Entropy-Mediated Stable Structural Evolution of Prussian White Cathodes for Long-Life Na-Ion Batteries.

The high-entropy approach is applied to monoclinic Prussian White (PW) Na-ion cathodes to address the issue of unfavorable multilevel phase transitions upon electrochemical cycling, leading to poor stability and capacity decay. A series of Mn-based samples with up to six metal species sharing the N-coordinated positions was synthesized. The material of composition Na1.65 Mn0.4 Fe0.12 Ni0.12 Cu0.12 Co0.12 Cd0.12 [Fe(CN)6 ]0.92 □0.08 ⋅ 1.09H2 O was found to exhibit superior cyclability over medium/low-entropy and conventional single-metal PWs. We also report, to our knowledge for the first time, that a high-symmetry crystal structure may be advantageous for high-entropy PWs during battery operation. Computational comparisons of the formation enthalpy demonstrate that the compositionally less complex materials are prone to phase transitions, which negatively affect cycling performance. Based on data from complementary characterization techniques, an intrinsic mechanism for the stability improvement of the disordered PW structure upon Na+ insertion/extraction is proposed, namely the dual effect of suppression of phase transitions and mitigation of gas evolution.

Single- to Few-Layer Nanoparticle Cathode Coating for Thiophosphate-Based All-Solid-State Batteries.

Bulk-type solid-state batteries (SSBs) composed of lithium thiophosphate superionic solid electrolytes (SEs) and high-capacity cathode active materials (CAMs) have recently attracted much attention for their potential application in next-generation electrochemical energy storage. However, compatibility issues between the key components in this kind of battery system are difficult to overcome. Here, we report on a protective cathode coating that strongly reduces the prevalence of detrimental side reactions between CAM and SE during battery operation. This is demonstrated using preformed HfO2 nanoparticles as a secondary particle coating for a layered Ni-rich oxide CAM, LiNi0.85Co0.1Mn0.05O2 (NCM85). The preparation of a stable dispersion of the HfO2 nanoparticles enabled the deposition of a uniform coating of thickness ≤11 nm. When incorporated into Li6PS5Cl-based, pellet-stack SSBs, the coated NCM85 showed superior performance in terms of reversibility, cell capacity, longevity, and rate capability over its uncoated counterpart. The effectiveness of the protective coating in mitigating electro-chemo-mechanical degradation was investigated using a suite of physical and electrochemical characterization techniques. In addition, the adaptability to wet processing of the coated NCM85 is demonstrated in slurry-cast SSBs and liquid-electrolyte-based Li-ion cells.

Design of Ordered Mesoporous CeO2-YSZ Nanocomposite Thin Films with Mixed Ionic/Electronic Conductivity via Surface Engineering.

Mixed ionic and electronic conductors represent a technologically relevant materials system for electrochemical device applications in the field of energy storage and conversion. Here, we report about the design of mixed-conducting nanocomposites by facile surface modification using atomic layer deposition (ALD). ALD is the method of choice, as it allows coating of even complex surfaces. Thermally stable mesoporous thin films of 8 mol-% yttria-stabilized zirconia (YSZ) with different pore sizes of 17, 24, and 40 nm were prepared through an evaporation-induced self-assembly process. The free surface of the YSZ films was uniformly coated via ALD with a ceria layer of either 3 or 7 nm thickness. Electrochemical impedance spectroscopy was utilized to probe the influence of the coating on the charge-transport properties. Interestingly, the porosity is found to have no effect at all. In contrast, the thickness of the ceria surface layer plays an important role. While the nanocomposites with a 7 nm coating only show ionic conductivity, those with a 3 nm coating exhibit mixed conductivity. The results highlight the possibility of tailoring the electrical transport properties by varying the coating thickness, thereby providing innovative design principles for the next-generation electrochemical devices.

High-Entropy Metal-Organic Frameworks for Highly Reversible Sodium Storage.

Prussian blue analogues (PBAs) are reported to be efficient sodium storage materials because of the unique advantages of their metal-organic framework structure. However, the issues of low specific capacity and poor reversibility, caused by phase transitions during charge/discharge cycling, have thus far limited the applicability of these materials. Herein, a new approach is presented to substantially improve the electrochemical properties of PBAs by introducing high entropy into the crystal structure. To achieve this, five different metal species are introduced, sharing the same nitrogen-coordinated site, thereby increasing the configurational entropy of the system beyond 1.5R. By careful selection of the elements, high-entropy PBA (HE-PBA) presents a quasi-zero-strain reaction mechanism, resulting in increased cycling stability and rate capability. The key to such improvement lies in the high entropy and associated effects as well as the presence of several active redox centers. The gassing behavior of PBAs is also reported. Evolution of dimeric cyanogen due to oxidation of the cyanide ligands is detected, which can be attributed to the structural degradation of HE-PBA during battery operation. By optimizing the electrochemical window, a Coulombic efficiency of nearly 100% is retained after cycling for more than 3000 cycles.

Ordered mesoporous metal oxides for electrochemical applications: correlation between structure, electrical properties and device performance.

Ordered mesoporous metal oxides with a high specific surface area, tailored porosity and engineered interfaces are promising materials for electrochemical applications. In particular, the method of evaporation-induced self-assembly allows the formation of nanocrystalline films of controlled thickness on polar substrates. In general, mesoporous materials have the advantage of benefiting from a unique combination of structural, chemical and physical properties. This Perspective article addresses the structural characteristics and the electrical (charge-transport) properties of mesoporous metal oxides and how these affect their application in energy storage, catalysis and gas sensing.

Cost-Utility Analysis of Dapagliflozin Versus Saxagliptin Treatment as Monotherapy or Combination Therapy as Add-on to Metformin for Treating Type 2 Diabetes Mellitus.

OBJECTIVE: To assess the long-term cost effectiveness of dapagliflozin (DAPA) and saxagliptin (SAXA) separately or together in patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin (MET). METHODS: Five head-to-head randomised controlled trials of the efficacy of DAPA and SAXA in type 2 diabetes mellitus (T2DM) patients were found by searching PubMed, Embase and Cochrane from inception to October 2019. The lifetime disease progression and long-term effectiveness of therapy in patients were projected by the United Kingdom Prospective Diabetes Study Outcome Model 2 (UKPDS OM2) in three T2DM therapeutic groups: DAPA + SAXA, DAPA and SAXA. Each group used DAPA and/or SAXA as an add-on therapy to MET. The study took the perspective of Chinese healthcare service providers. Univariate, scenario and probabilistic sensitivity analyses were performed. RESULTS: The quality-adjusted life-years (QALYs) value of the DAPA + SAXA, SAXA and DAPA groups were 11.28, 11.26 and 11.45 years, respectively. The total costs were US$27,954.84, US$23,254.46 and US$25,608.49, respectively. DAPA was dominant over DAPA + SAXA. The DAPA + SAXA group presented an estimated QALY gain of 0.02 and a total cost increase of US$4700.39 over the SAXA group, with an incremental cost of US$217,530.10 per QALY. Compared with the SAXA group, the DAPA group had a QALY gain of 0.19 years and a total cost increase of US$2354.04, for an incremental cost of US$12,191.97 per QALY. The pharmacoeconomic results were robust to univariate, scenario and probabilistic sensitivity analyses. CONCLUSIONS: Compared with DAPA + SAXA or SAXA, DAPA appears to be a cost-effective therapy as add-on to MET for Chinese patients whose T2DM is insufficiently controlled by MET.

Correlation between CYP11B2 polymorphism and the risk of preeclampsia.

BACKGROUND: Many studies have evaluated the association between aldosterone synthase (CYP11B2) C-344T polymorphism and preeclampsia (PE) susceptibility, however, the results from different studies are inconsistent. OBJECTIVE: The study aimed to derive a more precise estimation of this association. METHODS: We searched PubMed, Embase, Chinese National Knowledge Infrastructure, China Biological Medicine, and Wanfang Database. The association was evaluated by calculating the odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). RESULTS: Seven case-control studies with a total of 720 cases and 766 controls were eligible to be included in this meta-analysis. Overall, there was no significant association between CYP11B2 C-344T polymorphism and PE (for the allele model T vs.C: OR=0.78, 95%CI 0.60-1.01, p=0.06; for the codominant model CT vs. CC: OR=1.08, 95%CI 0.80-1.46, p=0.63; for the dominant model TT + CT vs. CC: OR=0.91, 95%CI 0.68-1.20, p=0.49). Similar results were obtained in sensitivity analysis. CONCLUSION: In summary, the present meta-analysis suggests that CYP11B2 C-344T polymorphism may not be associated with genetic susceptibility of PE, but the association remains indeterminate due to the insufficient evidence.

Microglia activation induces oxidative injury and decreases SIRT3 expression in dopaminergic neuronal cells.

Microglia activation-mediated neuroinflammation plays an important role in the progression of Parkinson's disease (PD). However, effects of microglia activation on dopaminergic neuronal cell (DAC) fate are still poorly understood. The objective of this study was to explore the neurotoxic effects of microglia activation-mediated oxidative injury in DACs and its possible mechanisms. In the present study, microglia-DACs co-culture systems (murine BV-2 and MN9D cells, or primary microglia and mesencephalic neurons) were used to display the crosstalk between both cell types. The cytotoxicity of lipopolysaccharide-induced microglia activation led to the accumulation of intracellular reactive oxygen species, increased cell apoptosis rate, reduced number of DACs, concomitant to cell cycle arrest at G1 phase. Molecular mechanisms of apoptosis caused by microglia activation-induced oxidative injury included the increased opening of mitochondrial permeability transition pore and enhanced membrane potential depolarization in MN9D cells, down-regulation of Bcl-2 and up-regulation of Bax, caspase-3 expression in DACs. In addition, microglia activation made a significant reduction of SIRT3 and superoxide dismutase 2 gene expression in DACs. Taken together, these data imply that microglia activation promotes cell apoptosis through mitochondrial pathway and decreases SIRT3 expression in DACs, which may provide some support for PD progression promoted by neuroinflammation.

Cobalt Disulfide Nanoparticles Embedded in Porous Carbonaceous Micro-Polyhedrons Interlinked by Carbon Nanotubes for Superior Lithium and Sodium Storage.

Transition metal sulfides are appealing electrode materials for lithium and sodium batteries owing to their high theoretical capacity. However, they are commonly characterized by rather poor cycling stability and low rate capability. Herein, we investigate CoS2, serving as a model compound. We synthesized a porous CoS2/C micro-polyhedron composite entangled in a carbon-nanotube-based network (CoS2-C/CNT), starting from zeolitic imidazolate frameworks-67 as a single precursor. Following an efficient two-step synthesis strategy, the obtained CoS2 nanoparticles are uniformly embedded in porous carbonaceous micro-polyhedrons, interwoven with CNTs to ensure high electronic conductivity. The CoS2-C/CNT nanocomposite provides excellent bifunctional energy storage performance, delivering 1030 mAh g-1 after 120 cycles and 403 mAh g-1 after 200 cycles (at 100 mA g-1) as electrode for lithium-ion (LIBs) and sodium-ion batteries (SIBs), respectively. In addition to these high capacities, the electrodes show outstanding rate capability and excellent long-term cycling stability with a capacity retention of 80% after 500 cycles for LIBs and 90% after 200 cycles for SIBs. In situ X-ray diffraction reveals a significant contribution of the partially graphitized carbon to the lithium and at least in part also for the sodium storage and the report of a two-step conversion reaction mechanism of CoS2, eventually forming metallic Co and Li2S/Na2S. Particularly the lithium storage capability at elevated (dis-)charge rates, however, appears to be substantially pseudocapacitive, thus benefiting from the highly porous nature of the nanocomposite.

Association of CD14-260 (-159) C/T and Alzheimer's disease: systematic review and trial sequential analyses.

Current studies have evaluated the association between CD14-260 (also known as -159) C/T polymorphism and Alzheimer's disease (AD) susceptibility. However, the association remains inconclusive. The aim of this study was to draw an accurate conclusion of the association. The literature search was conducted using PubMed, Embase, Chinese National Knowledge Infrastructure, China Biological Medicine Database, and Wanfang Databases for related articles. Four case-control studies with a total of 868 cases and 766 controls were eligible to be included in this meta-analysis. The association was evaluated by calculating the odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). Overall, there was no significant association between CD14-260C/T polymorphism and AD risk in all genetic models (the allele model T vs. C: OR = 1.06, 95% CI 0.92-1.21, p = 0.44; the homozygous model TT vs. CC: OR = 1.09, 95% CI 0.83-1.44, p = 0.53; the heterozygote model CT vs. CC: OR = 0.95, 95% CI 0.75-1.22, p = 0.71; the dominant model TT + CT vs. CC: OR = 1.05, 95% CI 0.84-1.32, p = 0.66; the recessive model TT vs. CT + CC: OR = 1.14, 95% CI 0.92-1.43, p = 0.24). The sample size of 5064 was calculated by applying trial sequential analysis. Cumulative z curve does not cross trial sequential monitoring boundary. In conclusion, the present meta-analysis suggests that the CD14-260C/T polymorphism may not be associated with genetic susceptibility of AD, but the association remains indeterminate due to the insufficient evidence.

Population pharmacokinetics of theophylline in adult Chinese patients with asthma and chronic obstructive pulmonary disease.

Background Theophylline has a narrow therapeutic range and large interindividual variability in blood levels, so a thorough understanding of its pharmacokinetic characteristics is essential. Population pharmacokinetic (PPK) approaches could achieve it and many PPK studies of theophylline have been reported in infants. However, none was conducted in Chinese adults and none has explored the effect of CYP1A2 genotypes on the PPK characteristics of theophylline in adults. Objective To evaluate the PPK characteristics of theophylline and to assess the possible influence of covariates, including CYP1A2 genotypes, on theophylline clearance in Chinese adult patients. Setting The study is conducted at the department of respiration in Zhujiang Hospital, Guangzhou, China. Methods Theophylline concentrations were obtained from eligible patients and were measured by high performance liquid chromatography. The polymorphisms of - 3860G > A, - 163C > A, C5347T (CYP1A2*1B) and G-3113A were genotyped using a direct sequencing method. Then, CYP1A2 genotypes, age, fat-free mass (FFM) and other covariates were used to develop a PPK model by NONMEM software. Bootstrap analysis was used to asses the accuracy and prediction of the PPK model. Main outcome measure The concentration and clearance of theophylline. Results A total of 134 theophylline concentrations from 95 patients were obtained. The final model was as follows: CL/F(L/h) = 4.530 × (FFM/56.1)0.75 × 0.713CYP1A2*1B, the inter-individual variability in clearance/bioavailability (CL/F) was 44.0%, and the residual variability was 9.8%. The final model was proved to be reliable by bootstrap analysis. Conclusion Theophylline clearance was significantly associated with FFM and CYP1A2*1B genotypes in Chinese adult patients.

Water decontamination by polyoxometalate-functionalized 3D-printed hierarchical porous devices.

The design of organic-inorganic hybrid composites has revolutionized application-driven materials design. Here, we show how hierarchically structured, 3D-printed ABS polymers can be surface-functionalized with lacunary polyoxometalate anions ([α-PW9O34]9-) featuring heavy-metal binding sites. The resulting composite is highly porous and can be used for the removal of transition-metal pollutants from water. Thus, a facile blueprint for decentralized production of water filtration devices is reported.

Remarkably Improvement in Antibacterial Activity of Carbon Nanotubes by Hybridizing with Silver Nanodots.

In view of their super capacity of adsorbing microbial, the carbon nanotubes (CNTs) were used as the carriers for in situ synthesizing well-dispersed and small-sized silver nanodots (AgND), to prepare a new type of antibacterial agent with remarkably improved activity. Polyethyleneimine (PEI) was introduced as a linkage for guaranteeing the as-generated AgND to be anchored onto the CNTs and to prevent them from agglomeration. The obtained hybridizing materials were characterized by transmission electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy, and the results showed that the AgND with an average size of 2.6 nm were uniformly loaded on surfaces of CNTs. There existed special interactions between silver atoms and CNTs. The antibacterial activities of the as-prepared hybrids against Escherichia coli were evaluated by disk diffusion assay method and minimal inhibitory concentration measurements. The results showed that the as-prepared hybrids displayed a remarkable improvement in antibacterial activity as compared to CNTs, acidified-CNTs and even the identical silver amount of AgNO3 solution, which was mainly attributed to the small size of AgND and the hybridizing effect between AgND and CNTs.

SIRT3 in Neural Stem Cells Attenuates Microglia Activation-Induced Oxidative Stress Injury Through Mitochondrial Pathway.

Sirtuin 3 (SIRT3), a mitochondrial protein, is involved in energy metabolism, cell apoptosis and mitochondrial function. However, the role of SIRT3 in neural stem cells (NSCs) remains unknown. In previous studies, we found that microglia activation-induced cytotoxicity negatively regulated survival of NSCs, along with mitochondrial dysfunction. The aim of this study was to investigate the potential neuroprotective effects of SIRT3 on the microglia activation-induced oxidative stress injury in NSCs and its possible mechanisms. In the present study, microglia-NSCs co-culture system was used to demonstrate the crosstalk between both cell types. The cytotoxicity of microglia activation by Amyloid-ß (Aß) resulted in the accumulation of reactive oxygen species (ROS) and down-regulation of SIRT3, manganese superoxide dismutase (MnSOD) gene expression in NSCs, concomitant to cell cycle arrest at G0/G1 phase, increased cell apoptosis rate and opening of the mitochondrial permeability transition pore (mPTP) and enhanced mitochondrial membrane potential (ΔΨm) depolarization. Furthermore, SIRT3 knockdown in NSCs via small interfering RNA (siRNA) accelerated cell injury, whereas SIRT3 overexpression provided resistance to microglia activation-induced oxidative stress cellular damage. The mechanisms of SIRT3 attenuated activated microglia-induced NSC dysfunction included the decreased mPTP opening and cyclophilin D (CypD) protein expression, inhibition of mitochondrial cytochrome C (Cyt C) release to cytoplasm, declined Bax/B-cell lymphoma 2 (Bcl-2) ratio and reduced caspase-3/9 activity. Taken together, these data imply that SIRT3 ameliorates microglia activation-induced oxidative stress injury through mitochondrial apoptosis pathway in NSCs, these results may provide a novel intervention target for NSC survival.

Efficacy and safety of Reduqing granules in the treatment of common cold with wind-heat syndrome: a randomized, double-blind, double-dummy, positive-controlled trial.

OBJECTIVE: To assess the efficacy and safety of Reduqing granules in patients with common cold with wind-heat syndrome (CCWHS). METHODS: A randomized, double-blind, double-dummy, parallel, positive- controlled trial included 72 CCWHS patients was performed. The participants were randomly assigned to two groups, Reduqing (RDQ) group and Lianhuaqingwen (LHQW) group, in a 1:1 ratio. Patients in RDQ group received Reduqing granules and dummy Lianhuaqingwen capsules three times a day and patients in LHQW group received Lianhuaqingwen capsules and dummy Reduqing granules three times daily. The duration of treatment and follow-up were four days. RESULTS: There were no statistically significant differences in total markedly effective rate and total effective rate between RDQ group and LHQW group after treatment. Traditional Chinese Medicine (TCM) symptom score was significantly reduced after treatment in RDQ group, as well as in LHQW group. However, the difference of change in TCM symptom score between two groups was not statistically significant (P > 0.05). There were no significant differences between two groups in the median time to fever relief [RDQ group (4 ± 8) h vs LHQW group (4 ± 5) h] or the median time to fever clearance (RDQ group 47 h vs LHQW 36 h). No serious adverse events were reported during the study. CONCLUSION: Compared with Lianhuaqingwen capsules, Reduqing granules achieved similar therapeutic effect in the treatment of CCWHS and no drug-related adverse events were reported during the study. Therefore, Reduqing granules might be effective and safe in the treatment of CCWHS.

Efficacy and safety of prostaglandin E1 plus lipoic acid combination therapy versus monotherapy for patients with diabetic peripheral neuropathy.

The aim of this report was to evaluate the efficacy and safety of prostaglandin E1 (PGE1) plus lipoic acid (LA) for the treatment of diabetic peripheral neuropathy (DPN) compared with that of PGE1 or LA monotherapy. Randomized controlled trials (RCT) published up to 3 August 2014 were reviewed. A random or fixed effect model was used to analyze outcomes expressed as risk ratios (RR) or mean difference (MD) with a 95% confidence interval (CI). I(2) statistic was used to assess heterogeneity. Subgroup and sensitivity analyses were performed. The outcomes measured were as follows: clinical efficacy, median motor nerve conduction velocity (MNCV), median sensory nerve conduction velocity (SNCV), peroneal MNCV, peroneal SNCV and adverse effects. Thirty-one RCT with 2676 participants were included. Clinical efficacy of PGE1+LA combination therapy was significantly better than monotherapy (p<0.00001, RR=1.32, 95% CI 1.26 to 1.38). Compared with monotherapy, PGE1+LA combination therapy led to significant improvements in median MNCV (p<0.00001, MD=4.69, 95% CI 3.16 to 6.23), median SNCV (p<0.00001, MD=5.46, 95% CI 4.04 to 6.88), peroneal MNCV (p<0.00001, MD=5.19, 95% CI 3.71 to 6.67) and peroneal SNCV (p<0.00001, MD=5.50, 95% CI 3.30 to 7.70). There were no serious adverse events associated with drug intervention. PGE1+LA combination therapy is superior to PGE1 or LA monotherapy for improvement of neuropathic symptoms and nerve conduction velocities in patients with DPN. These findings should be further validated by larger well-designed and high-quality RCT.

Signal Mechanisms of Vascular Remodeling in the Development of Pulmonary Arterial Hypertension.

Pulmonary artery hypertension (PAH) is a chronic progressive disease characterized by persistent elevation of pulmonary arterial vascular pressure. The disease severely limits the function of the right ventricle, causing organ failure and finally leading to death. Despite significant advances in pharmacological treatments, PAH remains an incurable disease with high morbidity and mortality. The histopathological change of PAH is featured by remodeling of the pulmonary vascular. Abnormal proliferation of pulmonary artery smooth muscle cells in peripheral vascular is 1 major pathological finding of pulmonary vascular remodeling. Current therapeutics available for PAH primarily aim at inhibiting the pulmonary vasoconstriction and resisting pulmonary vascular remodeling. To date, only some inhibitors targeting proliferative signaling pathways have been used to suppress the proliferation of pulmonary artery smooth muscle cells and reverse pulmonary vascular remodeling. However, because of serious side effects, their clinical use is limited, and more validation is needed before the inhibitors can be transferred into clinical use. This review will focus on signal mechanisms of vascular remodeling in the development of PAH and give an overview of recent advances in research on inhibitors targeting proliferative pathways.

Liquid-liquid interface-mediated room-temperature synthesis of amorphous NiCo pompoms from ultrathin nanosheets with high catalytic activity for hydrazine oxidation.

NixCoy alloy pompoms formed by the aggregation of nano ultrathin sheets were prepared by simultaneous reduction of NiCl2 and CoCl2 with NaBH4via a liquid-liquid interface reaction. Ni1Co3 pompoms produced markedly higher activity and stability as hydrazine oxidation catalysts than Ni, Co and other NixCoy pompom catalysts.

Evolution of nanoscale amorphous, crystalline and phase-segregated PtNiP nanoparticles and their electrocatalytic effect on methanol oxidation reaction.

The design of amorphous noble metallic nanoparticle electrocatalysts is an important fundamental and applied research challenge because their surface is rich in low-coordination sites and defects which could act as the active sites in various catalytic processes. Here we describe new findings on the amorphous platinum-nickel-phosphorous nanoparticles supported on carbon black (PtNiP(a)/C) and the comparison between their catalytic activity and that of the nanoscale crystalline and phase-segregated PtNiP nanoparticles. The nanoscale amorphous, crystalline and phase-segregated catalysts were probed as a function of surface composition, particle size, and thermal treatment conditions using X-ray diffraction, X-ray photoelectron spectroscopy, transmission electron microscopy, selected area electron diffraction and electrochemical characterization. The results provide the experimental evidence in support of nanoscale amorphous, crystalline, and phase-segregated PtNiP nanoparticles evolution dependence on the catalyst synthesis temperature. More importantly, the results of the electrochemical performance investigation showed that the amorphous structure has not only better catalytic activity for methanol oxidation but also stronger tolerance to carbon monoxide poisoning compared to the crystalline and phase-segregated structure. Besides, the thermal control of the formation of nanoscale amorphous, crystalline and phase-segregated structured catalysts provided the opportunity for establishing the correlation between the nanoscale phase structures of the catalysts and their electrocatalytic activity in methanol oxidation reaction, which plays an important role in developing highly active electrocatalysts for direct methanol fuel cells.