bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating Carboxylated Osteocalcin Correlates With Skeletal Muscle Mass and Risk of Fall in Postmenopausal Osteoporotic Women
Authors: Vitale Jacopo Antonino , Sansoni Veronica , Faraldi Martina , Messina Carmelo , Verdelli Chiara , Lombardi Giovanni , Corbetta Sabrina
Published: May 2021

Background

Bone and skeletal muscle represent a single functional unit. We cross-sectionally investigated body composition, risk of fall and circulating osteocalcin (OC) isoforms in osteoporotic postmenopausal women to test the hypothesis of an involvement of OC in the bone-muscle crosstalk.

Materials and Methods

Twenty-nine non-diabetic, non-obese, postmenopausal osteoporotic women (age 72.4 ± 6.8 years; BMI 23.0 ± 3.3 kg/m2) underwent to: 1) fasting blood sampling for biochemical and hormone assays, including carboxylated (cOC) and uncarboxylated (uOC) osteocalcin; 2) whole-body dual energy X-ray absorptiometry (DXA) to assess total and regional body composition; 3) magnetic resonance imaging to determine cross-sectional muscle area (CSA) and intermuscular adipose tissue (IMAT) of thigh muscles; 4) risk of fall assessment through the OAK system.

Results

Appendicular skeletal muscle index (ASMMI) was low in 45% of patients. Forty percent got a low OAK score, consistent with moderate-severe risk of fall, which was predicted by low legs lean mass and increased total fat mass. Circulating cOC levels showed significantly correlated with βCTx-I, lean mass parameters including IMAT, and OAK score. Fractured and unfractured women did not differ for any of the analyzed parameters, though cOC and uOC positively correlated with legs lean mass, OAK score and bone markers only in fractured women.

Conclusions

Data supported the relationship between OC and skeletal muscle mass and function in postmenopausal osteoporotic women. Serum cOC, but not uOC, emerges as mediator in the bone-muscle crosstalk. Circulating cOC and uOC levels may be differentially regulated in fractured and unfractured osteoporotic women, suggesting underlying differences in bone metabolism.
Hydrogen from Dark Fermentation of the Organic Fraction of Waste Diapers: Optimization Based on Response Surface Experiments
Authors: Sotelo-Navarro Perla X. , Poggi-Varaldo Héctor M.
Published: May 2021

Waste diapers (WD) handling and disposal in Mexico are typically based on their burial in dumping sites and landfills. Practically reclaiming and recycling of WD are non-existent. The clean diapers are composed of cellulose fibres (37–43% db), hemicellulose (5–9%), lignin (4–7%), protein (<1), plastics (polypropylene and polyethylene) (12–16%), absorbent sodium polyacrylate (14–18%), and elastic and adhesives tapes (9–12%). The latter can be valuable resources. WD composition is similar to clean diaper, although humidity is very high, and the ranges of faeces and urine are 1.5–2.5 and 6–9% dry weight, respectively. International literature searches indicate that there is some research on composting, fungal biodegradation, and methanogenic co-digestion of waste activated sludge with the organic fraction of waste diapers (OFWD.) However, research on dark fermentation of OFWD is limited. In this work, the generation of biohydrogen from dark fermentation of OFWD was optimised. We used the response surface methodology (RSM). Independent variables were the temperature of operation (37–55°C), ratio C/N of the feed (30, 40 gC/gN), and initial total solids of the feed (TSi) (15, 25%). The dependent (response) variables examined were Y’H2 (H2 produced per initial g of dry matter), contents of low molecular weight organic solvents and acids, lactic acid, the ratio A/B (acetic-to-butyric acid), and the quotient organic acids C2 to C4-to-solvents. The predicted maximum Y’H2 occurred at the combination of factors of 43 gC/gN, 12% and 31°C; its value was 2.79 mmolH2/gTS; its experimental validation gave 2.48 mmolH2/gTS, which shows a good agreement between values (11% lower than the predicted value). The maximum of Y’H2 with OFWD compared very favourably with bioH2 values obtained from a wide variety of wastes (organic municipal residues, agricultural wastes, etc.) using the same batch type fermentation with intermittent venting. Interestingly, the predicted temperature optimum fell in the lower side of the mesophilic range. Process heating savings would be in the order of 60.0 and 27.2% for thermophilic and mesophilic operation, respectively. In this way, it would be a contribution to the sustainability of the dark fermentation of OFWD. This result was somewhat counterintuitive and strongly indicates the usefulness of the response surface methodolog for analyzing the experimental results and uncovering favourable, although unexpected conditions.
Tree Species of Wet Tropical Forests Differ in Their Tissue Biochemistry and Effects on Soil Carbon Dynamics
Authors: Russell Ann E. , Marek Rachel F. , Olk Daniel C.
Published: May 2021

Given the hypothesized effects on soil organic matter (SOM) of polyphenols in plant tissues, differences among tree species in their biochemical composition could influence the turnover and accrual of SOM in various ways. The extent to which the biochemical composition of leaf and fine-root tissues differ among tropical tree species, and the effects on soil dynamics, are largely undocumented, however. We used cupric oxide analyses of plant tissues and soil in long-term, replicated, mono-dominant 15-year-old plantations at La Selva Biological Station, Costa Rica, to test for differences among six tree species. We related these results to companion studies in this experimental site to evaluate relationships between interspecific differences in tissue biochemistry and SOM dynamics. Newly senesced leaves and fine roots of the six species differed in their concentrations of three lignin-derived families of phenols, the cinnamyls, syringyls and vanillyls (p< 0.0001 for all tests). Cinnamyl and syringyl phenols in soil differed significantly among species (p= 0.0408, 0.0071, respectively), whereas vanillyl phenols did not (p= 0.83). The degree of decomposition of syringyl and vanillyl phenols in soil also differed (p= 0.0015, 0.0027, respectively), as evidenced by the ratio of carboxylic acid to aldehyde compounds, based on the concept that carboxylic acids are a common by-product of oxidative decomposition of lignin by microorganisms. In our study in a single site, i.e., the same soil type, climate, and growth form of vegetation, total phenols in soil ranged from 5 to 21 mg g–1organic carbon (OC) across the 20 plots, and the endpoints were both broad-leaved evergreen species; even the means across species, 7–12 mg g–1OC, covered half the range of values reported in another study across a broad latitudinal range of sites. This study’s tree species differed in traits that influenced at least four factors that explained their differential effects on soil organic carbon (SOC) pools: (1) Fine-root detrital inputs; (2) Fine-root syringyl concentrations; (3) Soil pH; and (4) Macroaggregate structure. This trait-based approach provides a process-based understanding of how trees species influence SOC dynamics, and the consequences for ecosystem properties, under land-use change that involves shifts in species composition.
Agonistic β2-Adrenergic Receptor Autoantibodies Characterize the Aqueous Humor of Patients With Primary and Secondary Open-Angle Glaucoma
Authors: Hohberger Bettina , Wörn Max , Lämmer Robert , Mahajan Aparna , Mardin Christian , Schötzer-Schrehardt Ursula , Kunze Rudolph , Herrmann Martin , Wallukat Gerd
Published: May 2021

Purpose

Agonistic β2-adrenergic receptor autoantibodies (β2-agAAbs) were recently observed in sera of patients with ocular hypertension (OHT), primary (POAG), and secondary open-angle glaucoma (SOAG), yet not in healthy controls (HCs). It was the aim of the present study to investigate the presence of β2-agAAb in aqueous humor (AH) samples of OAG patients and to correlate these with the corresponding β2-agAAb serum data.

Material and Methods

Thirty-nine patients (21 male, 18 female) were recruited from the Department of Ophthalmology, University of Erlangen-Nürnberg: twenty-one POAG, 18 SOAG. Aqueous humor samples were collected during minimal invasive glaucoma surgery. Serum and AH samples were analyzed for β2-agAAb by a bioassay quantifying the beating rate of cultured cardiomyocyte (cut-off: 2 U).

Results

Thirty-six of 39 (92.3%) and 34 of 39 (87.2%) of OAG patients showed a β2-agAAb in their sera and AH samples, respectively. All β2-agAAb AH-positive OAG patients were also seropositive. We also observed a β2-agAAb seropositivity in 95 and 89% of patients with POAG and SOAG, respectively. Beta2-agAAbs were seen in 86% (POAG) and 78% (SOAG) of AH samples. The β2-agAAb adrenergic activity was increased in the AH of patients with POAG (6.5 ± 1.5 U) when compared with those with SOAG (4.1 ± 1.1 U; p = 0.004). Serum β2-agAAb adrenergic activity did not differ between the cohorts [POAG (4.5 ± 1.5 U); SOAG (4.6 ± 2.1 U; p=0.458)]. No correlation of the beating rates were observed between serum and AH samples for group and subgroup analyses.

Conclusion

The detection of β2-agAAb in systemic and local circulations supports the hypothesis of a direct functional impact of these agAAbs on ocular G-protein coupled receptors. The high prevalence of β2-agAAb in serum and AH samples of patients with POAG or SOAG suggests a common role of these AAbs in the etiopathogenesis of glaucoma, independent of open-angle glaucoma subtype.
Microplastics in the Mediterranean Sea: Sources, Pollution Intensity, Sea Health, and Regulatory Policies
Authors: Sharma Shivika , Sharma Vikas , Chatterjee Subhankar
Published: May 2021

Microplastic pollution is one of the emerging threats across the globe and is becoming a topic of intense study for environmental researchers. At present, almost all of the world’s oceans and seas are contaminated with microplastics but the Mediterranean Sea has been recognized as a target hotspot of the world as the microplastic concentration in this region is approximately four times greater than the North Pacific Ocean. Because of the distinguishing semi-enclosed morphology of the Mediterranean Sea, and different plastic waste generating activities originating from surrounding countries the Mediterranean Sea is highly vulnerable to microplastic pollution. Different plastic families have been reported in the Mediterranean Sea and the Physico-chemical features of these plastic polymers play an important role in the interactions between these plastic particles and other organic matter in the water bodies. The ingestion of microplastics by marine animals is an issue of concern as microplastic acts as vectors for other harmful pollutants adsorbed onto their surface. This review provides a detailed discussion on the persistence of microplastics in the Mediterranean Sea that have been identified in surface water and also in sediments and deep sea-floor. Various sources of these synthetic materials and the intensity of low and high-density polymers pollution in the Mediterranean Sea have also been discussed. This review also focuses on the threatened species in the Mediterranean Sea and the fate of the plastisphere community in its ecosystem. In the end, we highlight a series of important regulations and policies adopted by Mediterranean countries to control and manage the microplastic pollution in this region.
A Novel Method for Using Small Unoccupied Aerial Vehicles to Survey Wildlife Species and Model Their Density Distribution
Authors: Cleguer Christophe , Kelly Natalie , Tyne Julian , Wieser Martin , Peel David , Hodgson Amanda
Published: May 2021

There is growing interest from research and conservation groups in the potential for using small unoccupied aerial vehicles (UAVs; <2 kg) to conduct wildlife surveys because they are affordable, easy to use, readily available and reliable. However, limitations such as short flight endurance, and in many situations, aviation regulations, have constrained the use of small UAVs in survey applications. Thus, there is a need to refine survey methods adapted to small UAVs that conform to standard operations within aviation law. We developed a novel survey approach based on a grid sampling design using two multirotor UAVs (Phantom 4 Pros) flying simultaneously, within visual line of sight, from our vessel base-station. We used this approach to assess the fine-scale distribution and abundance of dugongs (Dugong dugon) in the remote waters of the Pilbara, Western Australia during three field seasons across 2 years. We surveyed 64 non-overlapping survey cells in random order one or more times and obtained complete image coverage of each surveyed cell of our 31 km2survey area. Our sampling design maximizes sampling effort while limiting survey time by surveying four cells, two at a time, from one location. Overall, we conducted 240 flights with up to 17 flights per day (mean = 14 flights per day) and could obtain complete coverage of up to 11.36 km2per day. A total of 149 dugongs were sighted within the 50,482 images which we manually reviewed. Spatially-explicit models of dugong density distribution (corrected for availability and perception bias) were produced using general additive models to identify areas more or less used by dugongs (range of corrected dugong densities across all field season = 0.002–1.79 dugongs per 0.04 km2). Dugong abundance estimates ranged from 47 individuals in June 2019 (CV = 0.17) to 103 individuals in May 2018 (CV = 0.36). Our method, which proved convincing in a real-word application by its feasibility, ease of implementation, and achievable surface coverage has the potential to be used in a wide range of applications from community-based local-scale surveys, to long-term repeated/intensive surveys, and impact assessments and environmental monitoring studies.
Prediction of Re-positivity for Coronavirus Nucleic Acid Among COVID-19 Patients in the Recovery Phase
Authors: Zhu Shu-fen , Sun Bo , Li Jin-kuang , Cai Yue , Li Peng-fei , Hong Ji-chang , Li Jin-hai , Xu Shi-wen , Li Xiao-yang , Xue Chen-wei , Gu Bin-bin , Wu Jian-fen , Zhou Xian-bin , Suo Hong , Duan Pei-lin , Wu Xin-xin , Li Shao-wei
Published: May 2021

Background and Objectives: Although the pathogenesis and treatment of coronavirus disease 2019 (COVID-19) have been gradually revealed, the risk for re-emergence of coronavirus nucleic acids in recovered patients remains poorly understood. Hence, this study evaluated the risk predictors associated with re-positivity for virus nucleic acid.

Methods: Between February 1 and March 20, 2020, we retrospectively reviewed the clinical epidemiological data of 129 COVID-19 patients who were treated at Zhongxiang People's Hospital of Hubei Province in China. Subsequently, a risk prediction model for the re-positivity of virus nucleic acid was developed, and a receiver operating characteristic (ROC) curve was drawn for further validation.

Results: In this study, the rate of re-positivity for virus nucleic acid was 17.8% (23/129) where all re-positivity cases were asymptomatic. The median time interval from discharge to nucleic acid re-positivity to discharge after being cured again was 11.5 days (range: 7–23 days). Multivariate logistic regression analysis showed that leukocytopenia [odds ratio (OR) 7.316, 95% confidence interval (CI) 2.319–23.080, p = 0.001], prealbumin < 150 mg/L (OR 4.199, 95% CI 1.461–12.071, p = 0.008), and hyperpyrexia (body temperature >39°C, OR 4.643, 95% CI 1.426–15.117, p = 0.011) were independent risk factors associated with re-positivity. The area under the ROC curve was 0.815 (95% CI, 0.729–0.902).

Conclusion: COVID-19 patients with leukocytopenia, low prealbumin level, and hyperpyrexia are more likely to test positive for virus nucleic acid after discharge. Timely and effective treatment and appropriate extension of hospital stays and quarantine periods may be feasible strategies for managing such patients.
Clonal Evolution Dynamics in Primary and Metastatic Lesions of Pancreatic Neuroendocrine Neoplasms
Authors: Tong Zhou , Wang Lin , Shi Weiwei , Zeng Yanwu , Zhang Hangyu , Liu Lulu , Zheng Yi , Chen Chunlei , Xia Weiliang , Fang Weijia , Zhao Peng
Published: May 2021

Background: Data on inter-tumoral heterogeneity and clonal evolution of pancreatic neuroendocrine neoplasms (panNENs) with liver metastasis are limited. The aim of this study was to explore different patterns of clonal evolution of pancreatic neuroendocrine neoplasms with liver metastasis and the possible distinctive signaling pathways involved between G2 neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs).

Methods: Tumor tissues of five patients (10 samples) with pancreatic neuroendocrine neoplasms with synchronous liver metastasis were analyzed using next-generation sequencing. PyClone, Gene Ontology, and Reactome pathway enrichment analysis were also applied.

Results: Mutated genes varied in individuals, reflecting the inter-tumoral heterogeneity of panNENs. The distribution of subclones varied during tumor metastasis, and different clonal evolution patterns were revealed between NETs and NECs. Gene Ontology and Reactome analyses revealed that in both NETs and NECs, signaling pathways and biological processes shared similarities and differences in the primary and metastatic lesions. In addition, the signaling pathway features were different between NETs and NECs. In the primary lesions, epigenetic changes and post-transcriptional modifications participated in NETs, while FGFR signaling, EGFR signaling, and NTRK2 signaling were largely involved in NECs. Although DNA repair and TP53 regulation were both involved in the metastatic lesions, most of the signaling pathways and biological processes disrupted by the mutated genes were different.

Conclusions: Our study revealed spatial inter-tumoral heterogeneity and temporal clonal evolution in PanNENs, providing potential therapeutic targets for further prospective clinical trials.
Case Report: Infective Endocarditis Caused by Aspergillus flavus in a Hemodialysis Patient
Authors: Dai Tingting , Hu Qinghua , Xie Zhongshang , Li Chunhui
Published: May 2021

Fungal endocarditis (FE) is a rare but fatal disease. The incidence of infective endocarditis (IE) in hemodialysis patients with catheters is thought to be obviously higher than that in the general population. We reported a case of IE caused by Aspergillus flavus (A. flavus) in a 36-year-old woman on hemodialysis. Because the blood cultures were persistently negative, so we used mNGS (Metagenomic next generation sequencing) for early clinical diagnosis. After treatment with voriconazole, the patient's condition improved rapidly. She continued oral voriconazole treatment 1 year after discharge and is in good condition. The diagnosis and treatment strategies of FE in hemodialysis patients were discussed.
Denitrification Biokinetics: Towards Optimization for Industrial Applications
Authors: Suri Navreet , Zhang Yuan , Gieg Lisa M. , Ryan M. Cathryn
Published: May 2021

Denitrification is a microbial process that converts nitrate (NO3–) to N2 and can play an important role in industrial applications such as souring control and microbially enhanced oil recovery (MEOR). The effectiveness of using NO3– in souring control depends on the partial reduction of NO3– to nitrite (NO2–) and/or N2O while in MEOR complete reduction of NO3– to N2 is desired. Thauera has been reported as a dominant taxon in such applications, but the impact of NO3– and NO2– concentrations, and pH on the kinetics of denitrification by this bacterium is not known. With the goal of better understanding the effects of such parameters on applications such as souring and MEOR, three strains of Thauera (K172, NS1 and TK001) were used to study denitrification kinetics when using acetate as an electron donor. At low initial NO3– concentrations (∼1 mmol L–1) and at pH 7.5, complete NO3– reduction by all strains was indicated by non-detectable NO3– concentrations and near-complete recovery (> 97%) of the initial NO3-N as N2 after 14 days of incubation. The relative rate of denitrification by NS1 was low, 0.071 mmol L–1 d–1, compared to that of K172 (0.431 mmol L–1 d–1) and TK001 (0.429 mmol L–1 d–1). Transient accumulation of up to 0.74 mmol L–1 NO2– was observed in cultures of NS1 only. Increased initial NO3– concentrations resulted in the accumulation of elevated concentrations of NO2– and N2O, particularly in incubations with K172 and NS1. Strain TK001 had the most extensive NO3– reduction under high initial NO3– concentrations, but still had only ∼78% of the initial NO3-N recovered as N2 after 90 days of incubation. As denitrification proceeded, increased pH substantially reduced denitrification rates when values exceeded ∼ 9. The rate and extent of NO3– reduction were also affected by NO2– accumulation, particularly in incubations with K172, where up to more than a 2-fold rate decrease was observed. The decrease in rate was associated with decreased transcript abundances of denitrification genes (nirS and nosZ) required to produce enzymes for reduction of NO2– and N2O. Conversely, high pH also contributed to the delayed expression of these gene transcripts rather than their abundances in strains NS1 and TK001. Increased NO2– concentrations, N2O levels and high pH appeared to cause higher stress on NS1 than on K172 and TK001 for N2 production. Collectively, these results indicate that increased pH can alter the kinetics of denitrification by Thauera strains used in this study, suggesting that liming could be a way to achieve partial denitrification to promote NO2– and N2O production (e.g., for souring control) while pH buffering would be desirable for achieving complete denitrification to N2 (e.g., for gas-mediated MEOR).
Development of Fast and Portable Frequency Magnetic Mixing-Based Serological SARS-CoV-2-Specific Antibody Detection Assay
Authors: Pietschmann Jan , Voepel Nadja , Voß Leonie , Rasche Stefan , Schubert Max , Kleines Michael , Krause Hans-Joachim , Shaw Tamlyn M. , Spiegel Holger , Schroeper Florian
Published: May 2021

A novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in China in December 2019, causing an ongoing, rapidly spreading global pandemic. Worldwide, vaccination is now expected to provide containment of the novel virus, resulting in an antibody-mediated immunity. To verify this, serological antibody assays qualitatively as well as quantitatively depicting the amount of generated antibodies are of great importance. Currently available test methods are either laboratory based or do not have the ability to indicate an estimation about the immune response. To overcome this, a novel and rapid serological magnetic immunodetection (MID) point-of-care (PoC) assay was developed, with sensitivity and specificity comparable to laboratory-based DiaSorin Liaison SARS-CoV-2 S1/S2 IgG assay. To specifically enrich human antibodies against SARS-CoV-2 in immunofiltration columns (IFCs) from patient sera, a SARS-CoV-2 S1 antigen was transiently produced in plants, purified and immobilized on the IFC. Then, an IgG-specific secondary antibody could bind to the retained antibodies, which was finally labeled using superparamagnetic nanoparticles. Based on frequency magnetic mixing technology (FMMD), the magnetic particles enriched in IFC were detected using a portable FMMD device. The obtained measurement signal correlates with the amount of SARS-CoV-2-specific antibodies in the sera, which could be demonstrated by titer determination. In this study, a MID-based assay could be developed, giving qualitative as well as semiquantitative results of SARS-CoV-2-specific antibody levels in patient’s sera within 21 min of assay time with a sensitivity of 97% and a specificity of 92%, based on the analysis of 170 sera from hospitalized patients that were tested using an Food and Drug Administration (FDA)-certified chemiluminescence assay.
Critical Role of Light in the Growth and Activity of the Marine N2-Fixing UCYN-A Symbiosis
Authors: Landa Marine , Turk-Kubo Kendra A. , Cornejo-Castillo Francisco M. , Henke Britt A. , Zehr Jonathan P.
Published: May 2021

The unicellular N2-fixing cyanobacteria UCYN-A live in symbiosis with haptophytes in theBraarudosphaera bigelowiilineage. Maintaining N2-fixing symbioses between two unicellular partners requires tight coordination of multiple biological processes including cell growth and division and, in the case of the UCYN-A symbiosis, N2fixation of the symbiont and photosynthesis of the host. In this system, it is thought that the host photosynthesis supports the high energetic cost of N2fixation, and both processes occur during the light period. However, information on this coordination is very limited and difficult to obtain because the UCYN-A symbiosis has yet to be available in culture. Natural populations containing the UCYN-A2 symbiosis were manipulated to explore the effects of alterations of regular light and dark periods and inhibition of host photosynthesis on N2fixation (single cell N2fixation rates),nifHgene transcription, and UCYN-A2 cell division (fluorescentin situhybridization andnifHgene abundances). The results showed that the light period is critical for maintenance of regular patterns of gene expression, N2fixation and symbiont replication and cell division. This study suggests a crucial role for the host as a producer of fixed carbon, rather than light itself, in the regulation and implementation of these cellular processes in UCYN-A.
Stability and Infectivity of SARS-CoV-2 and Viral RNA in Water, Commercial Beverages, and Bodily Fluids
Authors: Fukuta Mizuki , Mao Zhan Qiu , Morita Kouichi , Moi Meng Ling
Published: May 2021

The stability and infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in liquid samples are of great concern to virus transmission via common beverages and sewage water. Here, we investigated the stability of SARS-CoV-2 in 32 liquids including common beverages, bodily fluids, and commonly used viral transport media. Our results showed that the infectious virus could be recovered up to 77-days from common beverages including milk and water. Viral RNA could be detected at high levels in all samples up to 28-days, indicating that while viral RNA demonstrates higher stability than infectivity, viral RNA levels do not reflect the infectious capability of SARS-CoV-2. These results indicate that SARS-CoV-2 is highly stable in optimal conditions and a sufficient control measure is needed in reducing the risk of exposure and controlling and preventing future outbreaks.
Use of Protein Pegylation to Prolong the Antiviral Effect of IFN Against FMDV
Authors: Diaz-San Segundo Fayna , Medina Gisselle N. , Azzinaro Paul , Gutkoska Joseph , Mogulothu Aishwarya , Attreed Sarah E. , Lombardi Kimberly R. , Shields Jacob , Hudock Teresa A. , de los Santos Teresa
Published: May 2021

Interferons (IFNs) are considered the first line of defense against viral diseases. Due to their ability to modulate immune responses, they have become an attractive therapeutic option to control virus infections. In fact, like many other viruses, foot-and-mouth disease virus (FMDV), the most contagious pathogen of cloven-hoofed animals, is highly sensitive to the action of IFNs. Previous studies demonstrated that type I, II, and III IFNs, expressed using a replication defective human adenovirus 5 (Ad5) vector, can effectively block FMDV replication in vitro and can protect animals when challenged 1 day after Ad5-IFN treatment, in some cases providing sterile immunity. Rapidly spreading foot-and-mouth disease (FMD) is currently controlled with vaccination, although development of a protective adaptive immune response takes 5–7 days. Therefore, an optimal strategy to control FMD outbreaks is to block virus replication and spread through sustained IFN activity while the vaccine-stimulated adaptive immune response is developed. Challenges with methods of delivery and/or with the relative short IFN protein half-life in vivo, have halted the development of such approach to effectively control FMD in the animal host. One strategy to chemically improve drug pharmacodynamics is the use of pegylation. In this proof-of-concept study, we demonstrate that pegylated recombinant porcine (po)IFNα displays strong and long-lasting antiviral activity against FMDV in vitro and in vivo, completely protecting swine against FMD for at least five days after a single dose. These results highlight the potential of this biotherapeutics to use in combination with vaccines to fully control FMD in the field.
Efficacy and Safety of Combination Treatment With Apatinib and Osimertinib After Osimertinib Resistance in Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Carcinoma—A Retrospective Analysis of a Multicenter Clinical Study
Authors: Yang Xue , Xia Yang , Xu Liyan , Liang Li , Zhuo Minglei , Wu Meina , An Tongtong , Wang Ziping , Wang Yuyan , Li Jianjie , Zhong Jia , Chen Hanxiao , Jia Bo , Wang Jingjing , Zhao Jun
Published: May 2021

Currently, there are limited treatment options for patients who developed resistance to osimertinib, a third-generation epidermal growth factor receptor (EGFR) inhibitor. Resistance to EGFR inhibitors is frequently associated with enhanced vascular endothelial growth factor (VEGF) levels. This multicenter, retrospective study aimed to evaluate the efficacy of the combination treatment with apatinib and osimertinib in 39 patients with EGFR-mutant non-small cell lung carcinoma (NSCLC) who developed osimertinib resistance. The patients received the combination of oral apatinib 250 mg qd and osimertinib 80 mg qd. The efficacy was evaluated after the first month then every 2 months thereafter. The primary endpoint was progression-free survival (PFS). The overall response rate (ORR) and the disease control rate (DCR) of the combination of apatinib and osimertinib was 12.8% (5/39) and 79.5% (31/39), respectively. The median PFS was 4 months [95% confidence interval (CI): 3.5–4.5 months]. Fourteen patients were administered with at least 6 months of combination therapy, and 11 of them remained on treatment programs. The 6-month PFS rate was 38%. Nine patients underwent biopsies after failing osimertinib treatment, and five of six patients with TP53 mutations had PFS of less than 3 months. The spectrum of resistance to osimertinib mechanisms included c-mesenchymal-epithelial transition factor (c-Met) amplification, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gain-of-function mutation, phosphatase and tensin homolog (PTEN) loss-of-function mutation, Erb-B2 receptor tyrosine kinase 2 (ERBB2) amplification, and insulin-like growth factor 1 receptor (IGF1R) mutation. The most common adverse events were hypertension (30.7%, 12/39), diarrhea (15.4%, 6/39), and proteinuria (12.8%, 5/39). The combination of apatinib and osimertinib improved the ORR and the DCR of patients with osimertinib-refractory EGFR-positive NSCLC, thus making it a reasonable treatment choice after the development of osimertinib resistance.
A Strategy Based on Loop Analysis to Develop Peptide Epitopes: Application to SARS-CoV-2 Spike Protein
Authors: Di Vona Maria Luisa , Rossolini Gian Maria , Sette Marco
Published: May 2021

Many current strategies for inducing an immune response rely on the production of an antigenic protein. Such methods can be problematic if the folding of the antigenic protein is incorrect. To avoid this problem, we propose a method based on grafting specific regions of the chosen antigenic protein onto biocompatible polymeric matrices, so that they can mimic portions of the antigenic protein. These regions are selected following the criterion according to which they are not folded, are exposed to the solvent and are not already present in the human body, so that they are not recognized by the immune system as self. Regions are selected using the primary sequence of the protein and, where possible, its tertiary structure. The application of this strategy to the Spike protein of SARS-CoV-2 is presented.
Nicotine and Cognition in Cognitively Normal Older Adults
Authors: Nop Olivia , Senft Miller Anna , Culver Hannah , Makarewicz Jenna , Dumas Julie A.
Published: May 2021

The cholinergic system has been shown to be the primary neurotransmitter system which is responsible for the cognitive symptoms associated with dementia; its role in healthy non-demented older adults remains a gap in the literature. Understanding the effects of age-related functional changes on the nicotinic system will address this knowledge gap. As the older adult population grows and hence the importance of understanding cognitive changes that impact functional abilities and everyday life. In this article we examine the benefits of using nicotine as a method for improving cognition in non-demented healthy older adults which may have the potential for slowing neurodegeneration in aging. Furthermore, we discuss how nicotine can play a crucial role in maintaining cognitive abilities throughout normal cognitive aging.
Dopamine-Mediated Circadian and Light/Dark-Adaptive Modulation of Chemical and Electrical Synapses in the Outer Retina
Authors: Goel Manvi , Mangel Stuart C.
Published: May 2021

The vertebrate retina, like most other brain regions, undergoes relatively slow alterations in neural signaling in response to gradual changes in physiological conditions (e.g., activity changes to rest), or in response to gradual changes in environmental conditions (e.g., day changes into night). As occurs elsewhere in the brain, the modulatory processes that mediate slow adaptation in the retina are driven by extrinsic signals (e.g., changes in ambient light level) and/or by intrinsic signals such as those of the circadian (24-h) clock in the retina. This review article describes and discusses the extrinsic and intrinsic modulatory processes that enable neural circuits in the retina to optimize their visual performance throughout day and night as the ambient light level changes by ~10 billion-fold. In the first synaptic layer of the retina, cone photoreceptor cells form gap junctions with rods and signal cone-bipolar and horizontal cells (HCs). Distinct extrinsic and intrinsic modulatory processes in this synaptic layer are mediated by long-range feedback of the neuromodulator dopamine. Dopamine is released by dopaminergic cells, interneurons whose cell bodies are located in the second synaptic layer of the retina. Distinct actions of dopamine modulate chemical and electrical synapses in day and night. The retinal circadian clock increases dopamine release in the day compared to night, activating high-affinity dopamine D4receptors on cones. This clock effect controls electrical synapses between rods and cones so that rod-cone electrical coupling is minimal in the day and robust at night. The increase in rod-cone coupling at night improves the signal-to-noise ratio and the reliability of very dim multi-photon light responses, thereby enhancing detection of large dim objects on moonless nights.Conversely, maintained (30 min) bright illumination in the day compared to maintained darkness releases sufficient dopamine to activate low-affinity dopamine D1receptors on cone-bipolar cell dendrites. This non-circadian light/dark adaptive process regulates the function of GABAAreceptors on ON-cone-bipolar cell dendrites so that the receptive field (RF) surround of the cells is strong following maintained bright illumination but minimal following maintained darkness. The increase in surround strength in the day following maintained bright illumination enhances the detection of edges and fine spatial details.
Integrative Cell Type-Specific Multi-Omics Approaches Reveal Impaired Programs of Glial Cell Differentiation in Mouse Culture Models of DM1
Authors: González-Barriga Anchel , Lallemant Louison , Dincã Diana M. , Braz Sandra O. , Polvèche Hélène , Magneron Paul , Pionneau Cédric , Huguet-Lachon Aline , Claude Jean-Baptiste , Chhuon Cerina , Guerrera Ida Chiara , Bourgeois Cyril F. , Auboeuf Didier , Gourdon Geneviève , Gomes-Pereira Mário
Published: May 2021

Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a non-coding CTG repeat expansion in the DMPK gene. This mutation generates a toxic CUG RNA that interferes with the RNA processing of target genes in multiple tissues. Despite debilitating neurological impairment, the pathophysiological cascade of molecular and cellular events in the central nervous system (CNS) has been less extensively characterized than the molecular pathogenesis of muscle/cardiac dysfunction. Particularly, the contribution of different cell types to DM1 brain disease is not clearly understood. We first used transcriptomics to compare the impact of expanded CUG RNA on the transcriptome of primary neurons, astrocytes and oligodendrocytes derived from DMSXL mice, a transgenic model of DM1. RNA sequencing revealed more frequent expression and splicing changes in glia than neuronal cells. In particular, primary DMSXL oligodendrocytes showed the highest number of transcripts differentially expressed, while DMSXL astrocytes displayed the most severe splicing dysregulation. Interestingly, the expression and splicing defects of DMSXL glia recreated molecular signatures suggestive of impaired cell differentiation: while DMSXL oligodendrocytes failed to upregulate a subset of genes that are naturally activated during the oligodendroglia differentiation, a significant proportion of missplicing events in DMSXL oligodendrocytes and astrocytes increased the expression of RNA isoforms typical of precursor cell stages. Together these data suggest that expanded CUG RNA in glial cells affects preferentially differentiation-regulated molecular events. This hypothesis was corroborated by gene ontology (GO) analyses, which revealed an enrichment for biological processes and cellular components with critical roles during cell differentiation. Finally, we combined exon ontology with phosphoproteomics and cell imaging to explore the functional impact of CUG-associated spliceopathy on downstream protein metabolism. Changes in phosphorylation, protein isoform expression and intracellular localization in DMSXL astrocytes demonstrate the far-reaching impact of the DM1 repeat expansion on cell metabolism. Our multi-omics approaches provide insight into the mechanisms of CUG RNA toxicity in the CNS with cell type resolution, and support the priority for future research on non-neuronal mechanisms and proteomic changes in DM1 brain disease.
Can Deep Learning Hit a Moving Target? A Scoping Review of Its Role to Study Neurological Disorders in Children
Authors: Sargolzaei Saman
Published: May 2021

Neurological disorders dramatically impact patients of any age population, their families, and societies. Pediatrics are among vulnerable age populations who differently experience the devastating consequences of neurological conditions, such as attention-deficit hyperactivity disorders (ADHD), autism spectrum disorders (ASD), cerebral palsy, concussion, and epilepsy. System-level understanding of these neurological disorders, particularly from the brain networks' dynamic perspective, has led to the significant trend of recent scientific investigations. While a dramatic maturation in the network science application domain is evident, leading to a better understanding of neurological disorders, such rapid utilization for studying pediatric neurological disorders falls behind that of the adult population. Aside from the specific technological needs and constraints in studying neurological disorders in children, the concept of development introduces uncertainty and further complexity topping the existing neurologically driven processes caused by disorders. To unravel these complexities, indebted to the availability of high-dimensional data and computing capabilities, approaches based on machine learning have rapidly emerged a new trend to understand pathways better, accurately diagnose, and better manage the disorders. Deep learning has recently gained an ever-increasing role in the era of health and medical investigations. Thanks to its relatively more minor dependency on feature exploration and engineering, deep learning may overcome the challenges mentioned earlier in studying neurological disorders in children. The current scoping review aims to explore challenges concerning pediatric brain development studies under the constraints of neurological disorders and offer an insight into the potential role of deep learning methodology on such a task with varying and uncertain nature. Along with pinpointing recent advancements, possible research directions are highlighted where deep learning approaches can assist in computationally targeting neurological disorder-related processes and translating them into windows of opportunities for interventions in diagnosis, treatment, and management of neurological disorders in children.
Targeting Parthanatos in Ischemic Stroke
Authors: Koehler Raymond C. , Dawson Valina L. , Dawson Ted M.
Published: May 2021

Parthanatos is a cell death signaling pathway in which excessive oxidative damage to DNA leads to over-activation of poly(ADP-ribose) polymerase (PARP). PARP then generates the formation of large poly(ADP-ribose) polymers that induce the release of apoptosis-inducing factor from the outer mitochondrial membrane. In the cytosol, apoptosis-inducing factor forms a complex with macrophage migration inhibitory factor that translocates into the nucleus where it degrades DNA and produces cell death. In a review of the literature, we identified 24 publications from 13 laboratories that support a role for parthanatos in young male mice and rats subjected to transient and permanent middle cerebral artery occlusion (MCAO). Investigators base their conclusions on the use of nine different PARP inhibitors (19 studies) or PARP1-null mice (7 studies). Several studies indicate a therapeutic window of 4–6 h after MCAO. In young female rats, two studies using two different PARP inhibitors from two labs support a role for parthanatos, whereas two studies from one lab do not support a role in young female PARP1-null mice. In addition to parthanatos, a body of literature indicates that PARP inhibitors can reduce neuroinflammation by interfering with NF-κB transcription, suppressing matrix metaloproteinase-9 release, and limiting blood-brain barrier damage and hemorrhagic transformation. Overall, most of the literature strongly supports the scientific premise that a PARP inhibitor is neuroprotective, even when most did not report behavior outcomes or address the issue of randomization and treatment concealment. Several third-generation PARP inhibitors entered clinical oncology trials without major adverse effects and could be repurposed for stroke. Evaluation in aged animals or animals with comorbidities will be important before moving into clinical stroke trials.
A New Method of Haemorrhagic Stroke Detection Via Deep Magnetic Induction Tomography
Authors: Lv Yi , Luo Haijun
Published: May 2021

Hemorrhage imaging is one of the most common applications of magnetic induction tomography (MIT). Depth and the mass of stroke stimulated (MSS) are the most important issues that need to be solved for this application. Transcranial magnetic stimulation (TMS) is a technique belonging to the deep brain stimulation (DBS) field, which aims at overcoming human diseases such as depression. TMS coils, namely, circular, figure-8, and H-coils, play an important role in TMS. Among these, H-coils individually focus on the issues of achieving effective stimulation of deep region. MIT and TMS mechanisms are similar. Herein, for the first time, improved TMS coils, including figure-8 and H-coils, are applied as MIT excitation coils to study the possibility of achieving the mass of stroke stimulated and deep detection through MIT. In addition, the configurations of the detection coils are varied to analyze their influence and determine the optimal coils array. Finally, MIT is used to detect haemorrhagic stroke occurring in humans, and the application of deep MIT to the haemorrhagic stroke problem is computationally explored. Results show that among the various coils, the improved H-coils have MSS and depth characteristics that enable the detection of deep strokes through MIT. Although the detecting depth of the figure-8 coil is weaker, its surface signal is good. The deep MIT technique can be applied to haemorrhagic detection, providing a critical base for deeper research.
Association Between Dietary Inflammatory Index and Mental Health: A Systematic Review and Dose–Response Meta-Analysis
Authors: Chen Guo-Qiang , Peng Chun-Ling , Lian Ying , Wang Bo-Wen , Chen Peng-Yu , Wang Gang-Pu
Published: May 2021

Objective: We aimed to systematically evaluate the association between Dietary Inflammatory Index (DII) and mental health.

Methods: We searched PubMed, Embase, and Web of Science from their inception to December 31, 2020. Categorical meta-analysis and dose–response meta-analysis were performed to evaluate the association between DII and mental health.

Results: A total of 16 studies were included in this meta-analysis. Compared with the lowest DII category, the highest category was significantly associated with a variety of mental health outcomes, with the following pooled odds ratios (ORs) and 95% confidence intervals (95% CIs): 1.28 (1.17–1.39) for symptoms of depression, 1.27 (1.08–1.49) for symptoms of anxiety, 1.85 (1.43–2.40) for distress, and 4.27 (1.27–14.35) for schizophrenia. Furthermore, there was a linear dose–response relationship between DII and symptoms of depression in that a 1-unit increment in DII was associated with an increased risk of 6% for symptoms of depression (OR: 1.06, 95% CI: 1.03–1.19).

Conclusion: The present study indicates that more pro-inflammatory diet, as estimated by the higher DII score, is associated with symptoms of mental disorder. It may be of clinical and public health significance regarding the development of novel nutritional psychiatry approaches to promote good mental health.
Pharmacological Inhibition and Genetic Knockdown of BCL9 Modulate the Cellular Landscape of Cancer-Associated Fibroblasts in the Tumor-Immune Microenvironment of Colorectal Cancer
Authors: Yang Mengxuan , Wei Zhuang , Feng Mei , Zhu Yuanyuan , Chen Yong , Zhu Di
Published: May 2021

Cancer-associated fibroblasts (CAFs) exert a key role in cancer progression and liver metastasis. They are activated in the tumor microenvironment (TME), but their prometastatic mechanisms are not defined. CAFs are abundant in colorectal cancer (CRC). However, it is not clear whether they are raised from local tissue-resident fibroblasts or pericryptal fibroblasts and distant fibroblast precursors, and whether they may stimulate metastasis-promoting communication. B-cell lymphoma 9/B-cell lymphoma 9-like (BCL9/BCL9L) is the key transcription cofactor of β-catenin. We studied the TME of CRC with single-cell sequencing and consequently found that Bcl9 depletion caused a pro-tumor effect of CAFs, while inhibition of abnormal activation of Wnt/β-catenin signal through Bcl9 depletion benefited T-cell–mediated antitumor immune responses. We also identified and evaluated four types of CAFs in CRC with liver metastasis. In summary, we demonstrate cell type landscape and transcription difference upon BCL9 suppression in CAFs, as well as how CAF affects cancer associated immune surveillance by inhibition of Wnt signaling. Targeting the Wnt signaling pathway via modulating CAF may be a potential therapeutic approach.