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  • Many studies reporting on discoveries of


    Many studies reporting on discoveries of DUBs in the TGFβ and BMP pathways have relied on RNAi strategies to investigate loss-of-function impact. While RNAi strategies are useful tools, there are limitations ranging from limited knockdowns of targets to potential off-target effects. New and better technologies now exist that could and should be harnessed to definitively establish the roles of selective DUBs in the TGFβ and BMP pathways. Targeted DUB knockouts in 52 6 sale (either derived from knockout mice or using CRISPR/CAS9 technology [75], [76] to knockout genes in somatic cells) could allow for restoration of DUB mutants lacking catalytic activity or substrate-interaction determinant. Further issues of potential redundancy could be addressed in such systems. The next decade is sure to address the molecular mechanisms by which DUBs regulate the TGFβ and BMP pathways.
    Conflict of interest
    Introduction Gundrilling is a machining process to produce deep holes with length to diameter ratios greater than 10. The hole diameter range from 1 to 40mm are usually constructed by gun drills with a single lip design, consists of an outer and inner cutting edges located asymmetrically over the drill diameter. Material removal achieved by the cutting edges will be breaking into smaller segments known as chips and evacuated by the high pressure coolant. As illustrated in Fig. 1, high pressure coolant is supplied through internal conduits of the drill bit to the bottom of the hole, which will subsequently diverts rapidly towards the shoulder dub-off to facilitate the breaking of the chips and carry them out of the cutting zone through the v-channel flute. Chip evacuation has a direct impact on wear rate, failure mode and life span of gun drills [1]. Chips that are not effectively evacuated will inhibit the cooling of cutting edges where heat is generated by continuous chip flow through friction. While, lubrication on the bearing surfaces will be detrimentally affected without adequate exposure of the chip formation zone – leading to excessive burnishing against the hole. As a result, the overall cutting performance will deteriorate with the drastic increase in torsional load and followed by rapid development of drill degradation [2]. To improve chip evacuation through drill design and process parameter, the understanding of chip transportation behavior is critical. Osman and Chahil [3] investigated the effects of the interface in between the drill tip and v-channel flute with an open hydraulic circuit. Three types of coolant hole configurations namely single-hole, two-hole and kidney-shaped were studied. The results showed that the two-hole design gave the best performance due to minimum hydraulic pressure loss as compared to other designs. Following that, Astakhov et al. [4] developed a close circuit apparatus that was capable to measure coolant pressure at the bottom of the hole. It was discovered that pressure distribution around the drill tip is strongly influenced by the bottom hole geometries. As the shape bottom hole is defined by the designs of the drills, the authors concluded that the respective chip transportation behavior is also directly governed by the various drill designs. In a more detailed study, Astakhov et al. [5] focused their investigation on the effects of shoulder dub-off ranging from −9° to +20° as shown in Fig. 2. It was reported that the lost in coolant pressure can be improved by increasing the dub-off angle to +20°. Although the results were sound, the actual increase in chip evacuation efficiency was not known since all the experiments were conducted without chips. Realizing the constraints of experimental techniques from the literature, the present study is focused on the development of a realistic computational fluid dynamics (CFD) model to study chip flow trajectory of chips in gundrilling. Our goal was aimed to establish qualitative understanding of the effects of drill geometries through CFD simulations, which enables the improvement of chip evacuation efficiency through drill geometric optimization. In Histone deacetyltransferase ,HDAC paper, such capabilities are demonstrated with a focused case study on shoulder dub-off design for its significant influence on coolant flow in the vicinity of the cutting zone, as motivated by its significance in previous studies [4], [5].