Fully Optical Control of Polarization Current Direction in a Cyanide-Bridged Trinuclear Complex.

As a remote and non-contact stimulus, light offers the potential for manipulating the polarization of ferroelectric materials without physical contact. However, in current research, the non-contact write-read (erase) process lacks direct observation through the stable current as output signal. To address this limitation, we investigated the photoinduced polarization switching capabilities of the cyanide-bridged compound [Fe2Co] using visible light, leading to the achievement of rewritable polarization. By subjecting [Fe2Co] crystals to alternating irradiation with 785 nm and 532 nm light, the polarization changes exhibited a distinct square wave pattern, confirming the reliability of the writing and erasing processes. Initialization involved exposing specific crystal units to 532 nm light for storing "1" or "0" information, while reading was accomplished by scanning the units with 785 nm light, resulting in brief current pulses for "1" states and no current signal for "0" states. This research unveils new possibilities for optical storage systems, paving the way for efficient and rewritable data storage and retrieval technologies, such as the next-generation memories.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

A Fluorescent Probe Based on the Hydrazone Schiff Base for the Detection of Zn2+ and its Application on Test Strips.

A novel fluorescent probe SHK for Zn2+ detection was designed based on the hydrazone Schiff base, successfully synthesized by Suzuki coupling and condensation reactions. The probe SHK in DMSO/H2O showed extremely weak fluorescence. However, the solution exhibited an intensive yellow-green emission with the introduction of Zn2+. In contrast, negligible fluorescence change was observed when other metal ions were added, suggesting a high selectivity of SHK for Zn2+ detection. The Job's Plot analysis revealed that a 1:1 stoichiometric adduct SHK-Zn2+ formed during the Zn2+ sensing. The binding constant of the complex was determined to be 184 M- 1, and the detection limit for Zn2+ was calculated to be 112 µM. Moreover, the probe SHK achieved selective fluorescence sensing for Zn2+ on test strips, which guaranteed its practical application prospect.

Synthesis and Biological Activities of Luminescent 5,6-Membered Bis(Metallacyclic) Platinum(II) Complexes.

Four couples of 5,6-membered bis(metallacyclic) Pt(II) complexes with acetylide and isocyanide auxiliary ligands have been prepared and characterized. The structures of (-)-2 and (-)-3 are confirmed by single-crystal X-ray diffraction, showing a distorted square-planar coordination environment around the Pt(II) nucleus. Both solutions and solid samples of all complexes are emissive at RT. Acetylide-coordinated Pt(II) complexes have a lower energy emission than those isocyanide-coordinated ones. The emission spectra of N^N'*C-coordinated Pt(II) derivatives show a lower energy emission maximum relative to N^C*N'-coordinated complexes with the same auxiliary ligand. Moreover, the difference between cyclometalated N^N'*C and N^C*N' ligands exerts a more remarkable effect on the emission than the auxiliary ligands acetylide and isocyanide. Cytotoxicity and cell imaging of luminescent 5,6-membered bis(metallacyclic) Pt(II) complexes have been evaluated.

GlnR-mediated regulation of KstR controls cholesterol catabolism in Mycobacterium smegmatis.

Tuberculosis, caused by mycobacteria, continues to pose a substantial public health threat. Mycobacteria typically use cholesterol from the membranes of host macrophages as a carbon and energy source. Most genes that control cholesterol degradation are regulated by KstR, which is highly conserved in Mycobacterium tuberculosis and Mycobacterium smegmatis. Through bioinformatic analysis, we found a typical global nitrogen regulator (GlnR)-binding motif (CCGAC-AACAGT-GACAC) in the promoter region of kstR of M. smegmatis, and we determined its binding activity in vitro using electrophoretic mobility shift assays. Using RT-qPCR, we found that nine genes involved in side-chain or sterol-ring oxidation were upregulated in a ΔglnR M. smegmatis strain compared to the WT strain and glnR-complemented strains under nitrogen limitation. ATP assays in macrophages revealed that coordinated GlnR-KstR regulation significantly reduced the viability of M. smegmatis in macrophages. Thus, we found that various genes involved in cholesterol catabolism are regulated by GlnR via KstR in response to environmental nitrogen, and that they further affect the invasive ability of M. smegmatis. These findings revealed a novel regulatory mechanism of cholesterol catabolism, which may be useful in the development of new strategies for controlling tuberculosis.

Uncoupling Protein 2 Deficiency Enhances NLRP3 Inflammasome Activation Following Hyperglycemia-Induced Exacerbation of Cerebral Ischemia and Reperfusion Damage In Vitro and In Vivo.

Mitochondrial uncoupling protein 2 (UCP2) deficiency exacerbates brain damage following cerebral ischemia/reperfusion (I/R). The Nod-like receptor protein-3 (NLRP3) inflammasome also plays a vital role in cerebral I/R damage. However, the effect of UCP2 on NLRP3 inflammasome-mediated hyperglycemia and I/R damage is not clear. In the present study, UCP2-knockout (UCP2-/-) and wild-type (WT) mice were used to establish a model of middle cerebral artery occlusion (MCAO) and reperfusion under normo- and hyperglycemic conditions. HT22 cells were established as a model of oxygen-glucose deprivation and reoxygenation (OGD/R) with high glucose to mimic hyperglycemia and I/R in vitro. HT22 cells were treated with/without different concentrations of the UCP2-specific inhibitor genipin for different periods of time. The results showed that UCP2 deficiency significantly increased histopathological changes and apoptosis after cerebral I/R damage in hyperglycemic mice. Moreover, UCP2 deficiency enhanced NLRP3 inflammasome activation in neurons when cerebral I/R damage was exacerbated by hyperglycemia. Furthermore, UCP2 deficiency enhanced NLRP3 inflammasome activation and reactive oxygen species (ROS) production in HT22 cells under OGD/R and high-glucose conditions. UCP2 deficiency aggravated hyperglycemia-induced exacerbation of cerebral I/R damage. UCP2 deficiency also enhanced NLRP3 inflammasome activation and ROS production in neurons in vitro and in vivo. These findings suggest that UCP2 deficiency enhances NLRP3 inflammasome activation following hyperglycemia-induced exacerbation of cerebral I/R damage in vitro and in vivo. UCP2 may be a potential therapeutic target for hyperglycemia-induced exacerbation of cerebral I/R damage.

An Update on the Routes for the Delivery of Donepezil.

Dementia is a significant public health problem in the 21st century. Alzheimer's disease (AD) is an essential factor in dementia. Currently, the drugs used for the treatment of AD are mainly acetylcholine inhibitors (AChEIs). As an AChEI, donepezil (DP) can improve patients' cognitive ability with low side effects and has been accepted by most patients and doctors. For AD patients, the dosage regimen is also crucial due to aging and diseases. Although there are DP oral tablets on the market, there are still many problems to be solved. At present, more and more research is conducted to optimize the route of administration of DP to improve the self-administration of patients. The research fields of DP administration include oral administration, injection administration, intranasal administration, and transdermal administration. This Review is to present the development of different DP administrations and evaluates the advantages and limitations of those works, hoping to optimize the DP dosage regimen for AD patients.

Stability and Diffusion Properties of Insulin in Dissolvable Microneedles: A Multiscale Simulation Study.

Microneedle (MN) technology has been proven to be promising to become an effective drug delivery route of insulin for diabetes treatment, with the advantages of high delivery efficiency, convenient management, and minimal risk of infection. However, efforts are still required to verify the insulin activity in MNs for further clinical application. Moreover, it is also essential to study the diffusion properties of insulin to understand the ability of various MN materials to control insulin release. Herein, we have combined all-atom molecular dynamics simulation and coarse-grained dissipative particle dynamics to systematically study insulin's structural stability and diffusion coefficient in polyvinyl alcohol and hyaluronic acid solutions. The all-atom simulation reveals the dissimilarities in the interaction mode between insulin and the two polymers. It also points out that the presence of the two polymers would not irreversibly impact the secondary structure of insulin, thereby ensuring regular insulin expression in vivo. Mesoscopic simulation results manifest that the diffusion coefficient of insulin in hyaluronic acid (HA) solution is greater than that of the polyvinyl alcohol (PVA) system. Meanwhile, through the study of insulin centroid trajectory, we have claimed two different diffusion mechanisms of insulin in polymer solution: The movement of insulin in the HA and water solution follows the Brownian motion rule. In comparison, the hopping effect of insulin has been observed in the PVA solution due to poor intermolecular affinity as well as lower polymer water solubility. By summarizing different diffusion mechanisms, this study can provide theoretical guidance for preparing insulin-loaded dissolvable MNs.

Mesoscopic Simulation for the Effect of Cross-Linking Reactions on the Drug Diffusion Properties in Microneedles.

The drug diffusion issue in microneedles is the focus of its medical application. It will not only affect the distribution of drugs in the needle body but will also have an impact on the drug release performance of the microneedle. The utilization of cross-linked polymer materials to obtain the drug diffusion control has been experimentally verified as a feasible method. However, the mechanism research on the molecular level is still incomplete. In this study, the dissipative particle dynamics (DPD) simulation has been applied to study the effect of the cross-linking reaction on drug diffusion in hyaluronic acid microneedles. We have discovered that when the cross-linking degree reaches 90%, the diffusion coefficient of the drug is 6.45 times lower than that of the uncross-linked system. The main reason for the decline in drug diffusion ability is that the cross-linking reaction varies the conformation of the polymer. The amplification in the cross-linking degree makes the polymer coils more compact and approach each other, finally forming a continuously distributed cross-linked network, which reduces its degradation rate in the body. Simultaneously, these cross-linked networks can also hinder the interaction of soluble drugs with water, thereby preventing the premature release of drugs. The simulation results are consistent with the data collected in the previous microneedle experiment. This work will be an extension of DPD simulation in the application of biological materials.

A putative nuclear copper chaperone promotes plant immunity in Arabidopsis.

Copper is essential for many metabolic processes but must be sequestrated by copper chaperones. It is well known that plant copper chaperones regulate various physiological processes. However, the functions of copper chaperones in the plant nucleus remain largely unknown. Here, we identified a putative copper chaperone induced by pathogens (CCP) in Arabidopsis thaliana. CCP harbors a classical MXCXXC copper-binding site (CBS) at its N-terminus and a nuclear localization signal (NLS) at its C-terminus. CCP mainly formed nuclear speckles in the plant nucleus, which requires the NLS and CBS domains. Overexpression of CCP induced PR1 expression and enhanced resistance against Pseudomonas syringae pv. tomato DC3000 compared with Col-0 plants. Conversely, two CRISPR/Cas9-mediated ccp mutants were impaired in plant immunity. Further biochemical analyses revealed that CCP interacted with the transcription factor TGA2 in vivo and in vitro. Moreover, CCP recruits TGA2 to the PR1 promoter sequences in vivo, which induces defense gene expression and plant immunity. Collectively, our results have identified a putative nuclear copper chaperone required for plant immunity and provided evidence for a potential function of copper in the salicylic pathway.

Dissipative Particle Dynamics Aided Design of Drug Delivery Systems: A Review.

A nanocarrier drug delivery system, effectively assisting to improve the solubility, bioavailability, and targeting of drugs in the human body, is a crucial means for treating cancer and other diseases. However, drug carriers usually possess multiple components and complex microstructures, and studies on the formation mechanism and internal structural details of nanocarriers are still incomplete by experimental methods. In order to overcome this adversity, the dissipative particle dynamics (DPD) simulation has been widely used owing to its unique simulation time-space scale and satisfying computing efficiency. In the past decades, more and more kinds of complex nanocarriers with various structures have been successfully characterized, and influencing factors in mounting numbers have also been parametrized. Not only emphasizing on the self-assembly structure of nanocarriers, but the application area of DPD simulation has also become a complete system covering from the synthesis and preparation to interaction with the biomembrane. This article reviews the application of DPD simulations in drug delivery systems. We have established the connection between existing studies and proposed some outlooks for the further combination between DPD simulation and the design of a drug delivery system.

Modeling the response of a tumor-suppressive network to mitogenic and oncogenic signals.

Intrinsic tumor-suppressive mechanisms protect normal cells against aberrant proliferation. Although cellular signaling pathways engaged in tumor repression have been largely identified, how they are orchestrated to fulfill their function still remains elusive. Here, we built a tumor-suppressive network model composed of three modules responsible for the regulation of cell proliferation, activation of p53, and induction of apoptosis. Numerical simulations show a rich repertoire of network dynamics when normal cells are subject to serum stimulation and adenovirus E1A overexpression. We showed that oncogenic signaling induces ARF and that ARF further promotes p53 activation to inhibit proliferation. Mitogenic signaling activates E2F activators and promotes Akt activation. p53 and E2F1 cooperate to induce apoptosis, whereas Akt phosphorylates p21 to repress caspase activation. These prosurvival and proapoptotic signals compete to dictate the cell fate of proliferation, cell-cycle arrest, or apoptosis. The cellular outcome is also impacted by the kinetic mode (ultrasensitivity or bistability) of p53. When cells are exposed to serum deprivation and recovery under fixed E1A, the shortest starvation time required for apoptosis induction depends on the terminal serum concentration, which was interpreted in terms of the dynamics of caspase-3 activation and cytochrome c release. We discovered that caspase-3 can be maintained active at high serum concentrations and that E1A overexpression sensitizes serum-starved cells to apoptosis. This work elucidates the roles of tumor repressors and prosurvival factors in tumor repression based on a dynamic network analysis and provides a framework for quantitatively exploring tumor-suppressive mechanisms.

Cucumber mosaic virus coat protein modulates the accumulation of 2b protein and antiviral silencing that causes symptom recovery in planta.

Shoot apical meristems (SAM) are resistant to most plant viruses due to RNA silencing, which is restrained by viral suppressors of RNA silencing (VSRs) to facilitate transient viral invasion of the SAM. In many cases chronic symptoms and long-term virus recovery occur, but the underlying mechanisms are poorly understood. Here, we found that wild-type Cucumber mosaic virus (CMVWT) invaded the SAM transiently, but was subsequently eliminated from the meristems. Unexpectedly, a CMV mutant, designated CMVRA that harbors an alanine substitution in the N-terminal arginine-rich region of the coat protein (CP) persistently invaded the SAM and resulted in visible reductions in apical dominance. Notably, the CMVWT virus elicited more potent antiviral silencing than CMVRA in newly emerging leaves of infected plants. However, both viruses caused severe symptoms with minimal antiviral silencing effects in the Arabidopsis mutants lacking host RNA-DEPENDENT RNA POLYMERASE 6 (RDR6) or SUPPRESSOR OF GENE SILENCING 3 (SGS3), indicating that CMVWT induced host RDR6/SGS3-dependent antiviral silencing. We also showed that reduced accumulation of the 2b protein is elicited in the CMVWT infection and consequently rescues potent antiviral RNA silencing. Indeed, co-infiltration assays showed that the suppression of posttranscriptional gene silencing mediated by 2b is more severely compromised by co-expression of CPWT than by CPRA. We further demonstrated that CPWT had high RNA binding activity leading to translation inhibition in wheat germ systems, and CPWT was associated with SGS3 into punctate granules in vivo. Thus, we propose that the RNAs bound and protected by CPWT possibly serve as templates of RDR6/SGS3 complexes for siRNA amplification. Together, these findings suggest that the CMV CP acts as a central hub that modulates antiviral silencing and VSRs activity, and mediates viral self-attenuation and long-term symptom recovery.

Coordination of miR-192 and miR-22 in p53-Mediated Cell Fate Decision.

p53-targeted microRNAs (miRNAs) markedly affect cellular response to DNA damage. These miRNAs may contribute to either cell cycle arrest or apoptosis induction. However, how these miRNAs coordinate to modulate the decision between cell survival and death remains less understood. Here, we developed an integrated model of p53 signaling network to investigate how p53-targeted miR-192 and miR-22 modulate cellular outcome in response to DNA damage. By numerical simulations, we found that p53 is activated progressively depending on the extent of DNA damage. Upon moderate damage, p53 rises to medium levels and induces miR-192 to promote its own activation, facilitating p21 induction and cell cycle arrest. Upon severe damage, p53 reaches high levels and is fully activated due to phosphatase and tensin homolog (PTEN) induction. As a result, it transactivates miR-22 to repress p21 expression and activate E2F1, resulting in apoptosis. Therefore, miR-192 promotes primary activation of p53, while miR-22 promotes apoptosis by downregulating p21. This work may advance the understanding of the mechanism for cell fate decision between life and death by p53-inducible miRNAs.

[Clinical Features and Diagnosis of Encrusted Bladder Cancer].

Bladder cancer is a urological malignant tumor with high morbidity and mortality. Masses protruding into the bladder cavity is an important feature for clinical diagnosis of bladder cancer. However,patients with encrusted bladder cancer(EBC)do not present with masses protruding into the bladder cavity and thus this malignancy is often misdiagnosed. Four patients were admitted in Peking University People's Hospital from July 2015 to February 2017. All of them were males aged 40 to 77 years(mean:58 years). Patients were mainly manifested as frequent urination,urgency,nocturia,and decreased bladder capacity,with or without difficulty of voiding.Although the bladder walls were markedly thickened,there was no obvious mass on imaging scans. Three patients received urodynamic test,which showed the maximum capacity of the bladder was 41 to 128 ml(mean:91 ml). One patient presented with gross hematuria,two patients presented with microscopic hematuria,and the remaining one patient had no hematuria. No mass was observed by cystoscopy. All of the patients were diagnosed with bladder cancer by repeated biopsy or intraoperative frozen section analysis.

Controlled Delivery of Insulin Using Rapidly Separating Microneedles Fabricated from Genipin-Crosslinked Gelatin.

Rapidly separating genepin-crosslinked gelatin (RS-GC) microneedles (MNs) mounted on the polyvinyl alcohol (PVA)-coated polylactic acid (PLA) MNs (RS-PGC-MNs) are fabricated, in which GC-MNs deliver insulin within the skin and the PLA supporting array is easily separated by the dissolution of the PVA layer. The release of insulin is controlled by utilizing the virtue of genipin as a crosslinking agent for producing biocompatible GC-MNs. The degree of crosslinking enhances the mechanical strength as well as humidity resistance. The in vitro and in vivo insulin release tests show significant changes in the release rates in the RS-PGC-MNs with different crosslinking degree. The hypoglycemic effect in diabetic mice demonstrate that the higher crosslinking GC-MNs result in characteristic controlled insulin release compared with other treatments and prolonged effectiveness of the RS-PGC-MNs. The proposed RS-PGC-MNs is a promising device for effective use as a noninvasive and painless controlled insulin delivery system.

Eudesmanolides and Other Constituents from the Flowers of Wedelia trilobata.

Two eudesmane sesquiterpene lactones, wedetrilides B (1) and C (2), along with five known analogues (3 - 8), an ent-kaurane diterpenoid (9), a steroid (10), as well as cinnamic acid derivatives (11 - 13), were isolated from the flowers of Wedelia trilobata. Their structures were elucidated on the basis of extensive spectroscopic analyses and by comparison of their NMR data with those of related compounds. Furthermore, the structures of 1 and 3 - 5 were confirmed by X-ray single-crystal diffraction analyses. Compounds 4 and 5 exhibited weak cytotoxic activities against the MCF-7, HeLa, and A549 cell lines. Compounds 3 - 5 were also evaluated for their inhibitory effects against HIV lytic replication.

Subchronic Oral Toxicity of Silica Nanoparticles and Silica Microparticles in Rats.

OBJECTIVE: To investigate the subchronic oral toxicity of silica nanoparticles (NPs) and silica microparticles (MPs) in rats and to compare the difference in toxicity between two particle sizes. METHODS: Sprague-Dawley rats were randomly divided into seven groups: the control group; the silica NPs low-, middle-, and high-dose groups; and the silica MPs low-, middle-, and high-dose groups [166.7, 500, and 1,500 mg/(kg•bw•day)]. All rats were gavaged daily for 90 days, and deionized water was administered to the control group. Clinical observations were made daily, and body weights and food consumption were determined weekly. Blood samples were collected on day 91 for measurement of hematology and clinical biochemistry. Animals were euthanized for necropsy, and selected organs were weighed and fixed for histological examination. The tissue distribution of silicon in the blood, liver, kidneys, and testis were determined. RESULTS: There were no toxicologically significant changes in mortality, clinical signs, body weight, food consumption, necropsy findings, and organ weights. Differences between the silica groups and the control group in some hematological and clinical biochemical values and histopathological findings were not considered treatment related. The tissue distribution of silicon was comparable across all groups. CONCLUSION: Our study demonstrated that neither silica NPs nor silica MPs induced toxicological effects after subchronic oral exposure in rats.

The relationship between demands for lung cancer screening and the constructs of health belief model: a cross-sectional survey in Hefei, China.

The aim of investigation is to explore the relationship between demands for lung cancer screening (LCS) and the constructs derived from the health belief model (HBM) in Hefei. The study collected data about socio-demographics, health beliefs in and demands for LCS during early June to later July 2015. By constructing a LCS demands HBM constructs, it calculated indices of demands for LCS (DSI) and HBM constructs, which include perceived risk (PR) and seriousness (PS) of the cancers; and perceived effectiveness (PE), benefits (PB) and difficulties (PD) of the screening. It also performed descriptive and multivariate regression analysis of the demands and the HBM constructs. The amount of 823 respondents participated and completed the survey. 6.4% of them had ever undertaken LCS, whereas 60.1% of them expressed willingness to accept the service of LCS if it is free. In multiple regression analysis which used weights in calculating the HBM construct indices, education displayed significant positive associations with DSI (p = .044), and most of HBM constructs indices (PSI, PRI, PBI, and PDI) were statistically significant with DSI (p < .05). HBM-based constructs regarding LCS have important effects on demands for the service, and may provide effective paths to cancer screening promotion.