A biocompatible polydopamine platform for targeted delivery of nicotinamide mononucleotide and boosting NAD+ levels in the brain.

Nicotinamide mononucleotide (NMN), a precursor of the coenzyme nicotinamide adenine dinucleotide (NAD+), has gained wide attention as an anti-aging agent, which plays a significant role in intracellular redox reactions. However, its effectiveness is limited by easy metabolism in the liver and subsequent excretion as nicotinamide, resulting in low bioavailability, particularly in the brain. Additionally, the blood-brain barrier (BBB) further hinders NMN supply to the brain, compromising its potential anti-aging effects. Herein, we developed a biocompatible polydopamine (PDA) platform to deliver NMN for boosting NAD+ levels in the brain for the first time. The lactoferrin (Lf) ligand was covalently attached to the PDA spheres to improve BBB transport efficiency. The resultant PDA-based system, referred to as PDA-Lf-NMN, not only exhibited superior BBB penetration ability but also improved the utilization rate of brain NMN in elevating NAD+ levels compared to NMN alone for both young (3 months) and old (21 months) mice. Moreover, after the old mice were treated with low-dose PDA-Lf-NMN (8 mg kg-1 day-1), they exhibited improved spatial cognition. Importantly, these nanomedicines did not induce any cellular necrosis or apoptosis. It provides a promising avenue for delivering NMN specifically to the brain, boosting NAD+ levels for promoting longevity and treating brain aging-related diseases.

Perturbing TET2 condensation promotes aberrant genome-wide DNA methylation and curtails leukaemia cell growth.

The ten-eleven translocation (TET) family of dioxygenases maintain stable local DNA demethylation during cell division and lineage specification. As the major catalytic product of TET enzymes, 5-hydroxymethylcytosine is selectively enriched at specific genomic regions, such as enhancers, in a tissue-dependent manner. However, the mechanisms underlying this selectivity remain unresolved. Here we unveil a low-complexity insert domain within TET2 that facilitates its biomolecular condensation with epigenetic modulators, such as UTX and MLL4. This co-condensation fosters a permissive chromatin environment for precise DNA demethylation. Disrupting low-complexity insert-mediated condensation alters the genomic binding of TET2 to cause promiscuous DNA demethylation and genome reorganization. These changes influence the expression of key genes implicated in leukaemogenesis to curtail leukaemia cell proliferation. Collectively, this study establishes the pivotal role of TET2 condensation in orchestrating precise DNA demethylation and gene transcription to support tumour cell growth.

Exploring the Potential Role of Dexmedetomidine in Reducing Postoperative Cognitive Dysfunction in Elderly Hip Fracture Patients.

BACKGROUND: Hip fractures are prevalent in the elderly; however, Postoperative Cognitive Dysfunction (POCD) is a possible complication of hip fracture surgery in elderly patients. This study examines the influence and the underlying mechanism of dexmedetomidine on POCD in elderly patients following hip fracture surgery. METHODS: The retrospective study involved elderly patients with hip fracture who were treated at the Fifth Affiliated Hospital of Xinjiang Medical University from October 2021 to August 2022. During the surgery procedures, dexmedetomidine was administrated and the peripheral blood samples were collected from the patients. Inflammatory factors were measured using Enzyme-linked immunosorbent assay (ELISA), while pyroptosis-related proteins were detected through quantitative reverse transcription PCR (RT-qPCR) and western blot. Additionally, the levels of CD4+T and CD8+T cells were assessed using flow cytometry. An aged rats hip fracture model was established to further investigate the impact of dexmedetomidine on postoperative mobility, cognition function, pyroptosis and immune cells in rats. RESULTS: Postoperative cognitive function in patients did not show significant alteration when compared with pre-operation levels (p > 0.05). There were notable reduction in the levels of interleukin-18 (IL-18), Caspase-3, Gasdermin-D (GSDMD) and NLR Family Pyrin Domain Containing 3 (NLRP3) (p < 0.001), accompanied by an increase in the proportion of CD4+T cells and an decrease in CD8+T cells after operation (p < 0.01). In aged rats, postoperative exploratory activities increased compared to their preoperative state. Compared with preoperative levels, the levels of interleukin-1ß (IL-1ß), IL-18, Caspase-3, GSDMD, and NLRP3 were significantly decreased (p < 0.001), the proportion of CD4+T cells was increased, and the proportion of CD8+T cells was decreased postoperatively (p < 0.01). CONCLUSIONS: Although there was no significant alteration in postoperative cognitive function in patients, dexmedetomidine may still play a role in mitigating POCD potentially due to its effects on reducing immune inflammation and pyroptosis markers. Further research is needed to fully understand the underlying mechanisms and its clinical implications.

Immobilized Multi-Enzyme/Nanozyme Biomimetic Cascade Catalysis for Biosensing Applications.

Multiple enzyme-induced cascade catalysis has an indispensable role in the process of complex life activities, and is widely used to construct robust biosensors for analyzing various targets. The immobilized multi-enzyme cascade catalysis system is a novel biomimetic catalysis strategy that immobilizes various enzymes with different functions in stable carriers to simulate the synergistic catalysis of multiple enzymes in biological systems, which enables high stability of enzymes and efficiency enzymatic cascade catalysis. Nanozymes, a type of nanomaterial with intrinsic enzyme-like characteristics and excellent stabilities, are also widely applied instead of enzymes to construct immobilized cascade systems, achieving better catalytic performance and reaction stability. Due to good stability, reusability, and remarkably high efficiency, the immobilized multi-enzyme/nanozyme biomimetic cascade catalysis systems show distinct advantages in promoting signal transduction and amplification, thereby attracting vast research interest in biosensing applications. This review focuses on the research progress of the immobilized multi-enzyme/nanozyme biomimetic cascade catalysis systems in recent years. The construction approaches, factors affecting the efficiency, and applications for sensitive biosensing are discussed in detail. Further, their challenges and outlooks for future study are also provided.

Palladium nanoballs coupled with smartphone-thermal reader for photothermal lateral flow immunoassay of Aß 1-40.

Amyloid beta 1-40 (Aß 1-40) is one of the most abundant substances in the body with the capacity to form insoluble aggregates and is a universal biomarker for the prediction of Alzheimer's disease. Here, a palladium nanoball (PNB)-strip was developed and coupled with a smartphone-thermal reader as an ultrasensitive and cost-effective platform for Aß 1-40 detection. In this study, PNB was synthesized and introduced into lateral flow strips as an alternative signal source to gold nanoparticles to improve sensitivity because the PNB has a better heat generation ability. Quantitative analysis was performed using a self-developed smartphone-thermal reader, which is portable and cost-effective. The detection limit of the system was determined to be 20 pg mL-1, which fulfils the need for clinical diagnosis at the point-of-care. This work highlights a PNB-strip coupled smartphone-thermal reader for ultrasensitive and cost-effective Aß 1-40 detection.

Impact of prognostic nutritional index change on prognosis after colorectal cancer surgery under propofol or sevoflurane anesthesia.

BACKGROUND: The alteration of the prognostic nutritional index (PNI) or the utilization of distinct anesthesia strategies has been linked to the prognosis of various cancer types, but the existing evidence is limited and inconclusive, particularly for colorectal cancer (CRC). Our objective was to evaluate the association between PNI change and progression free survival (PFS) and overall survival (OS) in patients treated with CRC surgery after propofol-based or sevoflurane-based anesthesia. METHODS: We conducted a retrospective analysis of 414 patients with CRC who underwent surgical resection. Among them, 165 patients received propofol-based total intravenous anesthesia (TIVA-P), while 249 patients received sevoflurane-based inhalation anesthesia (IA-S). The PNI change (ΔPNI) was calculated by subtracting the pre-surgery PNI from the post-surgery PNI, and patients were categorized into high (≥ -2.25) and low (< -2.25) ΔPNI groups. Univariate and multivariate analyses were employed to evaluate the effects of the two anesthesia methods, ΔPNI, and their potential interaction on PFS and OS. RESULTS: The median duration of follow-up was 35.9 months (interquartile range: 18-60 months). The five-year OS rates were 63.0% in the TIVA-P group and 59.8% in the IA-S group (hazard ratio [HR]: 0.96; 95% confidence interval [CI]: 0.70-1.35; p = 0.864), while the five-year PFS rates were 55.8% and 51.0% (HR: 0.92; 95% CI: 0.68-1.26; p = 0.614), respectively. In comparison to patients in the low ΔPNI group, those in the high ΔPNI group exhibited a favorable association with both OS (HR: 0.57; 95% CI: 0.40-0.76; p < 0.001) and PFS (HR: 0.58; 95% CI: 0.43-0.79; p < 0.001). Stratified analysis based on ΔPNI revealed significant protective effects in the propofol-treated participants within the high ΔPNI group, whereas such effects were not observed in the low ΔPNI group, for both OS (p for interaction = 0.004) and PFS (p for interaction = 0.024). CONCLUSIONS: Our data revealed that among patients who underwent CRC surgery, those treated with TIVA-P exhibited superior survival outcomes compared to those who received IA-S, particularly among individuals with a high degree of PNI change.

Adalimumab induced exacerbation of psoriasis in patients with combined pemphigus: A case report.

RATIONALE: Psoriasis is an immune-related disease caused by genetic factors, abnormalities in the immune system and environmental factors, while pemphigus is an autoimmune disease caused by the autoimmune system attacking the skin and mucosal tissues. Herein, we aimed to report a rare case of adalimumab induced exacerbation of psoriasis patients with pemphigus. The rare disease causes considerable challenges for clinical diagnosis and treatment. PATIENT CONCERNS: The patient was a 43-year-old man with intermittent erythema and scaling all over the body for more than 20 years, and blisters and vesicles on the trunk and limbs for 1 month. Half a year ago, the patient had blisters on the limbs, and was diagnosed with deciduous pemphigus in a hospital, and the blisters subsided after being given traditional Chinese medicine orally. Half a month ago, the erythema area was enlarged, and adalimumab 80 mg intramuscular injection was given for 1 time after consultation in the hospital. On the following day, the area of erythema and scales was suddenly enlarged obviously compared with the previous 1, and obvious blisters and vesicles appeared on the limbs, neck, and trunk, which were aggravated progressively and accompanied by obvious itching and pain. DIAGNOSES: The patient was diagnosed with psoriasis in patients with combined pemphigus. INTERVENTION: After combined treatment with methylprednisolone and cyclosporine, the skin lesions have basically recovered. OUTCOMES: The skin lesions have basically healed. Follow up for 6 months without recurrence. LESSONS: Methylprednisolone combined with cyclosporine may be an option in treating patients with psoriasis patients with pemphigus.

Metal-Organic Framework-Based Artificial Organelle Corrects Microenvironment Interference for Accurate Intratumoral Glucose Analysis.

Enzymatic catalysis with high efficiency allows them a great prospect in metabolite monitoring in living cells. However, complex tumor microenvironments, such as acidity, H2 O2 , and hypoxia, are bound to disturb catalytic reactions for misleading results. Here, we report a spatially compartmentalized artificial organelle to correct intratumoral glucose analysis, where the zeolitic imidazolate framework-8 immobilized glucose oxidase-horseradish peroxidase cascade core and catalase-directed shell act as signal transduction and guarding rooms respectively. The acid-digested core and stable shell provide appropriate spaces to boost biocatalytic efficiency with good tolerability. Notably, the endogenous H2 O2 is in situ decomposed to O2 by catalase, which not only overcomes the interference in signal output but also alleviates the hypoxic states to maximize glucose oxidation. The marked protective effect and biocompatibility render artificial organelles to correct the signal transduction for dynamic monitoring glucose in vitro and in vivo, achieving our goal of accurate intratumoral metabolite analysis.

Biomimetic single Al-OH site with high acetylcholinesterase-like activity and self-defense ability for neuroprotection.

Neurotoxicity of organophosphate compounds (OPs) can catastrophically cause nervous system injury by inhibiting acetylcholinesterase (AChE) expression. Although artificial systems have been developed for indirect neuroprotection, they are limited to dissociating P-O bonds for eliminating OPs. However, these systems have failed to overcome the deactivation of AChE. Herein, we report our finding that Al3+ is engineered onto the nodes of metal-organic framework to synthesize MOF-808-Al with enhanced Lewis acidity. The resultant MOF-808-Al efficiently mimics the catalytic behavior of AChE and has a self-defense ability to break the activity inhibition by OPs. Mechanism investigations elucidate that Al3+ Lewis acid sites with a strong polarization effect unite the highly electronegative -OH groups to form the enzyme-like catalytic center, resulting in superior substrate activation and nucleophilic attack ability with a 2.7-fold activity improvement. The multifunctional MOF-808-Al, which has satisfactory biosafety, is efficient in reducing neurotoxic effects and preventing neuronal tissue damage.

Research progress of nanoparticle targeting delivery systems in bacterial infections.

Bacterial infection is a huge threat to the health of human beings and animals. The abuse of antibiotics have led to the occurrence of bacterial multidrug resistance, which have become a difficult problem in the treatment of clinical infections. Given the outstanding advantages of nanodrug delivery systems in cancer treatment, many scholars have begun to pay attention to their application in bacterial infections. However, due to the similarity of the microenvironment between bacterial infection lesions and cancer sites, the targeting and accuracy of traditional microenvironment-responsive nanocarriers are questionable. Therefore, finding new specific targets has become a new development direction of nanocarriers in bacterial prevention and treatment. This article reviews the infectious microenvironment induced by bacteria and a series of virulence factors of common pathogenic bacteria and their physiological functions, which may be used as potential targets to improve the targeting accuracy of nanocarriers in lesions.

Cascaded Nanozyme with In Situ Enhanced Photothermal Capacity for Tumor-Specific and Self-Replenishing Cancer Therapy.

Reactive oxygen species (ROS)-involved tumor therapeutic strategy, chemodynamic therapy (CDT), has attracted extensive research interest in the scientific community. However, the therapeutic effect of CDT is insufficient and unsustainable owing to the limited endogenous H2 O2 level in the tumor microenvironment. Here, peroxidase (POD)-like RuTe2 nanozyme with the immobilization of glucose oxidase (GOx) and allochroic 3,3',5,5'-tetramethylbenzidine (TMB) molecule have been synthesized to construct RuTe2 -GOx-TMB nanoreactors (RGT NRs) as cascade reaction systems for tumor-specific and self-replenishing cancer therapy. GOx in sequential nanocatalysts can effectively deplete glucose in tumor cells. Meanwhile, a sustainable supply of H2 O2 for subsequent Fenton-like reactions catalyzed by RuTe2 nanozyme is achieved in response to the mild acidic tumor microenvironment. Through this cascade reaction, highly toxic hydroxyl radicals (·OH) are produced, which can further oxidize TMB to trigger tumor-specific "turn-on" photothermal therapy (PTT). In addition, PTT and massive ROS can stimulate the tumor immune microenvironment and activate the systematic anti-tumor immune responses, exerting a notable effect on hindering tumor recurrence and metastasis. This study paves a promising paradigm for synergistic starvation therapy, PTT, and CDT cancer therapy with high efficiency.

Evaluation of the performance of a novel HIV-1 viral load assay for HIV quantification in China.

OBJECTIVES: Our objective was to assess the HIV-1 quantification performance of the Livzon HIV-1 viral load (VL) assay and the Roche Cobas HIV-1 assay to evaluate an HIV-1 VL testing reagent for application in China. METHOD: We compared the Livzon and Roche Cobas HIV-1 VL assays using ethylenediaminetetraacetic acid plasma samples collected between May 2021 and November 2021 from patients with HIV-1 and healthy controls. We used Cohen's κ coefficient to measure agreement of qualitative values and Pearson's correlation coefficient (r) values and the coefficient of determination (R2 ) to determine the linear relationship between the two assays. We performed a Bland-Altman analysis to assess VL quantification agreement. RESULTS: In total, 11 plasma samples from patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) and nine samples from healthy controls were undetectable on both assays. Overall agreement was seen in 419 of 500 specimens (91.40%), with a κ value of 0.59. Pearson's correlation coefficient between the two assays was 0.970. Using the Bland-Altman method, 95.14% (352/370) of paired VLs fell within the 95% confidence limits of agreement (-0.51 to 0.95 log10  copies/mL). Higher VLs had a better correlation and a smaller mean difference between the two assays. Pearson's correlation coefficient for the samples of subtype CRF01_AE, CRF07_BC, and CRF55_01B was 0.950, 0.935, and 0.952, respectively. CONCLUSION: The Livzon HIV-1 VL assay exhibits good precision and linearity and a high correlation with the Roche Cobas HIV-1 assay. The Livzon HIV-1 VL assay has salient advantages in terms of the lyophilized powder reagent, which gives the assay greater stability and sensitivity and can be readily used in low-resource areas.

Conformations of Steroid Hormones: Infrared and Vibrational Circular Dichroism Spectroscopy.

Steroid hormone molecules may exhibit very different functionalities based on the associated functional groups and their 3D arrangements in space, i.e., absolute configurations and conformations. Infrared (IR) and vibrational circular dichroism (VCD) spectra of four different steroid hormones, namely dehydroepiandrosterone (DHEA), 17α-methyltestosterone (MTTT), (16α,17)-epoxyprogesterone (Epoxy-P4), and dehydroepiandrosterone acetate (AcO-DHEA), were measured in deuterated dimethyl sulfoxide and some also in carbon tetrachloride. Extensive conformational searches were carried out using the recent developed conformer-rotamer ensemble sampling tool (CREST) which also accounts for solvent effects using an implicit solvation model. All the CREST conformational candidates were then reoptimized at the B3LYP-D3BJ/def2-TZVPD with the PCM of solvent. The good agreements between the experimental IR and VCD spectra and the theoretical simulations provide a conclusive information about their conformational distribution and absolute configurations. The experimental and theoretical IR and VCD spectra of AcO-DHEA in the carbonyl and alkene stretching region showed some discrepancies, and the possible causes related to solvent effects, large amplitude motions and levels of theory used in the modelling were explored in detail. As part of the investigation, additional calculations at the B3LYP-D3BJ/6-31++G (2d,p) and B3LYP-D3BJ/cc-pVTZ levels, as well as some 'mixed' calculations with the double-hybrid functional B2PLYP-D3 were also carried out. The results indicate that the double-hybrid functional is important for predicting the correct IR band pattern in the carbonyl and alkene stretching region.

Physicochemical properties, pharmacokinetics, toxicology and application of nanocarriers.

As a promising delivery nanosystem for drug controlled-release, nanocarriers (NCs) have been investigated widely. Although various studies have concentrated on the preparation and characterization of nanoparticles (NPs), clinical applications are rarely reported, due to the unclear distribution, absorption, metabolism, toxicology processes and drug release mechanism. The clinical application of NCs is therefore still a long way off. This review describes the effects of the properties of NCs (including size, shape, surface properties, porosity, elasticity and so on) on pharmacological and toxicological behaviours in vivo and medical applications. Moreover, this study is intended to help the readers understand the behaviours and mechanisms of NCs and positively face the challenges caused by the variety of complicated and limited processes of NCs in vivo. Importantly, this article provides some strategies for the clinical application of NCs and may provide ideas to enhance the therapeutic efficacy of NCs without increasing the toxicology, by introducing tracing technology, which can be more suitable in contributing to the development of safety and efficacy of NCs and the growth of nanotechnology.

Tuning iron spin states in single-atom nanozymes enables efficient peroxidase mimicking.

The large-scale application of nanozymes remains a significant challenge owing to their unsatisfactory catalytic performances. Featuring a unique electronic structure and coordination environment, single-atom nanozymes provide great opportunities to vividly mimic the specific metal catalytic center of natural enzymes and achieve superior enzyme-like activity. In this study, the spin state engineering of Fe single-atom nanozymes (FeNC) is employed to enhance their peroxidase-like activity. Pd nanoclusters (PdNC) are introduced into FeNC, whose electron-withdrawing properties rearrange the spin electron occupation in Fe(ii) of FeNC-PdNC from low spin to medium spin, facilitating the heterolysis of H2O2 and timely desorption of H2O. The spin-rearranged FeNC-PdNC exhibits greater H2O2 activation activity and rapid reaction kinetics compared to those of FeNC. As a proof of concept, FeNC-PdNC is used in the immunosorbent assay for the colorimetric detection of prostate-specific antigen and achieves an ultralow detection limit of 0.38 pg mL-1. Our spin-state engineering strategy provides a fundamental understanding of the catalytic mechanism of nanozymes and facilitates the design of advanced enzyme mimics.

Ultrasensitive lateral flow immunoassay for staphylococcal enterotoxin B using nanosized fluorescent metal-organic frameworks.

Owing to their outstanding optical properties and superior physical/chemical stability, dye-doped fluorescent nanoparticles (NPs) are growing exponentially as signal labels of immunochromatographic lateral flow immunoassay (LFA) for the detection of various analytes. However, the key challenge in the design of these fluorescent NPs is to confine the fluorophores inside NPs at extreme concentrations, at which dyes tend to self-quench resulting from the formation of non-fluorescent aggregates. Looking for other advantageous nanomaterials, we propose for the first time the use of a nanosized fluorescent metal-organic framework (nanoMOF) in LFA for the detection of staphylococcal enterotoxin B (SEB) as a model analyte. Featured by the chromophore assembly, the nanoMOF exhibited a high dye loading (∼60%) and strong fluorescence intensity, which was due to the reduced self-quenching of dyes in a variety of MOF matrices. The strong green fluorescence intensity of the nanoMOF gives a high contrast against the background of the strips and the sensitivity reflected by photoluminescence was improved by the enhanced antenna effect. Furthermore, due to the high surface area for antibody stemming, the limit of detection (LOD) of the MOF based LFA for SEB detection was as low as 0.025 ng mL-1. The compatibility of the MOF based LFA with dairy samples and its stability under long-term storage conditions were also demonstrated. The integration of a nanoMOF into LFA to detect toxins could inspire the utilization of such nanomaterial-based labels in similar immunochromatographic testing methods to improve their performance.

Association Between Grip Strength and Cognitive Function in US Older Adults of NHANES 2011-2014.

BACKGROUND: The relationship between grip strength and cognitive function remains no consensus in the older adults. OBJECTIVE: To investigate the association of grip strength with cognitive function and cognitive performance in different domains. METHODS: Participants of the present cross-sectional study were from the National Health and Nutrition Examination Survey 2011-2014. Grip strength was measured by grip dynamometer, and combined handgrip strength was the sum of the largest reading from each hand. Four cognitive domains (immediate and delayed memory, language, and attention) were assessed by a set of neuropsychological tests. The subjective cognitive decline was determined via self-report. RESULTS: Among 2,618 participants, combined grip strength was positively associated with scores on global cognitive function and each cognitive domain after controlling for demographic characteristics, lifestyle factors, and history of disease. In addition, compared to those with grip strength < 46.7 kg, participants with grip strength≥75.3 kg had odds ratios of 0.36 (95% CI: 0.21 to 0.63) for poor global cognitive function, 0.66 (95% CI: 0.38 to 1.13) for poor immediate memory, 0.53 (95% CI: 0.30 to 0.93) for poor delayed memory, 0.48 (95% CI: 0.27 to 0.86) for poor language function, 0.20 (95% CI: 0.11 to 0.35) for poor attention, and 0.36 (95% CI: 0.18 to 0.73) for subjective cognitive decline in fully adjusted model. CONCLUSION: Older adults with higher grip strength were significantly associated with better performance on cognition function included global and various domains such as memory, language, attention, and subjective cognitive decline.

Drug resistance and genetic transmission characteristics of HIV-1 CRF59_01B in infected patients in Guangdong Province, China.

OBJECTIVES: To comprehensively analyse the prevalence of drug resistance and the transmission characteristics of CRF59_01B strains in infected patients in Guangdong, China. METHODS: CRF59_01B-infected individuals were recruited, and the HIV-1 pol region was amplified. Drug resistance-associated mutations (DRMs) and antiretroviral susceptibility were examined using the Stanford University HIV Drug Resistance Database to analyse pretreatment drug resistance (PDR) and acquired drug resistance (ADR). Genetic transmission networks were extracted from the maximum likelihood phylogenetic tree with Cluster Picker and visualized with Cytoscape. RESULTS: Two hundred and twenty-five CRF59_01B-infected individuals, comprising 35 ART-experienced and 190 ART-naive individuals, were recruited. No patients harboured PI DRMs, 5.33% (12/225) of the patients harboured NRTI DRMs and 11.11% (25/225) of the patients harboured NNRTI DRMs. The overall prevalence of strains with ADR was 51.43% (18/35), while the prevalence of strains with PDR was 2.63% (5/190). A total of 20 transmission networks, involving 25.78% (58/225) database-derived sequences, were identified. The networks ranged in size from 2 to 10 individuals, of which most (55.00%, 11/20) were made up of two individuals. Among the 225 study subjects, 9.78% (22/225) had 1 link and 16.00% (36/225) had ≥2 links. CONCLUSIONS: The overall prevalence of CRF59_01B strains with ADR among the ART-experienced patients was high. Although the overall prevalence of CRF59_01B strains with PDR among the ART-naive patients was low, it is necessary to remain vigilant regarding some important DRMs.

Optical control of protein delivery and partitioning in the nucleolus.

The nucleolus is a subnuclear membraneless compartment intimately involved in ribosomal RNA synthesis, ribosome biogenesis and stress response. Multiple optogenetic devices have been developed to manipulate nuclear protein import and export, but molecular tools tailored for remote control over selective targeting or partitioning of cargo proteins into subnuclear compartments capable of phase separation are still limited. Here, we report a set of single-component photoinducible nucleolus-targeting tools, designated pNUTs, to enable rapid and reversible nucleoplasm-to-nucleolus shuttling, with the half-lives ranging from milliseconds to minutes. pNUTs allow both global protein infiltration into nucleoli and local delivery of cargoes into the outermost layer of the nucleolus, the granular component. When coupled with the amyotrophic lateral sclerosis (ALS)-associated C9ORF72 proline/arginine-rich dipeptide repeats, pNUTs allow us to photomanipulate poly-proline-arginine nucleolar localization, perturb nucleolar protein nucleophosmin 1 and suppress nascent protein synthesis. pNUTs thus expand the optogenetic toolbox by permitting light-controllable interrogation of nucleolar functions and precise induction of ALS-associated toxicity in cellular models.

Clinical significance and outcomes of bilateral and unilateral recurrent laryngeal nerve lymph node dissection in esophageal squamous cell carcinoma: A large-scale retrospective cohort study.

BACKGROUND: The survival benefits of recurrent laryngeal nerve lymph node dissection (RLNLD) in esophageal squamous cell carcinoma (ESCC) are still under debate, and the prognostic value of unilateral RLNLD has been rarely studied. Therefore, the aim of the present study was to investigate the clinical significance and outcomes of RLNLD in ESCC in a large-scale cohort study, to shed light on the outcomes of unilateral RLNLD, and to identify the factors that affect the prognostic outcome of RLNLD. METHODS: We retrospectively reviewed 1153 patients with thoracic ESCC who underwent right thoracotomy with lymphadenectomy. The impact of RLNLD on disease-free survival (DFS) and overall survival (OS) was estimated using the Kaplan-Meier method and Cox proportional hazard models. Inverse probability of treatment weighting (IPTW) was performed to adjust for differences in baseline variables in pairwise comparisons. Subgroup analysis of survival and postoperative complications was conducted for selective RLNLD. RESULTS: RLN lymph node (LN) metastasis was independently associated with tumor location and most other LN station metastases. RLNLD was an independent prognostic factor for DFS and OS. Both patients who underwent unilateral and bilateral RLNLD had significantly better DFS and OS than the non-RLNLD patients. Furthermore, pairwise comparisons with IPTW confirmed these results, and we found that patients who underwent bilateral RLNLD had better survival than those who underwent unilateral RLNLD. However, subgroup analysis showed that there was no survival benefit and higher morbidity after bilateral RLNLD for patients with cancer in the lower thoracic esophagus, and elderly and female patients. CONCLUSION: RLN LN metastasis is very frequent in ESCC, and both unilateral and bilateral RLNLD have considerable survival benefits. Selective RLNLD with better survival and lower morbidity was recommend for some defined subgroups.