An Overview of Optic Pathway Glioma With Neurofibromatosis Type 1: Pathogenesis, Risk Factors, and Therapeutic Strategies.

Optic pathway gliomas (OPGs) are most predominant pilocytic astrocytomas, which are typically diagnosed within the first decade of life. The majority of affected children with OPGs also present with neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome. OPGs in individuals with NF1 primarily affect the optic pathway and lead to visual disturbance. However, it is challenging to assess risk in asymptomatic patients without valid biomarkers. On the other hand, for symptomatic patients, there is still no effective treatment to prevent or recover vision loss. Therefore, this review summarizes current knowledge regarding the pathogenesis of NF1-associated OPGs (NF1-OPGs) from preclinical studies to seek potential prognostic markers and therapeutic targets. First, the loss of the NF1 gene activates 3 distinct Ras effector pathways, including the PI3K/AKT/mTOR pathway, the MEK/ERK pathway, and the cAMP pathway, which mediate glioma tumorigenesis. Meanwhile, non-neoplastic cells from the tumor microenvironment (microglia, T cells, neurons, etc.) also contribute to gliomagenesis via various soluble factors. Subsequently, we investigated potential genetic risk factors, molecularly targeted therapies, and neuroprotective strategies for tumor prevention and vision recovery. Last, potential directions and promising preclinical models of NF1-OPGs are presented for further research. On the whole, NF1-OPGs develop as a result of the interaction between glioma cells and the tumor microenvironment. Developing effective treatments require a better understanding of tumor molecular characteristics, as well as multistage interventions targeting both neoplastic cells and non-neoplastic cells.

Research on the toxicological prognostic significance of age-related genes in endometrial cancer unveiling key factors in patient prognosis.

This study investigates the influence of aging-related genes on endometrial cancer, a prominent gynecological malignancy with rising incidence and mortality. By analyzing gene expression differences between cancerous and normal endometrial tissues, 42 aging-related genes were identified as differentially expressed. Utilizing the TCGA-UCEC sample, consensus clustering divided the samples into two molecular subgroups, Aging low and Aging high, based on their expression profiles. These subgroups showed distinct prognoses and survival rates, with the Aging high group associated with DNA repair and cell cycle pathways, and the Aging low group showing suppressed metabolic pathways and increased immune cell infiltration, suggesting a potential for better immunotherapy outcomes. Mutation analysis did not find significant differences in mutation frequencies between the groups, but a high Tumor Mutation Burden (TMB) correlated with better prognosis. A risk score model was also developed, showcasing significant prognostic power. Further analysis of the SIX1 gene revealed its overexpression in cancer cells. Drug sensitivity tests indicated that the low-risk group might respond better to chemotherapy. This research underscores the significance of aging-related genes in endometrial cancer, offering insights into their prognostic value and therapeutic potential, which could lead to personalized treatment approaches and enhanced patient management.

A domino reaction for the synthesis of pyrrolo[2,1-a]isoquinolines from 2-aryl-pyrrolidines and alkynes promoted by a four-component catalytic system under aerobic conditions.

Pyrrolo[2,1-a]isoquinoline derivatives were synthesized from 2-aryl-pyrrolidines and alkynes via an oxidative dehydrogenation/cyclization coupling/dehydrogenative aromatization domino process. This reaction was promoted by a four-component catalytic system which included [RuCl2(p-cymene)]2, CuCl, copper acetate monohydrate and TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) under aerobic conditions.

Structural insight into why S-linked glycosylation cannot adequately mimic the role of natural O-glycosylation.

There is an increasing interest in using S-glycosylation as a replacement for the more commonly occurring O-glycosylation, aiming to enhance the resistance of glycans against chemical hydrolysis and enzymatic degradation. However, previous studies have demonstrated that these two types of glycosylation exert distinct effects on protein properties and functions. In order to elucidate the structural basis behind the observed differences, we conducted a systematic and comparative analysis of 6 differently glycosylated forms of a model glycoprotein, CBM, using NMR spectroscopy and molecular dynamic simulations. Our findings revealed that the different stabilizing effects of S- and O-glycosylation could be attributed to altered hydrogen-bonding capability between the glycan and the polypeptide chain, and their diverse impacts on binding affinity could be elucidated by examining the interactions and motion dynamics of glycans in substrate-bound states. Overall, this study underscores the pivotal role of the glycosidic linkage in shaping the function of glycosylation and advises caution when switching glycosylation types in protein glycoengineering.

Corrigendum: Improved single-cell genome amplification by a high-efficiency phi29 DNA polymerase.

[This corrects the article DOI: 10.3389/fbioe.2023.1233856.].

Optimization of the Methods to Develop Stable Polymer Gels for Water Management in Medium- and Ultra-High-Salinity Reservoirs.

Polymer gels suffer from a serious syneresis issue when exposed to high-temperature and high-salinity (HTHS) conditions, which limits their use as water-treatment agents in this type of reservoir. In this paper, the effects of the polymer type/concentration, deoxidizers, and stabilizers on the long-term stability of polymer gels were systematically studied; thus, the methods to develop stable polymer gels for two typical levels of salinity were optimized. The results show the following: (1) For a medium-salinity condition (TDS: 33,645.0 mg/L) at 125 °C, conventional HPAM gels completely dehydrate within only 1 day, and the addition of a deoxidizer hardly improved their stability. Some special polymers, e.g., AP-P5, MKY, and CPAM, are able to form stable gels if a high concentration of 0.8% is used; the syneresis rate of these gels is about 10% after 30 days. However, the addition of the complexant sodium oxalate significantly improves the stability of gels formed by all five of these different polymers, which behave with a 0% syneresis rate after 30 days pass. Complexants are the most economical and feasible agents to develop stable gels in medium-salinity water. (2) Gels enhanced using the methods above all become unstable in a more challenging ultra-high-saline condition (TDS: 225,068.0 mg/L). In this case, special calcium- and magnesium-resistant polymers are required to prepare stable gels, which show 0% syneresis rates after 30 days, have relatively low strengths, but do produce a good plugging effect in high-permeability cores.

Improved single-cell genome amplification by a high-efficiency phi29 DNA polymerase.

Single-cell genomic whole genome amplification (WGA) is a crucial step in single-cell sequencing, yet its low amplification efficiency, incomplete and uneven genome amplification still hinder the throughput and efficiency of single-cell sequencing workflows. Here we introduce a process called Improved Single-cell Genome Amplification (iSGA), in which the whole single-cell sequencing cycle is completed in a high-efficient and high-coverage manner, through phi29 DNA polymerase engineering and process engineering. By establishing a disulfide bond of F137C-A377C, the amplification ability of the enzyme was improved to that of single-cell. By further protein engineering and process engineering, a supreme enzyme named HotJa Phi29 DNA Polymerase was developed and showed significantly better coverage (99.75%) at a higher temperature (40°C). High single-cell genome amplification ability and high coverage (93.59%) were also achieved for commercial probiotic samples. iSGA is more efficient and robust than the wild-type phi29 DNA polymerase, and it is 2.03-fold more efficient and 10.89-fold cheaper than the commercial Thermo Scientific EquiPhi29 DNA Polymerase. These advantages promise its broad applications in large-scale single-cell sequencing.

The role of high-sensitivity C-reactive protein serum levels in the prognosis for patients with stroke: a meta-analysis.

Background: The impact of high-sensitivity C-reactive protein (hs-CRP) as a biomarker of inflammation on the prognosis of stroke patients remains controversial, this study was conducted to evaluate the prognostic value of hs-CRP levels for patients with stroke. Methods: PubMed, Web of Science, Embase, and Cochrane Library databases were searched from inception to October 28, 2022. Outcome measures were all-cause mortality, recurrent stroke, and poor prognosis. The relationship between the highest versus lowest levels of hs-CRP or per unit increment and outcomes as measured by risk ratio (RR) and corresponding 95% confidence intervals (CI). Results: A total of 39 articles were eligible for meta-analysis. High hs-CRP levels at admission were associated with mortality among patients with acute ischemic stroke (AIS) [RR = 3.84, 95% CI (2.41 ~ 6.111); p < 0.001], risk of recurrent stroke [RR = 1.88, 95%CI (1.41 ~ 2.52); p < 0.001], and poor prognosis [RR = 1.77, 95% CI (1.59 ~ 1.97); p < 0.001]. The risk ratios for the association of per unit increase in hs-CRP levels with mortality, risk of recurrent stroke, and poor prognosis were as follows, respectively: 1.42 [95% CI (1.19-1.69); p < 0.001], 1.03 [95% CI (1.01-1.04); p = 0.003], and 1.27 [95% CI (1.10-1.47); p = 0.001]. For hemorrhagic stroke (HS), the risk ratios (RR) for the highest versus the lowest (reference) category of hsCRP or per unit increment to all-cause mortality were 4.36 [95% CI (1.38-13.73); p = 0.012] and 1.03 [95% CI (0.98-1.08); p = 0.238]. Conclusion: Hs-CRP levels are strongly associated with mortality, risk of stroke recurrence and poor prognosis in stroke patients. Therefore, hs-CRP levels may contribute to the prognosis prediction of these patients.

Vibration phases estimation based on orthogonal interferometry of inner view field for ISAL imaging and detection.

Inverse synthetic aperture ladar (ISAL) has the capability to achieve high-resolution imaging of long-distance targets in a short time because of the laser's short wavelength. However, the unexpected phases introduced by target vibration in the echo can cause defocused imaging results of the ISAL. How to estimate the vibration phases has always been one of the difficulties in ISAL imaging. In this paper, in view of the echo's low signal-to-noise ratio, the orthogonal interferometry method based on time-frequency analysis is proposed to estimate and compensate the vibration phases of ISAL. The method can effectively suppress the influence of noise on the interferometric phases and accurately estimate vibration phases using multichannel interferometry in the inner view field. The effectiveness of the proposed method is validated through simulations and experiments, including a 1200 m distance cooperative vehicle experiment and a 250 m distance noncooperative unmanned aerial vehicle experiment.

Engineering the Active Site Lid Dynamics to Improve the Catalytic Efficiency of Yeast Cytosine Deaminase.

Conformational dynamics is important for enzyme catalysis. However, engineering dynamics to achieve a higher catalytic efficiency is still challenging. In this work, we develop a new strategy to improve the activity of yeast cytosine deaminase (yCD) by engineering its conformational dynamics. Specifically, we increase the dynamics of the yCD C-terminal helix, an active site lid that controls the product release. The C-terminal is extended by a dynamical single α-helix (SAH), which improves the product release rate by up to ~8-fold, and the overall catalytic rate kcat by up to ~2-fold. It is also shown that the kcat increase is due to the favorable activation entropy change. The NMR H/D exchange data indicate that the conformational dynamics of the transition state analog complex increases as the helix is extended, elucidating the origin of the enhanced catalytic entropy. This study highlights a novel dynamics engineering strategy that can accelerate the overall catalysis through the entropy-driven mechanism.

MYC-targeted genes predict distant recurrence in patients with ocular adnexal extranodal marginal zone lymphoma.

Ocular adnexal extranodal marginal zone lymphoma (OA-EMZL) is the most frequent subtype of ocular adnexal lymphoma, with a high propensity for recurrence. Distant recurrence (DR) as an essential prognostic event has unique clinical risk factors, but whether distinct molecular features exist remains poorly understood. Here, we identified potential biomarkers using proteomic analysis of 27 OA-EMZL samples. The MYC-targeted genes PCNA, MCM6, and MCM4 were identified as candidates. MYC-targeted genes were further identified as the most significantly activated gene set in patients with DR. The candidate genes were verified in samples from 11 patients with DR and 33 matched controls using immunohistochemistry. The 3-year and 5-year AUC values of MCM6 (0.699 and 0.757) were higher than those of Ki-67 (0.532 and 0.592). High expressions of MCM6 and MCM4 were significantly associated with shorter distant recurrence-free survival (Log-rank p = 0.017, Log-rank p = 0.0053). Multivariate Cox regression identified MCM6 expression as an independent risk factor for DR (HR, 6.86; 95% CI, 1.32-35.79; P = 0.02). Knockdown of c-Myc in B cells resulted in decreased MCM6 and MCM4 expression and reduced proliferative capacity. Our results suggest that activation of the MYC-targeted gene is a distinct molecular feature of DR in OA-EMZL. MYC-targeted gene, MCM6, is a promising pathological biomarker for DR.

Mixed-Component Metal-Organic Framework for Boosting Synergistic Photoactivation of C(sp3)-H and Oxygen.

Synergistic catalysis is an efficient and powerful strategy for simultaneously activating reactants by multiple active sites to promote the efficiency of difficult and challenging catalytic reactions. Meanwhile, enzymes with multi-active-site synergistic catalytic properties possessing high efficiency and high selectivity have become the goal pursued in the field of catalytic chemistry in recent years. Metal-organic frameworks (MOFs), as an effective heterogeneous catalytic platform, that can integrate multiple active sites for synergistic catalysis like enzymatic systems have recently attracted interest. Herein, we report a doubly interpenetrated metal-organic framework with dual active sites, MnIII-porphyrin sites to directly activate molecular oxygen and fluoren-9-one sites to produce a hydrogen atom transfer (HAT) agent by the proton-coupled electron transfer (PCET) process to simultaneously activate inert C(sp3)-H bonds for efficient inert C(sp3)-H bond oxidation under mild conditions. The bifunctional mixed-component MOF structure forced the two catalytic sites closer together to a more suitable distance, exhibiting high photocatalytic activity for inert C(sp3)-H bond oxidation with almost unique selectivity under mild conditions. The density functional theory (DFT) calculation of free energy during the whole catalytic process demonstrated that it is likely that the synergistic catalytic process occurred in the interframework to accelerate the catalytic reaction. The assembling mixed-component MOF for synergistic catalysis would be a prospective approach for the inert C(sp3)-H photoactivation and functionalization.

Ultrathin 2D Cerium-Based Metal-Organic Framework Nanosheet That Boosts Selective Oxidation of Inert C(sp3 )H Bond through Multiphoton Excitation.

The development of methodologies for inducing and tailoring activities of catalysts is an important issue in various catalysis. The ultrathin 2D monolayer metal-organic framework (MOF) nanosheets with more accessible active sites and faster diffusion obtained by exfoliating 3D layered MOFs are of great potential as heterogeneous catalysts, but the rational design and preparation of 3D layered MOFs remains a grand challenge. Herein, a novel weak electrostatic interaction strategy to construct a 3D layered cerium-bearing MOF by coordinating chlorine-capped cerium nodes and linear photoactive methyl viologen (MV+ ) organic linkers is used. Under multiphoton excitation, the MV+ ligands and CeCl chromophores are triggered consecutively to form the high activity chlorine radical (Cl• ) for activation of inert C(sp3 )H bond through a hydrogen atom transfer. Benefiting from framework confinement effects, synergistic effects of two active sites and/or flexibility of the ultrathin framework nanosheets with high surface utilization, the observed activities increase in the order CeCl3 /MV+  < bulk 3D MOF crystals < 2D MOF nanosheets in photocatalysis. This work not only contributes a new strategy to construct 3D layered MOFs and their ultrathin nanosheets but also paves the way to use nanostructured MOFs to handle synergy of multiple molecular catalysts.

Insights of Chinese herbal medicine for mitochondrial dysfunction in chronic cerebral hypoperfusion induced cognitive impairment: Existed evidences and potential directions.

Chronic cerebral hypoperfusion (CCH) is one of the main pathophysiological markers of cognitive impairment in central nervous system diseases. Mitochondria are cores of energy generation and information process. Mitochondrial dysfunction is the key upstream factors of CCH induced neurovascular pathology. Increasing studies explored the molecular mechanisms of mitochondrial dysfunction and self-repair for effective targets to improve CCH-related cognitive impairment. The clinical efficacy of Chinese herbal medicine in the treatment of CCH induced cognitive impairment is definite. Existed evidences from pharmacological studies have further proved that, Chinese herbal medicine could improve mitochondrial dysfunction and neurovascular pathology after CCH by preventing calcium overload, reducing oxidative stress damage, enhancing antioxidant capacity, inhibiting mitochondria-related apoptosis pathway, promoting mitochondrial biogenesis and preventing excessive activation of mitophagy. Besides, CCH mediated mitochondrial dysfunction is one of the fundamental causes for neurodegeneration pathology aggravation. Chinese herbal medicine also has great potential therapeutic value in combating neurodegenerative diseases by targeting mitochondrial dysfunction.

Clinical efficacy and safety of compound Congrong Yizhi Capsules on Alzheimer's disease in mainland China: A systematic review with trial sequential analysis and GRADE assessment.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is a degenerative disease of the central nervous system (CNS) with insidious onset. AD is also the most common cause of dementia. Compound Congrong Yizhi Capsules (CCYC), a traditional Chinese medicine compound developed by the team of Beijing University of Chinese Medicine, has been widely used to treat AD. AIM OF THIS STUDY: To systematically evaluate the clinical efficacy and safety of CCYC for AD by meta-analysis, Trial Sequential Analysis (TSA) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. METHODS: This study was registered at PROSPERO (CRD42022295496). Randomized controlled trials (RCTs) of CCYC as the treatment for AD published before December 1, 2021 were retrieved from 4 Chinses databases, 4 English databases and 2 clinical trials registration systems. RevMan 5.4 and STATA 17.0 was used to conduct the meta-analysis of the included studies, the quality of outcomes was rated by the GRADE system, the TSA was conducted by TSA 0.9.5.10 software. RESULTS: Seven studies were included, and the total sample size was 746. Meta-analysis showed that 6 months of treatment with CCYC plus conventional western medicine treatments (CTs) improved MMSE scores compared with CTs alone (WMD: 4.32, 95% CI: 3.23, 5.42), and TSA confirmed that more trials in the future will not reverse the result. Among which, CCYC combined with donepezil can significantly improve MMSE scores (WMD: 3.54, 95% CI: 2.86, 4.22). CCYC combined with olanzapine also showed good effect on both MMSE (WMD: 6.49, 95% CI: 5.54, 7.44) and ADL scores (WMD: 5.23, 95% CI: 4.63, 5.83). No serious adverse events were reported. The strengths of the evidences above are MODERATE. CONCLUSION: CCYC combined with cognition-modifying western medicine can improve cognitive function, mental behavioural symptoms, and activities of daily living in AD patients with good safety.

HIF-1α mediates CXCR4 transcription to activate the AKT/mTOR signaling pathway and augment the viability and migration of activated B cell-like diffuse large B-cell lymphoma cells.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy with a high relapse rate. We previously found that C-X-C motif chemokine receptor 4 (CXCR4) was highly expressed in DLBCL and associated with poor prognosis. This study focused on the effect of hypoxia-inducible factor-1α (HIF-1α) on CXCR4 expression and the DLBCL progression. Two activated B cell-like DLBCL cell lines Ly-3 and SUDHL2 were transfected with overexpression and knockdown plasmids or HIF-1α. The viability and migration of DLBCL cells were significantly increased under hypoxic conditions, or upon HIF-1α overexpression under normoxic conditions, but the HIF-1α downregulation led to inverse trends. However, the promoting effects of HIF-1α overexpression on DLBCL cells were suppressed by Plerixafor (a CXCR4 inhibitor). The luciferase and chromatin immunoprecipitation assays revealed that HIF-1α bound to the functional site HRE1 on CXCR4 promoter to activate its transcription. HIF-1α-mediated CXCR4 activation further led to increased phosphorylation of AKT/mTOR under hypoxic conditions. Taken together, this work reports that HIF-1α promotes viability and migration of activated B cell-like cells under hypoxia, which might involve the transcription of CXCR4 and the activation of the AKT/mTOR pathway. The finding may provide novel lights in the management of DCBCL.

Predicting the risk of distant and local recurrence for patients with ocular adnexal extranodal marginal zone lymphoma: a matched case-control study.

BACKGROUND/AIMS: Extranodal marginal zone lymphoma of ocular adnexa (OA-EMZL) is the most frequent type of ocular adnexal lymphomas, with a high rate of disease recurrence. Precise patient stratification based on disease recurrence is understudied. This study aims to identify risk factors of distant recurrence (DR) and local recurrence (LR) to construct a prognostic model optimising rapid decision of therapeutic strategies. METHODS: A total of 104 patients diagnosed with OA-EMZL between January 2011 and February 2020 were enrolled. Propensity score matching was performed for DR and LR groups. A nomogram was generated using a multivariate Cox proportional hazards model. RESULTS: After matching, different independent risk factors of DR and LR were identified. Monocyte percentage (p=0.015) and M category >0 (p=0.043) were significant independent risk factors of DR. Epiphora (p<0.001) was the significant independent risk factor of LR. Three factors (monocyte percentage, M category >0, age >60) were integrated into the nomogram to predict the risk of DR. It had a relatively better discriminative ability for distant recurrence-free survival (C-index: 3-year, 0.784; 6-year, 0.801) than IPI score (C-index: 3-year, 0.663; 6-year, 0.673) in the cohort of all patients. CONCLUSION: Our analyses suggested DR and LR as two distinct prognostic events, and additionally identified novel risk factors of them. The nomogram may serve as a practical tool for the prognostic estimation and rapid decision of therapeutic strategies for patients with OA-EMZL.

Long-term outcomes of a new anatomy-based method for finding the medial cut end during late canalicular repair.

BACKGROUND: Locating the medial cut end during late repair of canalicular lacerations can be challenging. OBJECTIVE: The aim of this study was to evaluate the effectiveness and long-term outcomes of a new anatomy-based method for solving the problem of locating the medial cut end. METHODS: This retrospective interventional study included 85 eyes of 85 consecutive adult patients with unilateral inferior canalicular lacerations who underwent late primary (≥2 days after injury) or secondary (≥6 months after initial treatment) surgery. Before surgery, the lacerations were classified as lateral, central, or medial according to the 'distance from the punctum to the distal end' of the lacerated inferior canaliculus. The time spent to locate the proximal lacerated end (TSL) was recorded. All patients were followed up for ≥1 year to evaluate the lacrimal passage patency and the distance between the superior and inferior punctum (DBSIP, to assess cosmesis). RESULTS: There were 16 (18.82%) lateral-type, 55 (64.71%) central-type, and 14 (16.47%) medial-type canalicular lacerations. The TSL was 3.48 ± 1.05 (range 0.9-6.8) min for all patients and differed significantly among the three types of canalicular lacerations (P < 0.001). Lacrimal irrigation showed patent lacrimal passages in 69 patients (81.18%) at 3 months and a further 4 patients (4.71%) at 6 months, residual stenosis without obstruction in 5 patients (5.88%), and obstruction in 7 patients (8.24%). The postoperative DBSIP on the affected side was shorter than the preoperative DBSIP (2.66 ± 0.66 vs. 3.09 ± 1.72 mm, P = 0.006) and comparable to that on the unaffected side (2.78 ± 0.40 mm). CONCLUSION: Our new anatomy-based method is efficient and achieves good long-term outcomes for all types of late canalicular repair.