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Pathogenic microorganisms are valuable biological resources, closely related to biosecurity, human health, environmental protection, and renewable energy. It is very important to properly preserve the microbial resources by methods to maintain the purity, viability, and integrity, and to avoid prolonged degradation. The present work aims to explore the cryopreservation technology of

An experimental study on heat and mass transfer characteristics of R124-NMP in a vertical glass bubble absorber has been conducted under operating conditions of air-cooled absorption system. The key operation parameters, solution volumetric flow rate, temperature and mass fraction at the absorption tube entrance, vapor volumetric flow rate, orifice diameter and absorption pressure, are converted into dimensionless numbers. A sensitive study of the key operation parameters on overall heat and mass transfer coefficients and two-phase mass transfer coefficient has been performed. The overall heat and mass transfer coefficients and two-phase mass transfer coefficient increase as Rev and absorption pressure increase and decrease as orifice diameter increases. The overall heat transfer coefficient increases as Res increases and decreases as solution temperature and mass fraction increase. This trend is reversed for overall mass transfer coefficient. The increase of solution inlet mass fraction can improve the two-phase mass transfer coefficient while the solution inlet temperature affects the two-phase mass transfer coefficient slightly. On the basis of the experimental data, dimensionless empirical correlations for overall and two-phase Sherwood numbers are proposed with error bands of ±10% to calculate the volumetric mass transfer coefficient for R124-NMP bubble absorption process in a vertical bubble absorber.

Rhodococcus equi is a zoonotic pathogen that can cause fatal disease in patients who are immunocompromised. At present, the epidemiology and pathogenic mechanisms of R. equi infection are not clear. This study characterized the genomes of 53 R. equi strains from different sources. Pan-genome analysis showed that all R. equi strains contained 11481 pan genes, including 3690 core genes and 602 ~ 1079 accessory genes. Functional annotation of pan genome focused on the genes related to basic lifestyle, such as the storage and expression of metabolic and genetic information. Phylogenetic analysis based on pan-genome showed that the R. equi strains were clustered into six clades, which was not directly related to the isolation location and host source. Also, a total of 84 virulence genes were predicted in 53 R. equi strains. These virulence factors can be divided into 20 categories related to substance metabolism, secreted protein and immune escape. Meanwhile, six antibiotic resistance genes (RbpA, tetA (33), erm (46), sul1, qacEdelta 1 and aadA9) were detected, and all strains carried RbpA related to rifamycin resistance. In addition, 28 plasmids were found in the 53 R. equi strains, belonging to Type-A (n = 14), Type-B (n = 8) and Type-N (n = 6), respectively. The genetic structures of the same type of plasmid were highly similar. In conclusion, R. equi strains show different genomic characteristics, virulence-related genes, potential drug resistance and virulence plasmid structures, which may be conducive to the evolution of its pathogenesis.

Owing to its 100% theoretical salt rejection capability, membrane distillation (MD) has emerged as a promising seawater desalination approach to address freshwater scarcity. Ideal MD requires high vapor permeate flux established by cross-membrane temperature gradient (∆T) and excellent membrane durability. However, it's difficult to maintain constant ∆T owing to inherent heat loss at feedwater side resulting from continuous water-to-vapor transition and prevent wetting transition-induced membrane fouling and scaling. Here, we develop a Ti

Brachial plexus injury (BPI) is a type of peripheral nerve injury, which is mainly manifested as upper limb sensory and motor dysfunction. Although the injury will not endanger life, it can cause serious functional loss and high disability rate, and eventually lead to patients unable to live normally. At present, the treatment methods for BPI mainly include conservative treatment, such as limb massage, exercise, drug therapy, autonomous movement and strength training; In clinic, nerve repair, nerve transplantation and muscle transfer can also be used. Although surgical treatment can better restore the function of injured brachial plexus, there is a certain risk, so it is not the first choice of treatment. As a mature electrical stimulation method, functional electrical stimulation (FES) can play a good role in promoting injured nerve regeneration and preventing skeletal muscle denervation atrophy, so it can be widely used in the treatment and functional recovery of BPI. This article will review the research progress of FES in the treatment of BPI.

As a dual-specificity protein kinase, monopolar spindle 1 (Mps1) is one of the main kinases involved in kinetochore localization and the spindle assembly checkpoint (SAC). Cancer cells often display chromosomal instability, which is a consequence of disfunction of cell cycle checkpoints partially. Mps1 is overexpressed in multiple cancer types to face the pressure from aberrant chromosomes and centrosomes. Therefore, Mps1 is a potential targeting approach to cancer treatment. Several compounds targeting Mps1 have been developed and approved to begin clinical trials for advanced nonhaematologic malignancies treatments, including but not limited to triple negative breast cancer (TNBC) treatment. In this review, we will highlight typical Mps1 inhibitors developed during the last decade and provide a reference for more potential Mps1 inhibitors exploration in the future.

A comparing investigation between the simulated model and experimental verifications for the R124 (2-chloro-l,l,l,2,-tetrafluoroethane)-DMAC (N′, N′- dimethylacetamide) bubble absorption process in a vertical tubular absorber were performed. The objective of the investigation was to model the R124-DMAC bubble absorption process and to verify the model results with visual and non-visual experiments under similar operating conditions. The comparing results between the model and experiments were consistent well. The two-phase and single-phase convective heat transfer coefficient and two-phase mass transfer coefficient enhanced with increase of vapor and solution flow rates, and decreased with increase of solution inlet temperature, solution inlet mass fraction and nozzle orifice diameter. The two-phase mass transfer coefficient varied slightly with vapor flow rates rising. Finally, new correlations of the bubble absorption height, two-phase and single-phase convective heat transfer coefficients and two-phase mass transfer coefficient for R124-DMAC bubble absorption process in a vertical tubular bubble absorber were proposed. All of the correlation equations could predict about 90% of these parameters at a margin of error less than 15% under the operating conditions.

In this work, cobalt phosphide nanoparticles (Co2P NPs) were prepared by simple and mild hydrothermal method without the use of harmful phosphorous source. The morphological structure and surface component of Co2P were characterized by transmission electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy measurements. Considering the excellent electrocatalytic reduction activity and good electrical conductivity of transition-metal phosphide, we fabricated Co2P NPs on indium tin oxide (ITO) substrate (Co2P/ITO) for H2O2 detection. The Co2P/ITO transducer displayed a rapid amperometric response less than 5 s, a broader response range from 0.001 to 10.0 mM and a low detection limit of 0.65 μM. In addition, the non-enzymatic Co2P/ITO sensor showed outstanding selectivity, reproducibility, repeatability and stability, all of which qualified the Co2P/ITO electrode for quite a reliable and promising biosensor for H2O2 sensing.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome as an arising health issue globally. Obesity and diabetes seem coherent with high NAFLD occurrence. Currently, its underlying mechanism of cause and progression remains to be elicited and effective therapy is unavailable. Huge investment on studying its pathogenesis and innovative therapy is underway. As mechanistic studies are more difficult or unethical to be performed in humans, animal model that recapitulates the human disease is urgently needed. Nonhuman primates (NHPs) with NAFLD can highly mimic the human disease. This study aimed to induce NAFLD by various diets (Table 1) in normoglycemic and diabetic NHPs with biomarker and histopathology assays to quantify NAFLD occurrence. Our data show that diabetic monkeys with high-fat-high-fructose (HFHF) diet developed NAFLD which could assemble to the human disease and be highly valuable for NAFLD research. However, low choline (LC), LC+10% fructose, LC+low methionine (LCM)+10% fructose diets for 31 weeks had no significant effects on liver function, except significant decrease in body weight and food intake in LCM+10%F group and some increase in liver histological scores in LC+10%F group (Table 1). In summary, normal diet with LC or LCM ± high fructose is hardly to induce NAFLD in normoglycemic NHPs, at least in 31 weeks. HFHF could induce or enhance NAFLD in diabetic NHPs. Disclosure J. Gao: Employee; Self; Crown Bioscience. D. Wang: Employee; Self; Crown Bioscience. Y. Ji: Employee; Self; Crown Bioscience. X. Zhang: Employee; Self; Crown Bioscience. C. Yang: None. J. Zhang: Employee; Self; Crown Bioscience. W. Ye: Employee; Self; Crown Bioscience. F. Shi: Employee; Self; Crown Bioscience. M. Jiang: Employee; Self; Crown Bioscience. Q. Jin: Employee; Self; Crown Bioscience. D. Zhang: None. X. Wang: None. W. Song: Employee; Self; Crown Bioscience. K. Chng: None. H. Jiang: Employee; Self; SYSE Bio-tec Co., Ltd. Y. Wang: None. Y. Xiao: Employee; Self; Crown Bioscience.

20(S)-Rh2 is a ginsenoside isolated from Panax ginseng, which exhibits anti-cancer activities on various human cancer cells. A novel 20(S)-Rh2 derivative, 2-Deoxy-Rh2 was synthesized and hybridized with protopanaxadiol and 2-deoxy-glucose in an attempt to enhance the anticancer activity. Through screening the antitumor effect against various cell lines by MTT assay, 2-Deoxy-Rh2 especially resulted in a concentration-dependent and time-dependent inhibition of viability in MCF-7 human breast cancer cells. Multiple methods were used to explore the cellular and molecular mechanisms of 2-Deoxy-Rh2 as a potent anti-cancer agent. In MCF-7 cells, 2-Deoxy-Rh2 triggered apoptosis, stimulated ROS production and disrupted normal mitochondrial membrane potential. Meantime, 2-Deoxy-Rh2 eff ;ectively suppressed the glucose uptake capabilities and intracellular ATP production. The cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were significantly decreased in response to 2-Deoxy-Rh2, which were carried out to assess the overall glycolytic flux and mitochondrial respiration. Docking studies and molecular dynamics simulations were performed to verify the binding mode of 2-DG and 2-Deoxy-Rh2 with hexokinase II, with results showing that 2-Deoxy-Rh2 could easily fit into the similar active site of 2-DG, finally binding to hexokinase II to suppress glycolysis. Taken together, the results suggest that 2-Deoxy-Rh2 exhibited remarkable anticancer activity based on regulating mitochondrial apoptosis pathway, dampening glycolysis and inhibiting mitochondrial respiration, which support development of 2-Deoxy-Rh2 as a potential agent for cancer therapy.

Domoic acid, namely amnesic shellfish toxin, is a highly neurotoxic substance to marine animals and humankind. To reduce the incidence of poisoning accidents, the exploitation of specific and rapid detection method for domoic acid monitoring is highly required. Herein, an electrochemical molecularly imprinted polymer (MIP) sensor based on polydopamine-reduced graphene oxide/polyacrylamide composite (PDA-rGO/PAM) was constructed successfully to detect domoic acid. The domoic acid molecule could be recognized in imprinted cavities of PAM reversibly through hydrogen bonding. PDA-rGO promoted the loading capacity of PAM and improved the charge transfer rate, which amplified the electrical signal response of the MIP sensor. The screen-printed electrode (SPE) modified with PDA-rGO/PAM displayed satisfactory response toward toxin contaminated sample at a linear range from 1 to 600 nM and a low detection limit of 0.31 nM, demonstrating the prospective application of the transducer as a portable sensing platform for the on-site detection of hazardous marine biotoxin. Moreover, benefiting from the superior specificity and stability of MIP, the fabricated sensor could be utilized to detect the domoic acid content in mussel extracts directly without complex pretreatment operation.

This study reviews the developments of bubble absorption refrigeration technologies. Firstly, the principles of the bubble absorption refrigeration systems as well as bubble absorbers were introduced; And then bubble behavior characteristics during the absorption process were observed and expressed graphically; Thirdly, available bubble absorbers were investigated, modeled and compared; In addition, current and potential refrigerant-absorbent pairs in the bubble absorption refrigeration systems were analyzed, and about fifty fluids were involved totally. What’s more, methods of enhancing bubble absorption performance were researched, and also the influence mechanisms of these physical and chemical methods were explained; Finally, the development of bubble absorption refrigeration technologies were discussed from the aspects of driving energies, performance enhancement and application extension. The tendency of bubble absorption refrigeration technologies is expected to be high efficiency, miniaturization, and intellectualization. The expressed contents in this paper are expected to be useful for readers in the fields of absorption refrigeration technologies and the medium-low grade heat utilization technologies, especially for the equipment operating in the unsteady conditions (e.g. swing, bump, jolt, scram, etc.).

Most existing solutions for thiol detection require the addition of extra chemical agents to produce detection signals. However, the tedious operations in the sensing process are unfavorable for the real-time dynamic detection of thiol molecules. Herein, we present an all-organic graphene/poly(1,3,5-triethynylbenzene) (PTEB) composite for rapid and direct photoelectrochemical (PEC) analysis of multi-sulfhydryl compounds through specific thiol-yne click reaction. The non-covalent interfacial π-π interaction between the graphene and PTEB improves the optoelectronic properties of PTEB, which sensitizes the photocathode toward thiol detection with high sensitivity, broad linear range, and low detection limit. The theoretical calculation reveals that abundant 1,3-diyne linkages of PTEB are -SH sensitive active sites in PEC detection. Furthermore, a homemade sensing instrument has achieved real-time monitoring of thiol, suggesting its feasibility as an online sensor or a reaction monitor embedded in the industrial production line. Such progress holds promise for developing a diacetylene functionalized conjugated polymers-based -SH responsive platform for practical application in chemical production and quality control.

Engineering nano-structured surfaces with mixed/thermo-responsive wettability offer a new approach to improve the boiling performances of advanced thermal systems, such as the solar system and the heat dissipation systems in nuclear power plants, where more efficient cooling and higher safety limits are extremely desirable. In this study, five groups of surfaces: a) plain surfaces, b) nanofilm coated surfaces, c) patterned surfaces with superhydrophilic nanograss, d) patterned surfaces with superhydrophobic nanograss, f) patterned surfaces with thermo-responsive wettable nanograss are investigated for their boiling performances. It is found that the nanofilm coated surfaces show improved maximum heat transfer coefficient (HTCmax) as well as critical heat flux (CHF) compared with the plain surface. The patterned surfaces shift the boiling curves to left, and the CHF increases with increasing nanograss cover density. The surfaces with thermo-responsive wettability, which responses to the external heating/cooling stimuli by gradually increasing or decreasing the wettability, show the most optimal CHF enhancement. This study serves as a proof-of-concept for efficient heat transfer through carefully fabricated nano-structured wettability-enhanced surfaces.

Transforming growth factor type 1 receptor (ALK5) is kinase associated with a wide variety of pathological processes, and inhibition of ALK5 is a good strategy to treat many kinds of cancer and fibrotic diseases. Recently, a series of compounds have been synthesized as ALK5 inhibitors. However, the study of their selectivity against other potential targets remains elusive. In this research, a data-set of ALK5 inhibitors were collected and studied based on the combination of 2D-QSAR, molecular docking and molecular dynamics simulation. The quality of QSAR models were assessed statistically by F, R

Vapor–liquid equilibrium data of binary working pairs play a crucial part in the research of absorption process and absorption refrigeration technology. In this paper, the VLE data of binary mixtures, R124-NMP and R124-DMF, were measured in a temperature range from 303.15 to 363.15 K, using a VLE measurement apparatus. The activity coefficient model of five-parameter nonrandom two liquid (NRTL) was selected to correlate all the VLE data acquired by measurement. The maximum relative deviation of the pressure between the measurement data and calculated data for R124-NMP and R124-DMF were 3.80% and 3.27% respectively, and the average relative deviation of the pressure were 1.25% and 1.17% respectively. The correlated results coincide well with the measurement data and show that the VLE characteristics of R124-NMP and R124-DMF mixtures have a negative deviation from Raoul’s law. Comparing three absorbents, DMF, DMAC and NMP, the activity coefficient of R124 in DMF is largest, that in DMAC is second, and that ...

Experimental investigation for a copper vertical tubular bubble absorber was done with R124 (2-chloro-l,l,l,2,-tetrafluoroethane)-DMAC (N′,N′-dimethylacetamide) as working fluid. The objective of the investigation was to explore key parameters affecting heat and mass transfer characteristics of the bubble absorber and propose new correlations for heat and mass transfer coefficients respectively for the R124-DMAC bubble absorption. The parameters include vapor and solution flow rates, solution inlet temperatures and mass fractions, nozzle orifice diameters and cooling water inlet temperatures. The results showed that to reduce the solution, cooling water inlet temperature and nozzle orifice diameter or to increase vapor and solution flow rate could enhance the heat and mass transfer performance of the absorber. Finally, correlations of Nusselt number and Sherwood number for calculating heat and mass transfer coefficients were proposed, respectively. Both correlations could predict about 90% of the experimental values at a margin of error less than 20%.

Experimental investigation for a visual vertical tubular bubble absorber was done with R124 (2-chloro-l,l,l,2,-tetrafluoroethane)-DMAC (N′,N′- dimethylacetamide) as working fluid. The objective of this investigation was to obtain key parameters that affect on the heat and mass transfer performance of R124-DMAC bubble absorption, such as vapor and solution flow rates, solution inlet temperatures and mass fractions, and nozzle orifice diameters. The results showed that the overall heat and volumetric mass transfer coefficients increased with increase of vapor and solution flow rates, and decreased with increase of solution inlet temperatures and mass fractions, and the nozzle orifice diameter. Especially, solution inlet mass fractions and the nozzle orifice diameter significantly influenced on mass transfer performance, while solution inlet temperatures and vapor flow rates influenced greatly on the heat transfer performance. A correlation of Sherwood number for R124-DMAC mixture in a visual vertical tubular bubble absorber was provided by the method of multiple linear regressions. The error band from the present study was within ±15%.

Purpose To investigate the potential protective effect of novel G protein coupled estrogen receptor (GPER1) against the neurotoxicity induced by NMDA in the mouse retina. Methods We induce retinal ganglion cells (RGCs) toxic injury through intravitreal injection of NMDA or acute ocular hypertension (AOH) induced by anterior chamber infusion with saline. Endogenous ligand 17-β-estradiol (E2), GPER1 agonist (G-1), and E2 with GPER1 antagonist (G-15) or classic estrogen receptor α and β (ERα and ERβ) antagonist tamoxifen (TAM) were subcutaneous administered before NMDA to identify the possible involved receptors. Immunofluorescence staining was performed to explore the survival of RGCs and Muller cell gliosis. TUNEL staining was used to evaluate the RGC apoptosis. The involved molecular pathway was detected via antibody array expression profiling. Results Activation of estrogen receptor by E2 or G-1 could significantly rescue the RGCs injury in NMDA administration. The protective effect was carried exclusively by GPER1 activation. E2 application can still mimicked the protective function when estrogen receptor α and β (ERα and ERβ) blocked by tamoxifen (TAM), while the effects was blocked by GPER1 antagonist G-15. Moreover, the TUNEL positive RGCs and GFAP expression level were both attenuated in G-1 application and the effects could be reversed by G-15. In addition, application of the PI3K/Akt antagonist LY294002 counteracted the effect of G-1. And a number of apoptosis regulatory factors decreased dramatically in the G-1 group, including Bad, Caspase 3, Caspase 7, Smad2, P-53 and TAK1. Also, similar protective effect of G-1 was spotted in acute ocular hypertension (AOH) model. Conclusion Estrogen played a protective role via a novel estrogen receptor, GPER1, instead of classical receptors ERα or ERβ. Activation of GPER1 attenuated RGCs apoptosis and Muller cells gliosis, indicating GPER1 as a potential treatment target in RGCs degeneration diseases.

With the increasing power consumption in the worldwide energy-intensive sectors, a more efficient thermal heat transfer during the boiling process is pressingly needed. The fundamental understanding of the boiling mechanism is essential for the enhanced heat transfer and subsequently the improvement of heat utilization. The present study decouples the contributions of the intrinsic surface wettability from the hierarchical (dual-layer) structure on the boiling enhancement by growing nanograss as the substructure and the micro flowers with different cover density as the superstructure. The structured surfaces show maximum critical heat flux (CHF) enhancement by 68%. While for the multi-orientated (from 0° to 180°) substrates, the surface orientation will influence the boiling performance through different physical mechanisms. It discloses that the departure time and the thickness of the fully developed vapor film of the inclined surfaces increase with increasing surface orientation, resulting in impeded boiling performance of the downward-facing surface. Moreover, enhanced critical heat flux and heat transfer coefficient can be observed for the nanograss surface with the downward-facing orientations. In addition, new correlations regarding the downward-facing CHF prediction based on the horizontal CHF are proposed for the future multi-oriented surface design in advanced heat-transfer applications.

A visual experimental platform for R124–DMAC bubble absorption in a vertical tube absorber was designed and built for this research. The bubble behaviors, flow pattern characteristics and distributions are observed and the bubble absorption heights (BAHs) were measured when the two kinds of different structure nozzles (single-orifice or multi-orifice nozzle) were applied in the absorber. The results showed that the BAH will heighten with increases of vapor flow rate and nozzle flow area. Based on visual experimental observations, the BAH or bubble absorption performance was significantly affected by the velocity of vapor from the nozzle rather than by the nozzle structure. The proportion of slug flow in BAH or the BAH can be decreased by using a multi-orifice nozzle in the absorber under the same flow area condition. However, the flow resistance of the vapor through the nozzle will increase, which has a negative action on the performance of absorption refrigeration systems. So, using multi-orifice nozzle does not improve the absorption performance of the bubble absorber under the same nozzle flow resistance condition.

Visual experimental investigations were carried out on a vertical co-current glass tube absorber to observe the behavior of the R124 (2-chloro-l,l,l,2,-tetrafluoroethane)–DMAC (N′,N′-dimethylacetamide) bubble absorption process and study the effects of different operating conditions on absorption performance. The results show that the refrigerant vapor flow rate, absorption solution flow rate, concentration, temperature and nozzle orifice diameter significantly affect the flow pattern and absorption height. As the vapor flow rate, absorption solution concentration and temperature, and nozzle orifice diameter increases, the absorption height increases. As the absorption solution flow rate increase, the absorption height reduces. Under the conditions of a large refrigerant vapor flow rate, high solution inlet concentration and temperature, three kinds of flow pattern, namely churn, slug and bubbly flow, can be simultaneously observed in the absorption tube.

A visual experimental research was conducted to investigate the flow patterns and absorption height (AH) in a vertical bubble absorption tube employing R124-NMP as working fluid. The effects of various operation parameters, solution inlet mass concentration, temperature and volumetric flow rate, vapor volumetric flow rate, absorption pressure and orifice diameter, on the flow patterns and AH were examined. The key operation parameters were all converted into dimensionless numbers and the influences of dimensionless operation parameters on dimensionless absorption height (DAH) were studied. The results showed that the AH increases with increasing solution inlet mass concentration and temperature, vapor volumetric flow rate and orifice diameter and decreases with increasing solution volumetric flow rate and absorption pressure. DAH exhibits nearly linear change along with dimensionless operation parameters. Comparisons between the flow patterns and AH of R124-NMP and R124-DMAC were performed. The compared results illustrated that employing R124-NMP as working fluid can shrink the vertical bubble absorber size. Finally, the experimental correlations of AH and DAH were developed with ±20% and ±15% error bands, respectively. The correlation of DAH maybe used to predict absorption height in the design of bubble absorber employing refrigerant-organic absorbent as working fluid.

Oxidative stress and P53 contribute to the pathogenesis of diabetic kidney disease (DKD). Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidant defense system, is negatively regulated by P53 and prevents DKD. Recent findings revealed an important role of mouse double minute 2 (MDM2) in protection against DKD. However, the mechanism remained unclear. We hypothesized that MDM2 enhances NRF2 antioxidant signaling in DKD given that MDM2 is a key negative regulator of P53. The MDM2 inhibitor nutlin3a elevated renal P53, inhibited NRF2 signaling and induced oxidative stress, inflammation, fibrosis, DKD-like renal pathology and albuminuria in the wild-type (WT) non-diabetic mice. These effects exhibited more prominently in nutlin3a-treated WT diabetic mice. Interestingly, nutlin3a failed to induce greater renal injuries in the Nrf2 knockout (KO) mice under both the diabetic and non-diabetic conditions, indicating that NRF2 predominantly mediates MDM2's action. On the contrary, P53 inhibition by pifithrin-α activated renal NRF2 signaling and the expression of Mdm2, and attenuated DKD in the WT diabetic mice, but not in the Nrf2 KO diabetic mice. In high glucose-treated mouse mesangial cells, P53 gene silencing completely abolished nutlin3a's inhibitory effect on NRF2 signaling. The present study demonstrates for the first time that MDM2 controls renal NRF2 antioxidant activity in DKD via inhibition of P53, providing MDM2 activation and P53 inhibition as novel strategies in the management of DKD.