bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome Editing Human Pluripotent Stem Cells to Model β-Cell Disease and Unmask Novel Genetic Modifiers
Authors: George Matthew N. , Leavens Karla F. , Gadue Paul
Published: June 2021

A mechanistic understanding of the genetic basis of complex diseases such as diabetes mellitus remain elusive due in large part to the activity of genetic disease modifiers that impact the penetrance and/or presentation of disease phenotypes. In the face of such complexity, rare forms of diabetes that result from single-gene mutations (monogenic diabetes) can be used to model the contribution of individual genetic factors to pancreatic β-cell dysfunction and the breakdown of glucose homeostasis. Here we review the contribution of protein coding and non-protein coding genetic disease modifiers to the pathogenesis of diabetes subtypes, as well as how recent technological advances in the generation, differentiation, and genome editing of human pluripotent stem cells (hPSC) enable the development of cell-based disease models. Finally, we describe a disease modifier discovery platform that utilizes these technologies to identify novel genetic modifiers using induced pluripotent stem cells (iPSC) derived from patients with monogenic diabetes caused by heterozygous mutations.
Recent Trends in Surgical Approach to Thyroid Cancer
Authors: Rossi Leonardo , Materazzi Gabriele , Bakkar Sohail , Miccoli Paolo
Published: June 2021

Over the past decade, the incidence of thyroid cancer has rapidly increased worldwide, and thyroid surgery has become one of the most common performed surgical procedure. Even though conventional open thyroidectomy remains the gold standard, this approach leaves a neck scar which could be worrying mainly for young women. The recent progress in surgical technology, as well as patient cosmetic requests, have led to the development of alternative access to the thyroid lodge. Thus, alternative techniques have been established in order to potentially provide a more appealing cosmetic result, both with a minimally-invasive cervical or remote-access approach. However, the introduction of these new techniques was initially approached with caution due to technical challenges, the introduction of new complications and, above all, skepticism about the oncologic effectiveness. Among several alternative approaches proposed, the minimally invasive video-assisted thyroidectomy and the robot-assisted transaxillary thyroidectomy became popular and obtained the favor of the scientific community. Moreover, the recent introduction of the trans-oral endoscopic thyroidectomy with vestibular approach, although the safety and the efficacy are still under discussion, deserves particular attention since it represents the only technique truly scarless and provides the best cometic result. The purpose of this article is to provide an overview of the current main alternative approaches for the treatment of thyroid cancer with particular focus on the oncological effectiveness of the procedures.
Experimental Measurement on Pebble Flow Discharge in a Hopper Silo Based on a Drainage Method
Authors: Liu Yujia , Peng Sifan , Gui Nan , Yang Xingtuan , Tu Jiyuan , Jiang Shengyao
Published: June 2021

The dropping of absorption sphere from the storage vessel under accident conditions and the transportation of spent fuel elements in the reactor will both lead to the pebble flow discharging process driven by gravity in a hopper silo. Therefore, the research on the gravity-driven discharging rate of pebbles in a hopper silo has significant engineering guidance for reactor safety. In general, the idea of falling pebbles weighing to obtain the discharging rate becomes the most common experimental measurement method. However, due to the limitation of response frequency and the disturbance of pebbles falling, the resolution of experimental results is limited, and the uncertainty is introduced into the data error, which is difficult to eliminate. In this experiment, a volume measurement based on drainage method is adopted. This is a new experimental method to measure the discharge process of hopper silo. The magnetostrictive liquid level sensor is applied to measure the rise of liquid level caused by the volume of falling pebbles. Compared with the weighing method, this method has two advantages. First, the resolution of this method has a higher controllability. On the one hand, the disturbance caused by the momentum of falling pebbles will not be introduced into this method, on the other hand, the measurement accuracy is determined by the multiple controllable factors. Second, this method can obtain higher measurement frequency. the sampling frequency of liquid level sensor is 1–2 orders of magnitude higher than that of electronictong balance. Based on this new experimental method, the reliability of the method is validated by comparing the experimental results of discharge flow rate with the Beverloo’s and Nedderman’s empirical formula. Furthermore, the effect of silo outlet size on pebble discharge flow rate fluctuation have been also analyzed in this study. By use of fast Fourier transform, the fluctuation of particle discharge flow rate is separated from the discharging sampling results of liquid level sensor.
Land Use and Cover Change in the Industrial Era: A Spatial Analysis of Alpine River Catchments and Fluvial Corridors
Authors: Hohensinner Severin , Atzler Ulrike , Berger Monika , Bozzetta Thomas , Höberth Christian , Kofler Martin , Rapottnig Leena , Sterle Yvonne , Haidvogl Gertrud
Published: June 2021

Land uses affect flood risks in various ways. The comparative analysis of the historical and current land cover/uses helps to better understand changing flood regimes. Based on historical cadastre maps from 1826 to 1859, the land cover/uses in the Austrian catchments of the rivers Rhine, Salzach and Drava were reconstructed to almost the level of exact plots of land. Catchment-wide analysis reveals a six-fold expansion of settlement areas, a decline of arable land by 69% and a shrinking of the formerly glaciated areas by 73% until 2016. In the Alpine fluvial corridors, i.e. flood-prone areas at the valley floors and valley sides at ca. 300-year floods, settlements even expanded 7.5-fold, severely increasing the potential for flood damages. At the same time, the overall channel area of running waters has been reduced by 40% and 95% the formerly large wetlands have been lost. Overall, the fluvial corridors were truncated by 203 km2 or 14%, thereby reducing flood retention capacity. The concentration of intensive forms of human land uses at lower altitudes, coupled with an upward shift of less intensively used, near-natural forms of land cover, has led to a both spatial and vertical separation of Alpine landscape features over the long term. Warmer temperatures due to climate change are expected to promote the demonstrated upward shifts of Alpine vegetation.
Gene Signature Associated With Bromodomain Genes Predicts the Prognosis of Kidney Renal Clear Cell Carcinoma
Authors: Lu Junwan , Qian Changrui , Ji Yongan , Bao Qiyu , Lu Bin
Published: June 2021

Bromodomain (BRD) proteins exhibit a variety of activities, such as histone modification, transcription factor recruitment, chromatin remodeling, and mediator or enhancer complex assembly, that affect transcription initiation and elongation. These proteins also participate in epigenetic regulation. Although specific epigenetic regulation plays an important role in the occurrence and development of cancer, the characteristics of the BRD family in renal clear cell carcinoma (KIRC) have not been determined. In this study, we investigated the expression of BRD family genes in KIRC at the transcriptome level and examined the relationship of the expression of these genes with patient overall survival. mRNA levels of tumor tissues and adjacent tissues were extracted from The Cancer Genome Atlas (TCGA) database. Seven BRD genes (KAT2A, KAT2B, SP140, BRD9, BRPF3, SMARCA2, and EP300) were searched by using LASSO Cox regression and the model with prognostic risk integration. The patients were divided into two groups: high risk and low risk. The combined analysis of these seven BRD genes showed a significant association with the high-risk groups and lower overall survival (OS). This analysis demonstrated that total survival could be predicted well in the low-risk group according to the time-dependent receiver operating characteristic (ROC) curve. The prognosis was determined to be consistent with that obtained using an independent dataset from TCGA. The relevant biological functions were identified using Gene Set Enrichment Analysis (GSEA). In summary, this study provides an optimized survival prediction model and promising data resources for further research investigating the role of the expression of BRD genes in KIRC.
Clinical Trials Supporting the Role of the IL-17/IL-23 Axis in Axial Spondyloarthritis
Authors: Ceribelli Angela , Motta Francesca , Vecellio Matteo , Isailovic Natasa , Ciccia Francesco , Selmi Carlo
Published: June 2021

The term spondyloarthritis (SpA) encompasses a heterogeneous group of inflammatory musculoskeletal diseases with several common genetic background and clinical features, including the possible involvement of the axial skeleton with peripheral mono- or oligo- arthritis and frequently coexisting skin, eye and intestinal manifestations. When the sacroiliac joints or other parts of the spine or thoracic wall are predominantly affected at magnetic resonance or X-ray imaging with inflammatory back pain, the disease is classified as axial SpA and the therapeutic choices are significantly different compared to cases of peripheral arthritis. Moving from the narrow effectiveness and safety profiles of non-steroidal anti-inflammatory drugs, there has been a significant research effort aimed at identifying new treatments based on our better understanding of the pathogenesis of SpA. Indeed, in parallel with the solid data demonstrating that IL-17 and IL-23 are key cytokines in the development of enthesitis and spondylitis, monoclonal antibodies interfering with this pathway have been developed for the treatment of axial SpA. Furthermore, the IL-17/IL-23 axis is key to extra-articular manifestations such as inflammatory bowel disease, uveitis, and psoriasis which are frequent comorbidities of SpA. Currently available drugs act through these mechanisms recognizing IL-23 and targeting IL-17, such as secukinumab and ixekizumab. These therapeutic approaches are now envisioned in the international treatment recommendations for psoriatic arthritis with an axial phenotype as well as for ankylosing spondylitis (AS). We will provide herein a concise comprehensive overview of the clinical evidence supporting the use of these and other drugs acting on IL-23 and IL-17 in axial SpA.
Resolvin E1 and Cytokines Environment in Skeletally Immature and Adult ACL Tears
Authors: Turati Marco , Franchi Silvia , Leone Giulio , Piatti Massimiliano , Zanchi Nicolò , Gandolla Marta , Rigamonti Luca , Sacerdote Paola , Rizzi Laura , Pedrocchi Alessandra , Omeljaniuk Robert J. , Zatti Giovanni , Torsello Antonio , Bigoni Marco
Published: June 2021

The intra-articular synovial fluid environment in skeletally immature patients following an ACL tear is complex and remains undefined. Levels of inflammatory and anti-inflammatory cytokines change significantly in response to trauma and collectively define the inflammatory environment. Of these factors the resolvins, with their inherent anti-inflammatory, reparative, and analgesic properties, have become prominent. This study examined the levels of resolvins and other cytokines after ACL tears in skeletally immature and adult patients in order to determine if skeletal maturity affects the inflammatory pattern. Skeletally immature and adult patients with an anterior cruciate ligament injury and meniscal tears were prospectively enrolled over a 5-month period. Synovial fluid samples were obtained before surgery quantifying Resolvin E1, IL-1β, TNF-α, and IL-10 by ELISA. Comparisons between skeletally immature patients and adults, the influence of meniscal tear, growth plate maturity and time from trauma were analyzed. Skeletally immature patients had significantly greater levels of Resolvin E1 and IL-10 compared with adults with an isolated anterior cruciate ligament lesion. Among the injured skeletally immature patients Resolvin E1 levels were greater in the open growth plate group compared with those with closing growth plates. Moreover, levels of Resolvin E1 and IL-10 appeared to decrease with time. Our results suggest that skeletally immature patients have a stronger activation of the Resolvin pattern compared to adult patients and that synovial fluid Resolvins could play an antinflammatory role in the knee after anterior cruciate ligament lesion and that its activity may be synergistic with that of IL-10.
Clinical Non-invasive Model to Predict Liver Inflammation in Chronic Hepatitis B With Alanine Aminotransferase ≤ 2 Upper Limit of Normal
Authors: Chen Shanshan , Huang Haijun
Published: June 2021

Background and Aim: Liver biopsy remains the gold standard for evaluating liver histology. However, it has certain limitations, and many patients refuse it. Non-invasive methods of liver evaluation are thus attracting considerable interest. In this study, we sought predictors of liver inflammation in chronic hepatitis B (CHB) patients with alanine aminotransferase (ALT) levels ≤ 2-fold the upper limit of normal (ULN); these may guide decisions on whether to commence antiviral therapy.

Methods: We retrospectively analyzed 720 patients with CHB who underwent liver biopsy and whose ALT levels were ≤2 ULN. The patients were randomly divided into a training and validation set. We used univariate and multivariate regression analyses of data from the training set to construct a model that predicted significant (grade ≥2) liver inflammation, and validated the model employing the validation set.

Results: Aspartate aminotransferase (AST) level, prothrombin time (PT), glutamyl transpeptidase (GGT) level, and anti-hepatitis B virus core antibody (anti-HBC) level were independent predictors of significant liver inflammation in CHB patients with ALT levels ≤ 2 ULN. A model featuring these four parameters afforded areas under the ROC curve of 0.767 and 0.714 for the training and validation sets. The model was more predictive than were the individual factors.

Conclusion: AST, GGT, anti-HBC, and PT reflect significant liver inflammation among CHB patients with ALT levels ≤ 2 ULN. Their combination indicates whether antiviral therapy is required.
Molecular Detection and Distribution of Six Medically Important Vibrio spp. in Selected Freshwater and Brackish Water Resources in Eastern Cape Province, South Africa
Authors: Abioye Oluwatayo E. , Osunla Ayodeji Charles , Okoh Anthony I.
Published: June 2021

Water resources contaminated with pathogenic Vibrio species are usually a source of devastating infection outbreaks that have been a public health concern in both developed and developing countries over the decades. The present study assessed the prevalence of six medically significant Vibrio species in some water resources in Eastern Cape Province, South Africa for 12 months. We detected vibrios in all the 194 water samples analyzed using polymerase chain reaction (PCR). The prevalence of Vibrio cholerae, Vibrio mimicus, Vibrio fluvialis, Vibrio vulnificus, Vibrio alginolyticus, and Vibrio parahaemolyticus in freshwater samples was 34, 19, 9, 2, 3, and 2%, and that in brackish water samples was 44, 28, 10, 7, 46, and 51%, respectively. The population of the presumptive Vibrio spp. isolated from freshwater (628) and brackish water (342) samples that were confirmed by PCR was 79% (497/628) and 85% (291/342), respectively. Twenty-two percent of the PCR-confirmed Vibrio isolates from freshwater (n = 497) samples and 41% of the PCR-confirmed Vibrio isolates from brackish water samples (n = 291) fall among the Vibrio species of interest. The incidences of V. cholerae, V. mimicus, V. fluvialis, V. vulnificus, V. alginolyticus, and V. parahaemolyticus amidst these Vibrio spp. of interest that were recovered from freshwater samples were 75, 14, 4, 6, 1, and 1%, whereas those from brackish water samples were 24, 7, 3, 3, 47, and 18%, respectively. Our observation during the study suggests pollution as the reason for the unusual isolation of medically important vibrios in winter. Correlation analysis revealed that temperature drives the frequency of isolation, whereas salinity drives the composition of the targeted Vibrio species at our sampling sites. The finding of the study is of public health importance going by the usefulness of the water resources investigated. Although controlling and preventing most of the factors that contribute to the prevalence of medically important bacteria, such as Vibrio species, at the sampling points might be difficult, regular monitoring for creating health risk awareness will go a long way to prevent possible Vibrio-related infection outbreaks at the sampling sites and their immediate environment.
Recent and Ongoing Horizontal Transfer of Mitochondrial Introns Between Two Fungal Tree Pathogens
Authors: Mayers Chase G. , Harrington Thomas C. , Wai Alvan , Hausner Georg
Published: June 2021

Two recently introduced fungal plant pathogens (Ceratocystis lukuohiaandCeratocystis huliohia) are responsible for Rapid ‘ōhi‘a Death (ROD) in Hawai‘i. Despite being sexually incompatible, the two pathogens often co-occur in diseased ‘ōhi‘a sapwood, where genetic interaction is possible. We sequenced and annotated 33 mitochondrial genomes of the two pathogens and related species, and investigated 35 totalCeratocystismitogenomes. Ten mtDNA regions [one group I intron, seven group II introns, and two autonomous homing endonuclease (HE) genes] were heterogeneously present inC. lukuohiamitogenomes, which were otherwise identical. Molecular surveys with specific primers showed that the 10 regions had uneven geographic distribution amongst populations ofC. lukuohia. Conversely, identical orthologs of each region were present in every studied isolate ofC. huliohiaregardless of geographical origin. Close relatives ofC. lukuohialacked or, rarely, had few and dissimilar orthologs of the 10 regions, whereas most relatives ofC. huliohiahad identical or nearly identical orthologs. Each region included or worked in tandem with HE genes or reverse transcriptase/maturases that could facilitate interspecific horizontal transfers from intron-minus to intron-plus alleles. These results suggest that the 10 regions originated inC. huliohiaand are actively moving to populations ofC. lukuohia, perhaps through transient cytoplasmic contact of hyphal tips (anastomosis) in the wound surface of ‘ōhi‘a trees. Such contact would allow for the transfer of mitochondria followed by mitochondrial fusion or cytoplasmic exchange of intron intermediaries, which suggests that further genomic interaction may also exist between the two pathogens.
Analysis of Antimicrobial Peptide Metabolome of Bacterial Endophyte Isolated From Traditionally Used Medicinal Plant Millettia pachycarpa Benth
Authors: Ngashangva Ng , Mukherjee Pulok , Sharma K. Chandradev , Kalita M. C. , Indira Sarangthem
Published: June 2021

Increasing prevalence of antimicrobial resistance (AMR) has posed a major health concern worldwide, and the addition of new antimicrobial agents is diminishing due to overexploitation of plants and microbial resources. Inevitably, alternative sources and new strategies are needed to find novel biomolecules to counter AMR and pandemic circumstances. The association of plants with microorganisms is one basic natural interaction that involves the exchange of biomolecules. Such a symbiotic relationship might affect the respective bio-chemical properties and production of secondary metabolites in the host and microbes. Furthermore, the discovery of taxol and taxane from an endophytic fungus, Taxomyces andreanae from Taxus wallachiana, has stimulated much research on endophytes from medicinal plants. A gram-positive endophytic bacterium, Paenibacillus peoriae IBSD35, was isolated from the stem of Millettia pachycarpa Benth. It is a rod-shaped, motile, gram-positive, and endospore-forming bacteria. It is neutralophilic as per Joint Genome Institute’s (JGI) IMG system analysis. The plant was selected based on its ethnobotany history of traditional uses and highly insecticidal properties. Bioactive molecules were purified from P. peoriae IBSD35 culture broth using 70% ammonium sulfate and column chromatography techniques. The biomolecule was enriched to 151.72-fold and the yield percentage was 0.05. Peoriaerin II, a highly potent and broad-spectrum antimicrobial peptide against Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, and Candida albicans ATCC 10231 was isolated. LC-MS sequencing revealed that its N-terminal is methionine. It has four negatively charged residues (Asp + Glu) and a total number of two positively charged residues (Arg + Lys). Its molecular weight is 4,685.13 Da. It is linked to an LC-MS/MS inferred biosynthetic gene cluster with accession number A0A2S6P0H9, and blastp has shown it is 82.4% similar to fusaricidin synthetase of Paenibacillus polymyxa SC2. The 3D structure conformation of the BGC and AMP were predicted using SWISS MODEL homology modeling. Therefore, combining both genomic and proteomic results obtained from P. peoriae IBSD35, associated with M. pachycarpa Benth., will substantially increase the understanding of antimicrobial peptides and assist to uncover novel biological agents.
Investigation of Spaceflight Induced Changes to Astronaut Microbiomes
Authors: Morrison Michael D. , Thissen James B. , Karouia Fathi , Mehta Satish , Urbaniak Camilla , Venkateswaran Kasthuri , Smith David J. , Jaing Crystal
Published: June 2021

The International Space Station (ISS) is a uniquely enclosed environment that has been continuously occupied for the last two decades. Throughout its operation, protecting the health of the astronauts on-board has been a high priority. The human microbiome plays a significant role in maintaining human health, and disruptions in the microbiome have been linked to various diseases. To evaluate the effects of spaceflight on the human microbiome, body swabs and saliva samples were collected from four ISS astronauts on consecutive expeditions. Astronaut samples were analyzed using shotgun metagenomic sequencing and microarrays to characterize the microbial biodiversity before, during, and after the astronauts’ time onboard the ISS. Samples were evaluated at an individual and population level to identify changes in microbial diversity and abundance. No significant changes in the number or relative abundance of taxa were observed between collection time points when samples from all four astronauts were analyzed together. When the astronauts’ saliva samples were analyzed individually, the saliva samples of some astronauts showed significant changes in the relative abundance of taxa during and after spaceflight. The relative abundance ofPrevotellain saliva samples increased during two astronauts’ time onboard the ISS while the relative abundance of other commensal taxa such asNeisseria,Rothia, andHaemophilusdecreased. The abundance of some antimicrobial resistance genes within the saliva samples also showed significant changes. Most notably, elfamycin resistance gene significantly increased in all four astronauts post-flight and a CfxA6 beta-lactam marker significantly increased during spaceflight but returned to normal levels post-flight. The combination of both shotgun metagenomic sequencing and microarrays showed the benefit of both technologies in monitoring microbes on board the ISS. There were some changes in each astronaut’s microbiome during spaceflight, but these changes were not universal for all four astronauts. Two antimicrobial resistance gene markers did show a significant change in abundance in the saliva samples of all four astronauts across their collection times. These results provide insight for future ISS microbial monitoring studies and targets for antimicrobial resistance screenings.
Counteracting Bacterial Motility: A Promising Strategy to Narrow Listeria monocytogenes Biofilm in Food Processing Industry
Authors: Doghri Ibtissem , Cherifi Tamazight , Goetz Coralie , Malouin François , Jacques Mario , Fravalo Philippe
Published: June 2021

Listeria monocytogenes (L. monocytogenes) is often associated with processed food as it can form biofilms that represent a source of contamination at all stages of the manufacturing chain. The control and prevention of biofilms in food-processing plants are of utmost importance. This study explores the efficacy of prospect molecules for counteracting bacterial mechanisms leading to biofilm formation. The compounds included the phytomolecule tomatidine, zinc chloride (ZnCl2), ethylenediaminetetraacetic acid (EDTA), and a more complexed mixture of bacterial compounds from coagulase-negative staphylococci (CNS exoproducts). Significant inhibition of L. monocytogenes biofilm formation was evidenced using a microfluidic system and confocal microscopic analyses (p < 0.001). Active molecules were effective at an early stage of biofilm development (≥50% of inhibition) but failed to disperse mature biofilms of L. monocytogenes. According to our findings, prevention of surface attachment was associated with a disruption of bacterial motility. Indeed, agar cell motility assays demonstrated the effectiveness of these molecules. Overall, results highlighted the critical role of motility in biofilm formation and allow to consider flagellum-mediated motility as a promising molecular target in control strategies against L. monocytogenes in food processing environments.
A Bacteriophage DNA Mimic Protein Employs a Non-specific Strategy to Inhibit the Bacterial RNA Polymerase
Authors: Wang Zhihao , Wang Hongliang , Mulvenna Nancy , Sanz-Hernandez Maximo , Zhang Peipei , Li Yanqing , Ma Jia , Wang Yawen , Matthews Steve , Wigneshweraraj Sivaramesh , Liu Bing
Published: June 2021

DNA mimicry by proteins is a strategy that employed by some proteins to occupy the binding sites of the DNA-binding proteins and deny further access to these sites by DNA. Such proteins have been found in bacteriophage, eukaryotic virus, prokaryotic, and eukaryotic cells to imitate non-coding functions of DNA. Here, we report another phage protein Gp44 from bacteriophage SPO1 of Bacillus subtilis, employing mimicry as part of unusual strategy to inhibit host RNA polymerase. Consisting of three simple domains, Gp44 contains a DNA binding motif, a flexible DNA mimic domain and a random-coiled domain. Gp44 is able to anchor to host genome and interact bacterial RNA polymerase via the β and β′ subunit, resulting in bacterial growth inhibition. Our findings represent a non-specific strategy that SPO1 phage uses to target different bacterial transcription machinery regardless of the structural variations of RNA polymerases. This feature may have potential applications like generation of genetic engineered phages with Gp44 gene incorporated used in phage therapy to target a range of bacterial hosts.
Neurotrophic Factors in Parkinson’s Disease: Clinical Trials, Open Challenges and Nanoparticle-Mediated Delivery to the Brain
Authors: Bondarenko Olesja , Saarma Mart
Published: June 2021

Neurotrophic factors (NTFs) are small secreted proteins that support the development, maturation and survival of neurons. NTFs injected into the brain rescue and regenerate certain neuronal populations lost in neurodegenerative diseases, demonstrating the potential of NTFs to cure the diseases rather than simply alleviating the symptoms. NTFs (as the vast majority of molecules) do not pass through the blood–brain barrier (BBB) and therefore, are delivered directly into the brain of patients using costly and risky intracranial surgery. The delivery efficacy and poor diffusion of some NTFs inside the brain are considered the major problems behind their modest effects in clinical trials. Thus, there is a great need for NTFs to be delivered systemically thereby avoiding intracranial surgery. Nanoparticles (NPs), particles with the size dimensions of 1-100 nm, can be used to stabilize NTFs and facilitate their transport through the BBB. Several studies have shown that NTFs can be loaded into or attached onto NPs, administered systemically and transported to the brain. To improve the NP-mediated NTF delivery through the BBB, the surface of NPs can be functionalized with specific ligands such as transferrin, insulin, lactoferrin, apolipoproteins, antibodies or short peptides that will be recognized and internalized by the respective receptors on brain endothelial cells. In this review, we elaborate on the most suitable NTF delivery methods and envision “ideal” NTF for Parkinson’s disease (PD) and clinical trial thereof. We shortly summarize clinical trials of four NTFs, glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), platelet-derived growth factor (PDGF-BB), and cerebral dopamine neurotrophic factor (CDNF), that were tested in PD patients, focusing mainly on GDNF and CDNF. We summarize current possibilities of NP-mediated delivery of NTFs to the brain and discuss whether NPs have impact in improving the properties of NTFs and delivery across the BBB. Emerging delivery approaches and future directions of NTF-based nanomedicine are also discussed.
QLCA and Entangled States as Single-Neuron Activity Generators
Authors: Roth Yehuda
Published: June 2021

Each neuron in the central nervous system has many dendrites, which provide input information through impulses. Assuming that a neuron's decision to continue or stop firing is made by rules applied to the dendrites' inputs, we associate neuron activity with a quantum like-cellular automaton (QLCA) concepts. Following a previous study that related the CA description with entangled states, we provide a quantum-like description of neuron activity. After reviewing and presenting the entanglement concept expressed by QLCA terminology, we propose a model that relates quantum-like measurement to consciousness. Then, we present a toy model that reviews the QLCA theory, which is adapted to our terminology. The study also focuses on implementing QLCA formalism to describe a single neuron activity.
Endovascular Therapy vs. Thrombolysis in Pre-stroke Dependent Patients With Large Vessel Occlusions Within the Anterior Circulation
Authors: Kastrup Andreas , Roth Christian , Politi Maria , Alexandrou Maria , Hildebrandt Helmut , Schröter Andreas , Papanagiotou Panagiotis
Published: June 2021

Background: In the past few years, several randomized trials have clearly shown that endovascular treatment (ET) in addition to intravenous thrombolysis (IVT) is superior to IVT alone in patients with proximal cerebral arterial occlusions. However, the effectiveness of ET in pre-stroke dependent patients (modified Rankin Scale ≥3) is uncertain.

Methods: Using our prospectively obtained stroke database, we analyzed the impact of pre-stroke dependence on the rates of poor outcome (discharge mRS 5–6), in-hospital death, infarct sizes, and symptomatic intracranial hemorrhage (SICH) in patients with distal intracranial carotid artery M1 and M2 occlusions during two time periods.

Results: From 1/2008 to 10/2012, a total of 544 patients (455 without and 89 with dependence) were treated with IVT, and from 11/2012 to 12/2019 a total of 1,061 patients (919 without and 142 with dependence) received ET (with or without IVT). Irrespective of the treatment modality, the dependent patients had significantly higher rates of poor outcome (55 vs. 32%, p < 0.001), death (24 vs. 11%; p < 0.001), or SICH (8.2 vs. 3.6%, p < 0.01) than independent patients. In dependent patients, ET significantly reduced the rates of poor outcome (49 vs. 64%, p < 0.01) and led to smaller infarcts, whereas the rates of in-hospital death (25 vs. 22%; p = 0.6) or SICH (8.5 vs. 7.9%, p = 0.9) were comparable between both treatment modalities.

Conclusions: Compared with IVT, ET avoids poor outcome and leads to smaller infarcts in dependent patients. However, the overall high rates of poor outcome in this patient population stress the importance to perform decisions based on a case-by-case basis.
The Electrophysiological Correlates of Phoneme Perception in Primary Progressive Aphasia: A Preliminary Case Series
Authors: Stalpaert Jara , Miatton Marijke , Sieben Anne , Van Langenhove Tim , van Mierlo Pieter , De Letter Miet
Published: June 2021

Aims: This study aimed to investigate phoneme perception in patients with primary progressive aphasia (PPA) by using the event-related potential (ERP) technique. These ERP components might contribute to the diagnostic process of PPA and its clinical variants (NFV: nonfluent variant, SV: semantic variant, LV: logopenic variant) and reveal insights about phoneme perception processes in these patients.

Method: Phoneme discrimination and categorization processes were investigated by the mismatch negativity (MMN) and P300 in eight persons with early- and late-stage PPA (3 NFV, 2 LV, 2 SV, and 1 PPA-NOS; not otherwise specified) and 30 age-matched healthy adults. The mean amplitude, the onset latency, and the topographic distribution of both components in each patient were compared to the results of the control group.

Results: The MMN was absent or the onset latency of the MMN was delayed in the patients with the NFV, LV, and PPA-NOS in comparison to the control group. In contrast, no differences in mean amplitudes and onset latencies of the MMN were found between the patients with the SV and the control group. Concerning the P300, variable results were found in the patients with the NFV, SV, and PPA-NOS, but the P300 of both patients with the LV was delayed and prolonged with increased mean amplitude in comparison to the control group.

Conclusion: In this preliminary study, phoneme discrimination deficits were found in the patients with the NFV and LV, and variable deficits in phoneme categorization processes were found in all patients with PPA. In clinical practice, the MMN might be valuable to differentiate the SV from the NFV and the LV and the P300 to differentiate the LV from the NFV and the SV. Further research in larger and independent patient groups is required to investigate the applicability of these components in the diagnostic process and to determine the nature of these speech perception deficits in the clinical variants of PPA.
Discovery of a Highly Conserved Peptide in the Iron Transporter Melanotransferrin that Traverses an Intact Blood Brain Barrier and Localizes in Neural Cells
Authors: Singh Chaahat S. B. , Eyford Brett A. , Abraham Thomas , Munro Lonna , Choi Kyung Bok , Okon Mark , Vitalis Timothy Z. , Gabathuler Reinhard , Lu Chieh-Ju , Pfeifer Cheryl G. , Tian Mei Mei , Jefferies Wilfred A.
Published: June 2021

The blood-brain barrier (BBB) hinders the distribution of therapeutics intended for treatment of diseases of the brain. Our previous studies demonstrated that that a soluble form of melanotransferrin (MTf; Uniprot P08582; also known as p97, MFI2, and CD228), a mammalian iron-transport protein, is an effective carrier for delivery of drug conjugates across the BBB into the brain and was the first BBB targeting delivery system to demonstrate therapeutic efficacy within the brain. Here, we performed a screen to identify peptides from MTf capable of traversing the BBB. We identified a highly conserved 12-amino acid peptide, termed MTfp, that retains the ability to cross the intact BBB undigested, distribute throughout the parenchyma, and enter endosomes and lysosomes within neurons, astrocytes and microglia in the brain. This peptide may provide a platform for the transport of therapeutics to the CNS, and thereby offers new avenues for potential treatments of neuropathologies that are currently refractory to existing therapies.
Detection Methods and Clinical Applications of Circulating Tumor Cells in Breast Cancer
Authors: Zhang Hongyi , Lin Xiaoyan , Huang Yuan , Wang Minghong , Cen Chunmei , Tang Shasha , Dique Marcia R. , Cai Lu , Luis Manuel A. , Smollar Jillian , Wan Yuan , Cai Fengfeng
Published: June 2021

Circulating Tumor Cells (CTCs) are cancer cells that split away from the primary tumor and appear in the circulatory system as singular units or clusters, which was first reported by Dr. Thomas Ashworth in 1869. CTCs migrate and implantation occurs at a new site, in a process commonly known as tumor metastasis. In the case of breast cancer, the tumor cells often migrate into locations such as the lungs, brain, and bones, even during the early stages, and this is a notable characteristic of breast cancer. Survival rates have increased significantly over the past few decades because of progress made in radiology and tissue biopsy, making early detection and diagnosis of breast cancer possible. However, liquid biopsy, particularly that involving the collection of CTCs, is a non-invasive method to detect tumor cells in the circulatory system, which can be easily isolated from human plasma, serum, and other body fluids. Compared to traditional tissue biopsies, fluid sample collection has the advantages of being readily available and more acceptable to the patient. It can also detect tumor cells in blood earlier and in smaller numbers, possibly allowing for diagnosis prior to any tumor detection using imaging methods. Because of the scarcity of CTCs circulating in blood vessels (only a few CTCs among billions of erythrocytes and leukocytes), thorough but accurate detection methods are particularly important for further clinical applications.
Knockdown of MUC16 (CA125) Enhances the Migration and Invasion of Hepatocellular Carcinoma Cells
Authors: Huang Yao , Huang Xiaoyu , Zeng Jianxing , Lin Jun
Published: June 2021

As an important global medical problem, hepatocellular carcinoma (HCC) has been recognized as the most frequent primary liver cancer and a leading cause of death among patients with cirrhosis. Surveillance of HCC using serum markers aims to reduce the disease-related mortality of HCC. MUC16 (mucin 16, also known as carbohydrate antigen 125, CA125) has been predicted as a tumor biomarker for many cancer types. Based on the high frequency mutation rate in a database from the Cancer Genome Atlas (TCGA), we investigated the effects of MUC16 knockdown and the regulatory profile of MUC16 in HepG2 and Huh7 cell lines. Knockdown of MUC16 was conducted via siRNA transfection, and the proliferation of cells was not affected by CCK8 assay results. Moreover, decreasing the expression of MUC16 enhanced the migration and invasion of cells, as shown by wound healing and transwell assays. Furthermore, RNA-seq was used to investigate the effect of MUC16 knockdown on the gene expression profile of HepG2 and Huh7 cells. Our study demonstrated the significant role of MUC16 in the inhibition of the migration and invasion of HepG2 and Huh7 cells.
Neuroprotective Potentials of Panax Ginseng Against Alzheimer’s Disease: A Review of Preclinical and Clinical Evidences
Authors: Li Jing , Huang Qingxia , Chen Jinjin , Qi Hongyu , Liu Jiaqi , Chen Zhaoqiang , Zhao Daqing , Wang Zeyu , Li Xiangyan
Published: June 2021

Alzheimer’s disease (AD), a neurodegenerative disorder, is a major health concern in the increasingly aged population worldwide. Currently, no clinically effective drug can halt the progression of AD. Panax ginseng C.A. Mey. is a well-known medicinal plant that contains ginsenosides, gintonin, and other components and has neuroprotective effects against a series of pathological cascades in AD, including beta-amyloid formation, neuroinflammation, oxidative stress, and mitochondrial dysfunction. In this review, we summarize the effects and mechanisms of these major components and formulas containing P. ginseng in neuronal cells and animal models. Moreover, clinical findings regarding the prevention and treatment of AD with P. ginseng or its formulas are discussed. This review can provide new insights into the possible use of ginseng in the prevention and treatment of AD.
Norepinephrine Is a Major Regulator of Pineal Gland Secretory Activity in the Domestic Goose (Anser anser)
Authors: Ziółkowska Natalia , Lewczuk Bogdan
Published: June 2021

This study determined the effect of norepinephrine and light exposure on melatonin secretion in goose pineal explants. Additionally, it investigated changes in the content of norepinephrine, dopamine, and their metabolites [3,4-dihydroxyphenylacetic acid; vanillylmandelic acid (VMA); homovanillic acid] in goose pineal glands in vivo under 12 h of light and 12 h of darkness (LD), a reversed cycle (DL), constant light (LL), and constant darkness (DD). In vitro content of melatonin was measured by radioimmunoassay; contents of catecholamines and their metabolites were measured by high-performance liquid chromatography. Exposure of pineal explants to LD or DL established rhythmic melatonin secretion; this rhythm was much better entrained with norepinephrine exposure during photophase than without it. When the explants were kept in LL or DD, the rhythm was abolished, unless NE was administered during natural scotophase of a daily cycle. In vivo, norepinephrine and dopamine levels did not display rhythmic changes, but their respective metabolites, HMV and VMA, displayed well-entrained diurnal rhythms. These results indicate that norepinephrine and sympathetic innervation play key roles in regulation of pineal secretory activity in geese, and that pineal levels of VMA and HMV provide precise information about the activity of sympathetic nerve fibers in goose pineal glands.
Black Soldier Fly-Composted Organic Fertilizer Enhances Growth, Yield, and Nutrient Quality of Three Key Vegetable Crops in Sub-Saharan Africa
Authors: Anyega Abel O. , Korir Nicholas K. , Beesigamukama Dennis , Changeh Ghemoh J. , Nkoba Kiatoko , Subramanian Sevgan , van Loon Joop J. A. , Dicke Marcel , Tanga Chrysantus M.
Published: June 2021

Worldwide, French beans (Phaseolus vulgaris L.), tomato (Solanum lycopersicum L.), and kales (Brassica oleracea L. var. acephala) are considered economically important food crops. There is a rapid decline in their yield due to severe soil degradation. Thus, high commercial fertilizer inputs are crucial, though they remain expensive and inaccessible to resource poor farmers. We investigated the comparative performance of composted black soldier fly frass fertilizer (BSFFF), conventionally composted brewer's spent grain (BSG), commercial organic fertilizer (Evergrow), and mineral [nitrogen, phosphorus, and potassium (NPK)] fertilizer on growth, yield, N use efficiency, and nutritional quality (crude protein, crude fiber, crude fats, ash, and carbohydrate concentrations) of tomatoes, kales, and French beans under greenhouse and open-field conditions for two seasons. The fertilizers were applied at rates equivalent to 371 kg of N ha−1. For each crop, the plots were treated with sole rates of BSFFF, BSG, Evergrow, and NPK to supply 100% of the N required. Additional treatments included a combination of BSFFF and NPK, and BSG and NPK so that each fertilizer supplies 50% of the N required. The control treatment consisted of unfertilized soil. Results show that vegetable yields achieved using a combination of BSFFF and NPK were 4.5, 2.4, and 5.4-folds higher than the yield from the control treatment for tomatoes, kales, and French beans, respectively. The combined application of BSFFF and NPK produced 22–135%, 20–27%, and 38–50% higher yields than sole NPK for tomatoes, kales, and French beans, respectively, under both greenhouse and open-field conditions. The highest agronomic N use efficiency was achieved in sole BSFFF-treated plots compared to sole BSG and Evergrow. The N taken up by the vegetables was significantly higher when BSFFF and NPK were integrated. Vegetables grown using a combination of BSFFF and NPK had the highest crude protein and ash concentrations. Our findings demonstrate that the integration of BSFFF and NPK in vegetable cropping systems at the recommended rate of 1.24 t ha−1 BSFFF and 322 kg ha−1 NPK would improve soil health, boost yield, and nutritional quality of vegetable crops.
Does Goal Conflict Necessarily Undermine Wellbeing? A Moderated Mediating Effect of Mixed Emotion and Construal Level
Authors: Sun Wujun , Zheng Zeqing , Jiang Yuan , Tian Li , Fang Ping
Published: June 2021

Development occurs through the process of setting and working toward goals, in which individuals are often working toward multiple goals that are likely to conflict with one another. Although motivation theories hold that goal conflict is a kind of potential stress that may damage individuals’ mental health and wellbeing, the empirical research results on the relationship between goal conflict and wellbeing are quite different. There may be unknown factors affecting the relationship between the two. Against this background, we conducted the exploration of the relationship between goal conflict and life satisfaction, mainly by analyzing the moderated mediating effect of mixed emotions and construal level. The results showed that the goal conflict did not directly affect life satisfaction (β = −0.01, p > 0.5) but indirectly influenced life satisfaction through mixed emotions (β = −0.17, p < 0.001). The construal level moderated the relationship between mixed emotions and life satisfaction (β = −0.08, p < 0.01), and the higher construal level will predict higher life satisfaction especially when mixed emotions were low (M − SD) or medium (M). Therefore, the hypothesis of moderated mediating effect is verified, and we can draw the following conclusions: (1) Goal conflict does not necessarily impair life satisfaction. (2) Goal conflict impairs life satisfaction conditional on the fact that it triggers mixed emotions. Since mixed emotions are often accompanied by feelings of ambivalence and discomfort, they reduce the individual’s evaluation of life satisfaction. (3) In the path of goal conflict reducing life satisfaction through mixed emotions, the higher construal level mitigates the adverse effects of mixed emotions to some extent.
Modeling Wording Effects Does Not Help in Recovering Uncontaminated Person Scores: A Systematic Evaluation With Random Intercept Item Factor Analysis
Authors: Nieto María Dolores , Garrido Luis Eduardo , Martínez-Molina Agustín , Abad Francisco José
Published: June 2021

The item wording (or keying) effect consists of logically inconsistent answers to positively and negatively worded items that tap into similar (but polarly opposite) content. Previous research has shown that this effect can be successfully modeled through the random intercept item factor analysis (RIIFA) model, as evidenced by the improvements in the model fit in comparison to models that only contain substantive factors. However, little is known regarding the capability of this model in recovering the uncontaminated person scores. To address this issue, the study analyzes the performance of the RIIFA approach across three types of wording effects proposed in the literature: carelessness, item verification difficulty, and acquiescence. In the context of unidimensional substantive models, four independent variables were manipulated, using Monte Carlo methods: type of wording effect, amount of wording effect, sample size, and test length. The results corroborated previous findings by showing that the RIIFA models were consistently able to account for the variance in the data, attaining an excellent fit regardless of the amount of bias. Conversely, the models without the RIIFA factor produced increasingly a poorer fit with greater amounts of wording effects. Surprisingly, however, the RIIFA models were not able to better estimate the uncontaminated person scores for any type of wording effect in comparison to the substantive unidimensional models. The simulation results were then corroborated with an empirical dataset, examining the relationship between learning strategies and personality with grade point average in undergraduate studies. The apparently paradoxical findings regarding the model fit and the recovery of the person scores are explained, considering the properties of the factor models examined.