bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered Neural Network Connectivity Predicts Depression in de novo Parkinson’s Disease
Authors: Xu Jianxia , Chen Yubing , Wang Hui , Li Yuqian , Li Lanting , Ren Jingru , Sun Yu , Liu Weiguo
Published: March 2022

Background

Depression, one of the most frequent non-motor symptoms in Parkinson’s disease (PD), was proposed to be related to neural network dysfunction in advanced PD patients. However, the underlying mechanisms in the early stage remain unclear. The study was aimed to explore the alterations of large-scale neural networks in de novo PD patients with depression.

Methods

We performed independent component analysis (ICA) on the data of resting-state functional magnetic resonance imaging from 21 de novo PD patients with depression (dPD), 34 de novo PD patients without depression (ndPD), and 43 healthy controls (HCs) to extract functional networks. Intranetwork and internetwork connectivity was calculated for comparison between groups, correlation analysis, and predicting the occurrence of depression in PD.

Results

We observed an ordered decrease of connectivity among groups within the ventral attention network (VAN) (dPD < ndPD < HCs), mainly located in the left middle temporal cortex. Besides, dPD patients exhibited hypoconnectivity between the auditory network (AUD) and default mode network (DMN) or VAN compared to ndPD patients or healthy controls. Correlation analysis revealed that depression severity was negatively correlated with connectivity value within VAN and positively correlated with the connectivity value of AUD-VAN in dPD patients, respectively. Further analysis showed that the area under the curve (AUC) for dPD prediction was 0.863 when combining the intranetwork connectivity in VAN and internetwork connectivity in AUD-DMN and AUD-VAN.

Conclusion

Our results demonstrated that early dPD may be associated with abnormality of attention bias and especially auditory attention processing. Altered neural network connectivity is expected to be a potential neuroimaging biomarker to predict depression in PD.
Functional Covariance Connectivity of Gray and White Matter in Olfactory-Related Brain Regions in Parkinson’s Disease
Authors: Wang Yiqing , Wei Hongyu , Du Shouyun , Yan Hongjie , Li Xiaojing , Wu Yijie , Zhu Jianbing , Wang Yi , Cai Zenglin , Wang Nizhuan
Published: March 2022

Before the onset of motor symptoms, Parkinson’s disease (PD) involves dysfunction of the anterior olfactory nucleus and olfactory bulb, causing olfactory disturbance, commonly resulting in hyposmia in the early stages of PD. Accumulating evidence has shown that blood oxygen level dependent (BOLD) signals in white matter are altered by olfactory disorders and related stimuli, and the signal changes in brain white matter pathways show a certain degree of specificity, which can reflect changes of early olfactory dysfunction in Parkinson’s disease. In this study, we apply the functional covariance connectivity (FCC) method to decode FCC of gray and white matter in olfactory-related brain regions in Parkinson’s disease. Our results show that the dorsolateral prefrontal, anterior entorhinal cortex and fronto-orbital cortices in the gray matter have abnormal connectivity with the posterior corona radiata and superior corona radiata in white matter in patients with Parkinson’s hyposmia. The functional covariance connection strength (FCS) of the right dorsolateral prefrontal cortex and white matter, and the covariance connection strength of the left superior corona radiata and gray matter function have potential diagnostic value. These results demonstrate that alterations in FCC of gray and white matter in olfactory-related brain regions can reflect the change of olfactory function in the early stages of Parkinson’s disease, indicating that it could be a potential neuroimaging marker for early diagnosis.
Multiple Roles of Actin in Exo- and Endocytosis
Authors: Wu Ling-Gang , Chan Chung Yu
Published: March 2022

Cytoskeletal filamentous actin (F-actin) has long been considered a molecule that may regulate exo- and endocytosis. However, its exact roles remained elusive. Recent studies shed new light on many crucial roles of F-actin in regulating exo- and endocytosis. Here, this progress is reviewed from studies of secretory cells, particularly neurons and endocrine cells. These studies reveal that F-actin is involved in mediating all kinetically distinguishable forms of endocytosis, including ultrafast, fast, slow, bulk, and overshoot endocytosis, likely via membrane pit formation. F-actin promotes vesicle replenishment to the readily releasable pool most likely via active zone clearance, which may sustain synaptic transmission and overcome short-term depression of synaptic transmission during repetitive firing. By enhancing plasma membrane tension, F-actin promotes fusion pore expansion, vesicular content release, and a fusion mode called shrink fusion involving fusing vesicle shrinking. Not only F-actin, but also the F-actin assembly pathway, including ATP hydrolysis, N-WASH, and formin, are involved in mediating these roles of exo- and endocytosis. Neurological disorders, including spinocerebellar ataxia 13 caused by Kv3.3 channel mutation, may involve impairment of F-actin and its assembly pathway, leading in turn to impairment of exo- and endocytosis at synapses that may contribute to neurological disorders.
Lactobacillus plantarum HFY05 Attenuates Carrageenan-Induced Thrombosis in Mice by Regulating NF-κB Pathway-Associated Inflammatory Responses
Authors: Zeng Shi , Yi Ruokun , Tan Fang , Sun Peng , Cheng Qiang , Zhao Xin
Published: March 2022

In this study, a carrageenan-induced thrombus model was established in mice to observe the ability ofLactobacillus plantarumKFY05 (LP-KFY05) to inhibit thrombosis through an NF-κB-associated pathway. Biochemical analysis, microscopical observations, quantitative polymerase chain reactions (qPCR) and western blot analysis were used to examine relevant serum and tissue indexes, and the composition of intestinal microorganisms was determined by examining the abundance of microorganisms in feces. The results showed that LP-KFY05 could markedly reduce the degree of black tail in thrombotic mice; increase the activated partial thromboplastin time (APTT); and decrease the thrombin time (TT), fibrinogen (FIB) level, and prothrombin time (PT). LP-KFY05 could also reduce tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) levels in sera and renal tissues of thrombotic mice. Hematoxylin and eosin staining showed that LP-KFY05 could alleviate renal tissue lesions and tail vein thrombosis. qPCR results showed that LP-KFY05 could down-regulate nuclear factor kappa-B (NF-κB) p65, IL-6, TNF-α, and interferon γ (IFN-γ) mRNA expression in renal tissues, as well as NF-κB p65, intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin mRNA expression in tail vein vascular tissues of thrombotic mice. Western blot analysis showed that LP-KFY05 also down-regulated NF-κB protein expression in renal and tail vein vascular tissues of thrombotic mice. Lastly, LP-KFY05 increased the abundances ofBacteroidetes, Lactobacillus, andBifidobacterium, as well as decreased the abundance ofFirmicutes. These results show that LP-KFY05 can reduce inflammation and inhibit thrombosis in thrombotic mice, and the effects of high concentrations of LP-KFY05 were most pronounced, which were similar to the effects of dipyridamole.
The Apparent Diffusion Coefficient of Diffusion-Weighted Whole-Body Magnetic Resonance Imaging Affects the Survival of Multiple Myeloma Independently
Authors: Zhang Bei , Bian Bingyang , Zhang Yanjiao , Zhang Li , Zhang Rongkui , Wang Jiping
Published: March 2022

Background

Diffusion-weighted whole-body MRI (DW-MRI) is increasingly used to evaluate bone diseases of multiple myeloma (MM), but there is lack of quantitative indicator for DW-MRI to reflect the prognosis of MM. Apparent diffusion coefficient (ADC) values in DW-MRI has potential correlations between some indexes of MM, but the influence of ADC on MM survival needs to be further verified.

Methods

A total of 381 newly diagnosed MM patients were enrolled in the study to analyze the effect of ADC values in DW-MRI on progression-free survival (PFS) and overall survival (OS). The Kaplan–Meier method was used to perform univariate survival analysis, and the Cox proportional hazards model was used for multivariate analysis. In addition to the ADC value, genetic and serological indexes were also included.

Results

The survivals were observed in univariate ADC stratification with median PFS of 52.0, 45.0, 34.0, and 26.0 months (the unit of ADC value was 10−3 mm2/s; the ADC ranges were ADC < 0.4886, 0.4886 ≤ ADC < 0.6545, 0.6545 ≤ ADC < 0.7750, and ADC ≥ 0.7750; 95% CI, 43.759–62.241, 46.336–53.664, 39.753–46.247, and 27.812–32.188). The OS were 81.0, 61.0, 47.0, and 36.0 months (p < 0.001; 95% CI, 71.356–82.644, 67.630–70.370, 57.031–60.969, and 36.107–43.893). In Cox proportional hazards model, the ADC value was considered to be an independent risk factor affecting PFS and OS of MM (both p < 0.001).

Conclusions

This study supports that ADC in DW-MRI may independently stratify MM patients and better predict their prognosis. The combined use of DW-MRI and other parameters allows more accurate evaluation of MM survival.

Trial Registration

http://www.chictr.org.cn/showproj.aspx?proj=49012, ChiCTR2000029587.
Initial PCV Chemotherapy Followed by Radiotherapy Is Associated With a Prolonged Response But Late Neurotoxicity in 20 Diffuse Low-Grade Glioma Patients
Authors: Blonski Marie , Obara Tiphaine , Brzenczek Cyril , Pouget Celso , Dillier Céline , Meyer Mylène , Lavigne Laura , Forthoffer Natacha , Broussois Aurélie , Gauchotte Guillaume , Baron Marie-Hélène , Rech Fabien , Mézières Sophie , Gaudeau Yann , Verger Antoine , Vogin Guillaume , Anxionnat René , Moureaux Jean-Marie , Taillandier Luc
Published: March 2022

Background

Study RTOG 9802 in high-risk diffuse low-grade gliomas (DLGGs) showed the potential synergistic effect on survival of the procarbazine, CCNU, and vincristine (PCV) radiotherapy (RT) combination. Limited data on long-term neurocognitive impact and quality of life (QoL) have yet been reported.

Patients and Methods

We described a monocentric series of patients treated at first line by the combination of PCV immediately followed by RT between January 01, 1982 and January 01, 2017. Radiological data were collected and included volume, velocity of diametric expansion (VDE), and MRI aspects. Long-term neurocognitive and QoL were analyzed.

Results

Twenty patients fulfilled the eligibility criteria. The median response rate was 65.1% (range, 9.6%–99%) at the time of maximal VDE decrease corresponding to a median volume reduction of 79.7 cm3 (range, 3.1 to 174.2 cm3), which occurred after a median period of 7.2 years (range, 0.3–21.9) after the end of RT. An ongoing negative VDE was measured in 13/16 patients after the end of RT, with a median duration of 6.7 years (range, 9 months–21.9 years). The median follow-up since radiological diagnosis was 17.5 years (range, 4.8 to 29.5). Estimated median survival was 17.4 years (95% CI: 12; NR). After a long-term follow-up, substantial neurotoxicity was noticed with dementia in six progression-free patients (30%), leading to ventriculo-peritoneal shunt procedures in three, and premature death in five. Thirteen patients (65%) were unable to work with disability status. Successive longitudinal neurocognitive assessments for living patients showed verbal episodic memory deterioration.

Conclusions

PCV-RT combination seems to have not only an oncological synergy but also a long-term neurotoxic synergy to consider before initial therapeutic decision.
Investigating the Clinico-Molecular and Immunological Evolution of Lung Adenocarcinoma Using Pseudotime Analysis
Authors: Lee Hyunjong , Choi Hongyoon
Published: March 2022

Introduction

As the molecular features of lung adenocarcinoma (LUAD) have been evaluated as a cross-sectional study, the course of tumor characteristics has not been modeled. The temporal evolution of the tumor immune microenvironment (TIME), as well as the clinico-molecular features of LUAD, could provide a precise strategy for immunotherapy and surrogate biomarkers for the course of LUAD.

Methods

A pseudotime trajectory was constructed in patients with LUAD from the Cancer Genome Atlas and non-small cell lung cancer radiogenomics datasets. Correlation analyses were performed between clinical features and pseudotime. Genes associated with pseudotime were selected, and gene ontology analysis was performed. F-18 fluorodeoxyglucose positron emission tomography images of subjects were collected, and imaging parameters, including standardized uptake value (SUV), were obtained. Correlation analyses were performed between imaging parameters and pseudotime. Correlation analyses were performed between the enrichment scores of various immune cell types and pseudotime. In addition, correlation analyses were performed between the expression of PD-L1, tumor mutation burden, and pseudotime.

Results

Pseudotime trajectories of LUAD corresponded to clinical stages. Molecular profiles related to cell division and natural killer cell activity were changed along the pseudotime. The maximal SUV of LUAD tumors showed a positive correlation with pseudotime. Type 1 helper T (Th1) cells showed a positive correlation, whereas M2 macrophages showed a negative correlation with pseudotime. PD-L1 expression showed a negative correlation, whereas tumor mutation burden showed a positive correlation with pseudotime.

Conclusion

The estimated pseudotime associated with the stage suggested that it could reflect the clinico-molecular evolution of LUAD. Specific immune cell types in the TIME as well as cell division and glucose metabolism were dynamically changed according to the progression of the pseudotime. As a molecular progression of LUAD, different cellular targets should be considered for immunotherapy.
Prognostic Significance of Neutrophil-to-Lymphocyte Ratio and C-Reactive Protein/Albumin Ratio in Luminal Breast Cancers With HER2-Negativity
Authors: Chen Fei , Chen Danzhi , Jin Lidan , Xu Chenpu , Zhao Wenhe , Hu Wenxian
Published: March 2022

Purpose

This study was determined to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein/albumin ratio (CAR) prior to surgery in luminal breast cancers (BC) with HER2-negativity.

Methods

The clinical data of 708 HER2-negative luminal BC patients from January 2013 to December 2016 were retrospectively collected and analyzed. The optimal cut-off value of NLR and CAR were determined via receiver operating characteristic (ROC) curve. The disease-free survival (DFS) and cancer specific survival (CSS) rates were estimated using the Kaplan−Meier method. Cox univariate and multivariate proportional hazards regression models were performed to identify significant predictors of DFS and CSS simultaneously.

Results

The mean age of the patients diagnosed was 52.43 years (range, 15–95 years), and the median follow-up was 62.71 months (range, 12-92 months). Univariate and multivariate analysis confirmed that NLR ≥2.2 was significantly associated with worse DFS (HR=2.886, 95%CI=1.756-4.745, p<0.001), and same results were obtained in terms of CSS (HR=3.999, 95%CI=2.002-7.987, p<0.001). Similarly, CAR ≥0.07 was independently and significantly associated with poor DFS (HR=3.858, 95%CI=2.346-6.345, p<0.001) and CSS (HR=6.563, 95%CI=3.558-12.106, p<0.001).

Conclusion

Preoperative evaluation of NLR and CAR were significant and independent prognostic indicators for luminal breast cancers with HER2-negativity.
SDK1-ALK Fusion in a Lung Adenocarcinoma Patient With Excellent Response to ALK Inhibitor Treatment: A Case Report
Authors: Ma Lin , Xiao Junjuan , Guan Yaping , Wu Dongfang , Gu Tiantian , Wang Jun
Published: March 2022

Background

Rearrangements of Anaplastic lymphoma kinase (ALK) have been discovered as a novel driver mutation in patients with non–small-cell lung cancer (NSCLC). Patients’ responses to ALK tyrosine kinase inhibitors (TKIs) may vary depending on the variations of ALK rearrangements they have. It is imperative for clinicians to identify druggable ALK fusions in routine practice.

Case Presentation

In this study, we discovered a rare ALK rearrangement type (SDK1–ALK) in a Chinese lung adenocarcinoma patient who responded well to ALK inhibitor SAF-189s. The positive expression of ALK in lung biopsy tissue was verified by IHC analysis. A new SDK1-ALK fusion was discovered using NGS. The patient was treated with SAF-189s (160 mg per day) as a first-line therapy and went into continuous remission, with a 12 months progression-free survival at the last follow-up.

Conclusion

This is the first case of SDK1-ALK fusion with an excellent response to an ALK inhibitor, which will provide better understanding of ALK-TKI applications for NSCLC patients with ALK fusion in the future.
The Effectiveness and Adverse Events of Amitriptyline and Aripiprazole in Very Elderly Patients With BMS
Authors: Watanabe Motoko , Takao Chihiro , Liu Zhenyan , Nayanar Gayatri , Suga Takayuki , Hong Chaoli , Tu Trang Thi Huyen , Yoshikawa Tatsuya , Takenoshita Miho , Motomura Haruhiko , Nagamine Takahiko , Toyofuku Akira
Published: March 2022

Burning mouth syndrome (BMS) is defined by chronic oral burning sensations without any corresponding abnormalities. Besides amitriptyline, aripiprazole has been reported as a possible medication to manage BMS. However, especially for elderly patients, the adverse events of these medications would be a problem. The aim of the present study was to investigate the differences in the effectiveness and adverse events of amitriptyline and aripiprazole in very elderly patients with BMS. This is a retrospective comparative study of 80 years old and older patients with BMS who were initially treated with amitriptyline or aripiprazole and who were new outpatients of our department from April 2017 to March 2020. All clinical data, including sex, age, comorbid physical diseases, comorbid psychiatric disorders, the prescribed doses (initial, maximum, and effective dose), prognosis, and adverse events, were collected from their medical charts. Each medication was selected considering their medical history. Amitriptyline was prescribed in 13 patients (11 women, 82.3 ± 2.1 years old) and aripiprazole was prescribed in 27 patients (26 women, 84.2 ± 3.8 years old). There were no significant between-group differences in sex, age, duration of illness, pain intensity, salivation, and psychiatric comorbidity at the first examination. Amitriptyline clinically improved more patients (7 patients, 53.8%) with the effective dose of 10 (7.5, 15.0) mg than aripiprazole (11 patients, 40.7%) of which the effective dose was 1.0 (0.5, 1.5) mg, although there were no significant between-group differences. The adverse events of amitriptyline were found in 9 patients (69.2%) and most patients had constipation (46.2%). For aripiprazole, 7 patients (25.9%) showed adverse events, most of them reported sleep disorder (11.1%). Amitriptyline had significantly longer duration taking medication (p = 0.021) and lower discontinuation (p = 0.043) despite of higher occurrence rate of adverse events (p = 0.015) compared to aripiprazole. These results suggest that both psychopharmacotherapies with a low dose of amitriptyline and aripiprazole are effective for the very elderly patients with BMS. Furthermore, aripiprazole may have some advantages in the adverse events compared to amitriptyline; however, the low dose amitriptyline monotherapy may have more benefit in the effectiveness and tolerability over prudent collaboration with primary physicians.
Impact of Umbilical Cord Milking on Hematological Parameters in Preterm Neonates With Placental Insufficiency
Authors: Nagy Mohammed , Nasef Nehad , Gibreel Ahmed , Sarhan Mohamed , Aldomiaty Hoda , Darwish Mohammed , Nour Islam
Published: March 2022

Background

Data is still lacking about the expediency of umbilical cord milking (UCM) in preterm neonates born to mothers with placental insufficiency (PI).

Objective

To study the effect of UCM in preterm neonates who had ante-natal evidence of placental insufficiency on peripheral blood cluster of differentiation 34 (CD34) percentage, hematological indices, and clinical outcomes.

Methods

Preterm neonates, <34 weeks' gestation, born to mothers with evidence of placental insufficiency that underwent UCM (PI+UCM group) were compared with historical controls whose umbilical stumps were immediately clamped [PI+ICC (immediate cord clamping) group] in a case-control study. Peripheral blood CD34 percentage as a measure of hematopoietic stem cell transfusion was the primary outcome. Early and late-onset anemia; polycythemia; frequency of packed red blood cells (PRBCs) transfusion during NICU stay; peak total serum bilirubin (TSB); incidence of phototherapy, admission rectal temperature; first 24 h hypothermia and hypoglycemia; episodes of hypotension and need for volume expander boluses and inotropic support during the first 24 h of age; duration of oxygen therapy; bronchopulmonary dysplasia (BPD); severe intra-ventricular hemorrhage (IVH); necrotizing enterocolitis (NEC); culture-proven late-onset sepsis; length of hospital stay; and in-hospital mortality were secondary outcomes.

Results

In preterm infants with placental insufficiency, umbilical cord milking was associated with greater peripheral blood CD34 percentage, hemoglobin levels initially and at postnatal age of 2 months, alongside significantly shorter duration of oxygen therapy compared with ICC group. Frequency of packed RBCs transfusion during hospital stay was comparable. Neonates in UCM group had a greater peak TSB level during admission with significantly higher need for phototherapy initiation compared with ICC. Logistic regression, adjusted for gestational age, revealed that UCM resulted in greater CD34 percentage, higher initial hemoglobin level, higher peak serum bilirubin, significant increase of phototherapy initiation, and higher hemoglobin level at 2 months.

Conclusions

UCM in preterm neonates born to mothers with placental insufficiency was feasible and resulted in greater CD34 percentage, higher initial hemoglobin level, higher peak serum bilirubin, significant increase of phototherapy initiation, and higher hemoglobin level at 2 months.
Preparing for Pediatrics: Experiential Learning Helps Medical Students Prepare for Their Clinical Placement
Authors: Sullivan Clare , Condron Claire , Mulhall Claire , Almulla Mohammad , Kelly Maria , O'Leary Daire , Eppich Walter
Published: March 2022

Despite the importance of effective communication skills in pediatrics, clinical placements may inadequately prepare undergraduate students to communicate with children. The integration of non-clinical interactions with healthy children within a pediatric curriculum has the potential to enhance learning. We designed and implemented a novel course involving experiential learning, including video-recorded consultations with simulated parents (SPs), team-based scenarios with a pediatric mannequin, interactions with healthy children through a pre-school visit and medical student led health workshops for primary school children. Medical students at the RCSI University of Medicine and Health Sciences took part in the course. We used a mixed methods approach to assess the impact of the course. We investigated medical students' perspectives through a pre- and post-intervention questionnaire and post-intervention focus group discussions (FGDs). We assessed participating children's health literacy at the start of the course. 144/279 (51.6%) of the fourth year medical student cohort on their pediatric rotation, consented to participate in the study. All 144 (100%) of consenting students completed the pre-intervention questionnaire. 59/144 (40.1%) of consenting students completed the post-intervention questionnaire. Results showed a statistically significant improvement in ratings (p < 0.05) for items related to managing a confrontational situation involving family members, completing a psychosocial assessment with an adolescent and effectiveness using evidence-based medicine (EBM) when motivating patients. There was a statistically significant decrease in how students rated their comfort at using EBM when motivating patients. Four themes relating to how students experienced the intervention were identified from eight FGDs (n = 35 students): Shaping Student Learning; Supporting Student Learning; Developing New Skills and Feeling More Prepared. 39/49 (79.6%) children completed a health literacy assessment. All questions had a high percentage of positive responses. Question 7, understanding your doctor, had the highest proportion of negative responses (27%). Ours is one of the first studies to design an educational intervention to enhance pediatrics teaching by combining interactions with healthy children outside of a clinical setting with more traditional simulation-based approaches. We conclude that this type of intervention supports students' learning of pediatric communication skills and enhances students' perceived preparation for clinical placement.
Comprehensive Metabolomics and Network Pharmacology to Explore the Mechanism of 5-Hydroxymethyl Furfural in the Treatment of Blood Deficiency Syndrome
Authors: Zhang Wensen , Cui Na , Su Fazhi , Wang Yangyang , Yang Bingyou , Sun Yanping , Guan Wei , Kuang Haixue , Wang Qiuhong
Published: March 2022

Radix Rehmanniae (RR, from Radix Rehmanniae (Gaertn.) DC.) is a natural medicine used in traditional Chinese medicine (TCM) since ancient times for the treatment of blood disorders. RR is steamed to get Rehmanniae Radix Praeparata (RP), which has a tonic effect on blood; the content of 5-hydromethylfurfural (5-HMF) increases more than four times after steaming. Studies have shown that 5-HMF has positive pharmacological effects on cardiovascular and hematological disorders. This study aimed to explore and verify the impact of 5-HMF on rats with chemotherapy-induced blood deficiency syndrome (BDS). Rats were given cyclophosphamide (CP) and acetophenhydrazine (APH) to induce BDS, the coefficients of some organs (liver, spleen, and kidney) were measured, and a routine blood test examined the coefficients of several peripheral blood cells. Metabolomics and network pharmacology were combined to find important biomarkers, targets, and pathways. Western blot was used to detect the expression of CYP17A1 and HSD3B1 proteins in the spleen. All these findings suggested that the 5-HMF significantly increased the number of peripheral blood cells and reversed splenomegaly in rats. In addition, 5-HMF upregulated CYP17A1 and HSD3B1 protein expression in splenic tissues. Also, 5-HMF ameliorated chemotherapy-induced BDS in rats, and its therapeutic mechanism might depend on steroid hormone biosynthesis and other pathways. It acts on blood deficiency via multiple targets and pathways, which is unique to Chinese medicine.
Immunotherapy for a POLE Mutation Advanced Non-Small-Cell Lung Cancer Patient
Authors: Fu Yang , Zheng Yue , Wang Pei-Pei , Chen Yue-Yun , Ding Zhen-Yu
Published: March 2022

Currently, the predictive role of POLE mutations for immunotherapy is under intense investigation. The POLE gene encodes one of the four subunits of DNA polymerase important for DNA replication and repair. POLE mutations are related to other favorable predicative factors such as high expression of PD-L1, high TMB, and infiltration of CD8+ cells in the tumor microenvironment. No formal clinical trials studied the efficacy of immunotherapy in lung patients harboring POLE mutation, and only few cases were mentioned in the literature. Moreover, lung cancer patients are prone to brain metastasis, which is notorious for the unresponsiveness to chemotherapy. The efficacy of immunotherapy for brain metastasis is still controversial. Here, we described a case of a POLEmt non-small-cell lung cancer (NSCLC) patient with brain metastasis who was treated with immunotherapy. His brain lesions disappeared after treatment. Our report strongly supported the benefit of immune-combined therapy for advanced NSCLC patients with POLE mutation, even with brain metastasis.
The Role of Peroxisome Proliferator-Activated Receptors in Kidney Diseases
Authors: Gao Jianjun , Gu Zhaoyan
Published: March 2022

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Accumulating evidence suggests that PPARs may play an important role in the pathogenesis of kidney disease. All three members of the PPAR subfamily, PPARα, PPARβ/δ, and PPARγ, have been implicated in many renal pathophysiological conditions, including acute kidney injury, diabetic nephropathy, and chronic kidney disease, among others. Emerging data suggest that PPARs may be potential therapeutic targets for renal disease. This article reviews the physiological roles of PPARs in the kidney and discusses the therapeutic utility of PPAR agonists in the treatment of kidney disease.
Elucidation of the Mechanisms and Effective Substances of Paeoniae Radix Rubra Against Toxic Heat and Blood Stasis Syndrome With a Stage-Oriented Strategy
Authors: Xu Jing-Jing , Xu Feng , Wang Wei , Zhang Yi-Fan , Hao Bei-Quan , Shang Ming-Ying , Liu Guang-Xue , Li Yao-Li , Yang Shu-Bin , Wang Xuan , Cai Shao-Qing
Published: March 2022

In the clinical practice of traditional Chinese medicine, toxic heat and blood stasis syndrome (THBSS) is a common syndrome observed in various critical diseases. Paeoniae Radix Rubra (PRR) has known therapeutic effects on THBSS. However, its pharmacodynamic mechanisms and effective substances in the treatment of THBSS still need further elucidation. Our previous study indicated that THBSS had three stages of progression, and the abnormal biochemical indices of each stage were different. Therefore, this study aimed to elucidate the pharmacodynamic mechanisms and effective substances of PRR for the treatment of THBSS with a stage-oriented strategy. Specifically, research was performed separately in two stable stages of THBSS: the excessive heat and little blood stasis (EHLBS) and blood stasis (BS) stages. THBSS model rats, at different time periods after syndrome initiation (first 5 h for EHLBS and 24 h later for BS), were used to conduct the two-stage investigation. Targeted metabonomics analysis was performed to elucidate the pharmacodynamic mechanisms of PRR in the treatment of EHLBS or BS. Based on the relationship between the individual differences in blood drug concentrations and pharmacodynamic effects, partial least squares regression analysis was employed to screen for the effective substances from the original constituents and metabolites of PRR. We found that PRR could upregulate primary bile acid biosynthesis, glycerophospholipid metabolism, ether lipid metabolism, and five amino acid metabolic pathways (e.g., arginine and proline metabolism) to treat EHLBS. Meanwhile, PRR alleviated BS by upregulating primary bile acid biosynthesis and downregulating glycerophospholipid metabolism. But PRR had no obvious effects on ether lipid metabolism and amino acid metabolism in this stage. In total, 17 and 9 potential effective substances were found in the EHLBS and BS stages, respectively, among which there were only five common compounds between the two stages. To our knowledge, sixteen compounds were regarded as potential effective substances of PRR for the first time. Therefore, the pharmacodynamic mechanisms and effective substances of PRR in the treatment of EHLBS and BS were partly different. Overall, this stage-oriented strategy provides a new way to study the pharmacodynamic mechanisms and effective substances of traditional Chinese drugs.
Drug Transporters ABCB1 (P-gp) and OATP, but not Drug-Metabolizing Enzyme CYP3A4, Affect the Pharmacokinetics of the Psychoactive Alkaloid Ibogaine and its Metabolites
Authors: F. Martins Margarida L. , Heydari Paniz , Li Wenlong , Martínez-Chávez Alejandra , Venekamp Nikkie , Lebre Maria C. , Lucas Luc , Beijnen Jos H. , Schinkel Alfred H.
Published: March 2022

The psychedelic alkaloid ibogaine is increasingly used as an oral treatment for substance use disorders, despite being unlicensed in most countries and having reported adverse events. Using wild-type and genetically modified mice, we investigated the impact of mouse (m)Abcb1a/1b and Abcg2 drug efflux transporters, human and mouse OATP drug uptake transporters, and the CYP3A drug-metabolizing complex on the pharmacokinetics of ibogaine and its main metabolites. Following oral ibogaine administration (10 mg/kg) to mice, we observed a rapid and extensive conversion of ibogaine to noribogaine (active metabolite) and noribogaine glucuronide. Mouse Abcb1a/1b, in combination with mAbcg2, modestly restricted the systemic exposure (plasma AUC) and peak plasma concentration (Cmax) of ibogaine. Accordingly, we found a ∼2-fold decrease in the relative recovery of ibogaine in the small intestine with fecal content in the absence of both transporters compared to the wild-type situation. Ibogaine presented good intrinsic brain penetration even in wild-type mice (brain-to-plasma ratio of 3.4). However, this was further increased by 1.5-fold in Abcb1a/1b;Abcg2−/− mice, but not in Abcg2−/− mice, revealing a stronger effect of mAbcb1a/1b in restricting ibogaine brain penetration. The studied human OATP transporters showed no major impact on ibogaine plasma and tissue disposition, but the mOatp1a/1b proteins modestly affected the plasma exposure of ibogaine metabolites and the tissue disposition of noribogaine glucuronide. No considerable role of mouse Cyp3a knockout or transgenic human CYP3A4 overexpression was observed in the pharmacokinetics of ibogaine and its metabolites. In summary, ABCB1, in combination with ABCG2, limits the oral availability of ibogaine, possibly by mediating its hepatobiliary and/or direct intestinal excretion. Moreover, ABCB1 restricts ibogaine brain penetration. Variation in ABCB1/ABCG2 activity due to genetic variation and/or pharmacologic inhibition might therefore affect ibogaine exposure in patients, but only to a limited extent. The insignificant impact of human CYP3A4 and OATP1B1/1B3 transporters may be clinically advantageous for ibogaine and noribogaine use, as it decreases the risks of undesirable drug interactions or interindividual variation related to CYP3A4 and/or OATP activity.
Rarefied Flow Simulation of Conical Intake and Plasma Thruster for Very Low Earth Orbit Spaceflight
Authors: Ferrato Eugenio , Giannetti Vittorio , Tisaev Mansur , Lucca Fabris Andrea , Califano Francesco , Andreussi Tommaso
Published: March 2022

Air-breathing electric propulsion has the potential to enable space missions at very low altitudes. This study introduces to a 0D hybrid formulation for describing the coupled intake and thruster physics of an air-breathing electric propulsion prototype. Model derivation is then used to formally derive main system’s key performance indicators and estimate the figure of merit for the design of rarefied flow air intakes. Achievable performance by conical intake shapes are defined and evaluated by Monte Carlo simulations. Influence of inlet flow variation is assessed by dedicated sensitivity analyses. The set of requirements and optimality conditions derived for the downstream plasma thruster suggest concept feasibility within an achievable performance range.
Thermoelectric Conversion From Interface Thermophoresis and Piezoelectric Effects
Authors: Zeng Yu-Jia , Liu Yue-Yang , Pan Hui , Ding Zhong-Ke , Zhou Wu-Xing , Tang Li-Ming , Li Baowen , Chen Ke-Qiu
Published: March 2022

Piezoelectric effect has proved itself to be a promising energy conversion mechanism that can convert mechanical energy into electricity. Here, we propose an indirect thermoelectric conversion mechanism based on a combination of the thermophoresis and piezoelectric effects. We first analyze this thermally driven mechanism using a simplified theoretical model and then numerically analyze a molecular dynamics (MD) simulation of a hybrid system constructed of a single-layer MoS2 nanoribbon and a concentric carbon nanotube. We show that the thermophoresis-induced piezoelectric output voltage can reach 3.5 V, and this value can be tuned using a temperature difference. The output voltage obtained using this mechanism is significantly higher than that obtained by heating piezoelectric materials directly. Given the generality of the thermophoresis effect in Van der Waals structures, this mechanism has potential applications in the conversion of thermal energy into electrical energy at the nanoscale level.
The Interaction of Central Nervous System and Acute Kidney Injury: Pathophysiology and Clinical Perspectives
Authors: Wang Yiru , Liu Siyang , Liu Qingquan , Lv Yongman
Published: March 2022

Acute kidney injury (AKI) is a common disorder in critically ill hospitalized patients. Its main pathological feature is the activation of the sympathetic nervous system and the renin-angiotensin system (RAS). This disease shows a high fatality rate. The reason is that only renal replacement therapy and supportive care can reduce the impact of the disease, but those measures cannot significantly improve the mortality. This review focused on a generalization of the interaction between acute kidney injury and the central nervous system (CNS). It was found that the CNS further contributes to kidney injury by regulating sympathetic outflow and oxidative stress in response to activation of the RAS and increased pro-inflammatory factors. Experimental studies suggested that inhibiting sympathetic activity and RAS activation in the CNS and blocking oxidative stress could effectively reduce the damage caused by AKI. Therefore, it is of significant interest to specify the mechanism on how the CNS affects AKI, as we could use such mechanism as a target for clinical interventions to further reduce the mortality and improve the complications of AKI.

Systematic Review Registration: [www.ClinicalTrials.gov], identifier [registration number].
Tissue Cytometry With Machine Learning in Kidney: From Small Specimens to Big Data
Authors: El-Achkar Tarek M. , Winfree Seth , Talukder Niloy , Barwinska Daria , Ferkowicz Michael J. , Al Hasan Mohammad
Published: March 2022

Advances in cellular and molecular interrogation of kidney tissue have ushered a new era of understanding the pathogenesis of kidney disease and potentially identifying molecular targets for therapeutic intervention. Classifying cells in situ and identifying subtypes and states induced by injury is a foundational task in this context. High resolution Imaging-based approaches such as large-scale fluorescence 3D imaging offer significant advantages because they allow preservation of tissue architecture and provide a definition of the spatial context of each cell. We recently described the Volumetric Tissue Exploration and Analysis cytometry tool which enables an interactive analysis, quantitation and semiautomated classification of labeled cells in 3D image volumes. We also established and demonstrated an imaging-based classification using deep learning of cells in intact tissue using 3D nuclear staining with 4′,6-diamidino-2-phenylindole (DAPI). In this mini-review, we will discuss recent advancements in analyzing 3D imaging of kidney tissue, and how combining machine learning with cytometry is a powerful approach to leverage the depth of content provided by high resolution imaging into a highly informative analytical output. Therefore, imaging a small tissue specimen will yield big scale data that will enable cell classification in a spatial context and provide novel insights on pathological changes induced by kidney disease.
Effects of Cardiorespiratory Fitness on Cerebral Oxygenation in Healthy Adults: A Systematic Review
Authors: Salzman Talia , Dupuy Olivier , Fraser Sarah Anne
Published: March 2022

Introduction

Exercise is known to improve cognitive functioning and the cardiorespiratory hypothesis suggests that this is due to the relationship between cardiorespiratory fitness (CRF) level and cerebral oxygenation. The purpose of this systematic review is to consolidate findings from functional near-infrared spectroscopy (fNIRS) studies that examined the effect of CRF level on cerebral oxygenation during exercise and cognitive tasks.

Methods

Medline, Embase, SPORTDiscus, and Web of Science were systematically searched. Studies categorizing CRF level using direct or estimated measures of V̇O2max and studies measuring cerebral oxygenation using oxyhemoglobin ([HbO2]) and deoxyhemoglobin ([HHb]) were included. Healthy young, middle-aged, and older adults were included whereas patient populations and people with neurological disorders were excluded.

Results

Following PRISMA guidelines, 14 studies were retained following abstract and full-text screening. Cycle ergometer or treadmill tests were used as direct measures of CRF, and one study provided an estimated value using a questionnaire. Seven studies examined the effects of CRF on cerebral oxygenation during exercise and the remaining seven evaluated it during cognitive tasks. Increased [HbO2] in the prefrontal cortex (PFC) was observed during cognitive tasks in higher compared to lower fit individuals. Only one study demonstrated increased [HHb] in the higher fit group. Exercise at submaximal intensities revealed increased [HbO2] in the PFC in higher compared to lower fit groups. Greater PFC [HHb] was also observed in long- vs. short-term trained males but not in females. Primary motor cortex (M1) activation did not differ between groups during a static handgrip test but [HHb] increased beyond maximal intensity in a lower compared to higher fit group.

Conclusion

Consistent with the cardiorespiratory hypothesis, higher fit young, middle-aged, and older adults demonstrated increased cerebral oxygenation compared to lower fit groups. Future research should implement randomized controlled trials to evaluate the effectiveness of interventions that improve CRF and cerebral oxygenation longitudinally.
Rapid Regulation of Alternative Splicing in Response to Environmental Stresses
Authors: Liu Xiao-Xiao , Guo Qian-Huan , Xu Wei-Bo , Liu Peng , Yan Kang
Published: March 2022

Plants overcome the changing environmental conditions through diverse strategies and complex regulations. In addition to direct regulation of gene transcription, alternative splicing (AS) also acts as a crucial regulatory mechanism to cope with various stresses. Generating from the same pre-mRNA, AS events allow rapid adjustment of the abundance and function of key stress-response components. Mounting evidence has indicated the close link between AS and plant stress response. However, the mechanisms on how environmental stresses trigger AS are far from understood. The advancing high-throughput sequencing technologies have been providing useful information, whereas genetic approaches have also yielded remarkable phenotypic evidence for AS control of stress responses. It is important to study how stresses trigger AS events for both fundamental science and applications. We review current understanding of stress-responsive AS in plants and discuss research challenges for the near future, including regulation of splicing factors, epigenetic modifications, the shared targets of splice isoforms, and the stress-adjusting ratios between splicing variants.
Altered Processing of Social Emotions in Individuals With Autistic Traits
Authors: Yang Di , Tao Hengheng , Ge Hongxin , Li Zuoshan , Hu Yuanyan , Meng Jing
Published: March 2022

Social impairment is a defining phenotypic feature of autism. The present study investigated whether individuals with autistic traits exhibit altered perceptions of social emotions. Two groups of participants (High-AQ and Low-AQ) were recruited based on their scores on the autism-spectrum quotient (AQ). Their behavioral responses and event-related potentials (ERPs) elicited by social and non-social stimuli with positive, negative, and neutral emotional valence were compared in two experiments. In Experiment 1, participants were instructed to view social-emotional and non-social emotional pictures. In Experiment 2, participants were instructed to listen to social-emotional and non-social emotional audio recordings. More negative emotional reactions and smaller amplitudes of late ERP components (the late positive potential in Experiment 1 and the late negative component in Experiment 2) were found in the High-AQ group than in the Low-AQ group in response to the social-negative stimuli. In addition, amplitudes of these late ERP components in both experiments elicited in response to social-negative stimuli were correlated with the AQ scores of the High-AQ group. These results suggest that individuals with autistic traits have altered emotional processing of social-negative emotions.
Burnout and Quality of Life in Professionals Working in Nursing Homes: The Moderating Effect of Stereotypes
Authors: López-Frutos Patricia , Pérez-Rojo Gema , Noriega Cristina , Velasco Cristina , Carretero Isabel , Martínez-Huertas José Ángel , Galarraga Leyre , López Javier
Published: March 2022

Objective

This study aimed to analyse how stereotypes towards older people moderate the relationship between burnout and quality of life (QoL) of professionals working in nursing homes.

Method

A total of 312 professionals were asked to complete questionnaires of burnout Maslach Burnout Inventory quality of Life (QPL-35) and aging stereotypes (CENVE). The moderation effects were tested using linear regression models.

Results

A negative association was observed between burnout and QoL. It was also found a statistically significant moderator effect of the total score of stereotypes and the health stereotypes, besides a marginally statistically significant moderator effect for motivational stereotypes. The moderator effects were different for people with low and high negative stereotypes. QoL was more affected under conditions of high burnout, in which people with more negative stereotypes tended to present higher QoL than people with lower negative stereotypes.

Conclusion

Highly burned-out professionals in nursing homes may avoid their negative feelings projecting them to residents through stereotypes, as a way of coping with burnout and increasing their QoL. However, this mechanism is an “aggressive reaction” and may have negative effects for both the older adult and the professional. The comprehension of these variables is essential for developing adequate intervention programs.
COVID-19 Induced Economic Slowdown and Mental Health Issues
Authors: Gong Yimiao , Liu Xiaoxing , Zheng Yongbo , Mei Huan , Que Jianyu , Yuan Kai , Yan Wei , Shi Le , Meng Shiqiu , Bao Yanping , Lu Lin
Published: March 2022

The COVID-19 pandemic has pressed a pause button on global economic development, and induced significant mental health problems. In order to demonstrate the progressed relationship between the pandemic, economic slowdown, and mental health burden, we overviewed the global-level gross domestic product changes and mental problems variation since the outbreak of COVID-19, and reviewed comprehensively the specific sectors influenced by the pandemic, including international trade, worldwide travel, education system, healthcare system, and individual employment. We hope to provide timely evidence to help with the promotion of policymakers’ effective strategies in mitigating economic losses induced by the pandemic; we suggest different governments or policy makers in different countries to share information and experience in dealing with COVID-19-induced economic slowdown and promote COVID-19 vaccine popularization plan to protect every individual worldwide against the coronavirus essentially; and we appeal international information share and collaboration to minimize stigmatization related to adverse mental consequences of COVID-19 and to increase mental health wellbeings of people all over the world.