Molecular Docking of Known Carcinogen 4- (Methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) with Cyclin Dependent Kinases towards Its Potential Role in Cell Cycle Perturbation

Cell cycle is maintained almost all the times and is controlled by various regulatory proteins and their complexes (Cdk+Cyclin) in different phases of interphase (G1, S and G2) and mitosis of cell cycle. A number of mechanisms have been proposed for the initiation and progression of carcinogenesis by abruption in cell cycle process. One of the important features of cancer/carcinogenesis is functional loss of these cell cycle regulatory proteins particularly in CDKs and cyclins. We hypothesize that there is a direct involvement of these cell cycle regulatory proteins not only at the genetic level but also proteins level, during the initiation of carcinogenesis. Therefore, it becomes significant to determine inconsistency in the functioning of regulatory proteins due to interaction with carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Hence, we investigated the interaction efficiency of NNK, against cell cycle regulatory proteins. We found a different value of ΔG (free energy of binding) among the studied proteins ranging between -3.29 to -7.25 kcal/mol was observed. To validate the results, we considered Human Oxy-Hemoglobin at 1.25 Å Resolution, [PDB_ID:1HHO] as a +ve control, (binding energy -6.06 kcal/mol). Finally, the CDK8 (PDB_ID:3RGF) and CDK2 (PDB_ID:3DDP) regulatory proteins showing significantly strong molecular interaction with NNK -7.25 kcal/mol, -6.19 kcal/mol respectively were analyzed in details. In this study we predicted that CDK8 protein fails to form functional complex with its complementary partner cyclin C in presence of NNK. Consequently, inconsistency of functioning in regulatory proteins might lead to the abruption in cell cycle progression; contribute to the loss of cell cycle control and subsequently increasing the possibility of carcinogenesis

Effect of laser micro-drilling parameters on hole geometry and hole formation of thin sheet SS304

The recent advances in manufacturing technology have led to the development of miniature products in the field of automobiles, aerospace, and robotics. Laser micro-drilling has developed as a potential substitute over conventional machining due to the advantages of operational precision, reduced operational costs, and a high-speed production rate. This process involves high power intensity from the laser to break down the bond between molecules of the workpiece and hence form a hole on the workpiece. This project aims to study the effect of laser power on the drilled hole geometry and to analyse the mechanism of the hole formation during laser micro-drilling. The material used in this project is SS304 sheet metal. The holes’ geometry and hole formation will be analysed by using an optical microscope. The size of the hole diameter for each power is almost the same in the range of 101.669–102.978 μm for the frontside. Meanwhile, the diameter of the backside hole increases from 64.343 μm to 88.852 μm at 15 W to 21 W of laser power respectively. For hole formation, the more material is ablated as the ablation process advances. As a result, the removal area from the micro-drilled hole grows from 3577.852 to 6516.237 m2. The shape of the hole is irregular due to the uneven power distribution of the laser towards the SS304 sheet metal when it undergoes an ablation process

Microstructure analysis and mechanical properties of dissimilar AA6061-AA7075 laser brazing with prefixed ER5356 filler

Laser brazing uses a filler metal for joining without melting the base material. This process is a versatile joining technique for a wide range of applications including automotive, aerospace, and medical field because of the ability in joining dissimilar metal and resulted good quality in surface's joint. This study consists of aluminium alloy of AA6061 and AA7075 as a base material with aluminium based ER5356 as a wire filler. Laser brazing was performed using 1.2 kW of laser power, while wire filler was let to be prefixed without using the wire feeder because of using the existing laser welding machine. Microstructure of the joints were studied using 3D measuring laser microscope OLS5000. Besides that, mechanical properties of the joints were evaluated by performing tensile test and hardness test. Microstructures of the brazed joints show the differences in the grain structure followed by the difference's hardness value on each region. The brazed joint shows the average ultimate tensile strength reached 154.71 MPa which was 50% of joint efficiency. However, there is porosities at the fracture surface of the joint

Effect of filler composition on microstructure and mechanical properties of MIG welded AA6061 and AA7075

Nowadays, aluminium alloy is hugely applied in the automotive and aircraft sector due to its lightweight and considerable hardness. For joining aluminium alloys, fusion welding methods are widely used due to its low cost. Apart from that, Metal Inert Gas (MIG) was generally applied by welders. Be that as it may, different filler compositions utilised in MIG welding dissimilar aluminum alloy can create a different microstructure, and defect happens during welding and influencing joint microstructure, and mechanical properties. The aim of this study is to identify the weldability, study the mechanical properties and investigate the effect of alloy element on microstructure of joining aluminium alloy AA6061 and AA7075. In order to achieve comparable welded quality and appearance, the welding parameters used for all setup must be the same. Four different types of filler metal were used, which were ER4043, ER4047, ER5183 and ER5356. For Vickers hardness and tensile test, a few samples from the welded specimens will be cut by using EDM wire cut machine, following the ASTM-E8 standard. The microstructure will be analysed using the same sample used for the hardness test. Meanwhile, for tensile test result, the ultimate tensile strength (UTS) of filler ER4047 with 13% silicon is the highest, 170.2 MPa, followed by filler ER5356 with 5% magnesium, 161.8 MPa, slightly decreased by filler ER4043 with 6% silicon and ER5183 with 4% magnesium are 159.78 and 159.6 MPa. All samples are fracture at AA6061 side for the hardness test. Base metal (BM) AA6061 gives a lower value than the heat affected zone (HAZ) and fusion (FZ) of both materials. The variations in the grain structure are seen by the microstructures of welded joints. By visual inspection, the defects presented in the welded joint were detected from its macrostructure

Effectiveness of Antibiotic Prophylaxis for Leptospirosis among Adults: A Systematic Review

Leptospirosis is one of the most widespread re-emerging zoonoses in the world. Malaysia is known to be an endemic country for human leptospirosis, with a case fatality rate of 2.11%, and an average annual incidence rate of 7.80 cases per 100,000 individuals. This systematic review is conducted to determine the effectiveness of antibiotic prophylaxis for leptospirosis among the adult populations who are highly at risk of getting infected. A systematic search was performed for the relevant titles, abstracts and keywords on PubMed, Scopus, Cochrane and Google Scholar from inception to November 2017 based on the PICO strategy; which returned 126 studies. Screening of abstracts had shortlisted 19 studies and data extraction was conducted for 8 studies which had been accepted after review of the full text. For the evaluation of antibiotics prophylaxis effectiveness against leptospirosis, only trials and cohort studies with risk ratio (RR) were selected. The articles were analyzed from the viewpoint of the dosage, adverse effects, study settings and effectiveness of the antibiotic prophylaxis. Using fixed effects model, pooled RR showed protective association between antibiotic prophylaxis use against the incidence of leptospirosis (RR = 0.31; 95% CI: 0.20, 0.48). Antibiotic prophylaxis for leptospirosis had been shown to be effective in preventing the incidence of the disease among high-risk populations and carries minimal adverse effects. It is recommended that the practice of antibiotic prophylaxis for leptospirosis is included in the standard protocol for leptospirosis prevention among people at high-risk, including disaster response teams and patrons of eco-sports tourism activities; with the drug of choice being doxycycline, either as a single 200 mg dose or weekly dose of 200 mg for the duration of exposure, based on the setting, duration of event and resources available

Brain-responsive neurostimulation for the treatment of adults with epilepsy in tuberous sclerosis complex: A case series

OBJECTIVE: Tuberous sclerosis complex (TSC) is a genetic disorder primarily characterized by the development of multisystem benign tumors. Epilepsy is the most common neurologic manifestation, affecting 80%-90% of TSC patients. The diffuse structural brain abnormalities and the multifocal nature of epilepsy in TSC pose diagnostic challenges when evaluating patients for epilepsy surgery. METHODS: We retrospectively reviewed the safety experience and efficacy outcomes of five adult TSC patients who were treated with direct brain-responsive neurostimulation (RNS System, NeuroPace, Inc). RESULTS: The average follow-up duration was 20 months. All five patients were responders (≥50% disabling seizure reduction) at last follow-up. The median reduction in disabling seizures was 58% at 1 year and 88% at last follow-up. Three of the five patients experienced some period of seizure freedom ranging from 3 months to over 1 year. SIGNIFICANCE: In this small case series, we report the first safety experience and efficacy outcomes in patients with TSC-associated drug-resistant focal epilepsy treated with direct brain-responsive neurostimulation

International Veterinary Epilepsy Task Force recommendations for a veterinary epilepsy-specific MRI protocol

Epilepsy is one of the most common chronic neurological diseases in veterinary practice. Magnetic resonance imaging (MRI) is regarded as an important diagnostic test to reach the diagnosis of idiopathic epilepsy. However, given that the diagnosis requires the exclusion of other differentials for seizures, the parameters for MRI examination should allow the detection of subtle lesions which may not be obvious with existing techniques. In addition, there are several differentials for idiopathic epilepsy in humans, for example some focal cortical dysplasias, which may only apparent with special sequences, imaging planes and/or particular techniques used in performing the MRI scan. As a result, there is a need to standardize MRI examination in veterinary patients with techniques that reliably diagnose subtle lesions, identify post-seizure changes, and which will allow for future identification of underlying causes of seizures not yet apparent in the veterinary literature. There is a need for a standardized veterinary epilepsy-specific MRI protocol which will facilitate more detailed examination of areas susceptible to generating and perpetuating seizures, is cost efficient, simple to perform and can be adapted for both low and high field scanners. Standardisation of imaging will improve clinical communication and uniformity of case definition between research studies. A 6–7 sequence epilepsy-specific MRI protocol for veterinary patients is proposed and further advanced MR and functional imaging is reviewed

The role of dialectical interrogation in review studies : theorizing from what we see rather than what we have already seen

Review‐centric works receive increasing attention for generating insightful contributions to management and organization studies. Despite this, the literature on theory building has taken little note of their place in the theorizing process. This deserves attention, however, given the challenges reviews face in theorizing in the absence of new empirical observations. Accordingly, these works run the risk of merely summarizing ‘what we have already seen’, instead of ‘maximizing what we see’. Drawing on the strategies of theorizing from similarities and theorizing from anomalies, we propose dialectical interrogation as a critical step in theorizing through which review scholars imaginatively engage in a back and forth inquiry between the phenomenal world of a given field and existing theory. By analyzing selected review studies from top management journals, we reveal that theorizing outcomes occur through two ways of dialectical interrogation (consolidative and disruptive). We contribute by demonstrating that review scholars can enter into powerful theorizing through the consolidative or disruptive interrogation of the review data with extant theory to detect emergence and novelty alongside puzzles, conflicts and paradoxes. Dialectical interrogation can address the shortcomings of current theorizing in review‐centric works and bears potential for advancing theories of management and organization studies.Publisher PDFPeer reviewe

Establishing a library of resources to help people understand key concepts in assessing treatment claims—The “Critical thinking and Appraisal Resource Library” (CARL)

Background People are frequently confronted with untrustworthy claims about the effects of treatments. Uncritical acceptance of these claims can lead to poor, and sometimes dangerous, treatment decisions, and wasted time and money. Resources to help people learn to think critically about treatment claims are scarce, and they are widely scattered. Furthermore, very few learning-resources have been assessed to see if they improve knowledge and behavior. Objectives Our objectives were to develop the Critical thinking and Appraisal Resource Library (CARL). This library was to be in the form of a database containing learning resources for those who are responsible for encouraging critical thinking about treatment claims, and was to be made available online. We wished to include resources for groups we identified as ‘intermediaries’ of knowledge, i.e. teachers of schoolchildren, undergraduates and graduates, for example those teaching evidence-based medicine, or those communicating treatment claims to the public. In selecting resources, we wished to draw particular attention to those resources that had been formally evaluated, for example, by the creators of the resource or independent research groups. Methods CARL was populated with learning-resources identified from a variety of sources—two previously developed but unmaintained inventories; systematic reviews of learning-interventions; online and database searches; and recommendations by members of the project group and its advisors. The learning-resources in CARL were organised by ‘Key Concepts’ needed to judge the trustworthiness of treatment claims, and were made available online by the James Lind Initiative in Testing Treatments interactive (TTi) English (www.testingtreatments.org/category/learning-resources).TTi English also incorporated the database of Key Concepts and the Claim Evaluation Tools developed through the Informed Healthcare Choices (IHC) project (informedhealthchoices.org). Results We have created a database of resources called CARL, which currently contains over 500 open-access learning-resources in a variety of formats: text, audio, video, webpages, cartoons, and lesson materials. These are aimed primarily at ‘Intermediaries’, that is, ‘teachers’, ‘communicators’, ‘advisors’, ‘researchers’, as well as for independent ‘learners’. The resources included in CARL are currently accessible at www.testingtreatments.org/category/learning-resources Conclusions We hope that ready access to CARL will help to promote the critical thinking about treatment claims, needed to help improve healthcare choices