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This paper deals with minimization of sink depths in injection-molded thermoplastic components by integrating finite element (FE) flow analysis with central composite design (CCD) of experiments and genetic algorithm (GA). Sink-mark depth depends on various process and design variables. Out of all, four most influential variables viz. melt temperature, mold temperature, pack pressure, and rib-to-wall ratio were used for optimization. A set of FE analyses were conducted at various combinations of variables based on the CCD array. A second-order-response surface regression model (RSRM) was developed based on the CCD. The second-order model was effectively coupled with GA for optimization of variables to minimize the sink depth. Results are encouraging and the proposed methodology could be used effectively in minimizing sink-mark depths.

This paper deals with prediction of sink mark defects and its intensities on injection-molded thermoplastics components. A nonlinear mathematical model, in terms of injection molding variables, was developed using response surface methodology. Fractional factorial design (FFD) of experiments was used for initial screening of variables. Based on FFD, the four most influential and controllable injection molding variables were selected. Central composite design (CCD) of experiments was structured and conducted using flow simulation to formulate the predictive nonlinear model. Statistical analysis and experimental results suggest that the proposed model could be used for predicting sink mark depths with adequate accuracy. It indicates that this predictive model can be used for drawing tailor-made guidelines for designing as well as for processing. If it is applied at design stage, corrective and iterative design steps can be initiated and implemented for better quality of products without resorting to physical trials on molds. Proposed methodology can also be effectively employed in controlling the quality of products throughout the product life cycle.

Biallelic mutations in ACP5, encoding tartrate-resistant acid phosphatase (TRACP), have recently been identified to cause the inherited immuno-osseous disorder, spondyloenchondrodysplasia (SPENCD). This study was undertaken to characterize the eight reported missense mutations in ACP5 associated with SPENCD on TRACP expression. ACP5 mutant genes were synthesized, transfected into human embryonic kidney (HEK-293) cells and stably expressing cell lines were established. TRACP expression was assessed by cytochemical and immuno-cytochemical staining with a panel of monoclonal antibodies. Analysis of wild (WT) type and eight mutant stable cell lines indicated that all mutants lacked stainable enzyme activity. All ACP5 mutant constructs were translated into intact proteins by HEK-293 cells. The mutant TRACP proteins displayed variable immune reactivity patterns, and all drastically reduced enzymatic activity, revealing that there is no gross inhibition of TRACP biosynthesis by the mutations. But they likely interfere with folding thereby impairing enzyme function. TRACP exists as two isoforms. TRACP 5a is a less active monomeric enzyme (35kD), with the intact loop peptide and TRACP 5b is proteolytically cleaved highly active enzyme encompassing two subunits (23 kD and 16 kD) held together by disulfide bonds. None of the mutant proteins were proteolytically processed into isoform 5b intracellularly, and only three mutants were secreted in significant amounts into the culture medium as intact isoform 5a-like proteins. Analysis of antibody reactivity patterns revealed that T89I and M264K mutant proteins retained some native conformation, whereas all others were in \"denatured\" or \"unfolded\" forms. Western blot analysis with intracellular and secreted TRACP proteins also revealed similar observations indicating that mutant T89I is amply secreted as inactive protein. All mutant proteins were attacked by Endo-H sensitive glycans and none could be activated by proteolytic cleavage in vitro. In conclusion, determining the structure-function relationship of the SPENCD mutations in TRACP will expand our understanding of basic mechanisms underlying immune responsiveness and its involvement in dysregulated bone metabolism.

Many intrinsically disordered proteins self-assemble into liquid droplets that function as membraneless organelles. Because of their biological importance and ability to colocalize molecules at high concentrations, these protein compartments represent a compelling target for bio-inspired materials engineering. Here we manipulated the intrinsically disordered, arginine/glycine-rich RGG domain from the P granule protein LAF-1 to generate synthetic membraneless organelles with controllable phase separation and cargo recruitment. First, we demonstrate enzymatically triggered droplet assembly and disassembly, whereby miscibility and RGG domain valency are tuned by protease activity. Second, we control droplet composition by selectively recruiting cargo molecules via protein interaction motifs. We then demonstrate protease-triggered controlled release of cargo. Droplet assembly and cargo recruitment are robust, occurring in cytoplasmic extracts and in living mammalian cells. This versatile system, which generates dynamic membraneless organelles with programmable phase behavior and composition, has important applications for compartmentalizing collections of proteins in engineered cells and protocells. Designer organelles with new biochemical functionalities are of great interest in synthetic biology and cellular engineering. Here the authors present a single-protein-based platform for generating synthetic membraneless compartments that is capable of enzymatically-triggered alterations to phase behavior and of recruiting and concentrating cargo proteins.

Polyubiquitination promotes proteasomal degradation, or signaling and localization, of targeted proteins. Here we show that the E3 ubiquitin ligase Hectd3 is necessary for pathogenic Th17 cell generation in experimental autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. Hectd3-deficient mice have lower EAE severity, reduced Th17 program and inefficient Th17 cell differentiation. However, Stat3, but not RORγt, has decreased polyubiquitination, as well as diminished tyrosine-705 activating phosphorylation. Additionally, non-degradative polyubiquitination of Malt1, critical for NF-κB activation and Th17 cell function, is reduced. Mechanistically, Hectd3 promotes K27-linked and K29-linked polyubiquitin chains on Malt1, and K27-linked polyubiquitin chains on Stat3. Moreover, Stat3 K180 and Malt1 K648 are targeted by Hectd3 for non-degradative polyubiquitination to mediate robust generation of RORγt + IL-17A hi effector CD4 + T cells. Thus, our studies delineate a mechanism connecting signaling related polyubiquitination of Malt1 and Stat3, leading to NF-kB activation and RORγt expression, to pathogenic Th17 cell function in EAE. Ubiquitination may control protein stability or function. Here the authors show that an ubiquitination enzyme, Hectd3, ubiquitinates Stat3 and Malt1 to modulate their function but not degradation in T cells, and thereby promoting the differentiation of pathogenic Th17 cells and susceptibility to a mouse model of multiple sclerosis.

The black clam ( Villorita cyprinoides Gray, 1825) is the most commercially important clam in India and the major share of its landing (around 25,000 tonnes/year) comes from Kochi backwaters (KBW), the largest estuarine system on the west coast of India, where approximately 4000 fishermen harvest them year-round. This study based on recent and historical data sets, comprehended how multiple anthropogenic stressors impact the black clam distribution in the KBW. In the first part, a recent data set from an extensive hydrographic and sediment sampling from 22 locations in the central and southern sections of the KBW during the Pre-Monsoon (March), Southwest Monsoon (July), and Northeast Monsoon (December) was introduced to demarcate the most conducive salinity and sediment textural conditions of black clam. Black clam in the KBW prefer midstream and upstream regions with mesohaline to oligohaline conditions and sand-dominant substratum, but their current distribution is shaped by multiple anthropogenic stressors, notably the consequence of the installation of the Thannermukkom Barrage (TB) in 1975 to prevent saltwater intrusion for paddy cultivation. The combination of current and historical data, supplemented with literature, demonstrates that TB generated various stressors on the natural distribution, resulting in a decrease in the abundance of black clam in the KBW. This includes (a) shrinkage and relocation of their most preferred salinity zones (mesohaline) for spawning from the south of TB (Vembanad) to the north of TB, (b) the increased siltation due to stagnancy in the Vembanad caused by TB increased the contribution of finer particles especially clay in the bottom substratum, which is less preferred over sand by black clam and (c) the opening and closing of the TB shutters cause salt shock causing vast mortality of black clam on both sides of TB. Secondary stressors of TB are affected by (a) poor water quality, eutrophication, and massive spread of hyacinth mats, making it difficult for local fishermen to exploit the black clam resource, and (b) overexploitation of the black clam in certain areas due to shrinkage in the total area and relocation of the conducive spawning environment in KBW.

The starch was blended with poly(vinyl) alcohol (PVA) to develop PVA/starch (PS) hydrogel. The physical interaction of PVA with starch was concluded by FTIR and XRD techniques. The thermal decomposition behavior of PS hydrogel was analyzed by thermogravimetric analysis. The swelling index and moisture loss analysis was carried out to comprehend the water absorption and retention behavior of PS hydrogel. The PS hydrogel was biocompatible with RBC due to its lower hemolysis value. The curcumin-loaded PS hydrogel showed an excellent anticancer activity against breast cancer cell line. The antibacterial activity of cephalosporin-loaded PS hydrogel was evaluated against the Staphylococcus aureus . Graphical abstract Highlights The PVA/mannitol hydrogel was prepared to study its drug delivery potential. The PM hydrogel effectively delivered the drugs against MCF-7 and pathogenic strains. The PM hydrogel exhibited an excellent water retention ability. The prepared PM hydrogel was non-hemolytic to red blood cells.

Selective logging disrupts forests, changing their structure and species composition. Long-term monitoring helps in identifying the factors influencing it and aids in designing management plans. We conducted a quantitative re-assessment of trees ≥ 30 cm girth at breast height in four 1 ha plots in logged and two 1 ha plots in adjacent unlogged compartments of Uppangala forest continuum in the Western Ghats, India to compare the structural and compositional changes after a decade (2010–2021). Altogether, four species disappeared and three species were newly recruited. Mean species richness and stem density of both the forest sites decreased. Logged plots showed a slight increase in basal area (2.5%) and biomass (5.1%), whereas unlogged plots showed a decline in basal area (3.92%) and biomass (2.9%). As compared to unlogged plots, all the demographic rates were higher for logged forest sites. Across the six individual plots, the growth rates varied significantly owing to wood density and forest strata categories. Non-metric multidimensional scaling (NMDS) identified three groups with significant difference in species composition, where logged and unlogged plots have a distinct composition except for one plot. Although species richness and stem diversity remained stable, the species composition is different 37 years after logging, and the impacts of logging are still evident in the forest.

Climate-related hazards, urban development and changing vulnerability patterns compel cities across the world to deal with new and emerging forms of risk. Academic literature and recent international policy documents suggest potentials of conceptually and practically linking the fields of climate change adaptation (CCA) and disaster risk reduction (DRR) and emphasize the need to mitigate climate-related risks at local level. However, there is limited knowledge on how this link is established at local levels and the role of ground-level actors and practices therein. Using the case of recurrent and disastrous floods, this paper discusses the significance of linking DRR and CCA in Mumbai. It analyses policies, plans, institutions and interventions related to DRR and CCA and uses interviews and a field study to assess flood risk governance at the level of municipal wards and neighbourhoods. The findings suggest that although flood risk governance has been significantly strengthened, three gaps exist: First, a lack of a comprehensive plan for Mumbai that anticipates future risks and vulnerabilities and integrates CCA and DRR down to local level. Second, a lack of an overarching and decentralized institutional framework across sectors and scales that recognizes the multiplicity of formal and informal actors. Third, the potential of civil society and informal actors for disaster risk management and adaptation planning has not been tapped into sufficiently. The paper argues that potential exists to reconceptualize flood risk governance in Mumbai by focusing on future risks and vulnerabilities and by recognizing the work of informal actors like emergent groups at local level.

Shortening tuberculosis (TB) treatment duration is a research priority. This paper presents data from a prematurely terminated randomized clinical trial, of 4-month moxifloxacin or gatifloxacin regimens, in South India. Newly diagnosed, sputum-positive HIV-negative pulmonary TB patients were randomly allocated to receive gatifloxacin or moxifloxacin, along with isoniazid and rifampicin for 4 months with pyrazinamide for first 2 months (G or M) or isoniazid and rifampicin for 6 months with ethambutol and pyrazinamide for first 2 months (C). All regimens were administered thrice-weekly. Clinical and bacteriological assessments were done monthly during treatment and for 24 months post-treatment. The Data and Safety Monitoring Board recommended termination of the trial due to high TB recurrence rates in the G and M regimens. Of 416 patients in intent-to-treat analysis, 6 (5%) of 124, 2 (2%) of 110 and 2 (2%) of 137 patients with drug-susceptible TB in the G, M and C arms respectively had unfavorable response at the end of treatment; during the next 24 months, 17 (15%) of 115, 11 (11%) of 104 and 8 (6%) of 132 patients respectively, had TB recurrence. Of 38 drug-resistant patients 1 of 8 and 3 of 26 in the G and C arms respectively had unfavourable response at the end of treatment; and TB recurrence occurred in 2 of 7 and 2 of 23 patients, respectively. The differences in TB recurrence rates between the G and C arms was statistically significant (p = 0.02). Gastro-intestinal symptoms occurred in 23%, 22% and 9% of patients in the G, M and C arms respectively, but most reactions were mild and manageable with symptomatic measures; 1% required regimen modification. 4-month thrice-weekly regimens of gatifloxacin or moxifloxacin with isoniazid, rifampicin and pyrazinamide, were inferior to standard 6-month treatment, in patients with newly diagnosed sputum positive pulmonary TB. Clinical Trials Registry of India CTRI/2012/10/003060.