Topological wetting states of microdroplets on closed-loop structured surfaces: Breakdown of the Gibbs equation at the microscale.

Microdroplets are a class of soft matter that has been extensively employed for chemical, biochemical, and industrial applications. However, fabricating microdroplets with largely controllable contact-area shape and apparent contact angle, a key prerequisite for their applications, is still a challenge. Here, by engineering a type of surface with homocentric closed-loop microwalls/microchannels, we can achieve facile size, shape, and contact-angle tunability of microdroplets on the textured surfaces by design. More importantly, this class of surface topologies (with universal genus value = 1) allows us to reveal that the conventional Gibbs equation (widely used for assessing the edge effect on the apparent contact angle of macrodroplets) seems no longer applicable for water microdroplets or nanodroplets (evidenced by independent molecular dynamics simulations). Notably, for the flat surface with the intrinsic contact angle ~0°, we find that the critical contact angle on the microtextured counterparts (at edge angle 90°) can be as large as >130°, rather than 90° according to the Gibbs equation. Experiments show that the breakdown of the Gibbs equation occurs for microdroplets of different types of liquids including alcohol and hydrocarbon oils. Overall, the microtextured surface design and topological wetting states not only offer opportunities for diverse applications of microdroplets such as controllable chemical reactions and low-cost circuit fabrications but also provide testbeds for advancing the fundamental surface science of wetting beyond the Gibbs equation.

Differential inhibition of sildenafil and macitentan on saxagliptin metabolism.

The development of diabetes mellitus (DM) is generally accompanied by erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), which increases the use of combination drug therapy and the risk of drug-drug interactions. Saxagliptin for the treatment of DM, sildenafil for the treatment of ED and PAH, and macitentan for the treatment of PAH are all substrates of CYP3A4, which indicates their potential involvement in drug-drug interactions. Therefore, we investigated potential pharmacokinetic interactions between saxagliptin and sildenafil/macitentan. We investigated this speculation both in vitro and in vivo, and explored the underlying mechanism using in vitro hepatic metabolic models and molecular docking assays. The results showed that sildenafil substantially inhibited the metabolism of saxagliptin by occupying the catalytic site of CYP3A4 in a competitive manner, leading to the alterations in the pharmacokinetic properties of saxagliptin in terms of increased maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0-∞)), decreased clearance rate (CLz/F), and prolonged terminal half-life (t1/2). In contrast, a slight inhibition was observed in saxagliptin metabolism when concomitantly used with macitentan, as no pharmacokinetic parameters were altered, except for CLz/F. Thus, dosage adjustment of saxagliptin may be required in combination with sildenafil to achieve safe therapeutic plasma concentrations and reduce the risk of potential toxicity, but it is not necessary for co-administration with macitentan.

Developments and current status of cell-free DNA in the early detection and management of hepatocellular carcinoma.

Nowadays, hepatocellular carcinoma (HCC) is still a major threat to human health globally, with a disappointing prognosis. Regular monitoring of patients at high risk, utilizing abdominal ultrasonography combined with alpha-fetoprotein (AFP) serum analysis, enables the early detection of potentially treatable tumors. However, the approach has limitations due to its lack of sensitivity. Meanwhile, the current standard procedure for obtaining a tumor biopsy in cases of HCC is invasive and lacks the ability to assess the dynamic progression of cancer or account for tumor heterogeneity. Hence, there is a pressing need to develop non-invasive, highly sensitive biomarkers for HCC which can improve the accuracy of early diagnosis, assess treatment response and accurately predict the prognosis. In contrast to the conventional method of tissue biopsy, liquid biopsy offers a non-invasive approach that can be readily repeated. As a liquid biopsy approach, the analysis of cell-free DNA (cfDNA) offers real-time insights that can accurately portray the tumor burden and provide a comprehensive depiction of the genetic profile associated with HCC. In this review, we present a comprehensive summary of the recent research findings pertaining to the significance and potential practicality of cfDNA analysis in the early detection and effective management of HCC.

Diverse field-effect characteristics and negative differential transconductance in a graphene/WS2/Au phototransistor with a Ge back gate.

We propose an infrared-sensitive negative differential transconductance (NDT) phototransistor based on a graphene/WS2/Au double junction with a SiO2/Ge gate. By changing the drain bias, diverse field-effect characteristics can be achieved. Typical p-type and n-type behavior is obtained under negative and positive drain bias, respectively. And NDT behavior is observed in the transfer curves under positive drain bias. It is believed to originate from competition between the top and bottom channel currents in stepped layers of WS2 at different gate voltages. Moreover, this phototransistor shows a gate-modulated rectification ratio of 0.03 to 88.3. In optoelectronic experiments, the phototransistor exhibits a responsivity of 2.76 A/W under visible light at 532 nm. By contrast, an interesting negative responsivity of -29.5 µA/W is obtained and the NDT vanishes under illumination by infrared light at 1550 nm. A complementary inverter based on two proposed devices of the same structure is constructed. The maximum voltage gain of the complementary inverter reaches 0.79 at a supply voltage of 1.5 V. These results demonstrate a new method of realizing next-generation two- and three-dimensional electronic and optoelectronic multifunctional devices.

Tunable bandpass microwave photonic filter with largely reconfigurable bandwidth and steep shape factor based on cascaded silicon nitride micro-ring resonators.

Bandpass microwave photonic filter (MPF) can be achieved based on the well-known phase to intensity conversion method by using phase modulation and single micro-ring resonator (MRR) notch filter. Since MRR could introduce residual phase in handling one optical sideband, the out-of-band radio frequency (RF) rejection ratio and the shape factor of the bandpass MPF are very limited. Here, by introducing another MRR to handle the other optical sideband, the residual phase can be greatly suppressed, thus the filter's performance can be greatly improved. The proposed bandpass MPF was both verified theoretically and experimentally. Compared with the single MRR, the out-of-band RF rejection ratio and the shape factor were improved by 20 dB and 1.67, respectively. Furthermore, the bandpass MPF's bandwidth is reconfigurable by adjusting the optical carrier's frequency or the two MRRs' amplitude coupling coefficients. The bandpass MPF's center frequency is also tunable by changing the resonant wavelengths of two MRRs in the opposite direction simultaneously. Experimentally, bandwidth reconfiguration from 0.38 GHz to 15.74 GHz, the shape factor optimization from 2 to 1.23, and frequency tuning from 4 GHz to 21.5 GHz were achieved. We believe that the proposed bandpass MPF has great potential for microwave photonic signal processing.

Achieving Fano resonance with an ultra-high slope rate by silicon nitride CROW embedded in a Mach-Zehnder interferometer.

Fano resonance with asymmetric line shape is very promising in many applications such as optical switching, sensing, slow light, laser. Fano resonances based on some integrated structures have been demonstrated on the silicon on insulator platform. However, the extinction ratios and slope rates of the most proposed integrated Fano resonances are relatively low, which limits their applications. In this paper, a tunable silicon nitride coupled resonator optical waveguide (CROW) embedded in a Mach-Zehnder interferometer (MZI) is proposed to achieve Fano resonance. Benefiting from fine tuning supported by the low thermo-optic coefficient of the silicon nitride optical waveguide, the optical amplitudes and phases in the two arms of the MZI were accurately adjusted to achieve destructive interference, which gives an ultra-high extinction ratio. Furthermore, high quality factor CROW, supported by the native low loss silicon nitride optical waveguide, greatly shrinks the resonance bandwidth. Combining the above two superiorities, a Fano resonance with a very high extinction ratio of up to 57 dB and slope rate as high as 8.1 × 104 dB/nm was obtained, which is an order of magnitude larger than the reported integrated Fano resonances. We believe that the proposed structure would be a promising candidate for high-performance switching and high-sensitivity sensing.

Tunable microwave frequency comb generation using a Si3N4-MDR based actively mode-locked OEO.

Microwave frequency combs (MFCs) have important applications in communication and sensing owing to their characteristics of large number of comb lines, wide frequency range, and high precision of comb spacing. In many applications, MFCs are required to emit signals with tunable center frequency and variable comb spacing to accommodate different operating frequency bands and accuracies. Here, we demonstrate a tunable MFC by injecting a low-frequency electrical signal into a tunable optoelectronic oscillator (OEO). Tuning of MFC's center frequency and comb spacing are realized, allowing a frequency tuning range from 1 to 22 GHz and 50 comb lines within a 5 MHz bandwidth obtained in the MFC generator. In addition, the introduction of the silicon nitride micro-disk resonator (Si3N4-MDR) in the system paves the way for the integration of MFC generator.

Low loss silicon nitride 1×4 microwave photonic beamforming chip.

In this paper, based on the low loss double strip silicon nitride platform, we designed and fabricated an ultra-low loss 1×4 microwave photonic beamforming chip, which contains a 1×4 beam splitter and four 5-bit optical delay lines. Each optical delay line can achieve 32 delay states varying from 0 ps to about 130 ps, which can support 21 different beamforming angles covers from -56.42° to 56.68° for 10 GHz RF signal. A low on-chip insertion loss of about 4 dB is achieved for each 5-bit optical delay line. Furthermore, a very low loss delay ratio of about 0.0016 dB/ps is achieved and a recorded low loss fluctuation of about 0.3 dB is obtained during the 32 states delay switching. In addition, the switching speed and driving power consumptions of the proposed beamforming chip were investigated. The proposed beamforming chip could have great potential in optical controlled phased antenna arrays systems.

Compact and broadband silicon mode-order converter using bricked subwavelength gratings.

A compact and broadband silicon mode-order converter (MOC) scheme by employing reciprocal mode evolution between asymmetric input/output taper and bricked subwavelength gratings (BSWG) is proposed. In the proposed MOC, a quasi-TE0 mode is generated in the BSWG region, which can be regarded as an effective bridge between the two TE modes to be converted. Flexible mode conversion can be realized by only choosing appropriate structure parameters for specific mode transitions between input/output modes and the quasi-TE0 mode. By combing 3D finite difference time domain (FDTD) and particle swarm optimization (PSO) method, TE0-TE1 and TE0-TE2 MOCs are optimal designed, which can efficiently convert TE0 mode to TE1 and TE2 modes with lengths of 9.39 µm and 11.27 µm, respectively. Results show that the insertion losses of <1 dB and crosstalk of <-15 dB are achieved for both TE0-TE1 and TE0-TE2 MOCs, the corresponding working bandwidth are 128 nm (1511∼1639 nm) and 126 nm (1527∼1653 nm), respectively. Additionally, the MOCs can be fabricated with only single etch step with minimum feature size of 145 nm.

Insights into Allosteric Mechanisms of the Lung-Enriched p53 Mutants V157F and R158L.

Lung cancer is a leading fatal malignancy in humans. p53 mutants exhibit not only loss of tumor suppressor capability but also oncogenic gain-of-function, contributing to lung cancer initiation, progression and therapeutic resistance. Research shows that p53 mutants V157F and R158L occur with high frequency in lung squamous cell carcinomas. Revealing their conformational dynamics is critical for developing novel lung therapies. Here, we used all-atom molecular dynamics (MD) simulations to investigate the effect of V157F and R158L substitutions on the structural properties of the p53 core domain (p53C). Compared to wild-type (WT) p53C, both V157F and R158L mutants display slightly lesser ß-sheet structure, larger radius of gyration, larger volume and larger exposed surface area, showing aggregation-prone structural characteristics. The aggregation-prone fragments (residues 249-267 and 268-282) of two mutants are more exposed to water solution than that of WT p53C. V157F and R158L mutation sites can affect the conformation switch of loop 1 through long-range associations. Simulations also reveal that the local structure and conformation around the V157F and R158L mutation sites are in a dynamic equilibrium between the misfolded and properly folded conformations. These results provide molecular mechanistic insights into allosteric mechanisms of the lung-enriched p53 mutants.

Parity-time symmetric tunable OEO based on dual-wavelength and cascaded PS-FBGs in a single-loop.

The ability to achieve low phase noise single-mode oscillation within an optoelectronic oscillator (OEO) is of fundamental importance. In the frequency-tunable OEO, the wide microwave photonic filter (MPF) bandwidth is detrimental to select single-mode among the large number of cavity modes, thus leading to low signal quality and spectral purity. Stable single-mode oscillation can be achieved in a large time delay OEO system by harnessing the mechanism from parity-time (PT) symmetry. Here, a PT-symmetric tunable OEO based on dual-wavelength and cascaded phase-shifted fiber gratings (PS-FBGs) in a single-loop is proposed and experimentally demonstrated. Combining the merits of wide frequency tuning of PS-FBG-based MPF and single mode selection completed by the PT-symmetric architecture of the OEO, where the gain and loss modes carried by dual-wavelengths to form two mutually coupled resonators in a single-loop, signals range from 1 GHz to 22 GHz with the low phase noise distributed in -122∼ -130 dBc/Hz at 10 kHz offset frequency are obtained in the experiment.

CHOmics: A web-based tool for multi-omics data analysis and interactive visualization in CHO cell lines.

Chinese hamster ovary (CHO) cell lines are widely used in industry for biological drug production. During cell culture development, considerable effort is invested to understand the factors that greatly impact cell growth, specific productivity and product qualities of the biotherapeutics. While high-throughput omics approaches have been increasingly utilized to reveal cellular mechanisms associated with cell line phenotypes and guide process optimization, comprehensive omics data analysis and management have been a challenge. Here we developed CHOmics, a web-based tool for integrative analysis of CHO cell line omics data that provides an interactive visualization of omics analysis outputs and efficient data management. CHOmics has a built-in comprehensive pipeline for RNA sequencing data processing and multi-layer statistical modules to explore relevant genes or pathways. Moreover, advanced functionalities were provided to enable users to customize their analysis and visualize the output systematically and interactively. The tool was also designed with the flexibility to accommodate other types of omics data and thereby enabling multi-omics comparison and visualization at both gene and pathway levels. Collectively, CHOmics is an integrative platform for data analysis, visualization and management with expectations to promote the broader use of omics in CHO cell research.

Molecular dynamics study on the inhibition mechanisms of ReACp53 peptide for p53-R175H mutant aggregation.

p53 mutant aggregation can lead to loss-of-function (LoF), dominant-negative (DN) and gain-of-function (GoF) effects, involving in tumor growth. Finding inhibition methods of p53 mutant aggregation is a key step for developing new therapeutics against aggregation-associated cancers. Recent studies have shown that a cell-permeable peptide, ReACp53, can inhibit aggregation of the p53 mutant and restore p53 nuclear function as a transcriptional factor, showing extraordinary therapeutic potential. However, the molecular mechanism underlying the inhibition of p53 mutant aggregation by the ReAp53 peptide is unclear. In this work, we used all-atom molecular dynamics (MD) simulations to investigate the effect of ReACp53 peptide on the structural and dynamic properties of the p53 core domain (p53C) of the aggregation-prone R175H mutant. Our simulations revealed that the ReACp53 peptide can stabilize the ordered secondary structure and decrease the flexibility of disordered loops of the R175H mutant through increasing the intra-interactions of p53C. Moreover, we found that ReACp53 peptide specifically binds to the fragment (residues 180-233) of the R175H mutant through strong hydrophobic interactions with residues L188 and L201 and a salt bridge or hydrogen bond formation with residues D186, E198, D204, E221 and E224. The specific binding pattern protects the aggregation-prone fragment (residues 182-213) from exposure to water. Hence, we suggested that the ReACp53 peptide inhibits aggregation of the R175H mutant by restoring the wild-type conformation from an aggregation-prone state and reducing the exposure of the aggregation-prone segment. These results provide molecular mechanistic insight into inhibition of the ReACp53 peptide on amyloid aggregation of the R175H mutant.

Exportin-5 SUMOylation promotes hepatocellular carcinoma progression.

Increasing evidence has shown that abnormal expression of XPO5 is found in many human cancers and acts as an oncoprotein in certain cancers. However, its functional role in hepatocellular carcinoma (HCC) remains unexplored. In our study, we found that XPO5 was highly expressed in HCC, which was associated with SUMO modification. Moreover, we found that XPO5 was SUMOylated by SUMO2 at K125. Functional experiments revealed that XPO5 SUMOylation could promote MHCC97H cell proliferation, migration and invasion. In addition, we found that the nuclear export of pre-miR-3184 was suppressed by SUMOylated XPO5. Moreover, PLCB1 was identified as the common target of miR-3184-5p and miR-3184-3p. The suppressed phenotype induced by miR-3184-5p and miR-3184-3p could be rescued by overexpression of PLCB1. Bioinformatics analysis showed that PLCB1 expression had a negative relationship with HCC patient survival. The inhibitory effects of MHCC97H cells resulted from abnormal XPO5 SUMO modification could be blocked by miR-3184 inhibitor or PLCB1 overexpression. In conclusion, our findings demonstrate a novel mechanism of XPO5 in HCC, that is, the SUMOylated XPO5 acts as an "oncogenic" role in MHCC97H cells proliferation, migration and invasion by controlling the nuclear-cytoplasm transportation of miR-3184, thus up-regulating PLCB1 expression.

Design and synthesis of novel tacrine-dipicolylamine dimers that are multiple-target-directed ligands with potential to treat Alzheimer's disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that has multiple causes. Therefore, multiple-target-directed ligands (MTDLs), which act on multiple targets, have been developed as a novel strategy for AD therapy. In this study, novel drug candidates were designed and synthesized by the covalent linkings of tacrine, a previously used anti-AD acetylcholinesterase (AChE) inhibitor, and dipicolylamine, an ß-amyloid (Aß) aggregation inhibitor. Most tacrine-dipicolylamine dimers potently inhibited AChE and Aß1-42 aggregation in vitro, and 13a exhibited nanomolar level inhibition. Molecular docking analysis suggested that 13a could interact with the catalytic active sites and the peripheral anion site of AChE, and bind to Aß1-42 pentamers. Moreover, 13a effectively attenuated Aß1-42 oligomers-induced cognitive dysfunction in mice by activating the cAMP-response element binding protein/brain-derived neurotrophic factor signaling pathway, decreasing tau phosphorylation, preventing synaptic toxicity, and inhibiting neuroinflammation. The safety profile of 13a in mice was demonstrated by acute toxicity experiments. All these results suggested that novel tacrine-dipicolylamine dimers, especially 13a, have multi-target neuroprotective and cognitive-enhancing potentials, and therefore might be developed as MTDLs to combat AD.

Gender Differences in Connectome-based Predictions of Individualized Intelligence Quotient and Sub-domain Scores.

Scores on intelligence tests are strongly predictive of various important life outcomes. However, the gender discrepancy on intelligence quotient (IQ) prediction using brain imaging variables has not been studied. To this aim, we predicted individual IQ scores for males and females separately using whole-brain functional connectivity (FC). Robust predictions of intellectual capabilities were achieved across three independent data sets (680 subjects) and two intelligence measurements (IQ and fluid intelligence) using the same model within each gender. Interestingly, we found that intelligence of males and females were underpinned by different neurobiological correlates, which are consistent with their respective superiority in cognitive domains (visuospatial vs verbal ability). In addition, the identified FC patterns are uniquely predictive on IQ and its sub-domain scores only within the same gender but neither for the opposite gender nor on the IQ-irrelevant measures such as temperament traits. Moreover, females exhibit significantly higher IQ predictability than males in the discovery cohort. This findings facilitate our understanding of the biological basis of intelligence by demonstrating that intelligence is underpinned by a variety of complex neural mechanisms that engage an interacting network of regions-particularly prefrontal-parietal and basal ganglia-whereas the network pattern differs between genders.

Structural Brain Architectures Match Intrinsic Functional Networks and Vary across Domains: A Study from 15 000+ Individuals.

Brain structural networks have been shown to consistently organize in functionally meaningful architectures covering the entire brain. However, to what extent brain structural architectures match the intrinsic functional networks in different functional domains remains under explored. In this study, based on independent component analysis, we revealed 45 pairs of structural-functional (S-F) component maps, distributing across nine functional domains, in both a discovery cohort (n = 6005) and a replication cohort (UK Biobank, n = 9214), providing a well-match multimodal spatial map template for public use. Further network module analysis suggested that unimodal cortical areas (e.g., somatomotor and visual networks) indicate higher S-F coherence, while heteromodal association cortices, especially the frontoparietal network (FPN), exhibit more S-F divergence. Collectively, these results suggest that the expanding and maturing brain association cortex demonstrates a higher degree of changes compared with unimodal cortex, which may lead to higher interindividual variability and lower S-F coherence.

Kinesin family member 2C promotes hepatocellular carcinoma growth and metastasis via activating MEK/ERK pathway.

The current work was intended to explore the function and mechanism of Kinesin family member 2C (KIF2C) in hepatocellular carcinoma (HCC). In this study, KIF2C expression was at a high level in HCC and indicated poor prognosis. Silencing KIF2C significantly suppressed the proliferation, migration, and invasion in HCC cells. Furthermore, silencing KIF2C markedly decreased the expression of Snail, Vimentin, p-MEK, and p-ERK, but increased E-cadherin expression in HCC cells. Moreover, we also found that MEK/ERK inhibitor U0126 could enhance the impact on cell proliferation, migration, and invasion induced by silencing KIF2C in HCC. On the contrary, MEK/ERK activator PAF could weaken the impact induced by silencing KIF2C in HCC. Thus, our findings indicate that KIF2C can promote the proliferation, migration, and invasion by activating MEK/ERK pathway in HCC.

Parity-time symmetric frequency-tunable optoelectronic oscillator based on a Si3N4 microdisk resonator.

The optoelectronic oscillator (OEO) generates low-phase noise and high-frequency microwave signals thanks to a high Q-factor cavity with long and low-loss fiber delay. Traditionally, for the desired mode selection from the ultradense cavity modes, a narrowband electrical filter is needed, whose frequency tuning is very limited. On the other hand, for a tunable OEO offered by a microwave photonic filter (MPF), a paradox existed between the large number of cavity modes and the wide MPF bandwidth. Here, we achieve a tunable OEO using the mode-selection mechanism of parity-time symmetry, which overcomes the paradox. A high Q-factor silicon nitride microdisk resonator (Si3N4 MDR) is introduced to achieve frequency filtering and tuning. Moreover, the experimental results reveal that the tunable OEO generates a signal range from 3 GHz to 20 GHz with a phase noise about -120dBc/Hz at a 10 kHz offset frequency.

Profiles of immune-related genes and immune cell infiltration in the tumor microenvironment of diffuse lower-grade gliomas.

The tumor microenvironment is highly correlated with tumor occurrence, progress, and prognosis. We aimed to investigate the immune-related gene (IRG) expression and immune infiltration pattern in the tumor microenvironment of lower-grade glioma (LGG). We employed the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm to calculate immune and stromal scores and identify prognostic IRG based on The Cancer Genome Atlas data set. The potential molecular functions of these genes were explored with the help of functional enrichment analysis and the protein-protein interaction network. Remarkably, three cohorts that were downloaded from the Chinese Glioma Genome Atlas database were analyzed to further verify the prognostic values of these genes. Moreover, the Tumor IMmune Estimation Resource (TIMER) algorithm was used to estimate the abundance of infiltrating immune cells and explore the immune infiltration pattern in LGG. And unsupervised cluster analysis determined three clusters of the immune infiltration pattern and indicated that CD8+ T cells and macrophages were significantly associated with LGG outcomes. Altogether, our study identified a list of prognostic IRGs and provided a perspective to explore the immune infiltration pattern in LGG.