bluuebunny/crossref_metadata_2025 huggingface dataset:
A Network Pharmacology Based Research on the Mechanism of Donepezil in Treating Alzheimer's Disease
Authors: Liu Lihua , Zhu Yingying , Fu Peng , Yang Jundong
Published: April 2022

Objective

In order to explore and further understand the efficacy of donepezil (DNP) in the treatment of Alzheimer's disease (AD), this research was conducted based on network pharmacology and molecular docking.

Method

Compounds of DNP and its effective targets were collected using the TCMSP Chinese medicine system pharmacology database. Disease targets were screened and selected utilizing GeneCards, TTD, DrugBank, CTD, and other online databases. Then, Venn diagrams were generated to identify the intersections. A diseases-drug-active ingredient-key target protein interaction (PPI) network was constructed using the STING database. GO and KEGG enrichment analyses were conducted to predict the function and mechanism of DNP, which were visualized by graphs and bubble charts. After the screening, the top five interacting targets in the PPI network and the compound containing the most active target were selected for molecular docking.

Results

The study received 110 potential targeting genes and 155 signaling pathways. A strong association between DNP and modulation of chemical synaptic transmission and the regulation of trans-synaptic signaling is noted. Signaling pathways related to the proliferation, differentiation, and survival of cells are also found positively relative. The results revealed that the mechanism of its therapeutic effect is multi-component, multi-target, and multi-pathway, laying a foundation for the follow-up in-depth study of the mechanism of DNP in the treatment of AD.

Conclusion

This research provides a superior prediction that AD could be treated using DNP which targets the key proteins and essential pathways associated with the recovery of AD.
Freezing of Gait in Multiple System Atrophy
Authors: Yang Huaguang , Liu Weiyin Vivian , Wang Shanshan , Yang Wenbin , Liu Changsheng , Wen Zhi , Hu Lanhua , Guo Jinxia , Fan Guoguang , Luo Xiaoguang , Zha Yunfei
Published: April 2022

Background and Purpose

Freezing of gait (FOG) is a common gait disturbance phenomenon in multiple system atrophy (MSA) patients. The current investigation assessed the incidence FOG in a cross-sectional clinical study, and clinical correlations associated with it.

Methods

Ninety-nine MSA patients from three hospitals in China were consecutively enrolled in the study. Eight patients were subsequently excluded from the analysis due to incomplete information. The prevalence of FOG symptoms in the MSA cohort was determined, and clinical manifestations in MSA patients with and without FOG were assessed.

Results

Of 91 MSA patients, 60 (65.93%) exhibited FOG. The incidence of FOG increased with disease duration and motor severity and was correlated with modified Hoehn and Yahr (H-Y) stages [odds ratio (OR), 0.54; 95% confidence interval (CI), 0.33–3.92], longer disease duration (OR, 0.54, 95% CI, 0.37–0.78), higher Unified Multiple System Atrophy Rating Scale (UMSARS) score (OR, 0.96, 95% CI, 0.93–0.99), MSA-cerebellum subtype (OR, 2.99, 95% CI, 1.22–7.33), levodopa-equivalent dose (LDED) (OR, 0.998, 95% CI, 0.997–1.00), and higher Scale for the Assessment and Rating of Ataxia (SARA) score (OR, 0.80, 95% CI, 0.72–0.89) (logistic regression). Motor dysfunction was significantly positively associated with lower quality of life scores (p < 0.01).

Conclusion

FOG is a common symptom in MSA patients and it is correlated with poor quality of life, disease progression and severity, levodopa-equivalent dose, and cerebellum impairment.
Quantitative Water Permeability Mapping of Blood-Brain-Barrier Dysfunction in Aging
Authors: Ford Jeremy N. , Zhang Qihao , Sweeney Elizabeth M. , Merkler Alexander E. , de Leon Mony J. , Gupta Ajay , Nguyen Thanh D. , Ivanidze Jana
Published: April 2022

Blood-brain-barrier (BBB) dysfunction is a hallmark of aging and aging-related disorders, including cerebral small vessel disease and Alzheimer’s disease. An emerging biomarker of BBB dysfunction is BBB water exchange rate (kW) as measured by diffusion-weighted arterial spin labeling (DW-ASL) MRI. We developed an improved DW-ASL sequence for Quantitative Permeability Mapping and evaluated whole brain and region-specific kW in a cohort of 30 adults without dementia across the age spectrum. In this cross-sectional study, we found higher kW values in the cerebral cortex (mean = 81.51 min–1, SD = 15.54) compared to cerebral white matter (mean = 75.19 min–1, SD = 13.85) (p < 0.0001). We found a similar relationship for cerebral blood flow (CBF), concordant with previously published studies. Multiple linear regression analysis with kW as an outcome showed that age was statistically significant in the cerebral cortex (p = 0.013), cerebral white matter (p = 0.033), hippocampi (p = 0.043), orbitofrontal cortices (p = 0.042), and precunei cortices (p = 0.009), after adjusting for sex and number of vascular risk factors. With CBF as an outcome, age was statistically significant only in the cerebral cortex (p = 0.026) and precunei cortices (p = 0.020). We further found moderate negative correlations between white matter hyperintensity (WMH) kW and WMH volume (r = −0.51, p = 0.02), and normal-appearing white matter (NAWM) and WMH volume (r = −0.44, p = 0.05). This work illuminates the relationship between BBB water exchange and aging and may serve as the basis for BBB-targeted therapies for aging-related brain disorders.
Phenotype and Distribution of Immature Neurons in the Human Cerebral Cortex Layer II
Authors: Coviello Simona , Gramuntell Yaiza , Klimczak Patrycja , Varea Emilio , Blasco-Ibañez José Miguel , Crespo Carlos , Gutierrez Antonio , Nacher Juan
Published: April 2022

This work provides evidence of the presence of immature neurons in the human brain, specifically in the layer II of the cerebral cortex. Using surgical samples from epileptic patients and post-mortem tissue, we have found cells with different levels of dendritic complexity (type I and type II cells) expressing DCX and PSA-NCAM and lacking expression of the mature neuronal marker NeuN. These immature cells belonged to the excitatory lineage, as demonstrated both by the expression of CUX1, CTIP2, and TBR1 transcription factors and by the lack of the inhibitory marker GAD67. The type II cells had some puncta expressing inhibitory and excitatory synaptic markers apposed to their perisomatic and peridendritic regions and ultrastructural analysis suggest the presence of synaptic contacts. These cells did not present glial cell markers, although astroglial and microglial processes were found in close apposition to their somata and dendrites, particularly on type I cells. Our findings confirm the presence of immature neurons in several regions of the cerebral cortex of humans of different ages and define their lineage. The presence of some mature features in some of these cells suggests the possibility of a progressively integration as excitatory neurons, as described in the olfactory cortex of rodents.
Age and Alzheimer’s Disease-Related Oligodendrocyte Changes in Hippocampal Subregions
Authors: DeFlitch Leah , Gonzalez-Fernandez Estibaliz , Crawley Ilan , Kang Shin H.
Published: April 2022

Oligodendrocytes (OLs) form myelin sheaths and provide metabolic support to axons in the CNS. Although most OLs develop during early postnatal life, OL generation continues in adulthood, and this late oligodendrogenesis may contribute to neuronal network plasticity in the adult brain. We used genetic tools for OL labeling and fate tracing of OL progenitors (OPCs), thereby determining OL population growth in hippocampal subregions with normal aging. OL numbers increased up to at least 1 year of age, but the rates and degrees of this OL change differed among hippocampal subregions. In particular, adult oligodendrogenesis was most prominent in the CA3 and CA4 subregions. In Alzheimer’s disease-like conditions, OL loss was also most severe in the CA3 and CA4 of APP/PS1 mice, although the disease did not impair the rate of OPC differentiation into OLs in those regions. Such region-specific, dynamic OL changes were not correlated with those of OPCs or astrocytes, or the regional distribution of Aβ deposits. Our findings suggest subregion-dependent mechanisms for myelin plasticity and disease-associated OL vulnerability in the adult hippocampus.
Seven Years of Selective Genetic Screening Program and Follow-Up of Asymptomatic Carriers With Hereditary Transthyretin Amyloidosis in Bulgaria
Authors: Chamova Teodora , Gospodinova Mariana , Asenov Ognian , Todorov Tihomir , Pavlova Zornitsa , Kirov Andrey , Cherninkova Sylvia , Kastreva Kristina , Taneva Ani , Blagoeva Stanislava , Zhelyazkova Sashka , Antimov Plamen , Chobanov Kaloian , Todorova Albena , Tournev Ivailo
Published: April 2022

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare, autosomal-dominant (AD) multisystem disorder resulting from the extracellular deposition of amyloid fibrils formed by a destabilized mutant form of transthyretin (TTR), a transport protein predominantly produced by the liver.

Aim

The aims of the current study are to demonstrate the Bulgarian experience with the screening programs among the high-risk patient population over the last 7 years, to present the results from the therapy with TTR stabilizer in our cohort, as well as to stress on the importance of a follow-up of asymptomatic carriers with TTR pathogenic variants by a multidisciplinary team of specialists.

Materials and Methods

In 2014, a screening program among the high-risk patient population for ATTRv was initiated in Bulgaria. On one hand, it was conducted to identify new patients and families among people with “red flag” clinical features, while on the other hand, the program aimed to identify TTR mutation carriers among the families with already genetically proven diagnoses. Sanger sequencing methodology was used to make fast target testing for mutations in the TTR gene in the suspected individuals. All of the identified carriers underwent subsequent evaluation for neurological, cardiac, gastroenterological, and neuro-ophthalmological involvement. Those considered affected were provided with multidisciplinary treatment and a follow-up.

Results

As a result of a 7-year selective screening program among the high-risk patient population and relatives of genetically verified affected individuals, 340 carriers of TTR mutations were identified in Bulgaria with the following gene defects: 78.53% with Glu89Gln, 10.29% with Val30Met, 8.24% with Ser77Phe, 2.06% with Gly47Glu, and 0.59% with Ser52Pro. All of these affected displayed a mixed phenotype with variable ages at onset and rate of progression, according to their mutation. From the 150 patients treated with TTR stabilizer, 84 remained stable, while in other 66 patients the treatment was terminated either because of polyneuropathy progression or due to death. A program for a regular follow-up of asymptomatic carriers in the last 3 years enabled us to detect the transition of 39/65 to symptomatic patients and to initiate treatment in a timely manner.

Conclusion

Bulgarian ATTRv patients display a mixed phenotype with some clinical peculiarities for each mutation that should be considered when treating the affected and the follow-up of the asymptomatic carriers of a specific gene defect.
Remote Memory in Epilepsy: Assessment, Impairment, and Implications Regarding Hippocampal Function
Authors: Rastogi Sanya , Meador Kimford J. , Barr William B. , Devinsky Orrin , Leeman-Markowski Beth A.
Published: April 2022

Studies of epilepsy patients provide insight into the neuroscience of human memory. Patients with remote memory deficits may learn new information but have difficulty recalling events from years past. The processes underlying remote memory impairment are unclear and likely result from the interaction of multiple factors, including hippocampal dysfunction. The hippocampus likely has a continued role in remote semantic and episodic memory storage over time, and patients with mesial temporal lobe epilepsy (TLE) are at particular risk for deficits. Studies have focused on lateralization of remote memory, often with greater impairment in left TLE, which may relate to verbal task demands. Remote memory testing is restricted by methodological limitations. As a result, deficits have been difficult to measure. This review of remote memory focuses on evidence for its underlying neurobiology, theoretical implications for hippocampal function, and methodological difficulties that complicate testing in epilepsy patients.
Impact of Spatial Orientation Ability on Air Traffic Conflict Detection in a Simulated Free Route Airspace Environment
Authors: Zhong Jimmy Y. , Goh Sim Kuan , Woo Chuan Jie , Alam Sameer
Published: April 2022

In the selection of job candidates who have the mental ability to become professional ATCOs, psychometric testing has been a ubiquitous activity in the ATM domain. To contribute to psychometric research in the ATM domain, we investigated the extent to which spatial orientation ability (SOA), as conceptualized in the spatial cognition and navigation literature, predicted air traffic conflict detection performance in a simulated free route airspace (FRA) environment. The implementation of free route airspace (FRA) over the past few years, notably in Europe, have facilitated air traffic services by giving greater flexibility to aviation operators in planning and choosing preferred air routes that can lead to quicker arrivals. FRA offers enhanced system safety and efficiency, but these benefits can be outweighed by the introduction of air traffic conflicts that are geometrically more complex. Such conflicts can arise from increased number and distribution of conflict points, as well as from elevated uncertainty in aircraft maneuvering (for instance, during heading changes). Overall, these issues will make conflict detection more challenging for air traffic controllers (ATCOs). Consequently, there is a need to select ATCOs with suitably high levels of spatial orientation ability (SOA) to ensure flight safety under FRA implementation. In this study, we tested 20 participants who are eligible for ATCO job application, and found that response time-based performance on a newly developed, open access, computerized spatial orientation test (SOT) predicted time to loss of minimum separation (tLMS) performance on an air traffic conflict detection task (AT-CDT) we designed. We found this predictive relationship to be significant to a moderately large extent under scenarios with high air traffic density (raw regression coefficient = 0.58). Moreover, we demonstrated our AT-CDT as a valid test in terms of eliciting well-known mental workload and spatial learning effects. We explained these findings in light of similar or overlapping mental processes that were most likely activated optimally under task conditions featuring approximately equal numbers of outcome-relevant stimuli. We conclude by discussing the further application of the SOT to the selection of prospective ATCOs who can demonstrate high levels of conflict detection performance in FRA during training simulations.
Why Would the Brain Need Dormant Neuronal Precursors?
Authors: Benedetti Bruno , Couillard-Despres Sebastien
Published: April 2022

Dormant non-proliferative neuronal precursors (dormant precursors) are a unique type of undifferentiated neuron, found in the adult brain of several mammalian species, including humans. Dormant precursors are fundamentally different from canonical neurogenic-niche progenitors as they are generated exquisitely during the embryonic development and maintain a state of protracted postmitotic immaturity lasting up to several decades after birth. Thus, dormant precursors are not pluripotent progenitors, but to all effects extremely immature neurons. Recently, transgenic models allowed to reveal that with age virtually all dormant precursors progressively awaken, abandon the immature state, and become fully functional neurons. Despite the limited common awareness about these cells, the deep implications of recent discoveries will likely lead to revisit our understanding of the adult brain. Thus, it is timely to revisit and critically assess the essential evidences that help pondering on the possible role(s) of these cells in relation to cognition, aging, and pathology. By highlighting pivoting findings as well as controversies and open questions, we offer an exciting perspective over the field of research that studies these mysterious cells and suggest the next steps toward the answer of a crucial question: why does the brain need dormant neuronal precursors?
Neuroscientific Methods for Exploring User Perceptions While Dealing With Mobile Advertising: A Novel and Integrated Approach
Authors: Mancini Marco , Cherubino Patrizia , di Flumeri Gianluca , Cartocci Giulia , Martinez Ana , Sanchez Alessandro , Santillo Chiara , Modica Enrica , Vozzi Alessia , Ronca Vincenzo , Trettel Arianna , Borghini Gianluca , Babiloni Fabio
Published: April 2022

Display and native ads represent two of the most widely used digital advertising formats employed by advertisers that aim to grab the attention of online users. In recent years, the native format has become very popular because it relies on deceptive features that make harder the recognition of its advertising nature, reducing avoiding behaviors such as the banner blindness phenomena, traditionally associated to display advertising, and so increasing its advertising effectiveness. The present study, based on a forefront research protocol specifically designed for the advertising research on smartphone devices, aims to investigate through neurophysiological and self-reported measures, the perception of display and native ads placed within article webpages, and to assess the efficacy of an integrated approach. Eye-tracking results showed higher visual attention and longer viewing time associated with native advertisements in comparison to traditional display advertisements, confirming and extending evidence provided by previous research. Despite a significantly higher rate of self-reported advertising intent was detected for articles containing display ads when compared to articles containing native ads, no differences have been found while performing the same comparison for the neurophysiological measures of emotional involvement and approaching motivation of for the self-reported measures of pleasantness and annoyance. Such findings along with the employment of an innovative research protocol, contribute to providing further cues to the current debate related to the effectiveness of two of the most widely used digital advertising formats.
Using fNIRS to Identify Transparency- and Reliability-Sensitive Markers of Trust Across Multiple Timescales in Collaborative Human-Human-Agent Triads
Authors: Eloy Lucca , Doherty Emily J. , Spencer Cara A. , Bobko Philip , Hirshfield Leanne
Published: April 2022

Intelligent agents are rapidly evolving from assistants into teammates as they perform increasingly complex tasks. Successful human-agent teams leverage the computational power and sensory capabilities of automated agents while keeping the human operator's expectation consistent with the agent's ability. This helps prevent over-reliance on and under-utilization of the agent to optimize its effectiveness. Research at the intersection of human-computer interaction, social psychology, and neuroergonomics has identified trust as a governing factor of human-agent interactions that can be modulated to maintain an appropriate expectation. To achieve this calibration, trust can be monitored continuously and unobtrusively using neurophysiological sensors. While prior studies have demonstrated the potential of functional near-infrared spectroscopy (fNIRS), a lightweight neuroimaging technology, in the prediction of social, cognitive, and affective states, few have successfully used it to measure complex social constructs like trust in artificial agents. Even fewer studies have examined the dynamics of hybrid teams of more than 1 human or 1 agent. We address this gap by developing a highly collaborative task that requires knowledge sharing within teams of 2 humans and 1 agent. Using brain data obtained with fNIRS sensors, we aim to identify brain regions sensitive to changes in agent behavior on a long- and short-term scale. We manipulated agent reliability and transparency while measuring trust, mental demand, team processes, and affect. Transparency and reliability levels are found to significantly affect trust in the agent, while transparency explanations do not impact mental demand. Reducing agent communication is shown to disrupt interpersonal trust and team cohesion, suggesting similar dynamics as human-human teams. Contrasts of General Linear Model analyses identify dorsal medial prefrontal cortex activation specific to assessing the agent's transparency explanations and characterize increases in mental demand as signaled by dorsal lateral prefrontal cortex and frontopolar activation. Short scale event-level data is analyzed to show that predicting whether an individual will trust the agent, with data from 15 s before their decision, is feasible with fNIRS data. Discussing our results, we identify targets and directions for future neuroergonomics research as a step toward building an intelligent trust-modulation system to optimize human-agent collaborations in real time.
Neural Connectivity Underlying Reward and Emotion-Related Processing: Evidence From a Large-Scale Network Analysis
Authors: Yankouskaya Ala , Denholm-Smith Toby , Yi Dewei , Greenshaw Andrew James , Cao Bo , Sui Jie
Published: April 2022

Neuroimaging techniques have advanced our knowledge about neurobiological mechanisms of reward and emotion processing. It remains unclear whether reward and emotion-related processing share the same neural connection topology and how intrinsic brain functional connectivity organization changes to support emotion- and reward-related prioritized effects in decision-making. The present study addressed these challenges using a large-scale neural network analysis approach. We applied this approach to two independent functional magnetic resonance imaging datasets, where participants performed a reward value or emotion associative matching task with tight control over experimental conditions. The results revealed that interaction between the Default Mode Network, Frontoparietal, Dorsal Attention, and Salience networks engaged distinct topological structures to support the effects of reward, positive and negative emotion processing. Detailed insights into the properties of these connections are important for understanding in detail how the brain responds in the presence of emotion and reward related stimuli. We discuss the linking of reward- and emotion-related processing to emotional regulation, an important aspect of regulation of human behavior in relation to mental health.
Significant Nutritional Gaps in Tibetan Adults Living in Agricultural Counties Along Yarlung Zangbo River
Authors: Zhou Chen-ni , Li Mo , Xiao Ran , Zhao Fang-jie , Zhang Fu-suo
Published: April 2022

Background

Dietary intake and nutritional assessing data from a representative sample of adult population living in an agricultural zone on Tibet Plateau are still lacking nowadays. This study aimed to assess the daily dietary intakes and respective food sources in 552 local residents (≥ 18 years old, 277 men and 275 women) living in 14 agricultural counties along the Yarlung Zangbo River on Tibet Plateau.

Methods

Food consumption data were collected using a validated cultural-specific food frequency questionnaire that contained all local Tibetan foods and analyzed with three fixed factors: gender, age, and region. Nutrient intakes were calculated using Chinese food composition tables. Nutritional gaps and the percentages of participants who had inadequate and excessive nutrient intakes were calculated by estimated average requirement (EAR) cut-point methods.

Results

Compared with the dietary reference intakes, 68.4% of nutrient intakes were inadequate. Fiber, Ca, I, Zn, Se, and vitamin (Va, Vc, and folic acid) intakes appeared to be particularly deficient. The dietary energy intake was 7838.8 ± 537.1 KJ/d, with 78 and 84% of EAR values for men and women, respectively. The dietary intakes of most nutrients were below the estimated energy requirement/EAR or adequate intake values, while more than 70% of the participants had excessive intake of carbohydrate, especially the elderly (aged ≥ 51 years). The nutritional gap of Cu was more than 300%. Almost 100% of the participants was vulnerable to fiber, Se, and Va shortfalls due to the deficiency in sole food sources. The top five food sources of Se intake were highland barley (34.2%), meat (13%), rice (12.4%), eggs (12.2%), and cultural-specific beverages (7.8%). Eggs (42.1%), tubers (62.2%), vegetables (66.4%), and highland barley (49.7%) were the first contributors of Va, Ve, Vc, and folic acid, respectively.

Conclusion

The dietary intake of a large sample of Tibetan adult population living in agricultural counties of Tibetan Autonomous Region is alarmingly insufficient. Gender inequality is common, and regional difference is widespread due to rapid urbanization. Young Tibetan adults aged 18–30 years are particularly vulnerable to micronutrient shortfalls and currently facing the risk of nutrition-insecurity-related dietary inadequacy. The respondents who belong to the elderly category (≥51 years of age) are facing the risk of “double burden of malnutrition” characterized by the coexistence of undernutrition, including micronutrient deficiencies and overweight or obesity.
Predicting the Proliferation of Tongue Cancer With Artificial Intelligence in Contrast-Enhanced CT
Authors: Sun Ting-Guan , Mao Liang , Chai Zi-Kang , Shen Xue-Meng , Sun Zhi-Jun
Published: April 2022

Tongue squamous cell carcinoma (TSCC) is the most common oral malignancy. The proliferation status of tumor cells as indicated with the Ki-67 index has great impact on tumor microenvironment, therapeutic strategy making, and patients’ prognosis. However, the most commonly used method to obtain the proliferation status is through biopsy or surgical immunohistochemical staining. Noninvasive method before operation remains a challenge. Hence, in this study, we aimed to validate a novel method to predict the proliferation status of TSCC using contrast-enhanced CT (CECT) based on artificial intelligence (AI). CECT images of the lesion area from 179 TSCC patients were analyzed using a convolutional neural network (CNN). Patients were divided into a high proliferation status group and a low proliferation status group according to the Ki-67 index of patients with the median 20% as cutoff. The model was trained and then the test set was automatically classified. Results of the test set showed an accuracy of 65.38% and an AUC of 0.7172, suggesting that the majority of samples were classified correctly and the model was stable. Our study provided a possibility of predicting the proliferation status of TSCC using AI in CECT noninvasively before operation.
MRKNs: Gene, Functions, and Role in Disease and Infection
Authors: Wang Tongtong , Liu Wenqiang , Wang Changfa , Ma Xuelian , Akhtar Muhammad Faheem , Li Yubao , Li Liangliang
Published: April 2022

The makorin RING finger protein (MKRN) gene family encodes proteins (makorins) with a characteristic array of zinc-finger motifs present in a wide array from invertebrates to vertebrates. MKRNs (MKRN1, MKRN2, MKRN3, MKRN4) as RING finger E3 ligases that mediate substrate degradation are related with conserved RING finger domains that control multiple cellular components via the ubiquitin-proteasome system (UPS), including p53, p21, FADD, PTEN, p65, Nptx1, GLK, and some viral or bacterial proteins. MKRNs also served as diverse roles in disease, like MKRN1 in transcription regulation, metabolic disorders, and tumors; MKRN2 in testis physiology, neurogenesis, apoptosis, and mutation of MKRN2 regulation signals transduction, inflammatory responses, melanoma, and neuroblastoma; MKRN3 in central precocious puberty (CPP) therapy; and MKRN4 firstly reported as a novel E3 ligase instead of a pseudogene to contribute to systemic lupus erythematosus (SLE). Here, we systematically review advances in the gene’s expression, function, and role of MKRNs orthologs in disease and pathogens infection. Further, MKRNs can be considered targets for the host’s innate intracellular antiviral defenses and disease therapy.
Therapeutic Targeting of Alternative Splicing: A New Frontier in Cancer Treatment
Authors: Murphy Anthony J. , Li Alex H. , Li Peichao , Sun Hong
Published: April 2022

The ability for cells to harness alternative splicing enables them to diversify their proteome in order to carry out complex biological functions and adapt to external and internal stimuli. The spliceosome is the multiprotein-RNA complex charged with the intricate task of alternative splicing. Aberrant splicing can arise from abnormal spliceosomes or splicing factors and drive cancer development and progression. This review will provide an overview of the alternative splicing process and aberrant splicing in cancer, with a focus on serine/arginine-rich (SR) proteins and their recently reported roles in cancer development and progression and beyond. Recent mapping of the spliceosome, its associated splicing factors, and their relationship to cancer have opened the door to novel therapeutic approaches that capitalize on the widespread influence of alternative splicing. We conclude by discussing small molecule inhibitors of the spliceosome that have been identified in an evolving era of cancer treatment.
Posterior Capsular Outcomes of Pediatric Cataract Surgery With In-The-Bag Intraocular Lens Implantation
Authors: Fu Yana , Wang Dandan , Ding Xixia , Chang Pingjun , Zhao Yinying , Hu Man , Li Zhangliang , Zhao Yun-e
Published: April 2022

Aim

To investigate the change of posterior capsular outcomes of pediatric cataract surgery with primary in-the-bag intraocular lens (IOL) implantation.

Methods

We conducted a case series of pediatric cataract children who underwent cataract extraction with primary in-the-bag IOL implantation, posterior capsulorhexis or vitrectorhexis, and limited anterior vitrectomy at the Eye Hospital of Wenzhou Medical University between 2016 and 2019. Digital retro-illumination photographs of pediatric eyes were obtained at baseline and 6 months, 12 months, and the last visit postoperatively. Capsular outcomes of the posterior capsular opening area (PCOA) and lens reprolifration area at those time points were compared. Correlations between the PCOA and influential factors, such as age at surgery, axial growth, and follow-up duration, were analyzed. The study was registered at register.clinicaltrials.gov (NCT04803097).

Results

Data of 23 patients (27 eyes) were used in the final analysis. During follow-up, the PCOA enlarged at a rate of 0.29–0.32 mm2/month during the first six months postoperatively and 0.05–0.08 mm2/month over the next 1–2 years. Six months postoperatively, the PCOA enlargement statistically and positively correlated with the follow-up duration and axial growth. The area of lens reprolifration was 0.46 ± 1.00 mm2 at six months postoperatively and then remained stable.

Conclusion

The PCOA enlarged rapidly within the first six months after the pediatric cataract surgery with primary IOL implantation. Six months postoperatively, the enlargement of PCOA was positively correlated with follow-up duration and axial growth. Posterior capsulorhexis or capsulectomy should be performed with a diameter of 3.0 to 4.0 mm for good visual axis transparency and the protection of in-the-bag IOL.
Predictor of Syncopal Recurrence in Children With Vasovagal Syncope Treated With Metoprolol
Authors: Tao Chunyan , Xu Bowen , Liao Ying , Li Xueying , Jin Hongfang , Du Junbao
Published: April 2022

Objective

To explore the predictors for syncopal recurrence in a pediatric population with vasovagal syncope (VVS) treated with metoprolol.

Study Design

This study was conducted retrospectively among children suffering from VVS with or without syncopal recurrence. Data on the detailed medical history and auxiliary examinations were obtained from the electronic medical records. The risk factors for syncopal recurrence were studied by cox regression analyses and the corresponding best cutoff values were determined using receiver operating characteristic analysis. Kaplan–Meier curves were plotted to determine the trends of the syncopal recurrence-free survival rate.

Results

Forty-two consecutive VVS children were enrolled in the study. At the end of a median follow-up duration of 9.0 (4.8, 19.1) months, 12 patients (29%) experienced ≥1 syncopal episode. Cox regression analyses revealed that the number of previous syncopal episodes before treatment was a risk factor for syncopal recurrence (hazard ratio = 1.027, 95% confidence interval 1.009 – 1.045, P = 0.003). Moreover, 4 previous syncopal episodes were certified as the best cutoff value, and the Kaplan–Meier curves showed that the syncopal recurrence-free survival rate over time in patients with > 4 previous syncopal episodes was significantly lower than that in patients with ≤4 episodes (P = 0.019 at the log-rank test).

Conclusion

In a pediatric population with VVS while on the treatment of metoprolol, the number of previous syncopal episodes before treatment played a significant role in predicting syncopal recurrence.
Real-World Evidence Study on the Long-Term Safety of Everolimus in Patients With Tuberous Sclerosis Complex: Final Analysis Results
Authors: Ruiz-Falcó Rojas María Luz , Feucht Martha , Macaya Alfons , Wilken Bernd , Hahn Andreas , Maamari Ricardo , Hirschberg Yulia , Ridolfi Antonia , Kingswood John Chris
Published: April 2022

The TuberOus SClerosis registry to increase disease Awareness (TOSCA) Post-Authorization Safety Study (PASS) was a non-interventional, multicenter, safety substudy that assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) receiving everolimus for its licensed indications in the European Union (EU). This substudy also aimed to address TSC-associated neuropsychiatric disorders (TAND), sexual development, and male infertility. Eligible patients were enrolled from 39 sites across 11 countries in the EU. Outcomes of interest included the incidence of adverse events (AEs), serious adverse events (SAEs), treatment-related AEs (TRAEs), AEs leading to everolimus discontinuation, AEs of special interest (AESIs), the observed relationship between everolimus blood levels and incidence of AESIs, TAND, and reproductive clinical features. Herein, we present the final analysis results from this substudy (data cutoff date: 22 January 2020). At data cutoff, 179 patients were enrolled (female, 59.2%; age ≥18 years, 65.9%), of which the majority completed the study (76%). Overall, 121 patients (67.6%) had AEs regardless of causality. The most frequent TRAEs (≥5%) were stomatitis (7.8%), aphthous ulcer (6.7%), and hypercholesterolemia (6.1%). The most common treatment-related SAEs (>1%) were pneumonia (3.4%), influenza, pyelonephritis, aphthous ulcer, stomatitis, dyslipidemia, and hypercholesterolemia (1.1% each). Ten patients (5.6%) reported AEs leading to everolimus discontinuation. The common psychiatric disorders (N = 179) were autism spectrum disorder (21.8%), anxiety disorder (12.8%), “other” psychiatric disorders (8.9%), attention-deficit hyperactivity disorder, and depressive disorder (7.8% each). Of 179 patients, 88 (49.2%) had ≥1 behavioral problem. Of these (n = 88), the most common (>20%) were sleep difficulties (47.7%), anxiety (43.2%), mood swings (37.5%), depression mood (35.2%), impulsivity (30.7%), severe aggression (23.9%), and overactivity (22.7%). Of 179 patients, four (2.2%) reported abnormal puberty onset, and three (1.7%) reported other reproductive disorders. Of 106 females, 23 (21.7%) reported menstrual cycle disorders and 10 (9.4%) reported amenorrhea. Available data did not show delays in sexual maturation or an association between sexual development and infertility. The results demonstrate that everolimus has a manageable long-term safety profile in the TSC treatment setting. No new safety signals emerged. This substudy also contributed to the mapping of TAND and reproductive clinical features in patients with TSC.
Pharmacodynamics, Network Pharmacology, and Pharmacokinetics of Chinese Medicine Formula 9002A in the Treatment of Alzheimer’s Disease
Authors: Tang Chunlan , Fang Zhiling , Chu Donghui , Zhang Lulu , Tang Yuqing , Zhou Jinyue , Fang Rui , Ying Jiaming , Wang Fang , Zhou Yuping , Xu Chunshuang , Wang Qinwen
Published: April 2022

Alzheimer’s disease (AD) is a common and serious neurodegenerative disease in the elderly; however, the treatment of AD is still lacking of rational drugs. In this paper, the active constituents and targets of the self-developed Chinese medicine Formula 9002A in the treatment of AD were investigated from three aspects: pharmacodynamics based on cell and animal experiments, network pharmacology analysis, and pharmacokinetic analysis. A total of 124 compounds were screened in Formula 9002A, and four constituents including salidroside, gastrodin, niacinamide, and umbelliferone were screened as potential active components for the treatment of AD by network pharmacology. Among them, salidroside and gastrodin showed higher relevance with AD targets, such as ESR1 and AR. The pharmacokinetic study showed that they could be absorbed and identified in plasma; the half-life and mean residence times of salidroside and gastrodin in plasma were nearly increased 2-fold by the administration of Formula 9002A compared with those by the administration of a monomer, indicating the extended action time of active compounds in vivo. Formula 9002A exerted the efficacy in the treatment of AD mainly by regulating APP, GSK3β, ESR1, and AR targets based on the anti-β-amyloid protein deposition, anti-oxidation and anti-apoptosis pathways. Two genes enriched in Alzheimer’s disease pathway, APP and GSK3β, were further validated. The experiments also demonstrated that Formula 9002A could downregulate APP and GSK3β protein expression in the model mice brain and improved their cognitive ability. In summary, Formula 9002A has the characteristics of multiple targets and multiple pathways in the treatment of AD, and salidroside and gastrodin might be the main active constituents, which could provide a foundation for further research and application.
Transcriptomics and Metabolomics Identify Drug Resistance of Dormant Cell in Colorectal Cancer
Authors: Xie Lang , Huang Renli , Huang Hongyun , Liu Xiaoxia , Yu Jinlong
Published: April 2022

Background: Tumor dormancy is an important way to develop drug resistance. This study aimed to identify the characteristics of colorectal cancer (CRC) cell dormancy.

Methods: Based on the CRC cohorts, a total of 1,044 CRC patients were included in this study, and divided into a dormant subgroup and proliferous subgroup. Non-negative matrix factorization (NMF) was used to distinguish the dormant subgroup of CRC via transcriptome data of cancer tissues. Gene Set Enrichment Analysis (GSEA) was used to explore the characteristics of dormant CRC. The characteristics were verified in the cell model, which was used to predict key factors driving CRC dormancy. Potential treatments for CRC dormancy were also examined.

Results: The dormant subgroup had a poor prognosis and was more likely to relapse. GSEA analysis showed two defining characteristics of the dormant subgroup, a difference in energy metabolism and synergistic effects of cancer-associated fibroblasts (CAFs), which were verified in a dormant cell model. Transcriptome and clinical data identified LMOD1, MAB21L2, and ASPN as important factors associated with cell dormancy and verified that erlotinib, and CB-839 were potential treatment options.

Conclusion: Dormant CRC is associated with high glutamine metabolism and synergizes with CAFs in 5-FU resistance, and the key effectors are LMOD1, MAB21L2, and ASPN. Austocystin D, erlotinib, and CB-839 may be useful for dormant CRC.
Xanthone Biosynthetic Pathway in Plants: A Review
Authors: Remali Juwairiah , Sahidin Idin , Aizat Wan Mohd
Published: April 2022

Xanthones are secondary metabolites rich in structural diversity and possess a broad array of pharmacological properties, such as antitumor, antidiabetic, and anti-microbes. These aromatic compounds are found in higher plants, such as Clusiaceae, Hypericaceae, and Gentianaceae, yet their biosynthetic pathways have not been comprehensively updated especially within the last decade (up to 2021). In this review, plant xanthone biosynthesis is detailed to illuminate their intricacies and differences between species. The pathway initially involves the shikimate pathway, either through L-phenylalanine-dependent or -independent pathway, that later forms an intermediate benzophenone, 2,3′,4,6-tetrahydoxybenzophenone. This is followed by a regioselective intramolecular mediated oxidative coupling to form xanthone ring compounds, 1,3,5-trihydroxyxanthone (1,3,5-THX) or 1,3,7-THX, the core precursors for xanthones in most plants. Recent evidence has shed some lights onto the enzymes and reactions involved in this xanthone pathway. In particular, several biosynthetic enzymes have been characterized at both biochemical and molecular levels from various organisms including Hypericum spp., Centaurium erythraea and Garcinia mangostana. Proposed pathways for a plethora of other downstream xanthone derivatives including swertianolin and gambogic acid (derived from 1,3,5-THX) as well as gentisin, hyperixanthone A, α-mangostin, and mangiferin (derived from 1,3,7-THX) have also been thoroughly covered. This review reports one of the most complete xanthone pathways in plants. In the future, the information collected here will be a valuable resource for a more directed molecular works in xanthone-producing plants as well as in synthetic biology application.
Unexpected Intraspecific Variability of Perennial Ryegrass (Lolium perenne L.) in Response to Constant Temperature During Germination and Initial Heterotrophic Growth
Authors: Ahmed Lina Q. , Escobar-Gutiérrez Abraham J.
Published: April 2022

Lolium perenne (L.) is one of the most important species in temperate grasslands. Temperature is a major factor controlling plant development. Breeding L. perenne cultivars adapted to new ranges of temperature could be necessary under most climate change scenarios. However, before any breeding effort in such direction, knowing the intraspecific variability of responses to temperature is essential. Our objective was to analyze a sample of accessions of L. perenne for their response to constant temperature during germination and initial heterotrophic growth. Eight accessions were taken out from a genebank containing 160 accessions. Six accessions were wild populations collected in different places in France and the other two were populations from a selection program. For germination, four replicates of 100 seeds per accession were tested in Petri dishes in the dark at eight constant temperatures, from 5 to 40°C with increases of 5°C. Germination countings were carried out at variable time intervals and durations that depended on treatments. For initial heterotrophic growth analysis, seeds were germinated at 25°C. Sets of 30 seedlings per accession were placed in polypropylene boxes on blotter blue paper and transferred to each one of the eight treatments in the dark. They were pictured at variable time intervals for root and shoot growth measurement by image analysis. Neither seed germination nor heterotrophic growth was observed at 40°C, for any accession. Temperature and time course response surfaces were markedly different between accessions. Equally, maximum germinability and the shape of the response curves to temperature were significantly different between accessions. This means that limited similarities between responses were observed. Furthermore, germination rates followed the non-linear beta function with significant differences between some accessions. These also showed significant differences in their root and shoot growth rate in response to temperature. In general, the relative growth rates of roots and shoots were slow at 5°C, peaked between 25 and 30°C, and showed a sharp reduction afterward. These results reveal, for the first time, high genetic variability within L. perenne germplasm for the response to temperature in the initial life phases. This discovered variability should serve breeders to create perennial ryegrass varieties for the future.
The Role of Plant Growth Regulators in Modulating Root Architecture and Tolerance to High-Nitrate Stress in Tomato
Authors: Ji Rongting , Min Ju , Wang Yuan , Kronzucker Herbert J. , Shi Weiming
Published: April 2022

Plant growth regulators are known to exert strong influences on plant performance under abiotic stress, including exposure to high nitrate, as occurs commonly in intensive vegetable production. However, direct comparative evaluations of growth regulators under otherwise identical conditions in major crop species are scarce. In this study, tomato (Solanum lycopersicum L.) was used as a model crop, and the roles of four common exogenously applied plant growth regulators (MT, melatonin; SA, salicylic acid; HA, humic acid; SNP, sodium nitroprusside) in regulating crop growth were studied under high-nitrate stress. We provide a particular focus on root system architecture and root physiological responses. Our data show that all four growth regulators improve tomato tolerance under high nitrate, but that this occurs to differing extents and via differing mechanisms. Optimal concentrations of MT, SA, HA, and SNP were 50 μmol L–1, 25 μmol L–1, 25 mg L–1, and 50 μmol L–1, respectively. MT and SNP produced the strongest effects. MT enhanced root growth while SNP enhanced above-ground growth. Growth of coarse and thin lateral roots was significantly improved. Furthermore, an enhancement of root vitality and metabolism, improved integrity of root cell membranes, and an increase in antioxidant enzyme activities were found, but regulatory mechanisms were different for each growth regulator. Our results show that in particular the application of MT and SNP can improve growth of tomato in intensive vegetable production under high-nitrate stress and that root growth stimulation is of special importance in procuring these beneficial effects.