bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of Loss Due to Pharmaceutical Fraud: Evidence From the U.S.
Authors: Timofeyev Yuriy , Hayes Susan , Jakovljevic Mihajlo
Published: August 2021

BackgroundGlobally and in the U.S. in particular, pharmaceutical fraud account for a large number out of all crimes in healthcare, which result into severe costs to the society The Academy of Managed Care Pharmacists (2019) estimate that pharmacy fraud is 1% of costs, therefore estimating that pharmacy fraud costs at $3.5 billion, given that pharmacy costs are $358 billion (Statista, 2021). AimThis exploratory study aims to demonstrate a fraudster’s profile as well as to estimate average consequences in terms of costs and identify the loss predictors’ hierarchy in the pharmaceutical industry in the U.S. Materials and methodsData from the Corporate Prosecution Registry and mixed-effects models are utilized for this purpose. The dataset covers years 2001-2020 and 75 cases, falling into one of the following broad sub-categories: misbranding, counterfeit, off label use of drugs, off-label use of drugs / deceptive marketing; violation of the Food, Drug and Cosmetic Act.ResultsThe main factors positively associated with loss due to pharmaceutical fraud are (i) duration of (ii) the scheme and scheme being executed at a U.S. public company. Surprisingly, presence of collusion negatively and significantly effects the cost. Potential factors include (a) principal perpetrator being a white American and/or male, and (b) number of employees at individual and organizational level respectively.ConclusionThis study empirically justifies considering loss, due to pharmaceutical fraud, from a multi-level perspective. Identified profiles of a typical fraudster helped to elaborate on specific practical recommendations aimed at pharmaceutical fraud prevention in the U.S.
A Novel Method for the Assessment of Facial Palsy in a Rat Model: the Black Light-Assisted Scoring System
Authors: Miura Takahiro , Yamamoto Yuhei , Maeda Taku , Osawa Masayuki , Ishikawa Kosuke , Funayama Emi
Published: August 2021

Background: Facial palsyin humans is assessed using facial nerve grading systems. However, there is no standardized tool for the objective assessment of facial palsy in rat models. Here, we propose a novel black light-assisted scoring system (BASS)to assess facial palsy in rats.Methods: BASS has three key components: blacklight, high frame rate videography (iPhone), and motion analysis software (Kinovea). The system can detect movement of a specific whisker and whisker base and automatically assesstheir angular velocity. Our study included 12 male Wistar rats: 6 with normal facial nerve function and 6 witha unilateral facial nervecrush injury. Four angular velocities were investigated using BASS to confirm the accuracy of the system and determine the best parameter to be used for BASS.Results:The total velocity value (sum of maximum protraction velocity and maximum retraction velocity)had the least variation and highest reliability of all tested velocities.Conclusions: BASS allows for repeated quantification of the whisker movements and weekly measurements of the whisker base. Our findings suggest that BASS is reliable, reproducible, and useful for the assessment of facial palsy.
Adaptive Opposition Slime Mould Algorithm
Authors: Naik Manoj Kumar , Panda Rutuparna , Abraham Ajith
Published: August 2021

Recently, the slime mould algorithm (SMA) has become popular in function optimization, because it effectively uses exploration and exploitation to reach an optimal solution or near-optimal solution. However, the SMA uses two random search agents from the whole population to decide the future displacement and direction from the best search agents, which limits its exploitation and exploration. To solve this problem, we investigate an adaptive approach to decide whether opposition based learning (OBL) will be used or not. Sometimes the OBL is used to further increase the exploration. In addition, it maximizes the exploitation by replacing one random search agent with the best one in the position updating. The suggested technique is called an adaptive opposition slime mould algorithm (AOSMA). The qualitative and quantitative analysis of AOSMA is reported using 29 test functions consisting of 23 classical test functions and 6 recently used composition functions from the IEEE CEC 2014 test suite. The results are compared with state-of-the-art optimization methods. Results presented in this paper show that AOSMA’s performance is better than other optimization algorithms. The AOSMA is evaluated using Wilcoxon’s rank-sum test. It also ranked one in Friedman’s mean rank test. The proposed AOSMA algorithm would be useful for function optimization to solve real-world engineering problems.
Autophagy Markers p62, LC3II and Beclin1 Correlate with Clark Levels in Melanoma Tumors
Authors: Arani Reyhaneh Hizomi , Mohammadpour Hadiseh , Moosavi Mohammad Amin , Abdollahi Alireza , Rahmati Marveh
Published: August 2021

BackgroundThe prognosis of melanoma depends on early diagnosis and timely treatment. Autophagy as a mechanism of degradation/recycling of cellular debris, has potential to be evaluated as prognostic biomarker in current research. MethodsIn this study, ATG5 and Beclin 1 gene expression in different Clark levels of melanoma were evaluated in a retrospective study of 10 years in the cancer institute of Tehran, Iran. The autophagy activity and the correlation with clinicopathological data were also investigated in a tissue microarray series of 52 melanomas after immunohistochemical staining for the autophagy-associated proteins p62, LC3II and Beclin1. The possibility of autophagy biomarkers were assessed by ROC curve analysis.ResultsThe patterns of ATG5 and Beclin1 gene expression are different. While ATG5 was increased in the early stage and then decreased as the stage was progressed in comparison to tumor margin, the Beclin1 expression was decreased and not altered during tumor progression. However, Beclin1 expression at the protein level was increased with tumor progression. The expression of LC3II was also raised while the p62 levels were declined as the tumor progressed, suggesting an increased autophagy activity in melanoma patients. Melanoma ulceration was positively correlated with Beclin 1 and LC3II expression and inversely correlated with p62 (p<0.05). Autophagy markers expression did not significantly correlate with melanoma mitotic rate and thickness. ConclusionsAutophagy is a potential prognostic factor in the early stage of melanoma and could be considered as a therapeutic target.
Novel Hybrid Flow Diverter for Intracranial Aneurysm
Authors: Hsiao Hao-Ming , Hung Ming-Ya , Chou Tzu-Yun , Cheng Yu-Chieh , Lin Li-Han , Huang Tzu-Yu
Published: August 2021

An intracranial aneurysm is a weakened area in the wall of a cerebral artery which causes abnormal localized ballooning of the blood vessel. As an aneurysm grows, it puts pressure on adjacent structures and may eventually rupture, leading to severe complications or even sudden death. The standard treatments for intracranial aneurysms include traditional craniotomy and endovascular coiling. The purpose of these treatments is to stop the blood flow to an aneurysm to reduce the risk of rupture. In recent years, another new device, "flow diverter", has gained popularity. It is placed in the parent artery to divert the blood flow away from the weakened area, isolating aneurysms from normal circulation. Although flow diverter stents have great potential, there remains clinical issues to be resolved. This paper proposes a unique hybrid flow diverter, the first of its kind in the world, for treatment of the intracranial aneurysm. The hybrid flow diverter is designed to have variable mesh densities, with the denser side facing an aneurysm to block the blood flow and the lighter side facing the artery to prevent stenosis. It is deployed in the main cerebral artery next to an aneurysm to divert the blood flow away from the weakened aneurysm. Simulation results showed that the hybrid flow diverter reduced the blood flow into an aneurysm by a whopping 75-95%. The residence time of the blood flow inside an aneurysm was 12.47 times longer with the hybrid flow diverter, which may trigger thrombogenic reaction to fill an aneurysm and thus reduce the risk of rupture.
A Secure Anonymous Authentication Protocol for IoT Based Health-care System using Wireless Body Area Network
Authors: R Shanthapriya , V Vaithianathan
Published: August 2021

The current technology in healthcare and its information are enhanced with IoT system. In most of IoT system, there exists a gateway between a wireless body area network (WBAN) and the internet to upload and retrieve the health information. These IoT gateways normally transmit data to a cloud. Therefore, the importance of IoT devices and health care data could be critical. Hence security constraints are required to retain the data. This paper introduces a novel concept called a secure anonymous authentication protocol with advanced encryption standard (SAAPAES) a cryptographic scheme to guarantee the security services and to protect confidential client data in the healthcare system. Our SAAPAES protocol offer the following aspects 1. Anonymous authentication, this is one of the easy and efficient way to protect patient/doctor identities from the server on cloud storage by using hash key authentication algorithm by disclosing the security aspects like password and username. 2. Patient’s health information is encrypted with SAAPAES and then uploading these data in cloud. Finally, downloading the health information from personal data assistant (PDA) in decrypted form using SAAPAES. The proposed authentication approach provides an efficient authentication mechanism with high security in the health-care system.
Comparative Study of the Efficacy of the Abbott ID Now Rapid Assay with Real Time PCR for the Diagnosis of SARS-CoV-2 RNA
Authors: Chheda Pratiksha , Tavisha Dama , Rahul Bhalerao , Jamir Bagwan , Devdatta Bhat , Shivaprakash Shashikala
Published: August 2021

Rapid diagnostic tests are of great importance in hospital settings during the current outbreak of SARS-CoV-2. The clinical patient management and spread of infection is critically dependent on molecular assays with shortest possible turn-around time. Here we report performance of a point of care Abbott ID NOW COVID-19 assay in comparison to routinely used real-time RT-PCR assay on 205 clinical specimens. Overall agreement of ID NOW was found to be 93.7% with positive percent agreement (PPA) of 91.8% and negative percent agreement (NPA) of 95.4%. Based on our findings, low turnaround time, minimal infrastructure need and ease of performing the assay, Abbott ID NOW COVID-19 assay can be considered as a point of care test in hospital settings.
Prevalence and Genetic Characterizations of Enterocytozoon Bieneusi in Captive Red Pandas (Ailurus Fulgens) In Sichuan Province, Southwestern China
Authors: Zeng Yang-yang , Meng Wan-Yu , Liu Song-Rui , Yao Jin-Chuan , He Ming , Wang Li-Qin , Zuo Zhi-Li , Yue Chan-Juan , Deng Lei , Peng Guangneng
Published: August 2021

Background: Enterocytozoon bieneusi (E. bieneusi) can infect a broad range of animals, and also the major pathogen for human microsporidiosis. The risk of zoonosis is uncertain because of limited research on red pandas. In addition, the semi-free range breeding enables the red panda direct contact with tourists. It is essential to investigate the prevalence and genotypes and to evaluate the safety of this breeding mode. Methods: Based on nested PCR, 198 fecal specimens were sampled from 6 zoos in Sichuan province from July 2020 to December 2020, to identify positive samples by amplifying the internal transcribed spacer (ITS) region of ribosomal RNA with specific primers. The correlation analysis of infection rate was carried out between different breeding modes (captive and semi-free-range). To cluster the identified genotypes with related genotypes to deduce zoonotically potential by phylogenetic analysis. In addition, Multilocus genotypes (MLGs) in ITS-positive samples were performed using the Multilocus Sequence Typing (MLST) tool.Results: The Polymerase Chain Reaction (PCR) results showed that 12.1% (24/198) samples were positive for E.bieneusi. The infection rates varied from 0% to 18.0% in different zoos and were significantly different in different breeding methods (χ2=5.442, P=0.0197). Genotypes D, SC02, and SCR1(novel) were clustered in zoonotic group 1, while genotype PL2 is clustered in group 2-like with uncertain risk by phylogenetic analysis. Furthermore, 3 distinct multilocus genotyping were formed in ITS-positive isolates.Conclusions: These results revealed the circulating of E. bieneusi in zoo red pandas, indicating that red pandas may be a source of human microsporidiosis and that semi-free range breeding mode as a risk factor increased the E. bieneusi infection rate and potential cross-species transmission.
Insilico Designing of a Chimeric Vaccine Using EIS (Rv2416c) Protein Against Mycobacterium Tuberculosis H37Rv; An Immunoinformatics Approach
Authors: Radhakrishnan Logesh , V Lavanya , Jamal Shazia , Ahmed Neesar
Published: August 2021

Mycobacterium tuberculosis (Mtb) is a respiratory pathogen that causes Tuberculosis disease (TB). There are a large number of proteins that are involved in the pathogenesis of TB. Stimulating the immune response against TB is very important to clear the pathogens from host. In the present study, an Immunoinformatics conduit is used for epitope based chimeric vaccine designing against TB. Enhanced Intracellular Survival (EIS) protein from Mtb is used for designing the chimeric vaccine. 1 B-cell epitope, 8 cytotoxic T lymphocyte (CTL) and 6 Helper T lymphocyte (HTL) epitopes were predicted based on the MHC allele binding, immunogenicity, antigenicity, allergenicity, toxicity and IFN epitopes. The selected epitopes were used for chimeric vaccine designing. Further, 3D structure elucidation, structural refinement and validation of the designed chimeric vaccine was carried out. The 3D structure was used for Protein-Protein docking studies with Toll like receptor 4 (TLR-4), followed by molecular dynamic simulation (MDS) and the interaction between the chimeric vaccine and TLR-4 complex was verified.
Based on Robust Sliding Mode and Linear Active Disturbance Rejection Control for Attitude of Quadrotor Load UAV
Authors: Wang Zhaoji , Zhao Tong
Published: August 2021

In this paper, a mass adaptive control method combining robust sliding mode control (SMC) and linear active disturbance rejection control (LADRC) is designed for the quadrotor load unmanned aerial vehicle (UAV) with mass variation. The scheme combines the advantages of SMC and LADRC. SMC can enhance the robustness of the controller, improve the anti-disturbance performance and overcome the problem of low control precision caused by bandwidth limitation of LADRC. The linear extended state observer (LESO) can estimate the external and internal disturbances of the system in real time, and then compensate the total disturbance through the PD controller. In order to simplify parameter setting, adaptive control is introduced in LADRC to adjust controller parameters in real time. In addition, adaptive law is also used to control the mass variation of the quadrotor. Then the stability of the whole system is verified by Lyapunov stability theory. Finally, the comparison with LADRC shows the superiority of the designed scheme, which can track the reference signal stably and effectively.
Transient Evolution of Rheological Properties of Dense Granular Inertial Flow Under Plane Shear
Authors: Zhang Xuejie , Wang Wei , Liu Xiaojun , Liu Kun
Published: August 2021

Exploration on the transient evolution of the rheological properties of dense granular inertial flow is essential for revealing how the balance is established between the boundary drive strength and the internal shear strength. In this paper, discrete element method simulations are performed to study the transient flow characteristics of a dense granular system under plane shear in the inertial regime. To this end, we quantitatively analyze the changes in the system’s flow state, interfacial friction coefficient, internal friction coefficient, and microstructure. Simulation results show that the evolution of the horizontal flow experiences three typical stages, namely transmission, adjustment, and stabilization. Meanwhile, the shear dilatancy caused by the vertical movement of particles, gradually loosens the filling state, weakens the spatial geometric constraint and the system’s tangential load-bearing capacity, thereby decreasing the interfacial friction coefficient and reducing the boundary drive strength. On the other hand, the variations in the anisotropies of both contact orientation and contact forces, increase the internal friction coefficient and improve the internal shear strength. Therefore, the evolution of flow state from initially static to finally stable reduces the boundary drive strength while enhances the internal shear strength, and eventually a balance between them is achieved. Distinguished from the micromechanical behaviors, under different shear velocities the internal shear strength always mainly originates from the anisotropies in contact orientation and in normal contact force. Moreover, the contribution of the anisotropy in contact orientation becomes more predominant with the increase of shear velocity.
Apoptosis Induction in Human Lung and Colon Cancer Cells via Impeding VEGF Signaling Pathways
Authors: Behelgardi Maryam Farzaneh , Shahvir Zahra Gholami , Asghari S.Mohsen
Published: August 2021

There is ample evidence to suggest that vascular endothelial growth factor (VEGF) is a potent mitogen factor in vasculogenesis and angiogenesis and that blockade of VEGF-mediated signals can also prevent tumor growth via enforcing cell apoptosis. In the current study, we assessed the suppressing effect of VGB4, a VEGF antagonist peptide with the binding ability to both VEGF receptor1 and VEGF receptor2, on VEGF-induced proliferation and migration of the human lung adenocarcinoma cell line A549 and the human colon adenocarcinoma cell line HT29 using MTT assay, colony formation assay, and Scratch-wound assay. To evaluate the apoptotic inductive effect of VGB4 on A549 and HT29 cells, apoptosis assay was carried out by flow cytometry analysis. Likewise, p53 and PTEN expression level was examined by immunofluorescence microscopy. In addition, the level of proteins involved in VEGF signaling pathways related to apoptosis was investigated using western blot analysis. Our results indicated that VGB4 markedly inhibited VEGF-induced proliferation and migration, and induced apoptosis of A549 and HT29 cells dose dependently. Encouragingly, significant downregulation of B-cell lymphoma 2 (Bcl2), X-Linked Inhibitor of Apoptosis (XIAP), Procaspase9, and procaspase3, as well as upregulation of PTEN and P53 tumor suppressors, BCL2 Associated X (BAX), Cytochrome c, cleaved caspase9, and cleaved caspase3 in VGB4-treated A549 and HT29 cells, further confirmed the profound inductive influence of VGB4 on apoptotic pathways. These findings along with the results from our previous studies show that VGB4 may be considerable for cancer therapy.
TREM2 Limits Progression of Deficits and Spreading of Tau Pathology in Mice
Authors: Feiten Astrid F. , Au Carol , Hummel Annika van , Hoven Julia van der , Deng Yuanyuan , Przybyla Magdalena , Bright Fiona , Butler Troy , Delerue Fabien , Toutonji Amer , Guglietta Silvia , Wegmann Susanne , Hyman Bradley T. , Krieg Carsten , Ke Yazi D. , Ittner Lars
Published: August 2021

Background. Amyloid-β (Aβ) and tau form pathogenic lesions in Alzheimer’s disease (AD) brains. As ΑD clinically progresses, tau pathology propagates in a very distinct pattern between connected brain areas. The molecular mechanisms underlying this tau pathology spread remain largely unknown. Genome-wide association studies have identified polymorphisms in triggering receptor expressed on myeloid cells 2 ( TREM2 ) as genetic risk factors for AD and regulators of Aβ pathology-dependent tau propagation. Whether TREM2 contributes to neuron-to-neuron spreading of pathological tau remains unknown.Methods. Here, we crossed Trem2- deficient mice with P301S tau transgenic TAU58 mice and subjected the mice to behavioral testing and assessed neuropathology. Microglial activation states were determined using cytometry by of flight (CyTOF) and quantitative PCR. Tau spreading was assessed in vivo using tracing of focal tau expression.Results. Trem2 depletion significantly aggravated tau-induced early-onset motor and behavioural deficits. Neuropathologically, Trem2 reduction increased the number of hyperphosphorylated tau lesions in young TAU58 brains and reduced disease-associated microglia. Direct assessment of inter-neuronal spread of tau in vivo revealed significantly enhanced propagation of tau in the absence of Trem2 , suggesting that microglial TREM2 limits the progression of tau pathology in disease.Conclusion. Taken together, our data suggests that reduced TREM2 function accelerates the onset and progression of functional deficits and tau neuropathology in tau transgenic mice, which is - at least in part - due to increased tau spreading. Therefore, reduced TREM2 function may contribute to early AD by augmenting tau toxicity and its inter-neuronal propagation.
The roles of microRNA-328-3p on proliferation and radiotherapy in breast cancer
Authors: Shi Ying , Jiang Pengli , Li Jinqiu , Xu Shengnan , Liu Bin
Published: August 2021

Objectives

MicroRNAs regulates varieties of molecular pathways and involve in breast carcinogenesis. Here both breast cancer cell lines and human breast cancer tissues were used to investigate the roles of miR-328-3p in breast cancer.

Methods

The impact of miR-328-3p on proliferation of MDA-MB-231 and T47D cells was determined by MTT assay. transwell migration and matrigel invasion assays were performed to evaluate effects of miR-328-3p on migration and invasion of breast cancer cells. Caspase 3/7 activities were measured to examine the impact of miR-328-3p on radiotherapy-induced apoptosis in breast cancer cells. The possible binding site of miR-328-3p was verified by dual-luciferase reporter assay. Quantitative real-time polymerase chain reaction was performed to detect miR-328-3p expression level in breast cancer tissues. Western blot and immunohistochemical studies were used to examine protein expression in breast cancer cells and breast cancer tissue, respectively.

Results

miR-328-3p involved growth, migration and invasion in breast cancer cells and was associated with radiotherapy sensitivity. MiR-328-3p enhanced radiation-induced apoptosis in breast cancer cells by regulating BAX and Bcl-2 expression. Meanwhile, aberrant expression of miR-328-3p was associated with altered expression of PTEN and p-AKT in breast cancer cells. Further study showed miR-328-3p bound to 3’-UTR of PTEN. In addition, breast cancer tissues showed higher level of miR-328-3p than normal breast tissue and higher level of miR-328-3p was seen in lower stage in breast cancer.

Conclusions

miR-328-3p displayed essential functions in breast carcinogenesis and might be used to predict radiotherapy response and prognosis in breast cancer.
Quantitative CT Analysis to Predict Esophageal Fistula in Patients With Advanced Esophageal Cancer Treated by Chemotherapy or Chemoradiotherapy
Authors: Shi Yan-Jie , Liu Chang , Wei Yi-Yuan , Li Xiao-Ting , Shen Lin , Lu Zhi-Hao , Sun Ying-Shi
Published: August 2021

BackgroundEsophageal fistula is one of the most serious complications of chemotherapy or chemoradiotherapy (CRT) for advanced esophageal cancer. This study aimed to evaluate the performance of quantitative computed tomography (CT) analysis and to establish a practical imaging model for predicting esophageal fistula in esophageal cancer patients administered chemotherapy or chemoradiotherapy. MethodsThis study retrospectively enrolled 204 esophageal cancer patients (54 patients with fistula, 150 patients without fistula) and all patients were allocated to the test and validation cohorts according to the time of inclusion in a 1:1 ratio. Ulcer depth, tumor thickness and length, and minimum and maximum enhanced values for esophageal cancer were measured in pretreatment CT imaging. Logistic regression analysis was used to evaluate the associations of CT quantitative measurements with esophageal fistula. Receiver operating characteristic curve (ROC) analysis was also used. ResultsLogistic regression analysis showed that independent predictors of esophageal fistula included tumor thickness [odds ratio (OR)=1.167; p = 0.037], the ratio of ulcer depth to adjacent tumor thickness (OR=164.947; p < 0.001), and the ratio of minimum to maximum enhanced CT value (OR=0.006; p = 0.039) in the test cohort at baseline CT imaging. These predictors were used to establish a predictive model for predicting esophageal fistula, with areas under the receiver operating characteristic curves (AUCs) of 0.946 and 0.841 in the test and validation groups, respectively. ConclusionQuantitative pretreatment CT analysis has excellent performance for predicting fistula formation in esophageal cancer patients who treated by chemotherapy or chemoradiotherapy.
Knowledge and Practice on Prevention of Intestinal Parasitic Infection Among Mothers of Under-five Children in Bulehora Town, Bule Hora, Oromia Region, Southern Ethiopia
Authors: KASIMAYAN PANDIARAJAN , KASIRAJAN ANANDAPANDIAN KANAPATHY THANGAVEL , RAJAN DIVYA RANI , SUBBIAH SANKARALINGAM , BALASUNDARAM HARINATHAN
Published: August 2021

Background: Intestinal parasitic diseases are one of the general medical conditions in numerous networks, especially among youngsters in country spaces of agricultural nations. Ethiopian studies have concentrated on the commonness and circulation of 2 intestinal parasitic contaminations, fundamentally among younger students. A couple of studies have looked at the scope on knowledge of under-five children’s mothers regarding the prevention of parasitic infections. Methods: A community-based cross-sectional examination with a quantitative methodology was conducted from November 30 to December 30, 2020, among mothers of under-five children in Bule Hora town. The example size in this investigation was 403. The information will be coded, checked sent out to SPSS Statistics rendition 25 for investigation. Result: The general information and practice level concerning mothers of under-five kids in regards to counteraction of intestinal parasitic contaminations was, all among 51.6 % had poor knowledge and 53.1 % had poor practice. Nearly 50% of children not washing of hands and legs after a play in the soil and more than 55% of mothers not advising the child to wear footwear outside the home. Remaining all aspect shows considerably good practice from mother’s mention. In the Ethnic group, Oromo (AOR 2.199, 95% CI 1.05-4.59) people had good knowledge, mothers who not ready to peruse and compose (AOR 0.26, 95% CI 0.12-0.57) had poor knowledge than others. Further in age group (31-35) (AOR 2.94, 95% CI 1.38-6.24) had a good practice, Amara (AOR 0.39, 95% CI 0.18-0.85) people had poor practice and mothers who not able to read and write (AOR 3.97, 95% CI 1.26-12.49) had good practice than other educated.Conclusion: Mothers with children under the age of five have a considerably low degree of optimal awareness and experience when it comes to preventing intestinal parasitic infection. As a result, campaigns or formal training can be used to raise community consciousness about intestinal parasitic invasion counteraction and control.
14-3-3ζ Captures SET in the Cytoplasm, Mediating Tau Pathology and Cognitive Impairments
Authors: Xia Yiyuan , Zhang Qing , Wu Gang , Wang Erming , Wang Minghui , Huang Fang , Zeng Kuan , Vatansever Sezen , Guo Lei , Neff Ryan , Yu Kaiwen , Li Yuxin , Ke Dan , Wang Qun , Haroutunian Vahram , Peng Junmin , Wang Jian-Zhi , Liu Rong , Zhang Bin , Gao Xiang , Wang Xiaochuan
Published: August 2021

Background: 14-3-3ζ is overexpressed in brain regions affected by tau pathology in Alzheimer’s disease (AD), and its expression correlates with disease progression. The nuclear protein SET is a specific and efficient endogenous inhibitor of PP2A, which acts as a major protein phosphatase regulating tau phosphorylation and is compromised in AD. However, whether 14-3-3ζ mediates the cytoplasmic retention of SET and its related downstream events in AD remains elusive. Methods: We performed Spearman correlation analysis between 14-3-3 and SET in normal control brains and AD brains in a large-scale proteomic study of AD, and observed the distribution of SET and 14-3-3 in AD brain neurons, thus finding the cytoplasmic retention event of SET. We synthesized the peptides that prevented SET from binding to 14-3-3, and evaluated the effects of these peptides in blocking tau pathology. Results: Here, we reported that there is a significant increase in 14-3-3ζ interaction with SET during aging in 3´Tg AD mice and the human AD brain. 14-3-3ζ captures and sequesters SET in the cytoplasm and subsequently inhibits PP2A activity, induces tau hyperphosphorylation and triggers neurodegeneration, leading to behavioral impairments in mice infected with adeno-associated virus encoding 14-3-3ζ. Interestingly, as a dimer and scaffold protein, 14-3-3ζ was found to bind to SET while simultaneously recruiting CKII, which induced SET phosphorylation and cytoplasmic retention. Conversely, silencing 14-3-3ζ impeded CKII phosphorylation of SET. Moreover, blocking the 14-3-3ζ interaction with SET with the peptide NESGDPSSKST substantially induced SET translocation back to the nucleus, augmented PP2A activity and subsequently led to reduced tau hyperphosphorylation, decreased synapse loss and rescue of cognitive deficits in 14-3-3ζ mice. Furthermore, the peptide NESGDPSSKST but not the scramble peptide attenuated tau pathology and cognitive deficits in a 3´Tg AD mouse model. Conclusions: Our data strongly indicate that 14-3-3ζ captures SET in the cytoplasm and simultaneously recruits CKII, and this interaction plays a critical role in mediating tau-related clinical and neuropathological alterations. Inhibition of the 14-3-3ζ interaction with SET may be therapeutically useful for treating AD.
Key Measurement Concepts and Appropriate Clinical Outcome Assessments in Pediatric Achondroplasia Clinical Trials
Authors: Aldhouse Natalie Valerie Jane , Kitchen Helen , Johnson Chloe , Marshall Chris , Pegram Hannah , Pease Sheryl , Collins Sam , Baker Christine Lynn , Beaverson Katherine , Crews Chandler , Massey Jill , Wyrwich Kathleen W
Published: August 2021

Background: This study aimed to identify fit-for-purpose clinical outcome assessments (COAs) to evaluate physical function and social and emotional well-being in clinical trials enrolling a pediatric population with achondroplasia. Qualitative interviews lasting 90 minutes were conducted in the US with children/adolescents with achondroplasia and/or their caregivers. Interviews utilized concept elicitation methodology to explore experiences and priorities for treatment outcomes. Cognitive debriefing methodology explored relevance and understanding of selected COAs. Results: Interviews (N=36) were conducted with caregivers of children age 0–2 years (n=8) and 3–7 years (n=7) and child/caregiver dyads with children age 8–11 years (n=15) and 12–17 years (n=6). Children/caregivers identified pain, short stature, impacts on physical functioning (e.g. reach), and impacts on well-being (e.g. negative attention/comments) as key bothersome aspects of achondroplasia. Caregivers considered an increase in height (n=9/14, 64%) and an improvement in limb proportion (n=11/14, 71%) as successful treatment outcomes. The Childhood Health Assessment Questionnaire (CHAQ) and Quality of Life in Short Stature Youth (QoLISSY-Brief) were cognitively debriefed. CHAQ items evaluating activities, reaching, and hygiene were most relevant. QoLISSY-Brief items evaluating reaching, height bother, being treated differently, and height preventing doing things others could were most relevant. The CHAQ and QoLISSY-Brief instructions, item wording, response scales/options and recall period were well understood by caregivers and adolescents age 12–17. Some children aged 8–11 had difficulty reading, understanding, or required caregiver input. Feedback informed minor amendments to the CHAQ and the addition of a seven-day recall period to the QoLISSY-Brief. These amendments were subsequently reviewed and confirmed in N=12 interviews with caregivers of children age 0–11 (n=9) and adolescents age 12–17 (n=3).Conclusions: Achondroplasia impacts physical functioning and well-being. An increase in height and improvement in limb proportion are considered to be important treatment outcomes, but children/adolescents and their caregivers expect that a successful treatment should also improve important functional outcomes such as reach. The CHAQ (adapted for achondroplasia) and QoLISSY-Brief are relevant and appropriate measures of physical function and emotional/social well-being for pediatric achondroplasia trials; patient-report is recommended for age 12–17 years and caregiver-report is recommended for age 0–11 years.
Single-cell RNA Sequencing Reveals That Injected ADSCs Change the Macrophage Profile in a Murine Model of Pulmonary Fibrosis
Authors: Rahman Mamatali , Wang Zhao-Yan , Li Jun-Xiang , Xu Hao-Wei , Wu Qiong
Published: August 2021

Background: Idiopathic pulmonary fibrosis (IPF) is a deadly chronic interstitial lung disease with no effective treatment options other than lung transplantation. Allogeneic adipose-derived mesenchymal stem cells (ADSCs) are considered ideal as seed cells for stem cell-based therapy, and some studies illustrated the therapeutic effect of ADSCs on IPF, but the underlying mechanisms remain unclear.Methods: A single intratracheal dose of bleomycin (BLM) was administered to induce pulmonary injury/fibrosis in C57BL/6 mice, after GFP-labeled mouse ADSCs (mADSCs) were implanted intratracheally to explore their potential therapeutic effects in the inflamed/fibrotic lung microenvironment. The mADSCs were then retrieved through fluorescence-activated cell sorting and subjected to single-cell RNA sequencing (scRNA-seq).Results: Our data indicate that the single-dose intratracheal administration of mADSCs could significantly increase the life span of IPF mice by remodeling the extracellular matrix and promoting the polarization of macrophages to an anti-inflammatory phenotype. Conclusions: A single intratracheal injection of mADSCs alleviated BLM-induced pulmonary fibrosis by readjustment of the mouse lung microenvironment, which was reflected in changes of the lung C1QB+, APOE+ and TREM2+ macrophages in the mouse model.
Combination of Artesunate and WNT974 Induces KRAS Protein Degradation by Upregulating E3 Ligase ANACP2 and β-TrCP in the Ubiquitin–proteasome Pathway
Authors: Gong Rui-Hong , Chen Minting , Huang Chunhua , Wong Hoi Leong Xavier , Kwan Hiu Yee , Bian Zhaoxiang
Published: August 2021

BackgroundKRAS mutation is one of the dominant gene mutations in colorectal cancer (CRC). Up to present, targeting KRAS for CRC treatment remains a clinical challenge. WNT974 (LGK974) is a porcupine inhibitor that interferes Wnt signaling pathway. Artesunate (ART) is a water-soluble semi-synthetic derivative of artemisinin.MethodsThe synergistic effect of ART and WNT974 combination in reducing CRC cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RT-PCR was utilized for the mRNA levels of KRAS, CUL7, ANAPC2, UBE2M, RNF123, SYVN1, or β-TrCP. Western blot assay was utilized for the protein levels of KRAS, ANAPC2, β-TrCP, or GSK-3β. Xenograft mouse model assay was performed for the anti-CRC effect of combination of ART and WNT974 in vivo. IHC assay was utilized for the levels of KRAS, β-TrCP, or GSK-3β in tumor tissues.Results Our study shows that the combination of WNT974 and ART exhibits synergistic effect in reducing CRC growth. The combination treatment significantly reduces KRAS protein level and activity in CRC cells. Interestingly, the combination treatment increases E3 ligases ANAPC2 expression. Our data show that overexpression of ANAPC2 significantly reduces KRAS protein levels, which is reversed by MG132. Knockdown of ANAPC2 in CRC abolishes the combination treatment-reduce KRAS expression. Besides, the treatment also increases the expressions of GSK-3β and E3 ligase β-TrCP that is known to degrade GSK-3β-phosphorylated KRAS protein. Knockdown of β-TrCP- and inhibition of GSK-3β abolish the combination treatment-induce KRAS ubiquitination and reduction in expression.ConclusionsOur data clearly show that the combination treatment significantly enhances KRAS protein degradation via the ubiquitination ubiquitin–proteasome pathway, which is also demonstrated in xenograft mouse model. The study provides strong scientific evidence for the development of the combination of WNT974 and ART as KRAS-targeting therapeutics for CRC treatment.
Barriers and Facilitators of HIV and Hepatitis C Care Among People Who Inject Drugs in Nairobi, Kenya: A Qualitative Study with Peer Educators
Authors: Ludwig-Barron Natasha , Guthrie Brandon L , Mbogo Loice , Bukusi David , Sinkele William , Gitau Esther , Farquhar Carey , Monroe-Wise Aliza
Published: August 2021

Background: In Kenya, people who inject drugs (PWID) are disproportionately affected by HIV and hepatitis C (HCV) epidemics, including HIV-HCV coinfections; however, few have assessed factors affecting their access to and engagement in care through the lens of harm reduction specialists. This qualitative study leverages the personal and professional experiences of peer educators to help identify HIV and HCV barriers and facilitators to care among PWID in Nairobi, including resource recommendations to improve service uptake. Methods: We recruited peer educators from two harm reduction facilities in Nairobi, Kenya, using random and purposive sampling techniques. Semi-structured interviews explored circumstances surrounding HIV and HCV service access, prevention education and resource recommendations. A thematic analysis was conducted using the Modified Social Ecological Model (MSEM) as an underlying framework, with illustrative quotes highlighting emergent themes. Results: Twenty peer educators participated, including six women, with 2 months to 6 years of harm reduction service. Barriers to HIV and HCV care were organized by (a) individual-level themes including competing needs of addiction and misinterpreted symptoms; (b) network-level themes including social isolation and drug pusher interactions; (c) community-level themes including transportation, mental and rural healthcare services, and limited HCV resources; and (d) policy-level themes including nonintegrated services, clinical administration, and law enforcement. Stigma, an overarching barrier, was highlighted throughout the MSEM. Facilitators to HIV and HCV care were comprised of (a) individual-level themes including concurrent care, personal reflections, and religious beliefs; (b) network-level themes including community recommendations, navigation services, family commitment, and employer support; (c) community-level themes including quality services, peer support, and outreach; and (d) policy-level themes including integrated services and medicalized approaches within law enforcement. Participant resource recommendations include (i) additional medical, social and ancillary support services, (ii) national strategies to address stigma and violence and (iii) HCV prevention education. Conclusions : Peer educators provided intimate knowledge of PWID barriers and facilitators to HIV and HCV care that were described at each level of the MSEM, and should be given careful consideration when developing future initiatives. Recommendations emphasized policy and community-level interventions including educational campaigns and program suggestions to supplement existing HIV and HCV services.
Enhanced ROV Survey of Tropical Fish and Benthic Communities Associated With Shallow Oil and Gas Platforms
Authors: McLean Dianne L. , Birt Matthew
Published: August 2021

Understanding the ecology of oil and gas infrastructure in our oceans is required to inform decommissioning such that environmental impacts are minimised, and benefits maximised. This study equipped an industrial remotely operated vehicle (ROV) with a stereo-video system and collected seven hours of high-definition imagery of two platform jackets, for assessments of benthic (type, density, complexity) and fish assemblages (richness, abundance, length) present. Harriet Alpha (25 m depth) and Gibson/South Plato (8 m depth) are located ca. 120 km offshore of north-west Australia, adjacent to Varanus Island. Twenty-one ‘classes’ of benthic biota were observed in high density, with little bare structure on either platform. Encrusting sponges (average 19% cover per virtual quadrat), barnacles (17%) and sponges (16%) were common on Gibson/South Plato while encrusting sponges (16%) and macroalgae (18%) were ubiquitous on quadrats on Harriet Alpha. The sun coral Tubastraea faulkneri was common on Harriet Alpha (38% of quadrats), though coverage was low (<6%). A total of 102 fish species from 27 families were observed. This included 33 fishery target species with an estimated relative mass of 116 kg on Gibson/South Plato and 299 kg on Harriet Alpha, with these species typically concentrated near the seafloor-structure interface. Differences in benthic biota communities present on each platform likely reflect spatial variations in oceanographic processes, proximity to natural habitats and the age, configuration, cleaning regime and depth of the structures themselves. This study demonstrates the value of adding stereo-video systems to ROVs to undertake rapid scientific surveys of oil and gas infrastructure.
A Realist Review Protocol of Community Group-Based Programs to Promote Physical Activity in Immigrant Older Adults.
Authors: Flynn Rachel , Salma Jordana , Ali Sonam , Chamberlain Stephanie , Kennedy Megan , Tong Hongmei , Meherali Salima , Spence John , Jones Allyson
Published: August 2021

Background: Immigrants constitute 30% of Canada’s older adult population. Immigrant older adults have low levels of physical activity coupled with higher risks for cardiovascular disease and obesity in some sub-populations. Community group-based physical activity programs combine both physical and social benefits and are well received by older adults. These programs often lack sensitivity to the needs of equity-deserving groups, such as immigrants, who continue to experience lower levels of participation. Local, accessible, and culturally informed approaches are required to remedy these well documented inequities in who has access to and benefits from such programs. There is a gap, however, in our understanding of the characteristics and conditions for effective program design and delivery when the target population is immigrant older adults.Methods: The aim of this equity-focused realist review is to develop a programme theory that explains how, why, for whom, and under which circumstances community group-based physical activity programs work when delivered to older immigrants. We will first articulate an initial programme theory that explains tentatively how, why and for whom such programs work and then test and refine the programme theory using a systematic realist review process. The initial programme theory will draw from existing theories that inform group-based physical activity programs for older adults, intersectional theory, and stakeholder insights. PROGRESS-Plus factors will be explored in relation to relevance and impact for physical activity interventions. Stakeholders will include service providers, community volunteers and leaders who have extensive knowledge and interactions with immigrant communities. The initial programme theory will then be tested and refined using a systematic process of searching, retrieving, and reviewing literature on physical activity in immigrant populations. The final programme theory will be validated using stakeholder input and the research team’s expertise in aging, health equity, and physical activity. Discussion: Physical activity improves the wellbeing of older adults, decreases frailty, and supports aging in place. Ensuring that all older adults can participate in such programs entails understanding what works for whom, when and under which circumstances. This review will provide recommendations on best practices to support immigrant older adults’ participation in group-based physical activity programs.Systematic review registration: The protocol has been submitted to PROSPERO for registration (ID#258179, Date submitted May 30th, 2021.
Determinants of Financial Inclusion Gender Gap in Ethiopia: Evidence From Decomposition Analysis
Authors: Hundie Shemelis Kebede , Tulu Daniel Tadesse
Published: August 2021

In Ethiopia, the gender gap in financial inclusion is high, and the effect of socioeconomic variables on the gap is not well investigated. As a result, this study uses the World Bank’s Global Findex database from 2017 to analyze magnitude and determinants of the gender gap in financial inclusion in Ethiopia. Using Fairlie decomposition technique, we find statistically significant gender gap in all indicators of financial inclusion under study in Ethiopia. The result shows that the highest financial inclusion gender gap is observed in formal saving followed by formal account holding. The decomposition results show males are 16.5%, 16.6%, 8.9 %, 8.4 %t, and 5.8% more likely to have a formal account, formal saving, borrowing, emergency fund possibility, and debit card ownership, respectively. We further decompose these gaps using Daymont and Andrisani approach and the result reveals that differences in coefficients between males and females explain 57.7% in formal saving, 43.4% in formal account holding, and 110.9% in borrowing from formal financial institutions. About 54.2% of the total gender gap in possibility of raising emergcency fund is attributed to differences in characteristics/predictors between the two genders while gender gap in debit card holding is explained by the iteraction between differences in characterisctics and coefficients. Being older, more educated, and wealthier favor financial inclusion, with age, employment, and education having a greater effect. Furthermore, gaps in coefficients, productivity, and advantage to males and disadvantage to females aggravate the gender gap in financial inclusion in Ethiopia. Gender mainstreaming in economic activities to increase income, employment opportunities and education for females to bridge the gender gap in financial inclusion is important.