bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond Myelination: Possible Roles of the Immune Proteasome in Oligodendroglial Homeostasis and Dysfunction
Authors: Madeira Miguel M. , Hage Zachary , Tsirka Stella E.
Published: May 2022

Oligodendroglia play a critical role in CNS homeostasis by myelinating neuronal axons in their mature stages. Dysfunction in this lineage occurs when early stage OPCs are not able to differentiate to replace dying Mature Myelinating Oligodendrocytes. Many hypotheses exist as to why de- and hypo-myelinating disorders and diseases occur. In this review, we present data to show that oligodendroglia can adopt components of the immune proteasome under inflammatory conditions. The works reviewed further reflect that these immune-component expressing oligodendroglia can in fact function as antigen presenting cells, phagocytosing foreign entities and presenting them via MHC II to activate CD4+ T cells. Additionally, we hypothesize, based on the limited literature, that the adoption of immune components by oligodendroglia may contribute to their stalled differentiation in the context of these disorders and diseases. The present review will underline: (1) Mechanisms of neuroinflammation in diseases associated with Immune Oligodendroglia; (2) the first associations between the immune proteasome and oligodendroglia and the subtle distinctions between these works; (3) the suggested functionality of these cells as it is described by current literature; and (4) the hypothesized consequences on metabolism. In doing so we aim to shed light on this fairly under-explored cell type in hopes that study of their functionality may lead to further mechanistic understanding of hypo- and de-myelinating neuroinflammatory disorders and diseases.
Identification and Validation of Aging-Related Genes in Alzheimer’s Disease
Authors: Zhang Qian , Li Jian , Weng Ling
Published: May 2022

Aging is recognized as the key risk factor for Alzheimer’s disease (AD). This study aimed to identify and verify potential aging-related genes associated with AD using bioinformatics analysis. Aging-related differential expression genes (ARDEGs) were determined by the intersection of limma test, weighted correlation network analysis (WGCNA), and 1153 aging and senescence-associated genes. Potential biological functions and pathways of ARDEGs were determined by GO, KEGG, GSEA, and GSVA. Then, LASSO algorithm was used to identify the hub genes and the diagnostic ability of the five ARDEGs in discriminating AD from the healthy control samples. Further, the correlation between hub ARDEGs and clinical characteristics was explored. Finally, the expression level of the five ARDEGs was validated using other four GEO datasets and blood samples of patients with AD and healthy individuals. Five ARDEGs (GFAP, PDGFRB, PLOD1, MAP4K4, and NFKBIA) were obtained. For biological function analysis, aging, cellular senescence, and Ras protein signal transduction regulation were enriched. Diagnostic ability of the five ARDEGs in discriminating AD from the control samples demonstrated a favorable diagnostic value. Eventually, quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) validation test revealed that compared with healthy controls, the mRNA expression level of PDGFRB, PLOD1, MAP4K4, and NFKBIA were elevated in AD patients. In conclusion, this study identified four ARDEGs (PDGFRB, PLOD1, MAP4K4, and NFKBIA) associated with AD. They provide an insight into potential novel biomarkers for diagnosing AD and monitoring progression.
Leucine-Rich Repeats and Transmembrane Domain 2 Controls Protein Sorting in the Striatal Projection System and Its Deficiency Causes Disturbances in Motor Responses and Monoamine Dynamics
Authors: Ichise Misato , Sakoori Kazuto , Katayama Kei-ichi , Morimura Naoko , Yamada Kazuyuki , Ozawa Hiroki , Matsunaga Hayato , Hatayama Minoru , Aruga Jun
Published: May 2022

The striatum is involved in action selection, and its disturbance can cause movement disorders. Here, we show that leucine-rich repeats and transmembrane domain 2 (Lrtm2) controls protein sorting in striatal projection systems, and its deficiency causes disturbances in monoamine dynamics and behavior. The Lrtm2 protein was broadly detected in the brain, but it was enhanced in the olfactory bulb and dorsal striatum. Immunostaining revealed a strong signal in striatal projection output, including GABAergic presynaptic boutons of the SNr. In subcellular fractionation, Lrtm2 was abundantly recovered in the synaptic plasma membrane fraction, synaptic vesicle fraction, and microsome fraction. Lrtm2 KO mice exhibited altered motor responses in both voluntary explorations and forced exercise. Dopamine metabolite content was decreased in the dorsal striatum and hypothalamus, and serotonin turnover increased in the dorsal striatum. The prefrontal cortex showed age-dependent changes in dopamine metabolites. The distribution of glutamate decarboxylase 67 (GAD67) protein and gamma-aminobutyric acid receptor type B receptor 1 (GABABR1) protein was altered in the dorsal striatum. In cultured neurons, wild-type Lrtm2 protein enhanced axon trafficking of GAD67-GFP and GABABR1-GFP whereas such activity was defective in sorting signal-abolished Lrtm2 mutant proteins. The topical expression of hemagglutinin-epitope-tag (HA)-Lrtm2 and a protein sorting signal abolished HA-Lrtm2 mutant differentially affected GABABR1 protein distribution in the dorsal striatum. These results suggest that Lrtm2 is an essential component of striatal projection neurons, contributing to a better understanding of striatal pathophysiology.
Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection
Authors: Löscher Wolfgang , Howe Charles L.
Published: May 2022

Seizures are a common presenting symptom during viral infections of the central nervous system (CNS) and can occur during the initial phase of infection (“early” or acute symptomatic seizures), after recovery (“late” or spontaneous seizures, indicating the development of acquired epilepsy), or both. The development of acute and delayed seizures may have shared as well as unique pathogenic mechanisms and prognostic implications. Based on an extensive review of the literature, we present an overview of viruses that are associated with early and late seizures in humans. We then describe potential pathophysiologic mechanisms underlying ictogenesis and epileptogenesis, including routes of neuroinvasion, viral control and clearance, systemic inflammation, alterations of the blood-brain barrier, neuroinflammation, and inflammation-induced molecular reorganization of synapses and neural circuits. We provide clinical and animal model findings to highlight commonalities and differences in these processes across various neurotropic or neuropathogenic viruses, including herpesviruses, SARS-CoV-2, flaviviruses, and picornaviruses. In addition, we extensively review the literature regarding Theiler’s murine encephalomyelitis virus (TMEV). This picornavirus, although not pathogenic for humans, is possibly the best-characterized model for understanding the molecular mechanisms that drive seizures, epilepsy, and hippocampal damage during viral infection. An enhanced understanding of these mechanisms derived from the TMEV model may lead to novel therapeutic interventions that interfere with ictogenesis and epileptogenesis, even within non-infectious contexts.
Anticonvulsant Effect of Carbenoxolone on Chronic Epileptic Rats and Its Mechanism Related to Connexin and High-Frequency Oscillations
Authors: Liu Benke , Ran Xiao , Yi Yanjun , Zhang Xinyu , Chen Hengsheng , Hu Yue
Published: May 2022

Objective

This study was designed to investigate the influence and mechanism of gap junction carbenoxolone (CBX) on dynamic changes in the spectral power of ripples and fast ripples (FRs) in the hippocampus of chronic epileptic rats.

Methods

The lithium-pilocarpine (PILO) status epilepticus (SE) model (PILO group) and the CBX pretreatment model (CBX + PILO group) were established to analyze dynamic changes in the spectral power of ripples and FRs, and the dynamic expression of connexin (CX)26, CX32, CX36, and CX43 in the hippocampus of chronic epileptic rats.

Results

Within 28 days after SE, the number of spontaneous recurrent seizures (SRSs) in the PILO group was significantly higher than that in the CBX + PILO group. The average spectral power of FRs in the PILO group was significantly higher than the baseline level at 1 and 7 days after SE. The average spectral power of FRs in the PILO group was significantly higher than that in the CBX + PILO group at 1, 7, and 14 days after SE. Seizures induced an increase in CX43 expression at 1 and 7 days after SE, but had no significant effect on CX26, CX36, or CX32. CBX pretreatment did not affect the expression of CXs in the hippocampus of normal rats, but it inhibited the expression of CX43 in epileptic rats. The number of SRSs at 2 and 4 weeks after SE had the highest correlation with the average spectral power of FRs; the average spectral power of FRs was moderately correlated with the expression of CX43.

Conclusion

The results of this study indicate that the energy of FRs may be regulated by its interference with the expression of CX43, and thus, affect seizures. Blocking the expression of CX43 thereby reduces the formation of pathological high-frequency oscillations (HFOs), making it a promising strategy for the treatment of chronic epilepsy.
Endothelial β-Catenin Deficiency Causes Blood-Brain Barrier Breakdown via Enhancing the Paracellular and Transcellular Permeability
Authors: Hussain Basharat , Fang Cheng , Huang Xiaowen , Feng Ziying , Yao Yuxuan , Wang Yu , Chang Junlei
Published: May 2022

Disruption of the blood-brain barrier (BBB) causes or contributes to neuronal dysfunction and several central nervous system (CNS) disorders. Wnt/β-catenin signaling is essential for maintaining the integrity of the adult BBB in physiological and pathological conditions, including stroke. However, how the impairment of the endothelial Wnt/β-catenin signaling results in BBB breakdown remains unclear. Furthermore, the individual contributions of different BBB permeability-inducing mechanisms, including intercellular junction damage, endothelial transcytosis, and fenestration, remains unexplored. Here, we induced β-catenin endothelial-specific conditional knockout (ECKO) in adult mice and determined its impact on BBB permeability and the underlying mechanism. β-catenin ECKO reduced the levels of active β-catenin and the mRNA levels of Wnt target genes in mice, indicating downregulation of endothelial Wnt/β-catenin signaling. β-catenin ECKO mice displayed severe and widespread leakage of plasma IgG and albumin into the cerebral cortex, which was absent in wild-type controls. Mechanistically, both the paracellular and transcellular transport routes were disrupted in β-catenin ECKO mice. First, β-catenin ECKO reduced the tight junction protein levels and disrupted the intercellular junction ultrastructure in the brain endothelium. Second, β-catenin ECKO substantially increased the number of endothelial vesicles and caveolae-mediated transcytosis through downregulating Mfsd2a and upregulating caveolin-1 expression. Interestingly, fenestration and upregulated expression of the fenestration marker Plvap were not observed in β-catenin ECKO mice. Overall, our study reveals that endothelial Wnt/β-catenin signaling maintains adult BBB integrity via regulating the paracellular as well as transcellular permeability. These findings may have broad applications in understanding and treatment of CNS disorders involving BBB disruption.
Selective Recruitment of Presynaptic and Postsynaptic Forms of mGluR-LTD
Authors: Sanderson Thomas M. , Ralph Liam T. , Amici Mascia , Ng Ai Na , Kaang Bong-Kiun , Zhuo Min , Kim Sang Jeong , Georgiou John , Collingridge Graham L.
Published: May 2022

In area CA1 of the hippocampus, long-term depression (LTD) can be induced by activating group I metabotropic glutamate receptors (mGluRs), with the selective agonist DHPG. There is evidence that mGluR-LTD can be expressed by either a decrease in the probability of neurotransmitter release [P(r)] or by a change in postsynaptic AMPA receptor number. However, what determines the locus of expression is unknown. We investigated the expression mechanisms of mGluR-LTD using either a low (30 μM) or a high (100 μM) concentration of (RS)-DHPG. We found that 30 μM DHPG generated presynaptic LTD that required the co-activation of NMDA receptors, whereas 100 μM DHPG resulted in postsynaptic LTD that was independent of the activation of NMDA receptors. We found that both forms of LTD occur at the same synapses and that these may constitute the population with the lowest basal P(r). Our results reveal an unexpected complexity to mGluR-mediated synaptic plasticity in the hippocampus.
Amplitude and Temporal Dynamics of Motion Sickness
Authors: Irmak Tugrul , Kotian Varun , Happee Riender , de Winkel Ksander N. , Pool Daan M.
Published: May 2022

The relationship between the amplitude of motion and the accumulation of motion sickness in time is unclear. Here, we investigated this relationship at the individual and group level. Seventeen participants were exposed to four oscillatory motion stimuli, in four separate sessions, separated by at least 1 week to prevent habituation. Motion amplitude was varied between sessions at either 1, 1.5, 2, or 2.5 ms−2. Time evolution was evaluated within sessions applying: an initial motion phase for up to 60 min, a 10-min rest, a second motion phase up to 30 min to quantify hypersensitivity and lastly, a 5-min rest. At both the individual and the group level, motion sickness severity (MISC) increased linearly with respect to acceleration amplitude. To analyze the evolution of sickness over time, we evaluated three variations of the Oman model of nausea. We found that the slow (502 s) and fast (66.2 s) time constants of motion sickness were independent of motion amplitude, but varied considerably between individuals (slow STD = 838 s; fast STD = 79.4 s). We also found that the Oman model with output scaling following a power law with an exponent of 0.4 described our data much better as compared to the exponent of 2 proposed by Oman. Lastly, we showed that the sickness forecasting accuracy of the Oman model depended significantly on whether the participants had divergent or convergent sickness dynamics. These findings have methodological implications for pre-experiment participant screening, as well as online tuning of automated vehicle algorithms based on sickness susceptibility.
Estimating How Sounds Modulate Orientation Representation in the Primary Visual Cortex Using Shallow Neural Networks
Authors: McClure John P. , Erkat O. Batuhan , Corbo Julien , Polack Pierre-Olivier
Published: May 2022

Audiovisual perception results from the interaction between visual and auditory processing. Hence, presenting auditory and visual inputs simultaneously usually improves the accuracy of the unimodal percepts, but can also lead to audiovisual illusions. Cross-talks between visual and auditory inputs during sensory processing were recently shown to occur as early as in the primary visual cortex (V1). In a previous study, we demonstrated that sounds improve the representation of the orientation of visual stimuli in the naïve mouse V1 by promoting the recruitment of neurons better tuned to the orientation and direction of the visual stimulus. However, we did not test if this type of modulation was still present when the auditory and visual stimuli were both behaviorally relevant. To determine the effect of sounds on active visual processing, we performed calcium imaging in V1 while mice were performing an audiovisual task. We then compared the representations of the task stimuli orientations in the unimodal visual and audiovisual context using shallow neural networks (SNNs). SNNs were chosen because of the biological plausibility of their computational structure and the possibility of identifying post hoc the biological neurons having the strongest influence on the classification decision. We first showed that SNNs can categorize the activity of V1 neurons evoked by drifting gratings of 12 different orientations. Then, we demonstrated using the connection weight approach that SNN training assigns the largest computational weight to the V1 neurons having the best orientation and direction selectivity. Finally, we showed that it is possible to use SNNs to determine how V1 neurons represent the orientations of stimuli that do not belong to the set of orientations used for SNN training. Once the SNN approach was established, we replicated the previous finding that sounds improve orientation representation in the V1 of naïve mice. Then, we showed that, in mice performing an audiovisual detection task, task tones improve the representation of the visual cues associated with the reward while deteriorating the representation of non-rewarded cues. Altogether, our results suggest that the direction of sound modulation in V1 depends on the behavioral relevance of the visual cue.
Management of Malnutrition Based on Multidisciplinary Team Decision-Making in Chinese Older Adults (3M Study): A Prospective, Multicenter, Randomized, Controlled Study Protocol
Authors: Ji Tong , Zhang Li , Han Rui , Peng Linlin , Shen Shanshan , Liu Xiaolei , Shi Yanqing , Chen Xujiao , Chen Qiong , Li Yun , Ma Lina
Published: May 2022

Background

In hospital settings, malnutrition affects 30–50% of aged inpatients and is related to a higher risk of hospital complications and death. This study aims to demonstrate the effectiveness of a tailored optimum nutritional therapy in malnourished, elderly inpatients based on multidisciplinary team recommendations in hopes of decreasing the incidence of deleterious clinical outcomes.

Methods and Design

This trial will be a multicenter, open-label, randomized control trial conducted in the geriatric wards of at least five hospitals in five different regions. We aim to include 500 inpatients over the age of 60 with or at risk of malnutrition based on a Mini Nutritional Assessment Short-Form (MNA-SF) score of ≤ 11 points and the Global Leadership Initiative on Malnutrition with an expected length of stay of ≥ 7 days. Eligible inpatients will be randomized into a 1:1 ratio, with one receiving a multidisciplinary team intervention and the other receiving standard medical treatment or care alone. A structured comprehensive assessment of anthropometry, nutritional status, cognition, mood, functional performance, and quality of life will be conducted twice. These assessments will take place on the day of group allocation and 1 year after discharge, and a structured screening assessment for elderly malnutrition will be conducted at 3 and 6 months after discharge using the MNA-SF. The primary outcome will be nutritional status based on changes in MNA-SF scores at 3, 6 months, and 1 year. The secondary outcome will be changes in cognition, mood, functional status, length of hospital stay, and all-cause mortality 1 year after discharge.

Discussion

Guided by the concept of interdisciplinary cooperation, this study will establish a multidisciplinary nutrition support team that will develop an innovative intervention strategy that integrates nutritional screenings, evaluations, education, consultation, support, and monitoring. Moreover, nutritional intervention and dietary fortification will be provided to hospitalized elderly patients with or at risk of malnutrition. The nutrition support team will formulate a clinical map for malnutrition in elderly patients with standardized diagnosis and treatment for malnutrition in this population.

Clinical Trial Registration

[www.ClinicalTrials.gov], identifier [ChiCTR2200055331].
Polyphenol Supplementation Did Not Affect Insulin Sensitivity and Fat Deposition During One-Month Overfeeding in Randomized Placebo-Controlled Trials in Men and in Women
Authors: Segrestin Bérénice , Delage Pauline , Nemeth Angéline , Seyssel Kevin , Disse Emmanuel , Nazare Julie-Anne , Lambert-Porcheron Stéphanie , Meiller Laure , Sauvinet Valerie , Chanon Stéphanie , Simon Chantal , Ratiney Hélène , Beuf Olivier , Pralong François , Yassin Naba-al-Huda , Boizot Alexia , Gachet Mélanie , Burton-Pimentel Kathryn J. , Vidal Hubert , Meugnier Emmanuelle , Vionnet Nathalie , Laville Martine
Published: May 2022

Two randomized placebo-controlled double-blind paralleled trials (42 men in Lyon, 19 women in Lausanne) were designed to test 2 g/day of a grape polyphenol extract during 31 days of high calorie-high fructose overfeeding. Hyperinsulinemic-euglycemic clamps and test meals with [1,1,1-13C3]-triolein were performed before and at the end of the intervention. Changes in body composition were assessed by dual-energy X-ray absorptiometry (DEXA). Fat volumes of the abdominal region and liver fat content were determined in men only, using 3D-magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) at 3T. Adipocyte’s size was measured in subcutaneous fat biopsies. Bodyweight and fat mass increased during overfeeding, in men and in women. While whole body insulin sensitivity did not change, homeostasis model assessment of insulin resistance (HOMA-IR) and the hepatic insulin resistance index (HIR) increased during overfeeding. Liver fat increased in men. However, grape polyphenol supplementation did not modify the metabolic and anthropometric parameters or counteract the changes during overfeeding, neither in men nor in women. Polyphenol intake was associated with a reduction in adipocyte size in women femoral fat. Grape polyphenol supplementation did not counteract the moderated metabolic alterations induced by one month of high calorie-high fructose overfeeding in men and women. The clinical trials are registered under the numbers NCT02145780 and NCT02225457 at ClinicalTrials.gov and available at https://clinicaltrials.gov/ct2/show/NCT02145780 and https://clinicaltrials.gov/ct2/show/NCT02225457.
Hyperthermic Intraperitoneal Chemotherapy and Cytoreductive Surgery in Ovarian Cancer: An Umbrella Review of Meta-Analyses
Authors: Souadka Amine , Essangri Hajar , Majbar Mohammed Anass , Benkabbou Amine , Boutayeb Saber , You Benoit , Glehen Olivier , Mohsine Raouf , Bakrin Naoual
Published: May 2022

Background

The utility of heated intraperitoneal chemotherapy (HIPEC) in the management of epithelial ovarian cancer (EOC) has been assessed in several randomised clinical trials and meta-analyses, and it is still a subject of controversy. Therefore, we performed an umbrella review of existing meta-analyses to summarise the outcomes of HIPEC and cytoreductive surgery (CRS) association in ovarian cancer.

Methods

We examined the MEDLINE, Cochrane Library, Scopus, Prospero, Web of Science and Science Direct from inception to May 30, 2020, for meta-analyses of randomised controlled trials and observational studies. Analyses of overall survival, disease free survival and progression survival were performed separately for primary and recurrent ovarian cancers.

Results

We identified 6 meta-analyses investigating the association of HIPEC with CRS in the management of ovarian cancer. Three year overall survival was significantly improved by the association of CRS and HIPEC for primary (HR: 0.66, 95%CI:0.56-0.78) and recurrent ovarian cancers (HR:0.50, 95%CI:0.38-0.64). This benefit was also demonstrated on disease-free survival for primary (HR: 0.54, 95%CI:0.48-0.61) and recurrent ovarian cancer (HR: 0.60, 95%CI:0.46-0.78). The pooled hazard ratios confirmed the advantage of HIPEC and CRS association with respect to CRS alone on progression free survival for primary and recurrent ovarian cancer respectively with HR: 0.50, 95%CI: 0.43-0.58 and HR: 0.59, 95%CI: 0.41-0.85.

Conclusion

While waiting for the results of the current prospective studies, the present umbrella study suggests that HIPEC performed at the end of CRS may be a complementary effective asset for ovarian cancer patient management.
Advances in the Study of CircRNAs in Tumor Drug Resistance
Authors: Wang Song , Qian Long , Cao Tingting , Xu Li , Jin Yan , Hu Hao , Fu Qingsheng , Li Qian , Wang Ye , Wang Jiawei , Xia Yabin , Huang Xiaoxu
Published: May 2022

Recent studies have revealed that circRNAs can affect tumor DNA damage and repair, apoptosis, proliferation, and invasion and influence the transport of intratumor substances by acting as miRNA sponges and transcriptional regulators and binding to proteins in a variety of ways. However, research on the role of circRNAs in cancer radiotherapy and chemoresistance is still in its early stages. Chemotherapy is a common approach to oncology treatment, but the development of tumor resistance limits the overall clinical efficacy of chemotherapy for cancer patients. The current study suggests that circRNAs have a facilitative or inhibitory effect on the development of resistance to conventional chemotherapy in a variety of tumors, suggesting that circRNAs may serve as a new direction for the study of antitumor drug resistance. In this review, we will briefly discuss the biological features of circRNAs and summarize the recent progression of the involvement of circRNAs in the development and pathogenesis of cancer chemoresistance.
Preoperative Thyroid Peroxidase Antibody Predicts Recurrence in Papillary Thyroid Carcinoma: A Consecutive Study With 5,770 Cases
Authors: Wang Weibin , Wen Liping , Chen Shitu , Su Xingyun , Mao Zhuochao , Ding Yongfeng , Chen Zhendong , Chen Yiran , Ruan Jiaying , Yang Jun , Zhou Jie , Teng Xiaodong , Fahey Thomas J. , Li Zhongqi , Teng Lisong
Published: May 2022

Background

Thyroid autoimmunity is common in papillary thyroid carcinoma (PTC) and was believed to confer a better prognosis; however, controversy still remains. This study aimed to investigate the prognostic value of chronic lymphocytic thyroiditis (CLT) and preoperative thyroid peroxidase antibody (TPOAb) in PTC patients.

Methods

A retrospective analysis was performed on 5,770 PTC patients who underwent surgical treatment with pathologically confirmed PTC in our institution between 2012 to 2016. The patients were divided into groups with respect to the coexistence of CLT or preoperative TPOAb levels. The clinicopathological characteristics and disease-free survival (DFS) rates were compared between the groups.

Results

The coexistence of CLT was likely to have bilateral, multifocal tumors. Particularly, PTC patients with TPOAb++ (>1,000 IU/L) had a larger tumor size (p = 0.007) and higher rates of bilaterality and multifocality than those with TPOAb− (TPOAb< 100 IU/L), while for lymph node metastasis and extrathyroidal extension, there is no statistical difference. Tumor recurrence was found in 15 of 425 (3.5%), 9 of 436 (2.1%), and 56 of 3,519 (1.6%) patients with TPOAb++, TPOAb+, and TPOAb−, respectively (p = 0.017). On univariate analysis, TPOAb++ was correlated with tumor recurrence, with a hazard ratio of 2.20 [95% confidence interval (CI), 1.25–3.89], which remained as an independent risk factor at 1.98 (95% CI, 1.10–3.55) on multivariate analysis. PTC patients with TPOAb++ had the lowest DFS rates (96.5 vs. 97.9 vs. 98.4%, p = 0.020).

Conclusion

CLT is not a protective factor in PTC patients. We provide initial evidence that the preoperative TPOAb instead predicts recurrence in papillary thyroid carcinoma.
Andrographolide Inhibits ER-Positive Breast Cancer Growth and Enhances Fulvestrant Efficacy via ROS-FOXM1-ER-α Axis
Authors: Xu Tong , Jiang Yanyu , Yuan Shuying , Zhang Li , Chen Xihui , Zhao Weili , Cai Lili , Xiao Biying , Jia Lijun
Published: May 2022

Estrogen receptor (ER)-positive breast cancer is the main subtype of breast cancer (BRCA) with high incidence and mortality. Andrographolide (AD), a major active component derived from the traditional Chinese medicine Andrographis paniculate, has substantial anti-cancer effect in various tumors. However, the antitumor efficacy and the underlying molecular mechanisms of AD on ER-positive breast cancer are poorly understood. In the present study, we demonstrated that andrographolide (AD) significantly inhibited the growth of ER-positive breast cancer cells. Mechanistically, AD suppressed estrogen receptor 1 (ESR1, encodes ER-α) transcription to inhibit tumor growth. Further studies revealed that AD induced ROS production to down-regulate FOXM1-ER-α axis. Conversely, inhibiting ROS production with N-acetylcysteine (NAC) elevated AD-decreased ER-α expression, which could be alleviated by FOXM1 knockdown. In addition, AD in combination with fulvestrant (FUL) synergistically down-regulated ER-α expression to inhibit ER-positive breast cancer both in vitro and in vivo. These findings collectively indicate that AD suppresses ESR1 transcription through ROS-FOXM1 axis to inhibit ER-positive breast cancer growth and suggest that AD might be a potential therapeutic agent and fulvestrant sensitizer for ER-positive breast cancer treatment.
Characteristics and Outcomes of Cases of Children and Adolescents With Pediatric Inflammatory Multisystem Syndrome in a Tertiary Care Center in Mexico City
Authors: Gil Guevara Ricardo , Marroquín Yáñez María de Lourdes , Jiménez-Juárez Rodolfo Norberto , Olivar Lopez Víctor , Chávez Lopez Adrián , Sienra Monge Juan José Luis , Jamaica Balderas Lourdes Maria del Carmen , Martínez Herrera Silvia Alexandra , Domínguez-Barrera Clemen , Erdmenger Orellana Julio , Márquez González Horacio , Klünder-Klünder Miguel , Nieto Zermeño Jaime , Villa Guillen Mónica , González García Nadia , Castilla-Peon Maria F.
Published: May 2022

Background

Pediatric inflammatory multisystem syndrome (PIMS) is a complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children that resembles Kawasaki syndrome and places them at high risk of cardiorespiratory instability and/or cardiac damage. This study aims to describe the clinical presentation and outcomes of patients with PIMS in Mexico City.

Methods

This was an observational study of children hospitalized for PIMS based on the Centers for Disease Control and Prevention case definition criteria, in a single tertiary care pediatric center in Mexico City between May 1, 2020, and September 30, 2021. Demographic characteristics, epidemiological data, medical history, laboratory tests, cardiologic evaluations, treatment, and clinical outcomes were analyzed.

Results

Seventy-five cases fulfilled the case definition criteria for PIMS [median age: 10.9 years, Interquartile range (IQR): 5.6–15.6]. Fifteen (20%) patients had a severe underlying disease, 48 (64%) were admitted to the intensive care unit, 33 (44%) required invasive mechanical ventilation and 39 (52%) received vasopressor support. The patients were clustered through latent class analysis based on identified symptoms: Cluster 1 had rash or gastrointestinal symptoms (n = 60) and cluster 2 were those with predominantly respiratory manifestations (n = 15). Two patients (2.7%) died, and both had severe underlying conditions. Five patients (6.7%), all from cluster 1, developed coronary aneurysms.

Conclusion

There were a high proportion of patients with severe respiratory involvement and positive RT-PCR SARS-CoV-2 and very few cases of coronary aneurysms in our study which suggests that a high proportion of the children had severe acute COVID-19. The clinical manifestations and outcomes are comparable to previously reported international studies.
The Fragility Index of Randomized Controlled Trials for Preterm Neonates
Authors: Li Huiyi , Liang Zhenyu , Meng Qiong , Huang Xin
Published: May 2022

Background

As a metric to determine the robustness of trial results, the fragility index (FI) is the number indicating how many patients would be required to reverse the significant results. This study aimed to calculate the FI in randomized controlled trials (RCTs) involving premature.

Methods

Trials were included if they had a 1:1 study design, reported statistically significant dichotomous outcomes, and had an explicitly stated sample size or power calculation. The FI was calculated for binary outcomes using Fisher’s exact test, and the FIs of subgroups were compared. Spearman’s correlation was applied to determine correlations between the FI and study characteristics.

Results

Finally, 66 RCTs were included in the analyses. The median FI for these trials was 3.00 (interquartile range [IQR]: 1.00–5.00), with a median fragility quotient of 0.014 (IQR: 0.008–0.028). FI was ≤ 3 in 42 of these 66 RCTs (63.6%), and in 42.4% (28/66) of the studies, the number of patients lost to follow-up was greater than that of the FI. Significant differences were found in the FI among journals (p = 0.011). We observed that FI was associated with the sample size, total number of events, and reported p-values (rs = 0.437, 0.495, and −0.857, respectively; all p < 0.001).

Conclusion

For RCTs in the premature population, a median of only three events was needed to change from a “non-event” to “event” to render a significant result non-significant, indicating that the significance may hinge on a small number of events.
A Novel Immune-Prognosis Index Predicts the Benefit of Lung Adenocarcinoma Patients
Authors: Bai Yuquan , Pei Yun , Xia Liang , Ma Lin , Deng Senyi
Published: May 2022

Background: Constructed an immune-prognosis index (IPI) and divided lung adenocarcinoma (LUAD) patients into different subgroups according to IPI score, describe the molecular and immune characteristics of patients between different IPI subgroups, and explore their response to immune checkpoint blockade (ICB) treatment.

Methods: Based on the transcriptome profile of LUAD patients in TCGA and immune gene sets from ImmPort and InnateDB, 15 hub immune genes were identified through correlation and Bayesian causal network analysis. Then, IPI was constructed with 5 immune genes by using COX regression analysis and verified with external datasets (GSE30219, GSE37745, GSE68465, GSE126044 and GSE135222). Finally, the characteristics and the response to ICB treatment of LUAD patients between two different IPI subgroups were analyzed.

Results: IPI was constructed based on the expression of 5 genes, including A2M, ADRB1, ADRB2, VIPR1 and PTH1R. IPI-high LUAD patients have a better overall survival than IPI-low LUAD patients, consistent with the results in the GEO cohorts. The comprehensive results showed that patients in the IPI-high subgroup were exhibited characters as metabolism-related signaling pathways activation, lower TP53 and TTN mutation rate, more infiltrations of CD8 T cells, dendritic cells and macrophages M1, especially earned more benefit from ICB treatment. In contrast, patients in the IPI-low subgroup were exhibited characters as p53 signaling pathways activation, higher TP53 and TTN mutation rate, more infiltrations of resting memory CD4 T cells, macrophages M2, immune-suppressive response and less benefit from ICB treatment.

Conclusion: IPI is a potentially valuable prognostic evaluation method for LUAD, which works well in the benefit predicting of LUAD patients within ICB treatment.
Tetrandrine Citrate Suppresses Breast Cancer via Depletion of Glutathione Peroxidase 4 and Activation of Nuclear Receptor Coactivator 4-Mediated Ferritinophagy
Authors: Yin Jiameng , Lin Yajun , Fang Weiwei , Zhang Xin , Wei Jie , Hu Gang , Liu Pu , Niu Jie , Guo Jun , Zhen Yongzhan , Li Jian
Published: May 2022

Tetrandrine citrate (TetC), a novel tetrandrine salt with high water solubility, demonstrates a potent antitumor activity in chronic myeloid leukemia. Studies have indicated an important role of ferroptosis in breast cancer (BC). However, whether TetC inhibits BC progression via ferroptosis has never been explored. In the present study, we showed that TetC had a significant inhibitory effect on the proliferation and migration of MCF7 and MDA-MB-231 cells. Then, we combined TetC with different inhibitors to determine which form of cell death could be driven by TetC. MTT assay showed that ferrostatin (Fer-1) demonstrated the most potent effect on improving TetC-induced cell death in contrast to other inhibitors. TetC was also shown to significantly increase the mRNA level of prostaglandin-endoperoxide synthase 2 (Ptgs2), a ferroptosis marker. Further studies showed that TetC significantly suppressed the expression of glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) but increased the expression of nuclear receptor coactivator 4 (NCOA4) in MCF7 and MDA-MB-231 cells even in the presence of erastin or Ras-selective lethal 3 (RSL3). Collectively, we showed novel data that ferroptosis was a major form of TetC-induced cell death. Moreover, TetC-induced ferroptotic cell death was achieved via suppressing GPX4 expression and activating NCOA4-mediated ferritinophagy in BC cells.
Effects of Pereskia aculeate Miller Petroleum Ether Extract on Complete Freund’s Adjuvant-Induced Rheumatoid Arthritis in Rats and its Potential Molecular Mechanisms
Authors: Chen Yifei , Liu Kaifei , Qin Yingyuan , Chen Suyi , Guan Guokai , Huang Yao , Chen Yu , Mo Zhixian
Published: May 2022

Objective: To investigate the therapeutic effect of petroleum ether extract of P. aculeate Miller (PEEP) on rheumatoid arthritis (RA).

Methods:In vitro: The Cell Counting Kit-8 (CCK-8) was used to detect cell activity and select the optimal concentration of the extract; the effective site was screened by nitric oxide (NO) colorimetric method and Q-PCR method; the expression of p38, p-p38, p-MK2, and Tristetraprolin (TTP) in RAW 264.7 cells were detected by Western blot. In vivo: The rat model was established by complete Freund’s adjuvant (CFA). The different doses of PEEP on CFA rats were observed with life status, paw swelling, spleen index, X-ray, Hematoxylin eosin (HE) staining; the secretion of Tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and Prostaglandin E2 (PGE2) were detected by Enzyme linked immunosorbent assay (ELISA); the expressions of p38, p-p38, p-MK2, and TTP in the ankle joints of CFA rats were detected by Western blot.

Result:In vitro: PEEP, Ethyl Acetate Extract of P. aculeate Miller (EEEP), N-butanol Extract of P. aculeate Miller (BEEP) have no toxic effects on RAW264.7 macrophages. PEEP, EEEP, and BEEP reduce the secretion of NO in RAW264.7 cells induced by lipopolysaccharide (LPS), only PEEP significantly inhibited the mRNA expression levels of inflammatory factors TNF-α and IL-6; PEEP-dependently reduce the secretion of TNF-α and IL-6, decrease the expression of p-p38 and p-MK2, and the level of TTP phosphorylation in LPS-induced RAW264.7 cells. In vivo: PEEP improve the living conditions of CFA rats, reduce foot swelling, spleen index, bone surface erosion and joint space narrowing; reduce the formation of synovial cells, inflammatory cells and pannus in the foot and ankle joints. PEEP reduce the secretion of TNF-α, IL-6, PGE2 in rat serum, downregulate the expression of p-p38 and p-MK2 in the ankle joint, and reduce the phosphorylation of TTP.

Conclusion: PEEP improve the living conditions of CFA rats, reduce the degree of foot swelling, protect immune organs, reduce inflammatory cell infiltration, cartilage damage, pannus formation, reduce inflammation and RA damage. The mechanism through regulating the signal pathway of p38 mitogen-activated protein kinase (p38/MAPK), which reduces the release of TNF-α, IL-6, and PGE2 in the serum.
Obeticholic Acid Induces Hepatoxicity Via FXR in the NAFLD Mice
Authors: Lin Chuangzhen , Yu Bingqing , Chen Lixin , Zhang Zhaohui , Ye Weixiang , Zhong Hui , Bai Wenke , Yang Yuping , Nie Biao
Published: May 2022

Objective: Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, is a promising drug for nonalcoholic fatty liver disease (NAFLD); however, it can cause liver injury, especially at high doses. Here, we investigated the role of FXR in the high-dose OCA-induced hepatoxicity in the condition of the NAFLD mouse model.

Methods: Wild-type (WT) mice and FXR−/− mice were administered with over-dose OCA (0.40%) and high-dose OCA (0.16%), in a high-fat diet. RNA-seq on liver samples of mice fed with high-dose OCA was performed to dig out the prominent biological events contributing to hepatic fibrosis.

Results: Over-dose OCA induced liver injury and shortened survival in WT mice, but not FXR−/− mice. High-dose OCA caused hepatic stellate cell activation and liver fibrosis in the presence of FXR. Furthermore, high-dose OCA induced cholesterol accumulation in livers via the upregulation of genes involved in cholesterol acquisition and downregulation of genes regulating cholesterol degradation in liver, leading to the production of interleukin -1β and an FXR-mediated inflammatory response.

Conclusion: The high-dose OCA induced FXR-dependent hepatic injury via cholesterol accumulation and interleukin -1β pathway in the NAFLD mice.
Prototype Development and Validation of a Beam-Divergence Control System for Free-Space Laser Communications
Authors: Carrasco-Casado Alberto , Shiratama Koichi , Kolev Dimitar , Trinh Phuc V. , Fuse Tetsuharu , Fuse Shingo , Kawaguchi Koji , Hashimoto Yusuke , Hyodo Masamitsu , Sakamoto Takashi , Kunisada Terufusa , Toyoshima Morio
Published: May 2022

Being able to dynamically control the transmitted-beam divergence can bring important advantages in free-space optical communications. Specifically, this technique can help to optimize the overall communications performance when the optimum laser-beam divergence is not fixed or known. This is the case in most realistic space laser communication systems, since the optimum beam divergence depends on multiple factors that can vary with time, such as the link distance, or cannot be accurately known, such as the actual pointing accuracy. A dynamic beam-divergence control allows to optimize the link performance for every platform, scenario, and condition. NICT is currently working towards the development of a series of versatile lasercom terminals that can fit a variety of conditions, for which the adaptive element of the transmitted beam divergence is a key element. This manuscript presents a prototype of a beam-divergence control system designed and developed by NICT and Tamron to evaluate this technique and to be later integrated within the lasercom terminals. The basic design of the prototype is introduced as well as the first validation tests that demonstrate its performance.
Perfect Optical Vortex to Produce Controllable Spot Array
Authors: Jiang Xiaotong , Tian Yuyuan , Sun Meiyu , Li Zhigang , Zhang Dengying , Cao Kunjian , Shi Qiang , Zhu Linwei
Published: May 2022

The perfect optical vortex has successfully aroused substantial interest from researchers for its central dark hollow caused by spatial phase singularity in recent years. However, the traditional methods of combining the axicon and helical phase to generate the perfect optical vortex lead to an additional focus deviation in the tightly focused systems. Here, we report a multi-foci integration (MFI) method to produce the perfect optical vortex by accumulating a finite number of foci in the focal plane to overcome the additional focus deviation. Furthermore, based on MFI, we superposed two perfect optical vortices to obtain the spot array with controllable phase distribution and the number of spots. This work deepens our knowledge about superposed vortices and facilitates new potential applications. The micromanipulated experimental results agree well with our theoretical simulation. The spot array field provides new opportunities in direct laser writing, optical tweezers, optical communications, and optical storage.
Synthesis Design of Dual-Band Filtering Power Dividers Based on E-Shape Resonators
Authors: Shen Jiwei , Li Wei , Ping Kang , Zhang Zhuowei , Shu Minghan
Published: May 2022

In this study, a comprehensive design of dual-band filtering power dividers (FPDs) with arbitrary phase distribution is presented. With a series of analytical equations for the direct synthesis design, the proposed method shows its great capacity of designing dual-band FPDs with any pre-specified responses, arbitrary phase distribution, and high isolation. To verify this design method, a demonstrated dual-band FPD with 90° phase differences between two outputs based on E-shape resonators has been implemented. The emulational results coincide with the measured results well, showing the feasibility of the proposed method.
Longitudinally Tracking Maternal Autonomic Modulation During Normal Pregnancy With Comprehensive Heart Rate Variability Analyses
Authors: Bester Maretha , Joshi Rohan , Mischi Massimo , van Laar Judith O. E. H. , Vullings Rik
Published: May 2022

Changes in the maternal autonomic nervous system are essential in facilitating the physiological changes that pregnancy necessitates. Insufficient autonomic adaptation is linked to complications such as hypertensive diseases of pregnancy. Consequently, tracking autonomic modulation during progressing pregnancy could allow for the early detection of emerging deteriorations in maternal health. Autonomic modulation can be longitudinally and unobtrusively monitored by assessing heart rate variability (HRV). Yet, changes in maternal HRV (mHRV) throughout pregnancy remain poorly understood. In previous studies, mHRV is typically assessed only once per trimester with standard HRV features. However, since gestational changes are complex and dynamic, assessing mHRV comprehensively and more frequently may better showcase the changing autonomic modulation over pregnancy. Subsequently, we longitudinally (median sessions = 8) assess mHRV in 29 healthy pregnancies with features that assess sympathetic and parasympathetic activity, as well as heart rate (HR) complexity, HR responsiveness and HR fragmentation. We find that vagal activity, HR complexity, HR responsiveness, and HR fragmentation significantly decrease. Their associated effect sizes are small, suggesting that the increasing demands of advancing gestation are well tolerated. Furthermore, we find a notable change in autonomic activity during the transition from the second to third trimester, highlighting the dynamic nature of changes in pregnancy. Lastly, while we saw the expected rise in mean HR with gestational age, we also observed increased autonomic deceleration activity, seemingly to counter this rising mean HR. These results are an important step towards gaining insights into gestational physiology as well as tracking maternal health via mHRV.
Transcriptome Analysis of Antennal Chemosensory Genes in Curculio Dieckmanni Faust. (Coleoptera: Curculionidae)
Authors: Ma Xiaoqian , Lu Xinming , Zhang Ping , Deng Xun , Bai Jianyang , Xu Zhe , Diao Jian , Pang Hongyang , Wang Qi , Zhao Hongying , Ma Wei , Ma Ling
Published: May 2022

The olfactory system plays a key role in regulating insect behaviors, such as locating host plants, spawning sites, and mating partners and avoiding predators. Chemosensory genes are required for olfactory recognition in insects. Curculio dieckmanni Faust. (Coleoptera: Curculionidae) damages hazelnuts and causes severe economic losses. There are no effective control measures, but understanding the olfaction mechanisms of this insect could lead to a new approach for population management. However, the genes that perform chemosensory functions in C. dieckmanni are still unclear. Using high-throughput sequencing, we assembled the antennal transcriptome of C. dieckmanni and annotated the major chemosensory gene families. Of the chemosensory gene families, we found 23 odorant-binding proteins, 15 chemosensory proteins, 2 sensory neuron membrane proteins, 15 odorant receptors, 23 ionotropic receptors, and nine gustatory receptors. Using Blast sequence alignment and phylogenetic analysis, the sequences of these proteins were identified. Male- and female-specific chemosensory genes involved in odorant detection and recognition were validated by qRT-PCR. Among the chemosensory genes, we found significant differences in the expression of CdieOBP8, CdieOBP9, CdieOBP19, CdieOBP20, CdieOBP21, CdieCSP15, CdieOR13, and CdieOR15 between adult male and female C. dieckmanni. A total of 87 expressed chemosensory proteins were found in C. dieckmanni. Investigating these proteins will help reveal the molecular mechanism of odorant recognition in C. dieckmanni and may aid the development of novel control strategies for this species.