bluuebunny/crossref_metadata_2025 huggingface dataset:
Antarctic Water Tracks: Microbial Community Responses to Variation in Soil Moisture, pH, and Salinity
Authors: George Scott F. , Fierer Noah , Levy Joseph S. , Adams Byron
Published: January 2021

Ice-free soils in the McMurdo Dry Valleys select for taxa able to cope with challenging environmental conditions, including extreme chemical water activity gradients, freeze-thaw cycling, desiccation, and solar radiation regimes. The low biotic complexity of Dry Valley soils makes them well suited to investigate environmental and spatial influences on bacterial community structure. Water tracks are annually wetted habitats in the cold-arid soils of Antarctica that form briefly each summer with moisture sourced from snow melt, ground ice thaw, and atmospheric deposition via deliquescence and vapor flow into brines. Compared to neighboring arid soils, water tracks are highly saline and relatively moist habitats. They represent a considerable area (∼5–10 km2) of the Dry Valley terrestrial ecosystem, an area that is expected to increase with ongoing climate change. The goal of this study was to determine how variation in the environmental conditions of water tracks influences the composition and diversity of microbial communities. We found significant differences in microbial community composition between on- and off-water track samples, and across two distinct locations. Of the tested environmental variables, soil salinity was the best predictor of community composition, with members of the Bacteroidetes phylum being relatively more abundant at higher salinities and the Actinobacteria phylum showing the opposite pattern. There was also a significant, inverse relationship between salinity and bacterial diversity. Our results suggest water track formation significantly alters dry soil microbial communities, likely influencing subsequent ecosystem functioning. We highlight how Dry Valley water tracks could be a useful model system for understanding the potential habitability of transiently wetted environments found on the surface of Mars.
SARS-CoV-2 Proteins Exploit Host’s Genetic and Epigenetic Mediators for the Annexation of Key Host Signaling Pathways
Authors: Khan Md. Abdullah-Al-Kamran , Islam Abul Bashar Mir Md. Khademul
Published: January 2021

The constant rise of the death toll and cases of COVID-19 has made this pandemic a serious threat to human civilization. Understanding of host-SARS-CoV-2 interaction in viral pathogenesis is still in its infancy. In this study, we utilized a blend of computational and knowledgebase approaches to model the putative virus-host interplay in host signaling pathways by integrating the experimentally validated host interactome proteins and differentially expressed host genes in SARS-CoV-2 infection. While searching for the pathways in which viral proteins interact with host proteins, we discovered various antiviral immune response pathways such as hypoxia-inducible factor 1 (HIF-1) signaling, autophagy, retinoic acid-inducible gene I (RIG-I) signaling, Toll-like receptor signaling, fatty acid oxidation/degradation, and IL-17 signaling. All these pathways can be either hijacked or suppressed by the viral proteins, leading to improved viral survival and life cycle. Aberration in pathways such as HIF-1 signaling and relaxin signaling in the lungs suggests the pathogenic lung pathophysiology in COVID-19. From enrichment analysis, it was evident that the deregulated genes in SARS-CoV-2 infection might also be involved in heart development, kidney development, and AGE-RAGE signaling pathway in diabetic complications. Anomalies in these pathways might suggest the increased vulnerability of COVID-19 patients with comorbidities. Moreover, we noticed several presumed infection-induced differentially expressed transcription factors and epigenetic factors, such as miRNAs and several histone modifiers, which can modulate different immune signaling pathways, helping both host and virus. Our modeling suggests that SARS-CoV-2 integrates its proteins in different immune signaling pathways and other cellular signaling pathways for developing efficient immune evasion mechanisms while leading the host to a more complicated disease condition. Our findings would help in designing more targeted therapeutic interventions against SARS-CoV-2.
Co-morbidities to Vestibular Impairments—Some Concomitant Disorders in Young and Older Adults
Authors: Malmström Eva-Maj , Ekvall Hansson Eva , Hafström Anna , Magnusson Måns , Fransson Per-Anders
Published: January 2021

Background: Dizziness and pain are common complaints that often appear concomitantly, with or without a causal relationship. However, these symptoms might maintain and exacerbate each other and other co-morbidities. Therefore, adequate rehabilitation may have to include an expanded focus on other deficits and preconditions, especially in older adults and in patients.

Objective: To understand how frequently vestibular dysfunction coincided with medical conditions and aging, we studied two categories: Study 1: patients referred to a vestibular unit and Study 2: senior members in a fitness association.

Method: Study 1: 49 patients [34 females/15 males; mean age 52 years (SEM 2.0)] seeking health care for balance disorders and vestibular deficits were asked in questionnaires about their perception of dizziness and pain, and emotional and functional strains. Study 2: 101 senior members in a fitness association [91 females/10 males; mean age 75 years (SEM 0.6)], were assessed for vestibular and balance deficits and for any co-morbidities. The participants were monitored for falls for 12 months after the initial assessments.

Result: Study 1: Co-morbidity often existed between dizziness and pain (65%). The patients reported high emotional and functional strain related to their dizziness and pain. Patients older than 60 years reported longer durations of pain (p ≤ 0.028) but less emotional strain (p = 0.036), compared to younger patients. Study 2: 84% of the participants had a vestibular impairment, often without noticing any symptoms. Furthermore, 40% reported cardiovascular illnesses, 12% musculoskeletal disorders, and 63% reported other medical conditions. Forty-two percent experienced falls within 1 year after the initial assessments (thereof 42% in the group with vestibular deficits and 38% in the group without vestibular deficits).

Conclusion: To enhance and preserve postural control, both in patients with vestibular deficits and in older adults, we suggest an expanded clinical perspective. Hence, we recommend detailed examinations of the vestibular system but simultaneously probing for possible co-morbidities. Since aging often entails deterioration of multimodal processes related to maintained mobility and postural stability, our results add focus on the importance of addressing balance disorders together with additional medical conditions.
Validity and Reliability of the Semmes-Weinstein Monofilament Test and the Thumb Localizing Test in Patients With Stroke
Authors: Suda Mabu , Kawakami Michiyuki , Okuyama Kohei , Ishii Ryota , Oshima Osamu , Hijikata Nanako , Nakamura Takuya , Oka Asako , Kondo Kunitsugu , Liu Meigen
Published: January 2021

Background:Somatosensory impairment is common in patients who have had a stroke and can affect their motor function and activities of daily living (ADL). Therefore, detecting and treating somatosensory impairments properly is considered to be very important, and various examinations have been developed. However, the reliability and validity of few of them have been verified due to differences in the procedure of each examiner or poor quantification by the examination itself.

Objective:We hypothesized that, with fixed procedures two convenient clinical examinations, the Semmes-Weinstein Monofilament Test (SWMT) and the Thumb Localizing Test (TLT), could provide reliable assessments of light touch sensation and proprioception. The purpose of this study was to verify the reliability and validity of these two examinations as indices of somatosensory impairment of the upper extremity (UE) in patients with chronic post-stroke hemiparesis.

Methods:Fifty patients with chronic stroke (median time after onset of stroke, 848 [474–1708] days, mean age 57 [standard deviation 14] years) were enrolled at Keio University Hospital from 2017 to 2018. Examiners learned the original method of the SWMT and the TLT rigorously and shared it with each other. The TLT procedure was partially modified by dividing the location of the patient's thumb into four spaces. Two examiners evaluated the SWMT and the TLT for 2 days, and intra-rater and inter-rater reliabilities were calculated using weighted kappa statistics. In addition to this, the evaluator size score of the SWMT was assessed with Bland-Altman analysis to evaluate systematic bias. The Stroke Impairment Assessment Set (SIAS) sensory items were used to assess validity, and Spearman's rank correlation coefficients were calculated.

Results:Intra/inter-rater agreements of the SWMT grade score were 0.89 (thumb, 95%CI: 0.83–0.95)/ 0.75 (0.60–0.91) and 0.80 (index finger, 0.67–0.93)/0.79 (0.66–0.92), and of the TLT they were 0.83 (navel level proximal space, 0.71–0.95)/ 0.83 (0.73–0.92), 0.90 (navel level distal space, 0.85–0.96)/ 0.80 (0.69–0.90), 0.80 (shoulder level proximal space, 0.68–0.92)/ 0.77 (0.65–0.89), and 0.87 (shoulder level distal space, 0.80–0.93)/ 0.80 (0.68–0.92) (P< 0.001, each item). All of them showed substantial agreement, but the MDC of the SWMT evaluator size was 1.28 to 1.79 in the inter-rater test and 1.94–2.06 in the intra-rater test. The SWMT grade score showed a strong correlation with the SIAS light touch sensation item (r= 0.65,p< 0.001), as did the TLT with the SIAS position sense item (r= −0.70–0.62,p< 0.001 each space).

Conclusions:The reliability and validity of the SWMT and the TLT were verified. These tests can be used as reliable sensory examinations of the UE in patients with chronic stroke, and especially for the SWMT, it is more reliable for screening.
Evaluation of Cerebral Blood Flow Measured by 3D PCASL as Biomarker of Vascular Cognitive Impairment and Dementia (VCID) in a Cohort of Elderly Latinx Subjects at Risk of Small Vessel Disease
Authors: Jann Kay , Shao Xingfeng , Ma Samantha J. , Cen Steven Y. , D’Orazio Lina , Barisano Giuseppe , Yan Lirong , Casey Marlena , Lamas Jesse , Staffaroni Adam M. , Kramer Joel H. , Ringman John M. , Wang Danny J. J.
Published: January 2021

Cerebral small vessel disease (cSVD) affects arterioles, capillaries, and venules and can lead to cognitive impairments and clinical symptomatology of vascular cognitive impairment and dementia (VCID). VCID symptoms are similar to Alzheimer’s disease (AD) but the neurophysiologic alterations are less well studied, resulting in no established biomarkers. The purpose of this study was to evaluate cerebral blood flow (CBF) measured by 3D pseudo-continuous arterial spin labeling (pCASL) as a potential biomarker of VCID in a cohort of elderly Latinx subjects at risk of cSVD. Forty-five elderly Latinx subjects (12 males, 69 ± 7 years) underwent repeated MRI scans ∼6 weeks apart. CBF was measured using 3D pCASL in the whole brain, white matter and 4 main vascular territories (leptomeningeal anterior, middle, and posterior cerebral artery (leptoACA, leptoMCA, leptoPCA), as well as MCA perforator). The test-retest repeatability of CBF was assessed by intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). Absolute and relative CBF was correlated with gross cognitive measures and domain specific assessment of executive and memory function, vascular risks, and Fazekas scores and volumes of white matter hyperintensity (WMH). Neurocognitive evaluations were performed using Montreal Cognitive Assessment (MoCA) and neuropsychological test battery in the Uniform Data Set v3 (UDS3). Good to excellent test-retest repeatability was achieved (ICC = 0.77–0.85, wsCV 3–9%) for CBF measurements in the whole brain, white matter, and 4 vascular territories. Relative CBF normalized by global mean CBF in the leptoMCA territory was positively correlated with the executive function composite score, while relative CBF in the leptoMCA and MCA perforator territory was positively correlated with MoCA scores, controlling for age, gender, years of education, and testing language. Relative CBF in WM was negatively correlated with WMH volume and MoCA scores, while relative leptoMCA CBF was positively correlated with WMH volume. Reliable 3D pCASL CBF measurements were achieved in the cohort of elderly Latinx subjects. Relative CBF in the leptomeningeal and perforator MCA territories were the most likely candidate biomarker of VCID. These findings need to be replicated in larger cohorts with greater variability of stages of cSVD.
Reception of Dietary and Other Health-Related Lifestyle Advice to Address Non-communicable Diseases in a Primary Care Context: A Mixed-Method Study in Central Argentina
Authors: Sánchez Urbano Raúl E. , Paredes Ariel , Vargas Chambi Frank R. , Guedes Ruela Pedro , Olivares David E. V. , Souza Pereira Benicio T. , Pacheco Sandaly O. S. , Pacheco Fabio J.
Published: January 2021

An effective way to address risk factors for non-communicable chronic diseases (NCD) and reduce healthcare costs is by using sound health-related advice (HRA) to promote healthy lifestyle habits. In Argentina, however, few studies have examined the context in which HRA is communicated and undertaken by patients at the primary care level. In this study, we assessed the reception of HRA using a mixed-method approach in a central area of Argentina. A total of 1,044 participants from the community were contacted and sociodemographic characteristics, health-related lifestyle factors, and medical history were collected. A calendar with health messages was provided to participants and its usage was assessed after 1 year. Additionally, semi-structured interviews were conducted with 34 patients attending a local primary healthcare center. The results show that HRA was given more frequently to individuals with higher mean age, lower educational level, and to females. Participants with a chronic health condition are at a higher chance of receiving advice to reduce salt intake and maintain a healthy weight. Dietary advice is offered along with other lifestyle recommendations. The use of alcohol and tobacco is usually addressed together. HRA was primarily received in the context of an NCD diagnosis and advice was directed, especially, to risky behaviors. The HRA to increase the intake of fruits and vegetables was mentioned less frequently. Patients at the healthcare center greatly appreciated receiving an HRA, especially when given in a tailored, written, and detailed form, and acknowledged its importance to prevent or control a chronic health condition as part of the medical treatment but showed concern regarding the ability to fully incorporate the advice. Lifestyle recommendations are highly appreciated by patients but are still underutilized since they are offered mostly in the context of illness. The health calendar was shown to be useful to complement health intervention programs at the community level. The findings of our study underscore the acknowledged value of HRA by participants to tackle the risk factors of chronic diseases. If properly used HRA constitutes a simple and highly valued tool to help address patient's needs to prevent and control NCD in Argentina.
Circular RNA circ_0014717 Suppresses Hepatocellular Carcinoma Tumorigenesis Through Regulating miR-668-3p/BTG2 Axis
Authors: Ma Hongxi , Huang Chunchun , Huang Qiuhuan , Li Guangzhi , Li Jun , Huang Bin , Zhong Qiuhong , Cao Cong
Published: January 2021

Recent studies have reported a close association between circRNAs and cancer development. CircRNAs have been recognized to be involved in various biological processes. Up to now, the function of circRNAs in hepatocellular carcinoma (HCC) is still poorly known. qRT-PCR was used to test circ_0014717 expression in HCC tissue samples and cells was determined. It was shown that circ_0014717 was significantly decreased in HCC. Then, we observed overexpression of circ_0014717 obviously repressed HCC cell growth, migration and invasion. Next, we predicted circ_0014717 acted as a sponge of miR-668-3p. miR-668-3p has been reported to participate in several diseases. In our work, it was shown miR-668-3p was greatly increased in HCC and the direct binding sites between circ_0014717 and miR-668-3p were validated. In addition, B-cell translocation gene 2 (BTG2) is closely involved in cellular carcinogenic processes. BTG2 was predicted as a target for miR-668-3p. By performing rescue assays, we demonstrated that circ_0014717 repressed HCC progression via inhibiting BTG2 expression and sponging miR-668-3p. It was manifested loss of circ_0014717 induced HCC progression, which was reversed by BTG2 in Hep3B cells. In conclusion, our findings illustrated a novel circ_0014717/miR-668-3p/BTG2 regulatory signaling pathway in HCC.
MYCN Function in Neuroblastoma Development
Authors: Otte Jörg , Dyberg Cecilia , Pepich Adena , Johnsen John Inge
Published: January 2021

Dysregulated expression of the transcription factor MYCN is frequently detected in nervous system tumors such as childhood neuroblastoma. Here, gene amplification ofMYCNis a single oncogenic driver inducing neoplastic transformation in neural crest-derived cells. This abnormalMYCNexpression is one of the strongest predictors of poor prognosis. It is present at diagnosis and is never acquired during later tumorigenesis ofMYCNnon-amplified neuroblastoma. This suggests that increasedMYCNexpression is an early event in these cancers leading to a peculiar dysregulation of cells that results in embryonal or cancer stem-like qualities, such as increased self-renewal, apoptotic resistance, and metabolic flexibility.
Look Upstream: Measurement for Innovation on the Upper Rio Negro of the Amazon Basin
Authors: Shaw Kurt , da Silva Rita de Cácia Oenning
Published: January 2021

The growth of the randomized controlled trial (RCT) as the “gold standard” for evaluation has justly been praised as an advance in the professionalization of social programs and projects, an “adoption of science” - in the words of the Lancet. None the less, the emphasis on the RCT biases funding for projects that distribute private goods and which focus on “low hanging fruit” in health, nutrition, and sanitation, simply because those areas lend themselves to the sort of measurement that works with RCTs. As a result, many project developers in the government and NGO sectors lament that a hegemonic focus on RCTs impedes creativity or new models that challenge traditional paradigms. This case study of CanalCanoa, a community video coaching project for indigenous parents of young children in the Rio Negro region of the Amazon Basin, offers techniques to measure for innovation. Instead of developing a new RCT for an extremely diverse population (27 ethnic groups) where traditional childcare methods are in historical flux because of urbanization, CanalCanoa measured variables shown by previous RCTs to be causally connected with positive development results. By researching the impact of the intervention on nutrition, language (multilingualism, use of traditional songs and stories), and social network expansion, CanalCanoa measured upstream indicators, thus mixing scientific rigor with an opportunity for innovation and providing important insight and reform of a theory of change.
Persistent Abnormalities of Fatty Acids Profile in Children With Idiopathic Nephrotic Syndrome in Stable Remission
Authors: Turolo Stefano , Edefonti Alberto C. , Morello William , Syren Marie-Louise , De Cosmi Valentina , Ghio Luciana , Tamburello Chiara , Demarco Erika A. , Berrettini Alfredo , Manzoni Gianantonio , Agostoni Carlo , Montini Giovanni
Published: January 2021

Steroid-sensitive nephrotic syndrome is an immunological disorder mediated by still poorly defined circulating factor(s) that target the podocyte and damage the filtration barrier. Fatty acids (FA) have several biological roles and, in particular, are strictly involved in cell to cell communication, inflammatory processes and regulation of lymphocyte pools. Studies of FAs during INS have been mainly focused on biochemical changes during the phase of proteinuria; while no information is available about FA profile in patients with idiopathic nephrotic syndrome (INS) on stable remission. Aim of this study is to assess differences in blood FA profile between pediatric patients with INS during the phase of stable remission. Blood fatty acid profile of 47 pediatric patients on stable remission and 47 matched healthy controls were evaluated with gas chromatography. Patients with INS on stable remission had significantly higher levels of PUFA and omega-6 than controls (40.17 vs. 37.91% and 36.95 vs. 34.79%), lower levels of SFA and MUFA. Considering the single fatty acids, levels of omega-6 18:2n6 linoleic acid and omega-6 20:4n6 arachidonic acid were significantly higher in patients with INS than in controls (23.01 vs. 21.55%, p-value 0.003 and 10.37 vs. 9.65%, p-value 0.01). Moreover, patients with INS showed lower levels of SFA 14:0 (0.74 vs. 0.92%) and 18:0 (10.74 vs. 11.74%) and MUFA 18:1n9 oleic acid (18.50 vs. 19.83%). To the best of our knowledge this is the first study assessing FAs profile in children with INS in stable remission. In a population of 47 patients, we were able to demonstrate a higher blood level of linoleic and arachidonic acid, and consequently of omega-6 and PUFA, compared to controls. Persistently higher than normal levels of either linoleic or arachidonic acid, could be viewed as candidate biomarker for a state of risk of relapse in children with idiopathic nephrotic syndrome.
Aberrant Auditory Steady-State Response of Awake Mice Induced by Chronic Interferon-α Treatment
Authors: Li Yingzhuo , Wang Xuejiao , Chen Jingyu , Li Zijie , Yang Pingting , Qin Ling
Published: January 2021

Background: Patients receiving the cytokine immunotherapy of interferon-alpha (IFN-α) frequently present with depression. This is one of the excellent models to explore the action of peripheral cytokine on central nervous system (CNS) and to study the development of depression. The auditory steady-state response (ASSR), electroencephalogram (EEG) oscillations induced by periodic acoustic stimulation, is an effective approach to evaluate the neural function in mental illness including depression. The aim of the present study was to investigate the effect of IFN-α on the cortical ASSR and its correlation with depressive-like behavior.

Methods: Chronic electrodes were implanted on the skull over the auditory cortex (AC) of male C57BL/6 mice. The animals were treated with daily injection of IFN-α or saline (vehicle) for three weeks. EEGs were recorded in AC of the same mouse before and after the injection treatment to monitor the changes of ASSR induced by IFN-α. Depressive-like behavior was analyzed in the forced swim test (FST). Immunohistochemical staining was used to examine the status of neuron and glia in the hippocampus and AC.

Results: Compared to pretreatment condition, injection of IFN-α significantly reduced the power of 40 Hz ASSR in the mouse AC from the second week. Such a decrease continued to the third week. The immobility times of FST were significantly increased by a 3-week treatment of IFN-α and the immobility time was negatively correlated with the power of 40 Hz ASSR. Astrocytes and microglia in the hippocampus and AC were activated by IFN-α, but the density of neuron was not significantly affected.

Conclusion: Our results suggest that EEG measurement of ASSR may be used as a biomarker to monitor the CNS side effects of IFN-α treatment and to search a novel intervention with potential therapeutic implications.
Research Advance on Qingfei Paidu Decoction in Prescription Principle, Mechanism Analysis and Clinical Application
Authors: Ren Wei , Ma Yue , Wang Raoqiong , Liang Pan , Sun Qin , Pu Qingrong , Dong Li , Mazhar Maryam , Luo Gang , Yang Sijin
Published: January 2021

Since the sudden epidemic of coronavirus disease 2019 (COVID-19), the State Administration of Traditional Chinese Medicine immediately organized experts to formulate and screen the effective prescriptions of traditional Chinese medicine according to the characteristics of the novel coronavirus infection. Qingfei Paidu decoction (QFPDD) has been proven to be effective in multi-provincial clinical trials, and has been selected as a general prescription for the treatment of COVID-19 in different stages that was later promoted to be used nationwide. This review highlights the latest advances of QFPDD, focusing on the TCM theory, mechanism analysis, clinical application of QFPDD and its future perspectives. Moreover, an in-depth discussion of some valuable issues and possible development for future research on QFPDD is also discussed, aiming to provide a novel guide to combat the global epidemic COVID-19.
RETRACTED: Xianglian Pill Suppresses Inflammation and Protects Intestinal Epithelial Barrier by Promoting Autophagy in DSS Induced Ulcerative Colitis Mice
Authors: Wang Bingyu , Gong Zhiqiang , Zhan Jingyu , Yang Lei , Zhou Quanyu , Yuan Xingxing
Published: January 2021

Xianglian pill (XLP) is a typical traditional Chinese herbal medicine prescription composed of Coptidis Rhizoma and Aucklandiae Radix. It has been used to treat gastrointestinal disease for centuries. In the present study, the potential mechanisms of XLP in the treatment of ulcerative colitis (UC) were predicted by integrative pharmacology-based approach. Then, the main compounds of XLP were detected by liquid chromatography-mass spectrometry (LC-MS/MS). Finally, we verified the mechanism of XLP in the treatment of UC in a dextran sulfate sodium (DSS) model. C57BL/6 mice were randomly divided into the control group, DSS group, 5-aminosalicylic acid (5-ASA) group which was used as the positive drug control, XLP low, medium, and high dose group, with 10 mice per group. Except for the control group, acute colitis model was induced in the other mice by administering 3% DSS for consecutive 7 days. Mice in 5-ASA and XLP groups were administered with 5-ASA (50 mg/kg) or XLP (0.8, 1.6, 3.2 g/kg) via oral gavage once per day respectively. Body wight and disease activity index were assay during drug intervention. On day 8, all animals in this experiment were sacrificed and colon tissues were collected for analysis after measurement of the length. The results showed that XLP alleviate DSS -induced acute colitis in mice, including inhibition the secretion of pro-inflammatory cytokines, repairing the dysfunction of intestinal epithelial barrier, enhanced autophagy, and blocked the activation of PI3K/Akt/mTOR pathway. Furthermore, inhibiting autophagy by 3-methyladenine attenuated the protective effects of XLP on colitis. The underlying mechanism may be that Xianglian pill promote autophagy by blocking the activation of PI3K/Akt/mTOR signaling pathway.
In Silico, In Vitro and In Vivo Pharmacodynamic Characterization of Novel Analgesic Drug Candidate Somatostatin SST4 Receptor Agonists
Authors: Kántás Boglárka , Szőke Éva , Börzsei Rita , Bánhegyi Péter , Asghar Junaid , Hudhud Lina , Steib Anita , Hunyady Ágnes , Horváth Ádám , Kecskés Angéla , Borbély Éva , Hetényi Csaba , Pethő Gábor , Pintér Erika , Helyes Zsuzsanna
Published: January 2021

Background: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via its receptor subtype 4 (SST4) without influencing endocrine functions. Therefore, SST4 is considered to be a novel target for drug development in pain, especially chronic neuropathy which is a great unmet medical need.

Purpose and Experimental Approach: Here, we examined the in silico binding, SST4-linked G protein activation and β-arrestin activation on stable SST4 expressing cells and the effects of our novel pyrrolo-pyrimidine molecules (20, 100, 500, 1,000, 2,000 µg·kg−1) on partial sciatic nerve ligation-induced traumatic mononeuropathic pain model in mice.

Key Results: The novel compounds bind to the high affinity binding site of SST4 the receptor and activate the G protein. However, unlike the reference SST4 agonists NNC 26-9100 and J-2156, they do not induce β-arrestin activation responsible for receptor desensitization and internalization upon chronic use. They exert 65–80% maximal anti-hyperalgesic effects in the neuropathy model 1 h after a single oral administration of 100–500 µg·kg−1 doses.

Conclusion and Implications: The novel orally active compounds show potent and effective SST4 receptor agonism in vitro and in vivo. All four novel ligands proved to be full agonists based on G protein activation, but failed to recruit β-arrestin. Based on their potent antinociceptive effect in the neuropathic pain model following a single oral administration, they are promising candidates for drug development.
Small-Conductance Ca2+-Activated K+ Channels 2 in the Hypothalamic Paraventricular Nucleus Precipitates Visceral Hypersensitivity Induced by Neonatal Colorectal Distension in Rats
Authors: Ji Ning-Ning , Du Lei , Wang Ying , Wu Ke , Chen Zi-Yang , Hua Rong , Zhang Yong-Mei
Published: January 2021

Visceral hypersensitivity is one of the pivotal pathophysiological features of visceral pain in irritable bowel syndrome (IBS). Small-conductance Ca2+-activated K+ channel (SK) is critical for a variety of functions in the central nervous system (CNS), nonetheless, whether it is involved in the pathogenesis of visceral hypersensitivity remain elusive. In this study, we examined mechanism of SK2 in hypothalamic paraventricular nucleus (PVN) in the pathogenesis of visceral hypersensitivity induced by neonatal colorectal distension (CRD). Rats undergoing neonatal CRD presented with visceral hypersensitivity as well as downregulated membrane SK2 channel and p-PKA. Intra-PVN administration of either the membrane protein transport inhibitor dynasore or the SK2 activator 1-EBIO upregulated the expression of membrane SK2 in PVN and mitigated visceral hypersensitivity. In addition, 1-EBIO administration reversed the increase in neuronal firing rates in PVN in rats undergoing neonatal CRD. On the contrary, intra-PVN administration of either the SK2 inhibitor apamin or PKA activator 8-Br-cAMP exacerbated the visceral hypersensitivity. Taken together, these findings demonstrated that visceral hypersensitivity is related to the downregulation of membrane SK2 in PVN, which may be attributed to the activation of PKA; pharmacologic activation of SK2 alleviated visceral hypersensitivity, which brings prospect of SK2 activators as a new intervention for visceral pain.
Integrated Fecal Microbiome and Serum Metabolomics Analysis Reveals Abnormal Changes in Rats with Immunoglobulin A Nephropathy and the Intervention Effect of Zhen Wu Tang
Authors: Li Jicheng , Cao Yiwen , Lu Ruirui , Li Honglian , Pang Yu , Fu Hongxin , Fang Guoxing , Chen Qiuhe , Liu Bihao , Wu Junbiao , Zhou Yuan , Zhou Jiuyao
Published: January 2021

Immunoglobulin A nephropathy (IgAN), an autoimmune renal disease with complicated pathogenesis, is one of the principal reasons for end-stage renal disease in the clinic. Evidence has linked apparent alterations in the components of the microbiome and metabolome to renal disease in rats. However, thus far, there is insufficient evidence that supports the potential relationship between gut microbiome, circulating metabolites, and IgAN. This study was designed to probe the effects of IgAN on intestinal microecology and metabolic phenotypes and to understand the possible underlying mechanisms. Fecal and serum samples were collected from IgAN rats. Composition of the gut microbiota and biochemical changes in the metabolites was analyzed using 16S rDNA sequencing and untargeted metabolomics. The IgAN rats exhibited renal insufficiency and increased concentration of 24-h urine protein, in addition to deposition of IgA and IgG immune complexes in the kidney tissues. There was a disturbance in the balance of gut microbiota in IgAN rats, which was remarkably associated with renal damage. Marked changes in microbial structure and function were accompanied by apparent alterations in 1,403 serum metabolites, associated with the disorder of energy, carbohydrate, and nucleotide metabolisms. Administration of Zhen Wu Tang ameliorated microbial dysbiosis and attenuated the renal damage. Besides, treatment with Zhen Wu Tang modulated the metabolic phenotype perturbation in case of gut microbiota dysbiosis in IgAN rats. In conclusion, these findings provided a comprehensive understanding of the potential relationship between the intestinal microbiota and metabolic phenotypes in rats with IgAN. Elucidation of the intestinal microbiota composition and metabolic signature alterations could identify predictive biomarkers for disease diagnosis and progression, which might contribute to providing therapeutic strategies for IgAN.
Protective Effect of Arbidol Against Pulmonary Fibrosis and Sepsis in Mice
Authors: Li Hailong , Liu Rui , Zhang Ruotong , Zhang Shanshan , Wei Yiying , Zhang Liang , Zhou Honggang , Yang Cheng
Published: January 2021

From the perspective of epidemiology, viral immunology and current clinical research, pulmonary fibrosis may become one of the complications of patients with Coronavirus Disease 2019 (COVID-19). Cytokine storm is a major cause of new coronavirus death. The purpose of this study was to explore the effects of antiviral drug arbidol on cytokine storm and pulmonary fibrosis. Here, we use a mouse model of bleomycin-induced pulmonary fibrosis and a mouse model of fecal dilution-induced sepsis to evaluate the effects of arbidol on pulmonary fibrosis and cytokine storm. The results showed that arbidol significantly reduced the area of pulmonary fibrosis and improved lung function (reduced inspiratory resistance, lung dynamic compliance and forced vital capacity increased). Treatment with arbidol promoted reduced sepsis severity 48 h after sepsis induction, based on weight, murine sepsis score and survival rate. Arbidol observably alleviates inflammatory infiltrates and injury in the lungs and liver. Finally, we also found that arbidol reduced serum levels of pro-inflammatory factors such as TNF-α and IL-6 induced by fecal dilution. In conclusion, our results indicate that arbidol can alleviate the severity of pulmonary fibrosis and sepsis, and provide some reference for the treatment of cytokine storm and sequelae of pulmonary fibrosis in patients with COVID-19.
The Acetylcholine-Activated Potassium Current Inhibitor XAF-1407 Terminates Persistent Atrial Fibrillation in Goats
Authors: Sobota Vladimír , Gatta Giulia , van Hunnik Arne , van Tuijn Iris , Kuiper Marion , Milnes James , Jespersen Thomas , Schotten Ulrich , Verheule Sander
Published: January 2021

Aims: The acetylcholine-activated inward rectifier potassium current (IKACh) has been proposed as an atrial-selective target for the treatment of atrial fibrillation (AF). Using a novel selective IKACh inhibitor XAF-1407, the study investigates the effect of IKACh inhibition in goats with pacing-induced, short-term AF.

Methods: Ten goats (57 ± 5 kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during intravenous infusion of XAF-1407 (0.3, 3.0 mg/kg) in conscious animals before and after 2 days of electrically induced AF. Following a further 2 weeks of sustained AF, cardioversion was attempted with either XAF-1407 (0.3 followed by 3 mg/kg) or with vernakalant (3.7 followed by 4.5 mg/kg), an antiarrhythmic drug that inhibits the fast sodium current and several potassium currents. During a final open chest experiment, 249 unipolar electrograms were recorded on each atrium to construct activation patterns and AF cardioversion was attempted with XAF-1407.

Results: XAF-1407 prolonged atrial effective refractory period by 36 ms (45%) and 71 ms (87%) (0.3 and 3.0 mg/kg, respectively; pacing cycle length 400 ms, 2 days of AF-induced remodeling) and showed higher cardioversion efficacy than vernakalant (8/9 vs. 5/9). XAF-1407 caused a minor decrease in the number of waves per AF cycle in the last seconds prior to cardioversion. Administration of XAF-1407 was associated with a modest increase in QTc (<10%). No ventricular proarrhythmic events were observed.

Conclusion: XAF-1407 showed an antiarrhythmic effect in a goat model of AF. The study indicates that IKACh represents an interesting therapeutic target for treatment of AF. To assess the efficacy of XAF-1407 in later time points of AF-induced remodeling, follow-up studies with longer period of AF maintenance would be necessary.
Berberine Protects Against NLRP3 Inflammasome via Ameliorating Autophagic Impairment in MPTP-Induced Parkinson’s Disease Model
Authors: Huang Shuxuan , Liu Hanqun , Lin Yuwan , Liu Muchang , Li Yanhua , Mao Hengxu , Zhang Zhiling , Zhang Yunlong , Ye Panghai , Ding Liuyan , Zhu Ziting , Yang Xinling , Chen Chaojun , Zhu Xiaoqin , Huang Xiaoyun , Guo Wenyuan , Xu Pingyi , Lu Lin
Published: January 2021

The NLR family pyrin domain containing 3 (NLRP3) inflammasome was reported to be regulated by autophagy and activated during inflammatory procession of Parkinson’s disease (PD). Berberine (BBR) is well-studied to play an important role in promoting anti-inflammatory response to mediate the autophagy activity. However, the effect of Berberine on NLRP3 inflammasome in PD and its potential mechanisms remain unclear. Hence, in this study, we investigated the effects of BBR on 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, by evaluating their behavioral changes, dopaminergic (DA) neurons loss, neuroinflammation, NLRP3 inflammasome and autophagic activity. BBR was also applied in BV2 cells treated with 1-methyl-4-pehnyl-pyridine (MPP+). The autophagy inhibitor 3-Methyladenine (3-MA) was administrated to block autophagy activity both in vivo and in vitro. In our in vivo studies, compared to MPTP group, mice in MPTP + BBR group showed significant amelioration of behavioral disorders, mitigation of neurotoxicity and NLRP3-associated neuroinflammation, enhancement of the autophagic process in substantia nigra (SN). In vitro, compared to MPP+ group, BBR significantly decreased the level of NLRP3 inflammasome including the expressions of NLRP3, PYD and CARD domain containing (PYCARD), cleaved caspase 1 (CASP1), and mature interleukin 1 beta (IL1B), via enhancing autophagic activity. Furthermore, BBR treatment increased the formation of autophagosomes in MPP+-treated BV2 cells. Taken together, our data indicated that BBR prevents NLRP3 inflammasome activation and restores autophagic activity to protect DA neurons against degeneration in vivo and in vitro, suggesting that BBR may be a potential therapeutic to treat PD.
Analgesics for Dental Implants: A Systematic Review
Authors: Melini Matteo , Forni Andrea , Cavallin Francesco , Parotto Matteo , Zanette Gastone
Published: January 2021

Postsurgical pain is commonly associated with dental and oral surgery, and the use of analgesics has been investigated in the management of postoperative pain. This systematic review summarizes available evidence on analgesics used to manage dental implant surgery postoperative pain, to identify best therapeutic protocols and knowledge gap. A comprehensive search was conducted including MEDLINE/Pubmed, EMBASE, SCOPUS, clinicaltrials.gov, and the Cochrane Database of Systematic Reviews through May 2020. Only randomized controlled trials were included. PRISMA guidelines were followed, and risk of bias was appraised using Cochrane RoB2 tool. Eleven trials (762 patients overall) were included. Some aspects limited the feasibility of a meaningful meta-analysis; thus, a narrative synthesis was conducted. Risk of bias was low in four studies and high in two studies, while five studies raised some concerns due to the randomization process. Analgesic use seemed to be associated with improved postoperative outcomes (pain, patient’s satisfaction, and need for rescue medication) when compared to placebo. Overall, this review suggests that the administration of analgesics may provide some advantages in the management of postoperative outcomes after dental implant placement, while indications about the best analgesics cannot be provided.
A Highly Sensitive Time-Gated Fluorescence Immunoassay Platform Using Mn-Doped AgZnInS/ZnS Nanocrystals as Signal Transducers
Authors: Gallian Brandon , Zaeimian Masoumeh Saber , Hau Derrick , AuCoin David , Zhu Xiaoshan
Published: January 2021

In this work, a time-gated immunoassay platform using low-energy excitable and fluorescence long-lived Mn:AgZnInS/ZnS nanocrystals as signal transducers was developed and applied to the detection of the capsular polysaccharide (CPS) of Burkholderia pseudomallei, a Gram-negative bacterium that is the causative agent of melioidosis. CPS is a high molecular weight antigen displayed and is shed from the outer membrane of B. pseudomallei. The immunoassay using the time-gated platform presents a limit of detection at around 23 pg/ml when CPS is spiked in human serum.
Tapping Diversity From the Wild: From Sampling to Implementation
Authors: Hübner Sariel , Kantar Michael B.
Published: January 2021

The diversity observed among crop wild relatives (CWRs) and their ability to flourish in unfavorable and harsh environments have drawn the attention of plant scientists and breeders for many decades. However, it is also recognized that the benefit gained from using CWRs in breeding is a potential rose between thorns of detrimental genetic variation that is linked to the trait of interest. Despite the increased interest in CWRs, little attention was given so far to the statistical, analytical, and technical considerations that should guide the sampling design, the germplasm characterization, and later its implementation in breeding. Here, we review the entire process of sampling and identifying beneficial genetic variation in CWRs and the challenge of using it in breeding. The ability to detect beneficial genetic variation in CWRs is strongly affected by the sampling design which should be adjusted to the spatial and temporal variation of the target species, the trait of interest, and the analytical approach used. Moreover, linkage disequilibrium is a key factor that constrains the resolution of searching for beneficial alleles along the genome, and later, the ability to deplete linked deleterious genetic variation as a consequence of genetic drag. We also discuss how technological advances in genomics, phenomics, biotechnology, and data science can improve the ability to identify beneficial genetic variation in CWRs and to exploit it in strive for higher-yielding and sustainable crops.
Feeling Every Bit of Winter – Distributed Temperature Sensitivity in Vernalization
Authors: Antoniou-Kourounioti Rea L. , Zhao Yusheng , Dean Caroline , Howard Martin
Published: January 2021

Temperature intrinsically influences all aspects of biochemical and biophysical processes. Organisms have therefore evolved strategies to buffer themselves against thermal perturbations. Many organisms also use temperature signals as cues to align behavior and development with certain seasons. These developmentally important thermosensory mechanisms have generally been studied in constant temperature conditions. However, environmental temperature is an inherently noisy signal, and it has been unclear how organisms reliably extract specific temperature cues from fluctuating temperature profiles. In this context, we discuss plant thermosensory responses, focusing on temperature sensing throughout vernalization in Arabidopsis. We highlight many different timescales of sensing, which has led to the proposal of a distributed thermosensing paradigm. Within this paradigm, we suggest a classification system for thermosensors. Finally, we focus on the longest timescale, which is most important for sensing winter, and examine the different mechanisms in which memory of cold exposure can be achieved.
Mirror Neuron Activity During Audiovisual Appreciation of Opera Performance
Authors: Tanaka Shoji
Published: January 2021

Opera is a performing art in which music plays the leading role, and the acting of singers has a synergistic effect with the music. The mirror neuron system represents the neurophysiological mechanism underlying the coupling of perception and action. Mirror neuron activity is modulated by the appropriateness of actions and clarity of intentions, as well as emotional expression and aesthetic values. Therefore, it would be reasonable to assume that an opera performance induces mirror neuron activity in the audience so that the performer effectively shares an embodied performance with the audience. However, it is uncertain which aspect of opera performance induces mirror neuron activity. It is hypothesized that although auditory stimuli could induce mirror neuron activity, audiovisual perception of stage performance is the primary inducer of mirror neuron activity. To test this hypothesis, this study sought to correlate opera performance with brain activity as measured by electroencephalography (EEG) in singers while watching an opera performance with sounds or while listening to an aria without visual stimulus. We detected mirror neuron activity by observing that the EEG power in the alpha frequency band (8–13 Hz) was selectively decreased in the frontal-central-parietal area when watching an opera performance. In the auditory condition, however, the alpha-band power did not change relative to the resting condition. This study illustrates that the audiovisual perception of an opera performance engages the mirror neuron system in its audience.
Amateur and Recreational Athletes’ Motivation to Exercise, Stress, and Coping During the Corona Crisis
Authors: Lautenbach Franziska , Leisterer Sascha , Walter Nadja , Kronenberg Lara , Manges Theresa , Leis Oliver , Pelikan Vincent , Gebhardt Sabrina , Elbe Anne-Marie
Published: January 2021

The COVID-19 pandemic has negatively impacted mobility worldwide. As a corollary, the health of top- and lower-level athletes alike is profoundly reliant on movement and exercise. Thus, the aim of this study is to understand impacts of the COVID-19 pandemic lockdown on athletes’ motivation to exercise and train. In detail, we aim to better understand who (i.e., demographic, sport-specific, and psychological state and trait variables) reported a change in motivation to train due to the lockdown, why they reported lower motivation (i.e., open-ended questions on problems), what they did to help themselves, what support they received from others, and what they are looking forward to after the lockdown (i.e., open questions). Questionnaire data and answers to these open-ended questions were assessed via an online questionnaire, completed by 95 amateur and recreational athletes during the first COVID-19 lockdown in Germany (April to mid-May 2020). Results show that greater numbers of female athletes are less motivated to train in comparison to male athletes (p = 0.029). No differences in motivation were found regarding type of sport (individual vs. team sport) and number of competitions during the year. Also, more motivated to train amateur and recreational athletes showed lower athletic identity than athletes who reported no change in motivation to exercise during the lockdown (p = 0.03). Additionally, differences in state emotional, perceived stress, and personality variables (i.e., orientation to happiness, volition) were found between athletes who stated that they were less motivated to train compared to athletes who reported no changes in motivation. In particular, closure of sports facilities and social distancing measures were perceived to be highly problematic. Even though athletes received emotional support, organized themselves via routines and schedules, and trained using online tools, they predominately stated that they wished that their coaches would have supported them more. Understanding the impacts of a pandemic-related lockdown on athletes’ motivation, athletes’ coping strategies, and their desired support will help better support them in future crises.