bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Gene Expression Profiles, Cytokines, and Bacterial Loads Relevant to Alcoholic Liver Disease Mice Infected With V. vulnificus
Authors: Feng Zi-Han , Li Shi-Qing , Zhang Jia-Xin , Ni Bin , Bai Xin-Ru , Xu Jian-Hao , Liu Zhen-Bo , Xin Wen-Wen , Kang Lin , Gao Shan , Wang Jing , Li Yan-Wei , Li Jia-Xin , Yuan Yuan , Wang Jing-Lin
Published: August 2021

Patients with liver disease are susceptible to infection with Vibrio vulnificus (V. vulnificus), but the specific reasons remain elusive. Through RNA-seq, we found that when mice with alcoholic liver disease (ALD) were infected with V. vulnificus by gavage, compared with the Pair group, the small intestinal genes affecting intestinal permeability were upregulated; and the number of differentially expressed genes related to immune functions (e.g., such as cell chemotaxis, leukocyte differentiation, and neutrophil degranulation) decreased in the liver, spleen, and blood. Further analysis showed that the number of white blood cells decreased in the Pair group, whereas those in the ALD mice did not change significantly. Interestingly, the blood bacterial load in the ALD mice was about 100 times higher than that of the Pair group. After the ALD mice were infected with V. vulnificus, the concentrations of T cell proliferation-promoting cytokines (IL-2, IL-23) decreased. Therefore, unlike the Pair group, ALD mice had weaker immune responses, lower T cell proliferation-promoting cytokines, and higher bacterial loads post-infection, possibly increasing their susceptibility to V. vulnificus infection. These new findings we presented here may help to advance the current understanding of the reasons why patients with liver disease are susceptible to V. vulnificus infection and provides potential targets for further investigation in the context of treatment options for V. vulnificus sepsis in liver disease patient.
Beyond the Driver Mutation: Immunotherapies in Gastrointestinal Stromal Tumors
Authors: Roulleaux Dugage Matthieu , Jones Robin Lewis , Trent Jonathan , Champiat Stéphane , Dumont Sarah
Published: August 2021

Gastrointestinal stromal tumors (GISTs) are a subtype of soft tissue sarcoma (STS), and have become a concept of oncogenic addiction and targeted therapies.The large majority of these tumors develop after a mutation in KIT or platelet derived growth factor receptor α (PDGFRα), resulting in uncontrolled proliferation. GISTs are highly sensitive to imatinib. GISTs are immune infiltrated tumors with a predominance of tumor-associated macrophages (TAMs) and T-cells, including many CD8+ T-cells, whose numbers are prognostic. The genomic expression profile is that of an inhibited Th1 response and the presence of tertiary lymphoid structures and B cell signatures, which are known as predictive to response to ICI. However, the microtumoral environment has immunosuppressive attributes, with immunosuppressive M2 macrophages, overexpression of indoleamine 2,3-dioxygenase (IDO) or PD-L1, and loss of major histocompatibility complex type 1. In addition to inhibiting the KIT oncogene, imatinib appears to act by promoting cytotoxic T-cell activity, interacting with natural killer cells, and inhibiting the expression of PD-L1. Paradoxically, imatinib also appears to induce M2 polarization of macrophages. There have been few immunotherapy trials with anti-CTLA-4 or anti-PD-L1drugs and available clinical data are not very promising. Based on this comprehensive analysis of TME, we believe three immunotherapeutic strategies must be underlined in GIST. First, patients included in clinical trials must be better selected, based on the identified driver mutation (such as PDGFRα D842V mutation), the presence of tertiary lymphoid structures (TLS) or PD-L1 expression. Moreover, innovative immunotherapeutic agents also provide great interest in GIST, and there is a strong rationale for exploring IDO targeting after disease progression during imatinib therapy. Finally and most importantly, there is a strong rationale to combine of c-kit inhibition with immune checkpoint inhibitors.
Tuning the Immunostimulation Properties of Cationic Lipid Nanocarriers for Nucleic Acid Delivery
Authors: Dey Arindam K. , Nougarède Adrien , Clément Flora , Fournier Carole , Jouvin-Marche Evelyne , Escudé Marie , Jary Dorothée , Navarro Fabrice P. , Marche Patrice N.
Published: August 2021

Nonviral systems, such as lipid nanoparticles, have emerged as reliable methods to enable nucleic acid intracellular delivery. The use of cationic lipids in various formulations of lipid nanoparticles enables the formation of complexes with nucleic acid cargo and facilitates their uptake by target cells. However, due to their small size and highly charged nature, these nanocarrier systems can interact in vivo with antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages. As this might prove to be a safety concern for developing therapies based on lipid nanocarriers, we sought to understand how they could affect the physiology of APCs. In the present study, we investigate the cellular and metabolic response of primary macrophages or DCs exposed to the neutral or cationic variant of the same lipid nanoparticle formulation. We demonstrate that macrophages are the cells affected most significantly and that the cationic nanocarrier has a substantial impact on their physiology, depending on the positive surface charge. Our study provides a first model explaining the impact of charged lipid materials on immune cells and demonstrates that the primary adverse effects observed can be prevented by fine-tuning the load of nucleic acid cargo. Finally, we bring rationale to calibrate the nucleic acid load of cationic lipid nanocarriers depending on whether immunostimulation is desirable with the intended therapeutic application, for instance, gene delivery or messenger RNA vaccines.
HCV Cure With Direct-Acting Antivirals Improves Liver and Immunological Markers in HIV/HCV-Coinfected Patients
Authors: Brochado-Kith Óscar , Martínez Isidoro , Berenguer Juan , González-García Juan , Salgüero Sergio , Sepúlveda-Crespo Daniel , Díez Cristina , Hontañón Víctor , Ibañez-Samaniego Luis , Pérez-Latorre Leire , Fernández-Rodríguez Amanda , Ángeles Jiménez-Sousa María , Resino Salvador
Published: August 2021

Hepatitis C virus (HCV) cure after all-oral direct-acting antiviral (DAA) therapy greatly improves the liver and immune system. We aimed to assess the impact of this HCV clearance on immune system-related markers in plasma and the gene expression profile in human immunodeficiency virus (HIV)/HCV-coinfected patients with advanced cirrhosis. We performed a prospective study on 33 HIV/HCV-coinfected patients at baseline and 36 weeks after the sustained virological response. Gene expression was evaluated by RNA-seq analysis on peripheral blood mononuclear cells (PBMCs) and plasma biomarkers by multiplex immunoassays. We found a decrease in plasma biomarkers (PD1, PDL1, CXCL10, CXCL8, IL12p70, IL10, and TGFβ) and liver disease markers (stiffness measurement (LSM), hepatic venous pressure gradient (HVPG), and transaminases, among others). Furthermore, decreased plasma levels of CXCL8, CXCL10, IL10, and PD1 were associated with reduced LSM values. We also found two upregulated (HAS1 and IRG1) and 15 downregulated (CXCL11, CCL8, CCL7, CCL2, ADARB2, RRAD, MX1, SIGLEC1, IFI44L, IFI44, IFI27, IFI6, IFIT3, IFIT1B, and IFIT1) genes at the end of follow-up, all interferon-stimulated genes (ISGs) grouped into four pathways (“cytokine-cytokine receptor interaction”, “viral protein interaction with cytokine and cytokine receptor”, “chemokine signaling pathway”, and “hepatitis C”). Additionally, the decrease in most of these ISGs was significantly related to reduced LSM and HVPG values. In conclusion, HIV/HCV-coinfected patients with advanced-HCV-related cirrhosis who eradicated HCV following DAA therapy exhibited an improvement in liver disease markers and a significant decrease in plasma biomarkers and gene expression related to antiviral/inflammatory response, particularly in levels of several chemokines and ISGs.
Elevated pCO2 Impedes Succession of Phytoplankton Community From Diatoms to Dinoflagellates Along With Increased Abundance of Viruses and Bacteria
Authors: Huang Ruiping , Sun Jiazhen , Yang Yunlan , Jiang Xiaowen , Wang Zhen , Song Xue , Wang Tifeng , Zhang Di , Li He , Yi Xiangqi , Chen Shouchang , Bao Nanou , Qu Liming , Zhang Rui , Jiao Nianzhi , Gao Yahui , Huang Bangqin , Lin Xin , Gao Guang , Gao Kunshan
Published: August 2021

Eutrophic coastal regions are highly productive and greatly influenced by human activities. Primary production supporting the coastal ecosystems is supposed to be affected by progressive ocean acidification driven by increasing CO2 emissions. In order to investigate the effects of high pCO2 (HC) on eutrophic plankton community structure and ecological functions, we employed 9 mesocosms and carried out an experiment under ambient (∼410 ppmv) and future high (1000 ppmv) atmospheric pCO2 conditions, using in situ plankton community in Wuyuan Bay, East China Sea. Our results showed that HC along with natural seawater temperature rise significantly boosted biomass of diatoms with decreased abundance of dinoflagellates in the late stage of the experiment, demonstrating that HC repressed the succession from diatoms to dinoflagellates, a phenomenon observed during algal blooms in the East China Sea. HC did not significantly influence the primary production or biogenic silica contents of the phytoplankton assemblages. However, the HC treatments increased the abundance of viruses and heterotrophic bacteria, reflecting a refueling of nutrients for phytoplankton growth from virus-mediated cell lysis and bacterial degradation of organic matters. Conclusively, our results suggest that increasing CO2 concentrations can modulate plankton structure including the succession of phytoplankton community and the abundance of viruses and bacteria in eutrophic coastal waters, which may lead to altered biogeochemical cycles of carbon and nutrients.
Macrobenthic Assessment of the South Sandwich Islands Reveals a Biogeographically Distinct Polar Archipelago
Authors: Hogg Oliver T. , Downie Anna-Leena , Vieira Rui P. , Darby Chris
Published: August 2021

The sub-Antarctic South Sandwich Islands forms part of one of the largest marine protected areas (MPAs) in the world. Whilst the neighbouring island of South Georgia is known to be a biodiversity hotspot, very little was known about the benthic biodiversity or biogeography of the South Sandwich Islands. Here we present findings from the first biophysical assessment of this polar archipelago. Using open-access datasets, alongside results from a recent UK Government-funder Blue Belt expedition to the region, we assess how the island’s biodiversity is structured spatially and taxonomically and how this is driven by environmental factors. The South Sandwich Islands are shown to be both biologically rich, and biogeographically distinct from their neighbouring provinces. A gradient forest approach was used to map the archipelago’s benthic habitats which, based on the functional composition of benthic fauna and environmental characterisation of the benthic environment, demonstrated a distinct biogeographical north-south divide. This faunal and environmental discontinuity between the South Sandwich Islands and the rest of the MPA and between the different islands of the archipelago itself, highlights the importance of the zoned protection across the South Georgia and South Sandwich Islands Marine Protected Area.
Northern Mid-Atlantic Ridge Hydrothermal Habitats: A Systematic Review of Knowledge Status for Environmental Management
Authors: Boschen-Rose Rachel E. , Colaço Ana
Published: August 2021

Highly specialised biota occurring at hydrothermally active vents on the northern Mid-Atlantic Ridge (nMAR: from south of Iceland to the Equator) have been the subject of numerous research projects over the 36-year period since these habitats were first discovered in the region. When hydrothermal activity ceases, biota endemic to hydrothermally active habitats are lost, and a new biota colonise these sites. Little is known about the biota colonising hydrothermally inactive sulphide habitats on the nMAR, although these sites may be the target of deep-sea mining within the next decade. In this review, we seek to clarify the current knowledge of biological communities colonising hydrothermally active habitats and inactive sulphide habitats on the nMAR. To achieve this, we (1) used a systematic review process to update the species list of benthic invertebrates associated with hydrothermally active habitats, (2) conducted a regional biogeographic analysis of hydrothermally active vent fields on the nMAR, (3) undertook a comprehensive literature review to provide a descriptive account of biological communities, and (4) identified key knowledge gaps in the current understanding of nMAR hydrothermally active and inactive ecosystems. Our updated species list increases the number of benthic invertebrates recorded from hydrothermally active habitats on the nMAR to 158 taxa. Our regional biogeographic analysis separates nMAR hydrothermal vent fields into distinct clusters based on depth/latitude and chimney composition. Vent fields close to the Azores (Menez Gwen, Lucky Strike, Rainbow) formed a separate cluster from those at greater depths south of the Azores (Broken Spur, TAG, Snake Pit, Logatchev, and Ashadze-1). Moytirra, located north of the Azores, clustered separately, as did Lost City with its unique carbonate chimneys. We present detailed information on the biological communities at hydrothermally active and inactive habitats in this region, and discuss the information available on the diversity, ecosystem function, trophic relationships, connectivity, temporal variability, and resilience and recovery of these communities. Many knowledge gaps still exist, with detailed information needed on all aspects of the biological communities at hydrothermally active habitats and inactive sulphide habitats on the nMAR to understand and predict impacts from natural and human-induced disturbances in the region.
Density Decline in a Mediterranean Seahorse Population: Natural Fluctuations or New Emerging Threats?
Authors: Pierri Cataldo , Cardone Frine , Corriero Giuseppe , Lazic Tamara , Quattrocchi Federico , Alabiso Giorgio , Gristina Michele
Published: August 2021

Illegal wildlife trade is considered one of the most serious threats to biodiversity worldwide, along with habitat loss/degradation and overfishing of wild stocks. Seahorses are considered at high risk as these fish represent an important component of traditional Chinese medicine but are also sold as curios and ornamental fish. On a worldwide level, illegal trade is controlled by numerous laws and regulations, but it seems to continue by assuming more dynamic routes. In the Mediterranean Sea, Hippocampus guttulatus formed one of the largest populations at Mar Piccolo di Taranto in South-Eastern Italy. During the routine monitoring of this population in 2016, a dramatic density decrease was observed. By using questionnaires and long-term datasets, the present study determined possible causes of this decline by investigating habitat changes, temperature trends and the existence of seahorse trafficking while also examining abundance trends during the last decade. The results indicated a sharp density decline starting from 2015, co-occurring with the period of high temperatures, while habitats remained almost constant. However, interviews with main stakeholders described both illegal and legal fishing activities as the main drivers for the declining seahorse density. Indeed, at one of the studied sites, which was under strict military control, seahorse abundance started to decline only after the intensification of fishing pressure in the basin. The study suggests that Mar Piccolo di Taranto could be one of the sources for international seahorse trade, thus highlighting the need for more intense and effective actions to prevent and combat illegal poaching, while threatened populations are requiring continuous and close monitoring. Due to unfavorable socio-economic conditions, a viable and thriving seahorse population at Mar Piccolo di Taranto could contribute to the revitalization of the coastal economy and the development of environmental awareness.
The Behavioural Impacts of Commercial Swimming With Whale Tours on Humpback Whales (Megaptera novaeangliae) in Hervey Bay, Australia
Authors: Stack Stephanie H. , Sprogis Kate R. , Olson Grace L. , Sullivan Florence A. , Machernis Abigail F. , Currie Jens J.
Published: August 2021

Swim-with-whale tourism has expanded across several countries globally, with humpback whales (Megaptera novaeangliae) being the most commonly targeted species of baleen whale. Behavioural responses from humpback whales to swim-with-whale tours have been reported, however, responses are likely context-dependent. In 2014, swimming with humpback whales began in Hervey Bay, Queensland, Australia, an important resting ground and migratory stopover for humpback whales. The behavioural responses of humpback whales to this swim-with-whale industry have not been examined in Queensland, preventing informed management of this industry. The aims of this study were to: (1) examine short-term behavioural responses in whalesbefore, during, andafterswim-with-whale tours, and (2) investigate behavioural responses of whales throughout swim-with-whale tours compared to whale watch tours. Data were collected on board a commercial vessel, wherebefore, duringandafterdata were collected during swim-with-whale tours (250 h) and whale watch tours (150 h). Within the swim-with-whale tours, behavioural changes were detectedbefore, during, andafterthe vessel approached and placed swimmers in the water on a mermaid line, with the majority of significant changes occurring in theduringandafterphases. The number of direction changes made by the whales was highest when swimmers were in the water and the whales did not resume undisturbed behaviour after the swimmers exited the water. There was a 50% reduction in the proportion of time that whales spent resting during swim-tours compared to during whale watch tours. In both tour types, the time spent engaging in various behaviours was impacted by the distance between the vessel and the whale(s). These results support the conclusion that the behaviour of humpback whales in Hervey Bay was altered in response to swim-with-whale tourism. As humpback whales are capital breeders with limited energy reserves, reducing disturbance to them is of high importance for their continued population recovery and for the sustainability of the marine tourism industry. In Australia, where swim-with-whale tourism is becoming more established, robust education and enforcement programs, combined with continued monitoring of population dynamics through scientific research, are needed to minimise impacts to the population and guide adaptive management strategies.
The Effect of Ryegrass Silage Feeding on Equine Fecal Microbiota and Blood Metabolite Profile
Authors: Zhu Yiping , Wang Xuefan , Liu Bo , Yi Ziwen , Zhao Yufei , Deng Liang , Holyoak Reed , Li Jing
Published: August 2021

Silage is fed to horses in China and other areas in the world, however, knowledge about the impact of feeding silage on horse health is still limited. In the current study, 12 horses were assigned into two groups and fed ryegrass silage and ryegrass hay, respectively, for 8 weeks. High-throughput sequencing was applied to analyze fecal microbiota, while liquid chromatography–tandem mass spectrometry (LC–MS/MS) based metabolomics technique was used for blood metabolite profile to investigate the influence of feeding ryegrass silage (group S) compared to feeding ryegrass hay (group H) on equine intestinal and systemic health. Horses in group S had significantly different fecal microbiota and blood metabolomes from horses in group H. The results showed that Verrucomicrobia was significantly less abundant which plays important role in maintaining the mucus layer of the hindgut. Rikenellaceae and Christensenellaceae were markedly more abundant in group S and Rikenellaceae may be associated with some gut diseases and obesity. The metabolomics analysis demonstrated that ryegrass silage feeding significantly affected lipid metabolism and insulin resistance in horses, which might be associated with metabolic dysfunction. Furthermore, Pearson’s correlation analysis revealed some correlations between bacterial taxa and blood metabolites, which added more evidence to diet-fecal microbiota-health relationship. Overall, ryegrass silage feeding impacted systemic metabolic pathways in horses, especially lipid metabolism. This study provides evidence of effects of feeding ryegrass silage on horses, which may affect fat metabolism and potentially increase risk of insulin resistance. Further investigation will be promoted to provide insight into the relationship of a silage-based diet and equine health.
Possible Immunotherapeutic Strategies Based on Carcinogen-Dependent Subgroup Classification for Oral Cancer
Authors: Sun Jiwei , Tang Qingming , Zhang Junyuan , Chen Guangjin , Peng Jinfeng , Chen Lili
Published: August 2021

The oral cavity serves as an open local organ of the human body, exposed to multiple external factors from the outside environment. Coincidentally, initiation and development of oral cancer are attributed to many external factors, such as smoking and drinking, to a great extent. This phenomenon was partly explained by the genetic abnormalities traditionally induced by carcinogens. However, more and more attention has been attracted to the influence of carcinogens on the local immune status. On the other hand, immune heterogeneity of cancer patients is a huge obstacle for enhancing the clinical efficacy of tumor immunotherapy. Thus, in this review, we try to summarize the current opinions about variant genetic changes and multiple immune alterations induced by different oral cancer carcinogens and discuss the prospects of targeted immunotherapeutic strategies based on specific immune abnormalities caused by different carcinogens, as a predictive way to improve clinical outcomes of immunotherapy-treated oral cancer patients.
Pericyte Contractile Responses to Endothelin-1 and Aβ Peptides: Assessment by Electrical Impedance Assay
Authors: Hibbs Elliott , Love Seth , Miners J. Scott
Published: August 2021

Pericytes are vascular mural cells that contract and relax in response to vasoactive stimuli to regulate neurovascular coupling and cerebral blood flow. Pericytes are damaged and degenerate in Alzheimer’s disease (AD). We previously showed that the level of the regulatory vasoconstrictor, endothelin-1 (EDN1), is elevated in AD cerebral cortex and upregulated by amyloid-beta (Aβ). We have used electrical impedance analysis to monitor the contractile and proliferative response of cultured human fetal and adult brain-derived pericytes to EDN1 in real-time. EDN1 caused transient, dose-dependent contraction of fetal and adult brain pericytes that was mediated by EDN1 type A receptors and increased the subsequent proliferation of fetal but not adult cells. The contractile responses to EDN1 were weaker in the adult pericytes. The EDN1-mediated contractile response of fetal pericytes was unchanged after exposure to Aβ1–40 or Aβ1–42 (0.1–10 μM) for 1 h but both contraction and subsequent relaxation were significantly impaired upon exposure to Aβ for 24 h. These data suggest that chronic exposure to Aβ interferes with EDN1-mediated pericyte contractility, potentially contributing to neurovascular uncoupling and reduced cerebral blood flow in AD.
Research Progress on the Mechanism of Cochlear Hair Cell Regeneration
Authors: Xu Shan , Yang Ning
Published: August 2021

Mammalian inner ear hair cells do not have the ability to spontaneously regenerate, so their irreversible damage is the main cause of sensorineural hearing loss. The damage and loss of hair cells are mainly caused by factors such as aging, infection, genetic factors, hypoxia, autoimmune diseases, ototoxic drugs, or noise exposure. In recent years, research on the regeneration and functional recovery of mammalian auditory hair cells has attracted more and more attention in the field of auditory research. How to regenerate and protect hair cells or auditory neurons through biological methods and rebuild auditory circuits and functions are key scientific issues that need to be resolved in this field. This review mainly summarizes and discusses the recent research progress in gene therapy and molecular mechanisms related to hair cell regeneration in the field of sensorineural hearing loss.
Brain Function Network: Higher Order vs. More Discrimination
Authors: Guo Tingting , Zhang Yining , Xue Yanfang , Qiao Lishan , Shen Dinggang
Published: August 2021

Brain functional network (BFN) has become an increasingly important tool to explore individual differences and identify neurological/mental diseases. For estimating a “good” BFN (with more discriminative information for example), researchers have developed various methods, in which the most popular and simplest is Pearson's correlation (PC). Despite its empirical effectiveness, PC only encodes the low-order (second-order) statistics between brain regions. To model high-order statistics, researchers recently proposed to estimate BFN by conducting two sequential PCs (denoted as PC2 in this paper), and found that PC2-based BFN can provide additional information for group difference analysis. This inspires us to think about (1) what will happen if continuing the correlation operation to construct much higher-order BFN by PCn (n>2), and (2) whether the higher-order correlation will result in stronger discriminative ability. To answer these questions, we use PCn-based BFNs to predict individual differences (Female vs. Male) as well as identify subjects with mild cognitive impairment (MCI) from healthy controls (HCs). Through experiments, we have the following findings: (1) with the increase of n, the discriminative ability of PCn-based BFNs tends to decrease; (2) fusing the PCn-based BFNs (n>1) with the PC1-based BFN can generally improve the sensitivity for MCI identification, but fail to help the classification accuracy. In addition, we empirically find that the sequence of BFN adjacency matrices estimated by PCn (n = 1,2,3,⋯ ) will converge to a binary matrix with elements of ± 1.
Dynamics of Visual Adaptation With Simultaneous Stimulation of Two Visual Pathways
Authors: Paz-Filgueira Clemente , Tan Michael , Elliott Sarah , Cao Dingcai
Published: August 2021

Primates’ retinal ganglion cells in different visual pathways have been shown to adapt independently (Current Biology 22 (2012) 220–224). However, the manner in which adaptation occurs under simultaneous stimulation of two visual pathways has not yet been explored. In this study, the dynamics of color afterimages were measured while stimulating one or two visual pathway using a time-varying afterimage paradigm. The dynamics of adaptation was approximately equivalent among the three primary visual pathways, but adaptation was slower for simultaneous stimulation of two visual pathways compared to the stimulation of one visual pathway. In addition, we found that the speed of adaptation also depends upon which two pathways are combined. We developed a two-stage adaptation model, both with the same dynamics, to account for the results with simultaneous stimulation of two pathways.
Social Cognition in Patients With Cerebellar Neurodegenerative Disorders
Authors: Tamaš Olivera , Kostić Milutin , Kačar Aleksandra , Stefanova Elka , Ðokić Biljana Salak , Stanisavljević Dejana , Milovanović Andona , Ðorđević Mirjana , Glumbić Nenad , Dragašević-Mišković Nataša
Published: August 2021

Objective

Cerebellar neurodegenerative disorders (CDs) are a heterogeneous group of disorders. It is known that the cerebellum plays a role not only in motor, but also in cognitive and social cognitive functions. The aim of this study was to investigate social cognition in patients with different CDs.

Materials and Methods

Social cognition was examined in 34 patients, 12 with spinocerebellar ataxia type 1 (SCA1), 6 with spinocerebellar ataxia type 2 (SCA2), and 16 with idiopathic late onset cerebellar ataxia (ILOCA). All patients were clinically evaluated using the Scale for the Rating and Assessment of Ataxia. In addition, 34 age, sex, and education-matched healthy control (HC) subjects were similarly analyzed. Social cognition was studied using two tests: the Faux Pas Recognition Test and the Reading the Mind in the Eyes Test (RMET). An appropriate array of neuropsychological tests was used to assess the global cognitive status as well as the frontal functions and mood.

Results

CD patients achieved significantly worse results on both tests of social cognition compared to the HCs. The SCA1 + 2 group achieved the poorest results on the Faux Pas Recognition Test and exhibited poor performance on all cognitive tests, but was only significantly worse compared to the ILOCA group on the Free and Cued Selective Reminding Test (FCSRT) – recognition. The patients in the SCA1 + 2 and ILOCA groups obtained similar scores on RMET. In the SCA1 + 2 group the findings significantly correlated with clinical parameters of disease severity and duration and executive functions (EFs), and with mood and executive functions in the ILOCA group. In the SCA group EFs appeared as the only significant predictor of RMET achievement. The Boston Naming Test (BTN) was a significant predictor of the CD patients’ achievement on RMET, while the BTN, the Trail Making Test Part A and FCSRT – Delayed free recall predicted their performance on the Faux Pas Recognition Test.

Conclusion

Patients with CD have social cognitive impairments as demonstrated by the Faux Pas Test and the RMET test results. The SCA1 and 2 patients exhibited a more pronounced impairment compared with the ILOCA patients. The independent cognitive predictors of social cognition impairment were EFs and language.
Lifestyle Changes Related to Eating Habits, Physical Activity, and Weight Status During COVID-19 Quarantine in Italy and Some European Countries
Authors: Catucci Arianna , Scognamiglio Umberto , Rossi Laura
Published: August 2021

Novel human coronavirus disease (COVID-19), an infectious respiratory disease, has affected more than 50 million people around the world up to November 2020, thereby becoming the fifth documented pandemic since the Spanish flu in 1918. SARS-CoV-2 virus originated in China and evolved for 4 months within the country before becoming a global threat. There is currently no drug approved by the Food and Drug Administration (FDA) for which efficacy on the virus has been proved. Therefore, the only strategy against this virus is to apply measures that are capable of reducing its spread, such as isolation and quarantine, social distancing, community-wide containment, and strict enforcement of hygiene. Quarantine has proved to be effective in combating the spread of the virus; however, it has inevitably led to a radical change in the lives of people. Studies have been conducted in Italy and some European countries to highlight the role that quarantine has played in determining the lifestyle changes both in eating habits and physical activity and their possible correlation with increase in weight. The selection criteria involved answering a questionnaire that included information on the weight status and at least one of the other two aspects: changes in eating habits and/or physical activity during the quarantine period. The results obtained indicate, in general, that the negative effect of quarantine was on eating habits and physical activity. This was based on the observation that there has been an increase in food consumption and a reduction in physical activity with a consequent increase in weight.
The Combined Treatment With the FLT3-Inhibitor AC220 and the Complex I Inhibitor IACS-010759 Synergistically Depletes Wt- and FLT3-Mutated Acute Myeloid Leukemia Cells
Authors: Lu Xiyuan , Han Lina , Busquets Jonathan , Collins Meghan , Lodi Alessia , Marszalek Joseph R. , Konopleva Marina , Tiziani Stefano
Published: August 2021

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a high mortality rate and relapse risk. Although progress on the genetic and molecular understanding of this disease has been made, the standard of care has changed minimally for the past 40 years and the five-year survival rate remains poor, warranting new treatment strategies. Here, we applied a two-step screening platform consisting of a primary cell viability screening and a secondary metabolomics-based phenotypic screening to find synergistic drug combinations to treat AML. A novel synergy between the oxidative phosphorylation inhibitor IACS-010759 and the FMS-like tyrosine kinase 3 (FLT3) inhibitor AC220 (quizartinib) was discovered in AML and then validated by ATP bioluminescence and apoptosis assays. In-depth stable isotope tracer metabolic flux analysis revealed that IACS-010759 and AC220 synergistically reduced glucose and glutamine enrichment in glycolysis and the TCA cycle, leading to impaired energy production and de novo nucleotide biosynthesis. In summary, we identified a novel drug combination, AC220 and IACS-010759, which synergistically inhibits cell growth in AML cells due to a major disruption of cell metabolism, regardless of FLT3 mutation status.
Targeted Therapy for RET Fusion Lung Cancer: Breakthrough and Unresolved Issue
Authors: Takamori Shinkichi , Matsubara Taichi , Haratake Naoki , Toyokawa Gouji , Fujishita Takatoshi , Toyozawa Ryo , Ito Kensaku , Yamaguchi Masafumi , Taguchi Kenichi , Okamoto Tatsuro , Seto Takashi
Published: August 2021

Molecular drugs targeting mutated or rearranged oncogene drivers have become one of the standard recognized treatments in patients with advanced and recurrent non-small cell lung cancer. RET is located in the long arm of human chromosome 10 and encodes a receptor tyrosine kinase protein, and RET fusion-positive lung adenocarcinoma occurs in 1%–2% of cases. Clinical trials of multikinase inhibitors, including cabozantinib, vandetanib, sorafenib, and lenvatinib, that inhibit RET oncogene activity have shown their antitumor efficacy. Recently, RET inhibitors such as pralsetinib and selpercatinib that are specialized for RET kinase have also been developed, and their efficacy was investigated in previous clinical trials (BLU-667 and LOXO-292). In this review, we summarized the effects and adverse events of multikinase and selective RET inhibitors and the various diagnostic techniques for RET gene fusion. In the perspective part, we focused on the unsolved issues on treatment for RET fusion-positive lung cancer and future developments.
Anti-Thymocyte Globulin Prophylaxis in Patients With Hematological Malignancies Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: An Updated Meta-Analysis
Authors: Yang Xue , Li Dongjun , Xie Yao
Published: August 2021

Background

Anti-thymocyte globulin (ATG) prophylaxis reduces graft-versus-host disease (GVHD) incidence. This meta-analysis aimed to explore the long-term efficacy of ATG and the influencing factors in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Methods

PubMed, Embase, and Cochrane databases were searched for the relevant studies published up to August 2020. Data from randomized controlled trials (RCTs) on ATG prophylaxis for GVHD prevention in allo-HSCT patients were extracted.

Results

A total of eight relevant RCTs (1,348 patients) were included. ATG significantly reduced the incidence of grade III–IV aGVHD (P = 0.001) and cGVHD (P < 0.001). ATG significantly improved the GVHD relapse-free survival (GRFS) (P < 0.001). The immunosuppressive regimen (number and dose of immunosuppressants) was significantly reduced when using ATG (P = 0.005). Epstein-Barr virus (EBV) reactivation was high in patients receiving ATG (P = 0.003). No significant differences were detected in relapses, overall survival (OS), relapse-free survival (RFS), and non-relapse mortality (NRM) between the ATG and no ATG groups. Subgroup analyses revealed that the donor type and ATG formulation might be the possible sources of heterogeneity among the included studies. Meta-regression analysis showed that the cumulative dose of ATG did not affect GVHD, OS, relapse, RFS, and NRM.

Conclusion

Although ATG had no significant effect on relapse, RFS, and NRM, it significantly reduced the occurrence and severity of GVHD, improved the GRFS, and reduced the number and dose of immunosuppressants in patients undergoing allo-HSCT.
An Analysis Based on Molecular Docking and Molecular Dynamics Simulation Study of Bromelain as Anti-SARS-CoV-2 Variants
Authors: Tallei Trina Ekawati , Fatimawali  , Yelnetty Afriza , Idroes Rinaldi , Kusumawaty Diah , Emran Talha Bin , Yesiloglu Talha Zahid , Sippl Wolfgang , Mahmud Shafi , Alqahtani Taha , Alqahtani Ali M. , Asiri Saeed , Rahmatullah Mohammed , Jahan Rownak , Khan Md. Arif , Celik Ismail
Published: August 2021

The rapid spread of a novel coronavirus known as SARS-CoV-2 has compelled the entire world to seek ways to weaken this virus, prevent its spread and also eliminate it. However, no drug has been approved to treat COVID-19. Furthermore, the receptor-binding domain (RBD) on this viral spike protein, as well as several other important parts of this virus, have recently undergone mutations, resulting in new virus variants. While no treatment is currently available, a naturally derived molecule with known antiviral properties could be used as a potential treatment. Bromelain is an enzyme found in the fruit and stem of pineapples. This substance has been shown to have a broad antiviral activity. In this article, we analyse the ability of bromelain to counteract various variants of the SARS-CoV-2 by targeting bromelain binding on the side of this viral interaction with human angiotensin-converting enzyme 2 (hACE2) using molecular docking and molecular dynamics simulation approaches. We have succeeded in making three-dimensional configurations of various RBD variants using protein modelling. Bromelain exhibited good binding affinity toward various variants of RBDs and binds right at the binding site between RBDs and hACE2. This result is also presented in the modelling between Bromelain, RBD, and hACE2. The molecular dynamics (MD) simulations study revealed significant stability of the bromelain and RBD proteins separately up to 100 ns with an RMSD value of 2 Å. Furthermore, despite increases in RMSD and changes in Rog values of complexes, which are likely due to some destabilized interactions between bromelain and RBD proteins, two proteins in each complex remained bonded, and the site where the two proteins bind remained unchanged. This finding indicated that bromelain could have an inhibitory effect on different SARS-CoV-2 variants, paving the way for a new SARS-CoV-2 inhibitor drug. However, morein vitroandin vivoresearch on this potential mechanism of action is required.
Case Report: Rehabilitation After Platelet-Rich Growth Factors’ Intra-Articular Injections for Knee Osteoarthritis: Two Case Reports of a Home-Based Protocol
Authors: Negrini Francesco , De Lucia Francesco , Negrini Stefano , Tornese Davide , Facchini Francesca , Vecchio Michele , de Girolamo Laura
Published: August 2021

Knee osteoarthritis (KOA) is a chronic progressive disease that can cause pain, functional impairment, and ultimately disability. A novel and promising therapeutic approach to KOA is the so-called regenerative medicine, a set of procedures designed to harness tissue regenerative capacity and optimize functional recovery. Increasing evidence points out that platelet-rich plasma (PRP) intra-articular injections can decrease pain and improve functional abilities in KOA patients. In the present case reports, we analyze two patients who were treated with PRP injections coupled with a posttreatment home-based rehabilitation program. The two patients were selected to represent two different populations: patient 1 was an 85-year-old with severe impairment of functional abilities, while patient 2 was a younger (59 years old) and more active patient. The protocol consisted in a series of exercise to be performed at home, during the five days following PRP injection for two consecutive weeks (10 days in total). The exercises were designed to reduce the inflammation after the injection, enhance the proprioceptive control of the treated lower limb, and strengthen hip and knee flexors and extensors, mainly by isometric work. Results were evaluated at two time points: before and 2 months after the first PRP injection. The outcomes considered were as follows: visual analog scale for pain, EuroQol 5 dimensions questionnaire, Tegner Activity Scale for functioning, and Knee Injury and Osteoarthritis Outcome Score (KOOS). Both patients did not report any side effects from the treatment. Improvement in patient 1 was drastic at the two months follow-up as far as pain and functional abilities are concerned. Patient 2’s improvement was less evident, probably due to the higher starting point in both pain and functionality. Overall, the developed program seemed safe and was tolerated by the patients analyzed in the study, who performed it with good compliance.
Chimeric Antigen Receptor-T Cells: A Pharmaceutical Scope
Authors: Hernández-López Alejandrina , Téllez-González Mario A. , Mondragón-Terán Paul , Meneses-Acosta Angélica
Published: August 2021

Cancer is among the leading causes of death worldwide. Therefore, improving cancer therapeutic strategies using novel alternatives is a top priority on the contemporary scientific agenda. An example of such strategies is immunotherapy, which is based on teaching the immune system to recognize, attack, and kill malignant cancer cells. Several types of immunotherapies are currently used to treat cancer, including adoptive cell therapy (ACT). Chimeric Antigen Receptors therapy (CAR therapy) is a kind of ATC where autologous T cells are genetically engineered to express CARs (CAR-T cells) to specifically kill the tumor cells. CAR-T cell therapy is an opportunity to treat patients that have not responded to other first-line cancer treatments. Nowadays, this type of therapy still has many challenges to overcome to be considered as a first-line clinical treatment. This emerging technology is still classified as an advanced therapy from the pharmaceutical point of view, hence, for it to be applied it must firstly meet certain requirements demanded by the authority. For this reason, the aim of this review is to present a global vision of different immunotherapies and focus on CAR-T cell technology analyzing its elements, its history, and its challenges. Furthermore, analyzing the opportunity areas for CAR-T technology to become an affordable treatment modality taking the basic, clinical, and practical aspects into consideration.
Dual Negative Differential of Heat Generation in a Strongly Correlated Quantum Dot Side-Coupled to Majorana Bound States
Authors: Wang Zhu-Hua , Huang Wen-Cheng
Published: August 2021

We study theoretically the properties of local heat originated from energy exchange between electrons passing through a quantum dot (QD) coupled to a phonon bath. The dot is sandwiched between two normal metal leads and also side-coupled to Majorana bound states (MBSs) formed at opposite ends of a topological superconductor nanowire. We find that in addition to the negative differential of heat generation (NDHG) in the Coulomb blockade regime, another NDHG emerges near the leads’ Fermi level due to the dot-MBS coupling. This dual NDHG effect is robust against the variation of intradot Coulomb interaction strength, and disappears if the QD is coupled to regular Fermions. Direct hybridization between the MBSs reduces their impacts on the electronic transport processes, and eliminates the dual NDHG effect. Our results show that the dual NDHG effect is quite efficient for inferring the existence of MBSs, and may remedy some limitations of the detection schemes relying on tunneling spectroscopy technique.
Effect of Different Extraction Methods on the Quality and Biochemical Attributes of Pomegranate Juice and the Application of Fourier Transformed Infrared Spectroscopy in Discriminating Between Different Extraction Methods
Authors: Arendse Ebrahiema , Nieuwoudt Helene , Fawole Olaniyi Amos , Opara Umezuruike Linus
Published: August 2021

This study investigated the effects of extraction methods on the physicochemical, phytochemical, and antioxidant properties of pomegranate juice (cv. Wonderful). In addition, the application of attenuated total reflectance Fourier transformed mid-infrared (ATR-FT-MIR) spectroscopy and chemometrics were explored in order to discriminate between different extraction methods. Juice variants evaluated included juice extracted without crushing the seeds (arils only) using a juice extractor (JE), juice extracted by crushing the seeds using a blender (arils plus seed) (JB), and juice extracted from half fruit using a commercial hand press juicer (CH). Juice extracted from CH had higher total soluble solid (TSS) content (18.20%), TSS/TA ratio (15.83), and color properties (a* = 32.67, b* = 11.80, C* = 34.77) compared with extraction methods JE and JB. The juice extracted from JB showed the highest titratable acidity (2.17%), cloudiness (0.43), and lowest pH value (2.69). The total phenolics and anthocyanin content in the investigated juice ranged from 1.87 to 3.04 g gallic acid equivalent (GAE)/L and 37.74–43.67 mg cyanidin 3-glucoside equivalent/L of crude juice, respectively. Juice extracted from JB and CH was significantly higher in phenolic and anthocyanin compared with JE. Orthogonal partial least squares discriminant analysis (OPLS-DA) and principal component analysis (PCA) were used for classification. Classification accuracy of 100% was achieved between the three methods. The S-line plot revealed that the corresponding wavelength bands within the following regions 1,090, 1,250, 1,750, and 3,200 cm−1 were responsible for discrimination between the different extraction methods. Our results suggest that the main contributor to the discrimination between extraction methods were TSS, TSS/TA, color attributes, and anthocyanin content. Overall, this study has demonstrated that ATR-FT-MIR spectroscopy provides a powerful way to discriminate between juice extraction methods.