PRKDC Induces Chemoresistance in Osteosarcoma by Recruiting GDE2 to Stabilize GNAS and Activate AKT.

Chemoresistance is one of the major causes of poor prognosis in osteosarcoma. Alternative therapeutic strategies for osteosarcoma are limited, indicating that increasing sensitivity to currently used chemotherapies could be an effective approach to improve patient outcomes. Using a kinome-wide CRISPR screen, we identified PRKDC as a critical determinant of doxorubicin (DOX) sensitivity in osteosarcoma. Analysis of clinical samples demonstrated that PRKDC was hyperactivated in osteosarcoma, and functional experiments showed that loss of PRKDC significantly increased sensitivity of osteosarcoma to DOX. Mechanistically, PRKDC recruited and bound GDE2 to enhance the stability of GNAS. The elevated GNAS protein levels subsequently activated AKT phosphorylation and conferred resistance to DOX. The PRKDC inhibitor AZD7648 and DOX synergized and strongly suppressed the growth of osteosarcoma in mouse xenograft models and human organoids. In conclusion, the PRKDC-GDE2-GNAS-AKT regulatory axis suppresses DOX sensitivity and comprises targetable candidates for improving the efficacy of chemotherapy in osteosarcoma.

Efficient Biodegradation of the Neonicotinoid Insecticide Flonicamid by Pseudaminobacter salicylatoxidans CGMCC 1.17248: Kinetics, Pathways, and Enzyme Properties.

Nitrile-containing insecticides can be converted into their amide derivatives by Pseudaminobacter salicylatoxidans. N-(4-trifluoromethylnicotinoyl) glycinamide (TFNG-AM) is converted to 4-(trifluoromethyl) nicotinoyl glycine (TFNG) using nitrile hydratase/amidase. However, the amidase that catalyzes this bioconversion has not yet been fully elucidated. In this study, it was discovered that flonicamid (FLO) is degraded by P. salicylatoxidans into the acid metabolite TFNG via the intermediate TFNG-AM. A half-life of 18.7 h was observed for P. salicylatoxidans resting cells, which transformed 82.8% of the available FLO in 48 h. The resulting amide metabolite, TFNG-AM, was almost all converted to TFNG within 19 d. A novel amidase-encoding gene was cloned and overexpressed in Escherichia coli. The enzyme, PmsiA, hydrolyzed TFNG-AM to TFNG. Despite being categorized as a member of the amidase signature enzyme superfamily, PsmiA only shares 20-30% identity with the 14 previously identified members of this family, indicating that PsmiA represents a novel class of enzyme. Homology structural modeling and molecular docking analyses suggested that key residues Glu247 and Met242 may significantly impact the catalytic activity of PsmiA. This study contributes to our understanding of the biodegradation process of nitrile-containing insecticides and the relationship between the structure and function of metabolic enzymes.

The long transcript of lncRNA TMPO-AS1 promotes bone metastases of prostate cancer by regulating the CSNK2A1/DDX3X complex in Wnt/ß-catenin signaling.

The second most common male cancer is prostate cancer (PCa), which has a high tendency for bone metastasis. Long non-coding RNAs, including TMPO-AS1, play a crucial role in PCa progression. However, TMPO-AS1's function in PCa bone metastasis (BM) and its underlying molecular mechanisms are unclear. Herein, we found that the long transcript of TMPO-AS1 (TMPO-AS1L) was upregulated in PCa tissues with bone metastasis, and overexpression of TMPO-AS1L correlated with advanced clinicopathological features and reduced BM-free survival in patients with PCa. Upregulated TMPO-AS1L promoted, whereas downregulated TMPO-AS1L inhibited, the PCa cell bone metastatic capacity in vitro and in vivo. Mechanistically, TMPO-AS1L was demonstrated to act as a scaffold, that strengthened the interaction of casein kinase 2 alpha 1 (CSNK2A1) and DEAD-box helicase 3 X-linked (DDX3X), and activated the Wnt/ß-catenin signaling pathway, thus promoting BM of PCa. Moreover, upregulation of TMPO-AS1L in PCa resulted from transcription elongation modulated by general transcription factor IIF subunit 2 (GTF2F2). Collectively, our study provides critical insights into the role of TMPO-AS1L in PCa BM via Wnt/ß-catenin signaling, identifying TMPO-AS1L as a candidate marker of PCa bone metastasis prognosis and therapeutic target.

Low-Temperature Observation of the Excited-State Decay of Ruthenium-(Mono-2,2':6',2″-Terpyridine) Ions with Innocent Ligands: DFT Modeling of an 3MLCT-3MC Intersystem Crossing Pathway.

The synthesis, electrochemistry, and photophysical characterization of five 2,2':6',2″-terpyridine ruthenium complexes (Ru-tpy complexes) is reported. The electrochemical and photophysical behavior varied depending on the ligands, i.e., amine (NH3), acetonitrile (AN), and bis(pyrazolyl)methane (bpm), for this series of Ru-tpy complexes. The target [Ru(tpy)(AN)3]2+ and [Ru(tpy)(bpm)(AN)]2+ complexes were found to have low-emission quantum yields in low-temperature observations. To better understand this phenomenon, density functional theory (DFT) calculations were performed to simulate the singlet ground state (S0), Te, and metal-centered excited states (3MC) of these complexes. The calculated energy barriers between Te and the low-lying 3MC state for [Ru(tpy)(AN)3]2+ and [Ru(tpy)(bpm)(AN)]2+ provided clear evidence in support of their emitting state decay behavior. Developing a knowledge of the underlying photophysics of these Ru-tpy complexes will allow new complexes to be designed for use in photophysical and photochemical applications in the future.

BHLHE22 drives the immunosuppressive bone tumor microenvironment and associated bone metastasis in prostate cancer.

BACKGROUND: The molecular characteristics of prostate cancer (PCa) cells and the immunosuppressive bone tumor microenvironment (TME) contribute to the limitations of immune checkpoint therapy (ICT). Identifying subgroups of patients with PCa for ICT remains a challenge. Herein, we report that basic helix-loop-helix family member e22 (BHLHE22) is upregulated in bone metastatic PCa and drives an immunosuppressive bone TME. METHODS: In this study, the function of BHLHE22 in PCa bone metastases was clarified. We performed immunohistochemical (IHC) staining of primary and bone metastatic PCa samples, and assessed the ability to promote bone metastasis in vivo and in vitro. Then, the role of BHLHE22 in bone TME was determined by immunofluorescence (IF), flow cytometry, and bioinformatic analyses. RNA sequencing, cytokine array, western blotting, IF, IHC, and flow cytometry were used to identify the key mediators. Subsequently, the role of BHLHE22 in gene regulation was confirmed using luciferase reporter, chromatin immunoprecipitation assay, DNA pulldown, co-immunoprecipitation, and animal experiments. Xenograft bone metastasis mouse models were used to assess whether the strategy of immunosuppressive neutrophils and monocytes neutralization by targeting protein arginine methyltransferase 5 (PRMT5)/colony stimulating factor 2 (CSF2) could improve the efficacy of ICT. Animals were randomly assigned to treatment or control groups. Moreover, we performed IHC and correlation analyses to identify whether BHLHE22 could act as a potential biomarker for ICT combination therapies in bone metastatic PCa. RESULTS: Tumorous BHLHE22 mediates the high expression of CSF2, resulting in the infiltration of immunosuppressive neutrophils and monocytes and a prolonged immunocompromised T-cell status. Mechanistically, BHLHE22 binds to the CSF2 promoter and recruits PRMT5, forming a transcriptional complex. PRMT5 epigenetically activates CSF2 expression. In a tumor-bearing mouse model, ICT resistance of Bhlhe22+ tumors could be overcome by inhibition of Csf2 and Prmt5. CONCLUSIONS: These results reveal the immunosuppressive mechanism of tumorous BHLHE22 and provide a potential ICT combination therapy for patients with BHLHE22+ PCa.

Artificial Neural Network-Assisted Classification of Hearing Prognosis of Sudden Sensorineural Hearing Loss With Vertigo.

This study aimed to determine the impact on hearing prognosis of the coherent frequency with high magnitude-squared wavelet coherence (MSWC) in video head impulse test (vHIT) among patients with sudden sensorineural hearing loss with vertigo (SSNHLV) undergoing high-dose steroid treatment. This study was a retrospective cohort study. SSNHLV patients treated at our referral center from December 2016 to December 2020 were examined. The cohort comprised 64 patients with SSNHLV undergoing high-dose steroid treatment. MSWC was measured by calculating the wavelet coherence analysis (WCA) at various frequencies from a vHIT. The hearing prognosis were analyzed using a multivariable Cox regression model and convolution neural network (CNN) of WCA. There were 64 patients with a male-to-female ratio of 1:1.67. The greater highest coherent frequency of the posterior semicircular canal (SCC) was associated with the complete recovery (CR) of hearing. After adjustment for other factors, the result remained robust (hazard ratio [HR] 2.11, 95% confidence interval [CI] 1.86-2.35). In the feature extraction with Resnet-50 and proceeding SVM in the horizontal image cropping style, the classification accuracy [STD] for (CR vs. partial + no recovery [PR + NR]), (over-sampling of CR vs. PR + NR), (extensive data extraction of CR vs. PR + NR), and (interpolation of time series of CR vs. PR + NR) were 83.6% [7.4], 92.1% [6.8], 88.9% [7.5], and 91.6% [6.4], respectively. The high coherent frequency of the posterior SCC was a significantly independent factor that was associated with good hearing prognosis in the patients who have SSNHLV. WCA may be provided with comprehensive ability in vestibulo-ocular reflex (VOR) evaluation. CNN could be utilized to classify WCA, predict treatment outcomes, and facilitate vHIT interpretation. Feature extraction in CNN with proceeding SVM and horizontal cropping style of wavelet coherence plot performed better accuracy and offered more stable model for hearing outcomes in patients with SSNHLV than pure CNN classification. Clinical and Translational Impact Statement-High coherent frequency in vHIT results in good hearing outcomes in SSNHLV and facilitates AI classification.

Cu-Ag Nanocomposite Pastes for Low Temperature Bonding and Flexible Interlayer-Interconnections.

Cu-Ag composite pastes consisting of carboxylate-capped Ag nanoparticles, spray-pyrolyzed Ag submicron particles, and copper formate were developed in this study for low-temperature low-pressure bonding. The joints between the Cu, Ni/Au, and Ag finished substrates can be well formed at temperatures as low as 160 °C under a load pressure of 1.6 MPa. The joints with Cu substrates possess 18.0 MPa bonding strength, while those with Ag surface finish could be enhanced to 23.3 MPa. When subject to sintering under 10 MPa at 160 °C, the electrical resistivity of the sintered structure on metal-coated polymeric substrates was around 11~17 µΩ-cm and did not differ too much when subjected to harsh reliability tests such as mechanical bending and thermal cycling tests, as well as electrical current stressing. This low-temperature, low-pressure nanocomposite paste shows great potential as interconnect materials for microelectronics or flexible device assembly.

Syndromic and non-syndromic etiologies causing neonatal hypocalcemic seizures.

Background: The diagnosis of neonatal hypocalcemic seizures (HS) in newborns is made based on clinical signs and serum calcium level. Their etiology is broad and diverse, and timely detection and initiation of treatment is essential. Methods: We retrospectively reviewed 1029 patients admitted to the neonatal intensive care unit. Neonatal HS were diagnosed in 16 patients, and we compared etiologies and clinical outcomes, including clinical seizures and neurodevelopment at least over 1 year old. Results: The etiologies can be broadly categorized into 5 syndromic and 11 non-syndromic neonatal HS. Syndromic neonatal HS included 3 Digeorge syndrome, 1 Kleefstra syndrome and 1 Alström syndrome. Non-syndromic neonatal HS included 8 vitamin D deficiency, 1 hypoparathyroidism, and 2 hypoxic-ischemic encephalopathy. Patients with syndromic neonatal HS were found to have worse clinical outcomes than those with nonsyndromic HS. In eight patients with vitamin D deficiency, neurodevelopment was normal. Five of five patients (100%) with syndromic HS used two or more antiseizure drugs. However, among patients with non-syndromic neonatal HS, only one of 11 (9.1%) used more than one drug (p = 0.001). Conclusion: This finding highlighted that syndromic hypocalcemic seizures in newborns have worse neurodevelopmental outcomes and are more often difficult to manage, and would benefit from a genetic diagnostic approach.

Ultra-compact hybrid silicon:chalcogenide waveguide temperature sensor.

We demonstrate a real-time, reusable, and reversible integrated optical sensor for temperature monitoring within harsh environments. The sensor architecture combines the phase change property of chalcogenide glasses (ChG) with the high-density integration advantages of high index silicon waveguides. To demonstrate sensor feasibility, ChG composition Ge40S60, which is characterized by a sharp phase transition from amorphous to crystalline phase around 415 °C, is deposited over a 50 µm section of a single mode optical waveguide. The phase transition changes the behavior of Ge40S60 from a low loss to high loss material, thus significantly affecting the hybrid waveguide loss around the phase transition temperature. A transmission power drop of over 40dB in the crystalline phase compared to the amorphous phase is experimentally measured. Moreover, we recover the amorphous phase through the application of an electrical pulse, thus showing the reversible nature of our compact temperature sensor. Through integrating multiple compositions of ChG with well-defined phases transition temperatures over a silicon waveguide array, it is possible to determine, in real-time, the temperature evolution within a harsh environment, such as within a nuclear reactor cladding.

Modeling the Impact of Vaccination on COVID-19 and Its Delta and Omicron Variants.

Vaccination is an important means to fight against the spread of the SARS-CoV-2 virus and its variants. In this work, we propose a general susceptible-vaccinated-exposed-infected-hospitalized-removed (SVEIHR) model and derive its basic and effective reproduction numbers. We set Hong Kong as an example and calculate conditions of herd immunity for multiple vaccines and disease variants. The model shows how the number of confirmed COVID-19 cases in Hong Kong during the second and third waves of the COVID-19 pandemic would have been reduced if vaccination were available then. We then investigate the relationships between various model parameters and the cumulative number of hospitalized COVID-19 cases in Hong Kong for the ancestral, Delta, and Omicron strains. Numerical results demonstrate that the static herd immunity threshold corresponds to one percent of the population requiring hospitalization or isolation at some point in time. We also demonstrate that when the vaccination rate is high, the initial proportion of vaccinated individuals can be lowered while still maintaining the same proportion of cumulative hospitalized/isolated individuals.

Does COVID-19 Vaccination Cause Storage Lower Urinary Tract Symptoms?

We investigated the storage lower urinary tract symptoms (LUTS) before and after the first dose of coronavirus disease 2019 (COVID-19) vaccine and the association between pre-vaccinated overactive bladder (OAB) and the worsening of storage LUTS following COVID-19 vaccination. This cross-sectional study in a third-level hospital in Taiwan used the validated pre- and post-vaccinated Overactive Bladder Symptom Score (OABSS). Diagnosis of OAB was made using pre-vaccinated OABSS. The deterioration of storage LUTS was assessed as the increased score of OABSS following vaccination. Of 889 subjects, up to 13.4% experienced worsened storage LUTS after vaccination. OAB was significantly associated with an increased risk of worsening urinary urgency (p = 0.030), frequency (p = 0.027), and seeking medical assistance due to urinary adverse events (p < 0.001) after vaccination. The OAB group faced significantly greater changes in OABSS-urgency (p = 0.003), OABSS-frequency (p = 0.025), and total OABSS (p = 0.014) after vaccination compared to those observed in the non-OAB group. Multivariate regression revealed that pre-vaccinated OAB (p = 0.003) was a risk for the deterioration of storage LUTS. In conclusion, storage LUTS may deteriorate after vaccination. OAB was significantly associated with higher risk and greater changes in worsening storage LUTS. Storage LUTS should be closely monitored after COVID-19 vaccination, especially in those OAB patients.

An Adapted Hybrid Model for Hands-On Practice on Disaster and Military Medicine Education in Undergraduate Medical Students During the COVID-19 Pandemic.

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in substantial impacts on all aspects of medical education. Modern health systems must prepare for a wide variety of catastrophic scenarios, including emerging infectious disease outbreaks and human and natural disasters. During the COVID-19 pandemic, while the use of traditional teaching methods has decreased, the use of online-based teaching methods has increased. COVID-19 itself and the accompanying infection control measures have restricted full-scale practice. Therefore, we developed an adapted hybrid model that retained adequate hands-on practice and educational equality, and we applied it with a group of undergraduate medical students participating in a mandatory disaster education course in a military medical school. Methods: The course covered the acquisition of skills used in emergency and trauma scenarios through designated interdisciplinary modules on disaster responses. Several asynchronous and synchronous online webinars were used in this one-credit mandatory disaster and military medicine education course. To allow opportunities for hands-on practice and ensure education equality, the students were divided into 15 groups, with 12 students in each group. The hands-on practice exercises were also recorded and disseminated to the students in the designated area for online learning. Results: A total of 164 3rd-year medical students participated in this mandatory disaster and military medicine course during the COVID-19 pandemic. The satisfaction survey response rate was 96.5%. The students were satisfied with the whole curriculum (3.8/5). Most of the free-text comments regarding the course represented a high level of appreciation. The students felt more confident in the knowledge and skills they gained in hands-on exercises than they did in the knowledge and skills they gained in online exercises. The students showed significant improvements in knowledge after the course. Conclusions: We demonstrated that this adapted hybrid arrangement provided an enhanced learning experience, but we also found that medical students were more confident in their knowledge and skills when they had real hands-on practice.

High Intrinsic Phosphorescence Efficiency and Density Functional Theory Modeling of Ru(II)-Bipyridine Complexes with π-Aromatic-Rich Cyclometalated Ligands: Attributions of Spin-Orbit Coupling Perturbation and Efficient Configurational Mixing of Singlet Excited States.

A series of π-aromatic-rich cyclometalated ruthenium(II)-(2,2'-bipyridine) complexes ([Ru(bpy)2(πAr-CM)]+) in which πAr-CM is diphenylpyrazine or 1-phenylisoquinoline were prepared. The [Ru(bpy)2(πAr-CM)]+ complexes had remarkably high phosphorescence rate constants, k RAD(p), and the intrinsic phosphorescence efficiencies (ιem(p) = k RAD(p)/(νem(p))3) of these complexes were found to be twice the magnitudes of simply constructed cyclometalated ruthenium(II) complexes ([Ru(bpy)2(sc-CM)]+), where νem(p) is the phosphorescence frequency and sc-CM is 2-phenylpyridine, benzo[h]quinoline, or 2-phenylpyrimidine. Density functional theory (DFT) modeling of the [Ru(bpy)2(CM)]+ complexes indicated numerous singlet metal-to-ligand charge transfers for 1MLCT-(Ru-bpy) and 1MLCT-(Ru-CM), excited states in the low-energy absorption band and 1ππ*-(aromatic ligand) (1ππ*-LAr) excited states in the high-energy band. DFT modeling of these complexes also indicated phosphorescence-emitting state (Te) configurations with primary MLCT-(Ru-bpy) characteristics. The variation in ιem(p) for the spin-forbidden Te (3MLCT-(Ru-bpy)) excited state of the complex system that was examined in this study can be understood through the spin-orbit coupling (SOC)-mediated sum of intensity stealing (∑SOCM-IS) contribution from the primary intensity of the low-energy 1MLCT states and second-order intensity perturbation from the significant configuration between the low-energy 1MLCT and high-energy intense 1ππ*-LAr states. In addition, the observation of unusually high ιem(p) magnitudes for these [Ru(bpy)2(πAr-CM)]+ complexes can be attributed to the values for both intensity factors in the ∑SOCM-IS formalism being individually greater than those for [Ru(bpy)2(sc-CM)]+ ions.

A stochastic SEIHR model for COVID-19 data fluctuations.

Although deterministic compartmental models are useful for predicting the general trend of a disease's spread, they are unable to describe the random daily fluctuations in the number of new infections and hospitalizations, which is crucial in determining the necessary healthcare capacity for a specified level of risk. In this paper, we propose a stochastic SEIHR (sSEIHR) model to describe such random fluctuations and provide sufficient conditions for stochastic stability of the disease-free equilibrium, based on the basic reproduction number that we estimated. Our extensive numerical results demonstrate strong threshold behavior near the estimated basic reproduction number, suggesting that the necessary conditions for stochastic stability are close to the sufficient conditions derived. Furthermore, we found that increasing the noise level slightly reduces the final proportion of infected individuals. In addition, we analyze COVID-19 data from various regions worldwide and demonstrate that by changing only a few parameter values, our sSEIHR model can accurately describe both the general trend and the random fluctuations in the number of daily new cases in each region, allowing governments and hospitals to make more accurate caseload predictions using fewer compartments and parameters than other comparable stochastic compartmental models.

Synthesis and Luminescence Properties of Two-Electron Bimetallic Cu-Ag and Cu-Au Nanoclusters via Copper Hydride Precursors.

The synthesis, structural characteristics, and photophysical properties of luminescent Cu-rich bimetallic superatomic clusters [Au@Cu12(S2CNnPr2)6(C≡CPh)4]+ (1a+), [Au@Cu12{S2P(OR)2}6(C≡CPh)4]+ (2+), (2a+ = iPr; 2b+ = nPr), [Au@Cu12{S2P(C2H4Ph)2}6(C≡CPh)4]+ (2c+), and [Ag@Cu12{S2P(OnPr)2}6(C≡CPh)4]+ (3+) were studied. Compositionally uniform clusters 1+-3+ were isolated from the reaction of dithiolato-stabilized, polyhydrido copper clusters with phenylacetylene in the presence of heterometal salts. By using X-ray diffraction, the structures of 1a+, 2a+, 2b+, and 3+ were able to be determined. ESI-mass spectrometry and elemental analysis confirmed their compositions and purity. The structural characteristics of these clusters are similar with respect to displaying gold (or silver)-centered Cu12 cuboctahedra surrounded by six dithiocarbamate/dithiophosph(in)ate and four alkynyl ligands. The doping of Au and Ag atoms into the polyhydrido copper nanoclusters significantly enhances their PL quantum yields from Ag@Cu12 (0.58%) to Au@Cu12 (55%) at ambient temperature in solution. In addition, the electrochemical properties of the new alloys were investigated by cyclic voltammetry.

m6 A modification of lncRNA PCAT6 promotes bone metastasis in prostate cancer through IGF2BP2-mediated IGF1R mRNA stabilization.

BACKGROUND: Bone metastasis is the leading cause of tumor-related death in prostate cancer (PCa) patients. Long noncoding RNAs (lncRNAs) have been well documented to be involved in the progression of multiple cancers. Nevertheless, the role of lncRNAs in PCa bone metastasis remains largely unclear. METHODS: The expression of prostate cancer-associated transcripts was analyzed in published datasets and further verified in clinical samples and cell lines by RT-qPCR and in situ hybridization assays. Colony formation assay, MTT assay, cell cycle analysis, EdU assay, Transwell migration and invasion assays, wound healing assay, and in vivo experiments were carried out to investigate the function of prostate cancer-associated transcript 6 (PCAT6) in bone metastasis and tumor growth of PCa. Bioinformatic analysis, RNA pull-down, and RIP assays were conducted to identify the proteins binding to PCAT6 and the potential targets of PCAT6. The therapeutic potential of targeting PCAT6 by antisense oligonucleotides (ASO) was further explored in vivo. RESULTS: PCAT6 was upregulated in PCa tissues with bone metastasis and increased PCAT6 expression predicted poor prognosis in PCa patients. Functional experiments found that PCAT6 knockdown significantly inhibited PCa cell invasion, migration, and proliferation in vitro, as well as bone metastasis and tumor growth in vivo. Mechanistically, METTL3-mediated m6 A modification contributed to PCAT6 upregulation in an IGF2BP2-dependent manner. Furthermore, PCAT6 upregulated IGF1R expression by enhancing IGF1R mRNA stability through the PCAT6/IGF2BP2/IGF1R RNA-protein three-dimensional complex. Importantly, PCAT6 inhibition by ASO in vivo showed therapeutic potential against bone metastasis in PCa. Finally, the clinical correlation of METTL3, IGF2BP2, IGF1R, and PCAT6 was further demonstrated in PCa tissues and cells. CONCLUSIONS: Our study uncovers a novel molecular mechanism by which the m6 A-induced PCAT6/IGF2BP2/IGF1R axis promotes PCa bone metastasis and tumor growth, suggesting that PCAT6 may serve as a promising prognostic marker and therapeutic target against bone-metastatic PCa.

Near-IR Charge-Transfer Emission at 77 K and Density Functional Theory Modeling of Ruthenium(II)-Dipyrrinato Chromophores: High Phosphorescence Efficiency of the Emitting State Related to Spin-Orbit Coupling Mediation of Intensity from Numerous Low-Energy Singlet Excited States.

Efficient charge-transfer (CT) phosphorescence in the near-IR (NIR) spectral region is reported for four substituted Ru-(R-dipyrrinato) complexes, [Ru(bpy)2(R-dipy)](PF6), where bpy is 2,2'-bipyridine and the substituent R is phenyl (ph), 2,4,6-trimethylphenyl, 4-carboxyphenyl (HOOC-ph), or 4-pyridinyl. The experimentally determined phosphorescence efficiency, ιem(p) = kRAD(p)/(νem(p))3 (where kRAD(p) and νem(p) are the phosphorescence rate constant and the phosphorescence frequency, respectively), of the [Ru(bpy)2(R-dipy)]+ complexes was approximately double that of [Ru(bpy)(Am)4]2+ complexes (Am = ammine ligand) in the NIR region. Density functional theory (DFT) modeling indicated two strikingly different electronic configurations of the triplet emitting state (Te) in the two types of complexes. The Te of [Ru(bpy)2(R-dipy)]+ complexes shows a CT-type corresponding to the metal-to-ligand charge transfer (MLCT)-(Ru-(R-dipy)) and the ππ*-(R-dipy) moiety configurations, and the Te state in the [Ru(bpy)(Am)4]2+ complexes corresponds to an approximately MLCT excited state consisting of mostly MLCT-(Ru-bpy) with a minimal ππ*(bpy) contribution. DFT modeling also indicated that the low-energy singlet excited states in the Te geometry (Sn(T)) of the [Ru(bpy)2(ph-dipy)]+ complex consist of numerous CT-Sn(T)-type states of the Ru-dipy and Ru-bpy moieties, whereas the [Ru(bpy)(Am)4]2+ ions show quite simple MLCT-Sn(T)-type states of the Ru-bpy moiety. Based on experimental observations, DFT modeling, and the plain spin-orbit coupling (SOC) principle, we conclude that the remarkably high ιem(p) amplitudes of the [Ru(bpy)2(R-dipy)]+ complexes relative to those of [Ru(bpy)(Am)4]2+ complexes can be attributed to the relatively substantial contribution of intrinsic SOC-mediated intensity stealing from the numerous low-energy CT-type Sn(T) states.

Discoidin domain receptor 1 regulates endochondral ossification through terminal differentiation of chondrocytes.

Chondrocytes in growth plates are responsible for longitudinal growth in long bones during endochondral ossification. Discoidin domain receptor 1 (Ddr1) is expressed in chondrocytes, but the molecular mechanisms by which DDR1 regulates chondrocyte behaviors during the endochondral ossification process remain undefined. To elucidate Ddr1-mediate chondrocyte functions, we generated chondrocyte-specific Ddr1 knockout (CKOΔDdr1) mice in this study. The CKOΔDdr1 mice showed delayed development of the secondary ossification center and increased growth plate length in the hind limbs. In the tibial growth plate in CKOΔDdr1 mice, chondrocyte proliferation was reduced in the proliferation zone, and remarkable downregulation of Ihh, MMP13, and Col-X expression in chondrocytes resulted in decreased terminal differentiation in the hypertrophic zone. Furthermore, apoptotic chondrocytes were reduced in the growth plates of CKOΔDdr1 mice. We concluded that chondrocytes with Ddr1 knockout exhibit decreased proliferation, terminal differentiation, and apoptosis in growth plates, which delays endochondral ossification and results in short stature. We also demonstrated that Ddr1 regulates the Ihh/Gli1/Gli2/Col-X pathway to regulate chondrocyte terminal differentiation. These results indicate that Ddr1 is required for chondrocytes to regulate endochondral ossification in skeletal development.

Modeling the COVID-19 Pandemic Using an SEIHR Model With Human Migration.

The 2019 novel coronavirus disease (COVID-19) outbreak has become a worldwide problem. Due to globalization and the proliferation of international travel, many countries are now facing local epidemics. The existence of asymptomatic and pre-symptomatic transmissions makes it more difficult to control disease transmission by isolating infectious individuals. To accurately describe and represent the spread of COVID-19, we suggest a susceptible-exposed-infected-hospitalized-removed (SEIHR) model with human migrations, where the "exposed" (asymptomatic) individuals are contagious. From this model, we derive the basic reproduction number of the disease and its relationship with the model parameters. We find that, for highly contagious diseases like COVID-19, when the adjacent region's epidemic is not severe, a large migration rate can reduce the speed of local epidemic spreading at the price of infecting the neighboring regions. In addition, since "infected" (symptomatic) patients are isolated almost immediately, the transmission rate of the epidemic is more sensitive to that of the "exposed" (asymptomatic) individuals. Furthermore, we investigate the impact of various interventions, e.g. isolation and border control, on the speed of disease propagation and the resultant demand on medical facilities, and find that a strict intervention measure can be more effective than closing the borders. Finally, we use some real historical data of COVID-19 caseloads from different regions, including Hong Kong, to validate the modified SEIHR model, and make an accurate prediction for the third wave of the outbreak in Hong Kong.

Chemical constituents of Bletilla striata.

A new triphenanthrene compound named 2,2',2'',7,7',7''-hexahydroxy-4,4',4''-trimethoxy-[9,9',9'',10,10',10'']-hexahydro-1,8,1',6''-triphenanthrene (1), together with eleven known compounds (2－12), were isolated from tubers of Bletilla striata. Their structures were determined by analysis of spectroscopic data.