[Therapeutic effect and mechanism of piracetam for the treatment of spinal cord injury in rats through MAPK pathway].

OBJECTIVE: To explore mechanism of piracetam for the treatment of spinal cord injury in rats through mitogen-activated protein kinase (MAPK) pathway. METHODS: Fifty-four healthy 6-week-old SD female rats with body weight of 80 to 100 g were divided into sham operation group, spinal cord injury group and piracetam group by random number table method, with 18 rats in each group. Spinal cord injury model was established in spinal cord injury group and piracetam group using percussion apparatus, while sham operation group did not damage spinal cord. Piracetam group was injected with piracetam injection through tail vein according to 5 ml·kg-1 standard, once a day for 3 days;the other two groups were injected with normal saline at the same dose, the same frequency and the same duration. The rats were sacrificed at 1, 3, and 7 days after surgery, and changes of Basso, Beattie and Bresnahan (BBB) locomotor rating scale was observed and compared. Enzyme-linked immunosorbent assay (ELISA) was used to detect spinal cord inflammatory factors, such as interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-1ß (interleukin-1ß), necrosis factor-α (IL-1ß) and tumor necrosis factor-α (TNF-α);HE staining was used to observe morphological changes of rats with spinal cord injury, and immunohistochemistry was used to observe expression level of aquaporin 4 (AQP4). The activation of MAPK signaling pathway in spinal cord of rats after spinal cord injury was observed by western blotting (WB). RESULTS: BBB scores of sham operation group on 1, 3 and 7 day were 21 points. In spinal cord injury group, the scores were (1±1), (4±1) and (7±2);piracetam group was (1±1), (5±1), (9±2), respectively;the difference between spinal cord injury group and sham operation group was statistically significant (P<0.05). HE staining showed that no abnormality was found in sham operation group. In spinal cord injury group, bleeding and degeneration of spinal cord tissue appeared at 1 day after operation; flaky necrotic areas were appeared in spinal cord at 3 days after surgery, and spinal cord tissue began to slowly repair at 7 days after surgery. In piracetam group, the bleeding area was less than that of spinal cord injury group at 1 day after surgery;at 3 days after operation, the necrotic area was reduced and the range of nuclear disappearance was reduced; and the spinal cord began to recover slowly at 7 days after surgery. AQP4 staining of spinal cord of rats in sham operation group was weak at 1, 3 and 7 days after modeling, AQP4 staining was deepened and area increased in spinal cord injury group, AQP4 staining of piracetam group was lighter than that of spinal cord injury group, and the positive cells were slightly increased and the staining was slightly darker than that of sham operation group. At 1, 3 and 7 days, the level of IL-6, IL-10, IL-1ß and TNF-α in spinal cord injury group were higher than those in sham operation group and piracetam group(P<0.05). Compared with spinal cord injury group, the area of spinal cord bleeding and necrosis were decreased by HE staining in piracetam group, and AQP4 staining was decreased by immunohistochemistry. WB results showed that P-ERK, P-JNK and P-P38 levels in spinal cord injury group at 3 days were higher than those in sham operation group and piracetam group(P<0.05). CONCLUSION: Piracetam not only showed significant effect in promoting motor function recovery after spinal cord injury, but also showed positive therapeutic potential in reducing lesion area, regulating AQP4 expression to reduce edema, and reducing inflammatory response by regulating MAPK signaling pathway.

Therapeutic effect of Periploca forrestii on collagen-induced arthritis in rats through JAK2/Nf-κB pathway.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects the body. Periploca forrestii was a miao ethnic drug in China that was used to treat arthritis for hundreds of years. But, the therapeutic mechanism is so far unknown. Therefore, the chemical component and effect of Periploca forrestii on arthritis in rats were studied using HPLC-QTOF MS, micro-CT, and other experiments in this paper. Method: Male Sprague-Dawley rats were used to assess the in vivo activity. HPLC QTOF-MS was used to analyze the chemical profile of the P. forrestii (PF). Bovine type II collagen and Complete Freund's Adjuvant were used to stimulate and construct the collagen-induced arthritis (CIA) model. Three dosages of PF (100 mg/kg, 200 mg/kg, 400 mg/kg) were used to evaluate in vivo activity. Methotrexate was used as the positive drug. H/E staining and micro-CT methods were used to monitor the pathological changes of CIA rats. ELISA method was used to assess the serum level of immune- and inflammation-related cytokines. Immunohistochemical experiments were used to test the gene expression in JAK and Nf-κB pathways. Results: 42 compounds were identified from PF. PF administration lowered the increased spleen index compared with that of control and MTX groups, and partially restored body weight, reduced paw swelling, and arthritis score compared with the model group. Macroscopic assessment indicated inflamed paw with significant swelling in the model group, while the extent of inflammation and swelling was attenuated by both MTX and PF. H/E staining experiments demonstrated that pathological changes of synovial cells and infiltration of inflammatory cells were observed in the model group. In contrast, the MTX and PF treatment partially reversed these pathological changes. Micro-CT examination showed severe injuries and scars caused by inflammation for the model group, and in the high-dosage group (400 mg/kg) the inflammation-caused injuries and scars were dramatically ameliorated. Mechanism study showed that PF restored Nf-κB phosphorylation and JAK2 expression compared with the model group. Conclusion: P. forrestii possesses a potent effect on CIA rats. Nf-κB and JAK2 pathways are involved in its protective effect on CIA.

New coccidian Eimeria iyoensis n. sp. (Apicomplexa: Eucoccidiorida: Eimeriidae) in farmed ring-necked pheasants (Phasianus colchicus L.) in Ehime, Japan.

Eight Eimeria spp. (Apicomplexa: Eimeriidae) have been isolated from the ring-necked pheasant (Phasianus colchicus Linnaeus), native to the temperate zone of Asia and eastern regions of Europe. Enteric coccidiosis has become a major issue associated with the breeding of farmed pheasants for game bird release or meat production. In this study, 35 fecal samples were collected from two-to-three-month-old ring-necked pheasants from four pheasant-rearing farms in Ehime Prefecture, Japan. Microscopic examination using a saturated sugar solution technique detected numerous subspherical oocysts from the samples of one farm and ellipsoidal Eimeria phasiani Tyzzer, 1929 oocysts from the three other farms. The subspherical oocysts were artificially sporulated and measured 18.6 µm by 15.7 µm with a 1.18 shape index (n = 150). Each oocyst contained four 10.7 µm × 5.8 µm sporocysts (n = 30) and one coarse refractile polar granule; no micropyle or residua were detected. Each sporocysts contained two sporozoites with one large and one small refractile body and sparsely distributed residua. The complete, 1,443-bp cytochrome c oxidase subunit I gene (cox1) of this isolate exhibited low sequence identity with published Eimeria spp. sequences including E. phasiani that was previously recorded in the same area. Meanwhile, the oocyst morphology most closely resembled that of Eimeria tetartooimia Wacha, 1973, but with distinct refractile polar granules and sporocyst residua. The available GenBank cox1 sequence of E. tetartooimia exhibited a sequence identity of < 94.5% with the study isolate. Here, the coccidian isolate identified in this study represents a new Eimeria iyoensis n. sp. capable of infecting ring-necked pheasant.

Identification of HTRA4 as a Transcriptional Target of p63 in Trophoblast.

The placenta plays a crucial role in pregnancy success. ΔNp63α (p63), a transcription factor from the TP53 family, is highly expressed in villous cytotrophoblasts (CTBs), the epithelial stem cells of the human placenta, and is involved in CTB maintenance and differentiation. We examined the mechanisms of action of p63 by identifying its downstream targets. Gene expression changes were evaluated following overexpression and knockdown of p63 in the JEG3 choriocarcinoma cell line, using microarray-based RNA profiling. High-temperature requirement A4 (HTRA4), a placenta-specific serine protease involved in trophoblast differentiation and altered in preeclampsia, was identified as a gene reciprocally regulated by p63, and its expression was characterized in primary human placental tissues by RNA-sequencing and in situ hybridization. Potential p63 DNA-binding motifs were identified in the HTRA4 promoter, and p63 occupancy at some of these sites was confirmed using chromatin immunoprecipitation, followed by quantitative PCR in both JEG3 and trophoblast stem cells. These data begin to identify members of the transcriptional network downstream of p63, thus laying the groundwork for probing mechanisms by which this important transcription factor regulates trophoblast stemness and differentiation.

Ultrastable Luminol-OH--(Ni-WOx-CNT) ECL System with High Strength and Its Applications in Sensing.

In traditional luminol electrochemiluminescence (ECL) systems, hydrogen peroxide (H2O2) and dissolved oxygen (DO) are the commonly used coreactants to generate reactive oxygen species (ROS) for ECL emission. However, the self-decomposition of hydrogen peroxide and the limited solubility and content of oxygen in solution undoubtedly restrict the luminescence efficiency and stability of the luminol ECL system. Inspired by the ROS-mediated ECL mechanism, we pioneered hydroxide ion as an advanced luminol ECL coreactant using nickel-doped and carbon nanotube-modified tungsten oxide (Ni-WOx-CNT) as the coreactant accelerator. Owing to the excellent catalytic activity of Ni-WOx-CNT, amounts of ROS were generated from OH- at a low excitation voltage, which subsequently reacted with luminol anion radicals and triggered intense ECL signals. Experiments confirmed an impressive ECL behavior in terms of high luminescent intensity (85,563 a.u.) and super stability over 1300 consecutive tests; both are superior to those recently reported luminol-H2O2 and luminol-DO systems with smaller ECL intensities and consecutive tests less than 25 times. To validate the feasibility and versatility of the developed system in sensor, traditional three-electrodes system and closed bipolar electrodes system with various sensing strategies of direct oxidation, "gate-effect" of molecularly imprinted polymer, immune reaction, and enzyme-catalyzed reaction were proposed to monitor uric acid (UA), C-reactive protein (CRP), immunoglobulin G (IgG), and glucose (Glu). The superior sensing performances confirmed the great application potential of the developed ROS-mediated ECL system.

Laboratory testing consolidation and total laboratory automation improves service efficiency and effectiveness: a study of a medical center in Taiwan.

BACKGROUND: Test consolidation and total laboratory automation (TLA) were implemented in a core laboratory with a high volume of specimens in a medical center in Taiwan to reduce the costs of laboratory services and improve laboratory workflow and performance. METHODS: Using a retrospective research approach, 5 stat and 7 routine tests were used to analyze the in-laboratory to report turnaround time (IR-TAT). Mean, SD, medium, 90th percentile, outlier percentage of IR-TAT, full-time equivalents, productivity, tube touch moment (TTM), and financial impact were determined and compared pre- and post-TLA. RESULTS: The mean IR-TAT of overall stat chemical tests for inpatient and outpatient were 32.8% and 11.9% reductions, respectively. The productivity of each medical technologist increased by 32.4% per month, and there was a reduction of 5 medical technologists compared with the number required to complete the same tests before consolidation. The TTM of staff per year post-TLA decreased by 74.1% tube touches. CONCLUSION: The efficiency of laboratory services was improved by consolidation to the core laboratory along with TLA implementation coupled with logic rules such as delta-check and autoverification. Effectiveness was improved as measured by an increase in productivity, labor reduction, staff safety, and cost reduction.

Evaluating the role of heart rate variability in monitoring stress and sleep quality among nurses in the aftermath of the COVID-19 pandemic.

AIM: To assess heart rate variability (HRV) as a measure to assess job stress and sleep quality among nurses in the post-COVID-19 period. BACKGROUND: The COVID-19 pandemic significantly affected nurses, with heightened job stress and impaired sleep quality impacting their well-being and effectiveness in patient care. HRV could offer insights for supporting strategies in the pandemic aftermath. DESIGN: A quantitative cross-sectional study. METHODS: This study involved 403 clinical nurses recruited from a teaching hospital in Taiwan. Data on job stress, work frustration, sleep quality and HRV were collected and analysed. RESULTS: Among the nurses surveyed during the COVID-19 pandemic, 72.7% reported poor sleep quality (PSQI = 9.369). Job stress emerged as a strong predictor of work frustration. High stress levels and poor sleep quality were correlated with significantly decreased HRV, indicating a potential physiological impact of stress on the nurses' health and well-being. CONCLUSIONS: HRV is a valuable and cost-effective measure for monitoring and managing nurses' well-being in the post-COVID-19 era. Targeted interventions can be implemented to support nurses' overall performance and promote their well-being by identifying those at high risk of job stress and poor sleep quality.

The Puerto Rican Infant Metagenomic and Epidemiologic Study of Respiratory Outcomes (PRIMERO): Design and Baseline Characteristics for a Birth Cohort Study of Early-life Viral Respiratory Illnesses and Airway Dysfunction in Puerto Rican Children.

Epidemiologic studies demonstrate an association between early-life respiratory illnesses (RIs) and the development of childhood asthma. However, it remains uncertain whether these children are predisposed to both conditions or if early-life RIs induce alterations in airway function, immune responses, or other human biology that contribute to the development of asthma. Puerto Rican children experience a disproportionate burden of early-life RIs and asthma, making them an important population for investigating this complex interplay. PRIMERO, the Puerto Rican Infant Metagenomics and Epidemiologic Study of Respiratory Outcomes , recruited pregnant women and their newborns to investigate how the airways develop in early life among infants exposed to different viral RIs, and will thus provide a critical understanding of childhood asthma development. As the first asthma birth cohort in Puerto Rico, PRIMERO will prospectively follow 2,100 term healthy infants. Collected samples include post-term maternal peripheral blood, infant cord blood, the child's peripheral blood at the year two visit, and the child's nasal airway epithelium, collected using minimally invasive nasal swabs, at birth, during RIs over the first two years of life, and at annual healthy visits until age five. Herein, we describe the study's design, population, recruitment strategy, study visits and procedures, and primary outcomes.

Label-free Colorimetric Detection of Viral RNA Based on Clustered Regularly Interspaced Short Palindromic Repeats and Gold Nanoparticles with a Portable Device.

Viral infections, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are some of the most dangerous threats to humans. SARS-CoV-2 has caused a global pandemic, highlighting the unprecedented demand for rapid and portable diagnostic methods. To meet these requirements, we designed a label-free colorimetric platform that combines the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated proteins (Cas) 12a system for naked-eye detection (named LFP). This method utilizes reverse transcription loop-mediated isothermal amplification (RT-LAMP) and the trans-cleavage activity of the CRISPR/Cas12a system to increase the sensitivity and specificity of the reaction. This platform can detect as few as 4 copies/µL of RNA and produces no false positive results when tested against the influenza virus. To better meet the requirements of point-of-care (POC) detection, we developed a portable device that can be applied in resource-poor and densely populated regions. The LFP assay holds great potential for application in resource-limited settings, and the label-free gold nanoparticle (AuNPs) probe can reduce costs, making it suitable for large-scale screening. We expect that the LFP assay will be promising for the POC screening of COVID-19.

ABBV-319: A CD19-targeting glucocorticoid receptor modulator antibody-drug conjugate therapy for B-cell malignancies.

Glucocorticoids are key components of the current standard-of-care regimens (e.g., R-CHOP, EPOCH-R, Hyper-CVAD) for treatment of B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. CD19 displays restricted expression in normal B-cells and is up-regulated in B-cell malignancies. ABBV-319 is a CD19-targeting antibody-drug conjugate (ADC) engineered to reduce glucocorticoid-associated toxicities while possessing three distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced Fc-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven anti-tumor activity against multiple malignant B-cell lines in vitro as well as in cell line-derived xenografts (CDXs) and patient-derived xenografts (PDXs) in vivo. Remarkably, a single-dose of ABBV-319 induced sustained tumor regression and enhanced anti-tumor activity compared to repeat dosing of systemic prednisolone at the maximum tolerated dose (MTD) in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed anti-proliferative activity on a subset of B-cell lymphoma cell lines through the inhibition of PI3K signaling. Moreover, afucosylation of the CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity (ADCC), and this activity was maintained after conjugation with GRM payloads. Notably, ABBV-319 displayed superior efficacy compared to afucosylated CD19 mAb in human CD34+ PBMC-engrafted NSG-tg(Hu-IL15) transgenic mice, demonstrating enhanced anti-tumor activity when multiple MOAs are enabled. ABBV-319 also showed durable anti-tumor activity across multiple B-cell lymphoma PDX models, including non-germinal center B-cell (GCB) DLBCL and relapsed lymphoma post R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in Phase I clinical trial (NCT05512390).

Hepatocyte-specific METTL3 ablation by Alb-iCre mice (GPT), but not by Alb-Cre mice (JAX), resulted in acute liver failure (ALF) and postnatal lethality.

AIM: In 2019, to examine the functions of METTL3 in liver and underlying mechanisms, we generated mice with hepatocyte-specific METTL3 homozygous knockout (METTL3Δhep) by simultaneously crossing METTL3fl/fl mice with Alb-iCre mice (GPT) or Alb-Cre mice (JAX), respectively. In this study, we explored the potential reasons why hepatocyte-specific METTL3 homozygous disruption by Alb-iCre mice (GPT), but not by Alb-Cre mice (JAX), resulted in acute liver failure (ALF) and then postnatal lethality. MAIN METHODS: Mice with hepatocyte-specific METTL3 knockout were generated by simultaneously crossing METTL3fl/fl mice with Alb-iCre mice (GPT; Strain No. T003814) purchased from the GemPharmatech Co., Ltd., (Nanjing, China) or with Alb-Cre mice (JAX; Strain No. 003574) obtained from The Jackson Laboratory, followed by combined-phenotype analysis. The publicly available RNA-sequencing data deposited in the NCBI Gene Expression Omnibus (GEO) database under the accession No.: GSE198512 (postnatal lethality), GSE197800 (postnatal survival) and GSE176113 (postnatal survival) were mined to explore the potential reasons why hepatocyte-specific METTL3 homozygous deletion by Alb-iCre mice (GPT), but not by Alb-Cre mice (JAX), leads to ALF and then postnatal lethality. KEY FINDINGS: Firstly, we observed that hepatocyte-specific METTL3 homozygous deficiency by Alb-iCre mice (GPT) or by Alb-Cre mice (JAX) caused liver injury, abnormal lipid accumulation and apoptosis. Secondly, we are surprised to find that hepatocyte-specific METTL3 homozygous deletion by Alb-iCre mice (GPT), but not by Alb-Cre mice (JAX), led to ALF and then postnatal lethality. Our findings clearly demonstrated that METTL3Δhep mice (GPT), which are about to die, exhibited the severe destruction of liver histological structure, suggesting that METTL3Δhep mice (GPT) nearly lose normal liver function, which subsequently contributes to ALF, followed by postnatal lethality. Finally, we unexpectedly found that as the compensatory growth responses of hepatocytes to liver injury induced by METTL3Δhep (GPT), the proliferation of METTL3Δhep hepatocytes (GPT), unlike METTL3Δhep hepatocytes (JAX), was not evidenced by the significant increase of Ki67-positive hepatocytes, not accompanied by upregulation of cell-cycle-related genes. Moreover, GO analysis revealed that upregulated genes in METTL3Δhep livers (GPT), unlike METTL3Δhep livers (JAX), are not functionally enriched in terms associated with cell cycle, cell division, mitosis, microtubule cytoskeleton organization, spindle organization, chromatin segregation and organization, and nuclear division, consistent with the loss of compensatory proliferation of METTL3Δhep hepatocytes (GPT) observed in vivo. Thus, obviously, the loss of the compensatory growth capacity of METTL3Δhep hepatocytes (GPT) in response to liver injury might contribute to, at least partially, ALF and subsequently postnatal lethality of METTL3Δhep mice (GPT). SIGNIFICANCE: These findings from this study and other labs provide strong evidence that these phenotypes (i.e., ALF and postnatal lethality) of METTL3Δhep mice (GPT) might be not the real functions of METTL3, and closely related with Alb-iCre mice (GPT), suggesting that we should remind researchers to use Alb-iCre mice (GPT) with caution to knockout gene in hepatocytes in vivo.

Multifunctional Self-Signaling nanoMIP and Its Application for a Washing-Free Assay of Human Angiotensin-Converting Enzyme 2.

Molecular imprinting techniques have attracted a lot of attention as a potential biomimetic technology, but there are still challenges in protein imprinting. Herein, multifunctional nanosized molecularly imprinted polymers (nanoMIPs) for human angiotensin-converting enzyme 2 (ACE2) were prepared by epitope imprinting of magnetic nanoparticles-anchored peptide (magNP-P) templates, which were further applied to construct a competitive displacement fluorescence assay toward ACE2. A cysteine-flanked dodecapeptide sequence was elaborately selected as an epitope for ACE2, which was immobilized onto the surface of magnetic nanoparticles and served as a magNP-P template for imprinting. During polymerization, fluorescent monomers were introduced to endow fluorescence responsiveness to the prepared self-signaling nanoMIPs. A competitive displacement fluorescence assay based on the nanoMIPs was established and operated in a washing-free manner, yielding a wide range for ACE2 (0.1-6.0 pg/mL) and a low detection limit (0.081 pg/mL). This approach offers a promising avenue in the preparation of nanoMIPs for macromolecule recognition and expands potential application of an MIP in the detection of proteins as well as peptides.

Supramolecular Mimotope Peptide Nanofibers Promote Antibody-Ligand Polyvalent and Instantaneous Recognition for Biopharmaceutical Analysis.

Peptide-based supramolecules exhibit great potential in various fields due to their improved target recognition ability and versatile functions. However, they still suffer from numerous challenges for the biopharmaceutical analysis, including poor self-assembly ability, undesirable ligand-antibody binding rates, and formidable target binding barriers caused by ligand crowding. To tackle these issues, a "polyvalent recognition" strategy employing the CD20 mimotope peptide derivative NBD-FFVLR-GS-WPRWLEN (acting on the CDR domains of rituximab) was proposed to develop supramolecular nanofibers for target antibody recognition. These nanofibers exhibited rapid self-assembly within only 1 min and robust stability. Their binding affinity (179 nM) for rituximab surpassed that of the monomeric peptide (7 µM) by over 38-fold, highlighting that high ligand density and potential polyvalent recognition can efficiently overcome the target binding barriers of traditional supramolecules. Moreover, these nanofibers exhibited an amazing "instantaneous capture" rate (within 15 s), a high recovery (93 ± 3%), and good specificity for the target antibody. High-efficiency enrichment of rituximab was achieved from cell culture medium with good recovery and reproducibility. Intriguingly, these peptide nanofibers combined with bottom-up proteomics were successful in tracking the deamidation of asparagine 55 (from 10 to 16%) on the rituximab heavy chain after 21 day incubation in human serum. In summary, this study may open up an avenue for the development of versatile mimotope peptide supramolecules for biorecognition and bioanalysis of biopharmaceuticals.

Creatinine-to-cystatin C ratio and body composition predict response to PD-1 inhibitors-based combination treatment in metastatic gastric cancer.

Background: Creatinine-to-cystatin C ratio (CCR) and body composition (BC) parameters have emerged as significant prognostic factors in cancer patients. However, the potential effects of CCR in gastric cancer (GC) remains to be elucidated. This multi-center retrospective study explored the predictive and prognostic value of CCR and BC-parameters in patients with metastatic GC receiving PD-1 inhibitors-based combination therapy. Methods: One hundred and thirteen GC patients undergoing PD-1 inhibitors-based combination therapy were enrolled at three academic medical centers from January 2021 to July 2023. A deep-learning platform based on U-Net was developed to automatically segment skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI) and visceral adipose tissue index (VATI). Patients were divided into two groups based on the median of CCR or the upper tertile of BC-parameters. Logistic and Cox regression analysis were used to determine the effect of CCR and BC-parameters in predicting response rates and survival rates. Results: The CCR was positively correlated with SMI (r=0.43; P<0.001), but not with SATI or VATI (P>0.05). Multivariable logistic analysis identified that both low CCR (OR=0.423, P=0.066 for ORR; OR=0.026, P=0.005 for DCR) and low SATI (OR=0.270, P=0.020 for ORR; OR=0.149, P=0.056 for DCR) were independently associated with worse objective response rate (ORR) and disease control rate (DCR). Patients with low CCR or low SATI had significantly lower 8-month progression-free survival (PFS) rate and 16-month overall survival (OS) rate than those with high CCR (PFS rate, 37.6% vs. 55.1%, P=0.011; OS rate, 19.4% vs. 44.9%, P=0.002) or those with high SATI (PFS rate, 37.2% vs. 53.8%, P=0.035; OS rate, 8.0% vs. 36.0%, P<0.001). Multivariate Cox analysis showed that low CCR (HR=2.395, 95% CI: 1.234-4.648, P=0.010 for PFS rate; HR=2.528, 95% CI: 1.317-4.854, P=0.005 for OS rate) and low SATI (HR=2.188, 95% CI: 1.050-4.560, P=0.037 for PFS rate; HR=2.818, 95% CI: 1.381-5.752, P=0.004 for OS rate) were both independent prognostic factors of poor 8-month PFS rate and 16-month OS rate. A nomogram based on CCR and BC-parameters showed a good performance in predicting the 12- and 16-month OS, with a concordance index of 0.756 (95% CI, 0.722-0.789). Conclusions: Low pre-treatment CCR and SATI were independently associated with lower response rates and worse survival in patients with metastatic GC receiving PD-1 inhibitors-based combination therapy.

Construction of a Novel Semiautomated Electrochemical Sensor Array Platform and Its Application in Multiplexed Monitoring of Antibiotic Therapy.

At present, traditional analytical methods suffer from issues such as complex operation, expensive equipment, and a lengthy testing time. Electrochemical sensors have shown great advantages and application potential as an alternative solution. In this study, we proposed a novel semiautomated electrochemical sensor array (SAESA) platform. The sensor array was fabricated using screen-printed technology with a tubular design where all electrodes were printed on the inner wall. The integration of the tubular sensor array with a pipet allows for a semiautomated process including sampling and rinsing, which simplifies operation and reduces overall time. Each working electrode in the tubular sensor array underwent distinct decoration to get specific sensing responses toward the target analytes in a mixture environment (e.g., blood samples). To demonstrate the applicability of the developed sensing platform for simultaneous multianalyte detection, we chose antibiotic treatment for inflammatory infection as a model scenario and continuously measured three biomarkers, namely, tigecycline (TGC), procalcitonin (PCT), and alanine aminotransferase (ALT). The detection limits were 0.3 µM, 0.3 ng/L, and 2.76 U/L, respectively. The developed semiautomated electrochemical sensor array exhibits characteristics such as rapid and simple operation, portability, good selectivity, and excellent stability.

[Hydrochemical Characteristics and Control Factors of Shallow Groundwater in Anqing Section of the Yangtze River Basin].

Shallow groundwater is the main source of water for living and industrial and agricultural production in Anqing City, which is an important basic guarantee to maintain the sustainable development of the social economy and regional ecological environment. In order to further study the water chemical characteristics and controlling factors of shallow groundwater in Anqing City, 196 groups of shallow groundwater samples were collected. A Piper diagram graph, Gibbs chart, ion ratio, and mathematical statistics were comprehensively used to study the water chemical characteristics and controlling factors of groundwater in Anqing City, and the contribution of different sources to the water chemical components of groundwater was quantitatively evaluated. The results showed that the shallow groundwater in Anqing City was weakly alkaline, with pH values ranging from 5.84 to 8.38, with an average value of 7.21. The TDS ranged from 47 to 1 620 mg·L-1, with an average of 324.21 mg·L-1. HCO3- and Ca2+ were the main anions, and the water chemical type was HCO3-Ca type. The chemical components of groundwater were affected by rock weathering leaching, cation alternating adsorption, mineral dissolution and precipitation, and human activities. Ca2+, Mg2+, and HCO3- were mainly derived from the weathering dissolution of carbonate and silicate; Na+, Cl-, and SO42- were affected by industrial activities and domestic sewage discharge; and K+ and NO3- were affected by agricultural activities. The APCS-MLR receptor model analysis further revealed that the chemical components of groundwater were mainly geological factors, industrial factors, agricultural factors, and unknown sources, and their contribution rates were 45.35%, 14.19%, 25.38%, and 15.08%, respectively. Geological factors were important sources of hydrochemical components of shallow groundwater, and human activities aggravated the evolution of groundwater hydrochemistry.

ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia.

BACKGROUND: In recent years, the development of adjunctive therapeutic hyperthermia for cancer therapy has received considerable attention. However, the mechanisms underlying hyperthermia resistance are still poorly understood. In this study, we investigated the roles of cold­inducible RNA binding protein (Cirbp) in regulating hyperthermia resistance and underlying mechanisms in nasopharyngeal carcinoma (NPC). METHODS: CCK-8 assay, colony formation assay, tumor sphere formation assay, qRT-PCR, Western blot were employed to examine the effects of hyperthermia (HT), HT + oridonin(Ori) or HT + radiotherapy (RT) on the proliferation and stemness of NPC cells. RNA sequencing was applied to gain differentially expressed genes upon hyperthermia. Gain-of-function and loss-of-function experiments were used to evaluate the effects of RNAi-mediated Cirbp silencing or Cirbp overexpression on the sensitivity or resistance of NPC cells and cancer stem-like cells to hyperthermia by CCK-8 assay, colony formation assay, tumorsphere formation assay and apoptosis assay, and in subcutaneous xenograft animal model. miRNA transient transfection and luciferase reporter assay were used to demonstrate that Cirbp is a direct target of miR-377-3p. The phosphorylation levels of key members in ATM-Chk2 and ATR-Chk1 pathways were detected by Western blot. RESULTS: Our results firstly revealed that hyperthermia significantly attenuated the stemness of NPC cells, while combination treatment of hyperthermia and oridonin dramatically increased the killing effect on NPC cells and cancer stem cell (CSC)­like population. Moreover, hyperthermia substantially improved the sensitivity of radiation­resistant NPC cells and CSC­like cells to radiotherapy. Hyperthermia noticeably suppressed Cirbp expression in NPC cells and xenograft tumor tissues. Furthermore, Cirbp inhibition remarkably boosted anti­tumor­killing activity of hyperthermia against NPC cells and CSC­like cells, whereas ectopic expression of Cirbp compromised tumor­killing effect of hyperthermia on these cells, indicating that Cirbp overexpression induces hyperthermia resistance. ThermomiR-377-3p improved the sensitivity of NPC cells and CSC­like cells to hyperthermia in vitro by directly suppressing Cirbp expression. More importantly, our results displayed the significantly boosted sensitization of tumor xenografts to hyperthermia by Cirbp silencing in vivo, but ectopic expression of Cirbp almost completely counteracted hyperthermia-mediated tumor cell-killing effect against tumor xenografts in vivo. Mechanistically, Cirbp silencing-induced inhibition of DNA damage repair by inactivating ATM-Chk2 and ATR-Chk1 pathways, decrease in stemness and increase in cell death contributed to hyperthermic sensitization; conversely, Cirbp overexpression-induced promotion of DNA damage repair, increase in stemness and decrease in cell apoptosis contributed to hyperthermia resistance. CONCLUSION: Taken together, these findings reveal a previously unrecognized role for Cirbp in positively regulating hyperthermia resistance and suggest that thermomiR-377-3p and its target gene Cirbp represent promising targets for therapeutic hyperthermia.

Capacitive Pressure Sensor Combining Dual Dielectric Layers with Integrated Composite Electrode for Wearable Healthcare Monitoring.

Foot activity can reflect numerous physiological abnormalities in the human body, making gait a valuable metric in health monitoring. Research on flexible sensors for gait monitoring has focused on high sensitivity, wide working range, fast response, and low detection limit, but challenges remain in areas such as elasticity, antibacterial activity, user-friendliness, and long-term stability. In this study, we have developed a novel capacitive pressure sensor that offers an ultralow detection limit of 1 Pa, wide detection ranges from 1 Pa to 2 MPa, a high sensitivity of 0.091 kPa-1, a fast response time of 71 ms, and exceptional stability over 6000 cycles. This sensor not only has the ability of accurately discriminating mechanical stimuli but also meets the requirements of elasticity, antibacterial activity, wearable comfort, and long-term stability for gait monitoring. The fabrication method of a dual dielectric layer and integrated composite electrode is simple, cost-effective, stable, and amenable to mass production. Thereinto, the introduction of a dual dielectric layer, based on an optimized electrospinning network and micropillar array, has significantly improved the sensitivity, detection range, elasticity, and antibacterial performance of the sensor. The integrated flexible electrodes are made by template method using composite materials of carbon nanotubes (CNTs), two-dimensional titanium carbide Ti3C2Tx (MXene), and polydimethylsiloxane (PDMS), offering synergistic advantages in terms of conductivity, stability, sensitivity, and practicality. Additionally, we designed a smart insole that integrates the as-prepared sensors with a miniature instrument as a wearable platform for gait monitoring and disease warning. The developed sensor and wearable platform offer a cutting-edge solution for monitoring human activity and detecting diseases in a noninvasive manner, paving the way for future wearable devices and personalized healthcare technologies.

Kudoa tanakai n. sp. (Myxozoa: Myxosporea: Multivalvulida), a new kudoid species with spheroid myxospores from the scalpel sawtail (Actinopterygii: Prionurus scalparum) from western Japan.

We describe a new kudoid species, Kudoa tanakai n. sp., in the scalpel sawfish, Prionurus scalprum (Actinopterygii: Acanthuriformes: Acanthuridae), from the natural water around western Japan. The plasmodia were filamentous, localized in pseudocysts in the myofibers of the trunk muscles. The occurrence of plasmodia in the trunk muscle showed no site preference. Its myxospores were spheroid, measuring 6.6-7.6 (7.0) µm by 5.8-6.9 (6.3) µm in apical view (width) and 5.7-6.6 (6.2) in length (n = 30), with four shell valves and a corresponding number of spheroid polar capsules. Shell valves lacked apical protrusions, but scanning electron microscopy revealed that one of the four shell valves had two semi-lunar flaps at its apical terminus. Nucleotide sequencing of the small and large subunit ribosomal RNA genes of the present isolate showed phylogenetic affinities to kudoid species characterized by spheroid myxospores, such as K. musculoliquefaciens, K. hemiscylli, and K. carcharhini, but was molecularly and morphometrically distinct from these and other kudoid species. For direct comparison, Kudoa hemiscylli was collected from the Pacific spadenose shark, Scoliodon macrorhynchos (Elasmobranchii: Carcharhiniformes: Carcharhinidae), in the South China Sea off Guangdong Province, China, and the myxospore surface of the species was observed using scanning electron microscopy. Our study describes the new host and distribution record of this kudoid species originally described from a variety of elasmobranchs in the Australian Coral Sea.