Nucleotide excision repair gene polymorphisms and hepatoblastoma susceptibility in Eastern Chinese children: A five-center case-control study.

Objective: Nucleotide excision repair (NER) plays a vital role in maintaining genome stability, and the effect of NER gene polymorphisms on hepatoblastoma susceptibility is still under investigation. This study aimed to evaluate the relationship between NER gene polymorphisms and the risk of hepatoblastoma in Eastern Chinese Han children. Methods: In this five-center case-control study, we enrolled 966 subjects from East China (193 hepatoblastoma patients and 773 healthy controls). The TaqMan method was used to genotype 19 single nucleotide polymorphisms (SNPs) in NER pathway genes, including ERCC1, XPA, XPC, XPD, XPF, and XPG. Then, multivariate logistic regression analysis was performed, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were utilized to assess the strength of associations. Results: Three SNPs were related to hepatoblastoma risk. XPC rs2229090 and XPD rs3810366 significantly contributed to hepatoblastoma risk according to the dominant model (adjusted OR=1.49, 95% CI=1.07-2.08, P=0.019; adjusted OR=1.66, 95% CI=1.12-2.45, P=0.012, respectively). However, XPD rs238406 conferred a significantly decreased risk of hepatoblastoma under the dominant model (adjusted OR=0.68, 95% CI=0.49-0.95; P=0.024). Stratified analysis demonstrated that these significant associations were more prominent in certain subgroups. Moreover, there was evidence of functional implications of these significant SNPs suggested by online expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) analysis. Conclusions: In summary, NER pathway gene polymorphisms (XPC rs2229090, XPD rs3810366, and XPD rs238406) are significantly associated with hepatoblastoma risk, and further research is required to verify these findings.

Inner Doping of Carbon Nanotubes with Perovskites for Ultralow Power Transistors.

Semiconducting carbon nanotubes (CNTs) are considered as the most promising channel material to construct ultrascaled field-effect transistors, but the perfect sp2 C─C structure makes stable doping difficult, which limits the electrical designability of CNT devices. Here, an inner doping method is developed by filling CNTs with 1D halide perovskites to form a coaxial heterojunction, which enables a stable n-type field-effect transistor for constructing complementary metal-oxide-semiconductor electronics. Most importantly, a quasi-broken-gap (BG) heterojunction tunnel field-effect transistor (TFET) is first demonstrated based on an individual partial-filling CsPbBr3/CNT and exhibits a subthreshold swing of 35 mV dec-1 with a high on-state current of up to 4.9 µA per tube and an on/off current ratio of up to 105 at room temperature. The quasi-BG TFET based on the CsPbBr3/CNT coaxial heterojunction paves the way for constructing high-performance and ultralow power consumption integrated circuits.

Prevalence and factors associated with dyslipidemia in patients with first hospitalization for major depressive disorder: a large sample cross-sectional study.

BACKGROUND: Major depressive disorder (MDD) is a severe mental illness with high relapse rates and high mortality. Depression not only severely limits psychosocial functioning but also reduces quality of life. It can also negatively affect patients' clinical parameters, including lipid metabolism markers. This study aimed to investigate the prevalence and risk factors of hyperlipidemia (HL) in patients with MDD who were hospitalized for the first time. METHODS: In this study, we enrolled 981 patients with MDD who were hospitalized for the first time, collected their demographic data and biochemical indicators, and evaluated their clinical symptoms. We divided the patients into HL and non-HL subgroups based on whether they had co-morbid HL. We compared whether there were significant differences between the two groups regarding demographics and general clinical information. RESULTS: A total of 708 of 981 MDD patients were described as being in the hyperlipidemic group, with an incidence of 72.17%. Clinical Global Impression Scale-Severity of Illness (CGI-SI) score and Hamilton Depression Scale (HAMD) score are risk factors for co-morbid HL in patients with MDD. The area under the ROC curve for the CGI-SI and HAMD score and their combined discriminatory ability was approximately 63%, 67%, and 68%, respectively. CONCLUSION: The prevalence of HL was high in patients with MDD who were first hospitalized; Higher HAMD score and CGI-SI score were risk factors for the development of HL in MDD; The HAMD score and the CGI-SI score are predictive of the severity of HL.

Synergetic enhancement effect of two-dimensional MoS2 nanosheets and metal organic framework-derived porous ZnO nanorods for photodegradation performance.

Two-dimensional transition metal dichalcogenides and semiconductor metal oxides have shown great potential in photocatalysis. However, their stability and efficiency need to be further improved. In this paper, porous ZnO nanorods with high specific surface area were prepared from metal-organic framework ZIF-8 by a simple hydrothermal method. A MoS2/ZnO composite was constructed by loading MoS2 onto the surface of porous ZnO nanorods. Compared with ZnO materials prepared by other methods, MoS2/ZnO prepared in this paper exhibits superior photocatalytic performance. The enhanced photocatalytic activity of the MoS2/ZnO composite can be attributed to the formation of heterojunctions and strong interaction between them, which greatly facilitate the separation of electrons and holes at the contact interface. In addition, due to the wide absorption region of the visible spectrum, MoS2 can greatly broaden the light absorption range of the material after the formation of the composite material, increase the utilization rate of visible light, and reduce the combination of electrons and holes. This study provides a new way to prepare cheap and efficient photocatalysts.

Prevalence and Factors Associated with Subclinical Hypothyroidism in Major Depressive Disorder Patients with Dyslipidemia.

Background: Major depressive disorder (MDD) is a common psychiatric disorder with a high prevalence of comorbidity with subclinical hypothyroidism. The aim of this study was to investigate the prevalence and factors influencing the comorbidity of subclinical hypothyroidism in patients with dyslipidemic MDD who were hospitalized for the first time in a Chinese population. Methods: The study incorporated 708 first-time hospitalized MDD patients, all with dyslipidemia. Data collection encompassed socio-demographic information, blood pressure, fasting blood glucose (FBG), lipid, and thyroid hormone levels. Participants were evaluated using the Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Positive Symptom Subscale (PSS). Results: The prevalence of subclinical hypothyroidism in dyslipidemic MDD patients with the first hospitalization was 39.97%. The course of the disease, age at onset, HAMA score, and low-density lipoprotein cholesterol (LDL-C) were risk factors for subclinical hypothyroidism in dyslipidemic MDD patients. The course of disease, age at onset, HAMA score, HAMD score, FBG, and systolic blood pressure (SBP) levels were observed to influence serum Thyroid Stimulating Hormone (TSH) levels. Conclusion: MDD patients with dyslipidemia have a high prevalence of subclinical hypothyroidism, and the outcome is associated with anxiety, fasting glucose, and lipids. This study provides a potential biomarker for the identification of co-morbid subclinical hypothyroidism in MDD patients with dyslipidaemia.

Generation and application of endogenously floxed alleles for cell-specific knockout in zebrafish.

The zebrafish is amenable to a variety of genetic approaches. However, lack of conditional deletion alleles limits stage- or cell-specific gene knockout. Here, we applied an existing protocol to establish a floxed allele for gata2a but failed to do so due to off-target integration and incomplete knockin. To address these problems, we applied simultaneous co-targeting with Cas12a to insert loxP sites in cis, together with transgenic counterscreening and comprehensive molecular analysis, to identify off-target insertions and confirm targeted knockins. We subsequently used our approach to establish endogenously floxed alleles of foxc1a, rasa1a, and ruvbl1, each in a single generation. We demonstrate the utility of these alleles by verifying Cre-dependent deletion, which yielded expected phenotypes in each case. Finally, we used the floxed gata2a allele to demonstrate an endothelial autonomous requirement in lymphatic valve development. Together, our results provide a framework for routine generation and application of endogenously floxed alleles in zebrafish.

Prevalence and correlates of severe anxiety in patients with first hospitalization for major depressive disorder combined with dyslipidemia: a large sample cross-sectional study.

Background: Anxiety symptoms and dyslipidemia are common co-morbidities in patients with major depressive disorder (MDD), and there are complex pathophysiologic as well as clinical mechanisms underlying the association between the three. In this study, we investigated the prevalence and associated factors of severe anxiety in first-time hospitalized patients with MDD with dyslipidemia. Methods: We included 708 patients with major depressive disorder with comorbid dyslipidemia and collected their sociodemographic and general clinical data as well as biochemical parameters such as lipids, thyroid function, and blood glucose. We also completed the Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Positive Symptom Scale (PSS), and Clinical General Impression Scale (CGI) to assess their clinical symptoms. Results: The prevalence of severe anxiety disorder was 11.02% in patients with MDD with comorbid dyslipidemia. Suicidal history, female gender, body mass index (BMI), HAMD score, PSS score, and FT4 level were risk factors for the development of severe anxiety symptoms. Higher HAMD scores, higher PSS scores, and suicidal history were influential factors in exacerbating severe anxiety symptoms. Conclusion: This study reports and identifies the prevalence of severe anxiety symptoms in first-time hospitalized MDD patients with dyslipidemia, as well as risk factors for anxiety symptoms and factors influencing their severity, and these identified factors may be potentially helpful and informative in preventing and intervening in severe anxiety disorders in this target population.

Iron(II) Phthalocyanine Adsorbed on Defective Graphenes: A Density Functional Study.

The adsorptions of iron(II) phthalocyanine (FePc) on graphene and defective graphene were investigated systematically using density functional theory. Three types of graphene defects covering stone-wales (SW), single vacancy (SV), and double vacancy (DV) were taken into account, in which DV defects included DV(5-8-5), DV(555-777), and DV(5555-6-7777). The calculations of formation energies of defects showed that the SW defect has the lowest formation energy, and it was easier for DV defects to form compared with the SV defect. It is more difficult to rotate or move FePc on the surface of defective graphenes than on the surface of graphene due to bigger energy differences at different sites. Although the charge analysis indicated the charge transfers from graphene or defective graphene to FePc for all studied systems, the electron distributions of FePc on various defective graphenes were different. Especially for FePc@SV, the d xy orbital of Fe in the conduction band moved toward the Fermi level about 1 eV, and the d xz of Fe in the valence band for FePc@SV also moved toward the Fermi level compared with FePc@graphene and other FePc@defective graphenes. Between the planes of FePc and defective graphene, the electron accumulation occurs majorly in the position of the FePc molecular plane for FePc@SW, FePc@DV(5-8-5), and FePc@DV(5555-6-7777) as well as FePc@graphene. However, electrons were accumulated on the upper and lower surfaces of the FePc molecular plane for FePc@SV and FePc@DV(555-777). Thus, the electron distribution of FePc can be modulated by introducing the interfaces of different defective graphenes.

Factors Influencing the Knowledge Gap regarding Influenza and Influenza Vaccination in the Context of COVID-19 Pandemic: A Cross-Sectional Survey in China.

In the context of the COVID-19 global pandemic, promoting influenza knowledge and vaccine helps reduce the risk of dual pandemics and relieve the pressure on healthcare systems. Due to the low rate of influenza vaccination in China, we conducted a cross-sectional survey to investigate whether a knowledge gap regarding influenza and influenza vaccine exists between Chinese groups of different socioeconomic statuses and then explore the possible factors influencing knowledge level. A total of 951 valid questionnaires were collected online in this study. Variance analysis shows a knowledge gap regarding influenza and influenza vaccination between different socioeconomic status groups. Correlation analysis shows that internet media, social media, public communication, and interpersonal communication are positively associated with the knowledge level. Multilevel regression analysis shows a significant interaction between internet media and educational level. This study finds that internet media use helps narrow the knowledge gap between groups with different education levels. This article recommends a multi-channel promotion of influenza and vaccine knowledge and better pertinence between contents and readers.

Li8MnO6: A Novel Cathode Material with Only Anionic Redox.

In Li-excess transition metal-oxide cathode materials, anionic oxygen redox can offer high capacity and high voltages, although peroxo and superoxo species may cause oxygen loss, poor cycling performance, and capacity fading. Previous work showed that undesirable formation of peroxide and superoxide bonds was controlled to some extent by Mn substitution, and the present work uses density functional calculations to examine the reasons for this by studying the anionic redox mechanism in Li8MnO6. This material is obtained by substituting Mn for Sn in Li8SnO6 or for Zr in Li8ZrO6, and we also compare this to previous work on those materials. The calculations predict that Li8MnO6 is stable at room temperature (with a band gap of 3.19 eV as calculated by HSE06 and 1.82 eV as calculated with the less reliable PBE+U), and they elucidate the chemical and structural effects involved in the inhibition of oxygen release in this cathode. Throughout the whole delithiation process, only O2- ions are oxidized. The directional Mn-O bonds formed from unfilled 3d orbitals effectively inhibit the formation of O-O bonds, and the layered structure is maintained even after removing 3 Li per Li8MnO6 formula unit. The calculated average voltage for removal of 3 Li is 3.69 V by HSE06, and the corresponding capacity is 389 mAh/g. The high voltage of oxygen anionic redox and the high capacity result in a high energy density of 1436 Wh/kg. The Li-ion diffusion barrier for the dominant interlayer diffusion path along the c axis is 0.57 eV by PBE+U. These results help us to understand the oxygen redox mechanism in a new lithium-rich Li8MnO6 cathode material and contribute to the design of high-energy density lithium-ion battery cathode materials with favorable electrochemical properties based on anionic oxygen redox.

Theoretical study on Y-doped Na2ZrO3 as a high-capacity Na-rich cathode material based on anionic redox.

First-principles calculations based on density functional theory were utilized to study the performance of Na2ZrO3 (NZO) and yttrium-doped Na2ZrO3 (Y-NZO) as cathode materials for sodium ion batteries (SIBs), including the stability of the desodiated structures, desodiation energy, redox mechanism, and the diffusion of Na. When 62.5% sodium is removed from NZO, its structure and volume change little and the layered structure is retained, whereas the structure starts to distort and shift to the ZrO3 phase with the extraction of more than 62.5% sodium. As desodiation proceeds, oxygen anions act as the only redox center for charge compensation, yielding a high initial voltage of 4.03 eV vs. Na/Na+ by PBE + U-D3 functional and 4.82 eV vs. Na/Na+ by HSE06-D3 functional. When the desodiation content is less than 31.25%, O23- is formed with an O-O distance of 2.38 Å. At the desodiation content of 31.25%, peroxide dimer O22- starts to form; at the desodiation content of 56.25%, the O-O bond distance is further shortened to 1.3 Å, corresponding to the formation of superoxide O2-. However, for Y-NZO, the redox reaction firstly involves O2-/O1-, which does not occur in NZO. Peroxides and superoxides appear when the sodium removal concentration is 59.38% and 75%, respectively. This indicates that the O-O dimers appear in Y-NZO at much deeper sodium removal. The calculations of diffusion paths and barriers of Na ions in NZO by PBE + U-D3 predict that the barrier of Na escaping from the mixed layer to the Na layer in NZO is 0.48 eV (the reverse barrier is 0.76 eV), smaller than those of other O3-type layered transition metal compounds, such as Na2IrO3 and Na2RuO3. After yttrium doping, the diffusion of Na ions becomes easier, indicating that the Y-doping improves the diffusion ability. This investigation interprets the mechanism of oxygen oxidation of NZO as a cathode for SIBs, and provides theoretical support for a better design of Na-rich layered oxide Na2MO3 (M represents the transition metal element) in the future research.

The Prognostic Significance of C-Reactive Protein to Albumin Ratio in Patients With Severe Fever With Thrombocytopenia Syndrome.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with the high case-fatality rate, lacking effective therapies and vaccines. Inflammation-based indexes have been widely used to predict the prognosis of patients with cancers and some inflammatory diseases. In our study, we aim to explore the predictive value of the inflammation-based indexes in SFTS patients. Methods: We retrospectively analyzed 82 patients diagnosed with SFTS. The inflammation-based indexes, including neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), aggregate index of systemic inflammation (AISI) and C-reactive protein to albumin ratio (CAR), were compared between the survival and death patients. Receiver operating characteristic (ROC) curves were used to compare the predictive ability of MLR, AISI, and CAR. The survival analysis was based on the Kaplan-Meier (KM) method. Multivariate logistic regression analysis was used to analyze the independent risk factors of poor prognosis in patients with SFTS. Results: The CAR is higher in the death group while MLR and AISI were higher in the survival group. The ROC curve analysis indicated CAR exhibited more predictive value than the other indexes and the optimal cut-off value of CAR was equal to or greater than 0.14. KM survival curve showed that higher CAR was significantly correlated to the lower overall survival in SFTS patients. Multivariate logistic regression analysis indicated that CAR was an independent risk factor for poor prognosis in patients with SFTS. Conclusion: The CAR is an independent risk factor for death in patients with SFTS and could predict the poor prognosis of SFTS patients. It could be used as a biomarker to help physicians to monitor and treat patients more aggressively to improve clinical prognosis.

Neighborhood Effects on Tree Mortality Depend on Life Stage of Neighbors.

Neighborhood effects are a crucial ecological processes that allow species to coexist in a forest. Conspecific and heterospecific neighbors, as major group classifications, affect tree mortality through various mechanisms associated with neighbor life stages. However, the influence of neighbor life stages on neighborhood effects and by what mechanisms remains a knowledge gap. Here we censused the mortality of 82,202 trees belonging to 30 species in a 20-ha subtropical forest and classified their neighbors into the following life stages: earlier, same and later. Next, we implemented generalized linear mixed models to estimate the effect of neighbors at different life stages on tree mortality. Our results showed that conspecific later stage neighbors had a positive effect on tree mortality overall, while conspecific earlier stage neighbors had a negative effect on tree mortality. Furthermore, these opposing effects appear to offset each other so that the overall effect of conspecific neighbors on tree mortality is weakened. In contrast, heterospecific neighbors had a decreasing effect on tree mortality overall. These effects are consistent with those of later stage heterospecific neighbors. Our findings demonstrate that neighbors strongly impact tree mortality, and their specific effects are closely related to neighbor life stages. Further, any single effect from one neighbor life stage may disturb or dominate the total effects of the neighbors. Therefore, the neighbors must be divided into different life stages to best explain the neighborhood effect on forest dynamics.

Energy-Transfer-Mediated Photocatalysis by a Bioinspired Organic Perylenephotosensitizer HiBRCP.

Energy transfer plays a special role in photocatalysis by utilizing the potential energy of the excited state through indirect excitation, in which a photosensitizer determines the thermodynamic feasibility of the reaction. Bioinspired by the energy-transfer ability of natural product cercosporin, here we developed a green and highly efficient organic photosensitizer HiBRCP (hexaisobutyryl reduced cercosporin) through structural modification of cercosporin. After structural manipulation, its triplet energy was greatly improved, and then, it could markedly promote the efficient geometrical isomerization of alkenes from the E-isomer to the Z-isomer. Moreover, it was also effective for energy-transfer-mediated organometallic catalysis, which allowed realization of the cross-coupling of aryl bromides and carboxylic acids through efficient energy transfer from HiBRCP to nickel complexes. Thus, the study on the relationship between structural manipulation and their photophysical properties provided guidance for further modification of cercosporin, which could be applied to more meaningful and challenging energy-transfer reactions.

Innate Mechanisms of Heart Regeneration.

Heart regeneration is a remarkable process whereby regrowth of damaged cardiac tissue rehabilitates organ anatomy and function. Unfortunately, the human heart is highly resistant to regeneration, which creates a shortage of cardiomyocytes in the wake of ischemic injury, and explains, in part, why coronary artery disease remains a leading cause of death worldwide. Luckily, a detailed blueprint for achieving therapeutic heart regeneration already exists in nature because several lower vertebrate species successfully regenerate amputated or damaged heart muscle through robust cardiomyocyte proliferation. A growing number of species are being interrogated for cardiac regenerative potential, and several commonalities have emerged between those animals showing high or low innate capabilities. In this review, we provide a historical perspective on the field, discuss how regenerative potential is influenced by cardiomyocyte properties, mitogenic signals, and chromatin accessibility, and highlight unanswered questions under active investigation. Ultimately, delineating why heart regeneration occurs preferentially in some organisms, but not in others, will uncover novel therapeutic inroads for achieving cardiac restoration in humans.

A New Candidate in Polyanionic Compounds for a Potassium-Ion Battery Cathode: KTiOPO4.

First-principles computations were performed to investigate the performance of KTiOPO4 (KTP) as a cathode material for potassium-ion batteries (PIBs), including the stability and electronic properties of depotassiated structures and mechanisms of K deintercalation and diffusion. As depotassiation proceeds, oxygen hole polarons are produced, and there are not peroxides or superoxides formed after deep depotassiation. The anionic oxygen redox in KTP provides a voltage vs K/K+ over 4 V by the PBE+U method and over 5 V with the more reliable HSE06 hybrid functional. When all K in KTP is removed, the calculated volume compression is only 1.528%. The AIMD simulations at 300 K for TiOPO4 verify its thermal stability. The PBE+U calculations predict a low ion diffusion barrier of 0.29 eV in bulk KTP, indicating a good charge-discharge rate for KTP as a cathode for PIBs. All of the calculated results indicate that KTP can be a promising cathode material for PIBs.

Roussoelins A and B: two phenols with antioxidant capacity from ascidian-derived fungus Roussoella siamensis SYSU-MS4723.

Ascidian-derived microorganisms are a significant source of pharmacologically active metabolites with interesting structural properties. When discovering bioactive molecules from ascidian-derived fungi, two new phenols, roussoelins A (1) and B (2), and ten known polyketides (3-12) were isolated from the ascidian-derived fungus Roussoella siamensis SYSU-MS4723. The planar structure of compounds 1 and 2 was established by analysis of HR-ESIMS and NMR data. The conformational analysis of the new compounds was assigned according to coupling constants and selective gradient NOESY experiments, and absolute configurations were completed by the modified Mosher's method. Among the isolated compounds, 1, 2, and 9 showed moderate antioxidant capacity.

Cardiac Na+-Ca2+ exchanger 1 (ncx1h) is critical for the ventricular cardiomyocyte formation via regulating the expression levels of gata4 and hand2 in zebrafish.

Ca2+ signaling is critical for heart development; however, the precise roles and regulatory pathways of Ca2+ transport proteins in cardiogenesis remain largely unknown. Sodium-calcium exchanger 1 (Ncx1) is responsible for Ca2+ efflux in cardiomyocytes. It is involved in cardiogenesis, while the mechanism is unclear. Here, using the forward genetic screening in zebrafish, we identified a novel mutation at a highly-conserved leucine residue in ncx1 gene (mutantLDD353/ncx1hL154P) that led to smaller hearts with reduced heart rate and weak contraction. Mechanistically, the number of ventricular but not atrial cardiomyocytes was reduced in ncx1hL154P zebrafish. These defects were mimicked by knockdown or knockout of ncx1h. Moreover, ncx1hL154P had cytosolic and mitochondrial Ca2+ overloading and Ca2+ transient suppression in cardiomyocytes. Furthermore, ncx1hL154P and ncx1h morphants downregulated cardiac transcription factors hand2 and gata4 in the cardiac regions, while overexpression of hand2 and gata4 partially rescued cardiac defects including the number of ventricular myocytes. These findings demonstrate an essential role of the novel 154th leucine residue in the maintenance of Ncx1 function in zebrafish, and reveal previous unrecognized critical roles of the 154th leucine residue and Ncx1 in the formation of ventricular cardiomyocytes by at least partially regulating the expression levels of gata4 and hand2.

Activating transcription factor 3 coordinates differentiation of cardiac and hematopoietic progenitors by regulating glucose metabolism.

The cardiac and hematopoietic progenitors (CPs and HPs, respectively) in the mesoderm ultimately form a well-organized circulation system, but mechanisms that reconcile their development remain elusive. We found that activating transcription factor 3 (atf3) was highly expressed in the CPs, HPs, and mesoderm, in zebrafish. The atf3 -/- mutants exhibited atrial dilated cardiomyopathy and a high ratio of immature myeloid cells. These manifestations were primarily caused by the blockade of differentiation of both CPs and HPs within the anterior lateral plate mesoderm. Mechanistically, Atf3 targets cebpγ to repress slc2a1a-mediated glucose utilization. The high rate of glucose metabolism in atf3 -/- mutants inhibited the differentiation of progenitors by changing the redox state. Therefore, atf3 could provide CPs and HPs with metabolic adaptive capacity to changes in glucose levels. Our study provides new insights into the role of atf3 in the coordination of differentiation of CPs and HPs by regulating glucose metabolism.

Bis[pyrrolyl Ru(ii)] triads: a new class of photosensitizers for metal-organic photodynamic therapy.

A new family of ten dinuclear Ru(ii) complexes based on the bis[pyrrolyl Ru(ii)] triad scaffold, where two Ru(bpy)2 centers are separated by a variety of organic linkers, was prepared to evaluate the influence of the organic chromophore on the spectroscopic and in vitro photodynamic therapy (PDT) properties of the compounds. The bis[pyrrolyl Ru(ii)] triads absorbed strongly throughout the visible region, with several members having molar extinction coefficients (ε) ≥ 104 at 600-620 nm and longer. Phosphorescence quantum yields (Φ p) were generally less than 0.1% and in some cases undetectable. The singlet oxygen quantum yields (Φ Δ) ranged from 5% to 77% and generally correlated with their photocytotoxicities toward human leukemia (HL-60) cells regardless of the wavelength of light used. Dark cytotoxicities varied ten-fold, with EC50 values in the range of 10-100 µM and phototherapeutic indices (PIs) as large as 5400 and 260 with broadband visible (28 J cm-2, 7.8 mW cm-2) and 625 nm red (100 J cm-2, 42 mW cm-2) light, respectively. The bis[pyrrolyl Ru(ii)] triad with a pyrenyl linker (5h) was especially potent, with an EC50 value of 1 nM and PI > 27 000 with visible light and subnanomolar activity with 625 nm light (100 J cm-2, 28 mW cm-2). The lead compound 5h was also tested in a tumor spheroid assay using the HL60 cell line and exhibited greater photocytotoxicity in this more resistant model (EC50 = 60 nM and PI > 1200 with 625 nm light) despite a lower dark cytotoxicity. The in vitro PDT effects of 5h extended to bacteria, where submicromolar EC50 values and PIs >300 against S. mutans and S. aureus were obtained with visible light. This activity was attenuated with 625 nm red light, but PIs were still near 50. The ligand-localized 3ππ* state contributed by the pyrenyl linker of 5h likely plays a key role in its phototoxic effects toward cancer cells and bacteria.