bluuebunny/crossref_metadata_2025 huggingface dataset:
Mesenteric Lymph Node Transplantation in Mice to Study Immune Responses of the Gastrointestinal Tract
Authors: Shaikh Haroon , Vargas Juan Gamboa , Mokhtari Zeinab , Jarick Katja J. , Ulbrich Maria , Mosca Josefina Peña , Viera Estibaliz Arellano , Graf Caroline , Le Duc-Dung , Heinze Katrin G. , Büttner-Herold Maike , Rosenwald Andreas , Pezoldt Joern , Huehn Jochen , Beilhack Andreas
Published: July 2021

Mesenteric lymph nodes (mLNs) are sentinel sites of enteral immunosurveillance and immune homeostasis. Immune cells from the gastrointestinal tract (GIT) are constantly recruited to the mLNs in steady-state and under inflammatory conditions resulting in the induction of tolerance and immune cells activation, respectively. Surgical dissection and transplantation of lymph nodes (LN) is a technique that has supported seminal work to study LN function and is useful to investigate resident stromal and endothelial cell biology and their cellular interactions in experimental disease models. Here, we provide a detailed protocol of syngeneic mLN transplantation and report assays to analyze effective mLN engraftment in congenic recipients. Transplanted mLNs allow to study T cell activation and proliferation in preclinical mouse models. Donor mLNs proved viable and functional after surgical transplantation and regenerated blood and lymphatic vessels. Immune cells from the host completely colonized the transplanted mLNs within 7-8 weeks after the surgical intervention. After allogeneic hematopoietic cell transplantation (allo-HCT), adoptively transferred allogeneic CD4+ T cells from FVB/N (H-2q) mice homed to the transplanted mLNs in C57BL/6 (H-2b) recipients during the initiation phase of acute graft-versus-host disease (aGvHD). These CD4+ T cells retained full proliferative capacity and upregulated effector and gut homing molecules comparable to those in mLNs from unmanipulated wild-type recipients. Wild type mLNs transplanted into MHCII deficient syngeneic hosts sufficed to activate alloreactive T cells upon allogeneic hematopoietic cell transplantation, even in the absence of MHCII+ CD11c+ myeloid cells. These data support that orthotopically transplanted mLNs maintain physiological functions after transplantation. The technique of LN transplantation can be applied to study migratory and resident cell compartment interactions in mLNs as well as immune reactions from and to the gut under inflammatory and non-inflammatory conditions.
Individual HLA-A, -B, -C, and -DRB1 Genotypes Are No Major Factors Which Determine COVID-19 Severity
Authors: Schetelig Johannes , Heidenreich Falk , Baldauf Henning , Trost Sarah , Falk Bose , Hoßbach Christian , Real Ruben , Roers Axel , Lindemann Dirk , Dalpke Alexander , Kolditz Martin , de With Katja , Bornhäuser Martin , Bonifacio Ezio E. , Rücker-Braun Elke , Lange Vinzenz , Markert Jan , Barth Ralf , Hofmann Jan A. , Sauter Jürgen , Bernas Stefanie N. , Schmidt Alexander H.
Published: July 2021

HLA molecules are key restrictive elements to present intracellular antigens at the crossroads of an effective T-cell response against SARS-CoV-2. To determine the impact of the HLA genotype on the severity of SARS-CoV-2 courses, we investigated data from 6,919 infected individuals. HLA-A, -B, and -DRB1 allotypes grouped into HLA supertypes by functional or predicted structural similarities of the peptide-binding grooves did not predict COVID-19 severity. Further, we did not observe a heterozygote advantage or a benefit from HLA diplotypes with more divergent physicochemical peptide-binding properties. Finally, numbers of in silico predicted viral T-cell epitopes did not correlate with the severity of SARS-CoV-2 infections. These findings suggest that the HLA genotype is no major factor determining COVID-19 severity. Moreover, our data suggest that the spike glycoprotein alone may allow for abundant T-cell epitopes to mount robust T-cell responses not limited by the HLA genotype.
How to Meet New Global Targets in the Offshore Realms: Biophysical Guidelines for Offshore Networks of No-Take Marine Protected Areas
Authors: Ceccarelli Daniela M. , Davey Kate , Jones Geoffrey P. , Harris Peter T. , Matoto Sione V. , Raubani Jason , Fernandes Leanne
Published: July 2021

Networks of no-take marine protected areas (MPAs), where all extractive activities are prohibited, are the most effective tool to directly protect marine ecosystems from destructive and unsustainable human activities. No-take MPAs and MPA networks have been globally implemented in coastal seas, and their success has been significantly enhanced where science-based biophysical guidelines have informed their design. Increasingly, as human pressure on marine ecosystems is expanding further offshore, governments are establishing offshore MPAs—some very large—or MPA networks. Globally, there are growing calls from scientists, non-government organisations, and national governments to set global conservation targets upwards of 30%. Given that most of the ocean is found either in the high seas or offshore within national Exclusive Economic Zones, large offshore MPAs or networks of MPAs must be a major component of these global targets for ocean protection. However, without adequate design, these offshore MPAs risk being placed to minimise conflict with economic interests, rather than to maximise biodiversity protection. This paper describes detailed biophysical guidelines that managers can use to design effective networks of no-take MPAs in offshore environments. We conducted a systematic review of existing biophysical design guidelines for networks of MPAs in coastal seas, and found consistent elements relating to size, shape, connectivity, timeframes, and representation of biophysical features. However, few of the guidelines are tailored to offshore environments, and few of the large offshore MPAs currently in place were designed systematically. We discuss how the common inshore design guidelines should be revised to be responsive to the characteristics of offshore ecosystems, including giving consideration of issues of scale, data availability, and uncertainty. We propose 10 biophysical guidelines that can be used to systematically design offshore networks of MPAs which will also contribute to the global goal of at least 30% protection globally. Finally, we offer three priority guidelines that reflect the unique conservation needs of offshore ecosystems: emphasising the need for larger MPAs; maximising the inclusion of special features that are known and mapped; and representing minimum percentages of habitats, or, where mapped, bioregions. Ultimately, MPA guidelines need to be embedded within an adaptive management framework, and have the flexibility to respond to emerging knowledge and new challenges.
Aquaculture Impacts on China’s Marine Wild Fisheries Over the Past 30 Years
Authors: Zhao Kangshun , Zhang Min , Wang Kang , Zhu Konghao , Xu Congjun , Xie Jiayi , Xu Jun
Published: July 2021

China is the world’s largest producer of aquaculture and capture fisheries. How this country develops its aquaculture sector and whether such development can relieve pressure on wild fisheries remain a contentious issue in the past and for the future. This study aims to provide a broad assessment on the impact of aquaculture development in different periods on marine wild fisheries on the basis of aquaculture and marine wild fish catch data from all the coastal provinces of China. China’s aquaculture and capture fisheries have undergone substantial changes. From 1989 to 2002, China’s aquaculture, especially mariculture, had a strong relationship with marine wild fisheries. However, from 2003 to 2018, the impact of mariculture was weakened, whereas that of freshwater aquaculture had increased. Although aquaculture still puts pressure on marine wild fisheries, China’s aquaculture is currently moving toward sustainable development pattern with low input and high output. These results provide the first statistical evidence on the effects of aquaculture development on marine wild fisheries and contribute to the sustainable management of China’s aquaculture and marine capture fisheries.
Multi-Objective Optimization Methods for Designing Low-Carbon Concrete Mixtures
Authors: DeRousseau M.A. , Kasprzyk J.R. , Srubar W.V.
Published: July 2021

Concrete mixtures are complex material systems with a multitude of characteristics that decision-makers may deem important. These characteristics can include economic, environmental, mechanical, and durability-related properties of a concrete mixture. However, traditional concrete mixture design typically employs long-standing heuristics, which satisfy requirements for physical characteristics but are unable to minimize specific characteristics, such as the cost or carbon footprint of the concrete mixture. This work considers these performance characteristics by implementing simulation-optimization as a new paradigm for designing concrete mixtures. The utility of the simulation-optimization framework is tested for several concrete design case studies that simultaneously consider compressive strength, embodied carbon, service life, and cost. Results from these scenarios demonstrate that the local conditions of the case study dictate the most important parameters of the simulation-optimization (i.e., relative constituent costs, in situ service-life conditions). Out of all other parameters, constituent cost and service-life conditions impact the set of optimal concrete mixture designs in terms of the types and quantities of mixture ingredients that are utilized. We present a simulation-optimization framework that is demonstrated herein to be a holistic design tool that allows designers to quantify and visualize tradeoffs between critical concrete performance metrics. Such a tool can be used to precision-tailor low-carbon concrete mixtures to the exact preferences of the designer.
Deep Learning for Identification of Acute Illness and Facial Cues of Illness
Authors: Forte Castela , Voinea Andrei , Chichirau Malina , Yeshmagambetova Galiya , Albrecht Lea M. , Erfurt Chiara , Freundt Liliane A. , Carmo Luisa Oliveira e , Henning Robert H. , Horst Iwan C. C. van der , Sundelin Tina , Wiering Marco A. , Axelsson John , Epema Anne H.
Published: July 2021

Background: The inclusion of facial and bodily cues (clinical gestalt) in machine learning (ML) models improves the assessment of patients' health status, as shown in genetic syndromes and acute coronary syndrome. It is unknown if the inclusion of clinical gestalt improves ML-based classification of acutely ill patients. As in previous research in ML analysis of medical images, simulated or augmented data may be used to assess the usability of clinical gestalt.

Objective: To assess whether a deep learning algorithm trained on a dataset of simulated and augmented facial photographs reflecting acutely ill patients can distinguish between healthy and LPS-infused, acutely ill individuals.

Methods: Photographs from twenty-six volunteers whose facial features were manipulated to resemble a state of acute illness were used to extract features of illness and generate a synthetic dataset of acutely ill photographs, using a neural transfer convolutional neural network (NT-CNN) for data augmentation. Then, four distinct CNNs were trained on different parts of the facial photographs and concatenated into one final, stacked CNN which classified individuals as healthy or acutely ill. Finally, the stacked CNN was validated in an external dataset of volunteers injected with lipopolysaccharide (LPS).

Results: In the external validation set, the four individual feature models distinguished acutely ill patients with sensitivities ranging from 10.5% (95% CI, 1.3–33.1% for the skin model) to 89.4% (66.9–98.7%, for the nose model). Specificity ranged from 42.1% (20.3–66.5%) for the nose model and 94.7% (73.9–99.9%) for skin. The stacked model combining all four facial features achieved an area under the receiver characteristic operating curve (AUROC) of 0.67 (0.62–0.71) and distinguished acutely ill patients with a sensitivity of 100% (82.35–100.00%) and specificity of 42.11% (20.25–66.50%).

Conclusion: A deep learning algorithm trained on a synthetic, augmented dataset of facial photographs distinguished between healthy and simulated acutely ill individuals, demonstrating that synthetically generated data can be used to develop algorithms for health conditions in which large datasets are difficult to obtain. These results support the potential of facial feature analysis algorithms to support the diagnosis of acute illness.
Legal Challenges in Precision Medicine: What Duties Arising From Genetic and Genomic Testing Does a Physician Owe to Patients?
Authors: McGrath Scott P. , Peabody Arthur E. , Walton Derek , Walton Nephi
Published: July 2021

Precision medicine is increasingly incorporated into clinical practice via three primary data conduits: environmental, lifestyle, and genetic data. In this manuscript we take a closer look at the genetic tier of precision medicine. The volume and variety of data provides a more robust picture of health for individual patients and patient populations. However, this increased data may also have an adverse effect by muddling our understanding without the proper pedagogical tools. Patient genomic data can be challenging to work with. Physicians may encounter genetic results which are not fully understood. Genetic tests may also lead to the quandary of linking patients with diseases or disorders where there are no known treatments. Thus, physicians face a unique challenge of establishing the proper scope of their duty to patients when dealing with genomic data. Some of those scope of practice boundaries have been established as a result of litigation, while others remain an open question. In this paper, we map out some of the legal challenges facing the genomic component of precision medicine, both established and some questions requiring additional guidance. If physicians begin to perceive genomic data as falling short in overall benefit to their patients, it may detrimentally impact precision medicine as a whole. Helping to develop guidance for physicians working with patient genomic data can help avoid this fate of faltering confidence.
Associations Between Intellectual and Social Activities With Frailty Among Community-Dwelling Older Adults in China: A Prospective Cohort Study
Authors: Huang Yafang , Guo Xiangyu , Du Juan , Liu Yanli
Published: July 2021

Background: Frailty is one of the most important global health challenges. We aimed to examine the associations between frequency of intellectual and social activities and frailty among community-dwelling older adults in China.

Methods: This is a prospective analysis of older adults (aged ≥60 years) who had intellectual and social activity data and were free of frailty from the national representative China Health and Retirement Longitudinal Study (CHARLS). The exposure was frequency of intellectual and social activities. Frailty was measured by the frailty index (FI) and defined as FI ≥ 0.25. Frailty incidents were followed up for 2 years. We estimated the relative risks (RRs) with 95% confidence intervals (CIs) using log-linear binominal regression adjusting for potential confounders.

Results: We documented 655 frailty cases over the past 2 years. Participants who had frequent intellectual activities had a lower frailty risk compared with participants who did not have intellectual activity (adjusted RR = 0.65, 95%CI = 0.47–0.90). The adjusted RRs were 0.51 (95%CI = 0.33–0.77) for participants who did not have a slip or a fall accident and 1.06 (95%CI = 0.65–1.75) for participants who had experienced slip and fall accidents (P = 0.01 for interaction). Having frequent social activities was not associated with a significant decrease in frailty risk compared with participants who did not have social activity (adjusted RR = 0.93, 95%CI = 0.78–1.12).

Conclusions: This observational study showed that having frequent intellectual activities was associated with a decreased frailty risk. The association was likely to be stronger in participants without a slip or a fall accident. Randomized controlled trials are needed to confirm this observational finding.
Effects of Low-Speed and High-Speed Resistance Training Programs on Frailty Status, Physical Performance, Cognitive Function, and Blood Pressure in Prefrail and Frail Older Adults
Authors: Coelho-Júnior Hélio José , Uchida Marco Carlos
Published: July 2021

Aim: The current study investigated the effects of low-speed resistance training (LSRT) and high-speed resistance training (HSRT) on frailty status, physical performance, cognitive function and blood pressure in pre-frail and frail older people.

Material and Methods: Sixty older adults, 32 prefrail and 28 frail, were randomly allocated into LSRT, HSRT, and control group (CG). Before and after intervention periods frailty status, blood pressure, heart rate, and a set of physical performance capabilities and cognitive domains were assessed. Exercise interventions occurred over 16 weeks and included four resistance exercises with 4–8 sets of 4–10 repetitions at moderate intensity.

Results: The prevalence of frailty criteria in prefrail and frail older adults were reduced after both LSRT and HSRT. In prefrail, LSRT significantly improved lower-limb muscle strength, while mobility was only improved after HSRT. Muscle power and dual-task performance were significantly increased in both LSRT and HSRT. In frail, LSRT and HSRT similarly improved lower-limb muscle strength and power. However, exclusive improvements in dual-task were observed after LSRT. Memory was significantly increased in prefrail and frail, regardless of the type of resistance training. No significant changes were observed in blood pressure and heart rate.

Conclusion: Findings of the present study indicated that both LSRT and HSRT reversed frailty status and improved physical performance in prefrail and frail older adults. Notably, different patterns of improvement were observed among RT protocols. Regarding frailty status, LSRT seemed to be more effective in reverse prefrailty and frailty when compared to HSRT. Greater improvements in muscle strength and power were also observed after LSRT, while HSRT produced superior increases in mobility and dual-task performance. One-leg stand performance was significantly reduced in LSRT, but not HSRT and CG, after 16 weeks. In contrast, RT programs similarly improved verbal memory in prefrail. Finally, no changes in blood pressure and heart rate were observed, regardless of the type of RT.

Trial Registration: The protocol was approved by the University of Campinas Human Research Ethics Committee (Protocol No. 20021919.7.0000.5404) and retrospectively registered at ClinicalTrials.gov Protocol Registration and Results System: NCT04868071.
Selective Thermotolerant Lactic Acid Bacteria Isolated From Fermented Juice of Epiphytic Lactic Acid Bacteria and Their Effects on Fermentation Quality of Stylo Silages
Authors: Pitiwittayakul Nittaya , Bureenok Smerjai , Schonewille Jan Thomas
Published: July 2021

The aim of the present study was to isolate and identify lactic acid bacteria (LAB) from fermented juice of tropical crops such as Napier grass, Ruzi grass, Purple guinea grass, Stylo legume, and Leucaena and their application to improve the quality of tropical crop silage. Fifteen strains of LAB were isolated. The LAB strains were Gram-positive and catalase-negative bacteria and could be divided into three groups, i.e., Pediococcus pentosaceus, Lactiplantibacillus (para)plantarum, and Limosilactobacillus fermentum according to the biochemical API 50CH test. Based on the analysis of 16S rRNA sequence, the strains isolated in the group L. (para)plantarum were distinguished. Two isolates (N3 and G4) were identified as Lactiplantibacillus plantarum. Three isolates (St1, St2, and St3) were identified as L. paraplantarum. In addition, the identification of other isolates was confirmed in the group P. pentosaceus (R1, R4, R5, R8, R11, and L1) and the group L. fermentum (N4, G6, G7, and N4). All selected strains were able to grow at 50°C. All LAB strains showed antimicrobial activity against Escherichia coli ATCC 25922, Shigella sonnei ATCC 25931, Pseudomonas aeruginosa ATCC 27853, and Bacillus cereus ATCC 11778. Four selected LAB strains (St1, St3, N4, and R4) were tested for their capacity to successfully ensile Stylo legume (Stylosanthes guianensis CIAT184). Stylo silages treated with LAB were well preserved, the NH3–N and butyric acid contents were lower, and the lactic acid content was higher than those in the control (p < 0.05). The acetic acid content was the highest in R4-treated silage among the treatments (p < 0.05). The crude protein (CP) content of St1-silage was significantly (p < 0.05) higher than the others. The inoculation of thermotolerant LAB selected from fermented juice of epiphytic lactic acid bacteria (FJLB) was found to be highly instrumental to obtain well-preserved silage from the Stylo legume.
Periphytic Biofilm Formation on Natural and Artificial Substrates: Comparison of Microbial Compositions, Interactions, and Functions
Authors: Miao Lingzhan , Wang Chengqian , Adyel Tanveer M. , Zhao Jiaqi , Yan Ning , Wu Jun , Hou Jun
Published: July 2021

Periphytic biofilms have been widely used in wastewater purification and water ecological restoration, and artificial substrates have been progressively used for periphyton immobilisation to substitute natural substrates. However, there is insufficient knowledge regarding the interaction network structure and microbial functions in biofilm communities on artificial substrates, which are essential attribute affecting their applications in biofilm immobilisation. This study compared the community structure, co-occurrence network, and metabolic functions of bacterial and microeukaryotic periphytic biofilms during a 35-day indoor cultivation on artificial substrates, such as artificial carbon fibre (ACF) and polyvinyl chloride (PVC), and natural substrates, such as pebble and wood. Results demonstrated that different types of artificial substrates could affect the community composition and functional diversity of bacterial and microeukaryotic biofilms. The bacterial and microeukaryotic community on ACF and PVC showed significantly higher Simpson index compared to those on wood. Bacterial networks on artificial substrates were more complex than those on natural substrates, while the keystone species on natural substrates were more abundant, indicating that the bacterial communities on artificial substrates had stronger stability and resistance to external interference. Furthermore, the functional metabolic profiles predicted showed the abilities of bacterial communities to metabolise nitrogen and carbon sources colonised on artificial substrates were stronger than those on natural substrates. These findings demonstrated that artificial substrates could be special niches for microbial colonisation, possibly altering microbial compositions, interactions, and functions. Therefore, this study provides a powerful theoretical basis for choosing suitable artificial substrates for microbial aggregation and immobilisation technology.
Antimicrobial-Resistant Escherichia coli Strains and Their Plasmids in People, Poultry, and Chicken Meat in Laos
Authors: Moser Aline I. , Kuenzli Esther , Campos-Madueno Edgar I. , Büdel Thomas , Rattanavong Sayaphet , Vongsouvath Manivanh , Hatz Christoph , Endimiani Andrea
Published: July 2021

Antimicrobial resistant (AMR) Enterobacterales are widely distributed among the healthy population of the Indochinese peninsula, including Laos. However, the local reservoir of these pathogens are currently not known and possible sources such as agricultural settings and food have rarely been analyzed. In this work, we investigated the extended-spectrum cephalosporin- (ESC-) and colistin-resistantEscherichia colistrains (CST-R-Ec) isolated from the gut of local people, feces of poultry, and from chicken meat (60 samples each group) in Laos. Whole-genome sequencing (WGS) analysis based on both short- and long-read sequencing approaches were implemented. The following prevalence of ESC-R-Ecand CST-R-Ecwere recorded, respectively: local people (70 and 15%), poultry (20 and 23.3%), and chicken meat (21.7 and 13.3%). Core-genome analysis, coupled with sequence type (ST)/core-genome ST (cgST) definitions, indicated that no common AMR-Ecclones were spreading among the different settings. ESC-R-Ecmostly possessedblaCTX–M–15andblaCTX–M–55associated to ISEcp1or IS26. The majority of CST-R-Eccarriedmcr-1on IncX4, IncI2, IncP1, and IncHI1 plasmids similar or identical to those described worldwide; strains with chromosomalmcr-1or possessing plasmid-mediatedmcr-3were also found. These results indicate a high prevalence of AMR-Ecin the local population, poultry, and chicken meat. While we did not observe the same clones among the three settings, most of theblaCTX–Msandmcr-1/-3were associated with mobile-genetic elements, indicating that horizontal gene transfer may play an important role in the dissemination of AMR-Ecin Laos. More studies should be planned to better understand the extent and dynamics of this phenomenon.
Investigating Crosstalk Among PTMs Provides Novel Insight Into the Structural Basis Underlying the Differential Effects of Nt17 PTMs on Mutant Httex1 Aggregation
Authors: Chiki Anass , Zhang Zhidian , Rajasekhar Kolla , Abriata Luciano A. , Rostami Iman , Krapp Lucien F. , Boudeffa Driss , Dal Peraro Matteo , Lashuel Hilal A.
Published: July 2021

Post-translational modifications (PTMs) within the first 17 amino acids (Nt17) of the Huntingtin protein (Htt) have been shown to inhibit the aggregation and attenuate the toxicity of mutant Htt proteins in vitro and in various models of Huntington’s disease. Here, we expand on these studies by investigating the effect of methionine eight oxidation (oxM8) and its crosstalk with lysine 6 acetylation (AcK6) or threonine 3 phosphorylation (pT3) on the aggregation of mutant Httex1 (mHttex1). We show that M8 oxidation delays but does not inhibit the aggregation and has no effect on the final morphologies of mHttex1aggregates. The presence of both oxM8 and AcK6 resulted in dramatic inhibition of Httex1 fibrillization. Circular dichroism spectroscopy and molecular dynamics simulation studies show that PTMs that lower the mHttex1 aggregation rate (oxM8, AcK6/oxM8, pT3, pT3/oxM8, and pS13) result in increased population of a short N-terminal helix (first eight residues) in Nt17 or decreased abundance of other helical forms, including long helix and short C-terminal helix. PTMs that did not alter the aggregation rate (AcK6) of mHttex1 exhibit a similar distribution of helical conformation as the unmodified peptides. These results show that the relative abundance of N- vs. C-terminal helical conformations and long helices, rather than the overall helicity of Nt17, better explains the effect of different Nt17 PTMs on mHttex1; thus, explaining the lack of correlation between the effect of PTMs on the overall helicity of Nt17 and mHttex1 aggregation in vitro. Taken together, our results provide novel structural insight into the differential effects of single PTMs and crosstalk between different PTMs in regulating mHttex1 aggregation.
The Tumorigenic Properties of EZH2 are Mediated by MiR-26a in Uveal Melanoma
Authors: Li Yao , Zhang Mingmei , Feng Huayin , Mahati Shaya
Published: July 2021

Background: The polycomb group protein enhancer of zeste homolog 2 (EZH2) has been found to be highly expressed in various tumors, and microRNA-26a (miR-26a) is often unmodulated in cancers. However, the functions of these two molecules in uveal melanoma (UM) and their relationships have not been reported.

Methods: We explored the effects of the miR-26a–EZH2 axis in UM by examining the levels of miR-26a and EZH2. The EZH2 levels in various tumor types and the correlations between EZH2 levels and overall survival and disease-free survival were reanalyzed. The binding of miR-26a to the 3′-untranslated region of EZH2 mRNA was measured using the luciferase reporter assay. The regulation of EZH2 gene expression by miR-26a was also identified, and the effect of elevated EZH2 expression on UM cell function was further examined. Results: miR-26a was downregulated and EZH2 was upregulated in UM cells. Overexpression of miR-26a inhibited cell proliferation, and knockdown of EZH2 suppressed cell growth. EZH2 was a direct target of miR-26a in UM cells. The knockout of EZH2 mimicked the tumor inhibition of miR-26a in UM cells, whereas the reintroduction of EZH2 abolished this effect. In addition, a network of EZH2 and its interacting proteins (UBC, CDK1, HDAC1, SUZ12, EED) was found to participate in miR-26a-mediated tumor progression.

Conclusion: The newly identified miR-26a–EZH2 axis may be a potential target for the development of treatment strategies for UM.
Human Texture Vision as Multi-Order Spectral Analysis
Authors: Okada Kosuke , Motoyoshi Isamu
Published: July 2021

Texture information plays a critical role in the rapid perception of scenes, objects, and materials. Here, we propose a novel model in which visual texture perception is essentially determined by the 1st-order (2D-luminance) and 2nd-order (4D-energy) spectra. This model is an extension of the dimensionality of the Filter-Rectify-Filter (FRF) model, and it also corresponds to the frequency representation of the Portilla-Simoncelli (PS) statistics. We show that preserving two spectra and randomizing phases of a natural texture image result in a perceptually similar texture, strongly supporting the model. Based on only two single spectral spaces, this model provides a simpler framework to describe and predict texture representations in the primate visual system. The idea of multi-order spectral analysis is consistent with the hierarchical processing principle of the visual cortex, which is approximated by a multi-layer convolutional network.
Time Course of Peripheral Leukocytosis and Clinical Outcomes After Aneurysmal Subarachnoid Hemorrhage
Authors: Gusdon Aaron M. , Savarraj Jude P. J. , Shihabeddin Eyad , Paz Atzhiry , Assing Andres , Ko Sang-Bae , McCullough Louise D. , Choi Huimahn Alex
Published: July 2021

Objective:Systemic inflammation after subarachnoid hemorrhage (SAH) is implicated in delayed cerebral ischemia (DCI) and adverse clinical outcomes. We hypothesize that early changes in peripheral leukocytes will be associated with outcomes after SAH.

Methods:SAH patients admitted between January 2009 and December 2016 were enrolled into a prospective observational study and were assessed for Hunt Hess Scale (HHS) at admission, DCI, and modified Ranked Scale (mRS) at discharge. Total white blood cell (WBC) counts and each component of the differential cell count were determined on the day of admission (day 0) to 8 days after bleed (day 8). Global cerebral edema (GCE) was assessed on admission CT, and presence of any infection was determined. Statistical tests included student'st-test, Chi-square test, and multivariate logistic regression (MLR) models.

Results:A total of 451 subjects were analyzed. Total WBCs and neutrophils decreased initially reaching a minimum at day 4–5 after SAH. Monocyte count increased gradually after SAH and peaked between day 6–8, while basophils and lymphocytes decreased initially from day 0 to 1 and steadily increased thereafter. Neutrophil to lymphocyte ratio (NLR) reached a peak on day 1 and decreased thereafter. WBCs, neutrophils, monocytes, and NLR were higher in patients with DCI and poor functional outcomes. WBCs, neutrophils, and NLR were higher in subjects who developed infections. In MLR models, neutrophils and monocytes were associated with DCI and worse functional outcomes, while NLR was only associated with worse functional outcomes. Occurrence of infection was associated with poor outcome. Neutrophils and NLR were associated with infection, while monocytes were not. Monocytes were higher in males, and ROC curve analysis revealed improved ability of monocytes to predict DCI and poor functional outcomes in male subjects.

Conclusions:Monocytosis was associated with DCI and poor functional outcomes after SAH. The association between neutrophils and NLR and infection may impact outcomes. Early elevation in monocytes had an improved ability to predict DCI and poor functional outcomes in males, which was independent of the occurrence of infection.
MicroRNA 223 Targeting ATG16L1 Affects Microglial Autophagy in the Kainic Acid Model of Temporal Lobe Epilepsy
Authors: He Zhuoyi , Chen Houminji , Zhong Yongsheng , Yang Qihang , Wang Xuemin , Chen Rongqing , Guo Yanwu
Published: July 2021

This study aimed to explore whether microRNA (miR) 223 affects microglial autophagy by targeting autophagy-related 16-like 1 (ATG16L1) in the kainic acid (KA) model of temporal lobe epilepsy (TLE). The miRNA and mRNA expression levels were quantified using quantitative real-time polymerase chain reaction (qRT-PCR), and the protein expression was investigated using western blotting. A dual-luciferase reporter assay was used to test the direct interaction between miR 223 and ATG16L1. In situ hybridization was performed to measure the hippocampal expression of miR 223. We used immunofluorescence staining to assess the expression of ATG16L1 and microtubule-associated protein light chain 3 (LC3) in the murine hippocampal microglia. Inhibitor of miR 223 was utilized to investigate the role of miR 223 in TLE, and the epileptic activity was assessed using electroencephalography (EEG). The autophagosomes were observed by transmission electron microscopy. In patients with TLE, the murine KA model of TLE, and the KA-stimulated BV2 cells, miR 223, and sequestosome 1 (SQSTM1/P62) expressions were remarkably increased, whereas ATG16L1 and LC3 levels were significantly decreased. Using a dual-luciferase reporter assay, ATG16L1 was determined as a direct target of miR 223. Treatment with antagomir 223 alleviated epilepsy, prevented abnormalities in EEG recordings and increased the ATG16L1 and LC3 levels in KA-treated mice. Inhibition of miR 223 induced increased autophagy in BV2 cells upon Rapamycin stimulation. These findings show that miR 223 affects microglial autophagy via ATG16L1 in the KA model of TLE. The miR 223/ATG16L1 pathway may offer a new treatment option for TLE.
Cross-Modal Interaction Between Auditory and Visual Input Impacts Memory Retrieval
Authors: Marian Viorica , Hayakawa Sayuri , Schroeder Scott R.
Published: July 2021

How we perceive and learn about our environment is influenced by our prior experiences and existing representations of the world. Top-down cognitive processes, such as attention and expectations, can alter how we process sensory stimuli, both within a modality (e.g., effects of auditory experience on auditory perception), as well as across modalities (e.g., effects of visual feedback on sound localization). Here, we demonstrate that experience with different types of auditory input (spoken words vs. environmental sounds) modulates how humans remember concurrently-presented visual objects. Participants viewed a series of line drawings (e.g., picture of a cat) displayed in one of four quadrants while listening to a word or sound that was congruent (e.g., “cat” or ), incongruent (e.g., “motorcycle” or ), or neutral (e.g., a meaningless pseudoword or a tonal beep) relative to the picture. Following the encoding phase, participants were presented with the original drawings plus new drawings and asked to indicate whether each one was “old” or “new.” If a drawing was designated as “old,” participants then reported where it had been displayed. We find that words and sounds both elicit more accurate memory for what objects were previously seen, but only congruent environmental sounds enhance memory for where objects were positioned – this, despite the fact that the auditory stimuli were not meaningful spatial cues of the objects’ locations on the screen. Given that during real-world listening conditions, environmental sounds, but not words, reliably originate from the location of their referents, listening to sounds may attune the visual dorsal pathway to facilitate attention and memory for objects’ locations. We propose that audio-visual associations in the environment and in our previous experience jointly contribute to visual memory, strengthening visual memory through exposure to auditory input.
Abnormal Vision-Based Displacement Perception in Parkinson’s Disease
Authors: Bernardinis Matthew , Atashzar S. Farokh , Patel Rajni V. , Jog Mandar S.
Published: July 2021

In this work, we investigate the effect of Parkinson’s disease (PD), and common corresponding therapies on vision-based perception of motion, a critical perceptual ability required for performing a wide range of activities of daily livings. While PD has been recognized as mainly a motor disorder, sensory manifestation of PD can also play a major role in the resulting disability. In this paper, for the first time, the effect of disease duration and common therapies on vision-based perception of displacement were investigated. The study is conducted in a movement-independent manner, to reject the shadowing effects and isolate the targeted perceptual disorder to the maximum possible extent. Data was collected using a computerized graphical tool on 37 PD patients [6 early-stage de novo, 25 mid-stage using levodopa therapy, six later-stage using deep brain stimulation (DBS)] and 15 control participants. Besides the absolute measurement of perception through a psychometric analysis on two tested position reference magnitudes, we also investigated the linearity in perception using Weber’s fraction. The results showed that individuals with PD displayed significant perceptual impairments compared to controls, though early-stage patients were not impaired. Mid-stage patients displayed impairments at the greater of the two tested reference magnitudes, while late-stage patients were impaired at both reference magnitudes. Levodopa and DBS use did not cause statistically significant differences in absolute displacement perception. The findings suggest abnormal visual processing in PD increasing with disease development, perhaps contributing to sensory-based impairments of PD such as bradykinesia, visuospatial deficits, and abnormal object recognition.
Lovastatin Alleviates α-Synuclein Aggregation and Phosphorylation in Cellular Models of Synucleinopathy
Authors: Dai Lijun , Wang Jiannan , He Mingyang , Xiong Min , Tian Ye , Liu Chaoyang , Zhang Zhentao
Published: July 2021

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. Pathologically, it is characterized by the aberrant aggregation of α-synuclein (α-syn) in neurons. Clinical evidence shows that patients with hypercholesterolemia are more likely to get PD, while lovastatin users have a lower risk of suffering from it. In this study, we investigated the effects of lovastatin on the aggregation and phosphorylation of α-syn in vitro. Our results demonstrate that α-syn preformed fibrils induce the phosphorylation and aggregation of α-syn in HEK293 cells stably transfected with α-syn-GFP and SH-SY5Y cells as well, which could be attenuated by in a concentration-dependent manner. Besides, lovastatin inhibited oxidative stress, histone acetylation, and the activation of casein kinase 2 (CK2). Collectively, lovastatin alleviates α-syn aggregation and phosphorylation in cellular models of synucleinopathy, indicating its potential value of being adopted in the management of PD.
Association of Dietary Carrot Intake With Bladder Cancer Risk in a Prospective Cohort of 99,650 Individuals With 12.5 Years of Follow-Up
Authors: Xu Xin , Zhu Yi , Ye Sunyi , Li Shiqi , Xie Bo , Meng Hongzhou , Wang Shuo , Xia Dan
Published: July 2021

Previous studies have provided limited evidence for the effect of carrot intake on bladder cancer incidence. This study aimed to evaluate the association between carrot consumption and bladder cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening cohort. PLCO enrolled 154,897 participants between November 1993 and July 2001 from 10 clinical screening centers throughout the United States. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression model adjusting for confounders. A meta-analysis was also performed based on all available prospective studies with DerSimonian and Laird random-effects model to calculate summary relative risk (RR) and 95% CI. After a median of 12.5 years of follow-up, 762 incident bladder cancer cases occurred. We found no statistically significant association between dietary carrot intake and bladder cancer risk. The multivariate-adjusted HR of bladder cancer for participants in the highest category of total carrot intake compared with those in the lowest category was 0.96 (95% CI: 0.76–1.22; P for trend = 0.436). Corresponding adjusted HR was 0.98 (95% CI 0.90–1.06) per 1 SD increment of carrot intake. A meta-analysis based on two previous cohort studies and our study also found no significant association between carrot intake and bladder cancer risk (Summary HR 1.02, 95% CI 0.95–1.10) without obvious heterogeneity between studies (P = 0.859, I2 = 0.0%). In summary, analysis of the PLCO cohort did not provide evidence that dietary consumption of carrot was associated with the risk of bladder cancer.
Neither Postabsorptive Resting Nor Postprandial Fat Oxidation Are Related to Peak Fat Oxidation in Men With Chronic Paraplegia
Authors: Jacobs Kevin A. , McMillan David W. , Maher Jennifer L. , Bilzon James L. J. , Nash Mark S.
Published: July 2021

The peak rate of fat oxidation (PFO) achieved during a graded exercise test is an important indicator of metabolic health. In healthy individuals, there is a significant positive association between PFO and total daily fat oxidation (FO). However, conditions resulting in metabolic dysfunction may cause a disconnect between PFO and non-exercise FO. Ten adult men with chronic thoracic spinal cord injury (SCI) completed a graded arm exercise test. On a separate day following an overnight fast (≥ 10 h), they rested for 60 min before ingesting a liquid mixed meal (600 kcal; 35% fat, 50% carbohydrate, 15% protein). Expired gases were collected and indirect calorimetry data used to determine FO at rest, before and after feeding, and during the graded exercise test. Participants had “good” cardiorespiratory fitness (VO2peak: 19.2 ± 5.2 ml/kg/min) based on normative reference values for SCI. There was a strong positive correlation between PFO (0.30 ± 0.08 g/min) and VO2peak (r = 0.86, p = 0.002). Additionally, postabsorptive FO at rest was significantly and positively correlated with postprandial peak FO (r = 0.77, p = 0.01). However, PFO was not significantly associated with postabsorptive FO at rest (0.08 ± 0.02 g/min; p = 0.97), postprandial peak FO (0.10 ± 0.03 g/min; p = 0.43), or incremental area under the curve postprandial FO (p = 0.22). It may be advantageous to assess both postabsorptive FO at rest and PFO in those with SCI to gain a more complete picture of their metabolic flexibility and long-term metabolic health.
Preliminary Experience With a Novel Metallic Segmented Transcordal Stent Modified With Three-Dimensional Printing for Inoperable Malignant Laryngotracheal Stenosis
Authors: Shan Qungang , Huang Wei , Wang Ziyin , Xue Qingsheng , Shi Zhihong , Zhou Jianping , Wu Zhiyuan , Ding Xiaoyi , Mao Aiwu , Shang Mingyi , Wang Zhongmin
Published: July 2021

Background

This study aims to assess the feasibility of a novel metallic segmented transcordal stent modified with three-dimensional (3D) printing for treating inoperable malignant laryngotracheal stenosis and the tolerability of the stent.

Methods

This was a retrospective study. The stents were individually customized with the aid of 3D printing model based on the anatomic features of each patient’s airway. The stent was composed of two separate segments that corresponded to the larynx and the upper trachea. The stents were barrel-shaped at the proximal end to prevent migration. The proximal end of the stent was located slightly above the vocal cord. The technical and clinical success of stenting procedure, patient tolerability, and stent-related complications of patients were evaluated.

Results

Ten patients with dyspnea caused by malignant laryngotracheal stenosis underwent implantation of such stents. Technical and clinical success of the stenting procedure were achieved in all patients. For all patients, basic communication in life could be maintained by speaking softly. During follow-up, one patient showed intolerance to the stent, and the stent was retrieved 2 weeks after stenting. Stent migration was found in one patient, and the position of the stent was readjusted. Granulation tissue proliferation was found in two patients and was treated with cryotherapy by bronchoscopy. There were no deaths associated with stenting.

Conclusions

The individually customized metallic segmented transcordal stent is feasible and tolerable for patients with inoperable malignant laryngotracheal stenosis. The implantation of this stent may serve as a novel alternative treatment for patients who are not suitable for surgery or tracheotomy.
Prospective Exploratory Analysis of Angiogenic Biomarkers in Peripheral Blood in Advanced NSCLC Patients Treated With Bevacizumab Plus Chemotherapy: The ANGIOMET Study
Authors: Jantus-Lewintre Eloisa , Massutí Sureda Bartomeu , González Larriba José Luis , Rodríguez-Abreu Delvys , Juan Oscar , Blasco Ana , Dómine Manuel , Provencio Pulla Mariano , Garde Javier , Álvarez Rosa , Maestu Inmaculada , Pérez de Carrión Ramón , Artal Ángel , Rolfo Christian , de Castro Javier , Guillot Mónica , Oramas Juana , de las Peñas Ramón , Ferrera Lioba , Martínez Natividad , Serra Òlbia , Rosell Rafael , Camps Carlos
Published: July 2021

Finding angiogenic prognostic markers in advanced non-small-cell lung cancer is still an unmet medical need. We explored a set of genetic variants in the VEGF-pathway as potential biomarkers to predict clinical outcomes of patients with non-small-cell lung cancer treated with chemotherapy plus bevacizumab. We prospectively analyzed the relationship between VEGF-pathway components with both pathological and prognostic variables in response to chemotherapy plus bevacizumab in 168 patients with non-squamous non-small-cell lung cancer. Circulating levels of VEGF and VEGFR2 and expression of specific endothelial surface markers and single-nucleotide polymorphisms in VEGF-pathway genes were analyzed. The primary clinical endpoint was progression-free survival. Secondary endpoints included overall survival and objective tumor response. VEGFR-1 rs9582036 variants AA/AC were associated with increased progression-free survival (p = 0.012 and p = 0.035, respectively), and with improved overall survival (p = 0.019) with respect to CC allele. Patients with VEGF-A rs3025039 harboring allele TT had also reduced mortality risk (p = 0.049) compared with the CC allele. The VEGF-A rs833061 variant was found to be related with response to treatment, with 61.1% of patients harboring the CC allele achieving partial treatment response. High pre-treatment circulating levels of VEGF-A were associated with shorter progression-free survival (p = 0.036). In conclusion, in this prospective study, genetic variants in VEGFR-1 and VEGF-A and plasma levels of VEGF-A were associated with clinical benefit, progression-free survival, or overall survival in a cohort of advanced non-squamous non-small-cell lung cancer patients receiving chemotherapy plus antiangiogenic therapy.