Structural basis for mismatch surveillance by CRISPR-Cas9.

CRISPR-Cas9 as a programmable genome editing tool is hindered by off-target DNA cleavage1-4, and the underlying mechanisms by which Cas9 recognizes mismatches are poorly understood5-7. Although Cas9 variants with greater discrimination against mismatches have been designed8-10, these suffer from substantially reduced rates of on-target DNA cleavage5,11. Here we used kinetics-guided cryo-electron microscopy to determine the structure of Cas9 at different stages of mismatch cleavage. We observed a distinct, linear conformation of the guide RNA-DNA duplex formed in the presence of mismatches, which prevents Cas9 activation. Although the canonical kinked guide RNA-DNA duplex conformation facilitates DNA cleavage, we observe that substrates that contain mismatches distal to the protospacer adjacent motif are stabilized by reorganization of a loop in the RuvC domain. Mutagenesis of mismatch-stabilizing residues reduces off-target DNA cleavage but maintains rapid on-target DNA cleavage. By targeting regions that are exclusively involved in mismatch tolerance, we provide a proof of concept for the design of next-generation high-fidelity Cas9 variants.

Kardar-Parisi-Zhang Physics in the Density Fluctuations of Localized Two-Dimensional Wave Packets.

We identify the key features of Kardar-Parisi-Zhang (KPZ) universality class in the fluctuations of the wave density logarithm in a two-dimensional Anderson localized wave packet. In our numerical analysis, the fluctuations are found to exhibit an algebraic scaling with distance characterized by an exponent of 1/3, and a Tracy-Widom probability distribution of the fluctuations. Additionally, within a directed polymer picture of KPZ physics, we identify the dominant contribution of a directed path to the wave packet density and find that its transverse fluctuations are characterized by a roughness exponent 2/3. Leveraging on this connection with KPZ physics, we verify that an Anderson localized wave packet in 2D exhibits a stretched exponential correction to its well-known exponential localization.

A Pilot Study of the Use of Dexmedetomidine for the Control of Delirium by Reducing the Serum Concentrations of Brain-Derived Neurotrophic Factor, Neuron-Specific Enolase, and S100B in Polytrauma Patients.

BACKGROUND: Delirium is very common among patients with polytrauma, although no suitable means exist to feasibly reduce the incidence and duration of delirium in these patients. Recent reports have suggested that continuous intravenous (IV) infusions of dexmedetomidine, rather than benzodiazepine, be administered for sedation to reduce the duration of delirium in this population. However, serum neuron-specific enolase (NSE), S100 calcium binding protein B (S100B), and brain-derived neurotrophic factor (BDNF) levels have not yet been investigated in polytrauma patients who received sedation with dexmedetomidine rather than other conventional sedatives. The aim of this study was to assess the association of blood BDNF, NSE, and S100B with the occurrence of delirium among polytrauma patients who had been sedated with dexmedetomidine. MATERIALS AND METHODS: Consecutive patients were randomly assigned to 1 of 2 treatment study groups, namely the "dexmedetomidine group" or the "common group." This case-control study included 18 patients with delirium and 34 matched controls in a 63-bed general intensive care unit (ICU). Blood samples were collected from all patients upon ICU admission, on the day when delirium was diagnosed, and on days 3 and 5 following diagnosis. The serum levels of S100B, BDNF, and NSE were determined by enzyme-linked immunosorbent assay. The sedation levels and delirium were assessed using the Richmond Agitation and Sedation Scale and the Confusion Assessment Method for the ICU. RESULTS: The median BDNF, NSE, and S100B concentrations were significantly lower in the dexmedetomidine group than in the common group on the day when delirium was diagnosed and on the third day after delirium was diagnosed. The rate of delirium was significantly lower in the dexmedetomidine group than in the common group. There were clear differences in the BDNF, NSE, and S100B levels between the 2 groups on the fifth day after delirium was diagnosed. CONCLUSIONS: Our randomized controlled study suggests that the sedation of polytrauma patients with dexmedetomidine could help reduce the serum BDNF, S100B, and NSE levels, which appear to be associated with the occurrence of delirium in the dexmedetomidine group.

[Identification of endophytic bacteria BZJN1 and research on biological control of root rot of Atractylodes macrocephala].

In this study， an endophytic bacteria strain BZJN1 was isolated from Atractylodes macrocephala， and identified as Bacillus subtilis by physiological and biochemical tests and molecular identification. Strain BZJN1 could inhibit the growth of mycelia of Ceratobasidium sp. significantly， and the inhibition rate was more than 70%. The mycelium growth deformity with bulge as spherical and partially exhaustible in apex or central with microscopic observation. The inhibitory rates under 3% and 6% concentrations of the cell free fermentation were 22.7% and 38.7% expectively. The field test proved that the control efficacy of treatment of 1×108 cfu·mL⁻¹ is 75.27% and 72.37% after 10 and 20 days. All the treatments of strain BZJN1 was able to promote the growth of A. macrocephala， the treatment of 1×108 cfu·mL⁻¹ could able to increase the yield to 14.1%.

Structural Mechanism for the Fidelity Modulation of DNA Polymerase λ.

The mechanism of DNA polymerase (pol) fidelity is of fundamental importance in chemistry and biology. While high-fidelity pols have been well studied, much less is known about how some pols achieve medium or low fidelity with functional importance. Here we examine how human DNA polymerase λ (Pol λ) achieves medium fidelity by determining 12 crystal structures and performing pre-steady-state kinetic analyses. We showed that apo-Pol λ exists in the closed conformation, unprecedentedly with a preformed MgdNTP binding pocket, and binds MgdNTP readily in the active conformation in the absence of DNA. Since prebinding of MgdNTP could lead to very low fidelity as shown previously, it is attenuated in Pol λ by a hydrophobic core including Leu431, Ile492, and the Tyr505/Phe506 motif. We then predicted and demonstrated that L431A mutation enhances MgdNTP prebinding and lowers the fidelity. We also hypothesized that the MgdNTP-prebinding ability could stabilize a mismatched ternary complex and destabilize a matched ternary complex, and provided evidence with structures in both forms. Our results demonstrate that, while high-fidelity pols follow a common paradigm, Pol λ has developed specific conformations and mechanisms for its medium fidelity. Structural comparison with other pols also suggests that different pols likely utilize different conformational changes and microscopic mechanisms to achieve their catalytic functions with varying fidelities.

The ratio of Th17/Treg cells as a risk indicator in early acute respiratory distress syndrome.

INTRODUCTION: Recent studies have revealed that lung inflammation mediated by CD4+ T cells may contribute to the pathogenesis of acute respiratory distress syndrome (ARDS). The imbalance between CD4 + CD25 + Foxp3 + regulatory T (Treg) cells and T helper (Th)17 cells has been found in a number of different inflammation and autoimmune diseases, while the role of the Th17/Treg balance in ARDS remains largely unknown. The aim of this study was to investigate the Th17/Treg pattern and its impact on disease severity and outcomes in patients with ARDS. METHODS: This prospective, observational study enrolled 79 patients who fulfilled the Berlin definition of ARDS and 26 age- and sex-matched healthy controls. Circulation Th17 and Treg cell frequencies were analyzed by flow cytometry, and the expressions of Th17- and Treg-related cytokines in serum were measured by enzyme-linked immunosorbent assay (ELISA). Acute Physiologic and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, and the Lung Injury Score were also calculated at enrollment. RESULTS: Within 24 hours after the onset of ARDS, the changes of peripheral circulating Th17 and Treg cell frequencies gradually increased from mild to severe ARDS. Th17/Treg ratio was positively correlated with APACHE II score, SOFA score, and Lung Injury Score, while negatively correlated with PaO2/FiO2. The areas under the receiver operating characteristic (AUC) curves of Th17/Treg ratio for predicting 28-day mortality in ARDS patients was higher than that of APACHE II score, SOFA score, Lung injury score, as well as PaO2/FiO2. Using a Th17/Treg ratio cutoff value of >0.79 to determine 28-day mortality, the sensitivity was 87.5% with 68.1% specificity. Multivariate logistic regression showed Th17/Treg ratio >0.79 (odds ratio = 8.68, P = 0.002) was the independent predictor for 28-day mortality in patients with ARDS. Finally, cumulative survival rates at 28-day follow-up also differed significantly between patients with Th17/Treg ratio >0.79 and ≤0.79 (P <0.001). CONCLUSIONS: The Th17/Treg imbalance favoring a Th17 shift represents a potential therapeutic target to alleviate lung injury and a novel risk indicator in patients with early ARDS.

[Preliminary Research on Bubble Characteristics of Ancient Glaze Using OCT Technology].

The bubble is one of the most common feature in ancient glaze. The size and distribution of bubbles are closely associated with recipes of the raw materials for the body and glaze and the making process. To characterize the bubbles is essential for the study of ceramic production process, production places, times characteristics and so on. In order to explore the possibility of using the optical coherence tomography (OCT) imaging technology to characterize the bubbles and the bubble distribution characteristic in glaze of ancient porcelain, sweep frequency OCT imaging system is used to detect five different types ancient porcelain chips. According to the two dimensional sectional images and three dimensional tomographic images of the transparent layer of glaze obtained by the OCT imaging system, the two dimensional sectional images characteristics and three dimensional slices characteristics of the bubbles in glaze are studied. The bubble characteristics in the glaze and its possible causes that gases in the body of the ceramic overflow to the glaze layer in the firing process are comprehensively analyzed. Meantime, the size of bubble is calculated according to the two dimensional sectional images based on pixel, and the result is compared with the traditional microscopic test result. The bubble size, two dimensional sectional characteristics and three dimensional tomographic image characteristics of opaque glaze are also studied. Experimental results show that the bubble characteristics in glaze of different ancient porcelain chips are obvious difference, the result of the bubble size calculated based on pixel coincides with the result of the bubble size observed by traditional microscope with ten times magnification, slices of the body near the body-glaze binding region based on OCT imaging technology three dimensional tomography can effectively reflect the bubble characteristics in glaze. The measurement of using OCT imaging technology to characterize bubble characteristics of the glaze is proposed, and the feasibility and the validity of the measurement are certified, and the nondestructive detection of bubble characteristics in ancient porcelain glaze is realized. Especially for the analysis of bubble characteristics of opaque glaze, the OCT imaging technology overcomes the limitations of using the traditional microscope technology to study the distribution of bubble in glaze in the past, and provides a novel, reliable analysis method for the analysis of ceramic glaze bubble characteristics.

Chiral Perovskite Heterostructure Films of CsPbBr3 Quantum Dots and 2D Chiral Perovskite with Circularly Polarized Luminescence Performance and Energy Transfer.

This work reports the synthesis of chiral perovskite heterostructure films by combining a two-dimensional (2D) chiral (R-/S-MBA)2PbI4 perovskite with CsPbBr3 quantum dots (QDs). The as-synthesized chiral heterostructure films exhibit obvious circularly polarized luminescence (CPL) properties, even though pure 2D chiral perovskite cannot present photoluminescence. It indicates that the chirality of the excited state of the QDs originates from the 2D chiral perovskite. The circular polarization-resolved transient absorption (TA) spectra further demonstrate that the CPL response of heterostructure films originates from the energy transfer between the chiral perovskite layer and QDs layer and the suppression of spin relaxation, which induces the imbalance of the spin population of excited states in QDs layer. In addition, the photoluminescence (PL), circular dichroism (CD), and CPL spectra of these heterostructure films can be controlled by varying the thickness and component of the chiral perovskite layer, which demonstrates that the anion exchange between chiral perovskite and CsPbBr3 QDs can tune the chemical composition and optoelectronic properties due to the low bonding energy difference between them and decrease the strain within the QDs layer to reduce the radiative recombination lifetime. This work provides guidance for the synthesis of chiral perovskites with a strong CPL response and further provides insight into the origination of CPL.

Clinical study of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in hypertriglyceridemia-induced acute pancreatitis and acute biliary pancreatitis with persistent organ failure.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are novel inflammatory indicators that can be used to predict the severity and prognosis of various diseases. We categorize acute pancreatitis by etiology into acute biliary pancreatitis (ABP) and hypertriglyceridemia-induced acute pancreatitis (HTGP). AIM: To investigate the clinical significance of NLR and PLR in assessing persistent organ failure (POF) in HTGP and ABP. METHODS: A total of 1450 patients diagnosed with acute pancreatitis (AP) for the first time at Shanxi Bethune Hospital between January 2012 and January 2023 were enrolled. The patients were categorized into two groups according to the etiology of AP: ABP in 530 patients and HTGP in 241 patients. We collected and compared the clinical data of the patients, including NLR, PLR, and AP prognostic scoring systems, within 48 h of hospital admission. RESULTS: The NLR (9.1 vs 6.9, P < 0.001) and PLR (203.1 vs 160.5, P < 0.001) were significantly higher in the ABP group than in the HTGP group. In the HTGP group, both NLR and PLR were significantly increased in patients with severe AP and those with a SOFA score ≥ 3. Likewise, in the ABP group, NLR and PLR were significantly elevated in patients with severe AP, modified computed tomography severity index score ≥ 4, Japanese Severity Score ≥ 3, and modified Marshall score ≥ 2. Moreover, NLR and PLR showed predictive value for the development of POF in both the ABP and HTGP groups. CONCLUSION: NLR and PLR vary between ABP and HTGP, are strongly associated with AP prognostic scoring systems, and have predictive potential for the occurrence of POF in both ABP and HTGP.

A duplexed high-throughput mass spectrometry assay for bifunctional POLB polymerase and lyase activity.

Polymerase ß (POLB), with dual functionality as a lyase and polymerase, plays a critical role in the base excision repair (BER) pathway to maintain genomic stability. POLB knockout and rescue studies in BRCA1/2-mutant cancer cell lines revealed that inhibition of lyase and polymerase activity is required for the synthetic lethal interaction observed with PARP inhibitors, highlighting POLB as a valuable therapeutic target. Traditional biochemical assays to screen for enzyme inhibitors focus on a single substrate to product relationship and limit the comprehensive analysis of enzymes such as POLB that utilize multiple substrates or catalyze a multi-step reaction. This report describes the first high-throughput mass spectrometry-based screen to measure the two distinct biochemical activities of POLB in a single assay using a duplexed self-assembled monolayer desorption ionization (SAMDI) mass spectrometry methodology. A multiplexed assay for POLB dual enzymatic activities was developed optimizing for kinetically balanced conditions and a collection of 200,000 diverse small molecules was screened in the duplexed format. Small molecule modulators identified in the screen were confirmed in a traditional fluorescence-based polymerase strand-displacement assay and an orthogonal label-free binding assay using SAMDI affinity selection mass spectrometry (ASMS). This work demonstrates the flexibility of high-throughput mass spectrometry approaches in drug discovery and highlights a novel application of SAMDI technology that opens new avenues for multiplexed high-throughput screening.

[The effects of real-time continuous glucose monitoring on oxidative stress and mortality in critically ill patients].

OBJECTIVE: To evaluate the effects of real-time continuous glucose monitoring (RT-CGM) system on oxidative stress and mortality in critically ill patients and to explore the correlation between glucose index, oxidative stress and mortality. METHODS: Selected 123 cases of critically ill patients were enrolled in this prospective randomized controlled study. They were randomly divided into the RT-CGM group (n = 61) and blood glucose meter group (GM group, n = 62). The following parameters were compared between the two groups: mean amplitude of glucose excursions (MAGE), hypoglycemia incidence, low blood glucose index (LBGI), high blood glucose index (HBGI), 28-day mortality and plasma level of 8-iso-PGF2α (8-iso) at 48 hours (R2), 72 hours (R3) and 96 hours (R4) after admission to ICU. The correlation between glucose index and plasma level of 8-iso-PGF2α were analyzed. The correlation between glucose index, plasma 8-iso level and 28-day death were analyzed. RESULTS: The parameters of MAGE, hypoglycemia incidence, LBGI and HBGI in the RT-CGM group and the GM group were (3.73 ± 1.09) mmol/L and (4.19 ± 1.11) mmol/L (P = 0.02), 3.28% and 14.52% (P = 0.03), 0.0011 and 0.0119 (P < 0.01) and 0.2258 and 0.3697 (P < 0.01), respectively. The plasma levels of 8-iso at R2, R3, R4 in the RT-CGM group and the GM group were (111.44 ± 16.99) ng/L and (114.03 ± 14.64) ng/L (P = 0.37), (94.53 ± 14.92) ng/L and (110.31 ± 13.42) ng/L (P < 0.01) and (57.84 ± 12.22) ng/L and (84.41 ± 14.16) ng/L (P < 0.01), respectively. The r values between MAGE, LBGI, HBGI and the plasma level of 8-iso were 0.69, 0.71 and 0.67, respectively (all P values < 0.01). Multivariate stepwise regression analysis showed MAGE, LBGI, HBGI entered final models (corrected R2 = 0.61, P < 0.01) with ß values of 0.64, 0.65 and 0.6 respectively (all P values < 0.01). The 28-day mortality in the RT-CGM group and the GM group was 9.84% and 30.65% (P < 0.01). The OR values of MAGE, hypoglycemia incidence, LBGI, HBGI and the plasma level of 8-iso for 28-day death were 2.14 (0.98 - 4.35), 3.43 (1.12 - 5.82), 2.67 (1.01 - 5.14), 1.32 (0.24 - 2.96) and 1.89 (0.67 - 3.44), respectively. CONCLUSION: RT-CGM can optimize the care in critically ill patients by improving hypoglycemia, hyperglycemia, glucose variability and oxidative stress and bring more detailed concern in the process, and to reduce the mortality.

Transcriptomic and metabolomic analyses provide new insights into the appropriate harvest period in regenerated bulbs of Fritillaria hupehensis.

Introduction: The bulb of Fritillaria hupehensis, a traditional cough and expectorant medicine, is usually harvested from June to September according to traditional cultivation experience, without practical scientific guidance. Although steroidal alkaloid metabolites have been identified in F. hupehensis, the dynamic changes in their levels during bulb development and their molecular regulatory mechanisms are poorly understood. Methods: In this study, integrative analyses of the bulbus phenotype, bioactive chemical investigations, and metabolome and transcriptome profiles were performed to systematically explore the variations in steroidal alkaloid metabolite levels and identify the genes modulating their accumulation and the corresponding regulatory mechanisms. Results: The results showed that weight, size, and total alkaloid content of the regenerated bulbs reached a maximum at IM03 (post-withering stage, early July), whereas peiminine content reached a maximum at IM02 (withering stage, early June). There were no significant differences between IM02 and IM03, indicating that regenerated bulbs could be harvested appropriately in early June or July. Peiminine, peimine, tortifoline, hupehenine, korseveramine, delafrine, hericenone N-oxide, korseveridine, puqiedinone, pingbeinone, puqienine B, puqienine E, pingbeimine A, jervine, and ussuriedine levels were upregulated in IM02 and IM03, compared with IM01 (vigorous growth stage, early April). The Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that the accumulation of steroidal alkaloid metabolites mainly occurred prior to IM02. HMGR1, DXR, CAS1, CYP 90A1, and DET2 may play a positive role in peiminine, peimine, hupehenine, korseveramine, korseveridine, hericenone N-oxide, puqiedinone, delafrine, tortifoline, pingbeinone, puqienine B, puqienine E, pingbeimine A, jervine, and ussuriedine biosynthesis, whereas the downregulation of FPS1, SQE and 17-DHCR may lead to a reduction in peimisine levels. Weighted gene correlation network analysis showed that CYP 74A2-1, CYP 74A2-2, CYP 71A26-1, CYP 71A26-2, and CYP74A were negatively correlated with peiminine and pingbeimine A, whereas CYP R and CYP707A1 were positively correlated. . CYP 74A2-1 and CYP 74A2-2 may play a negative role in peimine and korseveridine biosynthesis, whereas CYP R plays a positive role. In addition, the highly expressed C2H2, HSF, AP2/ERF, HB, GRAS, C3H, NAC, MYB-related transcription factors (TFs), GARP-G2-like TFs, and WRKY may play positive roles in the accumulation of peiminine, peimine, korseveridine, and pingbeimine A. Discussion: These results provide new insights into scientific harvesting of F. hupehensis.

The Role of Polaronic States on the Spin Dynamics in Solution-Processed Two-Dimensional Layered Perovskite with Different Layer Thickness.

2D lead halide perovskites (LHPs) show strong excitonic and spin-orbit coupling effects, generating a facile spin injection. Besides, they possess a polaron character due to the soft crystal lattice, which can prolong the spin lifetime, making them favorable materials for spintronic applications. Here, the spin dynamics of 2D PEA2 PbI4 (MAPbI3 )n -l thin films with different layers by temperature- and pump fluence-dependent circularly polarization-resolved transient absorption (TA) measurements is studied. These results indicate that the spin depolarization mechanism is gradually converted from the Maialle-Silva-Sham (MSS) mechanism to the polaronic states protection mechanism with the layer number increasing from = 1 to 3, which is determined by the interplay between the strength of Coulomb exchange interaction and the strength of polaronic effect. While for ≥ 4, the Elliot-Yafet (EY) impurities mechanism is proposed, in which the formed polaronic states with free charge carriers no longer play the protective role.

Design, synthesis, and SAR study of novel flavone 1,2,4-oxadiazole derivatives with anti-inflammatory activities for the treatment of Parkinson's disease.

Inflammation is one of a major feature of Parkinson's disease (PD) which poses a threat to people's health in the world. It has been reported that antioxidation and anti-inflammation have significant effects on the treatment of PD. 1,2,4-oxadiazole and flavone derivatives have remarkable antioxidant and anti-inflammatory activities. In order to find highly effective drugs for PD treatment, based on the remarkable anti-inflammatory and antioxidant activities of the 1,2,4-oxadiazole pharmacophore and the flavonoid pharmacophore, we designed and synthesized a novel series of 3-methyl-8-(3-methyl-1,2,4-oxadiazol-5-yl)-2-phenyl-4H-chromen-4-one derivatives by pharmacophore combination, and evaluated their anti-inflammatory and antioxidation activities for PD treatment. Preliminary structure-activity relationship (SAR) analysis was conducted by their inhibitory activities against reactive oxygen species (ROS) and NO release in LPS-induced BV2 Microglia cells, and the optimal compound Flo8 exhibited the most potent anti-inflammatory and antioxidant activities. Both in vivo and in vitro results showed that Flo8 inhibited neuronal apoptosis by inhibiting inflammatory and apoptotic signaling pathways. In vivo studies also showed that the compound Flo8 ameliorated motor and behavioral deficits and increased serum dopamine levels in MPTP-induced PD model mice. Taken together, this study demonstrated the compound Flo8 could be a promising agent for the treatment of PD.

Design, synthesis and antitumor activity of 4-aminoquinazoline derivatives targeting VEGFR-2 tyrosine kinase.

We report herein the design and synthesis of novel 4-aminoquinazoline derivatives based on the inhibitors of VEGFR-2 tyrosine kinases. The VEGFR-2 inhibitory activities of these newly synthesized compounds were also evaluated and compared with that of ZD6474. We found that most of target compounds had good inhibitory potency. In particular, compounds 1h, 1n and 1o were found to be 6, 2 and 2-fold more potent than the positive control ZD6474. The leading compound 1h also showed an in vivo activity against HepG2 human tumor xenograft model in BALB/c-nu mice.

1-(3-Fluoro-phen-yl)-3-(4-nitro-phen-yl)urea.

In the title compound, C(13)H(10)FN(3)O(3), the dihedral angle between the fluoro-phenyl and nitro-phenyl ring planes is 6.51 (9)°. The crystal structure features N-H⋯O hydrogen bonds.

Exciton-Phonon Coupling of Chiral One-Dimensional Lead-Free Hybrid Metal Halides at Room Temperature.

The interaction between organic cations and inorganic metal halide octahedral units strongly affects the properties of organic-inorganic hybrid metal halides. The "soft" property of the lattice provides the possibility of its strong exciton-phonon interaction. Here we report one-dimensional (1D) lead-free chiral organic-inorganic hybrid metal halide single crystals of (R/S)-methylbenzylamine bismuth iodide (R/S-MBA)2Bi2I8, which exhibits a high level of octahedral bond distortion. The introduction of chiral amines leads to a strong chiroptical response in the range of 200-600 nm. The strong exciton-phonon coupling can be observed through the coherent oscillation spectrum of transient absorption dynamics at room temperature. The coherent phonon oscillation frequencies are ∼97 and ∼130 cm-1, corresponding to the symmetrical stretching or bending of the Bi-I octahedron. Our work provides new insights for the study of exciton-phonon coupling in 1D chiral hybrid metal halides.

[Effect of continuous renal replacement therapy started at different time on patients with multiple organ dysfunction syndrome].

OBJECTIVE: To explore the effects of continuous renal replacement therapy (CRRT) on serum cytokines and prognosis in multiple organ dysfunction syndrome (MODS) patients based on different therapeutic opportunities. METHODS: A total of 34 MODS patients in the treatment of CRRT after admission to ICU of our hospital between July 2008 and October 2010 were recruited. Based on the time interval from the onset of MODS to the initiation of CRRT, the patients were stratified into early group (0 - 3 days, n = 16) and late group (4 - 10 days, n = 18). Both groups of MODS patients received conventional treatment in addition to 72 hours of high-volume hemofiltration (HVHF). The serum levels of such inflammatory mediators as interleukin (IL)-1ß, interleukin-1 receptor antagonist (IL-1Ra), IL-6, tumor necrosis factor (TNF)-α, soluble tumor necrosis factor receptor1 (sTNFR1) and IL-10 were detected by enzyme linked immunosorbent assay (ELISA) before CRRT (0 h) and 6, 12, 18, 24, 48 and 72 h during the treatment of CRRT. Dynamic APACHEII scores were also evaluated. RESULTS: (1) The early group had lower serum levels of IL-1ß, IL-6, IL-10 and higher IL-1Ra, L-1Ra/IL-1ß ratio at 72 h than those of 0 h (P < 0.05). And the late group had a declining serum level of IL-1ß, IL-6, TNF-α and IL-10 and a rising ratio of IL-1Ra and IL-1Ra/IL-1ß during the first 24 h (P < 0.05). As compared with the late group, the early group had a lower level of IL-10 [(25 ± 12) vs (51 ± 33) ng/L] and higher ratios of IL-1Ra and IL-1Ra/IL-1ß at 72 h [(1382 ± 899 vs (683 ± 188) ng/L, (54 ± 10) vs (23 ± 6)] (both P < 0.05). (2) The early group had a lower APACHEIIscore than the late group at 0 h (P < 0.05). APACHEII score at 72 h was significantly lower than 0 h in the early group. And there was no obvious change in the late group. There was no statistical difference in the numbers of MODS patients with dysfunctional organs number ≥ 4 at 0 h in both groups. The number of MODS patients with dysfunctional organs number ≥ 4 at 72 h was lower than 0 h in the early group (P < 0.05). And there was no statistical difference in the late group. CONCLUSION: Regulating the ratio of anti-inflammatory/pro-inflammatory mediators is critical in the immunomodulation of CRRT. And CRRT may provide more clinical benefits in the early phase (0 - 3 days) of MODS.

Quantized classical response from spectral winding topology.

Topologically quantized response is one of the focal points of contemporary condensed matter physics. While it directly results in quantized response coefficients in quantum systems, there has been no notion of quantized response in classical systems thus far. This is because quantized response has always been connected to topology via linear response theory that assumes a quantum mechanical ground state. Yet, classical systems can carry arbitrarily amounts of energy in each mode, even while possessing the same number of measurable edge states as their topological winding. In this work, we discover the totally new paradigm of quantized classical response, which is based on the spectral winding number in the complex spectral plane, rather than the winding of eigenstates in momentum space. Such quantized response is classical insofar as it applies to phenomenological non-Hermitian setting, arises from fundamental mathematical properties of the Green's function, and shows up in steady-state response, without invoking a conventional linear response theory. Specifically, the ratio of the change in one quantity depicting signal amplification to the variation in one imaginary flux-like parameter is found to display fascinating plateaus, with their quantized values given by the spectral winding numbers as the topological invariants.