Hypothermia effects on neuronal plasticity post spinal cord injury.

BACKGROUND: SCI is a time-sensitive debilitating neurological condition without treatment options. Although the central nervous system is not programmed for effective endogenous repairs or regeneration, neuroplasticity partially compensates for the dysfunction consequences of SCI. OBJECTIVE AND HYPOTHESIS: The purpose of our study is to investigate whether early induction of hypothermia impacts neuronal tissue compensatory mechanisms. Our hypothesis is that although neuroplasticity happens within the neuropathways, both above (forelimbs) and below (hindlimbs) the site of spinal cord injury (SCI), hypothermia further influences the upper limbs' SSEP signals, even when the SCI is mid-thoracic. STUDY DESIGN: A total of 30 male and female adult rats are randomly assigned to four groups (n = 7): sham group, control group undergoing only laminectomy, injury group with normothermia (37°C), and injury group with hypothermia (32°C +/-0.5°C). METHODS: The NYU-Impactor is used to induce mid-thoracic (T8) moderate (12.5 mm) midline contusive injury in rats. Somatosensory evoked potential (SSEP) is an objective and non-invasive procedure to assess the functionality of selective neuropathways. SSEP monitoring of baseline, and on days 4 and 7 post-SCI are performed. RESULTS: Statistical analysis shows that there are significant differences between the SSEP signal amplitudes recorded when stimulating either forelimb in the group of rats with normothermia compared to the rats treated with 2h of hypothermia on day 4 (left forelimb, p = 0.0417 and right forelimb, p = 0.0012) and on day 7 (left forelimb, p = 0.0332 and right forelimb, p = 0.0133) post-SCI. CONCLUSION: Our results show that the forelimbs SSEP signals from the two groups of injuries with and without hypothermia have statistically significant differences on days 4 and 7. This indicates the neuroprotective effect of early hypothermia and its influences on stimulating further the neuroplasticity within the upper limbs neural network post-SCI. Timely detection of neuroplasticity and identifying the endogenous and exogenous factors have clinical applications in planning a more effective rehabilitation and functional electrical stimulation (FES) interventions in SCI patients.

Facile Peptide Macrocyclization and Multifunctionalization via Cyclen Installation.

Cyclen-peptide bioconjugates are usually prepared in multiple steps that require individual preparation and purification of the cyclic peptide and hydrophilic cyclen derivatives. An efficient strategy is discovered for peptide cyclization and functionalization toward lanthanide probe via three components intermolecular crosslinking on solid-phase peptide synthesis with high conversion yield. Multifunctionality can be conferred by introducing different modular parts or/and metal ions on the cyclen-embedded cyclopeptide. As a proof-of-concept, a luminescent Eu3+ complex and a Gd3+-based contrasting agent for in vitro optical imaging and in vivo magnetic resonance imaging, respectively, are demonstrated through utilizing this preparation of cyclen-embedded cyclic arginylglycylaspartic acid (RGD) peptide.

Ligand Regulation Strategy to Modulate ROS Nature in a Rhodamine-Iridium(III) Hybrid System for Phototherapy.

The efficacy of photodynamic therapy (PDT) is highly dependent on the photosensitizer features. The reactive oxygen species (ROS) generated by photosensitizers is proven to be associated with immunotherapy by triggering immunogenic cell death (ICD) as well. In this work, we establish a rhodamine-iridium(III) hybrid model functioning as a photosensitizer to comprehensively understand its performance and potential applications in photodynamic immunotherapy. Especially, the correlation between the ROS generation efficiency and the energy level of the Ir(III)-based excited state (T1'), modulated by the cyclometalating (C∧N) ligand, is systematically investigated and correlated. We prove that in addition to the direct population of the rhodamine triplet state (T1) formed through the intersystem crossing process with the assistance of a heavy Ir(III) metal center, the fine-tuned T1' state could act as a relay to provide an additional pathway for promoting the cascade energy transfer process that leads to enhanced ROS generation ability. Moreover, type I ROS can be effectively produced by introducing sulfur-containing thiophene units in C∧N ligands, providing a stronger M1 macrophage-activation efficiency under hypoxia to evoke in vivo antitumor immunity. Overall, our work provides a fundamental guideline for the molecular design and exploration of advanced transition-metal-based photosensitizers for biomedical applications.

Functionalized Nanomaterials Capable of Crossing the Blood-Brain Barrier.

The blood-brain barrier (BBB) is a specialized semipermeable structure that highly regulates exchanges between the central nervous system parenchyma and blood vessels. Thus, the BBB also prevents the passage of various forms of therapeutic agents, nanocarriers, and their cargos. Recently, many multidisciplinary studies focus on developing cargo-loaded nanoparticles (NPs) to overcome these challenges, which are emerging as safe and effective vehicles in neurotheranostics. In this Review, first we introduce the anatomical structure and physiological functions of the BBB. Second, we present the endogenous and exogenous transport mechanisms by which NPs cross the BBB. We report various forms of nanomaterials, carriers, and their cargos, with their detailed BBB uptake and permeability characteristics. Third, we describe the effect of regulating the size, shape, charge, and surface ligands of NPs that affect their BBB permeability, which can be exploited to enhance and promote neurotheranostics. We classify typical functionalized nanomaterials developed for BBB crossing. Fourth, we provide a comprehensive review of the recent progress in developing functional polymeric nanomaterials for applications in multimodal bioimaging, therapeutics, and drug delivery. Finally, we conclude by discussing existing challenges, directions, and future perspectives in employing functionalized nanomaterials for BBB crossing.

Urine spermine and multiparametric magnetic resonance imaging for prediction of prostate cancer in Japanese men.

Objectives: To investigate the role of urine spermine and spermine risk score in predicting prostate cancer (PCa) diagnoses in combination with multiparametric magnetic resonance imaging (mpMRI). Methods: Three hundred forty seven consecutive men with elevated prostate-specific antigen (PSA) with mpMRI examination were prospectively enrolled in this study. In 265 patients with PSA levels between 4 and20 ng/ml, pre-biopsy urine samples were analyzed for spermine levels with ultra-high performance liquid chromatography (UPLC-MS/MS). Transperineal image-guided prostate biopsies with 16-18 cores were performed. Logistic regressions were used to form different models for the prediction of the PCa, and the performances were compared using the area under the curve (AUC). Results: The median serum PSA level and prostate volume were 7.4 ng/mL and 33.9 mL, respectively. PCa and high-grade PCa (ISUP group ≥2, HGPCa) were diagnosed in 66.0% (175/265) and 132/265 (49.8%) cases, respectively. The urine spermine levels were significantly lower in men with PCa (0.87 vs. 2.20, P < 0.001). Multivariate analyses showed that age, PSA, PV, urine spermine level, and Prostate Imaging Reporting and Data System (PI-RADS) findings were independent predictors for PCa. The Spermine Risk Score is a multivariable model including PSA, age, prostate volume, and urine spermine. Adding the Spermine Risk Score to PI-RADS improved the AUC from 0.73 to 0.86 in PCa and from 0.72 to 0.83 in high grade PCa (HGPCa) prediction (both P < 0.001). At 90% sensitivity for HGPCa prediction using Spermine Risk Score, 31.1% of unnecessary biopsies could be avoided. In men with equivocal MRI PI-RADS score 3, the AUC for HGPCa prediction was 0.58, 0.79, and 0.87 for PSA, PSA density, and Spermine Risk Score, respectively. Conclusion: Urine Spermine Risk Score, including mpMRI could accurately identify men at high risk of HGPCa and reduce unnecessary prostate biopsies. Spermine Risk Score could more accurately predict HGPCa than PSA density in men with MRI showing equivocal PI-RADS 3 lesions.

Comment on "Charge Transfer-Triggered Bi3+ Near-Infrared Emission in Y2Ti2O7 for Dual-Mode Temperature Sensing".

Undoped Y2Ti2O7 exhibits impurity emission bands at low temperatures due to Mn4+ and Cr3+, as established by codoping with these ions. Contrary to a recent report by Wang et al., ACS Appl. Mater. Interfaces 2022, 14, 36834-36844, we do not observe Bi3+ emission in this codoped host, as also is the case for Fe3+. The emission reported in that paper as being due to Bi3+ in fact corresponds to Cr3+ emission. The Cr3+ and Mn4+ emissions are quenched with increasing temperature, so that Mn4+ emission is scarcely observed above 80 K. We present variable temperature optical data for Y2Ti2O7 and this host codoped with Mn, Cr, Fe, and Bi, as well as a theoretical justification of our results.

Responsive Regulation of Energy Transfer in Lanthanide-Doped Nanomaterials Dispersed in Chiral Nematic Structure.

The responsive control of energy transfer (ET) plays a key role in the broad applications of lanthanide-doped nanomaterials. Photonic crystals (PCs) are excellent materials for ET regulation. Among the numerous materials that can be used to fabricate PCs, chiral nematic liquid crystals are highly attractive due to their good photoelectric responsiveness and biocompatibility. Here, the mechanisms of ET and the photonic effect of chiral nematic structures on ET are introduced; the regulation methods of chiral nematic structures and the resulting changes in ET of lanthanide-doped nanomaterials are highlighted; and the challenges and promising opportunities for ET in chiral nematic structures are discussed.

Direct Construction of Corrole-Peptide Conjugates by Controllable Bilane Formation on Resin.

Corroles have attracted increasing research interests in recent decades owing to their unique properties over porphyrins. However, the relatively inefficient and tedious synthetic procedures of corrole building blocks with functional groups for bioconjugation hindered their bioapplications. Herein, we report a highly efficient protocol to synthesize corrole-peptide conjugates with good yields (up to 63 %) without using prepared corrole building blocks. By condensing two -COOH-bearing-dipyrromethane molecules onto an aldehyde group on resin-bound peptide chains in a controllable manner, a series of desired products with long (up to 25 residues) and bioactive peptide chains were obtained with at most one chromatographic purification. The synthesized compounds exhibited potential applications as chelators for metal ions for biomedical applications, as building blocks for supramolecular materials, as well as targeted fluorescent probes.

EBV latent membrane protein 1 augments γδ T cell cytotoxicity against nasopharyngeal carcinoma by induction of butyrophilin molecules.

Nasopharyngeal carcinoma (NPC) is a diverse cancer with no well-defined tumor antigen, associated with oncogenic Epstein-Barr Virus (EBV), and with usually late-stage diagnosis and survival <40%. Current radiotherapy and chemotherapy have low effectiveness and cause adverse effects, which calls for the need of new therapy. In this regard, adoptive immunotherapy using γδ T cells has potential, but needs to be coupled with butyrophilin 2A1 and 3A1 protein expression to achieve tumoricidal effect. Methods: Human γδ T cells were expanded (with Zol or PTA) and used for cytotoxicity assay against NPC cells, which were treated with the EBV EBNA1-targeting peptide (L2)P4. Effect of (L2)P4 on BTN2A1/BTN3A1 expression in NPC cells was examined by flow cytometry and Western blot. An NPC-bearing NSG mice model was established to test the effectiveness of P4 and adoptive γδ T cells. Immunofluorescence was performed on NPC tissue sections to examine the presence of γδ T cells and expression of BTN2A1 and BTN3A1. EBV gene expression post-(L2)P4 treatment was assessed by qRT-PCR, and the relationship of LMP1, NLRC5 and BTN2A1/BTN3A1 was examined by transfection, reporter assay, Western blot, and inhibition experiments. Results: Zol- or PTA-expanded the Vδ2 subset of γδ T cells that exerted killing against certain NPC cells. (L2)P4 reactivates latent EBV, which increased BTN2A1 and BTN3A1 expression and conferred higher susceptibility towards Vδ2 T cells cytotoxicity in vitro, as well as enhanced tumor regression in vivo by adoptive transfer of Vδ2 T cells. Mechanistically, (L2)P4 induced EBV LMP1, leading to IFN-γ/p-JNK and NLRC5 activation, and subsequently stimulated the expression of BTN2A1 and BTN3A1. Conclusions: This study demonstrated the effectiveness of using the EBV-targeting probe (L2)P4 and adoptive γδ T cells as a promising combinatorial immunotherapy against NPC. The identification of the LMP1-IFN-γ/p-JNK-NLRC5-BTN2A1/BTN3A1 axis may lead to new insight and therapeutic targets against NPC and other EBV+ tumors.

Energy Transfer Mechanism and Quantitative Modeling of Rate from an Antenna to a Lanthanide Ion.

The excitation energy transfer (ET) pathway and mechanism from an organic antenna to a lanthanide ion has been the subject of discussion for many decades. In the case of europium (Eu3+), it has been suggested that the transfer originates from the ligand singlet state or a triplet state. Taking the lanthanide complex Eu(TTA)3(H2O)2 as an example, we have investigated the spectra and luminescence kinetics, mainly at room temperature and 77 K, to acquire the necessary experimental data. We put forward an experimental and theoretical approach to measure the energy transfer rates from the antenna to different Eu3+ levels using the Dexter formulation. We find that transfer from the ligand singlet state to Eu3+ may account for the ET pathway, by combined electric dipole-electric dipole (ED-ED) and ED-electric quadrupole (EQ) mechanisms. The contributions from the triplet state by these mechanisms are very small. An independent systems rate equation approach can effectively model the experimental kinetics results. The model utilizes the cooperative processes that take place on the metal ion and ligand and considers S0, S1, and T1 ligand states in addition to 7F0,1, 5D0, 5D1, and 5DJ (=5L6, 5D3, 5D2 combined) Eu3+ states. The triplet exchange ET rate is estimated to be of the order 107 s-1. The observation of a nanosecond risetime for the Eu3+ 5D1 level does not enable the assignment of the ET route or the mechanism. Furthermore, the 5D1 risetime may be contributed by several processes. Observation of its temperature dependence and also that of the ground-state population can supply useful information concerning the mechanism because the change in metal-ion internal conversion rate has a greater effect than changes in singlet or triplet nonradiative rates. A critical comparison is included for the model of Malta employed in the online software LUMPAC and JOYSpectra. The theoretical treatment of the exchange mechanism and its contribution are now being considered.

Polymeric Dendrimers as Nanocarrier Vectors for Neurotheranostics.

Dendrimers are polymers with well-defined 3D branched structures that are vastly utilized in various neurotheranostics and biomedical applications, particularly as nanocarrier vectors. Imaging agents can be loaded into dendrimers to improve the accuracy of diagnostic imaging processes. Likewise, combining pharmaceutical agents and anticancer drugs with dendrimers can enhance their solubility, biocompatibility, and efficiency. Practically, by modifying ligands on the surface of dendrimers, effective therapeutic and diagnostic platforms can be constructed and implemented for targeted delivery. Dendrimer-based nanocarriers also show great potential in gene delivery. Since enzymes can degrade genetic materials during their blood circulation, dendrimers exhibit promising packaging and delivery alternatives, particularly for central nervous system (CNS) treatments. The DNA and RNA encapsulated in dendrimers represented by polyamidoamine that are used for targeted brain delivery, via chemical-structural adjustments and appropriate generation, significantly improve the correlation between transfection efficiency and cytotoxicity. This article reports a comprehensive review of dendrimers' structures, synthesis processes, and biological applications. Recent progress in diagnostic imaging processes and therapeutic applications for cancers and other CNS diseases are presented. Potential challenges and future directions in the development of dendrimers, which provide the theoretical basis for their broader applications in healthcare, are also discussed.

Biocompatible Porphyrin-Peptide Conjugates as Theranostic Agents Targeting the Epstein-Barr Virus.

Epstein-Barr virus (EBV) is a common human-infected virus related to many diseases and cancers. Recently, some peptides have been found to serve targeting and therapeutic roles by inhibiting EBNA1, an oncoprotein of the EBV. We herein report the conjugation of the EBNA1-targeting peptides and porphyrins which can bring synergistic effects by both introducing more specific treatments (photodynamic therapy) and improving the biocompatibility of the photosensitizer and the peptides. One of our compounds exhibited significant photo-cytotoxicity where the Lethal Concentration 50 (LC50 )=6.1 µM in EBV-positive cells. Besides, in vitro cell imaging and co-staining can also be achieved simultaneously and suggested the binding inside nucleus.

Upconversion in a d-f [RuYb3] Supramolecular Assembly.

We have prepared a hetero-tetrametallic assembly consisting of three ytterbium ions coordinated to a central [Ru(bpm)3]2+ (bpm = 2,2'-bipyrimidine) motif. Irradiation into the absorption band of the peripheral ytterbium ions at 980 nm engenders emission of the 3MLCT state of the central [Ru(bpm)3]2+ core at 636 nm, which represents the first example of f → d molecular upconversion (UC). Time-resolved measurements reveal a slow rise of the UC emission, which was modeled with a mathematical treatment of the observed kinetics according to a cooperative photosensitization mechanism using a virtual Yb centered doubly excited state followed by energy transfer to the Ru centered 1MLCT state.

Versatile Synthesis of Multivalent Porphyrin-Peptide Conjugates by Direct Porphyrin Construction on Resin.

Multifunctional porphyrin-peptide conjugates with different propensities for self-assembly into various supramolecular nanoarchitectures play important roles in advanced materials and biomedical research. However, preparing prefunctionalized core porphyrins by traditional low-yielding statistical synthesis and purifying them after peptide ligation through many rounds of HPLC purification is tedious and unsustainable. Herein, we report a novel integrated solid-phase synthetic protocol for the construction of porphyrin moieties from simple aldehydes and dipyrromethanes on resin-bound peptides directly to form mono-, cis/trans-di-, and trivalent porphyrin-peptide conjugates in a highly efficient and controllable manner; moreover, only single final-stage HPLC purification of the products is needed. This efficient strategy enables the rapid, greener, and substrate-controlled diversity-oriented synthesis of multivalent porphyrin-(long) peptide conjugate libraries for multifarious biological and materials applications.

Thermally Activated Photophysical Processes of Organolanthanide Complexes in Solution.

The effect of temperature upon the lanthanide luminescence lifetime and intensity has been investigated in toluene solution for the complexes LnPhen(TTA)3 (Ln = Eu, Sm, Nd, Yb; Phen = 1,10-phenanthroline; TTA = thenoyltrifluoroacetonate). Thermally excited back-transfer to a charge transfer state was found to occur for Ln = Eu and can be explained by lifetime and intensity back-transfer models. The emission intensity and lifetime were also quenched with increasing temperature for Ln = Sm, and the activation energy for nonradiative decay is similar to that for the thermal population of Sm3+ excited states. Unusual behavior for lifetime and intensity was found for both Ln = Nd, Yb. The usually assumed equivalence of τ/τ0 = I/I0 (where τ is lifetime and I is intensity) does not hold for these cases. We infer that for these lanthanide systems the intensity decreases with temperature in the stage prior to population of the luminescent state. The lifetime changes are discussed.

Correction: Incorporation of Fmoc-Dab(Mtt)-OH during solid-phase peptide synthesis: a word of caution.

Correction for 'Incorporation of Fmoc-Dab(Mtt)-OH during solid-phase peptide synthesis: a word of caution' by Pak-Lun Lam et al., Org. Biomol. Chem., 2022, DOI: 10.1039/d2ob00070a.

Incorporation of Fmoc-Dab(Mtt)-OH during solid-phase peptide synthesis: a word of caution.

As a commercially available and orthogonally protected amino acid building block, Fmoc-Dab(Mtt)-OH showed abnormally poor coupling efficiency during solid-phase peptide synthesis (SPPS). Herein, we reveal that Fmoc-Dab(Mtt)-OH undergoes rapid lactamization under a series of conditions with various coupling reagents. Although the complete incorporation of Fmoc-Dab(Mtt)-OH can be achieved using a multi-time and preincubation-free protocol with the coupling reagent DEPBT, alternative orthogonally protected building blocks are suggested to be used for avoiding such a costly and tedious procedure.

Intranasal Delivery of Functionalized Polymeric Nanomaterials to the Brain.

Intravenous delivery of nanomaterials containing therapeutic agents and various cargos for treating neurological disorders is often constrained by low delivery efficacy due to difficulties in passing the blood-brain barrier (BBB). Nanoparticles (NPs) administered intranasally can move along olfactory and trigeminal nerves so that they do not need to pass through the BBB, allowing non-invasive, direct access to selective neural pathways within the brain. Hence, intranasal (IN) administration of NPs can effectively deliver drugs and genes into targeted regions of the brain, holding potential for efficacious disease treatment in the central nervous system (CNS). In this review, current methods for delivering conjugated NPs to the brain are primarily discussed. Distinctive potential mechanisms of therapeutic nanocomposites delivered via IN pathways to the brain are then discussed. Recent progress in developing functional NPs for applications in multimodal bioimaging, drug delivery, diagnostics, and therapeutics is also reviewed. This review is then concluded by discussing existing challenges, new directions, and future perspectives in IN delivery of nanomaterials.

Charging and ultralong phosphorescence of lanthanide facilitated organic complex.

Emission from the triplet state of an organo-lanthanide complex is observed only when the energy transfer to the lanthanide ion is absent. The triplet state lifetime under cryogenic conditions for organo-lanthanide compounds usually ranges up to tens of milliseconds. The compound LaL1(TTA)3 reported herein exhibits 77 K phosphorescence observable by the naked eye for up to 30 s. Optical spectroscopy, density functional theory (DFT) and time-dependent DFT techniques have been applied to investigate the photophysical processes of this compound. In particular, on-off continuous irradiation cycles reveal a charging behaviour of the emission which is associated with triplet-triplet absorption because it shows a shorter rise lifetime than the corresponding decay lifetime and it varies with illumination intensity. The discovery of the behaviour of this compound provides insight into important photophysical processes of the triplet state of organo-lanthanide systems and may open new fields of application such as data encryption, anti-counterfeiting and temperature switching.

Enhancing Hybrid Upconversion Nanosystems via Synergistic Effects of Moiety Engineered NIR Dyes.

Hybrid upconversion nanosystems have been reported to improve the low absorption efficiency of lanthanide-doped upconversion nanoparticles (UCNPs). However, the low quantum yield and poor photostability of NIR dyes pose challenges for practical uses. Here, we introduce a bulky moiety, 4-(1,2,2-triphenylvinyl)-1,1'-biphenyl (TPEO), to enhance its quantum yield by suppressing the bond rotation and improve the stability by deactivating the photoinduced oxidization. Compared with the conventional IR806, the formed NIR dye, TPEO-Cy, has been characterized to deliver three times higher quantum yield and seven times better photostability. Moreover, we take advantage of the strong affinity of sulfonate chains on the TPEO-Cy to bind to the surface of UCNPs. Taking together the synergistic effect, we have achieved a 242-fold upconversion emission enhancement over the benchmark of IR806-sensitized system and an ∼800 000-fold increase than the bare UCNPs. Our design of the NIR dyes suggests a new scope to search for more efficient upconversion nanohybrids.