In Silico Identification of Carboxylate Clamp Type Tetratricopeptide Repeat Proteins in Arabidopsis and Rice As Putative Co-Chaperones of Hsp90/Hsp70

The essential eukaryotic molecular chaperone Hsp90 operates with the help of different co-chaperones, which regulate its ATPase activity and serve as adaptors to recruit client proteins and other molecular chaperones, such as Hsp70, to the Hsp90 complex. Several Hsp90 and Hsp70 co-chaperones contain the tetratricopeptide repeat (TPR) domain, which interacts with the highly conserved EEVD motif at the C-terminal ends of Hsp90 and Hsp70. The acidic side chains in EEVD interact with a subset of basic residues in the TPR binding pocket called a ‘carboxylate clamp’. Since the carboxylate clamp residues are conserved in the TPR domains of known Hsp90/Hsp70 co-chaperones, we carried out an in silico search for TPR proteins in Arabidopsis and rice comprising of at least one three-motif TPR domain with conserved amino acid residues required for Hsp90/Hsp70 binding. This approach identified in Arabidopsis a total of 36 carboxylate clamp (CC)-TPR proteins, including 24 novel proteins, with potential to interact with Hsp90/Hsp70. The newly identified CC-TPR proteins in Arabidopsis and rice contain additional protein domains such as ankyrin, SET, octicosapeptide/Phox/Bem1p (Phox/PB1), DnaJ-like, thioredoxin, FBD and F-box, and protein kinase and U-box, indicating varied functions for these proteins. To provide proof-of-concept of the newly identified CC-TPR proteins for interaction with Hsp90, we demonstrated interaction of AtTPR1 and AtTPR2 with AtHsp90 in yeast two-hybrid and in vitro pull down assays. These findings indicate that the in silico approach used here successfully identified in a genome-wide context CC-TPR proteins with potential to interact with Hsp90/Hsp70, and further suggest that the Hsp90/Hsp70 system relies on TPR co-chaperones more than it was previously realized

Leiomyoma of the vulva: a diagnostic challenge

Smooth muscle tumours of vulva are rare and therefore can be missed clinically. Our patient, 48-year-old lady presented with lump in the left vulva that was clinically diagnosed as Bartholin duct cyst. The lumpectomy was done under local anaesthesia and the lesion was sent for pathological examination. On gross examination the mass was 3.5 cm in diameter. The microscopic examination revealed the lump to be leiomyoma and no necrosis or atypia was present. The final diagnosis of “vulval leiomyoma” was given. Postoperative period was uneventful, and the patient is on regular follow up and there has been no recurrence. Leiomyoma should be kept as a differential diagnosis when a lady presents in late reproductive age group with unilateral swelling in vulvar region which is firm in consistency and the lump must be sent for histopathological examination for definitive diagnosis and rule out malignancy. The pathologists play a critical role in recognition and management of smooth muscle tumors of the vulva and to rule out leiomyosarcoma

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Formal verification of application and system programs based on a validated x86 ISA model

Two main kinds of tools available for formal software verification are point tools and general-purpose tools. Point tools are targeted towards bug-hunting or proving a fixed set of properties, such as establishing the absence of buffer overflows. These tools have become a practical choice in the development and analysis of serious software systems, largely because they are easy to use. However, point tools are limited in their scope because they are pre-programmed to reason about a fixed set of behaviors. In contrast, general-purpose tools,like theorem provers, have a wider scope. Unfortunately, they also have a higher user overhead. These tools often use incomplete and/or unrealistic software models, in part to reduce this overhead. Formal verification based on such a model can be restrictive because it does not account for program behaviors that rely on missing features in the model. The results of such formal verification undertakings may be unreliable --- consequently, they can offer a false sense of security. This dissertation demonstrates that formal verification of complex program properties can be made practical, without any loss of accuracy or expressiveness, by employing a machine-code analysis framework implemented using a mechanical theorem prover. To this end, we constructed a formal and executable model of the x86 Instruction-Set Architecture using the ACL2 theorem-proving system. This model includes a specification of 400+ x86 opcodes and architectural features like segmentation and paging. The model's high execution speed allows it to be validated routinely by performing co-simulations against a physical x86 processor --- thus, formal analysis based on this model is reliable. We also developed a general framework for x86 machine-code analysis that can lower the overhead associated with the verification of a broad range of program properties, including correctness with respect to behavior, security, and resource requirements. We illustrate the capabilities of our framework by describing the verification of two application programs, population count and word count, and one system program, zero copy.Computer Science

Isolation and Characterization of Aluminium and Copper Resistant 'P' Solubilizing Alkalophilic Bacteria

583-586Aluminium and copper resistant bacteria, isolated from contaminated soil, showed metal tolerance level of 3106M and 4398 M, respectively as evident by four select isolates based on their phosphorus solubilization potential (0.2-6.4 g ml-1). All four isolates could grow in a pH range of 5-11. Three isolates are member of Pseudomonadaceae family, Pseudomonas sp. (CD7),P. pseudomalli (CGI3) and P. maltophila (THI8). The isolates, CD7 and CG13, belong to siderovar group as the Pseudomonas sp. strain BI0, and are able to grow at 42°C. The CG13 is osmotolerant (10% NaCI). These isolates could be better bioinoculant candidate(s) for the contaminated alkalophilic sites

'In Silico' Identification of Carboxylate Clamp Type Tetratricopeptide Repeat Proteins in 'Arabidopsis' and Rice As Putative Co-Chaperones of Hsp90/Hsp70

The essential eukaryotic molecular chaperone Hsp90 operates with the help of different co-chaperones, which regulate its ATPase activity and serve as adaptors to recruit client proteins and other molecular chaperones, such as Hsp70, to the Hsp90 complex. Several Hsp90 and Hsp70 co-chaperones contain the tetratricopeptide repeat (TPR) domain, which interacts with the highly conserved EEVD motif at the C-terminal ends of Hsp90 and Hsp70. The acidic side chains in EEVD interact with a subset of basic residues in the TPR binding pocket called a 'carboxylate clamp'. Since the carboxylate clamp residues are conserved in the TPR domains of known Hsp90/Hsp70 co-chaperones, we carried out an in silico search for TPR proteins in 'Arabidopsis' and rice comprising of at least one three-motif TPR domain with conserved amino acid residues required for Hsp90/Hsp70 binding. This approach identified in Arabidopsis a total of 36 carboxylate clamp (CC)-TPR proteins, including 24 novel proteins, with potential to interact with Hsp90/Hsp70. The newly identified CC-TPR proteins in 'Arabidopsis' and rice contain additional protein domains such as ankyrin, SET, octicosapeptide/Phox/Bem1p (Phox/PB1), DnaJ-like, thioredoxin, FBD and F-box, and protein kinase and U-box, indicating varied functions for these proteins. To provide proof-of-concept of the newly identified CC-TPR proteins for interaction with Hsp90, we demonstrated interaction of AtTPR1 and AtTPR2 with AtHsp90 in yeast two-hybrid and 'in vitro' pull down assays. These findings indicate that the 'in silico' approach used here successfully identified in a genome-wide context CC-TPR proteins with potential to interact with Hsp90/Hsp70, and further suggest that the Hsp90/Hsp70 system relies on TPR co-chaperones more than it was previously realized