TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception.

Efforts on developing transient receptor potential vanilloid 1 (TRPV1) drugs for pain management have been hampered by deleterious hypo- or hyperthermia caused by TRPV1 agonists/antagonists. Here, we compared the effects of four antagonists on TRPV1 polymodal gating and core body temperature (CBT) in Trpv1+/+, Trpv1-/-, and Trpv1T634A/T634A. Neither the effect on proton gating nor drug administration route, hair coverage, CBT rhythmic fluctuations, or inflammation had any influence on the differential actions of TRPV1 drugs on CBT. We identified the S4-S5 linker region exposed to the vanilloid pocket of TRPV1 to be critical for hyperthermia associated with certain TRPV1 antagonists. PSFL2874, a TRPV1 antagonist we discovered, is effective against inflammatory pain but devoid of binding to the S4-S5 linker and inducing CBT changes. These findings implicate that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, opening avenues for the development of non-opioid analgesics without affecting CBT.

High-performance artificially reeled silkworm silk via a multi-task and high-efficiency centrifugal reeling technique and its application in soft actuators.

Silkworm silks show increasing potential in applications of bioengineering, sensors, optics, electronics, and actuators. However, their inherent irregular morphologies, structures, and properties greatly hinder the translation of these technologies to commercial applications. Herein, we report a facile and comprehensive strategy to fabricate high-performance silk materials by spinning silkworms artificially via a multi-task and high-efficiency centrifugal reeling technique. With this strategy, centrifugally reeled silks (CRSs) with long-uniform morphologies, excellent strength (844.83 ± 319.48 MPa), high toughness (121.07 ± 35.31 MJ m-3), and outstanding Young's modulus (27.72 ± 12.61 GPa) are developed. Remarkably, the maximum strength (1.45 GPa) of CRS is 3 times that of cocoon silk and even comparable to spider silk. Moreover, the centrifugal reeling technique realizes the one-step preparation of centrifugally reeled silk yarn (CRSY) from spinning silkworm, and the CRSYs show higher strength (877.38 ± 377.23 MPa) and superior torsional recovery performances. Furthermore, these CRSY-based soft pneumatic actuators (SPAs) exhibit light weight, high-loading capability, easy programmability in strength and motions, and fast responses, and therefore outperform currently reported elastomer-based SPAs, showing promising applications in flexible sensors, artificial muscles, and soft robotics. This work also provides a new guide for producing high-performance silks from silk-secreting insects and arthropods.

Broadening horizons: The role of ferroptosis in myocardial ischemia-reperfusion injury.

Ferroptosis is a novel type of regulated cell death (RCD) discovered in recent years, where abnormal intracellular iron accumulation leads to the onset of lipid peroxidation, which further leads to the disruption of intracellular redox homeostasis and triggers cell death. Iron accumulation with lipid peroxidation is considered a hallmark of ferroptosis that distinguishes it from other RCDs. Myocardial ischemia-reperfusion injury (MIRI) is a process of increased myocardial cell injury that occurs during coronary reperfusion after myocardial ischemia and is associated with high post-infarction mortality. Multiple experiments have shown that ferroptosis plays an important role in MIRI pathophysiology. This review systematically summarized the latest research progress on the mechanisms of ferroptosis. Then we report the possible link between the occurrence of MIRI and ferroptosis in cardiomyocytes. Finally, we discuss and analyze the related drugs that target ferroptosis to attenuate MIRI and its action targets, and point out the shortcomings of the current state of relevant research and possible future research directions. It is hoped to provide a new avenue for improving the prognosis of the acute coronary syndrome.

Study on the crystallization behavior and conformation adjustment scale of poly(lactic acid) in the terahertz frequency range.

The observed properties of crystalline polymers are determined by their internal structure, which in turn is the result of their different crystallization behaviors. Here, we investigate the crystallization behavior of poly(lactic acid) (PLA) by terahertz time-domain spectroscopy (THz-TDS) at varied temperatures. We find that the changes in the chain packing and conformation of PLA are characterized by THz spectroscopy. Combining X-ray diffraction (XRD) and infrared spectroscopy (IR), we attributed the blue-shift of the THz peak to the tightness of the chain packing, while its absorption enhancement is caused by the conformation transition. The effects of chain packing and chain conformation on the characteristic peak are phased. Furthermore, absorption discontinuities of the characteristic peaks of PLA crystallized at different temperatures are observed, which originated from differences in the degree of conformational transition caused by different thermal energies. We find that the crystallization temperature at which the absorption mutation of PLA occurs corresponds to the temperature at which the motion of the segment and molecular chain is excited, respectively. At these two temperatures, PLA exhibits different scales of conformational transitions leading to stronger absorption and larger absorption changes at higher crystallization temperatures. The results demonstrate that the driving force of PLA crystallization is indeed from changes in chain packing and chain conformation, and the molecular motion scale can also be characterized by THz spectroscopy.

Terahertz spectroscopy for quantitatively elucidating the crystal transformation of chiral histidine enantiomers to racemic compounds.

d-Histidine (d-His), l-Histidine (l-His), and their racemic compound dl-Histidine (dl-His) have different stereo chirality, making them intrinsic diverse functionalities to the living system. Identifying the configuration and crystal structures of enantiomers and the racemic compound is always the foremost requirement in processing protein foods. Although these features can be analyzed by spectroscopic technologies individually, it remains challenging to incorporate these complex methods into a facile analytical strategy. Herein, we propose a terahertz spectroscopy with solid-state density functional theory to both distinguish the configurational difference and quantify the crystal transformation from l-His and d-His to dl-His. By comparison with X-ray diffraction analysis, the validity of the crystal transformation evaluation based on terahertz spectroscopy is verified. A normalized fitting line regarding the terahertz absorption frequency and intensity is calculated to quantitatively elucidate the crystal transformation from enantiomers to dl-His. Our findings provide a new analytical approach to the research on food chemistry.

Risk factors for in-stent restenosis after coronary stent implantation in patients with coronary artery disease: A retrospective observational study.

To explore the risk factors for in-stent restenosis (ISR) after stent implantation in patients with coronary heart disease (CHD) using logistic regression analysis. From February 2020 to February 2022, 350 patients with CHD after percutaneous coronary intervention (PCI) were divided into a stent stenosis group and a stent nonstenosis group based on coronary angiography results performed 2 years after PCI. Univariate and multivariate logistic regressions were used to analyze the factors related to ISR after coronary stent implantation in patients with CHD. This study was approved by the Ethics Committee of Shandong University of Traditional Chinese Medicine. Patient signed informed consent. Of the 350 patients with CHD, 138 (39.43%) had stent restenosis while 212 did not. Univariate analysis showed that a family history of CHD, history of type 2 diabetes, hypertension, smoking, and drinking, discontinuation of aspirin, use of conventional dose statins, calcified lesions, ≥ 3 implanted stents, stent length ≥ 30 mm, stent diameter < 3 mm, and tandem stent increased the risk of restenosis. The incidence of restenosis was higher in the stent group than that in the nonstent group (P < .05). There were no significant differences in the blood lipid level, left ventricular ejection fraction, clopidogrel/ticagrelor or beta-blocker withdrawal, location of culprit vessels, and thrombotic lesions between the 2 groups (P > .05). Multivariate logistic regression analysis showed that family history of CHD, history of type 2 diabetes, hypertension, smoking, and drinking, aspirin withdrawal, use of conventional doses of statins, calcified lesions, ≥ 3 implanted stents, stent length ≥ 30 mm, stent diameter < 3 mm, and tandem stenting were risk factors for ISR within 2 years after PCI. A family history of CHD, history of type 2 diabetes, hypertension, smoking, and drinking, discontinuation of aspirin, use of conventional dose statins, calcified lesions, ≥ 3 stent implantations, stent length ≥ 30 mm, stent diameter < 3 mm, and tandem stenting are risk factors for ISR within 2 years after PCI in patients with CHD.

Study of Crystallinity and Conformation of Poly(lactic acid) by Terahertz Spectroscopy.

During crystallization, conformational changes are often accompanied by the formation of interactions. Terahertz (THz) spectroscopy exhibits strong responses to the crystalline poly(lactic acid) (PLA). Therefore, we estimate the relative crystallinity and investigate the effect of conformational transition on the vibration of PLA by THz spectroscopy. By comparing with the results of X-ray diffraction (XRD) and differential scanning calorimetry (DSC), the validity of THz spectroscopy to calculate crystallinity is verified. Furthermore, the peak intensity of PLA at 2.01 THz increases with crystallinity. Combined with Fourier transform infrared spectroscopy (FTIR), the vibrational intensity of PLA at 2.01 THz is highly correlated with the contribution of gt conformation, showing a linear relationship. In addition, the vibrational peak of PLA also reflects the interchain interactions. We believe that the increase in peak intensity with increasing crystallinity originates from the effect of the dipole-dipole interactions between the carbonyl groups. Our study demonstrates the ability of THz spectroscopy to estimate the crystallinity of PLA, and the peak at 2.01 THz shows conformational and interaction sensitivities.

Terahertz Spectroscopy Study of the Stereoisomers of Threonine.

The terahertz (THz) band contains a wealth of information about vibration and rotational energy levels, most of the vibration modes between amino acid molecules are in the THz band, so it reflects many unique absorption characteristics in the THz band. The use of terahertz time-domain spectroscopy can not only effectively identify different kinds of amino acids but also distinguish various isomers of the same amino acid due to the varied vibration modes. The absorption spectra of four stereoisomers of threonine were investigated by terahertz time-domain spectroscopy (THz-TDS) and Fourier transform infrared spectroscopy. The results show that the isomers show similarity in the infrared band, while manifest evidently the similarity between enantiomers L-threonine and D-threonine, and between L-allo-threonine and D-allo-threonine, and the difference between diastereoisomer L-threonine/D-threonine and L-allo-threonine/D-allo-threonine in the terahertz band. In order to fully understand the origin of the terahertz absorption characteristics of isomer molecules, simulation calculations were carried out in combination with density functional theory to connect the vibrational modes and molecular structures, Furthermore, the unit cell configurations of L-thr and L-allo-thr and the differences between various low-frequency vibrational modes are analyzed from the perspective of hydrogen bond configuration. By further extracting terahertz optical parameters such as refractive index and imaginary part of the dielectric constant of threonine isomers, the results show that the refractive index spectrum and dielectric loss spectrum can clearly show the response characteristics of the orientation polarization of dipole inside threonine isomers in terahertz band.

Terahertz spectroscopy for interpreting the formation and hierarchical structures of silk fibroin oligopeptides.

Determining the configuration and conformation of peptides is crucial for interpreting their structure-property relationships. In this work, we present nondestructive terahertz time-domain spectroscopy combined with density functional theory (DFT) and potential energy distribution (PED) analysis to identify the hierarchical structures of oligopeptides. The characteristic THz spectra of silk fibroin oligopeptides have been measured. Supported by DFT and PED analysis, the intrinsic differences among the dipeptides were identified by the collective vibrational modes of "R" groups and terminal groups linked by molecular chains of amido bonds or benzene rings. For tetrapeptides and hexapeptides, a few weak resonances and intensity differences were distinguished by the vibration mode of the molecular collective network formed by the interaction of amide planes and intramolecular hydrogen bond interactions. According to the THz absorption analyses of amide planes and intramolecular interactions within the molecular chains of silk fibroin oligopeptide isomer pairs, the formation and hierarchical structures were successfully interpreted using THz spectroscopy. This investigation develops a better understanding of the peptide formation mechanism, which further provides guidance in interpreting the formation of silk.

Terahertz spectroscopy of temperature-induced transformation between glutamic acid, pyroglutamic acid and racemic pyroglutamic acid.

Under heating conditions, L-Glutamic acid (L-Glu) can be dehydrated to form L-pyroglutamic acid (L-PGA), and L-PGA can racemize to form DL-PGA. Here, we characterized this transformation at different temperatures and times by terahertz time domain spectroscopy (THz-TDS). By Powder X-ray diffraction (PXRD), the validity of THz spectroscopy is verified. The results prove that the reaction rate of dehydration and racemization is significantly affected by temperature. The THz spectra divided the reactions into three stages. At 150-155 °C, the reaction changes drastically. Furthermore, we found that the absorption intensity at 0.97 and 1.55 THz has a good dependence on the reaction temperature and time, showing a non-linear relationship (R2 > 0.98). Our findings suggest that the chemical transformation and reaction rate can be sensitively probed by terahertz spectroscopy, which provides a potential method for the quantitative analysis of reaction products.

Evaluation of formation and proportion of secondary structure in γ-polyglutamic acid by terahertz time-domain spectroscopy.

The study of secondary structure is essential for understanding peptides and proteins. Here, we measured the terahertz (THz) spectra of γ-polyglutamic acid (γ-PGA) dominated by α-helix and random coil (RC) respectively. The α-helix has two absorption peaks in the THz region, but no absorption peak is observed in the RC conformation. We believe this is because the hydrogen bonding effect leads to a higher orientation in the helix-dominated γ-PGA. At lower pH, the absorption intensity of γ-PGA increases with the induction time. Similar changes were obtained in the Fourier infrared spectroscopy (FTIR). Through the correlation analysis of THz and IR spectroscopy, it is found that the characteristic peak at 1.2 THz can be used as a sensitive indicator of the intermediate conformation of the α-helical structure. In addition, the transformation of α-helix-RC conformation is related to the peak intensity at 1.99 THz (R2 = 0.991), which preliminarily indicates that terahertz time-domain spectroscopy (THz-TDS) has the potential to become a new effective method for characterizing and evaluating secondary structure.

The combination of living Bifidobacterium, Lactobacillus, and Streptococcus improves social ranking and relieves anxiety-like behaviors in competitive mice in a social dominance tube test.

INTRODUCTION: Social rank has a profound influence on the behavior and health of humans and animals. METHODS: To explore the effect of a combination of living Bifidobacterium, Lactobacillus and Streptococcus (CLB) on anxiety- and depression-like behaviors and social rank, mice were subjected to a social dominance tube test (SDTT). The behaviors, rank, gut microbiota, and expression of inflammatory cytokines and brain-derived neurotrophic factor (BDNF) in the hippocampus were measured. RESULTS: The results indicated that CLB improved the SDTT ranking score of the losers and alleviated anxiety-like behaviors of the winners. CLB decreased the level of Desulfovibrio and augmented the level of Mollicutes in the feces, increased BDNF content, and reduced the level of tumor necrosis factor-α in the hippocampus. CONCLUSION: These findings indicated that CLB may be used for the treatment of anxiety and improvement of the rank score via regulation of gut microbiota and anti-inflammatory effects.

Examination of proline, hydroxyproline and pyroglutamic acid with different polar groups by terahertz spectroscopy.

Hydroxyproline (HYP) and pyroglutamic acid (PGA), as amino acid derivatives, are highly similar in structure to proline (Pro). However, their low-frequency vibrations show significant differences in the range of 0.25-2.6 THz. Therefore, this study investigated the reasons for the differences combined with terahertz time domain spectroscopy (THz-TDS) and density functional theory (DFT). The results show that HYP and PGA have stronger absorption of terahertz waves due to the existence of polar substituents. Furthermore, the absorption peaks of HYP and PGA are significant red shifted and blue shifted, respectively. We believe that this is caused by the change in the strength of intermolecular hydrogen bonds. Our findings demonstrate that dipole and hydrogen bond effects play a significant role in low-frequency vibrations.