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A hypoglossal nerve stimulator (HGNS) is an invasive device that is used to treat obstructive sleep apnea (OSA) through electrical stimulation. The conventional implantable HGNS device consists of a stimuli generator, a breathing sensor, and electrodes connected to the hypoglossal nerve via leads. However, this implant is bulky and causes significant trauma. In this paper, we propose a minimally invasive HGNS based on an electrocardiogram (ECG) sensor and wireless power transfer (WPT), consisting of a wearable breathing monitor and an implantable stimulator. The breathing external monitor utilizes an ECG sensor to identify abnormal breathing patterns associated with OSA with 88.68% accuracy, achieved through the utilization of a convolutional neural network (CNN) algorithm. With a skin thickness of 5 mm and a receiving coil diameter of 9 mm, the power conversion efficiency was measured as 31.8%. The implantable device, on the other hand, is composed of a front-end CMOS power management module (PMM), a binary-phase-shift-keying (BPSK)-based data demodulator, and a bipolar biphasic current stimuli generator. The PMM, with a silicon area of 0.06 mm2 (excluding PADs), demonstrated a power conversion efficiency of 77.5% when operating at a receiving frequency of 2 MHz. Furthermore, it offers three-voltage options (1.2 V, 1.8 V, and 3.1 V). Within the data receiver component, a low-power BPSK demodulator was ingeniously incorporated, consuming only 42 μW when supplied with a voltage of 0.7 V. The performance was achieved through the implementation of the self-biased phase-locked-loop (PLL) technique. The stimuli generator delivers biphasic constant currents, providing a 5 bit programmable range spanning from 0 to 2.4 mA. The functionality of the proposed ECG- and WPT-based HGNS was validated, representing a highly promising solution for the effective management of OSA, all while minimizing the trauma and space requirements.

In transferable black-box attacks, adversarial samples remain adversarial across multiple models and are more likely to attack unknown models. From this view, acquiring and exploiting multiple models is the key to improving transferability. For exploiting multiple models, existing approaches concentrate on differences among models but ignore the underlying complex dependencies. This exacerbates the issue of unbalanced and inadequate attacks on multiple models. To this problem, this paper proposes a novel approach, called Relational Graph Ensemble Attack (RGEA), to exploit the dependencies among multiple models. Specifically, we redefine the multi-model ensemble attack as a multi-objective optimization and create a sub-optimization problem to compute the optimal attack direction, but there are serious time-consuming problems. For this time-consuming problem, we define the vector representation of the model, extract the dependency matrix, and then equivalently simplify the sub-optimization problem by utilizing the dependency matrix. Finaly, we theoretically extend to investigate the connection between RGEA and the traditional multiple gradient descent algorithm (MGDA). Notably, combining RGEA further enhances the transferability of existing gradient-based attacks. The experiments using ten normal training models and ten defensive models on the labeled face in the wild (LFW) dataset demonstrate that RGEA improves the success rate of white-box attacks and further boosts the transferability of black-box attacks.

Abstract SIRT2, an NAD+-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and function in various malignancies. Using murine allograft melanoma models, our results suggest increased systemic expression of SIRT2 promotes tumor progression. In this study, SIRT2-overexpressing mice exhibited enhanced tumor growth and larger tumor volumes compared to their wild-type littermates. Mechanistically, systemic overexpression of SIRT2 reduces the number of tumor-infiltrating natural killer (NK) cells and suppresses NK cell function and proliferation within the tumor microenvironment (TME). Furthermore, despite the enhancing effect of NK cell depletion on tumor volume and growth rate in wild-type littermate mice, this effect was diminished in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increases NK cell tumor infiltration and suppresses allograft melanoma tumor growth. The findings of this study identify a dynamic functional interaction between systemic SIRT2 and NK cell activity, which controls melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could present a new opportunity to mediate immunotherapy response and resistance.

Abstract Poly(ADP-ribose) polymerase (PARP) inhibitors represent one of the successful novel approaches to targeted cancer treatment. Indeed, the US Food and Drug Administration (FDA) has recently approved PARP inhibitors for the treatment of breast and ovarian cancers. Despite the proven efficacy of these agents, certain challenges remain with their use. Among the most important are primary and secondary resistance. Here, we review the mechanism of action of PARP inhibitors and their ability to exploit certain inherent deficiencies among malignant cells to improve cell killing, with a focus on deficiencies in homologous recombination among cells with BRCA1 and BRCA2 mutations. Moreover, we discuss the different mechanisms of resistance including development of secondary resistance and strategies to overcome them. Finally, we discuss the limitations of novel therapeutic interventions and possible future studies to exploit biochemical pathways in order to improve therapeutic efficacy of PARP inhibitors.

Abstract Background Chemotherapy-induced peripheral neuropathy is not only one of the most common causes of dose reduction or discontinuation of cancer treatment, but it can also permanently decrease the quality of life of cancer patients and survivors. Notably, Sirt2 protects many organs from various injuries, including diabetic peripheral neuropathy. As demonstrated previously by our laboratory and others, the overexpression of Sirt2 can improve cisplatin-induced neuropathy, although the mechanism is still unclear. Results In this study, the underlying mechanism by which Sirt2 protects neurons from cisplatin-induced injury was explored using the RNAseq technique in cultured rodent neurons. Sirt2 status was modified by genetic knockout (Sirt2/KO) and was then reconstituted in Sirt2/KO cells (Sirt2/Res). We observed 323 upregulated genes and 277 downregulated genes in Sirt2-expressing cells (Sirt2/Res) compared to Sirt2-deficient cells (Sirt2/KO). Pathway analysis suggested that Sirt2 may affect several pathways, such as MAPK, TNF, and cytokine–cytokine interaction. Furthermore, cisplatin-induced changes to the transcriptome are strongly associated with Sirt2 status. Cisplatin induced distinctive transcriptome changes for 227 genes in Sirt2-expressing cells and for 783 genes in Sirt2-deficient cells, while changes in only 138 of these genes were independent of Sirt2 status. Interestingly, changes in the p53 pathway, ECM–receptor interactions, and cytokine–cytokine receptor interactions were induced by cisplatin only in Sirt2-deficient cells. Conclusions This study demonstrated that Sirt2 regulates the transcriptome in cultured rodent neuronal cells. Furthermore, Sirt2-associated transcriptome regulation may be an important mechanism underlying the role of Sirt2 in organ protection, such as in cisplatin-induced neuronal injury. Sirt2 may be a potential target for the prevention and treatment of chemotherapy-induced neuropathy.

Stroke is the leading cause of death and disability after ischemic heart disease. However, there is lacking a non-invasive long-time monitoring technique for stroke diagnosis and therapy. The photoacoustic imaging approach reconstructs images of an object based on the energy excitation by optical absorption and its conversion to acoustic waves, due to corresponding thermoelastic expansion, which has optical resolution and acoustic propagation. This emerging functional imaging method is a non-invasive technique. Due to its precision, this method is particularly attractive for stroke monitoring purpose. In this paper, we review the achievements of this technology and its applications on stroke, as well as the development status in both animal and human applications. Also, various photoacoustic systems and multi-modality photoacoustic imaging are introduced as for potential clinical applications. Finally, the challenges of photoacoustic imaging for monitoring stroke are discussed.

The recent COVID-19 pandemic has caused tremendous damage to the social economy and people’s health. Some major issues fighting COVID-19 include early and accurate diagnosis and the shortage of ventilator machines for critical patients. In this manuscript, we describe a novel solution to deal with COVID-19: portable biosensing and wearable photoacoustic imaging for early and accurate diagnosis of infection and magnetic neuromodulation or minimally invasive electrical stimulation to replace traditional ventilation. The solution is a closed-loop system in that the three modules are integrated together and form a loop to cover all-phase strategies for fighting COVID-19. The proposed technique can guarantee ubiquitous and onsite detection, and an electrical hypoglossal stimulator can be more effective in helping severe patients and reducing complications caused by ventilators.

Obstructive sleep apnea (OSA), a common sleep disorder disease, affects millions of people. Without appropriate treatment, this disease can provoke several health-related risks including stroke and sudden death. A variety of treatments have been introduced to relieve OSA. The main present clinical treatments and undertaken research activities to improve the success rate of OSA were covered in this paper. Additionally, guidelines on choosing a suitable treatment based on scientific evidence and objective comparison were provided. This review paper specifically elaborated the clinically offered managements as well as the research activities to better treat OSA. We analyzed the methodology of each diagnostic and treatment method, the success rate, and the economic burden on the world. This review paper provided an evidence-based comparison of each treatment to guide patients and physicians, but there are some limitations that would affect the comparison result. Future research should consider the consistent follow-up period and a sufficient number of samples. With the development of implantable medical devices, hypoglossal nerve stimulation systems will be designed to be smart and miniature and one of the potential upcoming research topics. The transcutaneous electrical stimulation as a non-invasive potential treatment would be further investigated in a clinical setting. Meanwhile, no treatment can cure OSA due to the complicated etiology. To maximize the treatment success of OSA, a multidisciplinary and integrated management would be considered in the future.

Although tumor metastases remain significant drivers of mortality, the genetic factors that increase the risks of metastases are not fully identified. Interleukin 6 (IL-6) has emerged as an important factor in breast cancer progression with IL-6 single nucleotide polymorphism (SNP) variants shown to affect survival. We hypothesized that SNPs of the IL-6 promoter at rs1800795 in breast cancer patients are associated with distant metastases.We performed an initial case-control study using Vanderbilt University Medical Center's BioVU, a genomic biobank linked to de-identified electronic medical records in the Synthetic Derivative database, to identify germline SNPs that may predict the development of metastatic disease to any site from any solid tumor including breast cancer. We identified a SNP in IL-6: rs1800795 to be of significance and evaluated this finding using a separate, matched-pair cohort of breast cancer patients with and without metastases from The Ohio State University Wexner Medical Center.The initial study suggested that GG relative to CG at rs1800795 (OR 1.52; 95% CI 1.14-2.02; p = 0.004) was significantly associated with the development of metastases. This association was also observed in the Ohio State University cohort (OR 2.23; 95% CI 1.06-4.71; p = 0.001). There were no significant relationships between rs1800795 status and any patient or tumor characteristics, including estrogen receptor status.These findings suggest that GG SNP at IL-6: rs1800795 may indicate an increased risk of metastasis of primary breast cancer. Further studies in larger population sets are warranted as advanced screening and prophylactic intervention might be employed in GG carriers.

Replication fork stalling and collapse is a major source of genome instability leading to neoplastic transformation or cell death. Such stressed replication forks can be conservatively repaired and restarted using homologous recombination (HR) or non-conservatively repaired using micro-homology mediated end joining (MMEJ). HR repair of stressed forks is initiated by 5' end resection near the fork junction, which permits 3' single strand invasion of a homologous template for fork restart. This 5' end resection also prevents classical non-homologous end-joining (cNHEJ), a competing pathway for DNA double-strand break (DSB) repair. Unopposed NHEJ can cause genome instability during replication stress by abnormally fusing free double strand ends that occur as unstable replication fork repair intermediates. We show here that the previously uncharacterized Exonuclease/Endonuclease/Phosphatase Domain-1 (EEPD1) protein is required for initiating repair and restart of stalled forks. EEPD1 is recruited to stalled forks, enhances 5' DNA end resection, and promotes restart of stalled forks. Interestingly, EEPD1 directs DSB repair away from cNHEJ, and also away from MMEJ, which requires limited end resection for initiation. EEPD1 is also required for proper ATR and CHK1 phosphorylation, and formation of gamma-H2AX, RAD51 and phospho-RPA32 foci. Consistent with a direct role in stalled replication fork cleavage, EEPD1 is a 5' overhang nuclease in an obligate complex with the end resection nuclease Exo1 and BLM. EEPD1 depletion causes nuclear and cytogenetic defects, which are made worse by replication stress. Depleting 53BP1, which slows cNHEJ, fully rescues the nuclear and cytogenetic abnormalities seen with EEPD1 depletion. These data demonstrate that genome stability during replication stress is maintained by EEPD1, which initiates HR and inhibits cNHEJ and MMEJ.

53BP1 regulates DNA double-strand break (DSB) repair. In functional assays for specific DSB repair pathways, we found that 53BP1 was important in the conservative non-homologous end-joining (C-NHEJ) pathway, and this activity was dependent upon RNF8 and RNF168. We observed that 53BP1 protein was diffusely abundant in nuclei, and upon ionizing radiation, 53BP1 was everywhere degraded except at DNA damage sites. Depletion of RNF8 or RNF168 blocked the degradation of the diffusely localized nuclear 53BP1, and ionizing radiation induced foci (IRIF) did not form. Furthermore, when 53BP1 degradation was inhibited, a subset of 53BP1 was bound to DNA damage sites but bulk, unbound 53BP1 remained in the nucleoplasm, and localization of its downstream effector RIF1 at DSBs was abolished. Our data suggest a novel mechanism for responding to DSB that upon ionizing radiation, 53BP1 was divided into two populations, ensuring functional DSB repair: damage site-bound 53BP1 whose binding signal is known to be generated by RNF8 and RNF168; and unbound bulk 53BP1 whose ensuing degradation is regulated by RNF8 and RNF168.

Abstract Background There has been a significant surge in animal studies of stem cell-derived extracellular vesicles (EVs) therapy for the treatment of premature ovarian failure (POF) but its efficacy remains unknown and a comprehensive and up-to-date meta-analysis is lacking. Before clinical translation, it is crucial to thoroughly understand the overall impact of stem cell-derived EVs on POF. Methods PubMed, EMBASE, Cochrane Library, Web of Science were searched up to February 18, 2024. The risk of bias was evaluated according to Cochrane Handbook criteria, while quality of evidence was assessed using the SYRCLE system. The PRISMA guidance was followed. Trial sequential analysis was conducted to assess outcomes, and sensitivity analysis and publication bias analysis were performed using Stata 14. Results Data from 25 studies involving 339 animals were extracted and analyzed. The analysis revealed significant findings: stem cell-derived EVs increase ovary weight (SMD = 3.88; 95% CI: 2.50 ~ 5.25; P