bluuebunny/crossref_metadata_2025 huggingface dataset:
Grassification and Fast-Evolving Fire Connectivity and Risk in the Sonoran Desert, United States
Authors: Wilder Benjamin T. , Jarnevich Catherine S. , Baldwin Elizabeth , Black Joseph S. , Franklin Kim A. , Grissom Perry , Hovanes Katherine A. , Olsson Aaryn , Malusa Jim , Kibria Abu S.M.G. , Li Yue M. , Lien Aaron M. , Ponce Alejandro , Rowe Julia A. , Soto José R. , Stahl Maya R. , Young Nicholas E. , Betancourt Julio L.
Published: October 2021

In the southwestern United States, non-native grass invasions have increased wildfire occurrence in deserts and the likelihood of fire spread to and from other biomes with disparate fire regimes. The elevational transition between desertscrub and montane grasslands, woodlands, and forests generally occurs at ∼1,200 masl and has experienced fast suburbanization and an expanding wildland-urban interface (WUI). In summer 2020, the Bighorn Fire in the Santa Catalina Mountains burned 486 km2and prompted alerts and evacuations along a 40-km stretch of WUI below 1,200 masl on the outskirts of Tucson, Arizona, a metropolitan area of >1M people. To better understand the changing nature of the WUI here and elsewhere in the region, we took a multidimensional and timely approach to assess fire dynamics along the Desertscrub-Semi-desert Grassland ecotone in the Catalina foothills, which is in various stages of non-native grass invasion. The Bighorn Fire was principally a forest fire driven by a long-history of fire suppression, accumulation of fine fuels following a wet winter and spring, and two decades of hotter droughts, culminating in the hottest and second driest summer in the 125-yr Tucson weather record. Saguaro (Carnegia gigantea), a giant columnar cactus, experienced high mortality. Resprouting by several desert shrub species may confer some post-fire resiliency in desertscrub. Buffelgrass and other non-native species played a minor role in carrying the fire due to the patchiness of infestation at the upper edge of the Desertscrub biome. Coupled state-and-transition fire-spread simulation models suggest a marked increase in both burned area and fire frequency if buffelgrass patches continue to expand and coalesce at the Desertscrub/Semi-desert Grassland interface. A survey of area residents six months after the fire showed awareness of buffelgrass was significantly higher among residents that were evacuated or lost recreation access, with higher awareness of fire risk, saguaro loss and declining property values, in that order. Sustained and timely efforts to document and assess fast-evolving fire connectivity due to grass invasions, and social awareness and perceptions, are needed to understand and motivate mitigation of an increasingly fire-prone future in the region.
Genetic and Epigenetic Impact of Chronic Inflammation on Colon Mucosa Cells
Authors: He Jia , Han Jimin , Liu Jia , Yang Ronghua , Wang Jingru , Wang Xusheng , Chen Xiaodong
Published: October 2021

Chronic inflammation increases cancer risk, and cancer development is characterized by stepwise accumulation of genetic and epigenetic alterations. During chronic inflammation, infectious agents and intrinsic mediators of inflammatory responses can induce genetic and epigenetic changes. This study tried to evaluate both the genetic and epigenetic influence of chronic inflammation on colon mucosa cells. Repetitive dextran sulfate sodium (DSS) treatment induced chronic colitis model. Whole-exome sequencing (WES) (200× coverage) was performed to detect somatic variations in colon mucosa cells. With the use of whole-genome bisulfite sequencing (BS) at 34-fold coverage (17-fold per strand), the methylome of both the colitis and control tissue was comparatively analyzed. Bioinformatics assay showed that there was no significant single-nucleotide polymorphism/insertion or deletion (SNP/InDel) mutation accumulation in colitis tissue, while it accumulated in aged mice. Forty-eight genes with SNP/InDel mutation were overlapped in the three colitis tissues, two (Wnt3a and Lama2) of which are in the cancer development-related signaling pathway. Differentially methylated region (DMR) assay showed that many genes in the colitis tissue are enriched in the cancer development-related signaling pathway, such as PI3K–AKT, Ras, Wnt, TGF-beta, and MAPK signaling pathway. Together, these data suggested that even though chronic inflammation did not obviously increase genetic mutation accumulation, it could both genetically and epigenetically alter some genes related to cancer development.
Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases
Authors: Zhou Danlei , Rudnicki Michael , Chua Gilbert T. , Lawrance Simon K. , Zhou Bi , Drew Joanne L. , Barbar-Smiley Fatima , Armstrong Taylor K. , Hilt Miranda E. , Birmingham Daniel J. , Passler Werner , Auletta Jeffrey J. , Bowden Sasigarn A. , Hoffman Robert P. , Wu Yee Ling , Jarjour Wael N. , Mok Chi Chiu , Ardoin Stacy P. , Lau Yu Lung , Yu Chack Yung
Published: October 2021

Human complement C4 is one of the most diverse but heritable effectors for humoral immunity. To help understand the roles of C4 in the defense and pathogenesis of autoimmune and inflammatory diseases, we determined the bases of polymorphisms including the frequent genetic deficiency of C4A and/or C4B isotypes. We demonstrated the diversities of C4A and C4B proteins and their gene copy number variations (CNVs) in healthy subjects and patients with autoimmune disease, such as type 1 diabetes, systemic lupus erythematosus (SLE) and encephalitis. We identified subjects with (a) the fastest migrating C4B allotype, B7, or (b) a deficiency of C4B protein caused by genetic mutation in addition to gene copy-number variation. Those variants and mutants were characterized, sequenced and specific techniques for detection developed. Novel findings were made in four case series. First, the amino acid sequence determinant for C4B7 was likely the R729Q variation at the anaphylatoxin-like region. Second, in healthy White subject MS630, a C-nucleotide deletion at codon-755 led to frameshift mutations in his singleC4Bgene, which was a private mutation. Third, in European family E94 with multiplex lupus-related mortality and low serum C4 levels, the culprit was a recurrent haplotype withHLA-A30, B18andDR7that segregated with two defectiveC4Bgenes and identical mutations at the donor splice site of intron-28. Fourth, in East-Asian subject E133P with anti-NMDA receptor encephalitis, theC4Bgene had a mutation that changed tryptophan-660 to a stop-codon (W660x), which was present in a haplotype withHLA-DRB1*04:06andB*15:27. The W660x mutation is recurrent among East-Asians with a frequency of 1.5% but not detectable among patients with SLE. A meticulous annotation ofC4sequences revealed clusters of variations proximal to sites for protein processing, activation and inactivation, and binding of interacting molecules.
Pharmacological Activation Of Aldehyde Dehydrogenase 2 Protects Against Heatstroke-Induced Acute Lung Injury by Modulating Oxidative Stress and Endothelial Dysfunction
Authors: Tsai Hsiao-Ya , Hsu Yu-Juei , Lu Cheng-Yo , Tsai Min-Chien , Hung Wan-Chu , Chen Po-Chuan , Wang Jen-Chun , Hsu Lung-An , Yeh Yung-Hsin , Chu Pauling , Tsai Shih-Hung
Published: October 2021

Heatstroke (HS) can cause acute lung injury (ALI). Heat stress induces inflammation and apoptosis via reactive oxygen species (ROS) and endogenous reactive aldehydes. Endothelial dysfunction also plays a crucial role in HS-induced ALI. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that detoxifies aldehydes such as 4-hydroxy-2-nonenal (4-HNE) protein adducts. A single point mutation in ALDH2 at E487K (ALDH2*2) intrinsically lowers the activity of ALDH2. Alda-1, an ALDH2 activator, attenuates the formation of 4-HNE protein adducts and ROS in several disease models. We hypothesized that ALDH2 can protect against heat stress-induced vascular inflammation and the accumulation of ROS and toxic aldehydes. Homozygous ALDH2*2 knock-in (KI) mice on a C57BL/6J background and C57BL/6J mice were used for the animal experiments. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro experiment. The mice were directly subjected to whole-body heating (WBH, 42°C) for 1 h at 80% relative humidity. Alda-1 (16 mg/kg) was administered intraperitoneally prior to WBH. The severity of ALI was assessed by analyzing the protein levels and cell counts in the bronchoalveolar lavage fluid, the wet/dry ratio and histology. ALDH2*2 KI mice were susceptible to HS-induced ALI in vivo. Silencing ALDH2 induced 4-HNE and ROS accumulation in HUVECs subjected to heat stress. Alda-1 attenuated the heat stress-induced activation of inflammatory pathways, senescence and apoptosis in HUVECs. The lung homogenates of mice pretreated with Alda-1 exhibited significantly elevated ALDH2 activity and decreased ROS accumulation after WBH. Alda-1 significantly decreased the WBH-induced accumulation of 4-HNE and p65 and p38 activation. Here, we demonstrated the crucial roles of ALDH2 in protecting against heat stress-induced ROS production and vascular inflammation and preserving the viability of ECs. The activation of ALDH2 by Alda-1 attenuates WBH-induced ALI in vivo.
Cross-Reactivity to Mutated Viral Immune Targets Can Influence CD8+ T Cell Functionality: An Alternative Viral Adaptation Strategy
Authors: Currenti Jennifer , Law Becker M.P. , Qin Kai , John Mina , Pilkinton Mark A. , Bansal Anju , Leary Shay , Ram Ramesh , Chopra Abha , Gangula Rama , Yue Ling , Warren Christian , Barnett Louise , Alves Eric , McDonnell Wyatt J. , Sooda Anuradha , Heath Sonya L. , Mallal Simon , Goepfert Paul , Kalams Spyros A. , Gaudieri Silvana
Published: October 2021

Loss of T cell immunogenicity due to mutations in virally encoded epitopes is a well-described adaptation strategy to limit host anti-viral immunity. Another described, but less understood, adaptation strategy involves the selection of mutations within epitopes that retain immune recognition, suggesting a benefit for the virus despite continued immune pressure (termed non-classical adaptation). To understand this adaptation strategy, we utilized a single cell transcriptomic approach to identify features of the HIV-specific CD8+T cell responses targeting non-adapted (NAE) and adapted (AE) forms of epitopes containing a non-classical adaptation. T cell receptor (TCR) repertoire and transcriptome were obtained from antigen-specific CD8+T cells of chronic (n=7) and acute (n=4) HIV-infected subjects identified by either HLA class I tetramers or upregulation of activation markers following peptide stimulation. CD8+T cells were predominantly dual tetramer+, confirming a large proportion of cross-reactive TCR clonotypes capable of recognizing the NAE and AE form. However, single-reactive CD8+T cells were identified in acute HIV-infected subjects only, providing the potential for the selection of T cell clones over time. The transcriptomic profile of CD8+T cells was dependent on the autologous virus: subjects whose virus encoded the NAE form of the epitope (and who transitioned to the AE form at a later timepoint) exhibited an ‘effective’ immune response, as indicated by expression of transcripts associated with polyfunctionality, cytotoxicity and apoptosis (largely driven by the genes GZMB, IFNɣ, CCL3, CCL4 and CCL5). These data suggest that viral adaptation at a single amino acid residue can provide an alternative strategy for viral survival by modulating the transcriptome of CD8+T cells and potentially selecting for less effective T cell clones from the acute to chronic phase.
Mesenchymal Stromal Cells for the Treatment of Graft Versus Host Disease
Authors: Kelly Kilian , Rasko John E. J.
Published: October 2021

Graft versus host disease (GvHD) is a life-threating complication of allogeneic hematopoietic stem cell transplantation, which is initially treated with high dose corticosteroids. Approximately 50% of acute GvHD cases are resistant to steroid treatment, and two-year mortality rates in those steroid-resistant patients exceed 80%. Chronic GvHD necessitates prolonged corticosteroid use, which is typically associated with limited efficacy and troublesome adverse effects. No agent has yet been established as an optimal second line therapy for either acute or chronic GvHD, but mesenchymal stromal cells (MSCs) have shown substantial promise. MSCs promote an immunosuppressive and immunoregulatory environment via multifactorial mechanisms, including: secretion of proteins/peptides/hormones; transfer of mitochondria; and transfer of exosomes or microvesicles containing RNA and other molecules. A large number of clinical studies have investigated MSCs from various sources as a treatment for acute and/or chronic GvHD. MSCs are generally safe and well tolerated, and most clinical studies have generated encouraging efficacy results, but response rates have varied. Confounding factors include variability in MSC donor types, production methodology and dose regimens, as well as variations in study design. It is well-established that extensive culture expansion of primary donor-derived MSCs leads to marked changes in functionality, and that there is a high level of inter-donor variability in MSC properties. However, recent manufacturing innovations may be capable of overcoming these problems. Further adequately powered prospective studies are required to confirm efficacy and establish the place of MSC therapy in the treatment of this condition.
Antimicrobial Resistance Surveillance to Support Decision-Making in a High-Prevalence Region: An Evaluation
Authors: Goddard Laura , Wozniak Teresa M.
Published: October 2021

Despite a high use of antibiotics and a significant burden of infectious disease, ongoing monitoring and reporting of antimicrobial resistant pathogens in rural and regional Australia is insufficient. Many geographically isolated regions of Australia have limited infrastructure, resources and fall outside of surveillance reach, limiting health services’ ability to provide an early warning signal and appropriate response. To monitor trends in the development of antimicrobial resistance (AMR), identify high-risk populations and to evaluate effectiveness of control and prevention in rural and regional Australia, a subnational surveillance system termed HOTspots was developed. To promote the best use of public health resources through the development of effective and efficient surveillance systems, we evaluated HOTspots and its prototype surveillance platform for data quality, acceptability, representativeness, and timeliness. We used the Centers for Disease Prevention and Control (CDC) guidelines for evaluating public health surveillance systems and assessed the four attributes using a descriptive analysis of quantitative data and a thematic analysis of qualitative data. We report that the HOTspots surveillance system and its prototype platform effectively captures and represents AMR data across Northern Australia. The descriptive analysis of HOTspots data demonstrated some variation in data completeness but that data validity and representativeness were high. Thematic analysis of interview transcripts found that the system was acceptable, with almost all study participants identifying timeliness, online accessibility, and community representativeness as drivers for adoption of the system, and that the system provided timely data. The evaluation also identified areas for improvement and made recommendations to the HOTspots surveillance system and its associated prototype platform.
Unity or Fragmentation in the Deep Blue: Choices in Institutional Design for Marine Biological Diversity in Areas Beyond National Jurisdiction
Authors: Berry David S.
Published: October 2021

Delegations are in the final stages of negotiating the proposedAgreement under the United Nations Convention on the Law of the Sea on the conservation and sustainable use of marine biological diversity of areas beyond national jurisdiction(BBNJAgreementorAgreement). TheAgreementwill have tremendous scope. Geographically it covers all ocean areas beyond national jurisdiction, meaning approximately 60 percent of the earth’s surface. Substantively it deals with a range of complex topics necessary for the conservation and sustainable use of marine biological diversity of areas beyond national jurisdiction, including marine genetic resources, sharing of benefits, measures such as area-based management tools, including marine protected areas, environmental impact assessments and capacity-building and the transfer of marine technology. Existing scholarship primarily explores the substantive choices for theAgreement; little examines its proposed institutional structure. This article critically assesses the competing positions advanced during negotiations for theAgreement’sinstitutional structure – the ‘global’ and ‘regional’ positions – and reviews the middle, or ‘compromise’ position adopted by the draft text. It suggests that both global and regional actors will be necessary to conserve and sustainably use marine biological diversity of areas beyond national jurisdiction, and that some form of coordinating mechanism is required to allocate responsibility for particular tasks. Two principles are proposed for use in combination to provide a mechanism to help coordinateAgreementorgans (global) and regional or sectoral bodies, namely, the principles of subsidiarity and cooperation. These principles are found in existing international and regional structures but are advanced here in dynamic forms, allowing for temporary or quasi-permanent allocation of competences, which can change or evolve over time. This position is also grounded in the international law of treaties and furthers dynamic views of regional and global ocean governance by offering practical coordinating principles that work with the existingAgreementtext.
Deciphering the Action of Perfluorohexyloctane Eye Drops to Reduce Ocular Discomfort and Pain
Authors: Delicado-Miralles Miguel , Velasco Enrique , Díaz-Tahoces Ariadna , Gallar Juana , Acosta M. Carmen , Aracil-Marco Adolfo
Published: October 2021

Perfluorohexyloctane (F6H8) eyedrops have been recently introduced in Europe as a product to treat dry eye disease, based on its ability to reduce tear film instability in Meibomian gland dysfunction and evaporative dry eye disease, although its mechanism of action is still unknown. In the present pilot study, we evaluated the effects of the ocular instillation of a single drop of commercial F6H8 eyedrops in 20 healthy humans (9 women/11 men), measuring: (a) Corneal surface temperature (CST) from infrared video images; (b) tear volume using phenol red threads; (c) blinking frequency; and (d) ocular surface sensations (cold, dryness, pricking, foreign body, burning, itching, gritty, eye fatigue, watering eyes, and light-evoked discomfort sensations; scored using 10 cm Visual Analog Scales), before and 5–60 min after F6H8 or saline treatment. CST decreased and tearing and blinking frequency increased significantly after F6H8 but not after saline solution. When applied unilaterally, CST decreased only in the F6H8-treated eye. No sensations were evoked after F6H8 or saline. The corneal surface temperature reduction produced by topical F6H8 does not evoke conscious ocular sensations but is sufficient to increase the activity of corneal cold thermoreceptors, leading to an increased reflex lacrimation and blinking that may relieve dry eye condition thus reducing ocular discomfort and pain.
Research Trends and Hotspots of Extracorporeal Membrane Oxygenation: A 10-Year Bibliometric Study and Visualization Analysis
Authors: Wang Huaqin , Deng Siqi , Fan Xiaoyu , Li Jinxiu , Tang Li , Li Yamin , Yu Bo
Published: October 2021

Objective: To determine the research hotspots and trends in the field of extracorporeal membrane oxygenation (ECMO), and to provide a reference for further and wider research in the future.

Methods: The literatures on ECMO from January 2011 to July 2021 in the Web of Science Core Collection (WOSCC) database were searched, and Citespace5.8.R1 software was used to conduct bibliographic and visual analysis on the literature by country, institution, author and keywords.

Results: A total of 5,986 articles were enrolled. According to an observation, the number of articles published in the past decade has increased, especially from 2019 to 2020. The USA had the largest number of publications, while less ECMO related studies were conducted among non-developed countries. The University of Michigan (Univ Michigan) was the institution that had the largest number of publications and the highest centrality, and Daniel B was the author who had the largest number of publications. However, more inter-institutional cooperation among author teams was needed. The focus of existing ECMO research has primarily been on the treatment of patients suffering from severe cardiopulmonary failure, and the prevention and management of complications during the application ECMO.

Conclusion: Inter-regional and inter-institutional cooperation and exchanges should be carried out among ECMO research teams and institutions. The suggested research direction is to further broaden the application scope of ECMO, while determining the ways to reduce the incidence of complications and the cost, cultivate specialized team talents, and promote the application thereof.
Quality Improvement of Sample Collection Increases the Diagnostic Accuracy of Quantitative Fecal Immunochemical Test in Colorectal Cancer Screening: A Pilot Study
Authors: Zhou Ru-chen , Wang Pei-zhu , Li Yue-yue , Zhang Yan , Ma Ming-jun , Meng Fan-yi , Liu Chao , Yang Xiao-yun , Lv Ming , Zuo Xiu-li , Li Yan-qing
Published: October 2021

Objective: The diagnostic efficiency of the quantitative fecal immunochemical test (qFIT) has large variations in colorectal cancer (CRC) screening. We aimed to explore whether the practical sample collection operant training could improve the diagnostic accuracy of the qFIT in CRC screening.

Methods: Moderate-/high-risk individuals aged 50–75 years old were invited to participate in a prospective observational study between July 2020 and March 2021. Participants took a qFIT sample without fecal sample collection operant training in advance and then completed another qFIT sample after the operant training. The primary outcome was the sensitivity and specificity of the qFITs for CRC and advanced colorectal neoplasia (ACRN). The secondary outcome was the difference in the area under the curves (AUCs) and the concentrations of the fecal hemoglobin (Hb) between the qFIT without and after the operant training.

Results: Out of 913 patients, 81 (8.9%) patients had ACRN, including 25 (2.7%) patients with CRC. For CRC, the sensitivities of the qFIT without and after the operant training at 10 μg/g were 80.4 and 100.0%, respectively, and the specificities were 90.1 and 88.4%, respectively. For ACRN, the sensitivities were 49.4 and 69.1% and the specificities were 91.7 and 91.3%, respectively. The AUC of the qFIT after the operant training was significantly higher than that without the operant training for CRC (p = 0.027) and ACRN (p = 0.001). After the operant training, the concentration of the fecal Hb was significantly higher than that without the operant training (p = 0.009) for ACRN, but there was no significant difference for CRC (p = 0.367).

Conclusion: Practical sample collection operant training improves the diagnostic accuracy of the qFIT, which increases the detection of the low concentrations of fecal Hb. Improving the quality of the sample collection could contribute to the diagnostic efficiency of the qFIT in CRC screening.
Bacterial Sirtuins Overview: An Open Niche to Explore
Authors: Gallego-Jara Julia , Ortega Álvaro , Lozano Terol Gema , Sola Martínez Rosa A. , Cánovas Díaz Manuel , de Diego Puente Teresa
Published: October 2021

Sirtuins are deacetylase enzymes widely distributed in all domains of life. Although for decades they have been related only to histones deacetylation in eukaryotic organisms, today they are considered global regulators in both prokaryotes and eukaryotes. Despite the important role of sirtuins in humans, the knowledge about bacterial sirtuins is still limited. Several proteomics studies have shown that bacterial sirtuins deacetylate a large number of lysines in vivo, although the effect that this deacetylation causes in most of them remains unknown. To date, only the regulation of a few bacterial sirtuin substrates has been characterized, being their metabolic roles widely distributed: carbon and nitrogen metabolism, DNA transcription, protein translation, or virulence. One of the most current topics on acetylation and deacetylation focuses on studying stoichiometry using quantitative LC-MS/MS. The results suggest that prokaryotic sirtuins deacetylate at low stoichiometry sites, although more studies are needed to know if it is a common characteristic of bacterial sirtuins and its biological significance. Unlike eukaryotic organisms, bacteria usually have one or few sirtuins, which have been reported to have closer phylogenetic similarity with the human Sirt5 than with any other human sirtuin. In this work, in addition to carrying out an in-depth review of the role of bacterial sirtuins in their physiology, a phylogenetic study has been performed that reveals the evolutionary differences between sirtuins of different bacterial species and even between homologous sirtuins.
Broad-Spectrum Inhibitor of Bacterial Polyphosphate Homeostasis Attenuates Virulence Factors and Helps Reveal Novel Physiology of Klebsiella pneumoniae and Acinetobacter baumannii
Authors: Roberge Nathan , Neville Nolan , Douchant Katya , Noordhof Curtis , Boev Nadejda , Sjaarda Calvin , Sheth Prameet M. , Jia Zongchao
Published: October 2021

Acinetobacter baumannii and Klebsiella pneumoniae currently rank amongst the most antibiotic-resistant pathogens, responsible for millions of infections each year. In the wake of this crisis, anti-virulence therapeutics targeting bacterial polyphosphate (polyP) homeostasis have been lauded as an attractive alternative to traditional antibiotics. In this work, we show that the small molecule gallein, a known G-protein βγ subunit modulator, also recently proven to have dual-specificity polyphosphate kinase (PPK) inhibition in Pseudomonas aeruginosa, in turn exhibits broad-spectrum PPK inhibition in other priority pathogens. Gallein treatment successfully attenuated virulence factors of K. pneumoniae and A. baumannii including biofilm formation, surface associated motility, and offered protection against A. baumannii challenge in a Caenorhabditis elegans model of infection. This was highlighted most importantly in the critically understudied A. baumannii, where gallein treatment phenocopied a ppk1 knockout strain of a previously uncharacterized PPK1. Subsequent analysis revealed a unique instance of two functionally and phenotypically distinct PPK1 isoforms encoded by a single bacterium. Finally, gallein was administered to a defined microbial community comprising over 30 commensal species of the human gut microbiome, demonstrating the non-disruptive properties characteristic of anti-virulence treatments as microbial biodiversity was not adversely influenced. Together, these results emphasize that gallein is a promising avenue for the development of broad-spectrum anti-virulence therapeutics.
Immune Response in Myocardial Injury: In Situ Hybridization and Immunohistochemistry Techniques for SARS-CoV-2 Detection in COVID-19 Autopsies
Authors: Chong Pek Yoon , Iqbal Jabed , Yeong Joe , Aw Tar Choon , Chan Kian Sing , Chui Paul
Published: October 2021

Coronavirus disease-19 (COVID-19) is caused by the newly discovered coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the lung remains the primary target site of COVID-19 injury, damage to myocardium, and other organs also contribute to the morbidity and mortality of this disease. There is also increasing demand to visualize viral components within tissue specimens. Here we discuss the cardiac autopsy findings of 12 intensive care unit (ICU) naïve and PCR-positive COVID-19 cases using a combination of histological, Immunohistochemical/immunofluorescent and molecular techniques. We performed SARS-CoV-2 qRT-PCR on fresh tissue from all cases; RNA-ISH and IHC for SARS-CoV-2 were performed on selected cases using FFPE tissue from heart. Eight of these patients also had positive post-mortem serology for SARS-CoV-2. Histopathologic changes in the coronary vessels and inflammation of the myocardium as well as in the endocardium were documented which support the reports of a cardiac component to the viral infection. As in the pulmonary reports, widespread platelet and fibrin thrombi were also identified in the cardiac tissue. In keeping with vaccine-induced activation of virus-specific CD4+ and CD8+ T cells, and release of cytokines such as interferon-gamma (IFNγ), we observed similar immune cellular distribution and cytokines in these patients. Immunohistochemical and immunofluorescent localisation for the viral Spike (S-protein) protein and the nucleocapsid protein (NP) were performed; presence of these aggregates may possibly contribute to cardiac ischemia and even remodelling.
Discovery of Novel Inhibitors From Medicinal Plants for V-Domain Ig Suppressor of T-Cell Activation
Authors: Muneer Iqra , Ahmad Sajjad , Naz Anam , Abbasi Sumra Wajid , Alblihy Adel , Aloliqi Abdulaziz A. , Aba Alkhayl Faris F. , Alrumaihi Faris , Ahmad Sarfraz , El Bakri Youness , Tahir Ul Qamar Muhammad
Published: October 2021

V-domain Ig suppressor of T cell activation (VISTA) is an immune checkpoint and is a type I transmembrane protein. VISTA is linked to immunotherapy resistance, and it is a potential immune therapeutic target, especially for triple-negative breast cancer. It expresses at a high concentration in regulatory T cells and myeloid-derived suppressor cells, and its functional blockade is found to delay tumor growth. A useful medicinal plant database for drug designing (MPD3), which is a collection of phytochemicals from diverse plant families, was employed in virtual screening against VISTA to prioritize natural inhibitors against VISTA. Three compounds, Paratocarpin K (PubChem ID: 14187087), 3-(1H-Indol-3-yl)-2-(trimethylazaniumyl)propanoate (PubChem ID: 3861164), and 2-[(5-Benzyl-4-ethyl-1,2,4-triazol-3-yl)sulfanylmethyl]-5-methyl-1,3,4-oxadiazole (PubChem ID: 6494266), having binding energies stronger than −6 kcal/mol were found to have two common hydrogen bond interactions with VISTA active site residues: Arg54 and Arg127. The dynamics of the compound–VISTA complexes were further explored to infer binding stability of the systems. Results revealed that the compound 14187087 and 6494266 systems are highly stable with an average RMSD of 1.31 Å. Further affirmation on the results was achieved by running MM-GBSA on the MD simulation trajectories, which re-ranked 14187087 as the top-binder with a net binding energy value of −33.33 kcal/mol. In conclusion, the present study successfully predicted natural compounds that have the potential to block the function of VISTA and therefore can be utilized further in experimental studies to validate their real anti-VISTA activity.
Lutein and Zeaxanthin in the Lipid Bilayer–Similarities and Differences Revealed by Computational Studies
Authors: Makuch Krzysztof , Hryc Jakub , Markiewicz Michal , Pasenkiewicz-Gierula Marta
Published: October 2021

Lutein and zeaxanthin are two similar carotenoids of the xanthophyll subgroup. Carotenoids are synthesized almost entirely by plants but are also present in significant amounts in animals. They are essential components of the lipid matrix of biomembranes, and one of their functions is to protect cells from light radiation, free radicals and oxidative stress. Carotenoids, depending on their chemical structure, can locate at various positions and in different orientations in the bilayer. Xanthophylls (XAN) are polar and in the bilayer are positionally restricted. In the case of lutein and zeaxanthin, whose both ionone rings are hydroxy-substituted and as such are anchored in the lipid bilayer interfaces, the position is generally transmembrane. However, both experimental and computer modelling studies indicate that lutein can also locate horizontally below the bilayer interface. This location has never been observed for zeaxanthin. To find a molecular-level explanation for the difference in the orientations of the XAN molecules in the bilayer, a number of phosphatidylcholine-XAN bilayers were constructed and molecular dynamics (MD) simulated for 1.1 µs each. The all-trans XAN molecules were initially placed either parallel or perpendicular to the bilayer surface. With the exception of one lutein, the horizontally placed molecules adopted the transmembrane orientation within 100–600 ns. On the basis of detailed analyses of the XAN orientations and the numbers and lifetimes of their interactions in the bilayer, a plausible explanation is offered as to why a lutein molecule may remain in the horizontal orientation while zeaxanthin does not. Contrary to common believe, lutein horizontal orientation is not related to the ε-ring rotation around the C6′-C7′ bond.
Deep-Learning Radiomics for Discrimination Conversion of Alzheimer's Disease in Patients With Mild Cognitive Impairment: A Study Based on 18F-FDG PET Imaging
Authors: Zhou Ping , Zeng Rong , Yu Lun , Feng Yabo , Chen Chuxin , Li Fang , Liu Yang , Huang Yanhui , Huang Zhongxiong ,   the Alzheimer's Disease Neuroimaging Initiative
Published: October 2021

Objectives: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the older people. Some types of mild cognitive impairment (MCI) are the clinical precursors of AD, while other MCI forms tend to remain stable over time and do not progress to AD. To discriminate MCI patients at risk of AD from stable MCI, we propose a novel deep-learning radiomics (DLR) model based on 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) images and combine DLR features with clinical parameters (DLR+C) to improve diagnostic performance.

Methods:18F-fluorodeoxyglucose positron emission tomography (PET) data from the Alzheimer's disease Neuroimaging Initiative database (ADNI) were collected, including 168 patients with MCI who converted to AD within 3 years and 187 patients with MCI without conversion within 3 years. These subjects were randomly partitioned into 90 % for the training/validation group and 10 % for the independent test group. The proposed DLR approach consists of three steps: base DL model pre-training, network features extraction, and integration of DLR+C, where a convolution network serves as a feature encoder, and a support vector machine (SVM) operated as the classifier. In comparative experiments, we compared our DLR+C method with four other methods: the standard uptake value ratio (SUVR) method, Radiomics-ROI method, Clinical method, and SUVR + Clinical method. To guarantee the robustness, 10-fold cross-validation was processed 100 times.

Results: Under the DLR model, our proposed DLR+C was advantageous and yielded the best classification performance in the diagnosis of conversion with the accuracy, sensitivity, and specificity of 90.62 ± 1.16, 87.50 ± 0.00, and 93.39 ± 2.19%, respectively. In contrast, the respective accuracy of the other four methods reached 68.38 ± 1.27, 73.31 ± 6.93, 81.09 ± 1.97, and 85.35 ± 0.72 %. These results suggested the DLR approach could be used successfully in the prediction of conversion to AD, and that our proposed DLR-combined clinical information was effective.

Conclusions: This study showed DLR+C could provide a novel and valuable method for the computer-assisted diagnosis of conversion to AD from MCI. This DLR+C method provided a quantitative biomarker which could predict conversion to AD in MCI patients.
Altered Functional Segregated Sensorimotor, Associative, and Limbic Cortical-Striatal Connections in Parkinson's Disease: An fMRI Investigation
Authors: Mi Tao-Mian , Zhang Wei , Li Yu , Liu Ai-Ping , Ren Zhi-Li , Chan Piu
Published: October 2021

Multiple studies have identified segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. It has been suggested that in PD, preferential loss of dopamine in the posterior putamen may cause a major deficit in habitual control (mediated by the sensorimotor cortical-striatal loop), and the patients may therefore be forced into a progressive reliance on the goal-directed behavior (regulated by the associative cortical-striatal loop). Functional evidence supporting this point is scarce at present. This study aims to verify the functional connectivity changes within the sensorimotor, associative, and limbic cortical-striatal loops in PD. Resting-state fMRI of 70 PD patients and 30 controls were collected. Bilateral tripartite functional territories of basal ganglia and their associated cortical structures were chosen as regions of interest, including ventral striatum and ventromedial prefrontal cortex for limbic loop; dorsomedial striatum and dorsolateral prefrontal cortex for associative loop; dorsolateral striatum and sensorimotor cortex for sensorimotor loop. Pearson's correlation coefficients for each seed pair were calculated to obtain the functional connectivity. The relationships between functional connectivity and disease severity were further investigated. Functional connectivity between dorsolateral striatum and sensorimotor cortex is decreased in PD patients, and negatively correlated with disease duration; whereas functional connectivity between dorsomedial striatum and dorsolateral prefrontal cortex is also decreased but postitively correlated with disease duration. The functional connectivity within the sensorimotor loop is pathologically decreased in PD, while the altered connectivity within the associative loop may indicate a failed attempt to compensate for the loss of connectivity within the sensorimotor loop.
Case Report: Bow Hunter's Syndrome Caused by Compression of Extracranially Originated Posterior Inferior Cerebellar Artery
Authors: Enomoto Noriya , Yagi Kenji , Matsubara Shunji , Uno Masaaki
Published: October 2021

Bow hunter's syndrome (BHS) is most commonly caused by compression of the vertebral artery (VA). It has not been known to occur due to an extracranially originated posterior inferior cerebellar artery (PICA), the first case of which we present herein. A 71-year-old man presented with reproducible dizziness on leftward head rotation, indicative of BHS. On radiographic examination, the bilateral VAs merged into the basilar artery, and the left VA was predominant. The right PICA originated extracranially from the right VA at the atlas–axis level and ran vertically into the spinal canal. During the head rotation that induced dizziness, the right PICA was occluded, and a VA stenosis was revealed. Occlusion of the PICA was considered to be the primary cause of the dizziness. The patient underwent surgery to decompress the right PICA and VA via a posterior cervical approach. Following surgery, the patient's dizziness disappeared, and the stenotic change at the right VA and PICA improved. The PICA could be a causative artery for BHS when it originates extracranially at the atlas–axis level, and posterior decompression is an effective way to treat it.
Clinical, Neurophysiological, and MRI Markers of Fampridine Responsiveness in Multiple Sclerosis—An Explorative Study
Authors: Mamoei Sepehr , Jensen Henrik Boye , Pedersen Andreas Kristian , Nygaard Mikkel Karl Emil , Eskildsen Simon Fristed , Dalgas Ulrik , Stenager Egon
Published: October 2021

Objective: Persons with multiple sclerosis (PwMS), already established as responders or non-responders to Fampridine treatment, were compared in terms of disability measures, physical and cognitive performance tests, neurophysiology, and magnetic resonance imaging (MRI) outcomes in a 1-year explorative longitudinal study.

Materials and Methods: Data from a 1-year longitudinal study were analyzed. Examinations consisted of the timed 25-foot walk test (T25FW), six spot step test (SSST), nine-hole peg test (9-HPT), five times sit-to-stand test (5-STS), symbol digit modalities test (SDMT), transcranial magnetic stimulation (TMS) elicited motor evoked potentials (MEP) examining central motor conduction times (CMCT), peripheral motor conduction times (PMCT) and their amplitudes, electroneuronography (ENG) of the lower extremities, and brain structural MRI measures.

Results: Forty-one responders and eight non-responders to Fampridine treatment were examined. There were no intergroup differences except for the PMCT, where non-responders had prolonged conduction times compared to responders to Fampridine. Six spot step test was associated with CMCT throughout the study. After 1 year, CMCT was further prolonged and cortical MEP amplitudes decreased in both groups, while PMCT and ENG did not change. Throughout the study, CMCT was associated with the expanded disability status scale (EDSS) and 12-item multiple sclerosis walking scale (MSWS-12), while SDMT was associated with number of T2-weighted lesions, lesion load, and lesion load normalized to brain volume.

Conclusions: Peripheral motor conduction time is prolonged in non-responders to Fampridine when compared to responders. Transcranial magnetic stimulation-elicited MEPs and SDMT can be used as markers of disability progression and lesion activity visualized by MRI, respectively.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03401307.
Effects of Repetitive Transcranial Magnetic Stimulation in Patients With Mild Cognitive Impairment: A Meta-Analysis of Randomized Controlled Trials
Authors: Zhang Xinqi , Lan Xiaoyong , Chen Chanjuan , Ren Huixia , Guo Yi
Published: October 2021

Background: Mild cognitive impairment (MCI) is an intermediary state between normal aging and dementia. It has a high risk of progression in patients with Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique used to improve cognitive deficits in patients with MCI and AD. Although previous meta-analyses included studies carried on patients with MCI and AD, few studies have analyzed patients with MCI independently. This meta-analysis aimed to evaluate the effects and safety of rTMS on cognition function in patients with MCI and factors that may influence such effects.

Methods: Data used in this study were searched and screened from different databases, including PubMed, Web of Science, Embase, the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Chinese Technical Periodicals (VIP), Wanfang Database, and China BioMedical Literature Database (SinoMed). The retrieved studies were carefully reviewed, data were extracted, and the quality of data was assessed.

Results: A total of 12 studies involving 329 patients with MCI were included in the present meta-analysis. The analyses results revealed that rTMS improved cognitive function [standardized mean difference (SMD) = 0.83, 95% confidence interval (CI) = 0.44–1.22, p = 0.0009] and memory function (SMD = 0.73, 95% CI = 0.48–0.97, p < 0.00001) in the MCI + rTMS active group when compared to the sham stimulation group. The showed that: (1) cognitive improvement was more pronounced under high-frequency rTMS stimulation of multiple sites, such as the bilateral dorsolateral prefrontal cortex and (2) more than 10 rTMS stimulation sessions produced higher improvement on cognition function in patients with MCI.

Conclusions: This study shows that rTMS can improve cognitive function in patients with MCI, especially when applied at high frequency, multi-site, and for a prolonged period. However, further studies are required to validate these findings and explore more effective stimulation protocols and targets.

Systematic Review Registration: [http://www.crd.york.ac.uk/PROSPERO/], identifier: CRD 42021238708.
Optimizing In Situ Vaccination During Radiotherapy
Authors: Yasmin-Karim Sayeda , Wood Jana , Wirtz Johanna , Moreau Michele , Bih Noella , Swanson William , Muflam Ashley , Ainsworth Victoria , Ziberi Bashkim , Ngwa Wilfred
Published: October 2021

Effective in situ cancer vaccines require both a means of tumor cell death and a source of adjuvant to activate local dendritic cells. Studies have shown that the use of radiotherapy (RT) to induce tumor cell death and anti-CD40 to activate dendritic cells can result in in situ vaccination in animal models. Here, investigations are carried out on potential strategies to enhance such in situ vaccination. Strategies investigated include the use of smart immunogenic biomaterials (IBM) loaded with anti-CD40 in different tumor types including immunologically cold tumors like pancreatic and prostate tumors. The use of downstream checkpoint inhibitors to further boost such in situ vaccination is also examined. Results indicate that the use of IBM to deliver the anti-CD40 significantly enhances the effectiveness of in situ vaccination with anti-CD40 compared with direct injection in pancreatic and prostate cancers (p < 0.001 and p < 0.0001, respectively). This finding is consistent with significant increase in infiltration of antigen-presenting cells in the treated tumor, and significant increase in the infiltration of CD8+ cytotoxic T lymphocyte into distant untreated tumors. Moreover, in situ vaccination with IBM is consistently observed across different tumor types. Meanwhile, the addition of downstream immune checkpoint inhibitors further enhances overall survival when using the IBM approach. Overall, the findings highlight potential avenues for enhancing in situ vaccination when combining radiotherapy with anti-CD40.
Icaritin-Induced FAM99A Affects GLUT1-Mediated Glycolysis via Regulating the JAK2/STAT3 Pathway in Hepatocellular Carcinoma
Authors: Zheng Xia , Gou Yudong , Jiang Ziyu , Yang Aizhen , Yang Zhihui , Qin Shukui
Published: October 2021

Icaritin is a potential treatment option for hepatocellular carcinoma (HCC) based on the results of its phase 2 stage trial. Glucose transporter 1 (GLUT1), a critical gene in regulating glycolysis, has been recognized as a promising target in HCC treatment. Previous studies have reported that FAM99A, a new long noncoding (lncRNA), is associated with HCC metastasis. It has also been demonstrated that the JAK2/STAT3 pathway is related to HCC and is the target of icaritin treatment. However, whether FAM99A participates in icaritin treatment and regulates GLUT1-mediated glycolysis via the JAK2/STAT3 pathway in HCC cells remains to be explored. Our study aimed to clarify the mechanisms underlying glycolysis and understand the regulating effects of the FAM99A and JAK2/STAT3 pathway in HCC cells in icaritin treatment. Molecular mechanism studies were conducted to verify whether FAM99A could bind to the JAK2/STAT3 pathway and to identify the regulatory mechanisms in the HCC cells. It was revealed that icaritin inhibited proliferation, GLUT1 level, and the glycolysis of the HCC cells. FAM99A in HCC cells was upregulated after a high concentration treatment of icaritin. FAM99A inhibited GLUT1 by blocking the JAK2/STAT3 pathway. Mechanically, FAM99A interacted with EIF4B to inhibit gp130 and gp80 translation, which then interacted with miR-299-5p to upregulate SOCS3, causing the JAK2 pathway to inhibit STAT3 phosphorylation, so that JAK2/STAT3 was blocked in HCC cells. Overall, our study proved that icaritin-induced FAM99A can inhibit HCC cell viability and GLUT1-mediated glycolysis via blocking the JAK2/STAT3 pathway.