bluuebunny/crossref_metadata_2025 huggingface dataset:
Slingshot homolog-1 mediates the secretion of small extracellular vesicles containing misfolded proteins by regulating autophagy cargo receptors and actin dynamics
Authors: Cazzaro Sara , Fang Cenxiao , Khan Hirah , Witas Richard , Kee Teresa R. , Woo Jung-A. A. , Kang David E.
Published: August 2022

Increasing evidence indicates that the accumulation misfolded proteins in Alzheimer’s disease (AD) arises from clearance defects in the autophagy-lysosome pathway. Misfolded proteins such as Aβ and tau are secreted in small extracellular vesicles (i.e., exosomes) and are propagated from cell to cell in part through secreted small extracellular vesicles (sEVs). Recent studies suggest that autophagic activity and exosome secretion are coregulated events, and multiple autophagy-related proteins are found in sEVs, including the cargo receptors Sqstm1/p62 and optineurin. However, whether and how autophagy cargo receptors per se regulate the secretion of sEVs is unknown. Moreover, despite the prominent role of actin dynamics in secretory vesicle release, its role in EV secretion is unknown. In this study, we leveraged the dual axes of Slingshot Homolog-1 (SSH1), which inhibits Sqstm1/p62-mediated autophagy and activates cofilin-mediated actin dynamics, to study the regulation of sEV secretion. Here we show that cargo receptors Sqstm1/p62 and optineurin inhibit sEV secretion, an activity that requires their ability to bind ubiquitinated cargo. Conversely, SSH1 increases sEV secretion by dephosphorylating Sqstm1/p62 at pSer403, the phospho-residue that allows Sqstm1/p62 to bind ubiquitinated cargo. In addition, increasing actin dynamics through the SSH1-cofilin activation pathway also increases sEV secretion, which is mimicked by latrunculin B treatment. Finally, Aβ42 oligomers and mutant tau increase sEV secretion and are physically associated with secreted sEVs. These findings suggest that increasing cargo receptor engagement with autophagic cargo and reducing actin dynamics (i.e., SSH1 inhibition) represents an attractive strategy to promote misfolded protein degradation while reducing sEV-mediated cell to cell spread of pathology.
Natural, longitudinal recovery of adults with COVID-19 using standardized rehabilitation measures
Authors: Ciro Carrie A. , James Shirley A. , McGuire Hillary , Lepak Vince , Dresser Susan , Costner-Lark Amy , Robinson Wanda , Fritz Terrie
Published: August 2022

Background

While studies recommend rehabilitation following post-hospitalization recovery from COVID-19, few implement standardized tools to assess continued needs. The aim of this study was to identify post-hospitalization recommendations using an interdisciplinary needs assessment with standardized rehabilitation measures. A secondary aim was to use these tools to measure recovery over a 30-day period.

Materials and methods

Using a 30-day longitudinal design, we completed weekly rapid needs assessments in this convenience sample of 20 people diagnosed with COVID-19 discharged from the hospital to home. We computed summary statistics and used the Wilcoxon Signed Rank Test to assess change over the 4-week course of the study with alpha level = 0.05.

Results

Our sample (65% male, 47% over 50 years of age, 35% White, 37% with a confirmed diagnosis of diabetes, and 47% obese) included no patients who had required mechanical ventilation. Initial assessments demonstrated the majority of our participants were at an increased risk of falls, had disability in activities of daily living (ADL) and instrumental activities of daily living (IADL), mild cognitive impairment, and dyspnea. At the 30-day follow-up, most were independent in mobility and basic ADLs, with continued disability in IADLs and cognitive function.

Discussion

In this sample of patients who were not mechanically-ventilated, early and individualized rehabilitation was necessary. The results of this study suggest patients would benefit from a multi-disciplinary team needs assessment after medical stabilization to minimize fall risk and disability, and to prevent secondary complications resulting from post-hospital deconditioning due to COVID-19.
The application value of CT radiomics features in predicting pressure amplitude correlation index in patients with severe traumatic brain injury
Authors: Liu Jiaqi , Shan Yingchi , Gao Guoyi
Published: August 2022

Purpose

To explore the application value of a machine learning model based on CT radiomics features in predicting the pressure amplitude correlation index (RAP) in patients with severe traumatic brain injury (sTBI).

Methods

Retrospectively analyzed the clinical and imaging data in 36 patients with sTBI. All patients underwent surgical treatment, continuous ICP monitoring, and invasive arterial pressure monitoring. The pressure amplitude correlation index (RAP) was collected within 1 h after surgery. Three volume of interest (VOI) was selected from the craniocerebral CT images of patients 1 h after surgery, and a total of 93 radiomics features were extracted from each VOI. Three models were established to be used to evaluate the patients' RAP levels. The accuracy, precision, recall rate, F1 score, receiver operating characteristic (ROC) curve, and area under the curve (AUC) were used to evaluate the predictive performance of each model.

Results

The optimal number of features for three predicting models of RAP was five, respectively. The accuracy of predicting the model of the hippocampus was 77.78%, precision was 88.24%, recall rate was 60%, the F1 score was 0.6, and AUC was 0.88. The accuracy of predicting the model of the brainstem was 63.64%, precision was 58.33%, the recall rate was 60%, the F1 score was 0.54, and AUC was 0.82. The accuracy of predicting the model of the thalamus was 81.82%, precision was 88.89%, recall rate was 75%, the F1 score was 0.77, and AUC was 0.96.

Conclusions

CT radiomics can predict RAP levels in patients with sTBI, which has the potential to establish a method of non-invasive intracranial pressure (NI-ICP) monitoring.
Associations of sleep apnea risk and oxygen desaturation indices with cerebral small vessel disease burden in patients with stroke
Authors: Liu Xiaodi , Lam David Chi-Leung , Mak Henry Ka-Fung , Ip Mary Sau-Man , Lau Kui Kai
Published: August 2022

Background

Obstructive sleep apnea (OSA) is associated with cerebral small vessel disease (CSVD). Nonetheless, whether OSA-risk determined by a simple screening questionnaire or indices quantifying nocturnal hypoxemia other than the conventional apnea–hypopnea index (AHI) by the home sleep apnea test (HSAT) associated with CSVD burden remains uncertain.

Methods

From 2018 to 2021, we recruited patients with transient ischemic attack (TIA)/minor stroke from the Queen Mary Hospital Acute Stroke Unit and TIA/Stroke Outpatient Clinics. Logistic regression models were applied to determine the association of baseline OSA-risk (on STOP-BANG questionnaire) or HSAT-derived indices quantifying nocturnal hypoxemia with global burden/individual markers of CSVD on MRI. Indices included oxygen desaturation (≥3%) index (ODI), minimum oxygen saturation (SpO2), percentage of total sleep time with an oxygen saturation <90% (CT90%), and desaturation duration (≥3%, DesDur).

Results

In 283 patients with TIA/minor stroke (mean age 65 years, 64% men), OSA-risk was significantly associated with total CSVD score (multivariate-adjusted odds ratio: 1.23, 95% confidence interval 1.01–1.51), presence of lacunes [1.39 (1.09–1.79)] and burden of basal ganglia PVSs [1.32 (1.06–1.67)]. In 85/283 patients who completed HSAT, neither AHI, minimum SpO2 nor CT90% was associated with CSVD burden. Nonetheless, ODI and DesDur remained significantly associated with total CSVD score after covariate adjustment: ODI [1.04 (1.01–1.07)] and DesDur [1.04 (1.01–1.08)].

Conclusion

In patients with TIA/minor stroke, high OSA-risk was associated with a greater CSVD burden. Oxygen desaturation indices (ODI and DesDur) rather than AHI were independently associated with global CSVD burden, indicating that longer and more severe desaturations may contribute to the pathogenesis of CSVD.
Diagnostic yield of TOF-MRA for detecting incidental vascular lesions in patients with cognitive impairment: An observational cohort study
Authors: Park Ho Young , Suh Chong Hyun , Shim Woo Hyun , Heo Hwon , Kim Woo Seok , Lim Jae-Sung , Lee Jae-Hong , Kim Ho Sung , Kim Sang Joon
Published: August 2022

Objectives

The role of three-dimensional (3D) TOF-MRA in patients with cognitive impairment is not well established. We evaluated the diagnostic yield of 3D TOF-MRA for detecting incidental extra- or intracranial artery stenosis and intracranial aneurysm in this patient group.

Methods

This retrospective study included patients with cognitive impairment undergoing our brain MRI protocol from January 2013 to February 2020. The diagnostic yield of TOF-MRA for detecting incidental vascular lesions was calculated. Patients with positive TOF-MRA results were reviewed to find whether additional treatment was performed. Logistic regression analysis was conducted to identify the clinical risk factors for positive TOF-MRA findings.

Results

In total, 1,753 patients (mean age, 70.2 ± 10.6 years; 1,044 women) were included; 199 intracranial aneurysms were detected among 162 patients (9.2%, 162/1,753). A 3D TOF-MRA revealed significant artery stenoses (>50% stenosis) in 162 patients (9.2%, 162/1,753). The overall diagnostic yield of TOF-MRA was 16.8% (294/1,753). Among them, 92 patients (31.3%, 92/294) underwent either medical therapy, endovascular intervention, or surgery. In total, eighty-one patients with stenosis were prescribed with either antiplatelet medications or lipid-lowering agent. In total, fifteen patients (aneurysm: 11 patients, stenosis: 4 patients) were further treated with endovascular intervention or surgery. Thus, the “number needed to scan” was 19 for identifying one patient requiring treatment. Multivariate logistic regression analysis showed that being female (odds ratio [OR] 2.05) and old age (OR 1.04) were the independent risk factors for intracranial aneurysm; being male (OR 1.52), old age (OR 1.06), hypertension (OR 1.78), and ischemic heart disease history (OR 2.65) were the independent risk factors for significant artery stenosis.

Conclusions

Our study demonstrated the potential benefit of 3D TOF-MRA, given that it showed high diagnostic yield for detecting vascular lesions in patients with cognitive impairment and the considerable number of these lesions required further treatment. A 3D TOF-MRA may be included in the routine MR protocol for the work-up of this patient population, especially in older patients and patients with vascular risk factors.
The regulatory landscape of neurite development in Caenorhabditis elegans
Authors: Godini Rasoul , Fallahi Hossein , Pocock Roger
Published: August 2022

Neuronal communication requires precise connectivity of neurite projections (axons and dendrites). Developing neurites express cell-surface receptors that interpret extracellular cues to enable correct guidance toward, and connection with, target cells. Spatiotemporal regulation of neurite guidance molecule expression by transcription factors (TFs) is critical for nervous system development and function. Here, we review how neurite development is regulated by TFs in the Caenorhabditis elegans nervous system. By collecting publicly available transcriptome and ChIP-sequencing data, we reveal gene expression dynamics during neurite development, providing insight into transcriptional mechanisms governing construction of the nervous system architecture.
Regulation of dietary polyphenols on cancer cell pyroptosis and the tumor immune microenvironment
Authors: Huang Xiaoxia , Wang Yao , Yang Wenhui , Dong Jing , Li Lin
Published: August 2022

Cancer is a major public health problem that threatens human life worldwide. In recent years, immunotherapy has made great progress in both clinical and laboratory research. But the high heterogeneity and dynamics of tumors makes immunotherapy not suitable for all cancers. Dietary polyphenols have attracted researchers' attention due to their ability to induce cancer cell pyroptosis and to regulate the tumor immune microenvironment (TIME). This review expounds the regulation of dietary polyphenols and their new forms on cancer cell pyroptosis and the TIME. These dietary polyphenols include curcumin (CUR), resveratrol (RES), epigallocatechin gallate (EGCG), apigenin, triptolide (TPL), kaempferol, genistein and moscatilin. New forms of dietary polyphenols refer to their synthetic analogs and nano-delivery, liposomes. Studies in the past decade are included. The result shows that dietary polyphenols induce pyroptosis in breast cancer cells, liver cancer cells, oral squamous cells, carcinoma cells, and other cancer cells through different pathways. Moreover, dietary polyphenols exhibit great potential in the TIME regulation by modulating the programmed cell death protein 1(PD-1)/programmed death-ligand 1 (PD-L1) axis, enhancing antitumor immune cells, weakening the function and activity of immunosuppressive cells, and targeting tumor-associated macrophages (TAMs) to reduce their tumor infiltration and promote their polarization toward the M1 type. Dietary polyphenols are also used with radiotherapy and chemotherapy to improve antitumor immunity and shape a beneficial TIME. In conclusion, dietary polyphenols induce cancer cell pyroptosis and regulate the TIME, providing new ideas for safer cancer cures.
The impact of depression on survival of head and neck cancer patients: A population-based cohort study
Authors: Huang Ren-Wen , Chang Kai-Ping , Marchi Filippo , Loh Charles Yuen Yung , Lin Yu-Jr , Chang Chee-Jen , Kao Huang-Kai
Published: August 2022

Background

Depression is common among patients with head and neck cancer, thereby affecting their survival rate. However, whether close monitoring of depression affects the survival outcomes of these patients is unknown. Therefore, this study aimed to determine whether depression treatment continuity after the diagnosis of cancer affects the survival of these patients.

Methods

A total of 55,069 patients diagnosed with head and neck cancer in the Cancer Registration System database in Taiwan were enrolled. This cohort was followed from January 1, 2007 to December 31, 2017. Furthermore, the patients were divided into four groups, namely, “no depression,” “pre-cancer only,” “post-cancer only,” and “both before and after cancer,” on the basis of the diagnosis of depression and the duration of the follow-up period in the psychiatric clinic. Further, the Cox proportional hazard model was applied to estimate the hazard of death for the four groups.

Results

A total of 6,345 (11.52%) patients were diagnosed with depression in this cohort. The “pre-cancer only” group had a lower overall survival (HR = 1.18; 95% CI = 1.11–1.25) compared with the “no depression” group. Moreover, the “post-cancer only” group had better overall survival (HR = 0.88; 95% CI = 0.83–0.94) compared with the “no depression” group, especially in advanced-stage patients. Patients who were diagnosed with depression before cancer and had continuous depression treatments after the cancer diagnosis had better overall survival (HR = 0.78; 95% CI = 0.71–0.86) compared with patients who had treatment interruptions.

Conclusion

Patients with pre-cancer depression had poorer survival outcomes, especially those who did not receive psychiatric clinic visits after their cancer diagnosis. Nonetheless, in patients with advanced-stage cancer, depression treatment may improve overall survival.
Intraoperative low-dose dopamine is associated with worse survival in patients with hepatocellular carcinoma: A propensity score matching analysis
Authors: Wang Yan , Xue Ruifeng , Xing Wei , Li Qiang , Gei Liba , Yan Fang , Mai Dongmei , Zeng Weian , Yan Yan , Chen Dongtai
Published: August 2022

Background

Dopamine is widely used in patients during surgery. We evaluated the association between intraoperative low-dose dopamine administration and recurrence-free survival (RFS) and overall survival (OS) in patients with hepatocellular carcinoma (HCC).

Methods

Consecutive patients with nonmetastatic HCC who underwent radical hepatectomy were enrolled between 2008 and 2010. Univariate and multivariate logistic regression analyses were used to evaluate the prognostic factors for RFS and OS. Survival outcomes were evaluated using Kaplan–Meier analyses with the log-rank test. A one-to-one propensity score matching (PSM) analysis was performed to reduce confounding bias.

Results

A total of 805 HCC patients, including 699 patients who did not receive dopamine consumption and 106 patients who received low-dose dopamine during the operation, were retrospectively analyzed. The patients who were assigned low-dose dopamine had worse RFS (p = 0.009) and OS (p = 0.041) than those who did not receive dopamine. Multivariate regression analysis showed that the intraoperative administration of low-dose dopamine was an independent unfavorable predictor for RFS (p = 0.004) but not for OS (p = 0.059). After PSM, the low-dose dopamine-treated group still had significantly poorer RFS (p = 0.003) and OS (p = 0.002). When stratified by time of recurrence, patients with low-dose dopamine use had a significantly greater chance of recurrence within 2 years (p = 0.007) but not after 2 years (p = 0.186).

Conclusions

Intraoperative low-dose dopamine use has a negative impact on RFS and OS in HCC patients who have undergone radical hepatectomy. Further prospective studies are required to assess the effects of low-dose dopamine on surgical outcomes in HCC patients.
Fanconi anemia and dyskeratosis congenita/telomere biology disorders: Two inherited bone marrow failure syndromes with genomic instability
Authors: Fiesco-Roa Moisés Ó. , García-de Teresa Benilde , Leal-Anaya Paula , van ‘t Hek Renée , Wegman-Ostrosky Talia , Frías Sara , Rodríguez Alfredo
Published: August 2022

Inherited bone marrow failure syndromes (IBMFS) are a complex and heterogeneous group of genetic diseases. To date, at least 13 IBMFS have been characterized. Their pathophysiology is associated with germline pathogenic variants in genes that affect hematopoiesis. A couple of these diseases also have genomic instability, Fanconi anemia due to DNA damage repair deficiency and dyskeratosis congenita/telomere biology disorders as a result of an alteration in telomere maintenance. Patients can have extramedullary manifestations, including cancer and functional or structural physical abnormalities. Furthermore, the phenotypic spectrum varies from cryptic features to patients with significantly evident manifestations. These diseases require a high index of suspicion and should be considered in any patient with abnormal hematopoiesis, even if extramedullary manifestations are not evident. This review describes the disrupted cellular processes that lead to the affected maintenance of the genome structure, contrasting the dysmorphological and oncological phenotypes of Fanconi anemia and dyskeratosis congenita/telomere biology disorders. Through a dysmorphological analysis, we describe the phenotypic features that allow to make the differential diagnosis and the early identification of patients, even before the onset of hematological or oncological manifestations. From the oncological perspective, we analyzed the spectrum and risks of cancers in patients and carriers.
The hedgehog pathway in hematopoiesis and hematological malignancy
Authors: Lemos Tucker , Merchant Akil
Published: August 2022

The Hedgehog (HH) pathway is a promising therapeutic target in hematological malignancies. Activation of the pathway has been tied to greater chances of relapse and poorer outcomes in several hematological malignancies and inhibiting the pathway has improved outcomes in several clinical trials. One inhibitor targeting the pathway via the protein Smoothened (SMO), glasdegib, has been approved by the FDA for use with a low dose cytarabine regiment in some high-risk acute myeloid leukemia patients (AML). If further clinical trials in glasdegib produce positive results, there may soon be more general use of HH inhibitors in the treatment of hematological malignancies.While there is clinical evidence that HH inhibitors may improve outcomes and help prevent relapse, a full understanding of any mechanism of action remains elusive. The bulk of AML cells exhibit primary resistance to SMO inhibition (SMOi), leading some to hypothesize that that clinical activity of SMOi is mediated through modulation of self-renewal and chemoresistance in rare cancer stem cells (CSC). Direct evidence that CSC are being targeted in patients by SMOi has proven difficult to produce, and here we present data to support the alternative hypothesis that suggests the clinical benefit observed with SMOi is being mediated through stromal cells in the tumor microenvironment.This paper’s aims are to review the history of the HH pathway in hematopoiesis and hematological malignancy, to highlight the pre-clinical and clinical evidence for its use a therapeutic target, and to explore the evidence for stromal activation of the pathway acting to protect CSCs and enable self-renewal of AML and other diseases. Finally, we highlight gaps in the current data and present hypotheses for new research directions.
Epidemiological and clinical characteristics of congenital pseudarthrosis of the tibia in China
Authors: Zhou Yijun , Tan Qian , Liu Kun , Liu Yaoxi , Zhu Guanghui , Mei Haibo , Yang Ge
Published: August 2022

Background

Congenital pseudarthrosis of the tibia (CPT) is a refractory and rare disease. Because of its extremely low incidence, little is known about its clinical features. In this retrospective study, we aim to analyze the clinical characteristics of patients with CPT.

Materials and methods

This is a retrospective study of children with CPT identified by the radiological review. Investigations of CPT included general conditions, the characteristics of CPT, treatment methods, and surgical complications.

Results

We collected 514 CPT cases from March 1999 to March 2020 in our hospital, such as 317 (61.67%) boys, 197 (38.33%) girls; 330 (62.86%) in Crawford IV; 510 (97.14%) in mid and distal 1/3 tibia; 481 (93.58%) in less than 3 years at onset age; 297 (57.78%) in less than 3 years at the first outpatient visit. The most common post-operative complication was ankle valgus (101, 39.60%), followed by limb length discrepancy (91, 35.69%), refracture (38, 14.90%), osteomyelitis (15, 5.88%), and removal of internal fixation (10, 3.93%).

Conclusions

CPT with a higher incidence of Crawford IV frequently occurs in boys and the middle or distal part of the tibia; most patients have the onset age and first outpatient visit before 3 years; the major surgical complications are ankle valgus and limb length discrepancy.
An increasing tendency of precocious puberty among Korean children from the perspective of COVID-19 pandemic effect
Authors: Choi Kyu Hee , Park Seung Chan
Published: August 2022

Introduction

This study was conducted to investigate changes and new trends over the past 6 years by analyzing the current status of precocious puberty (PP) treatment and treatment costs in Korea between 2016 and 2021.

Materials and methods

Annual and monthly number of patients diagnosed with PP from 2016 to 2021 were reviewed using the data from Healthcare Bigdata Hub. Annual medical insurance expenses for the treatment of PP were also reviewed. The data were compared by the gender of the patients.

Results

The number of patients diagnosed with PP rose from 86,352 in 2016 to 166,645 in 2021, while medical expenses rose from KRW 64,111,689,000 in 2016 to KRW 134,642,100,000 in 2021. The percentage of male PP patients increased from 9.21% in 2016 to 19.55% in 2021.

Conclusion

Increasing numbers of Korean patients diagnosed with PP. Consistent with the situation in other countries, the rapid increase in the number of cases since April 2020 appears to be a result of the COVID-19 pandemic. In Korea, this is considered a nationwide phenomenon. Also on the rise is the incidence of PP in males, which appears to be due to an increased awareness of the phenomenon. Further investigations are required to determine the possible causes in increasing prevalence of PP.
Cost-effectiveness analysis of tislelizumab, nivolumab and docetaxel as second- and third-line for advanced or metastatic non-small cell lung cancer in China
Authors: Zhou Dongchu , Luo Xia , Zhou Zhen , Zeng Xiaohui , Wan Xiaomin , Tan Chongqing , Liu Qiao
Published: August 2022

Objective: Domestic PD-1inhibitor tislelizumab has emerged as a promising treatment for Chinese patients with driver-negative advanced or metastatic non-small cell lung cancer (NSCLC). The purpose of our study to evaluate whether tislelizumab is cost-effective as a second- or third-line treatment for this population compared with docetaxel (conventional chemotherapy) and nivolumab (imported PD-1inhibitor), from the perspective of the Chinese healthcare system.

Material and Methods: A Markov model with a 3-week Markov cycle and a 30-year time horizon was built to compare the cost-effectiveness of second- or third-line tislelizumab versus docetaxel and nivolumab. Transition probabilities, including disease progression, survival, and adverse events (AEs)-related treatment discontinuation event, were estimated from the clinical trials. Costs and health utilities were collected from local hospitals, public database and published literature.

Results: Compared with docetaxel, tislelizumab provided an additional 0.33 quality-adjusted life-years (QALYs) (1.37 vs. 1.04 QALYs) at an incremental cost of $9,286 ($23,646 vs. $14,360) for Chinese patients with driver-negative advanced or metastatic NSCLC, resulting in an incremental cost-effectiveness ratio (ICER) of $27,959/QALY under the WTP threshold of $35,663/QALY used in the model. Compared with nivolumab, tislelizumab was associated with a lower cost ($23,646 vs. $59,447) and higher QALYs (1.37 vs. 1.20 QALYs), resulting in its dominance of nivolumab.

Conclusion: From the perspective of the Chinese healthcare system, domestic PD-1inhibitor tislelizumab immunotherapy represents a cost-effective treatment strategy compared with conventional docetaxel chemotherapy and imported PD-1inhibitor nivolumab immunotherapy in the treatment of driver-negative advanced or metastatic NSCLC beyond the first-line setting. In the era of “Universal Medical Insurance System”, the rational use of domestic anticancer drugs guided by cost-benefit evidence would be an effective means to balance the limited expenditure of medical insurance fund and the growing demand for cancer treatments.
6-Gingerol attenuates subarachnoid hemorrhage-induced early brain injury via GBP2/PI3K/AKT pathway in the rat model
Authors: Tang Hui , Shao Chuan , Wang Xiaoya , Cao Yi , Li Zhou , Luo Xiaoquan , Yang Xiang , Zhang Yuekang
Published: August 2022

Numerous studies have elucidated the neuroprotective effect of 6-gingerol in central nervous system diseases. However, the potential role and mechanism of 6-gingerol on early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains poorly understood. Here, we report that 6-gingerol exerts a neuroprotective effect on SAH-induced EBI through the GBP2/PI3K/AKT pathway. A SAH rat model was established by injecting femoral artery blood into the cisterna magna. 6-gingerol or vehicle was injected intraperitoneally 1 hour post-SAH induction. We found that the neurological function score and brain edema of SAH rats were significantly improved after 6-gingerol treatment, as well as neuronal apoptosis was attenuated in SAH rats by Nissl staining assay and TUNEL assay. To further explore potential molecular mechanisms associated with 6-gingerol, RNA sequencing was implemented to investigate the differences in transcriptomes between SAH rats with and without 6-gingerol treatment; and found that the expression of guanylate-binding protein 2 (GBP2) evidently was suppressed with 6-gingerol treatment compared to vehicle group. In addition, dual immunofluorescence was also employed to investigate changes in neurons, astrocytes, and microglia after 6-gingerol treatment. The results showed that GBP2 was expressed in neurons but not astrocytes or microglia. Western blotting analysis results demonstrated that the PI3K/AKT pathway was activated in the SAH rats treated with 6-gingerol. Furthermore, recombinant GBP2 protein and LY294002 (PI3K inhibitor) treatment reversed the effects of 6-gingerol treatment in SAH rats. These results indicate that 6-gingerol suppressed the expression of GBP2 to activate the PI3K/AKT pathway, improve neurologic outcomes, reduce brain edema and neuronal apoptosis. In summary, our findings suggest that 6-gingerol could attenuate EBI post-SAH in rats, and 6-gingerol may serve as a novel candidate neuroprotective drug for SAH-induced EBI.
Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action
Authors: Daniel Julio Paulino , Mesquita Felipe Pantoja , Da Silva Emerson Lucena , de Souza Pedro Filho Noronha , Lima Luina Benevides , de Oliveira Lais Lacerda Brasil , de Moraes Maria Elisabete Amaral , Moreira-Nunes Caroline de Fátima Aquino , Burbano Rommel Mario Rodríguez , Zanatta Geancarlo , Montenegro Raquel Carvalho
Published: August 2022

Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, particularly the T315I gate-keeper mutation, cause resistance in patients. As a result, broad-spectrum ABL1 medicines are desperately needed. In order to screen potential drugs targeting CML, mebendazole (MBZ) was subjected to the in vitro test against CML cell lines (K562 and FEPS) and computational assays. The antiproliferative effect of MBZ and the combination with tyrosine kinase inhibitors (TKIs) was tested using end-point viability assays, cell cycle distribution analysis, cell membrane, and mitochondrial dyes. By interrupting the cell cycle and causing cell death, MBZ and its combination with imatinib and dasatinib have a significant antiproliferative effect. We identified MBZ as a promising “new use” drug targeting wild-type and mutant ABL1 using molecular docking. Meanwhile, we determined which residues in the allosteric site are important in ABL1 drug development. These findings may not only serve as a model for repositioning current authorized medications but may also provide ABL1-targeted anti-CML treatments a fresh lease of life.
Strategies to safely target widely expressed soluble adenylyl cyclase for contraception
Authors: Ferreira Jacob , Levin Lonny R. , Buck Jochen
Published: August 2022

In humans, the prototypical second messenger cyclic AMP is produced by 10 adenylyl cyclase isoforms, which are divided into two classes. Nine isoforms are G protein coupled transmembrane adenylyl cyclases (tmACs; ADCY1-9) and the 10th is the bicarbonate regulated soluble adenylyl cyclase (sAC; ADCY10). This review details why sAC is uniquely druggable and outlines ways to target sAC for novel forms of male and female contraception.
Application of metabolomics in the diagnosis of non-alcoholic fatty liver disease and the treatment of traditional Chinese medicine
Authors: Shao Mingmei , Lu Yifei , Xiang Hongjiao , Wang Junmin , Ji Guang , Wu Tao
Published: August 2022

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease around the world, and it often coexists with insulin resistance-related diseases including obesity, diabetes, hyperlipidemia, and hypertension, which seriously threatens human health. Better prevention and treatment strategies are required to improve the impact of NAFLD. Although needle biopsy is an effective tool for diagnosing NAFLD, this method is invasive and difficult to perform. Therefore, it is very important to develop more efficient approaches for the early diagnosis of NAFLD. Traditional Chinese medicine (TCM) can play a certain role in improving symptoms and protecting target organs, and its mechanism of action needs to be further studied. Metabolomics, the study of all metabolites that is thought to be most closely associated with the patients’ characters, can provide useful clinically biomarkers that can be applied to NAFLD and may open up new methods for diagnosis. Metabolomics technology is consistent with the overall concept of TCM, and it can also be used as a potential mechanism to explain the effects of TCM by measuring biomarkers by metabolomics. Based on PubMed/MEDLINE and other databases, this paper retrieved relevant literature NAFLD and TCM intervention in NAFLD using metabolomics technology in the past 5 years were searched, and the specific metabolites associated with the development of NAFLD and the potential mechanism of Chinese medicine on improving symptoms were summarized.
Simulations of graphite boronization: A molecular dynamics study of amorphization resulting from bombardment
Authors: Rau Aaditya , Jubin Sierra , Vella Joseph R. , Kaganovich Igor D.
Published: August 2022

The molecular dynamics code LAMMPS was used to simulate the bombardment of a graphite structure by atomic boron with impact energies ranging from 50–250 eV. The transient structural evolution, penetration depth, and amorphous layer thickness were analyzed. Simulations show that larger impact energies lead to a greater volume of amorphization and penetration of boron, but that the growth rate of the amorphous layer decreases with increasing fluence. Furthermore, the change in surface chemistry of the amorphized structures was studied using the ReaxFF formalism, which found that the amorphization process introduces dangling bonds thus increasing reactivity in the amorphous region.
The effect of interurban movements on the spatial distribution of population
Authors: Ye Jiachen , Hu Qitong , Ji Peng , Barthelemy Marc
Published: August 2022

Understanding how interurban movements can modify the spatial distribution of the population is important for transport planning but is also a fundamental ingredient for epidemic modeling. We illustrate this on vacation trips for all transportation modes in China during the Lunar New Year and compare the results for 2019 with the ones for 2020 where travel bans were applied for mitigating the spread of a novel coronavirus (COVID-19). We first show that inter-urban travel flows are broadly distributed and display both large temporal and spatial fluctuations, making their modeling very difficult. When flows are larger, they appear to be more dispersed over a larger number of origins and destinations, creating de facto hubs that can spread an epidemic at a large scale. These movements quickly induce (in about a week for this case) a very strong population concentration in a small set of cities. We characterize quantitatively the return to the initial distribution by defining a pendular ratio which allows us to show that this dynamics is in general very slow and even stopped for the 2020 Lunar New Year due to travel restrictions. Travel restrictions obviously limit the spread of the diseases between different cities, but have thus the counter-effect of keeping high concentration in a small set of cities, a priori favoring intra-city spread, unless individual contacts are strongly limited. These results shed some light on the statistics of interurban movements and how they modify the national distribution of populations, a crucial ingredient for devising effective control strategies at a national level.
Construction of optical system for an atomic clock-beyond atomic fountain
Authors: Wang Xiumei , He Jin , Wang Yifei , Wang Yunjia , Wang Wenming , Wang Weili , Li Shiguang , Zhu Xi , Liu Guodong , Liu Shuo , Wang Ye , Wang Liang , Liu Yaxuan , Yang Tongmin , Cao Chunyan , Wei Yiqun , Yue Yutao , Hu Guoqing , Liu Zhenfeng , Pan Yimin , Gao Lianshan
Published: August 2022

We demonstrate the construction of the optical system in the atomic clock-beyond atomic fountain based on 87Rb atom. The optical system includes a high-stability laser system and an optical lattice. The high-stability laser system with the new scheme of frequency locking and shift is introduced in detail, which is an important laser source for laser cooling. The optimized frequency and intensity stability are achieved to 4 × 10–14τ−1/2 (τ is the averaging time) and 4 × 10–5τ−1/2, respectively, which are highly stable. On the basis of the conventional atomic fountain clock, the optical lattice is specially investigated along the direction of gravity and its characteristics are studied systematically. For the optimized and novel exploration, we predict the achievable stability of 3.6×10−14τ−1/2 and it has the potential to be improved to 3.6×10−15τ−1/2. The realizability of the construction due to the stabilized laser and optical lattice makes the beyond fountain promising candidate for the next-generation high performance microwave atomic clock.
Brain-muscle interplay during endurance self-paced exercise in normobaric and hypobaric hypoxia
Authors: Rupp Thomas , Saugy Jonas J. , Bourdillon Nicolas , Millet Grégoire P.
Published: August 2022

Purpose: Hypoxia is one major environmental factor, supposed to mediate central motor command as well as afferent feedbacks at rest and during exercise. By using a comparison of normobaric (NH) and hypobaric (HH) hypoxia with the same ambient pressure in oxygen, we examined the potential differences on the cerebrovascular and muscular regulation interplay during a self-paced aerobic exercise.

Methods: Sixteen healthy subjects performed three cycling time-trials (250 kJ) in three conditions: HH, NH and normobaric normoxia (NN) after 24 h of exposure. Cerebral and muscular oxygenation were assessed by near-infrared spectroscopy, cerebral blood flow by Doppler ultrasound system. Gas exchanges, peripheral oxygen saturation, power output and associated pacing strategies were also continuously assessed.

Results: The cerebral oxygen delivery was lower in hypoxia than in NN but decreased similarly in both hypoxic conditions. Overall performance and pacing were significantly more down-regulated in HH versus NH, in conjunction with more impaired systemic (e.g. saturation and cerebral blood flow) and prefrontal cortex oxygenation during exercise.

Conclusions: The difference in pacing was likely the consequence of a complex interplay between systemic alterations and cerebral oxygenation observed in HH compared to NH, aiming to maintain an equivalent cerebral oxygen delivery despite higher adaptive cost (lower absolute power output for the same relative exercise intensity) in HH compared to NH.
Uncoupling of Voltage- and Ligand-Induced Activation in HCN2 Channels by Glycine Inserts
Authors: Yüksel Sezin , Bonus Michele , Schwabe Tina , Pfleger Christopher , Zimmer Thomas , Enke Uta , Saß Inga , Gohlke Holger , Benndorf Klaus , Kusch Jana
Published: August 2022

Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are tetramers that generate electrical rhythmicity in special brain neurons and cardiomyocytes. The channels are activated by membrane hyperpolarization. The binding of cAMP to the four available cyclic nucleotide-binding domains (CNBD) enhances channel activation. We analyzed in the present study the mechanism of how the effect of cAMP binding is transmitted to the pore domain. Our strategy was to uncouple the C-linker (CL) from the channel core by inserting one to five glycine residues between the S6 gate and the A′-helix (constructs 1G to 5G). We quantified in full-length HCN2 channels the resulting functional effects of the inserted glycines by current activation as well as the structural dynamics and statics using molecular dynamics simulations and Constraint Network Analysis. We show functionally that already in 1G the cAMP effect on activation is lost and that with the exception of 3G and 5G the concentration-activation relationships are shifted to depolarized voltages with respect to HCN2. The strongest effect was found for 4G. Accordingly, the activation kinetics were accelerated by all constructs, again with the strongest effect in 4G. The simulations reveal that the average residue mobility of the CL and CNBD domains is increased in all constructs and that the junction between the S6 and A′-helix is turned into a flexible hinge, resulting in a destabilized gate in all constructs. Moreover, for 3G and 4G, there is a stronger downward displacement of the CL-CNBD than in HCN2 and the other constructs, resulting in an increased kink angle between S6 and A′-helix, which in turn loosens contacts between the S4-helix and the CL. This is suggested to promote a downward movement of the S4-helix, similar to the effect of hyperpolarization. In addition, exclusively in 4G, the selectivity filter in the upper pore region and parts of the S4-helix are destabilized. The results provide new insights into the intricate activation of HCN2 channels.
Welfare implications for broiler chickens reared in an insect larvae-enriched environment: Focus on bird behaviour, plumage status, leg health, and excreta corticosterone
Authors: Biasato Ilaria , Bellezza Oddon Sara , Chemello Giulia , Gariglio Marta , Fiorilla Edoardo , Dabbou Sihem , Pipan Miha , Dekleva Dominik , Macchi Elisabetta , Gasco Laura , Schiavone Achille
Published: August 2022

The use of insect live larvae as environmental enrichment has recently been proposed in broiler chickens, but the concomitant administration of black soldier fly (BSF) and yellow mealworm (YM) has never been tested yet. Therefore, the present study aims to evaluate the effects of live BSF and YM larvae as environmental enrichments for broiler chickens by means of plumage status, behaviour, leg health, and excreta corticosterone metabolites (CM). A total of 180 4-day old male Ross 308 broiler chickens were randomly distributed in 3 experimental treatments (6 replicates/treatment, 10 birds/replicate) and fed for 35 days as follows: 1) control (C, commercial feed), 2) BSF: C + 5% of the expected daily feed intake [DFI] live BSF larvae and 3) YM: C + 5% of the expected DFI live YM larvae. Feathering, hock burn (HB) and footpad dermatitis (FPD) scores (end of the trial), as well as behavioural observations (beginning of the trial [T0] and every 11 days [T1, T2 and T3] during morning, larvae intake and afternoon) through video recordings, were assessed, and excreta samples collected to evaluate the CM. Feathering, HB and FPD scores, and excreta CM were unaffected by insect live larvae administration (p > 0.05). In the morning, the insect-fed birds displayed higher stretching, wing flapping, ground pecking (at T1 and T3), as well as lower preening (at T1 and T2), than the C group (p < 0.05). During the larvae intake, higher scratching, wing flapping and ground pecking, as well as lower stretching, preening and laying down, were observed in the insect-fed (scratching, stretching and laying down) or YM-fed (wing flapping, ground pecking and preening) groups than the C birds (p < 0.05). In the afternoon, insect live larvae administration increased wing flapping (YM) and laying down (BSF and YM), as well as decreased ground pecking (YM, p < 0.05). In conclusion, the administration of insect live larvae as environmental enrichment (especially YM) was capable of positively influencing the bird welfare through the stimulation of foraging behaviour, increase in activity levels, and reduction in bird frustration, without affecting the plumage status, leg health, and excreta CM.
Behavioral defects and downregulation of hippocampal BDNF and nNOS expression in db/db mice did not improved by chronic TGF-β2 treatment
Authors: Tomiga Yuki , Higaki Yasuki , Anzai Keizo , Takahashi Hirokazu
Published: August 2022

Epidemiological evidence suggests that there is a link between diabetes and mood disorders, such as depression and anxiety. Although peripheral or central inflammation may explain this link, the molecular mechanisms are not fully understood and few effective treatments for diabetes or mood disorders are available. In the present study, we aimed to determine whether transforming growth factor (TGF)-β2, an anti-inflammatory substance, might represent a potential therapeutic agent for diabetes-related mood behaviors. TGF-β2 expression in the hippocampus is affected by anxiolytic drugs and stress exposure, it is able to cross the blood-brain barrier, and it is as an exercise-induced physiological adipokine that regulates glucose homeostasis. Therefore, we hypothesized that a chronic TGF-β2 infusion would ameliorate diabetes-related glucose intolerance and mood dysregulation. To determine the effects of the chronic administration of TGF-β2 on diabetes, we implanted osmotic pumps containing TGF-β2 into type 2 diabetic mice (db/db mice), and age-matched non-diabetic control wild type mice and db/db mice were infused with vehicle (PBS), for 12 consecutive days. To assess anxiety-like behaviors and glucose homeostasis, the mice underwent elevated plus maze testing and intraperitoneal glucose tolerance testing. Hippocampal and perigonadal visceral white adipose tissue perigonadal white adipose tissue samples were obtained 12 days later. Contrary to our hypothesis, TGF-β2 infusion had no effect on diabetes-related glucose intolerance or diabetes-related behavioral defects, such as inactivity. In db/db mice, the expression of inflammatory markers was high in pgWAT, but not in the hippocampus, and the former was ameliorated by TGF-β2 infusion. The expression of brain-derived neurotrophic factor and neuronal nitric oxide synthase, important regulators of anxiety-like behaviors, was low in db/db mice, but TGF-β2 infusion did not affect their expression. We conclude that although TGF-β2 reduces the expression of pro-inflammatory markers in the adipose tissue of diabetic mice, it does not ameliorate their obesity or mood dysregulation.
Transcriptome-wide analyses of RNA m6A methylation in hexaploid wheat reveal its roles in mRNA translation regulation
Authors: Huang Tao , He Wei-Jie , Li Cheng , Zhang Jing-Bo , Liao Yu-Cai , Song Bo , Yang Peng
Published: August 2022

N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotic messenger RNAs. m6A was discovered in wheat about 40 years ago; however, its potential roles in wheat remain unknown. In this study, we profiled m6As in spikelets transcriptome at the flowering stage of hexaploid wheat and found that m6As are evenly distributed across the A, B, and D subgenomes but their extents and locations vary across homeologous genes. m6As are enriched in homeologous genes with close expression levels and the m6A methylated genes are more conserved. The extent of m6A methylation is negatively correlated with mRNA expression levels and its presence on mRNAs has profound impacts on mRNA translation in a location-dependent manner. Specifically, m6As within coding sequences and 3′UTRs repress the translation of mRNAs while the m6As within 5′UTRs and start codons could promote it. The m6A-containing mRNAs are significantly enriched in processes and pathways of “translation” and “RNA transport,” suggesting the potential role of m6As in regulating the translation of genes involved in translation regulation. Our data also show a stronger translation inhibition by small RNAs (miRNA and phasiRNA) than by m6A methylation, and no synergistical effect between the two was observed. We propose a secondary amplification machinery of translation regulation triggered by the changes in m6A methylation status. Taken together, our results suggest translation regulation as a key role played by m6As in hexaploid wheat.