describe the wealth of individuals in human society, and also characterize the temporal variation and resilience of foraging activity.
In Part III, I describe a system to track individual honeybees and their interactions inside a two-dimensional observation hive with high spatiotemporal resolution. At the level of individual honeybees, I study the temporal statistics of trophallaxis, an important social interaction that occurs in honeybee societies, and find that the distribution of trophallaxis durations is similar to the distribution of face-to-face interactions among humans. I propose a scaling argument to explain the scaling exponent of these distributions, and test the argument in simple random-walk models of proximity interactions. I then study the honeybee society at the collective scale of the trophallaxis interaction network, and find that although bees exhibit bursty patterns of trophallaxis just as humans do in communication, the dynamics of simulated spreading on the trophallaxis networks is fast relative to randomized reference models, unlike in human temporal networks
BIOFILM FORMATION OF METHICILLIN AND VANCOMYCIN RESISTANT STAPHYLOCOCCUS SPECIES ISOLATED FROM CELLULAR PHONES
Objective: The goal of the study was to explore the occurrence of methicillin and vancomycin-resistant Staphylococcus species from cellular phones and preventive measures to avoid contamination. Methods: The issues addressed in this investigation are i) Isolation of bacteria from 70 cellular phones through swab culture method ii) Characterization of the isolates by standard biochemical test iii) Antibiogram pattern study of the isolates iv) Molecular identification of the selected isolate through 16s rDNA sequencing v) Virulence study through biofilm assay vi) Susceptibility of the isolates against commonly used disinfectants and essential oils through disc diffusion. Results: All 70 different cellular phone used in this study harbored 120 isolates of bacteria. Of which, we recorded high incidence of Gram-positive cocci (51.6%) and 22 isolates were identified as Staphylococcus species. Three isolates (52N6, 53N9 and 53N6) were resistant to both methicillin and vancomycin, in addition, showed resistance against several other antibiotics. The strain 53N6 that exhibited multidrug resistance was further identified as Staphylococcus sp. strain CPC53N6 through 16s rDNA sequencing with NCBI accession no. KX858346. Virulence activity of the isolate was observed by its biofilm forming capacity as revealed from SEM imaging and the biofilms were composed of aggregated cocci and fibriform extracellular matrix. All the Staphylococcus isolates, including CPC53N6, were sensitive to disinfectants like dettol and cinnamon (Cinnamon zeylanicum) oil indicating their use as preventive measures. Conclusion: Thus, the methicillin and vancomycin-resistant Staphylococcus species of cellular phones can be decontaminated through cinnamon oil to minimize further transmission
Schwannoma of the base of tongue – A rare presentation
AbstractIntroductionSchwannomas are benign tumours arising from the Schwann cells. Only 1% of extracranial schwannomas occur intraorally and its pharyngeal presentations are rare.Case reportWe report a rare case of a 50year old lady who presented with frequent hawking sensation since one year. Video laryngoscopy showed polypoidal lesion in the base of tongue. CT imaging was done to know the extent of lesion. Excision biopsy of the lesion was done. To our surprise, the histologic examination and the immunohistochemistry confirmation with S100 proved it to be schwannoma of the base of tongue.DiscussionAbout a quarter of all schwannomas occur in the head and neck region. Only 1% of these occur intraorally, generally in the tongue. Pharyngeal presentations of schwannoma are rare.ConclusionSchwannomas arising in the base of tongue are rare and are not often included in the differential diagnosis. They are usually benign and have excellent prognosis as compared to the usual malignant lesions which occur in the tongue base
Structure of Cryptosporidium IMP deÂhydrogenase bound to an inhibitor with in vivo antiparasitic activity
Inosine 50-monophosphate dehydrogenase (IMPDH) is a promising target for the treatment of Cryptosporidium infections. Here, the structure of C. parvum IMPDH (CpIMPDH) in complex with inosine 50-monophosphate (IMP) and P131, an inhibitor with in vivo anticryptosporidial activity, is reported. P131 contains two aromatic groups, one of which interacts with the hypoxanthine ring of IMP, while the second interacts with the aromatic ring of a tyrosine in the adjacent subunit. In addition, the amine and NO2 moieties bind in hydrated cavities, forming water-mediated hydrogen bonds to the protein. The design of compounds to replace these water molecules is a new strategy for the further optimization of C. parvum inhibitors for both antiparasitic and antibacterial applications
Staging of Laryngeal and Hypopharyngeal Cancer: Computed Tomography versus Histopathology
Introduction: Computed tomography (CT) imaging is the choice of investigation for evaluation of extent of tumor under the mucosa, locally and regionally. This study was undertaken to assess the accuracy of preoperative CT imaging in the staging of carcinoma of the larynx and hypopharynx.  Materials and Methods: In this retrospective study, all cases who were clinically (c) staged T3–T4 and who underwent surgery were evaluated. The sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and accuracy (Ac) of a preoperative CT scan to detect cartilaginous penetration and spread outside the larynx was evaluated. Clinical T-stage by CT imaging was compared with postoperative histopathological T-stage.  Results: There were 22 (96%) male patients and one (4%) female patient. Patients were aged from 48 to 64 years (mean, 56 years). Twenty (87%) patients had laryngeal carcinoma, whereas three (13%) had hypopharyngeal carcinoma. Four (17%) patients had T3 tumors and 19 (83%) had T4a lesions. Preoperative imaging over-staged one of five pathological (p) T3 cases and three out of three pT2 cases, and was accurate in the remaining 19 cases. In a comparison of the results of imaging with histopathological T-classification, T-staging was found to be 82.6% accurate.  Conclusion: CT is a precise and non-invasive imaging method with high sensitivity but relatively lower specificity because of increased false positives. CT imaging may be useful to guide the choice of surgical procedure, which can heavily impact a patients’ quality of life
Triazole Inhibitors of Cryptosporidium parvum Inosine 5?-Monophosphate Dehydrogenase
Cryptosporidium parvum is an important human pathogen and potential bioterrorism agent. This protozoan parasite cannot salvage guanine or guanosine and therefore relies on inosine 5?-monophosphate dehydrogenase (IMPDH) for biosynthesis of guanine nucleotides and hence for survival. Because C. parvum IMPDH is highly divergent from the host counterpart, selective inhibitors could potentially be used to treat cryptosporidiosis with minimal effects on its mammalian host. A series of 1,2,3-triazole containing ether CpIMPDH inhibitors are described. A structure?activity relationship study revealed that a small alkyl group on the ?-position of the ether was required, with the (R)-enantiomer significantly more active than the (S)-enantiomer. Electron-withdrawing groups in the 3- and/or 4-positions of the pendent phenyl ring were best, and conversion of the quinoline containing inhibitors to quinoline-N-oxides retained inhibitory activity both in the presence and absence of bovine serum albumin. The 1,2,3-triazole CpIMPDH inhibitors provide new tools for elucidating the role of IMPDH in C. parvum and may serve as potential therapeutics for treating cryptosporidiosis
Selective and potent urea inhibitors of Cryptosporidium parvum inosine 5’-monophosphate dehydrogenase
Cryptosporidium parvum and related species are zoonotic intracellular parasites of the intestine. Cryptosporidium is a leading cause of diarrhea in small children around the world. Infection can cause severe pathology in children and immunocompromised patients. This waterborne parasite is resistant to common methods of water treatment and therefore a prominent threat to drinking and recreation water even in countries with strong water safety systems. The drugs currently used to combat these organisms are ineffective. Genomic analysis revealed that the parasite relies solely on inosine-5?-monophosphate dehydrogenase (IMPDH) for the biosynthesis of guanine nucleotides. Herein, we report a selective urea-based inhibitor of C. parvum IMPDH (CpIMPDH) identified by high-throughput screening. We performed a SAR study of these inhibitors with some analogues exhibiting high potency (IC50 1000-fold versus human IMPDH type 2 and good stability in mouse liver microsomes. A subset of inhibitors also displayed potent antiparasitic activity in a Toxoplasma gondii model
Isolated angioedema of the bowel due to C1 esterase inhibitor deficiency: a case report and review of literature
<p>Abstract</p> <p>Introduction</p> <p>We report a rare, classic case of isolated angioedema of the bowel due to C1-esterase inhibitor deficiency. It is a rare presentation and very few cases have been reported worldwide. Angioedema has been classified into three categories.</p> <p>Case presentation</p> <p>A 66-year-old Caucasian man presented with a ten-month history of episodic severe cramping abdominal pain, associated with loose stools. A colonoscopy performed during an acute attack revealed nonspecific colitis. Computed tomography of the abdomen performed at the same time showed a thickened small bowel and ascending colon with a moderate amount of free fluid in the abdomen. Levels of C4 (< 8 mg/dL; reference range 15 to 50 mg/dL), CH50 (< 10 U/mL; reference range 29 to 45 U/ml) and C1 inhibitor (< 4 mg/dL; reference range 14 to 30 mg/dL) were all low, supporting a diagnosis of acquired angioedema with isolated bowel involvement. Our patient's symptoms improved with antihistamine and supportive treatment.</p> <p>Conclusion</p> <p>In addition to a detailed comprehensive medical history, laboratory data and imaging studies are required to confirm a diagnosis of angioedema due to C1 esterase inhibitor deficiency.</p
- …