Tailoring Ni-Fe-B Electronic Effects in Layered Double Hydroxides for Enhanced Oxygen Evolution Activity.

NiFe layered double hydroxides (LDHs) are state-of-the-art catalysts for the oxygen evolution reaction (OER) in alkaline media, yet they still face significant overpotentials. Here, quantitative boron (B) doping is introduced in NiFe LDHs (ranging from 0% to 20.3%) to effectively tailor the Ni-Fe-B electronic interactions for enhanced OER performance. The co-hydrolysis synthesis approach synchronizes the hydrolysis rates of Ni and Fe precursors with the formation rate of B─O─M (M: Ni, Fe) bonds, ensuring precise B doping into the NiFe LDHs. It is demonstrated that B, as an electron-deficient element, acts as an "electron sink" at doping levels from 0% to 13.5%, facilitating the transition of Ni2+ to the active Ni3+δ, thereby accelerating OER kinetics. However, excessive B doping (13.5-20.3%) effectively generates oxygen vacancies in the LDHs, which increases electron density at Ni2+ sites and hinders their transition to Ni3+δ, thereby reducing OER activity. Optimal OER performance is achieved at a B doping level of 13.5%, with an overpotential of only 208 mV to reach a current density of 500 mA cm-2, placing it among the most effective OER catalysts to date. This Ni-Fe-B electronic engineering opens new avenues for developing highly efficient anode catalysts for water-splitting hydrogen production.

Lactylation drives hCG-triggered luteinization in hypoxic granulosa cells.

Hypoxia that occurs during the luteinization process of granulosa cells (GC) contributes to the formation of lactate in follicles. Lysine lactylation (Kla), a post-translational modification directly regulated by lactate levels, is a metabolic sensor that converts metabolic information into gene expression patterns. In this study, we employed human chorionic gonadotropin (hCG) to induce GCs luteinization and discovered that hypoxia enhances hCG-mediated GCs luteinization by stimulating lactate production/lactylation. The elevated levels of luteinization markers (including progesterone synthesis, expression of CYP11A1 and STAR) were accompanied by increased lactate production as well as enhanced lactylation in mouse ovarian GCs after the injection of hCG in vivo. By treating GCs with hypoxia in vitro, we found that hypoxia accelerated hCG-induced GCs luteinization, which was inhibited after blocking lactate production/lactylation. Further investigations revealed that H3K18la might contribute to hCG-induced luteinization in hypoxic GCs by upregulating CYP11A1 and STAR transcription. Additionally, we identified that CREB K136la is also required for hCG-induced GCs luteinization under hypoxia. Finally, the in vitro findings were verified in vivo, which showed impaired GCs luteinization and corpus luteum formation after blocking the lactate/lactylation by intraperitoneal injection of oxamate/C646 in mice. Taken together, this study uncovered a novel role of protein lactylation in the regulation of GCs luteinization.

Cognitive behavioral stress management effectively facilitates neurologic recovery, alleviates mental distress, and elevates health status in acute ischemic stroke patients.

Cognitive behavioral stress management (CBSM) relieves physical and psychological burdens in patients with some central nervous system diseases, while its utility in acute ischemic stroke (AIS) patients is unclear. This study aimed to explore the effect of CBSM on neurologic recovery and psychosomatic health in AIS patients. Totally, 176 naive AIS patients were randomized into routine care (RC) group (n=88) and CBSM group (n=88) to receive a 3-month corresponding intervention. Modified Rankin scale (mRS) scores at the first month after discharge (M1) (P=0.008) and the third month after discharge (M3) (P=0.016) were lower in the CBSM group than in the RC group. The proportion of AIS patients with mRS score >2 at M3 was reduced in CBSM group vs RC group (P=0.045). Hospital anxiety depression scale (HADS)-anxiety score at M3 (P=0.016), HADS-depression score at M3 (P=0.005), and depression rate at M3 (P=0.021) were decreased in the CBSM group vs the RC group. EuroQol-5 dimension scores at M1 (P=0.024) and M3 (P=0.012) were decreased, while EuroQol-visual analogue scale score at M3 (P=0.026) was increased in the CBSM group vs the RC group. By subgroup analyses, CBSM had favorable outcomes in AIS patients with age ≤65 years. CBSM was beneficial to neurologic recovery and distress relief in AIS patients with an education level of middle school or above, and to health status in those with an education level of primary school or uneducated. In conclusion, CBSM benefitted neurologic recovery and psychosomatic health in AIS patients with minor neurological deficits, however, further studies should verify these results with a larger sample size and longer follow-up.

High-precision high-stability acousto-optic pulse picking driver with a direct digital synthesis technique.

A method for maintaining a fixed phase relationship between the driving signal of acousto-optic modulator (AOM) and the original mode-locked seed laser is proposed and realized, which stabilizes the amplitude of diffracted signal output from the AOM for subsequent amplification. A field-programmable gate array (FPGA), combined with external summing amplifiers, is used to directly synthesize high-timing-precision driving signals that are synchronized with the seed laser pulses, and the accuracy of signal timing control reaches 160 ps. Using this driver, the standard deviation of the diffracted signal output from the AOM is significantly decreased from 0.52% to 0.18%. This pulse-picking solution also includes a control system that can flexibly control the frequency, gating width, etc., of the driving signal, which makes it more convenient for subsequent laser amplification and makes it suitable for a variety of mode-locked lasers.

Omaveloxolone Ameliorates Cognitive Deficits by Inhibiting Apoptosis and Neuroinflammation in APP/PS1 Mice.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease associated with aging, characterized by progressive cognitive impairment and memory loss. However, treatments that delay AD progression or improve its symptoms remain limited. The aim of the present study was to investigate the therapeutic effects of omaveloxolone (Omav) on AD and to explore the underlying mechanisms. Thirty-week-old APP/PS1 mice were selected as an experimental model of AD. The spatial learning and memory abilities were tested using the Morris water maze. Amyloid-beta (Aß) deposition in the brains was measured using immunohistochemistry. Network pharmacological analyses and molecular docking were conducted to gain insights into the therapeutic mechanisms of Omav. Finally, validation analyses were conducted to detect changes in the associated pathways and proteins. Our finding revealed that Omav markedly rescued cognitive dysfunction and reduced Aß deposition in the brains of APP/PS1 mice. Network pharmacological analysis identified 112 intersecting genes, with CASP3 and MTOR emerging as the key targets. In vivo validation experiments indicated that Omav attenuated neuronal apoptosis by regulating apoptotic proteins, including caspase 3, Bax, and Bcl-2. Moreover, Omav suppressed neuroinflammation and induced autophagy by inhibiting the phosphorylation of mTOR. These findings highlight the therapeutic efficacy of Omav in AD and that its neuroprotective effects were associated with inhibiting neuronal apoptosis and regulating neuroinflammation.

Codon-Optimized and de novo-Synthesized E-Selectin/AAV2 Dose-Response Study for Vascular Regeneration Gene Therapy.

OBJECTIVE: This study focuses on dose-response investigation using a codon-optimized and de novo-synthesized E-Selectin/AAV2 (E-Sel/AAV2) vector in preparation for Investigational New Drug enabling of subsequent clinical studies. BACKGROUND: Gene therapy is a potential solution for patients suffering from chronic limb-threatening ischemia. Understanding the dose for effective gene delivery is crucial for future Investigational New Drug-enabling studies. METHODS: Expression of the codon-optimized E-Selectin gene was assessed by flow cytometry following in vitro cell transfection assay and RT-qPCR for murine limbs injected in vivo with AAV-m-E-Selectin (E-Sel/AAV2). Dose-response studies involved 3 cohorts of FVB/NJ mice (n=6/group) with escalating log doses of E-Selectin/AAV2 injected intramuscularly in divided aliquots, ranging from 2 × 10 9 VG to 2 × 10 11 VG, into ischemic limbs created by left femoral artery/vein ligation/excision and administration of nitric oxide synthase inhibitor, L-NAME. Limb perfusion, extent of gangrene free limb, functional limb recovery, and therapeutic angiogenesis were assessed. RESULTS: Codon-optimized E-Sel/AAV2 gene therapy exhibits a superior expression level than WT E-Sel/AAV2 gene therapy both in vitro and in vivo. Mice treated with a high dose (2 × 10 11 VG) of E-Sel/AAV2 showed significantly improved perfusion indices, lower Faber scores, increased running stamina, and neovascularization compared with lower doses tested with control groups, indicating a distinct dose-dependent response. No toxicity was detected in any of the animal groups studied. CONCLUSIONS: E-Sel/AAV2 Vascular Regeneration Gene Therapy holds promise for enhancing the recovery of ischemic hindlimb perfusion and function, with the effective dose identified in this study as 2 × 10 11 VG aliquots injected intramuscularly.

Design and synthesis of novel site-specific antibody-drug conjugates that target TROP2.

The approval of Trodelvy® validates TROP2 as a druggable but challenging target for antibody-drug conjugates (ADCs) to treat metastatic triple-negative breast cancer (mTNBC). Here, based on the TROP2-targeted antibody sacituzumab, we designed and developed several site-specific ADC candidates, which employ MMAE (monomethyl auristatin E) as the toxin, via IgG glycoengineering or affinity-directed traceless conjugation. Systematic evaluation of these site-specific ADCs in homogeneity, hydrophilicity, stability, and antitumor efficiency was conducted. The results indicate that the site-specific ADCs gsADC 3b made from one-step glycoengineering exhibit good aggregation stability and in vivo efficacy, providing a new format of ADCs that target TROP2.

CDKN2A somatic copy number amplification in normal tissues surrounding gastric carcinoma reduces cancer metastasis risk in droplet digital PCR analysis.

BACKGROUND: The CDKN2A gene is frequently affected by somatic copy number variations (SCNVs, including deletions and amplifications [SCNdel and SCNamp]) in the cancer genome. Using surgical gastric margin tissue samples (SMs) as the diploid reference in SCNV analysis via CDKN2A/P16-specific real-time PCR (P16-Light), we previously reported that the CDKN2A SCNdel was associated with a high risk of metastasis of gastric carcinoma (GC). However, the status of CDKN2A SCNVs in SMs and their clinical significance have not been reported. METHODS: Peripheral white blood cell (WBC) and frozen GC and SM tissue samples were collected from patients (n = 80). Droplet digital PCR (ddPCR) was used to determine the copy number (CN) of the CDKN2A gene in tissue samples using paired WBCs as the diploid reference. RESULTS: A novel P16-ddPCR system was initially established with a minimal proportion (or limit, 10%) of the detection of CDKN2A CN alterations. While CDKN2A SCNamp events were detected in both SMs and GCs, fewer CDKN2A SCNdel events were detected in SMs than in GCs (15.0% vs. 41.3%, P = 4.77E-04). Notably, significantly more SCNamp and fewer SCNdel of the CDKN2A gene were detected in SMs from GC patients without metastasis than in those from patients with lymph node metastasis by P16-ddPCR (P = 0.023). The status of CDKN2A SCNVs in SM samples was significantly associated with overall survival (P = 0.032). No cancer deaths were observed among the 11 patients with CDKN2A SCNamp. CONCLUSION: CDKN2A SCNVs in SMs identified by P16-ddPCR are prevalent and significantly associated with GC metastasis and overall survival.

Locally Varying Surface Binding Affinity on Pd-Au Nanocrystals Enhances Electrochemical Ethanol Oxidation Activity.

Noble metal nanocrystals face challenges in effectively catalyzing electrochemical ethanol oxidation reaction (EOR)-represented multistep, multielectron transfer processes due to the linear scaling relationship among binding energies of intermediates, impeding independent optimization of individual elemental steps. Herein, we develop noble metal nanocrystals with a range of local surface binding affinities in close proximity to overcome this challenge. Experimentally, this is demonstrated by applying tensile strain to a Pd surface and decorating it with discrete Au atoms, forming a diversity of binding sites with varying affinities in close proximity for guest molecules, as evidenced by CO probing and density functional theory calculations. Such a surface enables reaction intermediates to migrate between different binding sites as needed for each elemental step, thereby reducing the energy barrier for the overall EOR when compared to reactions at a single site. On these tailored surfaces, we attain specific and mass activities of 32.7 mA cm-2 and 47.8 A mgPd-1 in EOR, surpassing commercial Pd/C by 10.9 and 43.8 times, respectively, and outperforming state-of-the-art Pd-based catalysts. These results highlight the promise of this approach in improving a variety of multistep, multielectron transfer reactions, which are crucial for energy conversion applications.

Monolithic integrated optoelectronic chip for vector force detection.

Sensors with a small footprint and real-time detection capabilities are crucial in robotic surgery and smart wearable equipment. Reducing device footprint while maintaining its high performance is a major challenge and a significant limitation to their development. Here, we proposed a monolithic integrated micro-scale sensor, which can be used for vector force detection. This sensor combines an optical source, four photodetectors, and a hemispherical silicone elastomer component on the same sapphire-based AlGaInP wafer. The chip-scale optical coupling is achieved by employing the laser lift-off techniques and the flip-chip bonding to a processed sapphire substrate. This hemispherical structure device can detect normal and shear forces as low as 1 mN within a measurement range of 0-220 mN for normal force and 0-15 mN for shear force. After packaging, the sensor is capable of detecting forces over a broader range, with measurement capabilities extending up to 10 N for normal forces and 0.2 N for shear forces. It has an accuracy of detecting a minimum normal force of 25 mN and a minimum shear force of 20 mN. Furthermore, this sensor has been validated to have a compact footprint of approximately 1.5 mm2, while maintaining high real-time response. We also demonstrate its promising potential by combining this sensor with fine surface texture perception in the fields of compact medical robot interaction and wearable devices.

High-efficiency single-frequency DBR fiber laser at 1091 nm utilizing a Yb:YAG crystal-derived silica fiber.

A single-frequency distributed Bragg Reflector (DBR) fiber laser operating at 1091 nm was demonstrated by using a Yb:YAG crystal-derived silica fiber (YDSF). The YDSF was prepared via the molten core (MC) method, with a Yb2O3 doping concentration of 5.60 wt.% in the core, resulting in a gain coefficient of 1.45 dB/cm at 1091 nm. Employing 0.8 cm of the YDSF, we attained a single-frequency laser with a maximum output power of 145 mW and a slope efficiency of 31.8%. The laser exhibited an optical signal-to-noise ratio (OSNR) exceeding 71 dB, a linewidth of ∼34 kHz, and a stabilized relative intensity noise (RIN) at -132 dB/Hz for frequencies over 4.5 MHz. The fiber laser could serve as an outstanding seed source for high-power, narrow-linewidth fiber amplifiers operating at 1091 nm.

Pharmacodynamic and pharmacokinetic profiles of a novel GLP-1 receptor biased agonist-SAL0112.

BACKGROUND AND PURPOSE: GLP-1 receptor agonists are clinically utilized for type 2 diabetes and obesity. In vitro and in vivo preclinical studies were performed to assess the druggability of a novel small molecule GLP-1 receptor biased agonist SAL0112. EXPERIMENTAL APPROACH: The HTRF assay, FLIPR assay, TR-FRET assay, and PathHunter assay were utilized for in vitro studies. Liver transporter tests were conducted using the HEK293-OATP1B1 and HEK293-OATP1B3 cell lines. In vitro stability assessments of various species and in vivo PK studies in rodents were performed. A model of type 2 diabetes and obesity induced by a high-energy diet in transgenic C57BL/6 mice expressing the human GLP-1 receptor gene was conducted. PRINCIPAL RESULTS: SAL0112 demonstrated high potency and selectivity in activating the Gαs pathway of the GLP-1 receptor, with no observed desensitization. SAL0112 demonstrated greater stability in human and rat liver microsomes compared to Danuglipron. In vivo PK studies revealed higher absorption of SAL0112 in rats. SAL0112 displayed a significantly lower potential for DDI on liver transporters compared to Danuglipron. SAL0112 led to significant reductions in body weight (P<0.001), blood glucose levels in OGTT (P<0.001), HbA1c (P<0.05) and improved insulin resistance (P<0.01). Notably, it increased peripheral adipocyte density and resolved hepatic steatosis. The efficacy of SAL0112 was found to be comparable to that of Danuglipron and Liraglutide. CONCLUSION: SAL0112 demonstrated potent and selective GLP-1 receptor biased agonism, effectively alleviating signs of type 2 diabetes in a mouse model. These promising findings pave the way for the advancement of SAL0112 into clinical trials.

Clonal transmission of blaIMP-4-carrying ST196 Klebsiella pneumoniae isolates mediated by the IncN plasmid in China.

OBJECTIVES: To investigate the clinical and molecular epidemiological characteristics of blaIMP-4-carrying Klebsiella pneumoniae in a tertiary hospital in China. METHODS: Ten carbapenem-resistant K. pneumoniae (CRKP) isolates carrying the blaIMP-4 gene were collected. Molecular characteristics were analysed using whole-genome sequencing. Plasmid conjugation experiments were used to analyse conjugation of the plasmids. We compared and analysed K. pneumoniae-carrying blaIMP-4 genomic datasets obtained from the National Center for Biotechnology Information (NCBI) with the strains in this study. RESULTS: All 10 CRKP isolates carrying blaIMP-4 were collected from 10 adult patients in the respiratory intensive care unit. These strains were only sensitive to polymyxins and tigecycline due to them simultaneously carrying multiple resistance genes, namely blaOKP-A-5, fosA, oqxA, and oqxB. Notably, R29 harboured two carbapenemase genes (blaNDM-1 and blaIMP-4). These strains had similar drug-resistant phenotypes and genes, all belonging to sequence type (ST)196. Additionally, the patients had experienced spatiotemporal intersection during hospitalization, suggesting that these strains underwent clonal transmission, but they belonged to different clonal clusters from the blaIMP-4-positive K. pneumoniae currently published in the NCBI. Among the 10 strains, blaIMP-4 was located on the IncN plasmid, and six strains had successfully transferred the plasmid to the recipient strain EC600 through plasmid conjugation. CONCLUSIONS: The blaIMP-4-positive ST196 CRKP isolate showed clonal distribution in the respiratory intensive care unit, which was mediated by the IncN plasmid. Consequently, there should be increased monitoring of carbapenem-resistant strains in clinical settings to prevent and control its transmission.

Cerebrospinal fluid α-synuclein adds the risk of cognitive decline and is associated with tau pathology among non-demented older adults.

BACKGROUND: The role of α-synuclein in dementia has been recognized, yet its exact influence on cognitive decline in non-demented older adults is still not fully understood. METHODS: A total of 331 non-demented individuals were included in the study from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants were divided into two distinct groups based on their α-synuclein levels: one with lower levels (α-synuclein-L) and another with higher levels (α-synuclein-H). Measurements included neuropsychiatric scales, cerebrospinal fluid (CSF) biomarkers, and blood transcriptomics. The linear mixed-effects model investigated the longitudinal changes in cognition. Kaplan-Meier survival analysis and the Cox proportional hazards model were utilized to evaluate the effects of different levels of α-synuclein on dementia. Gene set enrichment analysis (GSEA) was utilized to investigate the biological pathways related to cognitive impairment. Pearson correlation, multiple linear regression models, and mediation analysis were employed to investigate the relationship between α-synuclein and neurodegenerative biomarkers, and their potential mechanisms affecting cognition. RESULTS: Higher CSF α-synuclein levels were associated with increased risk of cognitive decline and progression to dementia. Enrichment analysis highlighted the activation of tau-associated and immune response pathways in the α-synuclein-H group. Further correlation and regression analysis indicated that the CSF α-synuclein levels were positively correlated with CSF total tau (t-tau), phosphorylated tau (p-tau) 181, tumor necrosis factor receptor 1 (TNFR1) and intercellular cell adhesion molecule-1 (ICAM-1). Mediation analysis further elucidated that the detrimental effects of CSF α-synuclein on cognition were primarily mediated through CSF t-tau and p-tau. Additionally, it was observed that CSF α-synuclein influenced CSF t-tau and p-tau181 levels via inflammatory pathways involving CSF TNFR1 and ICAM-1. CONCLUSIONS: These findings elucidate a significant connection between elevated levels of CSF α-synuclein and the progression of cognitive decline, highlighting the critical roles of activated inflammatory pathways and tau pathology in this association. They underscore the importance of monitoring CSF α-synuclein levels as a promising biomarker for identifying individuals at increased risk of cognitive deterioration and developing dementia.

Follicular fluid meiosis-activating sterol prevents porcine ovarian granulosa cells from hypoxia-induced apoptosis via inhibiting STAT4 expression.

Follicular fluid meiosis-activating sterol (FF-MAS) is a small molecule compound found in FF, named for its ability to induce oocyte resumption of meiosis. Granulosa cells (GCs) within the follicle are typically located in a hypoxic environment under physiologic conditions due to limited vascular distribution. Previous research suggests that hypoxia-induced cell cycle arrest and apoptosis in GCs may be crucial triggering factors in porcine follicular atresia. However, the impact of FF-MAS on GCs within follicles has not been explored so far. In this study, we uncovered a novel role of FF-MAS in facilitating GC survival under hypoxic conditions by inhibiting STAT4 expression. We found that STAT4 expression was upregulated in porcine GCs exposed to 1% O2. Both gain and loss of function assays confirmed that STAT4 was required for cell apoptosis under hypoxia conditions, and that the GC apoptosis caused by hypoxia was markedly attenuated following FF-MAS treatment through inhibition of STAT4 expression. Correlation analysis in vivo revealed that GC apoptosis was associated with increased STAT4 expression, while the FF-MAS content in follicular fluid was negatively correlated with STAT4 mRNA levels and cell apoptosis. These findings elucidate a novel role of FF-MAS-mediated protection of GCs by inhibiting STAT4 expression under hypoxia, which might contribute to the mechanistic understanding of follicular development.

Granulosa cells (GCs) influence follicle growth and development, with their proliferation and differentiation promoting follicle development and ovulation, while their programmed cell death and degeneration trigger follicular atresia. In this study, to investigate the effect of FF-MAS on GCs of follicles, we performed gene expression profiling in the domestic pig (Sus scrofa). We discovered STAT4 is required for GC apoptosis under hypoxia conditions both in vitro and in vivo and FF-MAS prevents porcine ovarian granulosa cells from hypoxia-induced apoptosis via inhibiting STAT4 expression.

Ultra-compact and high-performance suspended aluminum scandium nitride Lamb wave humidity sensor with a graphene oxide layer.

The utilization of Microelectromechanical Systems (MEMS) technology holds great significance for developing compact and high-performance humidity sensors in human healthcare, and the Internet of Things. However, several drawbacks of the current MEMS humidity sensors limit their applications, including their long response time, low sensitivity, relatively large sensing area, and incompatibility with a complementary metal-oxide-semiconductor (CMOS) process. To address these problems, a suspended aluminum scandium nitride (AlScN) Lamb wave humidity sensor utilizing a graphene oxide (GO) layer is firstly designed and fabricated. The theoretical and experimental results both show that the AlScN Lamb wave humidity sensor exhibits high sensing performance. The mass loading sensitivity of the sensor is one order higher than that of the normal surface acoustic wave (SAW) humidity sensor based on an aluminum nitride (AlN) film; thus the AlScN Lamb wave humidity sensor achieves high sensitivity (∼41.2 ppm per % RH) with only an 80 nm-thick GO film. In particular, the as-prepared suspended AlScN Lamb wave sensors are able to respond to the wide relative humidity (0-80% RH) change in 2 s, and the device size is ultra-compact (260 µm × 72 µm). Moreover, the sensor has an excellent linear response in the 0-80% RH range, great repeatability and long-term stability. Therefore, this work brings opportunities for the development of ultra-compact and high-performance humidity sensors.

Discovery of 2,3-Dihydro[1,4]dioxino[2,3-g]benzofuran Derivatives as Protease Activated Receptor 4 (PAR4) Antagonists with Potent Antiplatelet Aggregation Activity and Low Bleeding Tendency.

Patients with arterial embolic disease have benefited greatly from antiplatelet therapy. However, hemorrhage risk of antiplatelet agents cannot be ignored. Herein, we describe the discovery of 2,3-dihydro[1,4]dioxino[2,3-g]benzofuran compounds as novel PAR4 antagonists. Notably, the isomers 36 and 37 with the chemotype of phenoxyl methylene substituted on the 2,3-dihydro-1,4-dioxine ring exhibited potent in vitro antiplatelet activity (IC50 = 26.13 nM for 36 and 14.26 nM for 37) and significantly improved metabolic stability in human liver microsomes (T1/2 = 97.6 min for 36 and 11.1 min for BMS-986120). 36 also displayed good oral PK profiles (mice: T1/2 = 7.32 h and F = 45.11%). Both of them showed overall potent ex vivo antiplatelet activity at concentrations of 6 and 12 mg/kg, with no impact on the coagulation system and low bleeding liability. Our work will facilitate development of novel PAR4 antagonists as a safer therapeutic option for arterial embolism.

Somatic CDKN2A copy number variations are associated with the prognosis of esophageal squamous cell dysplasia.

BACKGROUND: Somatic copy number variations (SCNVs) in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma. However, whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia (ESCdys) is unknown. This study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate (m/M) ESCdys. METHODS: This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China (Ci County, Hebei Province; Yanting, Sichuan Province; Linzhou, Henan Province; Yangzhong, Jiangsu Province; and Feicheng, Shandong Province) from 2005 to 2019. Genomic DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients, and a quantitative polymerase chain reaction assay, P16-Light, was used to detect CDKN2A copy number. The cumulative regression and progression rates of ESCdys were evaluated using competing risk models. RESULTS: A total of 205 patients with baseline m/M ESCdys were enrolled. The proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts (18.8% [13/69] vs. 35.0% [28/80] vs. 51.8% [29/56], P  <0.001). In the univariable competing risk analysis, the cumulative regression rate was statistically significantly lower ( P = 0.008), while the cumulative progression rate was higher ( P = 0.017) in ESCdys patients with CDKN2A deletion than in those without CDKN2A deletion. CDKN2A deletion was also an independent predictor of prognosis in ESCdys ( P = 0.004) in the multivariable analysis. CONCLUSION: The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification.

Fibroblasts in Diabetic Foot Ulcers.

Fibroblasts are stromal cells ubiquitously distributed in the body of nearly every organ tissue. These cells were previously considered to be "passive cells", solely responsible for ensuring the turnover of the extracellular matrix (ECM). However, their versatility, including their ability to switch phenotypes in response to tissue injury and dynamic activity in the maintenance of tissue specific homeostasis and integrity have been recently revealed by the innovation of technological tools such as genetically modified mouse models and single cell analysis. These highly plastic and heterogeneous cells equipped with multifaceted functions including the regulation of angiogenesis, inflammation as well as their innate stemness characteristics, play a central role in the delicately regulated process of wound healing. Fibroblast dysregulation underlies many chronic conditions, including cardiovascular diseases, cancer, inflammatory diseases, and diabetes mellitus (DM), which represent the current major causes of morbidity and mortality worldwide. Diabetic foot ulcer (DFU), one of the most severe complications of DM affects 40 to 60 million people. Chronic non-healing DFU wounds expose patients to substantial sequelae including infections, gangrene, amputation, and death. A complete understanding of the pathophysiology of DFU and targeting pathways involved in the dysregulation of fibroblasts are required for the development of innovative new therapeutic treatments, critically needed for these patients.