bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and Comprehensive Analysis of FREM2 Mutation as a Potential Prognostic Biomarker in Colorectal Cancer
Authors: Du Hanpeng , Wang Haiyue , Kong Fandong , Wu Mingjian , Chen Wei , Lyu Jin , Zhou Sitong , Yang Ronghua
Published: February 2022

Gene mutations play an important role in tumor progression. This study aimed to identify genes that were mutated in colorectal cancer (CRC) and to explore their biological effects and prognostic value in CRC patients. We performed somatic mutation analysis using data sets from The Cancer Genome Atlas and International Cancer Genome Consortium, and identified that FREM2 had the highest mutation frequency in patients with colon adenocarcinoma (COAD). COAD patients were divided into FREM2-mutated type (n = 36) and FREM2-wild type (n = 278), and a Kaplan-Meier survival curve was generated to perform prognostic analysis. A FREM2-mutation prognosis model was constructed using random forest method, and the performance of the model was evaluated using receiver operating characteristic curve. Next, the random forest method and Cox regression analysis were used to construct a prognostic model based on the gene expression data of 36 FREM2-mutant COAD patients. The model showed a high prediction accuracy (83.9%), and 13 prognostic model characteristic genes related to overall survival were identified. Then, the results of tumor mutation burden (TMB) and microsatellite instability (MSI) analyses revealed significant differences in TMB and MSI among the risk scores of different prognostic models. Differentially expressed genes were identified and analyzed for functional enrichment and immune infiltration. Finally, 30 samples of CRC patients were collected for immunohistochemical staining to analyze the FREM2 expression levels, which showed that FREM2 was highly expressed in tumor tissues. In conclusion, CRC patients had a high level of FREM2 mutations associated with a worse prognosis, which indicated that FREM2 mutations may be potential prognostic markers in CRC.
Morphological and Hemodynamic Risk Factors for the Rupture of Proximal Anterior Cerebral Artery Aneurysms (A1 Segment)
Authors: Xu Mingwei , Lv Nan , Sun Kai , Hong Rujun , Wang Hao , Wang Xuhui , Xu Lunshan , Chen Lizhao , Xu Minhui
Published: February 2022

Objective

The treatment of unruptured small intracranial aneurysms remains controversial. A distinguishing characteristic of A1 segment aneurysms is that they tend to rupture when they are small, which may be related to their distinctive morphology and hemodynamics. Our study sought to investigate the rupture risk factors of A1 segment aneurysms by analyzing the clinical risk factors, morphology, and hemodynamic characteristics of A1 segment aneurysms.

Methods

We retrospectively enrolled 49 (23 ruptured, 26 unruptured) consecutive patients presenting to our institute with A1 segment aneurysms between January 2010 and March 2020. Independent risk factors associated with the rupture of A1 segment aneurysms were analyzed by multivariate regression analysis in the ruptured group and unruptured group.

Results

Clinical risk factors, including age, sex, hypertension, smoking history, and SAH family history revealed no difference between the ruptured and unruptured groups. The ruptured group presented a significantly larger size (Size, P = 0.007), aspect ratio (AR, P = 0.002), size ratio (SR, P = 0.001), bottleneck index (BN, P = 0.016), dome-to-neck ratio (DN, P = 0.001), and oscillatory shear index (OSI) (P = 0.001) than the unruptured group. The normalized wall shear stress (NWSS) of the ruptured aneurysms was lower than the unruptured group (P = 0.001). In the multivariate regression analysis, only SR (OR = 3.672, P = 0.003) and NWSS (OR = 0.474, P = 0.01) were independent risk factors in the A1 segment aneurysm rupture.

Conclusion

A higher SR and lower NWSS revealed a close connection with the rupture of A1 segment aneurysms in our study, thus providing a reference for clinical decision-making in treating A1 segment unruptured aneurysms.
Dissolution Effect of Alteplase on Arterial Blood Clot Model of Hypertensive Intracerebral Hemorrhage Patients in vitro
Authors: Jiang Xiaoming , Lu Yongyu , Hu Xiaogang , She Xiaochun
Published: February 2022

Objective

To explore the dissolution effect of alteplase (rt-PA) on arterial blood clots of patients with hypertensive cerebral hemorrhage in vitro and analyze the optimal concentration and action time of rt-PA for intracranial hematomas.

Methods

The arterial blood of 35 patients with confirmed hypertensive cerebral hemorrhage were collected, centrifuged, and the serum was aspirated to prepare the blood clot model. The 0.125, 0.25, 0.5, 1, 2, and 3 mg t-PA, 20,000 U, and 40,000 U urokinase (u-PA) were taken for the corresponding blood clot for dissolution test. The blood clot volume and dissolution volume was measured at 0, 30, 60, 90, 120, and 150 min.

Results

Without intervention, the blood clot volume of men was higher than that of women at 0, 30, 60, and 90 min (P < 0.05). Without intervention, hematocrit (HCT) was correlated with blood clot volume and the correlation decreased with time. The 30, 60, and 90 min dissolution curves of each group showed an upward trend (P < 0.05), and the dissolution curves tended to be flat at 120 min and 150 min. The dissolution volume of.125 mg/3 ml, 0.25 mg/3 ml, 0.5 mg/3 ml rt-PA, 20,000 U, 40,000 U u-PA was higher than that of 1, 2, 3 mg/ml rt-PA (P < 0.05). The dissolution volume of.125 mg/3 ml, 0.25 mg/3 ml, 0.5 mg/3 ml rt-PA was not significantly different from 20,000 and 40,000 U u-PA (P > 0.05). Gender differences did not affect the effects of the above drugs.

Conclusion

In vitro, low-concentration rt-PA has a better dissolution effect, and it shows a time-dependent effect, reaching the highest effect in 90 min.
Magnetic Resonance Image Guided Focused Ultrasound Thalamotomy. A Single Center Experience With 160 Procedures
Authors: Lak Asad M. , Segar David J. , McDannold Nathan , White Phillip Jason , Cosgrove Garth Rees
Published: February 2022

Introduction

MRgFUS thalamotomy has gained popularity as an FDA approved, non-invasive treatment for patients with Essential Tremor and tremor predominant Parkinson's Disease. We present our initial clinical experience with 160 consecutive cases of MRgFUS thalamotomy and describe the clinical outcomes with long term follow-up.

Methods

A retrospective chart review of all patients who underwent MRgFUS thalamotomy at our institution was performed. CRST Part A tremor scores were obtained pre-operatively and at each follow-up visit along with an assessment of side effects (SE). All patients had a post-operative MRI within 24 h to determine the location, size, and extent of the MRgFUS lesion.

Results

One hundred and sixty unilateral MRgFUS Thalamotomies (Left, n = 128; Right, n = 32) were performed for medically refractory essential Tremor (n = 150) or tremor predominant Parkinson's disease (n = 10). Mean age at surgery was 75 Years (range: 48-93) and the mean skull density ratio (SDR) was 0.48 (range: 0.32-0.75; median: 0.46). In ET patients, both rest and postural tremor was abolished acutely and remained so at follow-up whereas intention tremor was reduced acutely by 93% below baseline, 87% at 3 months, 83.0% at 1-year, and 78% at 2 years. On post-operative day 1, the most common SE's included imbalance (57%), sensory disturbances (25%), and dysmetria (11%). All adverse events were rated as mild on the Clavien-Dindo Scale and improved over time. At 2-years follow-up, imbalance was seen in 18%, sensory disturbance in 10% and dysmetria in 8% patients. Mean clinical follow-up for all patients was 14 months (range: 1-48 months).

Conclusion

MRgFUS thalamotomy is a safe and effective procedure for long term improvement of unilateral tremor symptoms, with the most common side-effects being imbalance and sensory disturbance.
Fatigue in Chinese Patients With Amyotrophic Lateral Sclerosis: Associated Factors and Impact on Quality of Life
Authors: An Ran , Li Cheng , Li Xin , Wu Yuan , He Xianghua , Ai Shaolong , Xu Yanming , He Chengqi
Published: February 2022

Objectives

Fatigue was considered as a common symptom in amyotrophic lateral sclerosis (ALS). Previous studies about the impact of fatigue on Quality of Life (QoL) in patients with ALS were limited and inconsistent. Besides, a systematic investigation of fatigue in Chinese patients with ALS was lacking. Therefore, this study aimed to comprehensively evaluate the frequency and associated factors of fatigue and impact on QoL in Chinese patients with ALS.

Participants and Methods

Probable and definitive patients with ALS and age- and gender-matched healthy controls (HCs) were consecutively recruited. The frequency of fatigue between both the groups was determined by the Fatigue Severity Scale (FSS). Disease severity, sleep quality, sleepiness, anxiety, depression, and QoL were evaluated in patients with ALS by the ALS Functional Rating Scale-revised (ALSFRS-R) and the ALS Severity Scale (ALSSS), the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Hamilton Anxiety Rating Scale (HARS), the Hamilton Depression Rating Scale (HDRS), and the McGill Quality of Life Questionnaire (MQOL). Then, clinical characteristics of patients with ALS with fatigue were compared with those without fatigue. Lastly, associated factors of fatigue and impact on QoL in Chinese patients with ALS were assessed.

Results

A total of 175 patients with ALS and 175 HCs were included. Fatigue was significantly more frequent in patients with ALS than in controls (32.6 vs. 17.7%, p = 0.001). Patients with ALS with fatigue scored lower on the ALSFRS-R, the ALSSS [lower extremity (LE) + upper extremity (UE)], the total ALSSS, higher in the HARS, HDRS, PSQI, ESS scores, and a poorer QoL. Daytime dysfunction and the ALSSS (LE + UE) score were associated with a higher risk of fatigue. The ALSSS (LE + UE), the FSS, age, the HARS, and the HDRS score were significantly associated with various aspects of QoL.

Conclusion

This study has described fatigue in Chinese patients with ALS and finding daytime dysfunction and the lower ALSSS (LE + UE) were associated with a higher risk of fatigue. Also, we identified an inverse relationship of fatigue intensity with the psychological domain of QoL.
Thalamo-Prefrontal Connectivity Correlates With Early Command-Following After Severe Traumatic Brain Injury
Authors: Cosgrove Megan E. , Saadon Jordan R. , Mikell Charles B. , Stefancin Patricia L. , Alkadaa Leor , Wang Zhe , Saluja Sabir , Servider John , Razzaq Bayan , Huang Chuan , Mofakham Sima
Published: February 2022

Recovery of consciousness after traumatic brain injury (TBI) is heterogeneous and difficult to predict. Structures such as the thalamus and prefrontal cortex are thought to be important in facilitating consciousness. We sought to investigate whether the integrity of thalamo-prefrontal circuits, assessed via diffusion tensor imaging (DTI), was associated with the return of goal-directed behavior after severe TBI. We classified a cohort of severe TBI patients (N = 25, 20 males) into Early and Late/Never outcome groups based on their ability to follow commands within 30 days post-injury. We assessed connectivity between whole thalamus, and mediodorsal thalamus (MD), to prefrontal cortex (PFC) subregions including dorsolateral PFC (dlPFC), medial PFC (mPFC), anterior cingulate (ACC), and orbitofrontal (OFC) cortices. We found that the integrity of thalamic projections to PFC subregions (L OFC, L and R ACC, and R mPFC) was significantly associated with Early command-following. This association persisted when the analysis was restricted to prefrontal-mediodorsal (MD) thalamus connectivity. In contrast, dlPFC connectivity to thalamus was not significantly associated with command-following. Using the integrity of thalamo-prefrontal connections, we created a linear regression model that demonstrated 72% accuracy in predicting command-following after a leave-one-out analysis. Together, these data support a role for thalamo-prefrontal connectivity in the return of goal-directed behavior following TBI.
Understanding Language Reorganization With Neuroimaging: How Language Adapts to Different Focal Lesions and Insights Into Clinical Applications
Authors: Pasquini Luca , Di Napoli Alberto , Rossi-Espagnet Maria Camilla , Visconti Emiliano , Napolitano Antonio , Romano Andrea , Bozzao Alessandro , Peck Kyung K. , Holodny Andrei I.
Published: February 2022

When the language-dominant hemisphere is damaged by a focal lesion, the brain may reorganize the language network through functional and structural changes known as adaptive plasticity. Adaptive plasticity is documented for triggers including ischemic, tumoral, and epileptic focal lesions, with effects in clinical practice. Many questions remain regarding language plasticity. Different lesions may induce different patterns of reorganization depending on pathologic features, location in the brain, and timing of onset. Neuroimaging provides insights into language plasticity due to its non-invasiveness, ability to image the whole brain, and large-scale implementation. This review provides an overview of language plasticity on MRI with insights for patient care. First, we describe the structural and functional language network as depicted by neuroimaging. Second, we explore language reorganization triggered by stroke, brain tumors, and epileptic lesions and analyze applications in clinical diagnosis and treatment planning. By comparing different focal lesions, we investigate determinants of language plasticity including lesion location and timing of onset, longitudinal evolution of reorganization, and the relationship between structural and functional changes.
Systemic Response to Infection Induces Long-Term Cognitive Decline: Neuroinflammation and Oxidative Stress as Therapeutical Targets
Authors: Reis Patricia Alves , Castro-Faria-Neto Hugo Caire
Published: February 2022

In response to pathogens or damage signs, the immune system is activated in order to eliminate the noxious stimuli. The inflammatory response to infectious diseases induces systemic events, including cytokine storm phenomenon, vascular dysfunction, and coagulopathy, that can lead to multiple-organ dysfunction. The central nervous system (CNS) is one of the major organs affected, and symptoms such as sickness behavior (depression and fever, among others), or even delirium, can be observed due to activation of endothelial and glial cells, leading to neuroinflammation. Several reports have been shown that, due to CNS alterations caused by neuroinflammation, some sequels can be developed in special cognitive decline. There is still no any treatment to avoid cognitive impairment, especially those developed due to systemic infectious diseases, but preclinical and clinical trials have pointed out controlling neuroinflammatory events to avoid the development of this sequel. In this minireview, we point to the possible mechanisms that triggers long-term cognitive decline, proposing the acute neuroinflammatory events as a potential therapeutical target to treat this sequel that has been associated to several infectious diseases, such as malaria, sepsis, and, more recently, the new SARS-Cov2 infection.
Revealing Whole-Brain Causality Networks During Guided Visual Searching
Authors: Kiefer Christian M. , Ito Junji , Weidner Ralph , Boers Frank , Shah N. Jon , Grün Sonja , Dammers Jürgen
Published: February 2022

In our daily lives, we use eye movements to actively sample visual information from our environment (“active vision”). However, little is known about how the underlying mechanisms are affected by goal-directed behavior. In a study of 31 participants, magnetoencephalography was combined with eye-tracking technology to investigate how interregional interactions in the brain change when engaged in two distinct forms of active vision: freely viewing natural images or performing a guided visual search. Regions of interest with significant fixation-related evoked activity (FRA) were identified with spatiotemporal cluster permutation testing. Using generalized partial directed coherence, we show that, in response to fixation onset, a bilateral cluster consisting of four regions (posterior insula, transverse temporal gyri, superior temporal gyrus, and supramarginal gyrus) formed a highly connected network during free viewing. A comparable network also emerged in the right hemisphere during the search task, with the right supramarginal gyrus acting as a central node for information exchange. The results suggest that all four regions are vital to visual processing and guiding attention. Furthermore, the right supramarginal gyrus was the only region where activity during fixations on the search target was significantly negatively correlated with search response times. Based on our findings, we hypothesize that, following a fixation, the right supramarginal gyrus supplies the right supplementary eye field (SEF) with new information to update the priority map guiding the eye movements during the search task.
The Effect of Breastfeeding on Intelligence Quotient and Social Intelligence Among Seven- to Nine-Year-Old Girls: A Pilot Study
Authors: AlThuneyyan Danyah Abdullah , AlGhamdi Faten Fahad , AlZain Ragad Nasser , AlDhawyan Zainab Sami , Alhmly Haya Fahad , Purayidathil Tunny Sebastian , AlGindan Yasmin Yussuf , Abdullah Ahmed Amr
Published: February 2022

Background

Breastfeeding is an optimal infant feeding method that provides adequate nutrients, achieves healthy growth and development, and enhances the health status of both infants and mothers. Breast milk contains a variety of substances that might positively affect cognition and the development of children's psychomotor abilities.

Objective

This study aimed to examine the variations in intelligence quotient (IQ), social intelligence (SI), and body mass index (BMI) among 7- to 9-year-old girls who were exclusively breastfed, exclusively bottle-fed, or mixed-fed during their first 6 months of life.

Methods

This study involved 111 healthy girls, aged 7 to 9 years, who were recruited from nine government and private schools in Dammam, Kingdom of Saudi Arabia. Raven's Coloured Progressive Matrices were used to measure the participants' IQs, and the Vineland Social Maturity Assessment was used to measure their SI through individual interviews. Anthropometric measurements were obtained using standard methods.

Results

The breastfed group showed a greater number of above-average IQ test scores (35 vs. 23%; P = 0.479) and better SI scores (78 vs. 55%; P = 0.066) compared with the bottle-fed group. The number of girls with normal BMIs was significantly higher in the breastfed group than in the bottle-fed (68 vs. 41%; P = 0.045) or mixed-fed groups.

Conclusion

Exclusively breastfed girls had higher IQ and SI results compared with bottle-fed girls. However, unlike the BMI differences, these results were not statistically significant. This study provides fundamental observational data and can be further modified for use on a larger national-scale level.
Combined Effect of Inflammation and Hyperglycemia on Mild Cognitive Impairment and Associated Dietary Patterns in an Older Taiwanese Population
Authors: Fan Yen-Chun , Chou Chia-Chi , Bintoro Bagas Suryo , Pan Wen-Harn , Bai Chyi-Huey
Published: February 2022

Background

Previous studies have demonstrated that C-reactive protein (CRP) and glycated hemoglobin (HbA1c) levels are independently associated with neurodegenerative diseases, which can be improved by altering dietary patterns. This study investigates the combined effect of CRP and HbA1c, as well as the influence of dietary patterns, on the risk of dementia.

Methods

A cross-sectional study was conducted with 536 participants aged ≥65 years who were recruited from the Nutrition and Health Survey in Taiwan between 2014 and 2016. The high levels of inflammation and glycation were defined as a CRP level of >0.21 mg/dl and a HbA1c level of ≥6.50%, respectively. Mild cognitive impairment (MCI) was evaluated using the Mini-Mental State Examination (MMSE) score. The dietary patterns associated with CRP and HbA1c levels were assessed using the reduced rank regression (RRR). Multivariate logistic regression analysis of both complete and imputed datasets was performed.

Results

Participants with high levels of both CRP and HbA1c were associated with the highest odds ratio (OR) of MCI (adjusted OR [aOR] = 3.52; 95% CI = 3.48, 3.56; p < 0.001), followed by a high level of only HbA1c (aOR = 1.73; p < 0.001) and a high level of CRP (aOR = 1.49; p < 0.001). Using the reduced rank regression, an inverse relationship between higher consumption nuts and seeds and lower levels of CRP and HbA1c was found (both factors loading < −0.2). Concerning the combined effect of tertiles among the factor 1 and factor 2 analyzed by dietary patterns, group 1 with both T3 (high tertiles) was associated with the greatest OR of MCI (aOR = 4.38; 95% CI = 4.34, 4.42; p < 0.001) using multiple imputation.

Conclusions

The combined effect of high levels of inflammation and hyperglycemia was associated with an increased likelihood of MCI. Moreover, dietary patterns positively related to inflammation and hyperglycemia were associated with MCI, while eating nuts and seeds promoted better cognition.
Multispectral Differential Reconstruction Strategy for Bioluminescence Tomography
Authors: Liu Yanqiu , Chu Mengxiang , Guo Hongbo , Hu Xiangong , Yu Jingjing , He Xuelei , Yi Huangjian , He Xiaowei
Published: February 2022

Bioluminescence tomography (BLT) is a promising in vivo molecular imaging tool that allows non-invasive monitoring of physiological and pathological processes at the cellular and molecular levels. However, the accuracy of the BLT reconstruction is significantly affected by the forward modeling errors in the simplified photon propagation model, the measurement noise in data acquisition, and the inherent ill-posedness of the inverse problem. In this paper, we present a new multispectral differential strategy (MDS) on the basis of analyzing the errors generated from the simplification from radiative transfer equation (RTE) to diffusion approximation and data acquisition of the imaging system. Through rigorous theoretical analysis, we learn that spectral differential not only can eliminate the errors caused by the approximation of RTE and imaging system measurement noise but also can further increase the constraint condition and decrease the condition number of system matrix for reconstruction compared with traditional multispectral (TM) reconstruction strategy. In forward simulations, energy differences and cosine similarity of the measured surface light energy calculated by Monte Carlo (MC) and diffusion equation (DE) showed that MDS can reduce the systematic errors in the process of light transmission. In addition, in inverse simulations and in vivo experiments, the results demonstrated that MDS was able to alleviate the ill-posedness of the inverse problem of BLT. Thus, the MDS method had superior location accuracy, morphology recovery capability, and image contrast capability in the source reconstruction as compared with the TM method and spectral derivative (SD) method. In vivo experiments verified the practicability and effectiveness of the proposed method.
Ciclopirox Olamine Exerts Tumor-Suppressor Effects via Topoisomerase II Alpha in Lung Adenocarcinoma
Authors: Yin Jie , Che Gang , Jiang Kan , Zhou Ziyang , Wu Lingyun , Xu Mengyou , Liu Jian , Yan Senxiang
Published: February 2022

Background

Globally, lung cancer is one of the most malignant tumors, of which lung adenocarcinoma (LUAD) is the most common subtype, with a particularly poor prognosis. Ciclopirox olamine (CPX) is an antifungal drug and was recently identified as a potential antitumor agent. However, how CPX and its mechanism of action function during LUAD remain unclear.

Methods

The effects of CPX on cell proliferation, cell cycle, reactive oxygen species (ROS) levels, and apoptosis were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, colony formation, western blotting, flow cytometry assays, and immunohistochemistry. Global gene expression levels were compared between control and CPX-treated LUAD cells. A LUAD xenograft mouse model was used to evaluate the potential in vivo effects of CPX.

Results

We observed that CPX displayed strong antitumorigenic properties in LUAD cells, inhibited LUAD proliferation, induced ROS production, caused DNA damage, and activated the ATR-CHK1-P53 pathway. Topoisomerase II alpha (TOP2A) is overexpressed in LUAD and associated with a poor prognosis. By analyzing differentially expressed genes (DEGs), TOP2A was significantly down-regulated in CPX-treated LUAD cells. Furthermore, CPX treatment substantially inhibited in vivo LUAD xenograft growth without toxicity or side effects to the hematological system and internal organs.

Conclusions

Collectively, for the first time, we showed that CPX exerted tumor-suppressor effects in LUAD via TOP2A, suggesting CPX could potentially function as a promising chemotherapeutic for LUAD treatment.
Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan
Authors: Sobkowiak-Sobierajska Agnieszka , Lindemans Caroline , Sykora Tomas , Wachowiak Jacek , Dalle Jean-Hugues , Bonig Halvard , Gennery Andrew , Lawitschka Anita
Published: February 2022

Herein we review current practice regarding the management of chronic graft-vs.-host disease (cGvHD) in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukaemia (ALL). Topics covered include: (i) the epidemiology of cGvHD; (ii) an overview of advances in our understanding cGvHD pathogenesis; (iii) current knowledge regarding risk factors for cGvHD and prevention strategies complemented by biomarkers; (iii) the paediatric aspects of the 2014 National Institutes for Health-defined diagnosis and grading of cGvHD; and (iv) current options for cGvHD treatment. We cover topical therapy and newly approved tyrosine kinase inhibitors, emphasising the use of immunomodulatory approaches in the context of the delicate counterbalance between immunosuppression and immune reconstitution as well as risks of relapse and infectious complications. We examine real-world approaches of response assessment and tapering schedules of treatment. Furthermore, we report on the optimal timepoints for therapeutic interventions and changes in relation to immune reconstitution and risk of relapse/infection. Additionally, we review the different options for anti-infectious prophylaxis. Finally, we put forth a theory of a holistic view of paediatric cGvHD and its associated manifestations and propose a checklist for individualised risk evaluation with aggregated considerations including site-specific cGvHD evaluation with attention to each individual's GvHD history, previous medical history, comorbidities, and personal tolerance and psychosocial circumstances. To complement this checklist, we present a treatment algorithm using representative patients to inform the personalised management plans for patients with cGvHD after HSCT for ALL who are at high risk of relapse.
Three-Dimensional Structure Characterization and Inhibition Study of Exfoliative Toxin D From Staphylococcus aureus
Authors: Ullah Anwar , Khan Ajmal , Al-Harrasi Ahmed , Ullah Kifayat , Shabbir Asghar
Published: February 2022

The Staphylococcus aureus exfoliative toxins (ETs) are the main toxins that produce staphylococcal scalded skin syndrome (SSSS), an abscess skin disorder. The victims of the disease are usually newborns and kids, as well as grown-up people. Five ETs namely, exfoliative toxins A, B, C, D, and E have been identified in S. aureus. The three-dimensional (3D) structure of exfoliative toxins A, B, C and E is known, while that of exfoliative toxin D (ETD) is still unknown. In this work, we have predicted the 3D structure of ETD using protein modeling techniques (software used for 3D structure modeling comprising the MODELLER 9v19 program, SWISS-Model, and I-TESSER). The validation of the build model was done using PROCHECK (Ramachandran plot), ERRAT2, and Verify 3D programs. The results from 3D modeling show that the build model was of good quality as indicated by a GMQE score of 0.88 and by 91.1% amino acid residues in the most favored region of the Ramachandran plot, the ERRAT2 quality factor of 90.1%, and a verify3D score of >0.2 for 99.59% of amino acid residues. The 3D structure analysis indicates that the overall structure of ETD is similar to the chymotrypsin-like serine protease fold. The structure is composed of 13 β-strands and seven α-helices that fold into two well-defined six-strand β-barrels whose axes are roughly perpendicular to each other. The active site residues include histidine-97, aspartic acid-147, and serine-221. This represents the first structure report of ETD. Structural comparison with the other ETs shows some differences, particularly in the loop region, which also change the overall surface charge of these toxins. This may convey variable substrate specificity to these toxins. The inhibition of these toxins by natural (2S albumin and flocculating proteins from Moringa oleifera seeds) and synthetic inhibitors (suramin) was also carried out in this study. The results from docking indicate that the inhibitors bind near the C-terminal domain which may restrict the movement of this domain and may halt the access of the substrate to the active site of this enzyme. Molecular dynamic simulation was performed to see the effect of inhibitor binding to the enzyme. This work will further elucidate the structure–function relationship of this enzyme. The inhibition of this enzyme will lead to a new treatment for SSSS.
Ethnobotanical Survey on Bitter Tea in Taiwan
Authors: Chao Jung , Chen Ting-Yang , Pao Li-Heng , Deng Jeng-Shyan , Cheng Yung-Chi , Su Shan-Yu , Huang Shyh-Shyun
Published: February 2022

Ethnopharmacological evidence: In Taiwan, herbal tea is considered a traditional medicine and has been consumed for hundreds of years. In contrast to regular tea, herbal teas are prepared using plants other than the regular tea plant, Camellia sinensis (L.) Kuntze. Bitter tea (kǔ-chá), a series of herbal teas prepared in response to common diseases in Taiwan, is often made from local Taiwanese plants. However, the raw materials and formulations have been kept secret and verbally passed down by store owners across generations without a fixed recipe, and the constituent plant materials have not been disclosed.

Aim of the study: The aim was to determine the herbal composition of bitter tea sold in Taiwan, which can facilitate further studies on pharmacological applications and conserve cultural resources.

Materials and methods: Interviews were conducted through a semi-structured questionnaire. The surveyed respondents were traditional sellers of traditional herbal tea. The relevant literature was collated for a systematic analysis of the composition, characteristics, and traditional and modern applications of the plant materials used in bitter tea. We also conducted an association analysis of the composition of Taiwanese bitter tea with green herb tea (qing-cao-cha tea), another commonly consumed herbal tea in Taiwan, as well as herbal teas in neighboring areas outside Taiwan.

Results: After visiting a total of 59 stores, we identified 32 bitter tea formulations and 73 plant materials. Asteraceae was the most commonly used family, and most stores used whole plants. According to a network analysis of nine plant materials used in high frequency as drug pairs, Tithonia diversifolia and Ajuga nipponensis were found to be the core plant materials used in Taiwanese bitter tea.

Conclusion: Plant materials used in Taiwanese bitter tea were distinct, with multiple therapeutic functions. Further research is required to clarify their efficacy and mechanisms.
Hengli® Chinese Botulinum Toxin Type A for Treatment of Patients With Overactive Bladder: A Multicenter, Prospective, Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Liao Limin , Liu Qinggang , Cong Huiling , Xu Zhihui , Li Enhui , Weng Zhiliang , Jiang Haihong , Liu Ben , Huang Xiao , Xia Shujie , Wen Wei , Wu Juan , Shi Guowei , Wang Yang , Li Peijun , Yu Yang , Fang Zujun , Zheng Jie , Tian Ye , Shang Donghao , Li Hanzhong , Huang Zhongming , Zhou Liqun , Xiao Yunxiang , Zhang Yaoguang , Wang Jianlong , Zhang Xiaodong , Zhang Peng , Wang Dongwen , Zhang Xuhui , Xie Keji , Wang Bin , Ma Lulin , Tian Xiaojun , Chen Lijun , Dong Jinkai
Published: February 2022

Objective: To evaluate the efficacy and safety of Hengli® Chinese botulinum toxin type A (BTX-A; 100 U) in Chinese patients with overactive bladder.

Methods: This study was a multicenter, randomized, double-blind, placebo-controlled trial in Chinese patients who were inadequately managed with anticholinergic medications. Eligible patients were randomized 2:1 to receive intradetrusor injections of Hengli® BTX-A (n = 144) or placebo (n = 72). The primary endpoint was the change in the number of daily micturition episodes at week 6 from baseline. The secondary efficacy endpoints included the average frequency of urgency and urinary incontinence (UI) episodes per day, urgency score, average micturition volume per day, OABSS, and QoL score.

Results: In the Hengli® BTX-A group, there was a significantly greater reduction in the average number of micturition episodes per 24 h compared with the placebo group (3.28 vs. 1.43; p = 0.003). Moreover, there was a significantly greater improvement in the daily number of urgency episodes, micturition volume and OABSS score. An increased post-void residual urine volume, dysuria, and urinary tract infection represented adverse events (AEs) in the Hengli® BTX-A group. Most AEs were mild or moderate in severity. One patient in the BTX-A group initiated clean intermittent catheterization (CIC) during treatment.

Conclusion: Hengli® BTX-A treatment was well-tolerated and resulted in significant improvements in OAB symptoms among Chinese patients inadequately managed by anticholinergics.

Clinical Trial Registration:http://www.chinadrugtrials.org.cn/clinicaltrials.prosearch.dhtml, Identifier: CTR20131190.
The Impact of a National Stewardship Policy on the Usage Patterns of Key Monitoring Drugs in a Tertiary Teaching Hospital: An Interrupted Time Series Analysis
Authors: Li Haiyan , McIver David J. , Ji Wenjing , Du Jiaxi , Zhao Hang , Jia Xiaoni , Zhai Yuyao , Xue Xiaorong
Published: February 2022

Background: The management of Key Monitoring Drugs has become one of important aspects to control the growth of pharmaceutical expenditures in China. The first batch of the China National Key Monitoring Drugs (NKMDs) policy was released in July 2019. However, little is known about the impact of the national stewardship on the trends of NKMDs prescribing practice in hospitals, especially in the Northwestern China.

Methods: We collected 8-years of monthly NKMDs usage data from a tertiary hospital between 2014 and 2021. A segmented regression model of interrupted time series (ITS) analysis was used to evaluate the Defined Daily Doses (DDDs) and spending trends of ten NMKDs in the hospital throughout the study period. The pre-implementation period was from January 2014 to November 2019 and the post-implementation period was from December 2019 to June 2021.

Results: Prior to the implementation of the NKMDs policy, there was an increasing trend both in DDDs and spending for 8 of 10 NKMDs. The interventions managed by clinical pharmacists after the implementation of the national stewardship policy led to a significant decreasing trend of DDDs in the 19 months following implementation, of 430 fewer DDDs per month in total, compared to the pre-implementation period (p < 0.001). A similar decrease in spending was seen in the post-implementation period, with a trend of $4,682 less total spending on medications in those months compared to the pre-implementation trend (p = 0.003). There was a significant decrease in both monthly DDDs and spending for 6 of the 10 medications in the post-implementation period, while there was a significant increased trend both in monthly DDDs and spending on 1 medication in that period.

Conclusion: Using ITS analysis, the total DDDs and spending on 10 NKMDs in this hospital indicated sustained reductions over 19 months after multidimensional interventions under the implementation of the national policy guidance. The national stewardship policy could therefore be considered an effective strategy. Additional comprehensive policies should be introduced to further improve the rational use of NKMDs.
Chemo-Mechanical Factors That Limit Cellular Force Generation
Authors: Vazquez-Hidalgo Esteban , Farris Carly M. , Rowat Amy C. , Katira Parag
Published: February 2022

Cellular traction forces that are dependent on actin-myosin activity are necessary for numerous developmental and physiological processes. As traction force emerges as a promising cancer biomarker there is a growing need to understand force generation in response to chemical and mechanical cues. Our goal is to present a unified modeling framework that integrates actin-myosin activity, substrate stiffness, integrin bond type, and adhesion complex dynamics to explain how force develops under specific conditions. Our simulation results show that substrate stiffness and number of myosin motors contribute to the maximum actin-myosin forces that can be generated but do not solely control the force transmitted by the cells to the surface, i.e., the traction force. The kinetics of the bonds between the cell and the substrate plays an equally important role. Overall, we find that while the cell can generate large actin-myosin forces in individual stress fibers (> 300 pN), the maximum force transmitted to the surface per cell-substrate attachment only reaches a fraction of these values (approx. 50 pN). Traction stress, the sum of forces transferred by all cell-substrate attachments in a unit area, is biphasic or sigmoidal with increasing substrate stiffness depending on the number of active myosin motors generating forces. Finally, we conclude that adhesions < 1 μm2 generate widely variable traction forces and that impulse, the magnitude and duration of a force generating event, is a key limiting factor in traction stress.
Statistical Properties of Labor Productivity Distributions
Authors: Ishikawa Atushi , Fujimoto Shouji , Mizuno Takayuki
Published: February 2022

We employed the latest version of the world’s largest corporate financial database and identified the following three statistical properties of the physical labor productivity of firms: 1) The probability density function (PDF) of labor productivity follows power-law and log-normal distributions in the large- and mid-scale ranges. 2) Time-reversal symmetry was observed in the correlation of labor productivities in two consecutive years, and the initial-value dependence of the growth-rate distribution has regularity. These two properties accurately derive the above two kinds of PDFs. 3) The dependence of labor productivity distribution is negligible on the number of employees. This indicates a slight difference in the distribution of labor productivity among large-, mid-, and small-sized firms.
Integrin Beta 4E Promotes Endothelial Phenotypic Changes and Attenuates Lung Endothelial Cell Inflammatory Responses
Authors: Chen Weiguo , Gard Jamie M. C. , Epshtein Yulia , Camp Sara M. , Garcia Joe G. N. , Jacobson Jeffrey R. , Cress Anne E.
Published: February 2022

We previously reported integrin beta 4 (ITGB4) is an important mediator of lung vascular protection by simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitor. In this study, we report increased endothelial cell (EC) expression specifically of ITGB4E, an ITGB4 mRNA splice variant, by simvastatin with effects on EC protein expression and inflammatory responses. In initial experiments, human pulmonary artery ECs were treated using simvastatin (5 μM, 24 h) prior to immunoprecipitation of integrin alpha 6 (ITGA6), which associates with ITGB4, and Western blotting for full-length ITGB4 and ITGB4E, uniquely characterized by a truncated 114 amino acid cytoplasmic domain. These experiments confirmed a significant increase in both full-length ITGB4 and ITGB4E. To investigate the effects of increased ITGB4E expression alone, ECs were transfected with ITGB4E or control vector, and cells were seeded in wells containing Matrigel to assess effects on angiogenesis or used for scratch assay to assess migration. Decreased angiogenesis and migration were observed in ITGB4E transfected ECs compared with controls. In separate experiments, PCR and Western blots from transfected cells demonstrated significant changes in EC protein expression associated with increased ITGB4E, including marked decreases in platelet endothelial cell adhesion molecule-1 (PECAM-1) and vascular endothelial-cadherin (VE-cadherin) as well as increased expression of E-cadherin and N-cadherin along with increased expression of the Slug and Snail transcription factors that promote endothelial-to-mesenchymal transition (EndMT). We, then, investigated the functional effects of ITGB4E overexpression on EC inflammatory responses and observed a significant attenuation of lipopolysaccharide (LPS)-induced mitogen-activated protein kinase (MAPK) activation, including decreased phosphorylation of both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), as well as reduced inflammatory cytokines (IL-6 and IL-8), expressed in the media of EC after either LPS or excessive cyclic stretch (CS). Finally, EC expression-increased ITGB4E demonstrated decreased barrier disruption induced by thrombin as measured by transendothelial electrical resistance. Our data support distinct EC phenotypic changes induced by ITGB4E that are also associated with an attenuation of cellular inflammatory responses. These findings implicate ITGB4E upregulation as an important mediator of lung EC protection by statins and may lead to novel therapeutic strategies for patients with or at risk for acute lung injury (ALI).
Altered Expiratory Flow Dynamics at Peak Exercise in Adult Men With Well-Controlled Type 1 Diabetes
Authors: Hyrylä Vesa V. , Rissanen Antti-Pekka E. , Peltonen Juha E. , Koponen Anne S. , Tikkanen Heikki O. , Tarvainen Mika P.
Published: February 2022

Type 1 diabetes may, in time, cause lung dysfunction including airflow limitation. We hypothesized that ventilatory flow morphology during a cardiopulmonary exercise test (CPET) would be altered in adult men with well-controlled type 1 diabetes. Thirteen men with type 1 diabetes [glycated hemoglobin A1c 59 (9) mmol/mol or 7.5 (0.8)%, duration of diabetes 12 (9) years, and age 33.9 (6.6) years] without diagnosed diabetes-related complications and 13 healthy male controls [age 37.2 (8.6) years] underwent CPET on a cycle ergometer (40 W increments every 3 min until volitional fatigue). We used a principal component analysis based method to quantify ventilatory flow dynamics throughout the CPET protocol. Last minute of each increment, peak exercise, and recovery were examined using linear mixed models, which accounted for relative peak oxygen uptake and minute ventilation. The type 1 diabetes participants had lower expiratory peak flow (P = 0.008) and attenuated slope from expiration onset to expiratory peak flow (P = 0.012) at peak exercise when compared with the healthy controls. Instead, during submaximal exercise and recovery, the type 1 diabetes participants possessed similar ventilatory flow dynamics to that of the healthy controls. In conclusion, men with relatively well-controlled type 1 diabetes and without clinical evidence of diabetes-related complications exhibited attenuated expiratory flow at peak exercise independently of peak oxygen uptake and minute ventilation. This study demonstrates that acute exercise reveals alterations in ventilatory function in men with type 1 diabetes but not until peak exercise.
Identification of Arabidopsis Phospholipase A Mutants With Increased Susceptibility to Plasmodiophora brassicae
Authors: Zhou Qinqin , Jayawardhane Kethmi N. , Strelkov Stephen E. , Hwang Sheau-Fang , Chen Guanqun
Published: February 2022

Clubroot, caused by the obligate parasite Plasmodiophora brassicae, is one of the most devastating diseases of canola (Brassica napus) in Canada. The identification of novel genes that contribute to clubroot resistance is important for the sustainable management of clubroot, as these genes may be used in the development of resistant canola cultivars. Phospholipase As (PLAs) play important roles in plant defense signaling and stress tolerance, and thus are attractive targets for crop breeding. However, since canola is an allopolyploid and has multiple copies of each PLA gene, it is time-consuming to test the functions of PLAs directly in this crop. In contrast, the model plant Arabidopsis thaliana has a simpler genetic background and only one copy of each PLA. Therefore, it would be reasonable and faster to validate the potential utility of PLA genes in Arabidopsis first. In this study, we identified seven homozygous atpla knockout/knockdown mutants of Arabidopsis, and tested their performance following inoculation with P. brassicae. Four mutants (pla1-iiα, pla1-iγ3, pla1-iii, ppla-iiiβ, ppla-iiiδ) developed more severe clubroot than the wild-type, suggesting increased susceptibility to P. brassicae. The homologs of these Arabidopsis PLAs (AtPLAs) in B. napus (BnPLAs) were identified through Blast searches and phylogenic analysis. Expression of the BnPLAs was subsequently examined in transcriptomic datasets generated from canola infected by P. brassicae, and promising candidates for further characterization identified.
Downregulation of miR156-Targeted PvSPL6 in Switchgrass Delays Flowering and Increases Biomass Yield
Authors: Cai Jinjun , Liu Wenwen , Li Weiqian , Zhao Lijuan , Chen Gang , Bai Yangyang , Ma Dongmei , Fu Chunxiang , Wang Yamei , Zhang Xinchang
Published: February 2022

MiR156/SQUAMOSA PROMOTER BINDING-LIKEs (SPLs) module is the key regulatory hub of juvenile-to-adult phase transition as a critical flowering regulator. In this study, a miR156-targeted PvSPL6 was identified and characterized in switchgrass (Panicum virgatum L.), a dual-purpose fodder and biofuel crop. Overexpression of PvSPL6 in switchgrass promoted flowering and reduced internode length, internode number, and plant height, whereas downregulation of PvSPL6 delayed flowering and increased internode length, internode number, and plant height. Protein subcellular localization analysis revealed that PvSPL6 localizes to both the plasma membrane and nucleus. We produced transgenic switchgrass plants that overexpressed a PvSPL6-GFP fusion gene, and callus were induced from inflorescences of selected PvSPL6-GFPOE transgenic lines. We found that the PvSPL6-GFP fusion protein accumulated mainly in the nucleus in callus and was present in both the plasma membrane and nucleus in regenerating callus. However, during subsequent development, the signal of the PvSPL6-GFP fusion protein was detected only in the nucleus in the roots and leaves of plantlets. In addition, PvSPL6 protein was rapidly transported from the nucleus to the plasma membrane after exogenous GA3 application, and returned from the plasma membrane to nucleus after treated with the GA3 inhibitor (paclobutrazol). Taken together, our results demonstrate that PvSPL6 is not only an important target that can be used to develop improved cultivars of forage and biofuel crops that show delayed flowering and high biomass yields, but also has the potential to regulate plant regeneration in response to GA3.