Mechanism of Musashi2 affecting radiosensitivity of lung cancer by modulating DNA damage repair.

Identifying new targets for overcoming radioresistance is crucial for improving the efficacy of lung cancer radiotherapy, given that tumor cell resistance is a leading cause of treatment failure. Recent research has spotlighted the significance of Musashi2 (MSI2) in cancer biology. In this study, we first demonstrated that MSI2 plays a key function in regulating the radiosensitivity of lung cancer. The expression of MSI2 is negatively correlated with overall survival in cancer patients, and the knockdown of MSI2 inhibits tumorigenesis and increases radiosensitivity of lung cancer cells. Cellular radiosensitivity, which is closely linked to DNA damage, is influenced by MSI2 interaction with ataxia telangiectasia mutated and Rad3-related kinase (ATR) and checkpoint kinase 1 (CHK1) post-irradiation; moreover, knockdown of MSI2 inhibits the ATR-mediated DNA damage response pathway. RNA-binding motif protein 17 (RBM17), which is implicated in DNA damage repair, exhibits increased interaction with MSI2 post-irradiation. We found that knockdown of RBM17 disrupted the interaction between MSI2 and ATR post-irradiation and increased the radiosensitivity of lung cancer cells. Furthermore, we revealed the potential mechanism of MSI2 recruitment into the nucleus with the assistance of RBM17 to activate ATR to promote radioresistance. This study provides novel insights into the potential application of MSI2 as a new target in lung cancer radiotherapy.

Effect of fascia iliaca compartment block combined with ropivacaine on post-operative outcomes in elderly patients undergoing hip fracture repair.

Objective: To explore the effect of fascia iliaca compartment block (FICB) in combination with ropivacaine on post-operative outcomes in elderly patients undergoing hip fracture (HF) repair. Methods: Retrospective analysis included data of 111 elderly patients who underwent HF surgery with FICB in Changxing County People's Hospital from October 2018 to October 2022. Observation group received 0.25% ropivacaine combined with FICB (n=52), and the control group was administered an intravenous injection of parecoxib sodium (n=59). Baseline characteristics of the patients, and indexes such as mean arterial pressure (MAP), heart rate (HR), and visual analogue scale (VAS) pain scores, were collected at one-, six-, 12- and 24-hours past surgery, both at rest and after passive movement. Results: VAS scores, MAP and HR at rest and after a passive movement in both groups were comparable before the surgery. VAS sores were significantly lower in the observation group at one-, six-, 12- and 24-hours after the surgery (P<0.05). Postoperative MAP in the observation group (80.83 ± 8.31) was significantly lower compared to the control group (95.29 ± 8.45 (t = -9.0659, p < 0.0001). Similarly, HR of the observation group was significantly lower one-hour post-surgery both at rest (t = -2.0468, p = 0.0431) and after passive movement (t = -6.0625, p < 0.001), and at all subsequent time intervals after the passive movement (P<0.05). Conclusions: Ropivacaine combined with FICB was associated with improved post-operative outcomes such as lower post-surgery VAS scores, MAP and HR compared to the intravenous injection of parecoxib sodium.

Substrate-free dissolving microneedles with barbed shape to increase adhesion and drug-delivery efficiency to skin.

Microneedle drug delivery has recently emerged as a clinical method, and dissolving microneedles (DMNs) offer exclusive simplicity and efficiency, compared to the other kinds of microneedles. The tips of most currently available DMNs are cone/house-shaped to result in a lower penetration force. Penetration of the needle tips into the skin relies mainly on the back tape or external pressure, and their adhesion to the skin is relatively low. In addition, only the drug in the part of tips that are pierced into the dermis can be dissolved, resulting in drug waste. Inspired from the barbed structure of the honeybee stinger, we reported substrate-free DMNs with a barbed structure by a dual-molding process, which is suitable for mass production. Those DMNs showed 3-fold greater adhesion force between the needle tips and the skin, better dissolution and deeper penetration than house-shaped DMNs in vivo under the same conditions. For the in situ treatment of psoriasis in mice, the barbed DMNs required only the half dose of house-shaped DMNs to achieve similar efficacy.

Comparison of analgesic effects between erector spinae and transversus abdominis plane blocks in patients undergoing laparoscopic cholecystectomy.

Objective: To compare the analgesic effects and incidence of postoperative adverse events after the erector spine plane (ESP) and transversus abdominis plane (TAP) blocks in patients undergoing laparoscopic cholecystectomy (LC). Methods: In this retrospective observational study, clinical data of 103 patients undergoing LC in Changxing County People's Hospital from October 2020 to October 2022 were retrospectively reviewed, and the patients were divided into ESP-group (n=56) and TAP-group (n=57) based on the block method. The operation time, the change of visual analogue scale (VAS) score of static (sVAS) and dynamic (dVAS) pain after operation, the patient-controlled dose, and the remedial analgesic dose at 24 hours after the operation were compared between the two groups. The occurrence of postoperative adverse reactions in both groups was recorded. Results: The dVAS scores of the ESP-group at one hour, three hours, six hours, and 12 hours after the operation were lower than those of the TAP-group (P<0.05). The patient-controlled dose and remedial analgesia dose of the ESP-group were significantly lower than those of the TAP-group (P<0.05). There was no difference in the incidence of postoperative nausea and vomiting between the two groups (P>0.05). Conclusions: ESP block and TAP block in LC patients have similar operation time and incidence of postoperative adverse events such as nausea and vomiting. However, short-term postoperative analgesic effect of ESP block is superior to TAP and requires a lower dose of analgesia.

Wireless facial biosensing system for monitoring facial palsy with flexible microneedle electrode arrays.

Facial palsy (FP) profoundly influences interpersonal communication and emotional expression, necessitating precise diagnostic and monitoring tools for optimal care. However, current electromyography (EMG) systems are limited by their bulky nature, complex setups, and dependence on skilled technicians. Here we report an innovative biosensing approach that utilizes a PEDOT:PSS-modified flexible microneedle electrode array (P-FMNEA) to overcome the limitations of existing EMG devices. Supple system-level mechanics ensure excellent conformality to the facial curvilinear regions, enabling the detection of targeted muscular ensemble movements for facial paralysis assessment. Moreover, our apparatus adeptly captures each electrical impulse in response to real-time direct nerve stimulation during neurosurgical procedures. The wireless conveyance of EMG signals to medical facilities via a server augments access to patient follow-up evaluation data, fostering prompt treatment suggestions and enabling the access of multiple facial EMG datasets during typical 6-month follow-ups. Furthermore, the device's soft mechanics alleviate issues of spatial intricacy, diminish pain, and minimize soft tissue hematomas associated with traditional needle electrode positioning. This groundbreaking biosensing strategy has the potential to transform FP management by providing an efficient, user-friendly, and less invasive alternative to the prevailing EMG devices. This pioneering technology enables more informed decision-making in FP-management and therapeutic intervention.

Astaxanthin protects the radiation-induced lung injury in C57BL/6 female mice.

Radiation-induced lung injury (RILI) is one of the common complications of radiotherapy for chest tumors and nuclear radiation accidents. The excessive reactive oxygen species induced by radiation is the main mediator. So far, the effective prevention and treatment for RILI are still lacking. Astaxanthin is a carotenoid that belongs to red natural lutein family and is commonly found in Marine organisms such as shrimp, oysters and salmon. It has been confirmed that astaxanthin has strong antioxidant and anti-inflammatory properties, therefore we speculated that astaxanthin may be a potential treatment for RILI. First, with a mice model of RILI, the protected effects of astaxanthin were observed. Furthermore, the experiments in vitro were performed by detecting apoptosis. As a result, astaxanthin protects the RILI, inhibits the process of pulmonary fibrosis, and reduces the elevation of inflammatory factors. The experiments in vitro demonstrated that astaxanthin could reduce radiation-induced apoptosis and especially inhibit activation of apoptosis pathway. In conclusion, astaxanthin could protect RILI of mice, which is mediated by inhibiting activation of apoptosis pathway.

Experimental Study of Bridge Expansion Joint Damage Based on Natural Frequency.

In this paper, three studies on modal bridge expansion joints were conducted through experiments. The advantages and disadvantages of acceleration and fiber optic strain sensors in the tested modal expansion joints were compared. Secondly, the variation in the natural frequency of the modal bridge expansion joints at different concrete curing periods was investigated. Finally, the effect of damage on natural frequency in different parts (the center beam, the support bar, and concrete in the anchorage zone) of the modal bridge expansion joint was analyzed. For this purpose, three specimens were cast, each with six damage states. Manual methods damaged the specimens. An impact hammer was used to excite the corresponding parts of the different components. The results showed that the acceleration sensor is optimal for the modal bridge expansion joint test. The specimen's natural frequency increased with the curing time's growth. The natural frequency increased by 10 Hz from day 3 to day 28 of curing. With the gradual increase in damage, the natural frequencies of the center beam and support bar showed a gradual decreasing trend. The damage to the concrete in the anchorage zone caused less significant changes in the natural frequency, but the overall natural frequency still had a decreasing trend. The sensitivity of each frequency to the damage was different in different parts.

Customized flexible hollow microneedles for psoriasis treatment with reduced-dose drug.

Microneedles, especially hollow microneedles (HMNs), play an important role in drug delivery, but most of the current HMNs are manufactured based on silicon microfabrication (lithography, etching, etc.), which are slightly conservative due to the lack of low-cost, batch-scale and customized preparation approach, especially for the HMNs with flexible substrate. For the first time, we propose the use of a high-precision 3D printed master mold followed by a dual-molding process for the preparation of HMNs with different shapes, heights, and inner and outer diameters to satisfy different drug delivery needs. The 3D printed master mold and negative mold can be reused, thereby significantly reducing the cost. HMNs are based on biocompatible materials, such as heat-curing polymers or light-curing resins. The thickness and rigidity/flexibility characteristics of the substrate can be customized for different applications. The drug delivery efficiency of the fabricated HMNs was verified by the in situ treatment of psoriasis on the backs of mice, which required only a 0.1-fold oral dose to achieve similar efficacy, and the associated side effects and drug toxicity were reduced. Thus, this dual-molding process can reinvigorate HMNs development.

TLR4 Agonist MPLA Ameliorates Heavy-Ion Radiation Damage via Regulating DNA Damage Repair and Apoptosis.

Heavy-ion radiation received during radiotherapy as well as the heavy-ion radiation received during space flight are equally considered harmful. Our previous study showed that TLR4 low toxic agonist, monophosphoryl lipid A (MPLA), alleviated radiation injury resulting from exposure to low-LET radiation. However, the role and mechanism of MPLA in heavy-ion-radiation injury are unclear. This study aimed to investigate the role of MPLA on radiation damage. Our data showed that MPLA treatment alleviated the heavy-ion-induced damage to microstructure and the spleen and testis indexes. The number of karyocytes in the bone marrow from the MPLA-treated group was higher than that in the irradiated group. Meanwhile, western blotting analysis of intestine proteins showed that pro-apoptotic proteins (cleaved-caspase3 and Bax) were downregulated while anti-apoptotic proteins (Bcl-2) were upregulated in the MPLA-treated group. Our in vitro study demonstrated that MPLA significantly improved cell proliferation and inhibited cell apoptosis after irradiation. Moreover, immunofluorescence staining and quantification of nucleic γ-H2AX and 53BP1 foci also suggested that MPLA significantly attenuated cellular DNA damage repair. Collectively, the above evidence supports the potential ability of MPLA to protect against heavy-ion-radiation injury by inhibiting apoptosis and alleviating DNA damage in vivo and vitro, which could be a promising medical countermeasure for the prevention of heavy-ion-radiation injury.

Sound Damage Detection of Bridge Expansion Joints Using a Support Vector Data Description.

A novel method is proposed for the damage identification of modal bridge expansion joints (MBEJs) based on sound signals. Two modal bridge expansion joint specimens were fabricated to simulate healthy and damaged states. A microphone was used to collect the impact signals from different specimens. The wavelet packet energy ratio of the sound signal was used to identify the difference in specimen state. Firstly, the wavelet packet energy ratio was used to establish the feature vectors, which were reduced dimensionality using principal component analysis. Subsequently, a support vector data description model was established to detect the difference in the signals. The identification effects of three parameter optimization methods (particle swarm optimization, genetic algorithm optimization, and Bayesian optimization) were compared. The results showed that the wavelet packet energy ratio of sound signals could effectively distinguish the state of the support bar. The support vector data description of Bayesian optimization worked best, and the proposed method could successfully detect damage to the support bar of MBEJs with an accuracy of 99%.

Recent Progress in Wearable Brain-Computer Interface (BCI) Devices Based on Electroencephalogram (EEG) for Medical Applications: A Review.

Importance: Brain-computer interface (BCI) decodes and converts brain signals into machine instructions to interoperate with the external world. However, limited by the implantation risks of invasive BCIs and the operational complexity of conventional noninvasive BCIs, applications of BCIs are mainly used in laboratory or clinical environments, which are not conducive to the daily use of BCI devices. With the increasing demand for intelligent medical care, the development of wearable BCI systems is necessary. Highlights: Based on the scalp-electroencephalogram (EEG), forehead-EEG, and ear-EEG, the state-of-the-art wearable BCI devices for disease management and patient assistance are reviewed. This paper focuses on the EEG acquisition equipment of the novel wearable BCI devices and summarizes the development direction of wearable EEG-based BCI devices. Conclusions: BCI devices play an essential role in the medical field. This review briefly summarizes novel wearable EEG-based BCIs applied in the medical field and the latest progress in related technologies, emphasizing its potential to help doctors, patients, and caregivers better understand and utilize BCI devices.

Ganciclovir-induced mutations are present in a diverse spectrum of post-transplant malignancies.

BACKGROUND: Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. METHODS: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCVsig) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. RESULTS: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCVsig were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCVsig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCVsig in cell lines and organoids. CONCLUSIONS: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.

A Low-Cost Flexible Perforated Respiratory Sensor Based on Platinum for Continuous Respiratory Monitoring.

Monitoring sleep conditions is of importance for sleep quality evaluation and sleep disease diagnosis. Accurate respiration detection provides key information about sleep conditions. Here, we propose a perforated temperature sensor that can be worn below the nasal cavity to monitor breath. The sensing system consists of two perforated temperature sensors, signal conditioning circuits, a transmission module, and a supporting analysis algorithm. The perforated structure effectively enhances the sensitivity of the system and shortens the response time. The sensor's response time is 0.07 s in air and sensitivity is 1.4‱°C-1. The device can achieve a monitoring respiratory temperature range between normal room temperature and 40 °C. The simple and standard micromachining process ensures low cost and high reproducibility. We achieved the monitoring of different breathing patterns, such as normal breathing, panting, and apnea, which can be applied to sleep breath monitoring and exercise information recording.

High-Performance Flexible Microneedle Array as a Low-Impedance Surface Biopotential Dry Electrode for Wearable Electrophysiological Recording and Polysomnography.

HIGHLIGHTS: Polyimide-based flexible microneedle array (PI-MNA) electrodes realize high electrical/mechanical performance and are compatible with wearable wireless recording systems. The normalized electrode-skin interface impedance (EII) of the PI-MNA electrodes reaches 0.98 kΩ cm2 at 1 kHz and 1.50 kΩ cm2 at 10 Hz, approximately 1/250 of clinical standard electrodes. This is the first report on the clinical study of microneedle electrodes. The PI-MNA electrodes are applied to clinical long-term continuous monitoring for polysomnography. Microneedle array (MNA) electrodes are an effective solution to achieve high-quality surface biopotential recording without the coordination of conductive gel and are thus very suitable for long-term wearable applications. Existing schemes are limited by flexibility, biosafety, and manufacturing costs, which create large barriers for wider applications. Here, we present a novel flexible MNA electrode that can simultaneously achieve flexibility of the substrate to fit a curved body surface, robustness of microneedles to penetrate the skin without fracture, and a simplified process to allow mass production. The compatibility with wearable wireless systems and the short preparation time of the electrodes significantly improves the comfort and convenience of electrophysiological recording. The normalized electrode-skin contact impedance reaches 0.98 kΩ cm2 at 1 kHz and 1.50 kΩ cm2 at 10 Hz, a record low value compared to previous reports and approximately 1/250 of the standard electrodes. The morphology, biosafety, and electrical/mechanical properties are fully characterized, and wearable recordings with a high signal-to-noise ratio and low motion artifacts are realized. The first reported clinical study of microneedle electrodes for surface electrophysiological monitoring was conducted in tens of healthy and sleep-disordered subjects with 44 nights of recording (over 8 h per night), providing substantial evidence that the electrodes can be leveraged to substitute for clinical standard electrodes.

The novel male meiosis recombination regulator coordinates the progression of meiosis prophase I.

Meiosis is a specialized cell division for producing haploid gametes in sexually reproducing organisms. In this study, we have independently identified a novel meiosis protein male meiosis recombination regulator (MAMERR)/4930432K21Rik and showed that it is indispensable for meiosis prophase I progression in male mice. Using super-resolution structured illumination microscopy, we found that MAMERR functions at the same double-strand breaks as the replication protein A and meiosis-specific with OB domains/spermatogenesis associated 22 complex. We generated a Mamerr-deficient mouse model by deleting exons 3-6 and found that most of Mamerr-/- spermatocytes were arrested at pachynema and failed to progress to diplonema, although they exhibited almost intact synapsis and progression to the pachytene stage along with XY body formation. Further mechanistic studies revealed that the recruitment of DMC1/RAD51 and heat shock factor 2-binding protein in Mamerr-/- spermatocytes was only mildly impaired with a partial reduction in double-strand break repair, whereas a substantial reduction in ubiquitination on the autosomal axes and on the XY body appeared as a major phenotype in Mamerr-/- spermatocytes. We propose that MAMERR may participate in meiotic prophase I progression by regulating the ubiquitination of key meiotic proteins on autosomes and XY chromosomes, and in the absence of MAMERR, the repressed ubiquitination of key meiotic proteins leads to pachytene arrest and cell death.

Screen identifies DYRK1B network as mediator of transcription repression on damaged chromatin.

DNA double-strand breaks (DSBs) trigger transient pausing of nearby transcription, an emerging ATM-dependent response that suppresses chromosomal instability. We screened a chemical library designed to target the human kinome for new activities that mediate gene silencing on DSB-flanking chromatin, and have uncovered the DYRK1B kinase as an early respondent to DNA damage. We showed that DYRK1B is swiftly and transiently recruited to laser-microirradiated sites, and that genetic inactivation of DYRK1B or its kinase activity attenuated DSB-induced gene silencing and led to compromised DNA repair. Notably, global transcription shutdown alleviated DNA repair defects associated with DYRK1B loss, suggesting that DYRK1B is strictly required for DSB repair on active chromatin. We also found that DYRK1B mediates transcription silencing in part via phosphorylating and enforcing DSB accumulation of the histone methyltransferase EHMT2. Together, our findings unveil the DYRK1B signaling network as a key branch of mammalian DNA damage response circuitries, and establish the DYRK1B-EHMT2 axis as an effector that coordinates DSB repair on transcribed chromatin.

Nucleolar residence of the seckel syndrome protein TRAIP is coupled to ribosomal DNA transcription.

The RING finger protein TRAIP protects genome integrity and its mutation causes Seckel syndrome. TRAIP encodes a nucleolar protein that migrates to UV-induced DNA lesions via a direct interaction with the DNA replication clamp PCNA. Thus far, mechanistically how UV mobilizes TRAIP from the nucleoli remains unknown. We found that PCNA binding is dispensable for the nucleolus-nucleoplasm shuttling of TRAIP following cell exposure to UV irradiation, and that its redistribution did not rely on the master DNA damage kinases ATM and ATR. Interestingly, I-PpoI-induced ribosomal DNA damage led to TRAIP exclusion from the nucleoli, raising the possibility that active ribosomal DNA transcription may underlie TRAIP retention in the nuclear sub-compartments. Accordingly, chemical inhibition of RNA polymerase I activity led to TRAIP diffusion into the nucleoplasm, and was coupled with marked reduction of DNA/RNA hybrids in the nucleoli, suggesting that TRAIP may be sequestered via binding to nucleic acid structures in the nucleoli. Consistently, cell pre-treatment with DNase/RNase effectively released TRAIP from the nucleoli. Taken together, our study defines a bipartite mechanism that drives TRAIP trafficking in response to UV damage, and highlights the nucleolus as a stress sensor that contributes to orchestrating DNA damage responses.

RNF169 limits 53BP1 deposition at DSBs to stimulate single-strand annealing repair.

Unrestrained 53BP1 activity at DNA double-strand breaks (DSBs) hampers DNA end resection and upsets DSB repair pathway choice. RNF169 acts as a molecular rheostat to limit 53BP1 deposition at DSBs, but how this fine balance translates to DSB repair control remains undefined. In striking contrast to 53BP1, ChIP analyses of AsiSI-induced DSBs unveiled that RNF169 exhibits robust accumulation at DNA end-proximal regions and preferentially targets resected, RPA-bound DSBs. Accordingly, we found that RNF169 promotes CtIP-dependent DSB resection and favors homology-mediated DSB repair, and further showed that RNF169 dose-dependently stimulates single-strand annealing repair, in part, by alleviating the 53BP1-imposed barrier to DSB end resection. Our results highlight the interplay of RNF169 with 53BP1 in fine-tuning choice of DSB repair pathways.