Ultrasensitive Ratiometric Fluorescent Nanothermometer with Reverse Signal Changes for Intracellular Temperature Mapping.

Sensing temperature at the subcellular level is pivotal for gaining essential thermal insights into diverse biological processes. However, achieving sensitive and accurate sensing of the intracellular temperature remains a challenge. Herein, we develop a ratiometric organic fluorescent nanothermometer with reverse signal changes for the ultrasensitive mapping of intracellular temperature. The nanothermometer is fabricated from a binary mixture of saturated fatty acids with a noneutectic composition, a red-emissive aggregation-caused quenching luminogen, and a green-emissive aggregation-induced emission luminogen using a modified nanoprecipitation method. Different from the eutectic mixture with a single phase-transition point, the noneutectic mixture possesses two solid-liquid phase transitions, which not only allows for reversible regulation of the aggregation states of the encapsulated luminogens but also effectively broadens the temperature sensing range (25-48 °C) across the physiological temperature range. Remarkably, the nanothermometer exhibits reverse and sensitive signal changes, demonstrating maximum relative thermal sensitivities of up to 63.66% °C-1 in aqueous systems and 44.01% °C-1 in the intracellular environment, respectively. Taking advantage of these outstanding thermometric performances, the nanothermometer is further employed to intracellularly monitor minute temperature variations upon chemical stimulation. This study provides a powerful tool for the exploration of dynamic cellular thermal activities, holding great promise in unveiling intricate physiological processes.

Quasi-bound states in the continuum empowering a transmissive terahertz narrowband filter with high Q and a broad sideband free of interferential distortion.

Most currently available terahertz (THz) narrowband filters contain a metal and a substrate, which introduce absorption loss and spectral fluctuations caused by a Fabry-Perot interference in substrates. To address these issues, we employ quasi-bound states in the continuum (BICs) for the design and realization of a substrate-free all-dielectric THz transmissive narrowband filter. Under oblique incidence, the symmetry-protected BICs break and collapse into high-Q transmissive quasi-BIC modes, thereby achieving narrowband filtering. The filter not only minimizes energy loss but also demonstrates a smooth filtering response without an interferential spectral fluctuation associated with the substrate. An experimental high Q value of ∼127 at 4.1 THz with a broad sideband of ∼1.5 THz with transmittance below 10% is achieved.

Novel druggable mechanism of Parkinson's disease: Potential therapeutics and underlying pathogenesis based on ferroptosis.

Genetics, age, environmental factors, and oxidative stress have all been implicated in the development of Parkinson's disease (PD); however, a complete understanding of its pathology remains elusive. At present, there is no cure for PD, and currently available therapeutics are insufficient to meet patient needs. Ferroptosis, a distinctive iron-dependent cell death mode characterized by lipid peroxidation and oxidative stress, has pathophysiological features similar to those of PD, including iron accumulation, reactive oxygen species-induced oxidative damage, and mitochondrial dysfunction. Ferroptosis has been identified as a specific pathway of neuronal death and is closely related to the pathogenesis of PD. Despite the similarities in the biological targets involved in PD pathogenesis and ferroptosis, the relationship between novel targets in PD and ferroptosis has been neglected in the literature. In this review, the mechanism of ferroptosis is discussed, and the potential therapeutic targets implicated in both PD and ferroptosis are compared. Furthermore, the anti-PD effects of several ferroptosis inhibitors, as well as clinical studies thereof, and the identification of novel lead compounds for the treatment of PD and the inhibition of ferroptosis are reviewed. It is hoped that this review can promote research to further elucidate the relationship between ferroptosis and PD and provide new strategies for the development of novel ferroptosis-targeting PD therapy.

Current non-invasive strategies for brain drug delivery: overcoming blood-brain barrier transport.

BACKGROUND: The blood-brain barrier (BBB) is a complex and dynamic structure that serves as a gatekeeper, restricting the migrations of most compounds and molecules from blood into the central nervous system (CNS). The BBB plays a crucial role in maintaining CNS physiological function and brain homeostasis. It can protect the CNS from the entrance of toxic and infectious agents, however, it also restricts the drug permeation into brain to play a therapeutic role. The BBB has been the biggest limiting hurdle to medications entering the brain excluding from the brain about 100% of large-molecule and more than 98% of all small-molecule neurotherapeutics. As a result, it is of inability for drug molecule to reach requisite concentrations within the brain. OBJECTIVE: With the aim of enhancing drug permeability and efficacy, a variety of strategies have been developed: invasive approaches, such as intraarterial delivery, intrathecal delivery, or administrating directly the drug intraventricularly and intracerebrally; non-invasive approaches that take advantage of innate BBB functions, using prodrugs, focused ultrasound, intranasal administration or nanotechnology. CONCLUSIONS: Here we mainly review recent developments and challenges related to non-invasive BBB-crossing techniques, whose benefits include higher efficacy, easier application, less treatment burden, better patient acceptability, and adherence. Additionally, we also analyze the potential of non-invasive methods in the treatment of CNS disorders and render them as a most suitable platform for the management of neurological diseases.

Reconstituting Low-Density Lipoprotein with NIR-Absorbing Organic Photothermal Agents for Targeted Killing of Cancer Cells.

Photothermal therapy (PTT) systems typically do not possess intrinsic tumor-targeting capability, resulting in indiscriminate thermal damage to both cancer and normal cells. Herein, a low-density lipoprotein (LDL)-based nanosystem (denoted as MTTQ@LDL) is reported for targeted photothermal killing of cancer cells. Such a nanosystem is fabricated by reconstituting the lipophilic core of LDL with an organic photothermal agent MTTQ. The reconstitution process improves the supramolecular photothermal effects of MTTQ assemblies, which contributes to the significantly enhanced photothermal conversion efficiency (41.3% vs. 16.2%). MTTQ@LDL can actively target LDL receptor-overexpressed cancer cells via receptor-mediated endocytosis, enabling the selective killing of cancer cells over normal cells (98% vs. 7%) post-NIR irradiation. Reconstituted LDL can serve as a promising platform for targeted delivery of functional materials, holding great promise in tumor eradication in vivo.

THz transmissive all-dielectric guided-mode resonance filter with high Q and tunability using suspended gratings.

Most currently available THz narrowband filters employ metal that introduces loss, or work in reflection mode, which limits their scope of application. Here, a transmissive all-dielectric guided-mode resonance filter in the THz region is presented. It contains a suspended grating layer and a waveguide layer, separated by an air layer. A fabrication process of the filter is proposed. Simulation results show that the designed filter exhibits excellent transmittance of ∼97.5% with a high Q value of ∼1500 at 1.64 THz. Furthermore, this transmission peak is surrounded by a wide and flat sideband with width of ∼0.75T H z and transmission below 10%. Moreover, tunability of the filter is realized by geometric scaling and by varying the thickness of the air layer. Using geometric scaling, the filtering frequency can be widely tuned from 0.54 to 1.64 THz, covering the 625-725 and 780-910 GHz wireless communication windows. Additionally, fine tuning achieved by varying the air layer thickness could be used to compensate for a tiny shift of the designed filtering frequency caused by errors introduced in the fabrication process. The Q value can be further boosted to ∼11,500 by adding another layer of waveguide. Due to its transmissive nature and high-Q resonant mode with a wide sideband and tunability, the presented filter exhibits great potential in THz applications such as spectroscopy, imaging, and communication.

Polarity-Sensitive Fluorescent Probe for Reflecting the Packing Degree of Bacterial Membrane Lipids.

The maintenance of an intact membrane structure is of great importance for bacteria to execute various biological functions. However, chemical probes for monitoring the dynamic changes of bacterial membranes are barely reported. Herein, we, for the first time, report a novel polarity-sensitive probe for reflecting the packing degree of bacterial membrane lipids. Specifically, we synthesize a membrane-targeting fluorescent probe (TICT-lipid) that possesses both twist intramolecular charge transfer and aggregation-induced emission properties. TICT-lipid exhibits sensitive responses to the minute difference in the packing degree of membrane lipids, facilitating rapid differentiation of Gram-negative and Gram-positive bacteria. Interestingly, in the presence of membrane-disrupting antibiotics, the localization of TICT-lipid shifts from the outer membrane to the cell membrane by outputting blue-shifted and enhanced emission, making the mechanism of action of antibiotics clearly visible. TICT-lipid is a polarity-sensitive fluorescent probe, holding great promise in the study of membrane-related bacterial processes and antibiotic screening.

Peak-Load-Regulation Nuclear Power Unit Fault Diagnosis Using Thermal Sensors Combined with Improved ICA-RF Algorithm.

Owing to the fact that large-scale peak-load-regulation nuclear power turbine units' thermal signal is greatly influenced by background noise and has non-stationary and nonlinear characteristics, this paper proposes a new fault diagnosis method for thermal sensors based on an improved independent component analysis (Improved-ICA) algorithm and random forest (RF) algorithm. This method is based on independent component analysis (ICA), which is not capable of extracting components independently. Therefore, we propose the use of the maximum approximate information negative entropy optimization model in order to improve the ICA algorithm's independent principal component extraction ability and obtain better non-Gaussian physical source signal separation results. The improved ICA algorithm is used for the blind source separation of the thermal parameters of peak-load-regulation nuclear power units. A series of stationary physical source functions and a series of non-stationary noise signals are obtained. Then, according to the specific signal format and data volume of the nuclear power parameter signal, the network parameters of the random forest algorithm are determined, giving rise to the fault diagnosis model. Finally, the real-time operation data of an 1121 MW nuclear power unit are used to complete the training and fault diagnosis of the random forest network and analyze the diagnosis results. The results indicate that the model can effectively mine the abnormal sample points of thermal parameters and classify the fault type of the thermal sensor during peak load operation of the nuclear power unit. The accuracy rate is found to be at the threshold of 99%.

Air pollutant emission characteristics and HYSPLIT model analysis during heating period in Shenyang, China.

To find out the characteristics and sources of atmospheric pollutants during heating period in Shenyang, the study investigated the temporal and spatial distribution of pollutants, using data of six typical atmospheric pollutants (SO2, NO2, PM10, PM2.5, O3, and CO) from November 2017 to March 2018 in 11 monitoring stations in Shenyang. These features were combined with the HYSPLIT model for backward trajectory simulation of heavily polluted weather. PM10 and PM2.5 are the main pollutants during heating period in Shenyang, with average concentrations of 90.26 µg/m3 and 56.92 µg/m3, respectively. The concentrations of various types of contaminants at the Taiyuan Street station were relatively high. PM10 and PM2.5 were relatively high in the southwestern area of Shenyang, gradually decreasing to the northeast. Only one heavy pollution event occurred during heating period in 2018. The results of the backward trajectory analysis of this heavy pollution event using HYSPLIT show that air masses from inland areas such as the southwest and northwest brought some particulate matter and atmospheric pollutants, which exacerbated Shenyang Air pollution in the city.

Quantitative Detection of Trace Level Cloxacillin in Food Samples Using Magnetic Molecularly Imprinted Polymer Extraction and Surface-Enhanced Raman Spectroscopy Nanopillars.

There is an increasing demand for rapid, sensitive, and low cost analytical methods to routinely screen antibiotic residues in food products. Conventional detection of antibiotics involves sample preparation by liquid-liquid or solid-phase extraction, followed by analysis using liquid chromatography-mass spectrometry (LC-MS), capillary electrophoresis (CE), or gas chromatography (GC). The process is labor-intensive, time-consuming, and expensive. In this study, we developed a new analytical method that combines magnetic molecularly imprinted polymer (MMIP)-based sample preparation with surface-enhanced Raman spectroscopy (SERS)-based detection for quantitative analysis of cloxacillin in pig serum. MMIP microspheres were synthesized using a core-shell technique. The large loading capacity and high selectivity of the MMIP microspheres enabled efficient extraction of cloxacillin, while the magnetically susceptible characteristics greatly simplified sample handling procedures. Low cost and robust SERS substrates consisting of vertical gold capped silicon nanopillars were fabricated and employed for the detection of cloxacillin. Quantitative SERS was achieved by normalizing signal intensities using an internal standard. By coherently combining MMIP extraction and silicon nanopillar-based SERS biosensor, good sensitivity toward cloxacillin was achieved. The detection limit was 7.8 pmol. Cloxacillin recoveries from spiked pig plasma samples were found to be more than 80%.

Enteric microbiome profiles during a randomized Phase 2 clinical trial of surotomycin versus vancomycin for the treatment of Clostridium difficile infection.

OBJECTIVES: The effects of surotomycin (CB-183,315, MK-4261), a bactericidal cyclic lipopeptide, and vancomycin, the current standard-of-care for Clostridium difficile infection (CDI), on intestinal pathogens and microbiota were evaluated parallel to a Phase 2 randomized, double-blind clinical trial. METHODS: The single-centre cohort included 26 patients receiving surotomycin [125 or 250 mg twice daily (n = 9 each)] or oral vancomycin [125 mg four times daily (n = 8)] for 10 days. Faecal samples were collected at days 0-42 to quantify both C. difficile by conventional culture and the major components of the microbiome by quantitative PCR. RESULTS: Surotomycin 250 mg twice daily or vancomycin 125 mg four times daily reduced faecal C. difficile counts from ∼105-107 log10 cfu/g at baseline to ≤ 102 cfu/g by days 4-10 of treatment. Day 10 counts of C. difficile in 3/9 patients receiving surotomycin 125 mg twice daily remained detectable, including one patient who failed to achieve clinical cure. Bacteroidetes and Prevotella mean counts increased 0.7 log10 or remained unchanged with surotomycin 125 and 250 mg twice daily, respectively, whereas vancomycin reduced counts by 2.5-3.2 log10 (P < 0.02). Vancomycin reduced Firmicutes counts by 2.5-2.8 log10; surotomycin moderately suppressed these microbes in a dose-dependent manner. CONCLUSIONS: In this Phase 2 trial substudy, compared with vancomycin 125 mg four times daily, surotomycin 250 mg twice daily is as active in vivo against C. difficile, but was more sparing of microbiota. Surotomycin is no longer in development due to failed Phase 3 efficacy results.

Lithography-Free Fabrication of Silica Nanocylinders with Suspended Gold Nanorings for LSPR-Based Sensing.

Tunable plasmonic platforms are important for a variety of applications such as photovoltaics, LED's, optoelectronics, medical research, and biosensors. In particular, development of label-free plasmonic biosensors is one of the key research areas that utilizes plasmonic nanostructures for detection of biologically relevant molecules at low concentrations. The authors have developed a cost-effective, fast, and lithography-free method to fabricate transparent fused silica nanocylinders. The technique allows tuning of nanocylinder height, diameter, and density and can be scaled to large surface areas, such as 8 in. wafers. The authors demonstrate that gold coated nanocylinders support localized surface plasmon resonances (LSPR) from visible to near infrared wavelengths. The plasmonic platform can be characterized as suspended gold nanorings and exhibits a sensitivity of 658 nm RIU-1 with a figure-of-merit of 10, comparable to other state-of-the-art LSPR sensing platforms that utilize more complex nanofabrication pathways. It was observed that the LSPR peak positions can be controlled by varying the geometry of the nanocylinders. The authors illustrate surface functionalization, biosensing, and surface regeneration properties of the platform using thiols and detection of bovine serum albumin (BSA). The observed LSPR shifts for 11-mercaptoundecanoic acid and BSA was 12 and 26 nm, respectively.

A Client-Centered Community Engagement Project: Improving the Health and Wellness of Older Adults in an Assisted Living Facility.

Central to nursing practice is the promotion of health and wellness practices. Drawing on the Community as Partner Model, nursing process, Nursing Interventions Classification, and Logic Model, second-year nursing students collaborated with staff and residents of an assisted living facility to promote health and wellness in the older adult population. Windshield surveys, resident surveys, key informant interviews, and focus group interviews were conducted to gain insight into the perceptions and experiences of staff and residents. The majority of residents indicated they were satisfied with life at the facility and their needs have been adequately met. Strengths and areas for improvement were identified in several aspects, including the facility atmosphere and location, quality of staff and health care services, recreational and dietary services, and social support networks. By partnering with community key stakeholders, valuing all different perspectives, and connecting theory to practice, a successful client-centered community clinical project was demonstrated. [Journal of Gerontological Nursing, 42(8), 44-51.].

Differences of the Fecal Microflora With Clostridium difficile Therapies.

BACKGROUND: During treatment of Clostridium difficile infection (CDI), patterns of pathogen reduction in relationship to changes in components of the normal microbiota are hypothesized to be predictive of response to treatment and subsequent sustained cure. METHODS: At a single center, subjects enrolled into phase 2 and 3 C. difficile treatment clinical trials (2003-2008) provided fecal samples to assess killing of C. difficile and changes to components of the microbiome. Quantitative bacterial cultures, measurement of C. difficile toxin titers, quantitative polymerase chain reaction of fecal samples for Bacteroidetes, Clostridium clusters XIVa and IV, and C. difficile were performed. RESULTS: Quantitative bacterial cultures showed a mean log10 C. difficile count (colony-forming units [CFU]) of 6.7 ± 2.0 at study entry; vancomycin treatment consistently reduced C. difficile counts to the limit of detection (2.0 log10 CFU/g), whereas metronidazole was associated with mean C. difficile counts 1.5-2 log10 higher at 10 days of treatment. In patients receiving tolevamer, C. difficile persisted in high counts during treatment; response to treatment was correlated with neutralization of toxin along with persistence of normal microbiota components. However, this was achieved in approximately half of subjects. Both vancomycin and metronidazole further suppressed microbiome components during treatment of CDI. Lactobacilli were observed to be a microbiome component that persisted during treatment of CDI. CONCLUSIONS: Differences of pathogen clearance and microbiome perturbation during treatment of CDI appear to explain treatment outcomes. The hypothesis that probiotic microbes could help prevent onset of CDI is supported by the observation of persistence of lactobacilli during and after treatment of CDI.

Plasmon resonances of Ag capped Si nanopillars fabricated using mask-less lithography.

Localized surface plasmon resonances (LSPR) and plasmon couplings in Ag capped Si Nanopillar (Ag NP) structures are studied using 3D FEM simulations and dark-field scattering microscopy. Simulations show that a standalone Ag NP supports two LSPR modes, i.e. the particle mode and the cavity mode. The LSPR peak position of the particle mode can be tuned by changing the size of the Ag cap, and can be hybridized by leaning of pillars. The resonance position of the cavity resonance mode can be tuned primarily via the diameter of the Si pillar, and cannot be tuned via leaning of Ag NPs. The presence of a substrate dramatically changes the intensity of these two LSPR modes by introducing constructive and destructive interference patterns with incident and reflected fields. Experimental scattering spectra can be interpreted using theoretical simulations. The Ag NP substrate displays a broad plasmonic resonance band due to the contribution from both the hybridized particle LSPR and the cavity LSPR modes.

Moments of zeta functions associated to hyperelliptic curves over finite fields.

Let q be an odd prime power, and Hq,d denote the set of square-free monic polynomials D(x)∈Fq[x] of degree d. Katz and Sarnak showed that the moments, over Hq,d, of the zeta functions associated to the curves y(2)=D(x), evaluated at the central point, tend, as q→∞, to the moments of characteristic polynomials, evaluated at the central point, of matrices in USp(2⌊(d-1)/2⌋). Using techniques that were originally developed for studying moments of L-functions over number fields, Andrade and Keating conjectured an asymptotic formula for the moments for q fixed and q→∞. We provide theoretical and numerical evidence in favour of their conjecture. In some cases, we are able to work out exact formulae for the moments and use these to precisely determine the size of the remainder term in the predicted moments.

Low-power photothermal probing of single plasmonic nanostructures with nanomechanical string resonators.

We demonstrate the direct photothermal probing and mapping of single plasmonic nanostructures via the temperature-induced detuning of nanomechanical string resonators. Single Au nanoslits and nanorods are illuminated with a partially polarized focused laser beam (λ = 633 nm) with irradiances in the range of 0.26-38 µW/µm(2). Photothermal heating maps with a resolution of ∼375 nm are obtained by scanning the laser over the nanostructures. Based on the string sensitivities, absorption efficiencies of 2.3 ± 0.3 and 1.1 ± 0.7 are extracted for a single nanoslit (53 nm × 1 µm) and nanorod (75 nm × 185 nm). Our results show that nanomechanical resonators are a unique and robust analysis tool for the low-power investigation of thermoplasmonic effects in plasmonic hot spots.

Ultrahigh-Q Polarization-Independent Terahertz Metamaterial Absorber Using Pattern-Free Graphene for Sensing Applications.

In contrast to noble metals, graphene exhibits significantly lower loss, especially useful for optical sensing applications that require ultrahigh Q factors, and offer wide range tunability via an adjustable Fermi level. However, precise graphene patterning is difficult, especially for large areas, severely limiting its applications. Here, a tunable terahertz metamaterial absorber (TMMA) with ultrahigh Q factors consisting of a continuous, pattern-free graphene is demonstrated. A graphene sheet is overlaid on an Al metal array, forming a structure that supports strong localized surface plasmon polaritons (LSPPs) with fields tightly confined in the graphene, minimizing loss. Theoretical results show that this TMMA exhibits an ultrahigh Q factor of 1730, a frequency sensitivity of 2.84 THz/RIU, and an excellent figure of merit (FoM) of 365.85 RIU-1, independent of polarization. A tunability from ~2.25 to ~3.25 THz is also achieved by tuning Ef of graphene from 0.3 to 0.7 eV. The proposed graphene-based TMMA holds many potential applications, particularly in the field of sensing.

Concave Version Printing of High-Performance Polymer THz Filters.

The development of high Q and tunable narrowband filters that can efficiently manipulate THz beams is critical for various THz applications, such as imaging and sensing. However, for filters made of metals and dielectrics, issues such as high losses, limited tunability, and lengthy process flows exist. Here, a scalable concave version reprinting technique to mass produce high-performance microstructured polymer filters is presented. The technique is extremely simple, eliminating the demand for the use of any large equipment including injection molding and thermal press printing machines, and is reliable; in the reprinted structures, there are no defects including gaps and air bubbles. The produced narrowband filters exhibit a high Q factor of 57 with wide tunability over the THz band from ∼80 to 160 µm in wavelength. The presented technique can be adopted to realize other devices as well using polymer materials with simplicity and high precision.

A universal strategy to enhance photothermal conversion efficiency by regulating the molecular aggregation states for safe photothermal therapy of bacterial infections.

Photothermal therapy (PTT) has emerged as a promising approach for treating bacterial infections. However, achieving a high photothermal conversion efficiency (PCE) of photothermal agents (PTAs) remains a challenge. Such a problem is usually compensated by the use of a high-intensity laser, which inevitably causes tissue damage. Here, we present a universal strategy to enhance PCE by regulating the molecular aggregation states of PTAs within thermoresponsive nanogels. We demonstrate the effectiveness of this approach using aggregation-induced emission (AIE) and aggregation-caused quenching (ACQ) PTAs, showing significant enhancements in PCE without the need for intricate molecular modifications. Notably, the highest PCEs reach up to 80.9% and 64.4% for AIE-NG and ACQ-NG, respectively, which are nearly 2-fold of their self-aggregate counterparts. Moreover, we elucidate the mechanism underlying PCE enhancement, highlighting the role of strong intermolecular π-π interactions facilitated by nanogel-induced volume contraction. Furthermore, we validate the safety and efficacy of this strategy in in vitro and in vivo models of bacterial infections at safe laser power densities, demonstrating its potential for clinical translation. Our findings offer a straightforward, universal, and versatile method to improve PTT outcomes while minimizing cytotoxicity, paving the way for enhanced treatment of bacterial infections with safe PTT protocols.