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Taniya Sharma Nikita Kundu Sarvpreet Kaur Amlan Chakraborty Aman Kumar Mahto Rikeshwer Prasad Dewangan Jadala Shankaraswamy Sarika Saxena 《RSC advances》2022,12(34):21760
Research in recent decades has revealed that the guanine (G)-quadruplex secondary structure in DNA modulates a variety of cellular events that are mostly related to serious diseases. Systems capable of regulating DNA G-quadruplex structures would therefore be useful for the modulation of various cellular events to produce biological effects. A high specificity for recognition of telomeric G-quadruplex has been observed for BLM helicase. We identified peptides from the HRDC domain of BLM using a molecular docking approach with various available solutions and crystal structures of human telomeres and recently created a peptide library. Herein, we tested one peptide (BLM HRDC peptide) from the library and examined its interaction with human telomeric variant-1 (HTPu-var-1) to understand the basis of G4-protein interactions. Our circular dichroism (CD) data showed that HTPu-var-1 folded into an anti-parallel G-quadruplex, and the CD intensity significantly decreased upon increasing the peptide concentration. There was a significant decrease in hypochromicity due to the formation of G-quadruplex-peptide complex at 295 nm, which indicated the unfolding of structure due to the decrease in stacking interactions. The fluorescence data showed quenching upon titrating the peptide with HTPu-var-1-G4. Electrophoretic mobility shift assay confirmed the unfolding of the G4 structure. Cell viability was significantly reduced in the presence of the BLM peptide, with IC50 values of 10.71 μM and 11.83 μM after 72 and 96 hours, respectively. These results confirmed that the selected peptide has the ability to bind to human telomeric G-quadruplex and unfold it. This is the first report in which a peptide was identified from the HRDC domain of the BLM G4-binding protein for the exploration of the G4-binding motif, which suggests a novel strategy to target G4 using natural key peptide segments.Schematic representation of (HTPu–var-1-G4) located at the 3′ end, formation of G-quadruplex, model of the G-quadruplex structure, base stacking between G-quadruplex planes, G-quadruplex structure-peptide complex and twisting of G-quadruplex planes upon peptide binding. 相似文献
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Venkata Subramanian Krishnaraju Harmandeep Singh Rajender Kumar Sarika Sharma Bhagwant Rai Mittal Anish Bhattacharya 《The British journal of radiology》2021,94(1122)
Localizing the sites of infection in the body is possible in nuclear medicine using a variety of radiopharmaceuticals that target different components of the infective and inflammatory cascade. Gamma(γ)-emitting agents such as [67Ga]gallium citrate were among the first tracers used, followed by development of positron-emitting tracers like 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG). Though these tracers are quite sensitive, they have limited specificity for infection due to their concentration in sites of non-infective inflammation. White blood cells (WBC) labelled with γ or positron emitters have higher accuracy for differentiating the infective processes from the non-infective conditions that may show positivity with tracers such as 18F-FDG. We present a pictorial review of potential clinical applications of PET/CT using 18F-FDG labelled WBC. 相似文献
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Peiwen Wu Yanxia Wang Mark E. Davis Jonathan E. Zuckerman Sarika Chaudhari Malcolm Begg Rong Ma 《Journal of the American Society of Nephrology : JASN》2015,26(11):2691-2702
Accumulation of extracellular matrix derived from glomerular mesangial cells is an early feature of diabetic nephropathy. Ca2+ signals mediated by store–operated Ca2+ channels regulate protein production in a variety of cell types. The aim of this study was to determine the effect of store–operated Ca2+ channels in mesangial cells on extracellular matrix protein expression. In cultured human mesangial cells, activation of store–operated Ca2+ channels by thapsigargin significantly decreased fibronectin protein expression and collagen IV mRNA expression in a dose-dependent manner. Conversely, inhibition of the channels by 2-aminoethyl diphenylborinate significantly increased the expression of fibronectin and collagen IV. Similarly, overexpression of stromal interacting molecule 1 reduced, but knockdown of calcium release–activated calcium channel protein 1 (Orai1) increased fibronectin protein expression. Furthermore, 2-aminoethyl diphenylborinate significantly augmented angiotensin II–induced fibronectin protein expression, whereas thapsigargin abrogated high glucose– and TGF-β1–stimulated matrix protein expression. In vivo knockdown of Orai1 in mesangial cells of mice using a targeted nanoparticle siRNA delivery system resulted in increased expression of glomerular fibronectin and collagen IV, and mice showed significant mesangial expansion compared with controls. Similarly, in vivo knockdown of stromal interacting molecule 1 in mesangial cells by recombinant adeno–associated virus–encoded shRNA markedly increased collagen IV protein expression in renal cortex and caused mesangial expansion in rats. These results suggest that store–operated Ca2+ channels in mesangial cells negatively regulate extracellular matrix protein expression in the kidney, which may serve as an endogenous renoprotective mechanism in diabetes. 相似文献
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Strand V Burmester GR Ogale S Devenport J John A Emery P 《Rheumatology (Oxford, England)》2012,51(10):1860-1869
Objective. To investigate the effect of tocilizumab on patient-reported outcomes (PROs) in RA patients with inadequate responses to TNF inhibitors (TNFis). Methods. In a Phase III randomized controlled trial, 489 patients received 4 or 8 mg/kg tocilizumab or placebo every 4 weeks plus MTX for 24 weeks. Mean changes from baseline over time and proportions of patients reporting improvements greater than or equal to minimum clinically important differences (MCIDs) in PROs were analyzed. Results. At week 24, 8?mg/kg resulted in significantly greater improvements vs placebo in pain, global assessment of disease activity (P?=?0.001), Health Assessment Questionnaire-Disability Index (HAQ-DI; P?0.0001), Functional Assessment of Chronic Illness Therapy-Fatigue (P?=?0.0150) and Medical Outcomes Survey Short Form 36 (SF-36 v2) Physical Component Summary (PCS; P?=?0.0003) scores, all greater than MCID; 4?mg/kg resulted in greater improvements in pain (P?=?0.0100), HAQ-DI (P?=?0.0030) and SF-36 PCS (P?=?0.0020) scores. Tocilizumab-associated improvements were evident as early as week 2. At week 24, more tocilizumab-treated than control patients reported improvements greater than or equal to MCID in SF-36 domain scores and related PROs (50.9-84.9% vs 35.0-51.7%) and achieved ACR50 responses and/or Disease Activity Score 28 (DAS28) remission with PRO improvements greater than or equal to MCID (36.2-51.2% vs 10-20.7% and 10.7-37.5% vs 0.0-3.4%, respectively). Conclusion. Tocilizumab treatment in patients with inadequate responses to TNFis resulted in rapid and sustained improvements in multiple PROs that were statistically significant and clinically meaningful, consistent with previous efficacy reports. Trial Registration. ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00106522. 相似文献
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Sarika Namjoshi Istvan Toth Joanne T. Blanchfield Nicholas Trotter Ricardo L. Mancera Heather A. E. Benson 《Pharmaceutical research》2014,31(12):3304-3312
Purpose
Efficient delivery of therapeutic peptides to the skin will facilitate better outcomes in dermatology. The tetrapeptide AAPV, an elastase inhibitor with potential utility in the management of psoriasis was coupled to short chain lipoamino acids (Laa: C6-C10) to enhance the peptide permeation into and through human epidermis.Methods
AAPV was conjugated to Laas by solid phase synthesis. Peptide stability, skin distribution and permeation, elastase activity and surface activity were determined.Results
Laas increased peptide permeation into the skin. The permeation lag time and amount of peptide remaining in the skin increased with the carbon chain length of the Laa conjugate. We also demonstrated stereoselective permeation enhancement in favour of the D-diastereomer. Importantly, the elastase inhibition activity of the peptide was largely retained after coupling to the Laa conjugates, showing potential therapeutic utility. The Laa-peptide structures were shown to be surface active, suggesting that this surfactant-like activity coupled with enhanced lipophilicity may contribute to their interaction with and permeation through the lipid domains of the stratum corneum.Conclusions
This study suggests that the Laa conjugation approach may be useful for enhancing the permeation of moderately sized peptide drugs with potential application in the treatment of skin disorders. 相似文献9.
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Rakesh Waghmare Itta Krishna Chaaithanya Sarika Zala Jitendra Deshmukh Prashant Uikey Sarika Wankhede Tushar Palve Shyamkumar Sirsam Rohidas Chavan Manjushri Waikar Anil Humane Akash Khobragade Monika Akare Ritesh K. Sondawale Rajat Sharma Vrushali Nandre Prashant Howal Deepak N. Modi Smita D. Mahale Rahul K. Gajbhiye 《Indian journal of hematology & blood transfusion》2022,38(1):191