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601.
602.
    
Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion of heme precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking α-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP.  相似文献   
603.
    
Favism uniquely arises from a genetic defect of the Glucose-6 Phosphate Dehydrogenase (G6PD) enzyme and results in a severe reduction of erythrocytes’ (RBCs) reducing power that impairs the cells’ ability to respond to oxidative stresses. After exposure to fava beans or a few other drugs, the patients experience acute hemolytic anemia due to RBCs’ lysis both intra and extra-vascularly. In the present paper, we compared selected biochemical, biophysical, and ultra-morphological properties of normal RBCs and cells from favism patients measured along cellular aging. Along the aging path, the cells’ characteristics change, and their structural and functional properties degrade for both samples, but with different patterns and effectors that have been characterized in biophysical and biochemical terms. In particular, the analysis revealed distinct metabolic regulation in G6DP-deficient cells that determines important peculiarities in the cell properties during aging. Remarkably, the initial higher fragility and occurrence of structural/morphological alterations of favism cells develop, with longer aging times, into a stronger resistance to external stresses and higher general resilience. This surprisingly higher endurance against cell aging has been related to a special mechanism of metabolic regulation that permits lower energy consumption in environmental stress conditions. Our results provided a direct and coherent link between the RBCs’ metabolic regulation and the cell properties that would not have been possible to establish without an investigation performed during aging. The consequences of this new knowledge, in particular, can be discussed in a more general context, such as understanding the role of the present findings in determining the characteristics of the favism pathology as a whole.  相似文献   
604.
    
The glymphatic system, a fluid-clearance pathway involved in brain waste clearance, is known to be impaired in neurological disorders, including Alzheimer’s disease (AD). For this reason, it is important to understand the specific mechanisms and factors controlling glymphatic function. This pathway enables the flow of cerebrospinal fluid (CSF) into the brain and subsequently the brain interstitium, supported by aquaporins (AQPs). Continuous CSF transport through the brain parenchyma is critical for the effective transport and drainage of waste solutes, such as toxic proteins, through the glymphatic system. However, a balance between CSF production and secretion from the choroid plexus, through AQP regulation, is also needed. Thus, any condition that affects CSF homeostasis will also interfere with effective waste removal through the clearance glymphatic pathway and the subsequent processes of neurodegeneration. In this review, we highlight the role of AQPs in the choroid plexus in the modulation of CSF homeostasis and, consequently, the glymphatic clearance pathway, with a special focus on AD.  相似文献   
605.
    
Imbalance of macrophage polarization characterized by an increase in the percentage of pro-inflammatory M1 macrophages and a decrease in anti-inflammatory M2 macrophages is considered a critical pathogenic mechanism of bisphosphonate-related osteonecrosis of the jaws (BRONJ). Because high levels of Toll-like receptor 4 (TLR4) mediates mitochondrial dyshomeostasis in Zoledronic Acid (ZA)-treated M1 macrophages, tetrahedral DNA nanomaterial (TDN)-modified with TLR4-siRNA on each vertex (TDN-TLR4-4siR) with excellent biocompatibility is synthesized. This novel TDN-TLR4-4siR nanomaterial reverses the polarization phenotype imbalance decreasing the percentage of M1 RAW264.7 macrophages. Mitochondrial dynamics analysis shows a shift from short rod-like ultrastructure to elongated shapes with more mitochondrial network continuity in ZA-primed M1 macrophages after treatment with TDN-TLR4-4siR, along with elevated expression of Mfn1 and Mfn2. TDN-TLR4-4siR further reduces intracellular ROS production and restored mitochondrial membrane potential. Furthermore, decreased sequestra formation and accelerated healing of the extraction wound are observed in the TDN-TLR4-4siR group, resulting in decreased incidence of rat BRONJ via reprogramming polarized macrophages. Consequently, this study establishes a novel strategy using TDN-TLR4-4siR nanomaterial to regulate mitochondrial homeostasis of polarized macrophages to prevent BRONJ.  相似文献   
606.
    
The purpose of this study was to observe the effect of Inonotus obliquus polysaccharide (IOP) on blood lipids and its regulation on the intestinal flora in hyperlipidemia rats, and explore the modern biological connotation of IOP in reducing blood lipids. In this study, we obtained the crude IOP by the water extraction and alcohol precipitation method, and then classified it by DEAE ion-exchange chromatography to obtain the acidic I. obliquus polysaccharide (IOP-A). After the administration of the IOP-A, the serum TC, TG, and LDL-C levels were significantly lower, while the serum HDL-C levels were significantly higher. The expression of CYP7A1 protein was considerably increased, whereas the expression of SREBP-1C protein was considerably decreased in the rat hepatic tissue. In addition, the IOP-A could significantly alleviate the hepatocyte fatty degeneration in the liver lobule of rats. We believe that the IOP-A can affect the composition of intestinal flora by reducing the relative abundance of Firmicutes and increasing the relative abundance of Bacteroidetes. These findings indicated that the IOP-A can regulate the dyslipidemia of hyperlipidemia rats, and its mechanism may be through regulating the CYP7A1 and SREBP-1C expression in the metabolism of lipids, and correcting the imbalance of intestinal flora structure caused by a high-fat diet.  相似文献   
607.
    
Accumulated evidence shows that melatonin possesses the potential to improve lipid metabolism by modifying gut microbiota and glucose metabolism via regulating the melatonin receptor signaling pathway. However, the contribution of melatonin consumption on glucose homeostasis by affecting gut microbiota has not been investigated in diabetes. In the current work, we investigated the effect of melatonin administration on gut microbiota and glucose homeostasis in db/db mice, a type 2 diabetes model with leptin receptor deficiency. Administration of melatonin through drinking water (at 0.25% and 0.50%) for 12 weeks decreased diabetic polydipsia and polyuria, increased insulin sensitivity and impeded glycemia. The accumulated fecal levels of total short-chain fatty acids (SCFAs) and acetic acid are positively correlated with diabetes-related parameters—homeostasis model assessment of insulin resistance (HOMA-IR) index and fasting blood glucose (FBG) level. The reprogramming of gut microbiota structure and abundance and the reduction of fecal levels of SCFAs, including acetic acid, butyric acid, isovaleric acid, caproic acid, and isobutyric acid, by melatonin may be beneficial for enhancing insulin sensitivity and lowering FBG, which were verified by the results of correlation analysis between acetic acid or total SCFAs and HOMA-IR and FBG. In addition, the melatonin downregulated hepatic genes, including fructose-1,6-bisphosphatase 1, forkhead box O1 alpha, thioredoxin-interacting protein, phosphoenolpyruvate carboxy-kinase (PEPCK), PEPCK1 and a glucose-6-phosphatase catalytic subunit, that responsible for gluconeogenesis support the result that melatonin improved glucose metabolism. Overall, results showed that the melatonin supplementation reduced fecal SCFAs level via reprogramming of gut microbiota, and the reduction of fecal SCFAs level is associated with improved glucose homeostasis in db/db mice.  相似文献   
608.
Previous studies show that city metrics having to do with growth, productivity and overall energy consumption scale superlinearly, attributing this to the social nature of cities. Superlinear scaling results in crises called ‘singularities’, where population and energy demand tend to infinity in a finite amount of time, which must be avoided by ever more frequent ‘resets’ or innovations that postpone the system''s collapse. Here, we place the emergence of cities and planetary civilizations in the context of major evolutionary transitions. With this perspective, we hypothesize that once a planetary civilization transitions into a state that can be described as one virtually connected global city, it will face an ‘asymptotic burnout’, an ultimate crisis where the singularity-interval time scale becomes smaller than the time scale of innovation. If a civilization develops the capability to understand its own trajectory, it will have a window of time to affect a fundamental change to prioritize long-term homeostasis and well-being over unyielding growth—a consciously induced trajectory change or ‘homeostatic awakening’. We propose a new resolution to the Fermi paradox: civilizations either collapse from burnout or redirect themselves to prioritizing homeostasis, a state where cosmic expansion is no longer a goal, making them difficult to detect remotely.  相似文献   
609.
    
Bone as a vigorous tissue is constantly undergoing bone remodeling. The homeostasis of bone remodeling requires combined efforts of multifarious bone cells. Amino acids (AA), known as essential components of life support, are closely related to the regulation of bone homeostasis. In recent years, the concept of functional amino acids (FAAs) has been proposed, which is defined as AA that regulate key metabolic pathways to improve health, survival, growth, development, lactation, and reproduction of organisms, to highlight their outstanding contributions in the body. In the hope of exploring new therapeutic strategies, this review focus on summarizing recent progress in the vital role of FAAs in bone homeostasis maintaining and potential implications of FAAs in bone-related diseases, and discussing related mechanisms. The results showed that FAAs are closely related to bone metabolism and therapeutic strategy targeting FAAs metabolism is one of the future trends for bone disorders, while the explorations about possible impact of FAAs-based diets are still limited.  相似文献   
610.
    
Redox homeostasis is vital for cell survival. Nowadays, developing novel nanoagents that can efficiently break the redox homeostasis, which includes improving the reactive oxygen species level while reducing the glutathione (GSH) level, has emerged as a promising but challenging strategy for tumor therapy. In this work, a novel albumin-based multifunctional nanoagent is developed for GSH-depletion assisted chemo-/chemodynamic combination therapy. Briefly, CuO and MnOX are in situ co-grown inside the albumin molecules through a facile biomineralization process, followed by the conjugation of Pt (IV) prodrug to obtain the final nanoagent. Thereinto, copper species can produce •OH with optimal efficiency under weakly acidic conditions (pH = 6.5), while MnOX can react with GSH, leading to the GSH depletion, which reduces the formation of GSH-Pt adducts and •OH consumption, thus favoring a better chemotherapy and chemodynamic therapy effect, respectively. Significantly, both GSH depletion and •OH generation contributes to the inhibited expression of GPX-4, which further increases the oxidative stress. Moreover, during the reaction between MnOX and GSH or H2O2, Mn2+ ions are released for MR imaging while O2 is produced for hypoxia relief. It is believed that the proposed strategy can provide a new perspective on effective tumor therapy.  相似文献   
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