Hard and soft multilayered SiCN nanocoatings with high hardness and toughness

Alternate hard and soft layers increase deformation accommodation as thin hard layers slide relative to each other due to shear deformation of low modulus layers. However, the processing of such multilayers is challenging. In the present paper the alternating soft and hard multilayered SiCN coating deposited by magnetron sputtering has been studied and presented. A hardness and modulus of 37 GPa and 317 GPa with elastic recovery of 62% are achieved by alternate hard and soft layer of Si-C-N by magnetron sputtering. The trilayer films sustained even 2000 gf under indentation without failure though substrate plastically deformed. The fracture toughness value K-IC was measured to be 9.5-10 MPa m(1/2), significantly higher than many reported hard coatings

Regulation of elongation factor-1α expression by growth factors and anti-receptor blocking antibodies

The Epidermal Growth Factor (EGF) family and its receptors regulate normal and cancerous epithelial cell proliferation, a process that could be suppressed by anti-receptor blocking antibodies. Polypeptide elongation factor-1α (EF-1α) is a multifunctional protein whose levels are positively correlated with the proliferative state of cells. To identify genes, whose expression may be modulated by anti-receptor blocking antibodies, we performed a differential display screening and isolated differentially expressed cDNAs. Isolates from one clone were 100% identical to human EF-1α. Both EGF and heregulin-β1 (HRG) induced EF-1α promoter activity and mRNA and protein expression. Growth factor-mediated EF-1α expression was effectively blocked by pretreatment with humanized anti-EGF receptor antibody C225 or anti-human epidermal growth factor receptor-2 (HER2) antibody herceptin. Mutants and pharmacological inhibitors of p38MAPK and MEK, but not phosphatidylinositol 3-kinase, suppressed both constitutive and HRG-induced stimulation of EF-1α promoter activity in MCF-7 cells. Deletion analysis of the promoter suggested the requirement of the −393 to −204 region for growth factor-mediated transcription of EF-1α. Fine mapping and point mutation studies revealed a role of the SP1 site in the observed HRG-mediated regulation of the EF-1α promoter. In addition, we also provide new evidence to suggest that HRG stimulation of the EF-1α promoter involves increased physical interactions with acetylated histone H3 and histone H4. These results suggest that regulation of EF-1α expression by extracellular signals that function through human EGF receptor family members that are widely deregulated in human cancers and that growth factor regulation of EF-1α expression involve histone acetylation

MTA1 Interacts with MAT1, a cyclin-dependent kinase-activating kinase complex ring finger factor and regulates estrogen receptor transactivation functions

The transcriptional activity of estrogen receptor-α is controlled by coregulators. MTA1 (metastasis-associated protein1) represses estrogen receptor-α-driven transcription by recruiting Histone Deacetylases (HDACs) to the estrogen response element containing target gene chromatin in breast cancer cells. Using a yeast two-hybrid screen with the MTA1 C-terminal domain as bait, we identified MAT1 (menage a trois 1) as an MTA1-binding protein. MAT1 is an assembly/targeting factor for cyclin-dependent kinase-activating kinase (CAK), which has been shown to functionally interact with general transcriptional factor TFIIH, a known inducer of ER transactivation. We show that estrogen signaling promotes nuclear translocation of MAT1 and that MTA1 interacts with MAT1 both in vitro and in vivo. MAT1 binds to the C-terminal 389–441 amino acids GATA domain and N-terminal 1–164 amino acids bromo-domain of MTA1, whereas MTA1 binds to the N-terminal ring finger domain of the MAT1. In addition, MAT1 interacts with the activation function 2 domain of ER and colocalizes with ER in activated cells. MTA1 deregulation in breast cancer cells led to its interactions with the CAK complex components, ER and HDAC2. Accordingly, MTA1 inhibited CAK stimulation of ER transactivation that was partially relieved by HDAC inhibitor trichostatin A, suggesting that MTA1 might inhibit CAK-induced transactivation function of ER by recruiting HDAC. Furthermore, MTA1 overexpression inhibited the ability of CAK complex to phosphorylate ER. Together, these findings identified MAT1 as a target of MTA1 and provided new evidence to suggest that the transactivation functions of ER might be influenced by the regulatory interactions between CAK and MTA1 in breast cancer cells

Development and Validation of a Digital (Peek) Near Visual Acuity Test for Clinical Practice, Community-Based Survey, and Research

PURPOSE: Unaddressed near vision impairment (NVI) affects more than 500 million people. Testing near vision is necessary to identify those in need of services. To make such testing readily accessible, we have developed and validated a new smartphone-based near visual acuity (NVA) test: Peek Near Vision (PeekNV). METHODS: Two forms of the PeekNV test were developed: (1) quantitative measurement of NVA, and (2) binary screening test for presence or absence of NVI. The validity study was carried out with 483 participants in Sagarmatha Choudhary Eye Hospital, Lahan, Nepal, using a conventional Tumbling "E" Near Point Vision Chart as the reference standard. Bland-Altman limits of agreement (LoA) were used to evaluate test agreement and test-retest repeatability. NVI screening was assessed using Cohen's kappa coefficient, sensitivity, and specificity. RESULTS: The mean difference between PeekNV and chart NVA results was 0.008 logMAR units (95% confidence interval [CI], -0.005 to 0.021) in right eye data, and the 95% LoA between PeekNV and chart testing were within 0.235 and -0.218 logMAR. As a NVI screening tool, the overall agreement between tests was 92.9% (κ = 0.85). The positive predictive value of PeekNV was 93.2% (95% CI, 89.6% to 96.9%), and the negative predictive value 92.7% (95% CI, 88.9% to 96.4%). PeekNV had a faster NVI screening time (11.6 seconds; 95% CI, 10.5 to 12.6) than the chart (14.9 seconds; 95% CI, 13.5 to 16.2; P < 0.001). CONCLUSIONS: The PeekNV smartphone-based test produces rapid NVA test results, comparable to those of an accepted NV test. TRANSLATIONAL RELEVANCE: PeekNV is a validated, reliable option for NV testing for use with smartphones or digital devices

Topical Chlorhexidine 0.2% versus Topical Natamycin 5% for the Treatment of Fungal Keratitis in Nepal: A Randomized Controlled Noninferiority Trial.

PURPOSE: To investigate if topical chlorhexidine 0.2%, which is low cost and easy to formulate, is noninferior to topical natamycin 5% for the treatment of filamentous fungal keratitis. DESIGN: Randomized controlled, single-masked, noninferiority clinical trial. PARTICIPANTS: Adults attending a tertiary-level ophthalmic hospital in Nepal with filamentous fungal infection confirmed on smear or confocal microscopy. METHODS: Participants were randomly allocated to receive topical chlorhexidine 0.2% or topical natamycin 5%. Primary analysis (intention-to-treat) was by linear regression, using baseline logarithm of the minimum angle of resolution (logMAR) best spectacle-corrected visual acuity (BSCVA) and treatment arm as prespecified covariates. Mixed fungal-bacterial infections were excluded from the primary analysis but included in secondary analyses and secondary safety-related outcomes. The noninferiority margin was 0.15 logMAR. This trial was registered with ISRCTN, number ISRCTN14332621. MAIN OUTCOME MEASURES: The primary outcome measure was BSCVA at 3 months. Secondary outcome measures included perforation or therapeutic penetrating keratoplasty by 90 days. RESULTS: Between June 3, 2019, and November 9, 2020, 354 eligible participants were enrolled and randomly assigned: 178 to chlorhexidine and 176 to natamycin. Primary outcome data were available for 153 and 151 of the chlorhexidine and natamycin groups, respectively. Of these, mixed bacterial-fungal infections were found in 20 cases (12/153 chlorhexidine, 8/151 natamycin) and excluded from the primary analysis. Therefore, 284 patients were assessed for the primary outcome (141 chlorhexidine, 143 natamycin). We did not find evidence to suggest chlorhexidine was noninferior to natamycin and in fact found strong evidence to suggest that natamycin-treated participants had significantly better 3-month BSCVA than chlorhexidine-treated participants, after adjusting for baseline BSCVA (regression coefficient, -0.30; 95% confidence interval [CI], -0.42 to -0.18; P < 0.001). There were more perforations and emergency corneal grafts in the chlorhexidine arm (24/175, 13.7%) than in the natamycin arm (10/173, 5.8%; P = 0.018, mixed infections included), whereas natamycin-treated cases were less likely to perforate or require an emergency corneal graft, after adjusting for baseline ulcer depth (odds ratio, 0.34; 95% CI, 0.15-0.79; P = 0.013). CONCLUSIONS: Treatment with natamycin is associated with significantly better visual acuity, with fewer adverse events, compared with treatment with chlorhexidine. Natamycin remains the preferred first-line monotherapy treatment for filamentous fungal keratitis

Role of traditional healers in the management of microbial keratitis in eastern Nepal [version 2; peer review: 1 approved, 1 approved with reservations]

Background Microbial Keratitis (MK) is a leading cause of corneal blindness due to infection and its consequences, with a higher incidence in resource-limited nations. Hospital-based patient records from different parts of Nepal suggest patients often use traditional eye medicine to treat MK. Traditional healers (TH) within the community are often the first point of care for MK management. Little is known of their practice, perceptions, and knowledge around MK management. We aimed to understand the role of traditional healers in the management of MK in south-eastern Nepal. Methods A cross-sectional, mixed method, descriptive study was conducted in the Siraha district of Nepal. A total of 109 traditional healers consented to participate in a survey of knowledge, attitude, and practices. Some participants were also invited to participate in in-depth interviews and focus group discussions. Interviews and focus groups were conducted and recorded in the Maithili language by a native speaking interviewer and transcribed into English. Descriptive analysis was performed for the survey. Data saturation was considered the endpoint for qualitative data collection, and a thematic was analysis applied. Results Traditional healers believe that infection of the eye can be caused by trauma, conjunctivitis, or evil spirits. They were unclear about differentiating MK from other eye conditions. They provided various types of treatment. Some were confident that they could treat severe ulcers that had not responded to medical therapy, while others thought treating larger diameter ulcers would be difficult. Although there were mixed responses in referring patients with MK, the majority of TH were willing to refer. Conclusion In a weak health system, traditional healers may help address barriers to healthcare access and reduce delays to definitive care, upon integration into the formal health system and referral pathway

Radiatively driven electron-positron jets from two component accretion flows

Matter accreting onto black holes has long been known to have standing or oscillating shock waves. The post-shock matter puffs up in the form of a torus, which intercepts soft photons from the outer Keplerian disc and inverse Comptonizes to produce hard photons. The post-shock region also produces jets. We study the interaction of both hard photons and soft photons, with on-axis electron-positron jets. We show that the radiation from post-shock torus accelerates the flow to relativistic velocities, while that from the Keplerian disc has marginal effect. We also show that, the velocity at infinity or terminal velocity ${\vartheta}$, depends on the shock location in the disc.Comment: 24 pages, 8 figures, accepted in MNRA

An integrated organic farming system: innovations for farm diversification, sustainability, and livelihood improvement of hill farmers

IntroductionOrganic farming is a promising solution for mitigating environmental burdens related to input-intensive agricultural practices. The major challenge in organic agriculture is the non-availability of large quantities of organic inputs required for crop nutrition and sustaining soil health, which can be resolved by efficient recycling of the available on- and off-farm resources and the integration of the components as per the specific locations.MethodsAn integrated organic farming system (IOFS) model comprising agricultural and horticultural crops, rainwater harvesting units, livestock components, and provisions for nutrient recycling was developed and disseminated in the adopted organic villages Mynsain, Pynthor, and Umden Umbathiang in the Ri-Bhoi District, Meghalaya, India, to improve the income and livelihood of farmers. Harvested rainwater in farm ponds and Jalkunds was used for live-saving irrigation in the winter months and diversified homestead farming activities, such as growing high-value crops and rearing cattle, pigs, and poultry.ResultsMaize, french bean, potato, ginger, tomato, carrot, and chili yields in the IOFS model increased by 20%−30%, 40%−45%, 25%−30%, 33%−40%, 45%−50%, 37%−50%, and 27%−30%, respectively, compared with traditional practices. Some farmers produced vermicompost in vermibeds (made of high-density polyethylene) and cement brick chambers, generating 0.4−1.25 tons per annum. Two individual farmers, Mr. Jrill Makroh and Mrs. Skola Kurbah obtained net returns (without premium price) of Rs. 46,695 ± 418 and Rs. 31,102 ± 501 from their respective 0.27- and 0.21-ha IOFS models, which is equivalent to Rs. 172,944 ± 1,548/ha/year and Rs. 148,105 ± 2,385/ha/year, respectively. The net returns obtained from the IOFS models were significantly higher than those obtained from the farmers' practice of maize-fallow or cultivation of maize followed by vegetable (~30% of the areas). It is expected that, with the certification of organic products, the income and livelihood of the farmers will improve further over the years. While Mr. Jrill Makroh's model supplied 95.1%, 82.0%, and 96.0% of the total N, P2O5, and K2O, respectively, needed by the system, Mrs. Skola Kurbah's model supplied 76.0%, 68.6%, and 85.5% of the total N, P2O5, and K2O, respectively.DiscussionThus, IOFS models should be promoted among hill farmers so that they can efficiently recycle farm resources and increase their productivity, net returns, and livelihood while reducing their dependence on external farm inputs

3, 3′5 Triiodo L Thyronine Induces Apoptosis in Human Breast Cancer MCF-7cells, Repressing SMP30 Expression through Negative Thyroid Response Elements

Thyroid hormones regulate cell proliferation, differentiation as well as apoptosis. However molecular mechanism underlying apoptosis as a result of thyroid hormone signaling is poorly understood. The antiapoptotic role of Senescence Marker Protein-30 (SMP30) has been characterized in response to varieties of stimuli as well as in knock out model. Our earlier data suggest that thyroid hormone 3, 3'5 Triiodo L Thyronine (T(3)), represses SMP30 in rat liver.In highly metastatic MCF-7, human breast cancer cell line T3 treatment repressed SMP30 expression leading to enhanced apoptosis. Analysis by flow cytometry and other techniques revealed that overexpression and silencing of SMP30 in MCF-7 resulted in decelerated and accelerated apoptosis respectively. In order to identify the cis-acting elements involved in this regulation, we have analyzed hormone responsiveness of transiently transfected hSMP30 promoter deletion reporter vectors in MCF-7 cells. As opposed to the expected epigenetic outcome, thyroid hormone down regulated hSMP30 promoter activity despite enhanced recruitment of acetylated H3 on thyroid response elements (TREs). From the stand point of established epigenetic concept we have categorised these two TREs as negative response elements. Our attempt of siRNA mediated silencing of TRβ, reduced the fold of repression of SMP30 gene expression. In presence of thyroid hormone, Trichostatin- A (TSA), which is a Histone deacetylase (HDAC) inhibitor further inhibited SMP30 promoter activity. The above findings are in support of categorisation of both the thyroid response element as negative response elements as usually TSA should have reversed the repressions.This is the first report of novel mechanistic insights into the remarkable downregulation of SMP30 gene expression by thyroid hormone which in turn induces apoptosis in MCF-7 human breast cancer cells. We believe that our study represents a good ground for future effort to develop new therapeutic approaches to challenge the progression of breast cancer

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure