bluuebunny/crossref_metadata_2025 huggingface dataset:
Endoplasmic Reticulum Stress and Intestinal Inflammation: A Perilous Union
Authors: Eugene Sanchez Preethi , Reddy Vadde Sudhakar , Trinath Jamma
Published: November 2020

The intestinal tract encompasses the largest mucosal surface fortified with a fine layer of intestinal epithelial cells along with highly sophisticated network of the lamina propria immune cells that are indispensable to sustain gut homeostasis. However, it can be challenging to uphold homeostasis when these cells in the intestine are perpetually exposed to insults of both endogenous and exogenous origin. The complex networking and dynamic microenvironment in the intestine demand highly functional cells ultimately burdening the endoplasmic reticulum (ER) leading to ER stress. Unresolved ER stress is one of the primary contributors to the pathogenesis of inflammatory bowel diseases (IBD). Studies also suggest that ER stress can be the primary cause of inflammation and/or the consequence of inflammation. Therefore, understanding the patterns of expression of ER stress regulators and deciphering the intricate interplay between ER stress and inflammatory pathways in intestinal epithelial cells in association with lamina propria immune cells contribute toward the development of novel therapies to tackle IBD. This review provides imperative insights into the molecular markers involved in the pathogenesis of IBD by potentiating ER stress and inflammation and briefly describes the potential pharmacological intervention strategies to mitigate ER stress and IBD. In addition, genetic mutations in the biomarkers contributing to abnormalities in the ER stress signaling pathways further emphasizes the relevance of biomarkers in potential treatment for IBD.
Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2
Authors: Xiao Xia , Wang Conghui , Chang De , Wang Ying , Dong Xiaojing , Jiao Tao , Zhao Zhendong , Ren Lili , Dela Cruz Charles S. , Sharma Lokesh , Lei Xiaobo , Wang Jianwei
Published: November 2020

COVID-19 pandemic has infected millions of people with mortality exceeding >1 million. There is an urgent need to find therapeutic agents that can help clear the virus to prevent severe disease and death. Identifying effective and safer drugs can provide more options to treat COVID-19 infections either alone or in combination. Here, we performed a high throughput screening of approximately 1,700 US FDA-approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 20 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, and thioridazine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating a wide therapeutic window compared to hydroxychloroquine which had a safety index of 22 in similar experiments. Mechanistically, five of the effective compounds (fendiline HCl, monensin sodium salt, vortioxetine, sertraline HCl, and salifungin) were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA-approved compounds can provide much needed therapeutic options that we urgently need during the midst of the pandemic.
CD45RA, CD8β, and IFNγ Are Potential Immune Biomarkers of Human Cognitive Function
Authors: Esgalhado André J. , Reste-Ferreira Débora , Albino Stephanie E. , Sousa Adriana , Amaral Ana Paula , Martinho António , Oliveira Isabel T. , Verde Ignacio , Lourenço Olga , Fonseca Ana M. , Cardoso Elsa M. , Arosa Fernando A.
Published: November 2020

There is increasing evidence that in humans the adaptive immunological system can influence cognitive functions of the brain. We have undertaken a comprehensive immunological analysis of lymphocyte and monocyte populations as well as of HLA molecules expression in a cohort of elderly volunteers (age range, 64–101) differing in their cognitive status. Hereby, we report on the identification of a novel signature in cognitively impaired elderly characterized by: (1) elevated percentages of CD8+ T effector-memory cells expressing high levels of the CD45RA phosphate receptor (Temrahi); (2) high percentages of CD8+ T cells expressing high levels of the CD8β chain (CD8βhi); (3) augmented production of IFNγ by in vitro activated CD4+ T cells. Noteworthy, CD3+CD8+ Temrahi and CD3+CD8βhi cells were associated with impaired cognition. Cytomegalovirus seroprevalence showed that all volunteers studied but one were CMV positive. Finally, we show that some of these phenotypic and functional features are associated with an increased frequency of the HLA-B8 serotype, which belongs to the ancestral haplotype HLA-A1, Cw7, B8, DR3, DQ2, among cognitively impaired volunteers. To our knowledge, this is the first proof in humans linking the amount of cell surface CD45RA and CD8β chain expressed by CD8+ Temra cells, and the amount of IFNγ produced by in vitro activated CD4+ T cells, with impaired cognitive function in the elderly.
Microstructure and Property of Sintered Fe-2Cu-0.8C-0.6Mo-2W Materials Prepared From Prediffused Powders
Authors: Chen Wenchao , Wang Jinghui , Chen Pengqi , Cheng Jigui
Published: November 2020

Prediffused Fe-W powder with 2 wt% of tungsten was prepared by heating Fe-W powder mixes at 800°C for 45 min in H2 atmosphere. Two kinds of Fe-2Cu-0.8C-0.6Mo-2W powder mixtures were obtained by mechanically mixing the prediffused Fe-W powders with the other elemental powders. After pressing and sintering, the sintered Fe-2Cu-0.8C-0.6Mo-2W materials were obtained from the two powder mixtures. The effects of the introducing methods of tungsten element and sintering conditions on microstructure, mechanical and wear properties of the sintered samples were investigated. The results show that with the increase of sintering temperature and time, hardness and strength of sintered samples increase. Prediffused treatment of Fe-W powder can improve density of green compacts and sintered samples. When W element introduced in the form of prediffused Fe-W powders, the compacts pressed at 700 MPa have a green density of 7.13 g/cm3, and after sintered at 1,150°C, the density, hardness, tensile strength and radial crushing strength of the sintered samples are 7.16 g/cm3, 95 HRB, 547 and 791 MPa, respectively, which are higher than those of the samples prepared from powder mixtures by mechanically mixing the elemental powders. Furthermore, the prediffused treatment of Fe-W powders can improve the distribution of W element and enhance wear resistance.
Comparative Transcriptome Analysis Reveals the Intensive Early Stage Responses of Host Cells to SARS-CoV-2 Infection
Authors: Sun Jiya , Ye Fei , Wu Aiping , Yang Ren , Pan Mei , Sheng Jie , Zhu Wenjie , Mao Longfei , Wang Ming , Xia Zanxian , Huang Baoying , Tan Wenjie , Jiang Taijiao
Published: November 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a widespread outbreak of highly pathogenic coronavirus disease 2019 (COVID-19). It is therefore important and timely to characterize interactions between the virus and host cell at the molecular level to understand its disease pathogenesis. To gain insights, we performed high-throughput sequencing that generated time-series data simultaneously for bioinformatics analysis of virus genomes and host transcriptomes implicated in SARS-CoV-2 infection. Our analysis results showed that the rapid growth of the virus was accompanied by an early intensive response of host genes. We also systematically compared the molecular footprints of the host cells in response to SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). Upon infection, SARS-CoV-2 induced hundreds of up-regulated host genes hallmarked by a significant cytokine production, followed by virus-specific host antiviral responses. While the cytokine and antiviral responses triggered by SARS-CoV and MERS-CoV were only observed during the late stage of infection, the host antiviral responses during the SARS-CoV-2 infection were gradually enhanced lagging behind the production of cytokine. The early rapid host responses were potentially attributed to the high efficiency of SARS-CoV-2 entry into host cells, underscored by evidence of a remarkably up-regulated gene expression of TPRMSS2 soon after infection. Taken together, our findings provide novel molecular insights into the mechanisms underlying the infectivity and pathogenicity of SARS-CoV-2.
Basolateral Amygdala to Nucleus Accumbens Communication Differentially Mediates Devaluation Sensitivity of Sign- and Goal-Tracking Rats
Authors: Kochli Daniel E. , Keefer Sara E. , Gyawali Utsav , Calu Donna J.
Published: November 2020

Rats rely on communication between the basolateral amygdala (BLA) and nucleus accumbens (NAc) to express lever directed approach in a Pavlovian lever autoshaping (PLA) task that distinguishes sign- and goal-tracking rats. During PLA, sign-tracking rats preferentially approach an insertable lever cue, while goal-tracking rats approach a foodcup where rewards are delivered. While sign-tracking rats inflexibly respond to cues even after the associated reward is devalued, goal-tracking rats flexibly reduce responding to cues during outcome devaluation. Here, we sought to determine whether BLA–NAc communication, which is necessary for sign, but not goal-tracking, drives a rigid appetitive approach of sign-tracking rats that are insensitive to manipulations of outcome value. Using a contralateral chemogenetic inactivation design, we injected contralateral BLA and NAc core with inhibitory DREADD (hm4Di-mCherry) or control (mCherry) constructs. To determine sign- and goal-tracking groups, we trained rats in five PLA sessions in which brief lever insertion predicts food pellet delivery. We sated rats on training pellets (devalued condition) or chow (valued condition) before systemic clozapine injections (0.1 mg/kg) to inactivate BLA and contralateral NAc during two outcome devaluation probe tests, in which we measured lever and foodcup approach. Contralateral BLA–NAc chemogenetic inactivation promoted a flexible lever approach in sign-tracking rats but disrupted the flexible foodcup approach in goal-tracking rats. Consistent with a prior BLA–NAc disconnection lesion study, we find contralateral chemogenetic inactivation of BLA and NAc core reduces lever, but not the foodcup approach in PLA. Together these findings suggest rigid appetitive associative encoding in BLA–NAc of sign-tracking rats hinders the expression of flexible behavior when outcome value changes.
Phase Coupled Firing of Prefrontal Parvalbumin Interneuron With High Frequency Oscillations
Authors: Yao Yanting , Wu Mengmeng , Wang Lina , Lin Longnian , Xu Jiamin
Published: November 2020

The prefrontal cortex (PFC) plays a central role in executive functions and inhibitory control over many cognitive behaviors. Dynamic changes in local field potentials (LFPs), such as gamma oscillation, have been hypothesized to be important for attentive behaviors and modulated by local interneurons such as parvalbumin (PV) cells. However, the precise relationships between the firing patterns of PV interneurons and temporal dynamics of PFC activities remains elusive. In this study, by combining in vivo electrophysiological recordings with optogenetics, we investigated the activities of prefrontal PV interneurons and categorized them into three subtypes based on their distinct firing rates under different behavioral states. Interestingly, all the three subtypes of interneurons showed strong phase-locked firing to cortical high frequency oscillations (HFOs), but not to theta or gamma oscillations, despite of behavior states. Moreover, we showed that sustained optogenetic stimulation (over a period of 10 s) of PV interneurons can consequently modulate the activities of local pyramidal neurons. Interestingly, such optogenetic manipulations only showed moderate effects on LFPs in the PFC. We conclude that prefrontal PV interneurons are consist of several subclasses of cells with distinct state-dependent modulation of firing rates, selectively coupled to HFOs.
Current Conceptual Understanding of the Epileptogenic Network From Stereoelectroencephalography-Based Connectivity Inferences
Authors: Gupta Kanupriya , Grover Pulkit , Abel Taylor J.
Published: November 2020

Localization of the epileptogenic zone (EZ) is crucial in the surgical treatment of focal epilepsy. Recently, EEG studies have revealed that the EZ exhibits abnormal connectivity, which has led investigators to now consider connectivity as a biomarker to localize the EZ. Further, abnormal connectivity of the EZ may provide an explanation for the impact of focal epilepsy on more widespread brain networks involved in typical cognition and development. Stereo-electroencephalography (sEEG) is a well-established method for localizing the EZ that has recently been applied to examine altered brain connectivity in epilepsy. In this manuscript, we review recent computational methods for identifying the EZ using sEEG connectivity. Findings from previous sEEG studies indicate that during interictal periods, the EZ is prone to seizure generation but concurrently receives inward connectivity preventing seizures. At seizure onset, this control is lost, allowing seizure activity to spread from the EZ. Regulatory areas within the EZ may be important for subsequently ending the seizure. After the seizure, the EZ appears to regain its influence on the network, which may be how it is able to regenerate epileptiform activity. However, more research is needed on the dynamic connectivity of the EZ in order to build a biomarker for EZ localization. Such a biomarker would allow for patients undergoing sEEG to have electrode implantation, localization of the EZ, and resection in a fraction of the time currently needed, preventing patients from having to endure long hospital stays and induced seizures.
Treatment of Intracranial Pseudoaneurysms With a Novel Covered Stent: A Series of 19 Patients With Midterm Follow-Up
Authors: Wang Wei , Liang Xihong , Chen Guangli , Yang Peng , Zhang Jialiang , Liu Haocheng , Zhao Shangfeng , Li Yong , Sun Bowen , Kang Jun
Published: November 2020

Background: The optimal treatment for intracranial pseudoaneurysm is unclear. This study aims to analyze the outcome of treating intracranial pseudoaneurysm with a novel covered stent.

Materials and Methods: The institutional imaging and clinical databases were retrospectively reviewed for patients with intracranial pseudoaneurysms treated with Willis covered stent from January 2017 to December 2019. The clinical presentations, etiology, intraoperative complications, and immediate and follow-up outcomes were analyzed.

Results: A total of 19 patients with 20 pseudoaneurysms were enrolled for analysis. Seventeen patients presented with vision loss and two with epistaxis. Nineteen Willis covered stents were used with one for each patient without technical failure. Intraoperative thrombosis was encountered in one patient (5.3%), which was recanalized by tirofiban. During clinical follow-up, no further epistaxis occurred, and visual acuity improved in three (17.6%) patients. Endoleak occurred in seven (36.8%) patients after the initial balloon inflation and persisted in one (5.3%) patient after balloon re-inflation. This endoleak disappeared at 8 month follow-up. Finally, during angiographic follow-up (median 13 months), parent artery occlusion and in-stent stenosis occurred in one (5.3%) patient. No stent-related ischemic event was encountered.

Conclusions: The Willis covered stent is feasible, safe, and efficient in treating intracranial pseudoaneurysms.
Methamphetamine Activates Trace Amine Associated Receptor 1 to Regulate Astrocyte Excitatory Amino Acid Transporter-2 via Differential CREB Phosphorylation During HIV-Associated Neurocognitive Disorders
Authors: Cisneros Irma E. , Ghorpade Anuja , Borgmann Kathleen
Published: November 2020

Methamphetamine (METH) use, referred to as methamphetamine use disorder (MUD), results in neurocognitive decline, a characteristic shared with HIV-associated neurocognitive disorders (HAND). MUD exacerbates HAND partly through glutamate dysregulation. Astrocyte excitatory amino acid transporter (EAAT)-2 is responsible for >90% of glutamate uptake from the synaptic environment and is significantly decreased with METH and HIV-1. Our previous work demonstrated astrocyte trace amine associated receptor (TAAR) 1 to be involved in EAAT-2 regulation. Astrocyte EAAT-2 is regulated at the transcriptional level by cAMP responsive element binding (CREB) protein and NF-κB, transcription factors activated by cAMP, calcium and IL-1β. Second messengers, cAMP and calcium, are triggered by TAAR1 activation, which is upregulated by IL-1β METH-mediated increases in these second messengers and signal transduction pathways have not been shown to directly decrease astrocyte EAAT-2. We propose CREB activation serves as a master regulator of EAAT-2 transcription, downstream of METH-induced TAAR1 activation. To investigate the temporal order of events culminating in CREB activation, genetically encoded calcium indicators, GCaMP6s, were used to visualize METH-induced calcium signaling in primary human astrocytes. RNA interference and pharmacological inhibitors targeting or blocking cAMP-dependent protein kinase A and calcium/calmodulin kinase II confirmed METH-induced regulation of EAAT-2 and resultant glutamate clearance. Furthermore, we investigated METH-mediated CREB phosphorylation at both serine 133 and 142, the co-activator and co-repressor forms, respectively. Overall, this work revealed METH-induced differential CREB phosphorylation is a critical regulator for EAAT-2 function and may thus serve as a mechanistic target for the attenuation of METH-induced excitotoxicity in the context of HAND.
Alterations in Sub-Axonal Architecture Between Normal Aging and Parkinson’s Diseased Human Brains Using Label-Free Cryogenic X-ray Nanotomography
Authors: Tran Hung Tri , Tsai Esther H. R. , Lewis Amanda J. , Moors Tim , Bol J. G. J. M. , Rostami Iman , Diaz Ana , Jonker Allert J. , Guizar-Sicairos Manuel , Raabe Joerg , Stahlberg Henning , van de Berg Wilma D. J. , Holler Mirko , Shahmoradian Sarah H.
Published: November 2020

Gaining insight to pathologically relevant processes in continuous volumes of unstained brain tissue is important for a better understanding of neurological diseases. Many pathological processes in neurodegenerative disorders affect myelinated axons, which are a critical part of the neuronal circuitry. Cryo ptychographic X-ray computed tomography in the multi-keV energy range is an emerging technology providing phase contrast at high sensitivity, allowing label-free and non-destructive three dimensional imaging of large continuous volumes of tissue, currently spanning up to 400,000 μm3. This aspect makes the technique especially attractive for imaging complex biological material, especially neuronal tissues, in combination with downstream optical or electron microscopy techniques. A further advantage is that dehydration, additional contrast staining, and destructive sectioning/milling are not required for imaging. We have developed a pipeline for cryo ptychographic X-ray tomography of relatively large, hydrated and unstained biological tissue volumes beyond what is typical for the X-ray imaging, using human brain tissue and combining the technique with complementary methods. We present four imaged volumes of a Parkinson’s diseased human brain and five volumes from a non-diseased control human brain using cryo ptychographic X-ray tomography. In both cases, we distinguish neuromelanin-containing neurons, lipid and melanic pigment, blood vessels and red blood cells, and nuclei of other brain cells. In the diseased sample, we observed several swellings containing dense granular material resembling clustered vesicles between the myelin sheaths arising from the cytoplasm of the parent oligodendrocyte, rather than the axoplasm. We further investigated the pathological relevance of such swollen axons in adjacent tissue sections by immunofluorescence microscopy for phosphorylated alpha-synuclein combined with multispectral imaging. Since cryo ptychographic X-ray tomography is non-destructive, the large dataset volumes were used to guide further investigation of such swollen axons by correlative electron microscopy and immunogold labeling post X-ray imaging, a possibility demonstrated for the first time. Interestingly, we find that protein antigenicity and ultrastructure of the tissue are preserved after the X-ray measurement. As many pathological processes in neurodegeneration affect myelinated axons, our work sets an unprecedented foundation for studies addressing axonal integrity and disease-related changes in unstained brain tissues.
Probing Neurovisceral Integration via Functional Near-Infrared Spectroscopy and Heart Rate Variability
Authors: Condy Emma E. , Friedman Bruce H. , Gandjbakhche Amir
Published: November 2020

The neurovisceral integration model (NVM) proposes that an organism’s ability to flexibly adapt to its environment is related to biological flexibility within the central autonomic network (CAN). One important aspect of this flexibility is behavioral inhibition (Thayer and Friedman, 2002). During a behavioral inhibition task, the CAN, which comprises a series of feedback loops, must be able to integrate information and react to these inputs flexibly to facilitate optimal performance. The functioning of the CAN is shown to be associated with respiratory sinus arrhythmia (RSA), as the vagus nerve is part of this feedback system. Although the NVM has been examined through neural imaging and RSA, only a few studies have examined these measures simultaneously during the neuroimaging procedure. Furthermore, these studies were done at rest or used tasks that were not targeted at processes associated with the NVM, such as behavioral inhibition and cognitive flexibility. For this reason, the present study assessed RSA and neural activation in the pre-frontal cortex simultaneously while participants completed a behavior inhibition task. RSA and functional near-infrared spectroscopy were collected in 38 adults, and resting levels of pre-frontal activation were negatively related to RSA, but pre-frontal activation during the behavior inhibition task was not. The negative relationship between RSA and oxygenated hemoglobin is consistent with previous functional magnetic resonance imaging work examining the NVM at baseline and should be further studied. Additional research investigating how this relationship may change based on task demands or environmental contexts would help clarify the applicability of the model.
The Molecular and Microenvironmental Landscape of Glioblastomas: Implications for the Novel Treatment Choices
Authors: Di Cintio Federica , Dal Bo Michele , Baboci Lorena , De Mattia Elena , Polano Maurizio , Toffoli Giuseppe
Published: November 2020

Glioblastoma (GBM) is the most frequent and aggressive primary central nervous system tumor. Surgery followed by radiotherapy and chemotherapy with alkylating agents constitutes standard first-line treatment of GBM. Complete resection of the GBM tumors is generally not possible given its high invasive features. Although this combination therapy can prolong survival, the prognosis is still poor due to several factors including chemoresistance. In recent years, a comprehensive characterization of the GBM-associated molecular signature has been performed. This has allowed the possibility to introduce a more personalized therapeutic approach for GBM, in which novel targeted therapies, including those employing tyrosine kinase inhibitors (TKIs), could be employed. The GBM tumor microenvironment (TME) exerts a key role in GBM tumor progression, in particular by providing an immunosuppressive state with low numbers of tumor-infiltrating lymphocytes (TILs) and other immune effector cell types that contributes to tumor proliferation and growth. The use of immune checkpoint inhibitors (ICIs) has been successfully introduced in numerous advanced cancers as well as promising results have been shown for the use of these antibodies in untreated brain metastases from melanoma and from non-small cell lung carcinoma (NSCLC). Consequently, the use of PD-1/PD-L1 inhibitors has also been proposed in several clinical trials for the treatment of GBM. In the present review, we will outline the main GBM molecular and TME aspects providing also the grounds for novel targeted therapies and immunotherapies using ICIs for GBM.
New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer
Authors: Han Ye , Yu Xiaopeng , Li Shuqiang , Tian Ye , Liu Caigang
Published: November 2020

Poly (ADP-ribose) polymerase (PARP) inhibitors are a therapeutic milestone exerting a synthetic lethal effect in the treatment of cancer involvingBRCA1/2mutation. Theoretically, PARP inhibitors (PARPi) eliminate tumor cells by disrupting DNA damage repair through either PARylation or the homologous recombination (HR) pathway. However, resistance to PARPi greatly hinders therapeutic effectiveness in triple-negative breast cancer (TNBC). Owing to the high heterogeneity and few genetic targets in TNBC, there has been limited therapeutic progress in the past decades. In view of this, there is a need to circumvent resistance to PARPi and develop potential treatment strategies for TNBC. We present, herein, a review of the scientific progress and explore the mechanisms underlying PARPi resistance in TNBC. The complicated mechanisms of PARPi resistance, including drug exporter formation, loss of poly (ADP-ribose) glycohydrolase (PARG), HR reactivation, and restoration of replication fork stability, are discussed in detail in this review. Additionally, we also discuss new combination therapies with PARPi that can improve the clinical response in TNBC. The new perspectives for PARPi bring novel challenges and opportunities to overcome PARPi resistance in breast cancer.
Long-Term Outcomes of Acute Osteoarticular Infections in Children
Authors: Manz Nora , Krieg Andreas H. , Buettcher Michael , Ritz Nicole , Heininger Ulrich
Published: November 2020

Background: Acute hematogenous osteomyelitis (OM) and septic arthritis require immediate diagnosis and treatment by an interdisciplinary team of pediatric infectious disease specialists and pediatric orthopedic surgeons. Adverse outcomes such as growth disturbance, bone deformity, and chronic infections have been described in older studies. However, there is only little known about long-term follow-up of patients of the last two decades. Therefore, we aimed to evaluate subjective and objective long-term outcomes of these children with osteoarticular infections treated in the millennial years.

Methods: Cross-sectional study performed in two pediatric centers including patients admitted for OM and/or SA between 2005 and 2014 and follow-up consultations in 2019. Patients with symptoms of ≤2 weeks duration at initial presentation were contacted. Subjective outcomes were assessed by standardized interview, objective outcomes by clinical examination. Medical charts were used to extract data from the initial presentations. Statistical analysis was performed by non-parametric tests and Fisher's exact test.

Results: Of 147 eligible patients 77 (52%) agreed to participate, of which 68 (88%) had an interview and physical examination and 9 (12%) an interview only. Thirty-three (39%) had OM, 26 (34%) SA, and 21 (27%) combined OM/SA. Median (IQR) age at follow-up was 13.3 (10.5–18.0) years with a median (IQR) follow-up of 7.1 (6.1–8.6) years. Persistent complaints including pain, functional differences and scar paresthesia, reported by 21 (28%) patients, were generally mild and only 3 (5%) required ongoing medical care. Objective sequelae including pain, limited range of motion, unilateral axis deformity or asymmetric gait were found in 8 (12%) participants. Older age, female sex, joint involvement, surgical intervention, persistent fever, and C-reactive protein elevation were associated with adverse clinical outcome.

Conclusions: Adverse outcomes were observed in a considerable number of patients, most of which were minor, and only few required ongoing medical care. Long-term follow up is advisable for patients with risk factors identified during the initial presentation.

This study was registered on ClinicalTrials.gov (NCT03827980).
Multispecies Evaluation of a Long-Acting Tenofovir Alafenamide Subdermal Implant for HIV Prophylaxis
Authors: Gunawardana Manjula , Remedios-Chan Mariana , Sanchez Debbie , Webster Simon , Galvan Patricia , Fanter Rob , Castonguay Amalia E. , Webster Paul , Moss John A. , Kuo Joseph , Gallay Philippe A. , Vincent Kathleen L. , Motamedi Massoud , Weinberger Dana , Marzinke Mark A. , Hendrix Craig W. , Baum Marc M.
Published: November 2020

New HIV-1 infection rates far outpace the targets set by global health organizations, despite important progress in curbing the progression of the epidemic. Long-acting (LA) formulations delivering antiretroviral (ARV) agents for HIV-1 pre-exposure prophylaxis (PrEP) hold significant promise, potentially facilitating adherence due to reduced dosing frequency compared to oral regimens. We have developed a subdermal implant delivering the potent ARV drug tenofovir alafenamide that could provide protection from HIV-1 infection for 6 months, or longer. Implants from the same lot were investigated in mice and sheep for local safety and pharmacokinetics (PKs). Ours is the first report using these animal models to evaluate subdermal implants for HIV-1 PrEP. The devices appeared safe, and the plasma PKs as well as the drug and metabolite concentrations in dermal tissue adjacent to the implants were studied and contrasted in two models spanning the extremes of the body weight spectrum. Drug and drug metabolite concentrations in dermal tissue are key in assessing local exposure and any toxicity related to the active agent. Based on our analysis, both animal models were shown to hold significant promise in LA product development.
Protein Kinase Inhibitor Peptide as a Tool to Specifically Inhibit Protein Kinase A
Authors: Liu Chong , Ke Ping , Zhang Jingjing , Zhang Xiaoying , Chen Xiongwen
Published: November 2020

The protein kinase enzyme family plays a pivotal role in almost every aspect of cellular function, including cellular metabolism, division, proliferation, transcription, movement, and survival. Protein kinase A (PKA), whose activation is triggered by cyclic adenosine monophosphate (cAMP), is widely distributed in various systems and tissues throughout the body and highly related to pathogenesis and progression of various kinds of diseases. The inhibition of PKA activation is essential for the study of PKA functions. Protein kinase inhibitor peptide (PKI) is a potent, heat-stable, and specific PKA inhibitor. It has been demonstrated that PKI can block PKA-mediated phosphorylase activation. Since then, researchers have a lot of knowledge about PKI. PKI is considered to be the most effective and specific method to inhibit PKA and is widely used in related research. In this review, we will first introduce the knowledge on the activation of PKA and mechanisms related on the inhibitory effects of PKI on PKA. Then, we will compare PKI-mediated PKA inhibition vs. several popular methods of PKA inhibition.
The Rebooting in Sports and Physical Activities After COVID-19 Italian Lockdown: An Exploratory Study
Authors: Guicciardi Marco , Pazzona Riccardo
Published: November 2020

The lockdown imposed in Italy to reduce the spread of COVID-19 posited unusual challenges to people practicing sports and physical activities. The rebooting of activities highlighted the need to cope with new behaviors and routines, such as wearing a face mask while exercising. We conducted a web-based survey in Italy at the start of physical activities’ rebooting, to investigate how people reacted to the new norms. Participants completed the questionnaires assessing insomnia, regulatory self-efficacy, optimism, mood states, and mental toughness. Age, gender, and environment were assumed as design variables. Results showed that in outdoor activities, the younger females as compared to the older manifest less regulatory self-efficacy, while the younger males manifest more regulatory self-efficacy than the older. In indoor activities, a reversed pattern of regulatory-self-efficacy was observed. Regarding life orientation, younger participants showed less optimism and positive expectation for the future and seem to be more exposed to the unexpected effects of the restrictions: they showed more sleep disturbances, confusion, depression, anger, and fatigue and less vigor and mental toughness than older participants. An understanding of the psychological implications of the rebooting phase can support the enactment of more appropriate behaviors to practice sports and physical activities when living at the time of the coronavirus.
Psychosocial Correlates of Mental Health and Well-Being During the COVID-19: The Spanish Case
Authors: Esteban-Gonzalo Sara , González-Pascual Juan Luis , Caballero-Galilea María , Esteban-Gonzalo Laura
Published: November 2020

Background

The COVID-19 pandemic has hit almost all countries around the globe, seriously affecting the welfare of populations. Spain is especially hard-hit. In this context, the purpose of the present study is to analyze social, demographic, and economic correlates of mental health during the COVID-19 pandemic in the population residing in Spain.

Method

The sample of this cross-sectional study was comprised of 801 participants aged 18 or older and residing in Spain. Data collection was carried out during March and April 2020. Data of mental health (GHQ12) and well-being (Positive and Negative Affect Schedule) indicators, and those of a wide number of social, demographic, and economic variables were recorded. Linear regression models were built to value associations between mental health and social, demographic, and economic indicators.

Results

Mental health morbidity was higher in women, younger people, individuals with medium studies, people with fewer children, singles, students, and unemployed individuals. Positive affect was higher among women, people with a high level of studies, those not co-living with dependent seniors, the self-employed, the employed, and those working outside home. Negative affect was negatively associated with age and number of children and was higher among women, people with basic studies, singles, individuals co-living with dependent seniors, homemakers, and students.

Conclusion

The most vulnerable populations were found to be women, younger people, people with basic or medium studies, students and individuals with no remunerated activities, single populations, and those co-living with dependent seniors as well as those with a reduced number of children.
Genetic Determinants of Gating Functions: Do We Get Closer to Understanding Schizophrenia Etiopathogenesis?
Authors: Rovný Rastislav , Besterciová Dominika , Riečanský Igor
Published: November 2020

Deficits in the gating of sensory stimuli, i.e., the ability to suppress the processing of irrelevant sensory input, are considered to play an important role in the pathogenesis of several neuropsychiatric disorders, in particular schizophrenia. Gating is disrupted both in schizophrenia patients and their unaffected relatives, suggesting that gating deficit may represent a biomarker associated with a genetic liability to the disorder. To assess the strength of the evidence for the etiopathogenetic links between genetic variation, gating efficiency, and schizophrenia, we carried out a systematic review of human genetic association studies of sensory gating (suppression of the P50 component of the auditory event-related brain potential) and sensorimotor gating (prepulse inhibition of the acoustic startle response). Sixty-three full-text articles met the eligibility criteria for inclusion in the review. In total, 117 genetic variants were reported to be associated with gating functions: 33 variants for sensory gating, 80 variants for sensorimotor gating, and four variants for both sensory and sensorimotor gating. However, only five of these associations (four for prepulse inhibition—CHRNA3 rs1317286, COMT rs4680, HTR2A rs6311, and TCF4 rs9960767, and one for P50 suppression—CHRNA7 rs67158670) were consistently replicated in independent samples. Although these variants and genes were all implicated in schizophrenia in research studies, only two polymorphisms (HTR2A rs6311 and TCF4 rs9960767) were also reported to be associated with schizophrenia at a meta-analytic or genome-wide level of evidence. Thus, although gating is widely considered as an important endophenotype of schizophrenia, these findings demonstrate that evidence for a common genetic etiology of impaired gating functions and schizophrenia is yet unsatisfactory, warranting further studies in this field.
Anxiety, Reinforcement Sensitivity and Social Context in Accepting the Experience of Pain Among Rheumatoid Arthritis Patients
Authors: Pinel Luis , Perez-Nieto Miguel A. , Redondo Marta , Rodríguez-Rodríguez Luis , León Leticia
Published: November 2020

Background:Acceptance has become one of the most widely studied processes regarding chronic pain because of its ability to influence participants' adaptation and coping responses. Leading researchers have found relationships between variables such as anxiety, reinforcement sensitivity, and the responses of the participants' environment to their behavior and acceptance. In contrast, few studies have been found that investigate the variables that predict the acceptance of pain. This study has set out to explore the relationships between pain-related anxiety, sensitivity to contingencies, and the punishment responses of significant people toward pain behaviors regarding pain acceptance.

Methods:With a view to fulfilling this purpose, a cohort of 62 participants with rheumatoid arthritis was chosen, and the subjects were assessed through the following self-report measures: Chronic Pain Acceptance Questionnaire, CPAQ; Pain Anxiety Symptoms Scale, PASS-20; The Sensitivity to Punishment and Sensitivity to Reward Questionnaire, SPSRQ, and The West Haven-Yale Multidimensional Pain Inventory, WHYMPI. The study's initial objectives were achieved by means of a stepwise multiple linear regression analysis.

Results:The linear regression analyses revealed a negative and significant correlation between anxiety, reinforcement sensitivity, and the significant persons' responses to pain behaviors and pain acceptance.

Conclusion:The results suggest that the identification of these variables might be important for addressing these participants' pain. Finally, the discussion focuses on our findings' implications as regards their use in clinical practice.
Understanding Contaminant Migration Within a Dynamic River Corridor Through Field Experiments and Reactive Transport Modeling
Authors: Chen Xingyuan , Zachara John M. , Vermuel Vince R. , Hammond Glenn , Freshley Mark , Fang Yilin
Published: November 2020

The behavior of a persistent uranium plume within an extended river corridor at the DOE Hanford site is dominantly controlled by river stage fluctuations in the adjacent Columbia River. The plume behavior is further complicated by substantial heterogeneity in physical and geochemical properties of the host aquifer sediments. Multi-scale field and laboratory experiments and reactive transport modeling were integrated to understand the complex plume behavior influenced by highly variable hydrologic and geochemical conditions in time and space. In this paper, we (1) describe multiple data sets from field-scale uranium adsorption and desorption experiments performed at our experimental well-field, (2) develop a reactive transport model that incorporates hydrologic and geochemical heterogeneities characterized from multi-scale and multi-type datasets and a surface complexation reaction network based on laboratory studies, and (3) compare the modeling and observation results to provide insights on how to refine the conceptual model and reduce prediction uncertainties. The experimental results revealed significant spatial variability in uranium adsorption/desorption behavior, while modeling demonstrated that ambient hydrologic and geochemical conditions and heterogeneities in sediment physical and chemical properties both contributed to complex plume behavior and its persistence. This research underscores the great challenges in adequately characterizing this type of site to model the reactive transport processes over scales of 10 m or more. Our analysis provides important insights into the characterization, understanding, modeling, and remediation of groundwater contaminant plumes influenced by dynamic surface water and groundwater interactions.
Iterative Tomography: A Key to Providing Time-Dependent 3-D Reconstructions of the Inner Heliosphere and the Unification of Space Weather Forecasting Techniques
Authors: Jackson Bernard V. , Buffington Andrew , Cota Lucas , Odstrcil Dusan , Bisi Mario M. , Fallows Richard , Tokumaru Munetoshi
Published: November 2020

Over several decades, UCSD has developed and continually updated a time-dependent iterative three-dimensional (3-D) reconstruction technique to provide global heliospheric parameters—density, velocity, and component magnetic fields. For expediency, this has used a kinematic model as a kernel to provide a fit to either interplanetary scintillation (IPS) or Thomson-scattering observations. This technique has been used in near real time over this period, employing Institute for Space-Earth Environmental Research, Japan, IPS data to predict the propagation of these parameters throughout the inner heliosphere. We have extended the 3-D reconstruction analysis to include other IPS Stations around the Globe in a Worldwide Interplanetary Scintillation Stations Network. In addition, we also plan to resurrect the Solar Mass Ejection Imager Thomson-scattering analysis as a basis for 3-D analysis to be used by the latest NASA Small Explorer heliospheric imagers of the Polarimeter to Unify the Corona and Heliosphere mission, the All Sky Heliospheric Imager, and other modern wide-field imagers. Better data require improved heliospheric modeling that incorporates non-radial transport of heliospheric flows, and shock processes. Looking ahead to this, we have constructed an interface between the 3-D reconstruction tomography and 3-D MHD models and currently include the ENLIL model as a kernel in the reconstructions to provide this fit. In short, we are now poized to provide all of these innovations in a next step: to include them for planned ground-based and spacecraft instruments, all to be combined into a truly global 3-D heliospheric system which utilizes these aspects in their data and modeling.
Climate Change Impact on Aflatoxin Contamination Risk in Malawi's Maize Crops
Authors: Warnatzsch Erika A. , Reay David S. , Camardo Leggieri Marco , Battilani Paola
Published: November 2020

Malawi is one of the poorest countries in the world, with high levels of malnutrition and little domestic mycotoxin regulation. Domestically grown maize is the largest single source of calories in the country and a large contributor to the economy. This research uses Regional Climate Models (RCMs) to determine the climatic conditions in the three regions of Malawi (Northern, Central and Southern) in 2035 (2020–2049) and 2055 (2040–2069) as compared to the baseline climate of 1971–2000. This climatic data is then used as inputs to the Food and Agriculture Organization's (FAO) AquaCrop model to assess the impact on the growth cycle of two maize varieties grown in each region and sown at three different times during the planting season. Finally, AFLA-maize, a mechanistic model, is applied to determine the impact of these projected changes on the aflatoxin B1(AFB1) contamination risk. We find that Malawi's climate is projected to get warmer (by 1–2.5°C) and drier (reduction of 0–4% in annual rainfall levels) in all regions, although some uncertainty remains around the changes in precipitation levels. These climatic changes are expected to shorten the growing season for maize, bringing the harvest date forward by between 10 and 25 days for the short-development variety and between 25 and 65 days for the long-development variety. These changes are also projected to make the pre-harvest conditions for Malawian maize more favorable for AFB1contamination and risk maps for the studied conditions were drawn. Exceedances of EU safety thresholds are expected to be possible in all regions, with the risk of contamination moving northwards in a warming climate.
Loci Associated With Antibody Response in Feral Swine (Sus scrofa) Infected With Brucella suis
Authors: Pierce Courtney F. , Brown Vienna R. , Olsen Steven C. , Boggiatto Paola , Pedersen Kerri , Miller Ryan S. , Speidel Scott E. , Smyser Timothy J.
Published: November 2020

Feral swine (Sus scrofa) are a destructive invasive species widespread throughout the United States that disrupt ecosystems, damage crops, and carry pathogens of concern for the health of domestic stock and humans includingBrucella suis—the causative organism for swine brucellosis. In domestic swine, brucellosis results in reproductive failure due to abortions and infertility. Contact with infected feral swine poses spillover risks to domestic pigs as well as humans, companion animals, wildlife, and other livestock. Genetic factors influence the outcome of infectious diseases; therefore, genome wide association studies (GWAS) of differential immune responses among feral swine can provide an understanding of disease dynamics and inform management to prevent the spillover of brucellosis from feral swine to domestic pigs. We sought to identify loci associated with differential antibody responses among feral swine naturally infected withB. suisusing a case-control GWAS. Tissue, serum, and genotype data (68,516 bi-allelic single nucleotide polymorphisms) collected from 47 feral swine were analyzed in this study. The 47 feral swine were culture positive forBrucellaspp. Of these 47, 16 were antibody positive (cases) whereas 31 were antibody negative (controls). Single-locus GWAS were performed using efficient mixed-model association eXpedited (EMMAX) methodology with three genetic models: additive, dominant, and recessive. Eight loci associated with seroconversion were identified on chromosome 4, 8, 9, 10, 12, and 18. Subsequent bioinformatic analyses revealed nine putative candidate genes related to immune function, most notably phagocytosis and induction of an inflammatory response. Identified loci and putative candidate genes may play an important role in host immune responses toB. suisinfection, characterized by a detectable bacterial presence yet a differential antibody response. Given that antibody tests are used to evaluate brucellosis infection in domestic pigs and for disease surveillance in invasive feral swine, additional studies are needed to fully understand the genetic component of the response toB. suisinfection and to more effectively translate estimates ofBrucellaspp. antibody prevalence among feral swine to disease control management action.