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101.
Krishna Kumar Aryal Suresh Mehata Sushhama Neupane Abhinav Vaidya Meghnath Dhimal Purushottam Dhakal Sangeeta Rana Chop Lal Bhusal Guna Raj Lohani Frank Herbert Paulin Renu Madanlal Garg Regina Guthold Melanie Cowan Leanne Margaret Riley Khem Bahadur Karki 《PloS one》2015,10(8)
Background
World Health Organization (WHO) estimates for deaths attributed to Non Communicable Diseases (NCDs) in Nepal have risen from 51% in 2010 to 60% in 2014. This study assessed the distribution and determinants of NCD risk factors among the Nepalese adult population.Methods and Findings
A nationally representative cross-sectional survey was conducted from Jan to June 2013 on the prevalence of NCD risk factors using the WHO NCD STEPS instrument. A multistage cluster sampling method was used to randomly select the 4,200 respondents. The adjusted prevalence ratio (APR) was used to assess the determinants of NCD risk factors using a Poisson regression model. The prevalence of current smoking (last 30 days) was 19% (95%CI:16.6-20.6), and harmful alcohol consumption (≥60 g of pure alcohol for men and ≥40 g of pure alcohol for women on an average day) was 2% (95%CI:1.4-2.9). Almost all (99%, 95%CI:98.3-99.3) of the respondents consumed less than five servings of fruits and vegetables combined on an average day and 3% (95%CI:2.7-4.3) had low physical activity. Around 21% (95%CI:19.3-23.7) were overweight or obese (BMI≥25). The prevalence of raised blood pressure (SBP≥140 mm of Hg or DBP≥90 mm of Hg) and raised blood glucose (fasting blood glucose ≥126 mg/dl), including those on medication were 26% (95%CI:23.6-28.0) and 4% (95%CI:2.9-4.5) respectively. Almost one quarter of respondents, 23% (95%CI:20.5-24.9), had raised total cholesterol (total cholesterol ≥190 mg/dl or under current medication for raised cholesterol). he study revealed a lower prevalence of smoking among women than men (APR:0.30; 95%CI:0.25-0.36), and in those who had higher education levels compared to those with no formal education (APR:0.39; 95%CI:0.26-0.58). Harmful alcohol use was also lower in women than men (APR:0.26; 95%CI:0.14-0.48), and in Terai residents compared to hill residents (APR:0.16; 95%CI:0.07-0.36). Physical inactivity was lower among women than men (APR:0.55; 95%CI:0.38-0.80), however women were significantly more overweight and obese (APR:1.19; 95%CI:1.02-1.39). Being overweight or obese was significantly less prevalent in mountain residents than in hill residents (APR:0.41; 95%CI:0.21-0.80), and in rural compared to urban residents (APR:1.39; 95%CI:1.15-1.67). Lower prevalence of raised blood pressure was observed among women than men (APR:0.69; 95%CI: 0.60-0.80). Higher prevalence of raised blood glucose was observed among urban residents compared to rural residents (APR:2.05; 95%CI:1.29-3.25). A higher prevalence of raised total cholesterol was observed among the respondents having higher education levels compared to those respondents having no formal education (APR:1.76; 95%CI:1.35-2.28).Conclusion
The prevalence of low fruit and vegetable consumption, overweight and obesity, raised blood pressure and raised total cholesterol is markedly high among the Nepalese population, with variation by demographic and ecological factors and urbanization. Prevention, treatment and control of NCDs and their risk factors in Nepal is an emerging public health problem in the country, and targeted interventions with a multi-sectoral approach need to be urgently implemented. 相似文献102.
103.
104.
Gregory L Moore Cristina Bautista Erik Pong Duc-Hanh T Nguyen Jonathan Jacinto Araz Eivazi Umesh S Muchhal Sher Karki Seung Y Chu Greg A Lazar 《MABS-AUSTIN》2011,3(6):546-557
Bispecific antibodies based on full-length antibody structures are more optimal than fragment-based formats because they benefit from the favorable properties of the Fc region. However, the homodimeric nature of Fc effectively imposes bivalent binding on all current full-length bispecific antibodies, an attribute that can result in nonspecific activation of cross-linked receptors. We engineered a novel bispecific format, referred to as mAb-Fv, that utilizes a heterodimeric Fc region to enable monovalent co-engagement of a second target antigen in a full-length context. mAb-Fv constructs co-targeting CD16 and CD3 were expressed and purified as heterodimeric species, bound selectively to their co-target antigens and mediated potent cytotoxic activity by NK cells and T cells, respectively. The capacity to co-engage distinct target antigens simultaneously with different valencies is an improved feature for bispecific antibodies with promising therapeutic implications.Key words: bispecific, mAb-Fv, Fc, heterodimer, CD16, CD3, HER2, HM1.24, anti-tumor, cancerDespite the enormous success of antibody-based therapeutics for the treatment of a variety of diseases, research efforts to improve their clinical efficacy continue. One avenue being explored is the engineering of new antigen binding sites to permit co-engagement of two distinct targets. Such engineered antibodies are commonly referred to as bispecifics, and a wide variety of formats have been described in references 1 and 2. Co-target antigens can include two targets believed to be causal in the pathology of a particular disease, e.g., two cytokines or growth factors.3–5 Alternatively, the co-target pair may be a cell surface antigen and an immune receptor such that a novel “effector” mechanism can be built into the antibody, beyond those mediated naturally by the Fc region.2In the 1980s, bispecific antibodies were made by fusing two cell lines that each produced a single monoclonal antibody (mAb).6 Although the resulting hybrid hybridoma or quadroma did produce bispecifics, they were only a minor population and extensive purification was required to isolate the desired antibody. Antibody fragments provided an engineering solution to this problem; because they lack the complex quaternary structure of a full-length antibody, multiple variable regions can be linked in single genetic constructs. Antibody fragments of many different forms have been generated, including diabodies, single chain diabodies, tandem scFvs and F(ab'')2 bispecifics.2,7 While these formats can be expressed at high levels in bacteria and, arguably, may have benefits due to their small size, they suffer from poor half-life in vivo and can present manufacturing challenges related to their production and stability. For example, the rapid clearance of some fragment-based bispecifics requires that they be infused continuously via a portable pump over one to two months.8 The principal source of these limitations for fragment formats is the lack of an antibody Fc region with its associated structural and functional benefits, including large size that precludes renal filtration; high stability; binding to various Fc ligands, one of which maintains serum persistence (the neonatal Fc receptor FcRn) and binding to proteins A and G, which facilitates large scale purification.Recent work has attempted to address the shortcomings of fragment-based bispecifics by engineering a second antigen binding site into full-length antibody-like formats.5,9–12 The presence of an Fc region in theory provides these formats with the developability and pharmacokinetic properties of standard IgG mAbs. However, because these constructs build new antigen binding sites on top of a homodimeric constant chain, binding to the new antigen is always bivalent. This consequence may pose a constraint depending on the co-targeting goal.For many immune receptors, cellular activation is accomplished by cross-linking of a monovalent binding interaction. The mechanism of cross-linking is typically mediated by antibody/antigen immune complexes, or via effector cell to target cell engagement. For example, the low affinity activating Fc gamma receptors (FcγRs) such as CD16 (FcγRIIIa) and CD32a (FcγRIIa) that mediate cellular killing bind monovalently to the antibody Fc region. While monovalent binding does not result in cellular signaling, upon effector cell engagement with the target cell, receptors are cross-linked and clustered on the cell surface, leading to activation.13 On T cells, CD3 activation occurs when its associated T-cell receptor (TCR) engages antigen-loaded major histocompatibility complex (MHC) on antigen-presenting cells in an avid cell-to-cell synapse.14 Bivalent antibodies targeting CD3 can elicit massive cytokine release, and the consequent toxicity has presented challenges for the development of anti-CD3 antibodies as drugs;15,16 in contrast, monovalent binding of CD3 in Fab17,18 and bispecific19 formats generates much lower levels of T-cell activation. For bispecifics, a consequence of this biology is that bivalent cross-linking of receptors can lead to non-specific activation of an effector cell in the absence of target cell.Thus, when the therapeutic goal is the co-engagement of an immune receptor, the desired binding may be monovalent rather than bivalent. This mode is incompatible with the majority of current full-length bispecifics. We describe an engineering solution to this problem that utilizes a heterodimeric Fc region to enable a single additional variable region to be built monomerically onto an antibody. Our new bispecific format, which we refer to as mAb-Fv, enables the simultaneous bivalent and monovalent co-engagement of distinct target antigens. 相似文献
105.
The zinc finger antiviral protein (ZAP) is a host factor that mediates inhibition of viruses in the Filoviridae, Retroviridae and Togaviridae families. We previously demonstrated that ZAP blocks replication of Sindbis virus (SINV), the prototype Alphavirus in the Togaviridae family at an early step prior to translation of the incoming genome and that synergy between ZAP and one or more interferon stimulated genes (ISGs) resulted in maximal inhibitory activity. The present study aimed to identify those ISGs that synergize with ZAP to mediate Alphavirus inhibition. Using a library of lentiviruses individually expressing more than 350 ISGs, we screened for inhibitory activity in interferon defective cells with or without ZAP overexpression. Confirmatory tests of the 23 ISGs demonstrating the largest infection reduction in combination with ZAP revealed that 16 were synergistic. Confirmatory tests of all potentially synergistic ISGs revealed 15 additional ISGs with a statistically significant synergistic effect in combination with ZAP. These 31 ISGs are candidates for further mechanistic studies. The number and diversity of the identified ZAP-synergistic ISGs lead us to speculate that ZAP may play an important role in priming the cell for optimal ISG function. 相似文献
106.
Thapa P Karki R Yoo HY Park PH Lee E Jeon KH Na Y Cho WJ Kwon Y Lee ES 《Bioorganic chemistry》2012,40(1):67-78
Designed and synthesized thirty-two 2,4-diaryl-5,6-dihydro-1,10-phenanthroline and 2,4-diaryl-5,6-dihydrothieno[2,3-h] quinoline derivatives as rigid analogs of 2,4,6-trisubstituted pyridines were evaluated for topoisomerase I and II inhibitory activities as well as cytotoxicities against several human cancer cell lines. Structure-activity relationship study showed that [2,2';6',2"]-terpyridine skeleton is important for the cytotoxicity against several human cancer cell lines. 相似文献
107.
PLAC-24 is a cytoplasmic dynein-binding protein that is recruited to sites of cell-cell contact 下载免费PDF全文
Karki S Ligon LA DeSantis J Tokito M Holzbaur EL 《Molecular biology of the cell》2002,13(5):1722-1734
We screened for polypeptides that interact specifically with dynein and identified a novel 24-kDa protein (PLAC-24) that binds directly to dynein intermediate chain (DIC). PLAC-24 is not a dynactin subunit, and the binding of PLAC-24 to the dynein intermediate chain is independent of the association between dynein and dynactin. Immunocytochemistry using PLAC-24-specific polyclonal antibodies revealed a punctate perinuclear distribution of the polypeptide in fibroblasts and isolated epithelial cells. However, as epithelial cells in culture make contact with adjacent cells, PLAC-24 is specifically recruited to the cortex at sites of contact, where the protein colocalizes with components of the adherens junction. Disruption of the cellular cytoskeleton with latrunculin or nocodazole indicates that the localization of PLAC-24 to the cortex is dependent on intact actin filaments but not on microtubules. Overexpression of beta-catenin also leads to a loss of PLAC-24 from sites of cell-cell contact. On the basis of these data and the recent observation that cytoplasmic dynein is also localized to sites of cell-cell contact in epithelial cells, we propose that PLAC-24 is part of a multiprotein complex localized to sites of intercellular contact that may function to tether microtubule plus ends to the actin-rich cellular cortex. 相似文献
108.
Pravesh M. Jain Denisse A. Gutierrez Prof. Dr. Sujeet Kumar Prof. Dr. Renato J. Aguilera Prof. Dr. Subhas S. Karki 《化学与生物多样性》2023,20(9):e202300843
A novel series of pyrazole-oxindole conjugates were prepared and characterized as potential cytotoxic agents by FT-IR, NMR and HR-MS. The cytotoxic activity of these compounds was tested in the Jurkat acute T cell leukemia, CEM acute lymphoblastic leukemia, MCF10 A mammary epithelial and MDA-MB 231 triple negative breast cancer cell lines. Among the tested conjugates, 5-methyl-3-((3-(1-phenyl)-3-(p-tolyl)-1H-pyrazol-4-yl)methylene)indolin-2-one 6h emerged as the most cytotoxic with a CC50 of 4.36+/−0.2 μM against Jurkat cells. The mechanism of cell death induced by 6h was investigated through the Annexin V-FITC assay via flow cytometry. Reactive oxygen species (ROS) accumulation, mitochondrial health and the cell cycle progression were also evaluated in cells exposed to 6h . Results demonstrated that 6h induces apoptosis in a dose-response manner, without generating ROS and/or altering mitochondrial health. In addition, 6h disrupted the cell cycle distribution causing an increase in DNA fragmentation (Sub G0-G1), and an arrest in the G0-G1 phase. Taken together, the 6h compound revealed a strong potential as an antineoplastic agent evidenced by its cytotoxicity in leukemia cells, the activation of apoptosis and restriction of the cell cycle progression. 相似文献
109.
Bandgap Narrowing in Non‐Fullerene Acceptors: Single Atom Substitution Leads to High Optoelectronic Response Beyond 1000 nm 下载免费PDF全文
Jaewon Lee Seo‐Jin Ko Martin Seifrid Hansol Lee Benjamin R. Luginbuhl Akchheta Karki Michael Ford Katie Rosenthal Kilwon Cho Thuc‐Quyen Nguyen Guillermo C. Bazan 《Liver Transplantation》2018,8(24)
Two narrow bandgap non‐fullerene acceptors (NBG‐NFAs), namely, COTIC‐4F and SiOTIC‐4F, are designed and synthesized for the fabrication of efficient near‐infrared organic solar cells (OSCs). The chemical structures of the NBG‐NFAs contain a D′‐D‐D′ electron‐rich internal core based on a cyclopentadithiophene (or dithienosilole) (D) and alkoxythienyl (D′) core, end‐capped with the highly electron‐deficient unit 2‐(5,6‐difluoro‐3‐oxo‐2,3‐dihydro‐1H‐inden‐1‐ylidene)malononitrile (A), ultimately providing a A‐D′‐D‐D′‐A molecular configuration that enhances the intramolecular charge transfer characteristics of the excited states. One can thereby reduce the optical bandgap (Egopt) to as low as ≈1.10 eV, one of the smallest values for NFAs reported to date. In bulk‐heterojunction (BHJ) OSCs, NBG‐NFA blends with the polymer donor PTB7‐Th yield power conversion efficiencies (PCE) of up to 9.0%, which is particularly high when compared against a range of NBG BHJ blends. Most significantly, it is found that, despite the small energy loss (Egopt ? eVOC) of 0.52 eV, the PTB7‐Th/NBG‐NFA bulk heterojunction blends can yield short‐circuit current densities of up to 22.8 mA cm?2, suggesting that the design and application of NBG‐NFA materials have substantial potential to further improve the PCE of OSCs. 相似文献
110.
Brecht Devleesschauwer Arjun Aryal Barun Kumar Sharma Anita Ale Anne Declercq Stephanie Depraz Tara Nath Gaire Gyanendra Gongal Surendra Karki Basu Dev Pandey Sher Bahadur Pun Luc Duchateau Pierre Dorny Niko Speybroeck 《PLoS neglected tropical diseases》2016,10(2)