Photoacoustic: A Versatile Nongenetic Method for High-Precision Neuromodulation.

High-precision neuromodulation plays a pivotal role in elucidating fundamental principles of neuroscience and treating specific neurological disorders. Optical neuromodulation, enabled by spatial resolution defined by the diffraction limit at the submicrometer scale, is a general strategy to achieve such precision. Optogenetics offers single-neuron spatial resolution with cellular specificity, whereas the requirement of genetic transfection hinders its clinical application. Direct photothermal modulation, an alternative nongenetic optical approach, often associates a large temperature increase with the risk of thermal damage to surrounding tissues.Photoacoustic (also called optoacoustic) neural stimulation is an emerging technology for neural stimulation with the following key features demonstrated. First, the photoacoustic approach demonstrated high efficacy without the need for genetic modification. The generated pulsed ultrasound upon ns laser pulses with energy ranging from a few µJ to tens of µJ is sufficient to activate wild-type neurons. Second, the photoacoustic approach provides sub-100-µm spatial precision. It overcomes the fundamental wave diffraction limit of ultrasound by harnessing the localized ultrasound field generated through light absorption. A spatial precision of 400 µm has been achieved in rodent brains using a fiber-based photoacoustic emitter. Single-cell stimulation in neuronal cultures in vitro and in brain slices ex vivo is achieved using tapered fiber-based photoacoustic emitters. This precision is 10 to 100 times better than that for piezo-based low-frequency ultrasound and is essential to pinpoint a specific region or cell population in a living brain. Third, compared to direct photothermal stimulation via temperature increase, photoacoustic stimulation requires 40 times less laser energy dose to evoke neuron activities and is associated with a minimal temperature increase of less than 1 °C, preventing potential thermal damage to neurons. Fourth, photoacoustics is a versatile approach and can be designed in various platforms aiming at specific applications. Our team has shown the design of fiber-based photoacoustic emitters, photoacoustic nanotransducers, soft biocompatible photoacoustic films, and soft photoacoustic lenses. Since they interact with neurons through ultrasound without the need for direct contact, photoacoustic enables noninvasive transcranial and dura-penetrating brain stimulation without compromising high precision.In this Account, we will first review the basic principles of photoacoustic and discuss the key design elements of PA transducers for neural modulation guided by the principle. We will also highlight how these design goals were achieved from a materials chemistry perspective. The design of different PA interfaces, their unique capability, and their applications in neural systems will be reviewed. In the end, we will discuss the remaining challenges and future perspectives for this technology.

Multi-scale analysis of acupuncture mechanisms for motor and sensory cortex activity based on SEEG data.

Acupuncture, a traditional Chinese therapy, is gaining attention for its impact on the brain. While existing electroencephalogram and functional magnetic resonance image research has made significant contributions, this paper utilizes stereo-electroencephalography data for a comprehensive exploration of neurophysiological effects. Employing a multi-scale approach, channel-level analysis reveals notable $\delta $-band activity changes during acupuncture. At the brain region level, acupuncture modulated connectivity between the paracentral lobule and the precentral gyrus. Whole-brain analysis indicates acupuncture's influence on network organization, and enhancing $E_{glob}$ and increased interaction between the motor and sensory cortex. Brain functional reorganization is an important basis for functional recovery or compensation after central nervous system injury. The use of acupuncture to stimulate peripheral nerve trunks, muscle motor points, acupoints, etc., in clinical practice may contribute to the reorganization of brain function. This multi-scale perspective provides diverse insights into acupuncture's effects. Remarkably, this paper pioneers the introduction of stereo-electroencephalography data, advancing our understanding of acupuncture's mechanisms and potential therapeutic benefits in clinical settings.

Predictive Model for Cell Positioning during Periodic Lateral Migration in Spiral Microchannels.

The periodic lateral migration of submicrometer cells is the primary factor leading to low precision in a spiral microchannel during cell isolation. In this study, a mathematical predictive model (PM) is derived for the lateral position of cells during the periodic lateral migration process. We analyze the relationship of migration period, migration width, and starting point of lateral migration with microchannel structure and flow conditions and determine the empirical coefficients in PM. Results indicate that the aspect ratio of the microchannel and the Reynolds number (Re) are key factors that influence the periodicity of the cell lateral migration. The lateral migration width is jointly affected by Re, the cell blockage ratio, and the microchannel curvature radius. The inlet structure of the microchannel and the ratio of the cell sample to the sheath flow rate are critical parameters for regulating the initial position. Moreover, the structure of the pressure field at the inlet constrains the distribution range of the starting point of the lateral migration. Regardless of whether the particles/cells undergo 0.5, 1, or multiple lateral migration cycles, the lateral positions predicted by PM align well with the experimental observations, thus verifying the accuracy of PM. This research helps to elucidate the characteristics of periodic lateral migration of cells in spiral microchannels and can provide practical guidance for the development and optimization of miniature spiral microchannel chips for precise cell isolation.

The efficacy and safety of pH-responsive and photothermal-sensitive multifunctional nanoparticles loaded with cryptotanshinone for the treatment of gastric cancer.

A multifunctional polydopamine/mesoporous silica nanoparticles loaded cryptotanshinone (PDA/MSN@CTS) was synthesized and subjected to investigating its physicochemical properties and anti-gastric cancer (GC) effects. Utilizing network pharmacology and molecular docking techniques, CTS was identified as our final research target. The structural morphology and physicochemical properties of PDA/MSN@CTS were examined. Near-infrared (NIR) laser was employed to evaluate the photothermal properties of the PDA/MSN@CTS, along with pH-responsive and NIR-triggered release assessments. In vitro experiments evaluated the impact of PDA/MSN@CTS on the malignant behavior of AGS gastric cells. A subcutaneous tumor model was further established to evaluate the in vivo safety of PDA/MSN@CTS. Furthermore, the in vivo photothermal efficacy of PDA/MSN@CTS, in addition to its combined effect with photothermal therapy (PTT), was investigated. Uniform and stable PDA/MSN@CTS had been successfully synthesized and demonstrated efficient release under tumor environment and NIR irradiation. Upon increasing NIR laser conditions, in vivo cytotoxicity, apoptosis rate, reactive oxygen species scavenging ability, and suppression of migration and invasion of AGS cells by PDA/MSN@CTS were significantly enhanced. In vivo assessments revealed excellent blood compatibility and biosafety of PDA/MSN@CTS, alongside robust tumor tissue targeting. Combining nanoparticles with PTT facilitated the anti-GC effects of PDA/MSN@CTS. Compared to free drugs, PDA/MSN@CTS exhibits higher selectivity towards cancer cells, demonstrating effective anticancer activity and biocompatibility both in vitro and in vivo. Furthermore, our nanomaterial possesses excellent photothermal properties, and under NIR conditions, PDA/MSN@CTS exhibits synergistic therapeutic effects.

Addressing age measurement errors in fish growth estimation from length-stratified samples.

Fish growth models are crucial for fisheries stock assessments and are commonly estimated using fish length-at-age data. This data is widely collected using length-stratified age sampling (LSAS), a cost-effective two-phase response-selective sampling method. The data may contain age measurement errors (MEs). We propose a methodology that accounts for both LSAS and age MEs to accurately estimate fish growth. The proposed methods use empirical proportion likelihood methodology for LSAS and the structural errors in variables methodology for age MEs. We provide a measure of uncertainty for parameter estimates and standardized residuals for model validation. To model the age distribution, we employ a continuation ratio-logit model that is consistent with the random nature of the true age distribution. We also apply a discretization approach for age and length distributions, which significantly improves computational efficiency and is consistent with the discrete age and length data typically encountered in practice. Our simulation study shows that neglecting age MEs can lead to significant bias in growth estimation, even with small but non-negligible age MEs. However, our new approach performs well regardless of the magnitude of age MEs and accurately estimates SEs of parameter estimators. Real data analysis demonstrates the effectiveness of the proposed model validation device. Computer codes to implement the methodology are provided.

Visible Light-Induced Polymerization to Access Polyamides.

Visible light-induced polymerization, as a promising and green strategy, is showing great potential in preparing value-added polymers. Herein, a visible light photoredox catalysis method is reported to afford a library of polyamide with high yields (up to 99%) and high molecular weights (Mws) (up to 71 000 g mol-1). Dithioacids and diamines as the monomers, and 9-mesityl-10-methylacridinium tetrafluoroborate (Mes-Acr-MeBF4) as the organic photoredox catalyst give the polyamides with structural diversity in air under mild conditions without extra metal, base, or additives.

Electrochemical Polymerization to Access CS2-Derived Polythioureas at Room Temperature.

Electrochemistry has been widely used in energy storage, metallurgy, chemical synthesis and other fields since its birth using electricity as one of the cheapest reagents. However, compared with the revival of electrochemical synthesis of small molecules, the electrochemical polymerization for preparing macromolecules is still rudimentary due to formidable challenges. Herein, A unique electrochemical polymerization is disclosed between CS2 and diamines at room temperature in an electrolyte-free manner to access poly thioureas. Polythioureas have high selectivity for four metal ions, including Au3+, Ag+, Pt4+, and Hg2+, and can be used as an efficient adsorbent for recovering gold from metal waste.

Utilizing nanotechnology and advanced machine learning for early detection of gastric cancer surgery.

Nanotechnology has emerged as a promising frontier in revolutionizing the early diagnosis and surgical management of gastric cancers. The primary factors influencing curative efficacy in GIC patients are drug inefficacy and high surgical and pharmacological therapy recurrence rates. Due to its unique optical features, good biocompatibility, surface effects, and small size effects, nanotechnology is a developing and advanced area of study for detecting and treating cancer. Considering the limitations of GIC MRI and endoscopy and the complexity of gastric surgery, the early diagnosis and prompt treatment of gastric illnesses by nanotechnology has been a promising development. Nanoparticles directly target tumor cells, allowing their detection and removal. It also can be engineered to carry specific payloads, such as drugs or contrast agents, and enhance the efficacy and precision of cancer treatment. In this research, the boosting technique of machine learning was utilized to capture nonlinear interactions between a large number of input variables and outputs by using XGBoost and RNN-CNN as a classification method. The research sample included 350 patients, comprising 200 males and 150 females. The patients' mean ± SD was 50.34 ± 13.04 with a mean age of 50.34 ± 13.04. High-risk behaviors (P = 0.070), age at diagnosis (P = 0.034), distant metastasis (P = 0.004), and tumor stage (P = 0.014) were shown to have a statistically significant link with GC patient survival. AUC was 93.54%, Accuracy 93.54%, F1-score 93.57%, Precision 93.65%, and Recall 93.87% when analyzing stomach pictures. Integrating nanotechnology with advanced machine learning techniques holds promise for improving the diagnosis and treatment of gastric cancer, providing new avenues for precision medicine and better patient outcomes.

Smart nano generation of transgenic algae expressing white spot syndrome virus in shrimps for inner ear-oral infection treatments using the spotted hyena optimizer (SHO)-Long short-term memory algorithm.

Nanotechnology offers a promising avenue to amplify the effectiveness and precision of using transgenic algae in managing WSSV in shrimp by possibly crafting nano-carriers for targeted therapeutic agent delivery or modifying algae cells at a molecular level. Leveraging the capabilities of nano-scale interventions, this study could explore innovative means to manipulate cellular processes, control biological interactions, and enhance treatment efficacy while minimizing undesirable impacts in aquatic environments. The White Spot Syndrome Virus (WSSV) is a double-stranded DNA virus with a tail and rod form that belongs to theNimaviridaefamily. There is no workable way to manage this illness at the moment. This research proposes a new model based on the Long Short-Term Memory (LSTM) and Spotted Hyena Optimizer (SHO) method to control the inner ear-oral infection, utilizing transgenic algae (Chlamydomonas reinhardtii). It is pretty tricky to modify the weight matrix in LSTM. The output will be more accurate if the weight of the neurons is exact. Histological examinations and nested polymerase chain reaction (PCR) testing were performed on the challenged shrimp every 4 h to assess the degree of white spot disease. The SHO-LSTM has shown the highest accuracy and Roc value (98.12% and 0.93, respectively) and the lowest error values (MSE = 0.182 and MAE = 0.48). The hybrid optimized model improves the overall inner ear-oral linked neurological diseases detection ratio. Additionally, with the slightest technical complexity, it effectively controls the forecast factors required to anticipate the ENT. Algal cells were found to be particularly well-suited for inner ear-oral infections, and shrimps fed a transgenic line had the best survival ratio in WSSV infection studies, with 87% of the shrimp surviving. This shows that using this line would effectively stop the spread of WSSV in shrimp populations.

Epiberberine: a potential rumen microbial urease inhibitor to reduce ammonia release screened by targeting UreG.

Rumen microbial urease inhibitors have been proposed for regulating nitrogen emission and improving nitrogen utilization efficiency in ruminant livestock industry. However, studies on plant-derived natural inhibitors of rumen microbial urease are limited. Urease accessory protein UreG, plays a crucial role in facilitating urease maturation, is a new target for design of urease inhibitor. The objective of this study was to select the potential effective inhibitor of rumen microbial urease from major protoberberine alkaloids in Rhizoma Coptidis by targeting UreG. Our results showed that berberine chloride and epiberberine exerted superior inhibition potential than other alkaloids based on GTPase activity study of UreG. Berberine chloride inhibition of UreG was mixed type, while inhibition kinetics type of epiberberine was uncompetitive. Furthermore, epiberberine was found to be more effective than berberine chloride in inhibiting the combination of nickel towards UreG and inducing changes in the second structure of UreG. Molecular modeling provided the rational structural basis for the higher inhibition potential of epiberberine, amino acid residues in G1 motif and G3 motif of UreG formed interactions with D ring of berberine chloride, while interacted with A ring and D ring of epiberberine. We further demonstrated the efficacy of epiberberine in the ruminal microbial fermentation with low ammonia release and urea degradation. In conclusion, our study clearly indicates that epiberberine is a promising candidate as a safe and effective inhibitor of rumen microbial urease and provides an optimal strategy and suitable feed additive for regulating nitrogen excretion in ruminants in the future. KEY POINTS: • Epiberberine is the most effective inhibitor of rumen urease from Rhizoma Coptidis. • Urease accessory protein UreG is an effective target for design of urease inhibitor. • Epiberberine may be used as natural feed additive to reducing NH3 release in ruminants.

AXIN1/MYC Axis Mediated the Osimertinib Resistance in EGFR Mutant Non-Small Cell Lung Cancer Cells.

Osimertinib, a promising and approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is a standard strategy for EGFR-mutant non-small cell lung cancer (NSCLC) patients. However, developed resistance is unavoidable, which reduces its long-term effectiveness. In this study, RNA sequencing was performed to analyze differentially expressed genes (DEGs). The PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA) were used to identify the key genes for clinical prognosis and gene correlation respectively. Protein expression was determined by western blot analysis. Cell viability assay and Ki67 staining were used to evaluate the effect of osimertinib on tumor cells. Finally, we screened out two hub genes, myelocytomatosis oncogene (Myc) and axis inhibition protein 1 (Axin1), upregulated in three osimertinib-resistant cell lines through RNA sequencing and bioinformatics analysis. Next, cell experiment confirmed that expression of C-MYC and AXIN1 were elevated in different EGFR mutant NSCLC cell lines with acquired resistance to osimertinib, compared with their corresponding parental cell lines. Furthermore, we demonstrated that AXIN1 upregulated the expression of C-MYC and mediated the acquired resistance of EGFR mutant NSCLC cells to osimertinib in vitro. In conclusion, AXIN1 affected the sensitivity of EGFR mutant NSCLC to osimertinib via regulating C-MYC expression in vitro. Targeting AXIN1/MYC signaling may be a potential new strategy for overcoming acquired resistance to osimertinib.

Omics analysis revealed the intestinal toxicity induced by aflatoxin B1 and aflatoxin M1.

Aflatoxin B1 (AFB1), a common mycotoxin, can occur in agricultural products. As a metabolite of AFB1, aflatoxin M1 (AFM1) mainly exist in dairy products. These two mycotoxins threaten human health, although it is unclear how they affect the function of the intestinal barrier. In this study, mice were exposed to AFB1 (0.3 mg/kg body b.w.) and AFM1(3.0 mg/kg b.w.) either individually or in combination for 28 days to explore the main differentially expressed proteins (DEPs) and the associated enriched pathways. These findings were preliminarily verified by the transcriptomic and proteomic analyses in differentiated Caco-2 cells. The results revealed that AFB1 and AFM1 exposure in mice disrupted the function of the intestinal barrier, and the combined toxicity was greater than that of each toxin alone. Further proteomic analysis in mice demonstrated that the mechanisms underlying these differences could be explained as follows: (i) lipid metabolism was enriched by AFB1-induced DEPs. (ii) protein export pathway was stimulated by AFM1-induced DEPs. (iii) cell metabolic ability was inhibited (as evidenced by changes in UDP-GT1, UDP-GT2, and Gatm6), apoptosis was induced (MAP4K3), and epithelial cell integrity was disrupted (Claudin7 and IQGAP2), resulting in more extensive intestinal damage after combined treatment. In conclusion, the hazardous impact of co-exposure to AFB1 and AFM1 from proteomic perspectives was demonstrated in the present study.

Medial-pivot total knee arthroplasty enhances tibiofemoral axial rotation stability in weight-bearing mid-range flexion compared to posterior-stabilised system.

PURPOSE: Total knee arthroplasty (TKA) stands as a primary intervention for severe knee ailments, yet concerns remain regarding postoperative patient satisfaction and flexion instability. This study aims to evaluate the in-vivo kinematics of medial-pivot (MP) and posterior-stabilised (PS) designs during step-up activity, in comparison to the kinematics of the nonoperated contralateral knee. METHODS: Sixteen patients with PS-TKA and 14 with MP-TKA were retrospectively examined. Clinical outcomes were assessed using patient-completed questionnaires. Motion during step-up was captured using a dual fluoroscopic system. Statistical analysis was applied to evaluate the in-vivo tibiofemoral six-degree-of-freedom kinematics and articular contact positions between the two groups. RESULTS: Despite being older, patients in the MP group reported higher postoperative subjective scores for weight-bearing functional activities. The axial rotation centres of MP-TKA located on the medial tibial plateau exhibited less variance compared to PS-TKA and contralateral knees. Compared to the contralateral knee (contralateral to medial-pivot [C-MP] or contralateral to posterior-stabilised [C-PS]), the MP group exhibited limited range of motion in terms of anteroposterior translation (MP: 3.6 ± 1.3 mm vs. C-MP: 7.4 ± 2.5 mm, p < 0.01) and axial rotation (MP: 6.6 ± 1.9° vs. C-MP: 10.3 ± 4.9°, p = 0.02), as well as in the PS group for anteroposterior translation (PS: 3.9 ± 1.7 mm vs. C-PS: 7.2 ± 3.7 mm, p < 0.01). CONCLUSION: The MP group with better postoperative ratings demonstrated a more stable MP axial rotation pattern during step-up activity compared to the PS group, underscoring the pivotal role of prosthetic design in optimising postoperative rehabilitation and functional recovery. LEVEL OF EVIDENCE: Level III.

Dietary L-carnitine supplementation changes lipid metabolism and glucose utilization of Rhynchocypris lagowskii fed diets with different lipid sources.

The widely available crop oil is an effective alternative to the increasingly scarce marine fish oil. However, simple alternative strategies have led to declining growth and the edible value of farmed fish. It is worthwhile to explore the effects of micro supplements in diets to improve the tolerance of fish to different dietary lipid sources, which finally optimizes the feeding strategies. This study aimed to investigate the regulation of L-carnitine and dietary oil conditions on nutrient composition, lipid metabolism, and glucose regulation of Rhynchocypris lagowskii. Four diets were prepared according to fish oil, fish oil supplemented with L-carnitine, corn oil, and corn oil supplemented with L-carnitine, and FO, LCFO, CO, and LCCO were labeled, respectively. R. lagowskii was fed experimental diets for 8 weeks, and the glucose tolerance test was performed. The CO diet significantly resulted in higher crude lipid content in muscle but a lower level of serum lipid parameters of R. lagowskii than the FO diet. However, dietary L-carnitine supplementation significantly reduced the crude lipid content in the hepatopancreas and muscle of the fish fed with the CO diet yet increased the serum lipid parameters. Additionally, the crude lipid content of muscle was reduced in the fish fed with an FO diet supplemented with L-carnitine. Compared with the FO diet, the CO diet significantly reduced the ratio of n3/n6 polyunsaturated fatty acid in the hepatopancreas and muscle of R.lagowskii. Dietary L-carnitine supplementation significantly reduced the contents of total saturated fatty acids and total monounsaturated fatty acids in hepatopancreas under both dietary lipid sources. The CO diet significantly up-regulated the expression of genes related to lipid uptake and adipogenesis in hepatopancreas, including lipoprotein lipase (lpl), acetyl-coenzyme A carboxylase alpha (accα), and sterol regulatory element binding protein-1 (srebp1), compared with the FO diet. While dietary L-carnitine supplementation significantly down-regulated the expressions of lpl, accα, srebp1, and fatty acid synthase in hepatopancreas and muscle of fish under both dietary lipid sources, along with up-regulated expression of carnitine palmitoyltransferase 1 in hepatopancreas. Moreover, the fish fed with a CO diet significantly increased the expression of glucose uptake and clearance and significantly down-regulated the expressions of glucose regulation-related genes, including glucose transporter 1, glycogen synthase 1, and phosphofructokinase in hepatopancreas and muscle, resulting in slower glucose uptake and clearance than fish fed with FO diet. Nevertheless, dietary L-carnitine supplementation up-regulated the expression of gluconeogenesis-related genes, including glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the hepatopancreas of R. lagowskii under both dietary lipid sources. In conclusion, a higher dietary n6 PUFA resulted in lipid deposition, decreased serum lipid parameters, and limited serum glucose utilization of R. lagowskii. While the regulatory effect of L-carnitine on lipid metabolism and glucose utilization of R. lagowskii varies with dietary lipid sources and tissues.

Magnetic resonance imaging-based classification of the myodural bridge complex and its influencing factors.

Cerebrospinal fluid (CSF) circulation is considered the third circulation of the human body. Recently, some scholars have proposed the myodural bridge (MDB) as a novel power source for CSF flow. Moreover, the suboccipital muscles can exert a driving force on the CSF via the MDB. This hypothesis is directly supported by head rotation and nodding movements, which can affect CSF circulation. The MDB has been validated as a normal structure in humans and mammals. In addition, the fusion of MDB fibers of different origins that act in concert with each other forms the MDB complex (MDBC). The MDBC may be associated with several CSF disorder-related neurological disorders in clinical practice. Therefore, the morphology of the MDBC and its influencing factors must be determined. In this study, T2-weighted imaging sagittal images of the cervical region were analyzed retrospectively in 1085 patients, and magnetic resonance imaging (MRI) typing of the MDBC was performed according to the imaging features of the MDBC in the posterior atlanto-occipital interspace (PAOiS) and posterior atlanto-axial interspace (PAAiS). The effects of age and age-related degenerative changes in the cervical spine on MRI staging of the MDBC were also determined. The results revealed four MRI types of the MDBC: type A (no MDBC hyposignal shadow connected to the dura mater in either the PAOiS or PAAiS), type B (MDBC hyposignal shadow connected to the dura mater in the PAOiS only), type C (MDBC hyposignal shadow connected to the dura mater in the PAAiS only), and type D (MDBC hyposignal shadow connected to the dura mater in both the PAOiS and PAAiS). The influencing factors for the MDBC typing were age (group), degree of intervertebral space stenosis, dorsal osteophytosis, and degenerative changes in the cervical spine (P < 0.05). With increasing age (10-year interval), the incidence of type B MDBC markedly decreased, whereas that of type A MDBC increased considerably. With the deepening of the degree of intervertebral space stenosis, the incidence of type C MDBC increased significantly, whereas that of type A MDBC decreased. In the presence of dorsal osteophytosis, the incidence of type C and D MDBCs significantly decreased, whereas that of type A increased. In the presence of protrusion of the intervertebral disc, the incidence of type B, C, and D MDBCs increased markedly, whereas that of type A MDBC decreased considerably, with cervical degenerative changes combined with spinal canal stenosis. Moreover, the incidence of both type C and D MDBCs increased, whereas that of type A MDBC decreased. Based on the MRI signal characteristics of the dural side of the MDBC, four types of the MDBC were identified. MDBC typing varies dynamically according to population distribution, depending on age and cervical degeneration (degree of intervertebral space stenosis, vertebral dorsal osteophytosis formation, simple protrusion of intervertebral disc, and cervical degeneration changes combined with spinal canal stenosis, except for the degree of protrusion of the intervertebral disc and the degree of spinal canal stenosis); however, it is not influenced by sex.

[Common Malignant Tumors in the Reproductive System of Chinese Women: Disease Burden During 1990-2019 and Prediction of Future Trend].

Objective To analyze the trends of disease burden of cervical cancer,uterine cancer,and ovarian cancer among Chinese women from 1990 to 2019,and to provide a basis for formulating precise prevention and control measures in China. Methods The global disease burden data in 2019 were used to describe the changes in indicators such as incidence,mortality,years of life lost due to premature mortality(YLL),years lived with disability(YLD),and disability-adjusted life year(DALY) of cervical,uterine,and ovarian cancers in China from 1990 to 2019.Furthermore,the Bayesian age-period-cohort model was adopted to predict the incidence and mortality of the cancers from 2020 to 2030. Results From 1990 to 2019,the incidence rates and mortality of cervical,uterine,and ovarian cancers in Chinese women showed an upward trend,and the age-standardized incidence rate of ovarian cancer increased the most(0.78%).In 2019,the incidence of cervical cancer and uterine cancer concentrated in the women of 55-59 years old,and ovarian cancer mainly occurred in the women of 70-74 years old.The DALY,YLL,and YLD of cervical,uterine,and ovarian cancers all presented varying degrees of growth at all ages.The Bayesian age-period-cohort model predicted that from 2020 to 2030,the incidence and mortality of cervical cancer in China showed a decreasing trend,while those of uterine cancer and ovarian cancer showed an increasing trend.There was no significant change in the age with high incidence of the three cancers. Conclusions From 1990 to 2019,the overall disease burden of cervical,uterine,and ovarian cancers in China increased,while the disease burden of cervical cancer decreased after 2020.It is recommended that the efforts should be doubled for the prevention and control of cervical,uterine,and ovarian cancers.

[Changes in the disease burden of male urinary and reproductive system tumors in China from 1990 to 2019: Analysis with a prediction of the future trend].

OBJECTIVE: To analyze the changes in the disease burden of prostate, testis, kidney and bladder cancers among urinary and reproductive system tumors in Chinese men from 1990 to 2019 with a prediction of the future trend. METHODS: We retrieved the data on the incidence, mortality and disease burden of prostate, testis, kidney and bladder cancers in Chinese men between 1990 and 2019 from the database of Global Burden of Disease Study 2019. Using the Joinpoint regression model, we analyzed the trend of changes in the disease burden, and predicted the prevalence of the tumors with the ARIMA model. RESULTS: From 1990 to 2019, the standardized incidence and prevalence of prostate, testis, kidney and bladder cancers were on the rise in Chinese men, and those of testis cancer increased most significantly, by 326.79% and 1070.93% respectively. The disease burden of PCa was the highest, with standardized incidence, prevalence and mortality ratios of 17.34/100 000, 117.65/100 000 and 7.79/100 000 respectively in 2019. The standardized mortality and disability-adjusted life years (DALY) of kidney cancer were increased by 103.59% and 103.17% respectively. The highest incidence, mortality and DALY of prostate, kidney and bladder cancers in 2019 were found in 90－94 years old males, the highest prevalence rates of prostate, kidney and bladder cancers in the 70－89-year-olds, and the highest prevalence of testis cancer in the 25－49-year-olds. ARIMA model prediction showed that the standardized incidence rates of prostate, testis, kidney and bladder cancers in Chinese men kept rising from 2020 to 2029. CONCLUSION: The disease burden of prostate, testis, kidney and bladder cancers in Chinese men is on the rise, and their standardized incidence rates will be even higher by 2029, with a significant increase in the disease burden in young men, which suggests the need of more attention to the prevention and treatment of genitourinary system tumors in young males.

Hypoxic preconditioned mesenchymal stem cells ameliorate rat brain injury after cardiopulmonary resuscitation by suppressing neuronal pyroptosis.

Cardiac arrest (CA) can result in cerebral ischaemia-reperfusion injury and poor neurological outcomes. While bone marrow-derived mesenchymal stem cells (BMSCs) have been shown to have protective effects in brain ischaemic disease, their efficacy can be reduced by the poor oxygen environment. In this study, we investigated the neuroprotective effects of hypoxic preconditioned BMSCs (HP-BMSCs) and normoxic BMSCs (N-BMSCs) in a cardiac arrest rat model by examining their ability to ameliorate cell pyroptosis. The mechanism underlying the process was also explored. Cardiac arrest was induced in rats for 8 min and surviving rats received 1 × 106 normoxic/hypoxic BMSCs or PBS via intracerebroventricular (ICV) transplantation. Neurological function of rats was evaluated using neurological deficit scores (NDSs) and examined for brain pathology. Serum S100B and neuron-specific enolase (NSE) levels and cortical proinflammatory cytokines were measured to evaluate brain injury. Pyroptosis-related proteins in the cortex after cardiopulmonary resuscitation (CPR) were measured using western blotting and immunofluorescent staining. Transplanted BMSCs were tracked using bioluminescence imaging. Results showed significantly better neurological function and neuropathological damage after transplantation with HP-BMSCs. In addition, HP-BMSCs reduced levels of pyroptosis-related proteins in the rat cortex after CPR and significantly reduced levels of biomarkers for brain injury. Mechanistically, HP-BMSCs alleviated brain injury by reducing the expressions of HMGB1, TLR4, NF-κB p65, p38 MAPK and JNK in the cortex. Our study demonstrated that hypoxic preconditioning could enhance the efficacy of BMSCs in alleviating post-resuscitation cortical pyroptosis. This effect may be related to the regulation of the HMGB1/TLR4/NF-κB, MAPK signalling pathways.

FDA approval summary for lonafarnib (Zokinvy) for the treatment of Hutchinson-Gilford progeria syndrome and processing-deficient progeroid laminopathies.

The U.S. Food and Drug Administration recently approved lonafarnib as the first treatment for Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies. This approval was primarily based on a comparison of patients with HGPS treated with lonafarnib in 2 open-label trials with an untreated patient cohort. With up to 11 years of follow-up, it was found that the lonafarnib treated patients with HGPS had a survival benefit of 2.5 years compared with the untreated patients with HGPS. This large treatment effect on the objective endpoint of mortality using a well-matched comparator group mitigated potential sources of bias and together with other evidence, established compelling evidence of a drug effect with benefits that outweighed the risks. This approval is an example of U.S. Food and Drug Administration's regulatory flexibility for a rare disease while ensuring that standards for drug approval are met.

Inside Out Computational Redesign of Cavities for Improving Thermostability and Catalytic Activity of Rhizomucor Miehei Lipase.

Cavities are created by hydrophobic interactions between residue side chain atoms during the folding of enzymes. Redesigning cavities can improve the thermostability and catalytic activity of the enzyme; however, the synergistic effect of cavities remains unclear. In this study, Rhizomucor miehei lipase (RML) was used as a model to explore volume fluctuation and spatial distribution changes of the internal cavities, which could reveal the roles of internal cavities in the thermostability and catalytic activity. We present an inside out cavity engineering (CE) strategy based on computational techniques to explore how changes in the volumes and spatial distribution of cavities affect the thermostability and catalytic activity of the enzyme. We obtained 12 single-point mutants, among which the melting temperatures (Tm) of 8 mutants showed an increase of more than 2°C. Sixteen multipoint mutations were further designed by spatial distribution rearrangement of internal cavities. The Tm of the most stable triple variant, with mutations including T21V (a change of T to V at position 21), S27A, and T198L (T21V/S27A/T198L), was elevated by 11.0°C, together with a 28.7-fold increase in the half-life at 65°C and a specific activity increase of 9.9-fold (up to 5,828 U mg-1), one of the highest lipase activities reported. The possible mechanism of decreased volumes and spatial rearrangement of the internal cavities improved the stability of the enzyme, optimizing the outer substrate tunnel to improve the catalytic efficiency. Overall, the inside out computational redesign of cavities method could help to deeply understand the effect of cavities on enzymatic stability and activity, which would be beneficial for protein engineering efforts to optimize natural enzymes. IMPORTANCE In the present study, R. miehei lipase, which is widely used in various industries, provides an opportunity to explore the effects of internal cavities on the thermostability and catalytic activity of enzymes. Here, we execute high hydrostatic pressure molecular dynamics (HP-MD) simulations to screen the critical internal cavity and reshape the internal cavities through site-directed mutation. We show that as the global internal cavity volume decreases, cavity rearrangement can improve the stability of the protein while optimizing the substrate channel to improve the catalytic efficiency. Our results provide significant insights into understanding the mechanism of action of the internal cavity. Our strategy is expected to be applied to other enzymes to promote increases in thermostability and catalytic activity.