Muscle activity and hypoalgesia in blood flow restricted versus unrestricted effort-matched resistance exercise in healthy adults.

This study assessed muscle activity (root mean square, RMS, and median frequency, MDF) to evaluate the acute response to blood flow restriction (BFR) resistance exercise (RE) and conventional moderate intensity (MI) RE. We also performed exploratory analyses of differences based on sex and exercise-induced hypoalgesia (EIH). Fourteen asymptomatic individuals performed four sets of unilateral leg press with their dominant leg to volitional fatigue under two exercise conditions: BFR RE and MI RE. Dominant side rectus femoris (RF) and vastus lateralis (VL) muscle activity were measured using surface electromyography (sEMG) through exercise. RMS and MDF were calculated and compared between conditions and timepoints using a linear mixed model. Pressure pain thresholds (PPT) were tested before and immediately after exercise and used to quantify EIH. Participants were then divided into EIH responders and nonresponders, and the differences on RMS and MDF were compared between the two groups using Hedges' g. RMS significantly increased over time (RF: p = 0.0039; VL: p = 0.001) but not between conditions (RF: p = 0.4; VL: p = 0.67). MDF decreased over time (RF: p = 0.042; VL: p < 0.001) but not between conditions (RF: p = 0.74; VL: p = 0.77). Consistently lower muscle activation was found in females compared with males (BRF, RF: g = 0.63; VL, g = 0.5. MI, RF: g = 0.72; VL: g = 1.56), with more heterogeneous findings in MDF changes. For BFR, EIH responders showed greater RMS changes (Δ RMS) (RF: g = 0.90; VL: g = 1.21) but similar MDF changes (Δ MDF) (RF: g = 0.45; VL: g = 0.28) compared to nonresponders. For MI, EIH responders demonstrated greater increase on Δ RMS (g = 0.61) and decrease on Δ MDF (g = 0.68) in RF but similar changes in VL (Δ RMS: g = 0.40; Δ MDF: g = 0.39). These results indicate that when exercising to fatigue, no statistically significant difference was observed between BFR RE and conventional MI RE in Δ RMS and Δ MDF. Lower muscle activity was noticed in females. While exercising to volitional fatigue, muscle activity may contribute to EIH.

Mutualistic Synthesis from Orthogonal Dynamic Covalent Reactions.

Mutualisms are interactions that benefit all species involved. It has been widely investigated in neighbouring subjects, such as biology, ecology, sociology, and economics. However, such a reciprocal relationship in synthetic chemical systems has rarely been studied. Here, we demonstrate a mutualistic synthesis where byproducts from two orthogonal chemical reactions aid each other's production. Disulfide exchange and hydrazone exchange were chosen to generate two dynamic combinatorial libraries. A minor tetrameric macrocycle from the active disulfide library was quantitatively amplified in the presence of the hydrazone library. This incorporation also turned on the previously inert hydrazone reaction, producing a linear species that formed a "handcuffs" catenane with the disulfide tetramer. These findings not only lend robust support to the hypothesis of "RNA-peptide coevolution" for the origin of life but also broaden the scope of synthetic chemistry, highlighting the untapped potential of minor products from different reactions. Additionally, the co-self-assembly of these mutualistic entities to form supramolecular structures opens new avenues for future development of composite nanosystems with synergistic properties.

Genome-wide comparative analysis reveals selection signatures for reproduction traits in prolific Suffolk sheep.

The identification of genome-wide selection signatures can reveal the potential genetic mechanisms involved in the generation of new breeds through natural or artificial selection. In this study, we screened the genome-wide selection signatures of prolific Suffolk sheep, a new strain of multiparous mutton sheep, to identify candidate genes for reproduction traits and unravel the germplasm characteristics and population genetic evolution of this new strain of Suffolk sheep. Whole-genome resequencing was performed at an effective sequencing depth of 20× for genomic diversity and population structure analysis. Additionally, selection signatures were investigated in prolific Suffolk sheep, Suffolk sheep, and Hu sheep using fixation index (F ST) and heterozygosity H) analysis. A total of 5,236.338 Gb of high-quality genomic data and 28,767,952 SNPs were obtained for prolific Suffolk sheep. Moreover, 99 selection signals spanning candidate genes were identified. Twenty-three genes were significantly associated with KEGG pathway and Gene Ontology terms related to reproduction, growth, immunity, and metabolism. Through selective signal analysis, genes such as ARHGEF4, CATIP, and CCDC115 were found to be significantly correlated with reproductive traits in prolific Suffolk sheep and were highly associated with the mTOR signaling pathway, the melanogenic pathway, and the Hippo signaling pathways, among others. These results contribute to the understanding of the evolution of artificial selection in prolific Suffolk sheep and provide candidate reproduction-related genes that may be beneficial for the establishment of new sheep breeds.

Image fusion-based low-dose CBCT enhancement method for visualizing miniscrew insertion in the infrazygomatic crest.

Digital dental technology covers oral cone-beam computed tomography (CBCT) image processing and low-dose CBCT dental applications. A low-dose CBCT image enhancement method based on image fusion is proposed to address the need for subzygomatic small screw insertion. Specifically, firstly, a sharpening correction module is proposed, where the CBCT image is sharpened to compensate for the loss of details in the underexposed/over-exposed region. Secondly, a visibility restoration module based on type II fuzzy sets is designed, and a contrast enhancement module using curve transformation is designed. In addition to this, we propose a perceptual fusion module that fuses visibility and contrast of oral CBCT images. As a result, the problems of overexposure/underexposure, low visibility, and low contrast that occur in oral CBCT images can be effectively addressed with consistent interpretability. The proposed algorithm was analyzed in comparison experiments with a variety of algorithms, as well as ablation experiments. After analysis, compared with advanced enhancement algorithms, this algorithm achieved excellent results in low-dose CBCT enhancement and effective observation of subzygomatic small screw implantation. Compared with the best performing method, the evaluation metric is 0.07-2 higher on both datasets. The project can be found at: https://github.com/sunpeipei2024/low-dose-CBCT .

Force Transduction Through Distant Force-Bearing Regioisomeric Linkages Affects the Mechanochemical Reactivity of Cyclobutane.

Fundamental understanding of mechanochemical reactivity is important for designing new mechanophores. Besides the core structure of mechanophores, substituents on a mechanophore can affect its mechanochemical reactivity through electronic stabilization of the intermediate or effectiveness of force transduction from the polymer backbone to the mechanophore. The latter factor represents a unique mechanical effect in considering polymer mechanochemistry. Here, we show that regioisomeric linkage that is not directly adjacent to the first cleaving bond in cyclobutane can still significantly affect the mechanochemical reactivity of the mechanophore. We synthesized three non-scissile 1,2-diphenyl cyclobutanes, varying their linkage to the polymer backbone via the o, m, or p-position of the diphenyl substituents. Even though the regioisomers share the same substituted cyclobutane core structure and similar electronic stabilization of the diradical intermediate from cleaving the first C-C bond, the p isomer exhibited significantly higher mechanochemical reactivity than the o and m isomers. The observed difference in reactivity can be rationalized as the much more effective force transduction to the scissile bond through the p-position than the other two substitution positions. These findings point to the importance of considering force-bearing linkages that are more distant from the bond to be cleaved when incorporating mechanophores into polymer backbones.

SLC15A3 is transcriptionally regulated by HIF1α and p65 to worsen neuroinflammation in experimental ischemic stroke.

Systemic inflammatory stimulus is a risk factor for the incidence of ischemic stroke and contributes to poorer clinical outcomes. Solute carrier 15A3 (SLC15A3) is a peptide/histidine transporter that is implicated in regulating inflammatory responses. However, whether SLC15A3 affects the progression of ischemic stroke associated with systemic inflammation is unclear. The transient middle cerebral artery occlusion (tMCAO) mice with LPS administration (LPS/tMCAO) were prepared as an in vivo model, and LPS-induced BV2 cells under oxygen-glucose deprivation (OGD) exposure were utilized as an in vitro model. We found that SLC15A3 was highly expressed in the ischemic penumbra of LPS/tMCAO mice, and its inhibition reduced infarct area, attenuated neurological deficit, recovered motor function, and mitigated apoptotic neurons. Knockdown of SLC15A3 suppressed the proinflammatory M1-type markers and promoted the levels of M2-associated genes. The in vitro results confirmed that SLC15A3 overexpression promoted microglia polarizing towards M1 subtypes, while SLC15A3 inhibition exerted an opposite effect. In addition, we demonstrated that the p65 signaling pathway and HIF1α were activated by LPS/OGD. Luciferase reporter assay showed that inhibiting p65 using its specific inhibitor BAY 11-7082 or silencing HIF1α using siRNAs reduced the transcriptional activity of SLC15A3 in LPS/OGD-induced BV2 cells. Results in NIH 3T3 cells also confirmed that p65 and HIF1α directly bound to the SLC15A3 promoter to activate SLC15A3 transcription. In conclusion, this work shows that SLC15A3, transcriptionally activated by p65 and HIF1α, contributes to poor outcomes in ischemic stroke associated with systemic inflammation by promoting microglial cells polarizing towards M1 types.

Longitudinal Analysis of Humoral and Cellular Immune Response up to 6 Months after SARS-CoV-2 BA.5/BF.7/XBB Breakthrough Infection and BA.5/BF.7-XBB Reinfection.

The rapid mutation of SARS-CoV-2 has led to multiple rounds of large-scale breakthrough infection and reinfection worldwide. However, the dynamic changes of humoral and cellular immunity responses to several subvariants after infection remain unclear. In our study, a 6-month longitudinal immune response evaluation was conducted on 118 sera and 50 PBMC samples from 49 healthy individuals who experienced BA.5/BF.7/XBB breakthrough infection or BA.5/BF.7-XBB reinfection. By studying antibody response, memory B cell, and IFN-γ secreting CD4+/CD8+ T cell response to several SARS-CoV-2 variants, we observed that each component of immune response exhibited distinct kinetics. Either BA.5/BF.7/XBB breakthrough infection or BA.5/BF.7-XBB reinfection induces relatively high level of binding and neutralizing antibody titers against Omicron subvariants at an early time point, which rapidly decreases over time. Most of the individuals at 6 months post-breakthrough infection completely lost their neutralizing activities against BQ.1.1, CH.1.1, BA.2.86, JN.1 and XBB subvariants. Individuals with BA.5/BF.7-XBB reinfection exhibit immune imprinting shifting and recall pre-existing BA.5/BF.7 neutralization antibodies. In the BA.5 breakthrough infection group, the frequency of BA.5 and XBB.1.16-RBD specific memory B cells, resting memory B cells, and intermediate memory B cells gradually increased over time. On the other hand, the frequency of IFN-γ secreting CD4+/CD8+ T cells induced by WT/BA.5/XBB.1.16 spike trimer remains stable over time. Overall, our research indicates that individuals with breakthrough infection have rapidly declining antibody levels but have a relatively stable cellular immunity that can provide some degree of protection from future exposure to new antigens.

Abietane-Type Diterpenoids from the Arils of Torreya grandis.

A chemical investigation of the arils of Torreya grandis led to the isolation of seven abietane-type diterpenoids (compounds 1-7) including three previously undescribed compounds, one unreported natural product, and three known analogs. The structures of these compounds were determined by means of spectroscopy, single-crystal X-ray diffraction, and ECD spectra. An antibacterial activity assay showed that compounds 5 and 6 had significant inhibitory effects on methicillin-resistant Staphylococcus aureus, with MIC values of 100 µM. Moreover, compounds 1, 3, 4, and 7 exhibited anti-neuroinflammatory activity in LPS-stimulated BV-2 microglia cells, with the IC50 values ranging from 38.4 to 67.9 µM.

Application of Oxygen Saturation Test after Replantation of Avulsed Immature Permanent Teeth: A Prospective Observational Study.

INTRODUCTION: The evaluation of pulp status is crucial for avulsed immature permanent teeth after replantation. In addition to commonly used clinical and radiographic examinations providing clinical evidence, the oxygen saturation test may offer valuable assistance. The aim of this study was to analyze the efficacy of a pulse oximeter in evaluating pulp status in avulsed and replanted immature permanent teeth. METHODS: A prospective observational study was performed including 51 avulsed and replanted immature permanent teeth. Routine clinical and radiographic examinations were performed and used as the basis for the diagnosis of pulp status during the 1-year follow-up period. Meanwhile, the oxygen saturation values of these teeth were recorded using a modified pulse oximeter at each visit. RESULTS: Seven teeth completed pulp revascularization (success group), whereas 44 teeth failed to revascularize (failure group). Abnormal clinical and/or radiographic manifestations in the failure group were observed at an average period of 42.7 days, which was too late because a high incidence of inflammatory root resorption (43.18%) had occurred. For oxygen saturation tests, teeth in the success group showed an immediate postreplantation oxygen value of 70.71 ± 3.35, then an upward trend starting from the 2-week postreplantation visit, and a significantly increased final value of 81.86 ± 2.34 at the 1-year visit. In contrast, no increase trend was found for teeth in the failure group because abnormal clinical and/or radiographic manifestations emerged. CONCLUSIONS: The oxygen saturation test is a reliable diagnostic method to evaluate pulp status of avulsed teeth as early as 2 weeks after replantation.

Hypoalgesia and Conditioned Pain Modulation in Blood Flow Restriction Resistance Exercise.

We compared the magnitude of exercise-induced hypoalgesia and conditioned pain modulation between blood-flow restriction (BFR) resistance exercise (RE) and moderate-intensity RE. Twenty-five asymptomatic participants performed unilateral leg press in two visits. For moderate-intensity RE, subjects exercised at 50% 1RM without BFR, whereas BFR RE exercised at 30% 1RM with a cuff inflated to 60% limb occlusion pressure. Exercise-induced hypoalgesia was quantified by pressure pain threshold changes before and after RE. Conditioned pain modulation was tested using cold water as the conditioning stimulus and mechanical pressure as the test stimulus and quantified as pressure pain threshold change. Difference in conditioned pain modulation pre- to post-RE was then calculated. The differences of RE on pain modulations were compared using paired t-tests. Pearson's r was used to examine the correlation between exercise-induced hypoalgesia and changes in conditioned pain modulation. We found greater hypoalgesia with BFR RE compared to moderate-intensity RE (p=0.008). Significant moderate correlations were found between exercise-induced hypoalgesia and changes in conditioned pain modulation (BFR: r=0.63, moderate-intensity: r=0.72). BFR RE has favorable effects on pain modulation in healthy adults and the magnitude of exercise-induced hypoalgesia is positively correlated with conditioned pain modulation activation.

A metal-organic cage-derived cascade antioxidant nanozyme to mitigate renal ischemia-reperfusion injury.

In the field of contemporary medicine, inflammation has emerged as a significant concern in global public health. Among the current anti-inflammatory strategies, nanozymes possess distinctive advantages and demonstrate unexpected efficacy in combating inflammation. However, the indeterminate structures and limited enzyme-like activity exhibited by most developed nanozymes impede their clinical translation and therapeutic effectiveness. In this paper, we developed a nanozyme derived from a well-defined metal-organic cage (MOC). The oxidized MOC (MOC-O), containing pyridine nitrogen oxide moieties, exhibited effective cascade superoxide dismutase (SOD) and catalase (CAT)-like activities for scavenging reactive oxygen species (ROS). This ROS scavenging ability was confirmed through flow cytometry analysis using DCFH-DA in a hypoxia/reoxygenation (H/R) model, where MOC-O significantly alleviated oxidative stress. Furthermore, the administration of MOC-O resulted in preserved renal function during renal ischemia-reperfusion (I/R) injury due to downregulated oxidative stress levels and reduced cell apoptosis.

Recent advances in carbon monoxide-releasing nanomaterials.

As an endogenous signaling molecule, carbon monoxide (CO) has emerged as an increasingly promising option regarding as gas therapy due to its positive pharmacological effects in various diseases. Owing to the gaseous nature and potential toxicity, it is particularly important to modulate the CO release dosages and targeted locations to elucidate the biological mechanisms of CO and facilitate its clinical applications. Based on these, diverse CO-releasing molecules (CORMs) have been developed for controlled release of CO in biological systems. However, practical applications of these CORMs are limited by several disadvantages including low stability, poor solubility, weak releasing controllability, random diffusion, and potential toxicity. In light of rapid developments and diverse advantages of nanomedicine, abundant nanomaterials releasing CO in controlled ways have been developed for therapeutic purposes across various diseases. Due to their nanoscale sizes, diversified compositions and modified surfaces, vast CO-releasing nanomaterials (CORNMs) have been constructed and exhibited controlled CO release in specific locations under various stimuli with better pharmacokinetics and pharmacodynamics. In this review, we present the recent progress in CORNMs according to their compositions. Following a concise introduction to CO therapy, CORMs and CORNMs, the representative research progress of CORNMs constructed from organic nanostructures, hybrid nanomaterials, inorganic nanomaterials, and nanocomposites is elaborated. The basic properties of these CORNMs, such as active components, CO releasing mechanisms, detection methods, and therapeutic applications, are discussed in detail and listed in a table. Finally, we explore and discuss the prospects and challenges associated with utilizing nanomaterials for biological CO release.

Rapid detection of clarithromycin resistance in clinical samples of nontuberculous mycobacteria by nucleotide MALDI-TOF MS.

The multidrug resistance of nontuberculous mycobacteria (NTM) poses a significant therapeutic challenge. Rapid and reliable drug susceptibility testing is urgently needed for evidence-based treatment decision, especially for macrolides. This study evaluated the utility of nucleotide matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (NMTMS) in detecting clarithromycin resistance. Sixty-four clinical isolates were identified to species by NMTMS, and mutations associated with clarithromycin resistance were detected. Twenty-three M. abscessus (MAB) isolates and 30 M. intracellulare isolates (including M. intracellulare alone and M. intracellulare in combination with other SGM species) were included for analysis. The predictive sensitivity of NMTMS in detecting clarithromycin resistance was 82.35% (95% CI, 56.57% to 96.20%), with an AUC of 0.89 (95% CI, 0.77 to 0.96) in all MAB and M. intracellulare (n = 53), and up to 93.33% (95% CI, 68.05% to 99.83%) in MAB alone (n = 23). The assay provides a rapid, high-throughput, and highly sensitive tool for detecting clarithromycin resistance in NTM, especially in MAB. Optimization of the panel is necessary to enhance diagnostic accuracy.

Transmission of fluoroquinolones resistance among multidrug-resistant tuberculosis in Shanghai, China: a retrospective population-based genomic epidemiology study.

Fluoroquinolones (FQ) are essential for the treatment of multidrug-resistant tuberculosis (MDR-TB). The FQ resistance (FQ-R) rate in MDR-TB in China and its risk factors remain poorly understood. We conducted a retrospective, population-based genomic epidemiology study of MDR-TB patients in Shanghai, China, from 2009 to 2018. A genomic cluster was defined as strains with genetic distances ≤ 12 single nucleotide polymorphisms. The transmitted FQ-R was defined as the same FQ resistance-conferring mutations shared by ≥ 2 strains in a genomic cluster. We used multivariable logistic regression analysis to identify the risk factors for drug resistance. Among the total 850 MDR-TB patients included in the study, 72.8% (619/850) were male, the median age was 39 (interquartile range 28, 55) years, 52.7% (448/850) were migrants, and 34.5% (293/850) were previously treated patients. Most of the MDR-TB strains belong to the Beijing lineage (91.7%, 779/850). Overall, the genotypic resistance rate of FQ was 34.7% (295/850), and 47.1% (139/295) FQ-R patients were in genomic clusters, of which 98 (33.2%, 98/295) were presumed as transmitted FQ-R. Patients with treatment-naïve (aOR = 1.84; 95% CI: 1.09, 3.16), diagnosed in a district-level hospital (aOR = 2.69; 95% CI: 1.56, 4.75), and streptomycin resistance (aOR = 3.69; 95% CI: 1.65, 9.42) were significantly associated with the transmission of FQ-R. In summary, the prevalence of FQ-R among MDR-TB patients was high in Shanghai, and at least one-third were transmitted. Enforced interventions including surveillance of FQ drug susceptibility testing and screening among MDR-TB before initiation of treatment were urgently needed.

Detection and complete genome sequence analysis of human adenovirus in children with acute diarrhea in Yunnan, China, 2015-2021.

The aims of this study were to determine the distribution and prevalence of gastroenteritis caused by human adenovirus (HAdV) in children in Yunnan province, China, in 2015-2021 and to identify preventive measures that can be taken to reduce morbidity and mortality in children.HAdV is a significant agent of diarrhea in children, but limited data are available regarding the epidemiology and genetic diversity of HAdV in children with diarrhea in Yunnan province, China. A total of 1754 fecal samples were subjected to real-time RT-PCR to detect and quantify HAdV. Positive samples were further analyzed using next-generation sequencing (NGS), and epidemiological data were analyzed as well.1754 patients with diarrhea were enrolled, of which 1041 were male and 713 were female (M:F ratio: 1.46). Seventy-two stool samples out of 1754 (4.10%) were positive for HAdV. The detection rates of all age groups varied from 2.50-4.78%. The highest incidence of HAdV was observed in children under 2 years of age, especially in children 12-24 months-old. From 2015-2021, the annual detection rate ranged from 1.62-12.26%. HAdV was detected throughout the year, but with marked seasonality. Children were most likely to be positive for HAdV in June and November. We detected HAdV in 15.53% (16/103) of samples collected in June and in 8.19% (14/171) of those collected in November. The entire viral genome was successfully sequenced for 13 of the 72 HAdV-positive samples, and 76.92% (10/13) of these were classified as genotype F41 and 23.08% (3/13) were classified as genotype C2.ConclusionsIn Yunnan province, children of all ages are susceptible to HAdV infection, but there has been marked variation in the yearly prevalence. The highest rate of HAdV detection was in June, followed by November. Priority should be given to disease prevention over the development of targeted antiviral therapies, and effective vaccines for preventing HAdV diarrhea are needed. It is also important to establish a surveillance system to collect relevant clinical and epidemiological data quickly in order to assess the potential risk of HAdV infection in children and to identify epidemic strains for the development of effective vaccines.

In Vitro and In Vivo Supplementation with Curcumin Promotes Hippocampal Neuronal Synapses Development in Rats by Inhibiting GSK-3ß and Activating ß-catenin.

The human fetal thyroid gland is not capable of producing thyroid hormones independently until 20 weeks of gestation, and if maternal thyroid hormone synthesis is inadequate in early pregnancy, fetal brain and nerve development may be affected by maternal hypothyroidism. Curcumin, which is isolated from turmeric (Curcuma longa), has been shown to be effective in repairing neurological disorders and is effective in relieving nerve damage when consumed over a long period of time. In this experiment, we investigated the effect of curcumin supplementation on synaptic development of rat hippocampal neurons. A cell model of oxidative damage and a young rat model of hypothyroidism were constructed, and model cells and rats were treated with triiodothyronine (T3), tetraiodothyronine (T4), and curcumin, respectively. Damage of nerve cells and animal brain tissues was examined, and the effect of curcumin in alleviating the blocked neurodevelopment was investigated. Further modulation of GSK-3ß/ß-catenin was performed to investigate the mechanism of action of curcumin. Ultimately, we found that T3-, T4-, and curcumin-treated model cells and young rats had increased numbers of synapses and good neurodevelopment. At the same time, we found that curcumin inhibited the production of GSK-3ß and Axin to activate ß-catenin. The inhibition of ß-catenin weakened the therapeutic effect of curcumin, and the differences between the indicators and the model group disappeared. Both cellular and animal experiments supported that curcumin effectively alleviated the oxidative cell damage caused by thyroxine deficiency and activated the synaptogenic ability of nerve synapses by inhibiting GSK-3ß and protecting ß-catenin activity.

Mechanochemistry of Pterodactylane.

Pterodactylane is a [4]-ladderane with substituents on the central rung. Comparing the mechanochemistry of the [4]-ladderane structure when pulled from the central rung versus the end rung revealed a striking difference in the threshold force of mechanoactivation: the threshold force is dramatically lowered from 1.9 nN when pulled on the end rung to 0.7 nN when pulled on the central rung. We investigated the bicyclic products formed from the mechanochemical activation of pterodactylane experimentally and computationally, which are distinct from the mechanochemical products of ladderanes being activated from the end rung. We compared the products of pterodactylane's mechanochemical and thermal activation to reveal differences and similarities in the mechanochemical and thermal pathways of pterodactylane transformation. Interestingly, we also discovered the presence of elementary steps that are accelerated or suppressed by force within the same mechanochemical reaction of pterodactylane, suggesting rich mechanochemical manifolds of multicyclic structures. We rationalized the greatly enhanced mechanochemical reactivity of the central rung of pterodactylane and discovered force-free ground state bond length to be a good low-cost predictor of the threshold force for cyclobutane-based mechanophores. These findings advance our understanding of mechanochemical reactivities and pathways, and they will guide future designs of mechanophores with low threshold forces to facilitate their applications in force-responsive materials.

Bedaquiline, Delamanid, Linezolid, Clofazimine, and Capreomycin MIC Distributions for Drug Resistance Mycobacterium tuberculosis in Shanghai, China.

Background: New antituberculosis drugs have recently been approved for the treatment of multidrug-resistant tuberculosis TB (MDR-TB). We aimed to describe the distributions of bedaquiline, delamanid, linezolid, clofazimine, and capreomycin MIC values for M. tuberculosis. Methods: M. tuberculosis clinical isolates were originally isolated from 2020 to 2021 from 1452 different pulmonary tuberculosis patients of the Shanghai Pulmonary Hospital in China. The drug susceptibility testing was performed using the Sensititre custom plates (SHTBMY) (TREK Diagnostic Systems, Thermo Fisher Scientific In., USA) consisting of a 96-well microtitre plate containing 4 (bedaquiline, delamanid, clofazimine, capreomycin) antimicrobial agents. MICs were determined for linezolid using a microdilution method. Results: Based on the latest definitions, 156 (10.74%) were MDR-TB, 93 (6.40%) were pre-XDR-TB, and 27 (1.86%) were XDR-TB. The rate of BDQ resistance in cases of MDR-TB was 7.69%, while it was observed to be 10.75% in cases of pre-XDR-TB, and significantly higher at 37.04% in cases of XDR-TB. The lowest rate of drug resistance against M. tuberculosis was DLM (0.14%). For LZD, 11 (0.76%) clinical isolates were resistant, based on the CLSI breakpoint of 1µg/mL. The five strains with a MIC value of >32 for LZD resistance were XDR-TB isolates. Among all MDR, pre-XDR, and XDR isolates tested, LZD' MIC50 increased from 0.25 and 0.5 to 1µg/mL. The MIC90 value of LZD against XDR-TB isolates was 32µg/mL. For CFZ, six isolates with elevated MICs of ≥2µg/mL. CFZ's MIC50 and MIC90 values in all isolates were 0.12µg/mL and 0.25µg/mL, respectively. Conclusion: The study findings indicate that BDQ, DLM, CFZ, and LZD may exhibited excellent in vitro activity against MDR-TB isolates. Detection of resistance to BDQ and LZD was alarming for XDR-TB isolates. It is necessary to perform universal drug sensitivity testing for M. tuberculosis, especially MDR-TB and XDR-TB patients.

Erythropoietin inhibits neutrophil extracellular traps formation to ameliorate lung injury in a pneumonia model.

BACKGROUND: Severe pneumonia is a kind of disease that develops from lung inflammation, and new drugs are still required to treat the same. Erythropoietin (EPO) is widely used to treat anemia in patients. However, there are fewer studies on the role of EPO in neutrophil extracellular trappings (NETs) and pneumonia, and the mechanism is unclear. OBJECTIVE: To investigate the possible effects of EPO on the formation of NETs and progression of pneumonia. METHODS: Mice pneumonia model was induced by tracheal lipopolysaccharide (LPS) administration. Hematoxylin and eosin (H&E) staining and automatic blood cell analysis were performed in this model to confirm the effects of EPO on lung injury. Flow cytometry, enzyme-linked immunosorbent serological assay, and immunostaining assay were conducted to detect the effects of EPO on the inflammation as well as formation of NETs in mice. Immunoblot was further conducted to confirm the mechanism. RESULTS: EPO alleviated LPS-induced lung injury. EPO reduced the release of inflammatory factors induced by LPS. In addition, EPO inhibited the formation of NETs. Mechanically, EPO inhibited tumor necrosis factor (TNF) receptor associated factor 2 (TRAF2)/nuclear factor kappa-B (NF-κB) activity in mouse models, and therefore suppressed the progression of pneumonia. CONCLUSION: EPO inhibited formation of NETs to ameliorate lung injury in a pneumonia model, and could serve as a drug of pneumonia.

Nanodrugs Reprogram Cancer-Associated Fibroblasts and Normalize Tumor Vasculatures for Sequentially Enhancing Photodynamic Therapy of Hepatocellular Carcinoma.

Background: The failure of cancer photodynamic therapy (PDT) is largely ascribed to excessive stroma and defective vasculatures that restrain the photosensitizer permeation and the oxygen perfusion in tumors. Method and Results: In this study, a nanodrug that integrated the cancer-associated fibroblast (CAF) regulation with tumor vessel normalization was tailored to sequentially sensitize PDT. The nanodrug exhibited high targeting towards CAFs and efficiently reversed the activated CAFs into quiescence, thus decreasing collagen deposition in the tumor microenvironment (TME), which overcame the protective physical barrier. Furthermore, the nanodrug regulated vascular endothelial cells and restored the tumor vasculatures, thereby improving vascular permeability. Based on the combined effects of reprogramming the TME, the nanodrug improved tumor accumulation of photosensitizers and alleviated hypoxia in the TME, which facilitated the subsequent PDT. Importantly, the nanodrug regulated the immunosuppressive TME by favoring the infiltration of immunostimulatory cells over immunosuppressive cells, which potentiated the PDT-induced immune response. Conclusion: Our work demonstrates a sequential treatment strategy in which the combination of the CAF regulation and tumor vasculature normalization, followed by PDT, could be a promising modality for sensitizing tumor to PDT.