bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluorination Enables Tunable Molecular Interaction and Photovoltaic Performance in Non-Fullerene Solar Cells Based on Ester-Substituted Polythiophene
Authors: Liang Ziqi , Gao Mengyuan , Zhang Bo , Wu Junjiang , Peng Zhongxiang , Li Miaomiao , Ye Long , Geng Yanhou
Published: May 2021

Owing to the advantages of low synthetic cost and high scalability of synthesis, polythiophene and its derivatives (PTs) have been of interest in the community of organic photovoltaics (OPVs). Nevertheless, the typical efficiency of PT based photovoltaic devices reported so far is much lower than those of the prevailing push-pull type conjugated polymer donors. Recent studies have underscored that the excessively low miscibility between PT and nonfullerene acceptor is the major reason accounting for the unfavorable active layer morphology and the inferior performance of OPVs based on a well-known PT, namely PDCBT-Cl and a non-halogenated nonfullerene acceptor IDIC. How to manipulate the miscibility between PT and acceptor molecule is important for further improving the device efficiency of this class of potentially low-cost blend systems. In this study, we introduced different numbers of F atoms to the end groups of IDIC to tune the intermolecular interaction of the hypo-miscible blend system (PDCBT-Cl:IDIC). Based on calorimetric, microscopic, and scattering characterizations, a clear relationship between the number of F atoms, miscibility, and device performance was established. With the increased number of F atoms in IDIC, the resulting acceptors exhibited enhanced miscibility with PDCBT-Cl, and the domain sizes of the blend films were reduced substantially. As a result, distinctively different photovoltaic performances were achieved for these blend systems. This study demonstrates that varying the number of F atoms in the acceptors is a feasible way to manipulate the molecular interaction and the film morphology toward high-performance polythiophene:nonfullerene based OPVs.
Panomics: New Databases for Advancing Cardiology
Authors: Vakili Dara , Radenkovic Dina , Chawla Shreya , Bhatt Deepak L.
Published: May 2021

The multifactorial nature of cardiology makes it challenging to separate noisy signals from confounders and real markers or drivers of disease. Panomics, the combination of various omic methods, provides the deepest insights into the underlying biological mechanisms to develop tools for personalized medicine under a systems biology approach. Questions remain about current findings and anticipated developments of omics. Here, we search for omic databases, investigate the types of data they provide, and give some examples of panomic applications in health care. We identified 104 omic databases, of which 72 met the inclusion criteria: genomic and clinical measurements on a subset of the database population plus one or more omic datasets. Of those, 65 were methylomic, 59 transcriptomic, 41 proteomic, 42 metabolomic, and 22 microbiomic databases. Larger database sample sizes and longer follow-up are often better suited for panomic analyses due to statistical power calculations. They are often more complete, which is important when dealing with large biological variability. Thus, the UK BioBank rises as the most comprehensive panomic resource, at present, but certain study designs may benefit from other databases.
Applying Simulated Seismic Damage Scenarios in the Volcanic Region of Mount Etna (Sicily): A Case-Study From the MW 4.9, 2018 Earthquake
Authors: Pessina Vera , Meroni Fabrizio , Azzaro Raffaele , D’Amico Salvatore
Published: May 2021

An application for a quick earthquake damage scenario assessment is here presented as a potential tool for planning prevention actions or managing seismic emergencies in the volcanic region of Mt. Etna (Italy). As case-study, we considered the December 26, 2018 earthquake that, with a magnitude MW 4.9, represents the largest event occurring in the area during the last 70 years. The QUEST working group (the INGV macroseismic team) carried out a detailed survey in the damage area, collecting data on the number of buildings in the different vulnerability classes and related damage, with the aim to assign intensity. The maximum intensity reached degree VIII EMS along a narrow strip extending for 5 km astride the Fiandaca fault. In this paper, we simulated the damage scenario in the most struck municipalities of the epicentral area by testing different methodological approaches proposed in the literature using the information of the ISTAT census data collected by the Italian Institute of Statistics. We evaluated the damage level of the residential buildings and we validated the results comparing with the real damage data recognized in the field. Our analysis highlighted the difficulty of applying methods calibrated for larger earthquakes in tectonic domains, to small magnitude events in volcanic zones, where some operating assumptions must be introduced. Despite this, the results confirm the potential of the simulations based on statistical damage assessment methods also in these peculiar conditions, opening the way to finalized plans of pre- and post-earthquake interventions.
Test on the Reliability of the Subsurface Fault Geometry Estimated by Deformed River Terraces Along the Bailang River, North Front of the Qilian Shan (North West China)
Authors: Hu Xiaofei , Ji Xianghe , Cao Xilin , Chen Jiuying , Pan Baotian
Published: May 2021

The subsurface fault geometry is the base for understanding a process of crust deformation and mountain building. Based on kinematic models for fault-related folds, a geomorphic method is recently applied to estimate the subsurface fault geometry, while the validation on its reliability is lacking. In this study, we surveyed a suit of river terrace surfaces across an active fold at the north front of the Qilian Shan. According to the deformation geometry of the terraces, the fold deformation is interpreted by a listric fault fold model, and based on this kinematic model, the fault geometry underlying the fold is estimated. In comparison between the estimated fault geometry and a seismic reflection profile, we found that the decollement depth and the back thrust are highly consistent with each other. Although some small fault bends or internal shearing cannot be estimated solely by the terrace deformation, the overall fault geometry is successfully revealed by the terrace deformation. Using this fault geometry and the terrace dating results, the region deformation kinematics are re-evaluated, which suggest that the dip slip (in a rate of 1.8 ± 0.4 mm/a) along the decollement is mainly accommodated by two structures, one is the blind-back-thrust fault within the piggy basin in a dip-slip rate of 0.9 ± 0.3 mm/a and another is the thrust and fold at the west portion of the Yumu Shan range.
In Vivo and In Situ Approach to Study Islet Microcirculation: A Mini-Review
Authors: Dybala Michael P. , Hara Manami
Published: May 2021

The pancreas is regarded as consisting of two separate organ systems, the endocrine and exocrine pancreas. While treatment of a disease with either an endocrine or exocrine pathogenesis may affect the function of the entire pancreas, the pancreatic diseases have been treated by clinicians in different medical disciplines, including endocrinologists and gastroenterologists. Islet microcirculation has long been considered to be regulated independently from that of the exocrine pancreas. A new model proposes that pancreatic islet blood flow is integrated with the surrounding exocrine capillary network. This recent model may provide revived or contrasting hypotheses to test, since the pancreatic microcirculation has critical implications for the regulation of islet hormones as well as acinar pancreas functions. In this mini-review, practical applications ofin vivoandin situstudies of islet microcirculation are described with a specific emphasis on large-scale data analysis to ensure sufficient sample size accounting for known islet heterogeneity. Forin vivosmall animal studies, intravital microscopy based on two-photon excitation microscopes is a powerful tool that enables capturing the flow direction and speed of individual fluorescent-labeled red blood cells. Complementarily, for structural analysis of blood vessels, the recent technical advancements of confocal microscopy and tissue clearing have enabled us to image the three-dimensional network structure in thick tissue slices.
A Handful of Details to Ensure the Experimental Reproducibility on the FORCED Running Wheel in Rodents: A Systematic Review
Authors: Garrigos Daniel , Martínez-Morga Marta , Toval Angel , Kutsenko Yevheniy , Barreda Alberto , Do Couto Bruno Ribeiro , Navarro-Mateu Fernando , Ferran José Luis
Published: May 2021

A well-documented method and experimental design are essential to ensure the reproducibility and reliability in animal research. Experimental studies using exercise programs in animal models have experienced an exponential increase in the last decades. Complete reporting of forced wheel and treadmill exercise protocols would help to ensure the reproducibility of training programs. However, forced exercise programs are characterized by a poorly detailed methodology. Also, current guidelines do not cover the minimum data that must be included in published works to reproduce training programs. For this reason, we have carried out a systematic review to determine the reproducibility of training programs and experimental designs of published research in rodents using a forced wheel system. Having determined that most of the studies were not detailed enough to be reproducible, we have suggested guidelines for animal research using FORCED exercise wheels, which could also be applicable to any form of forced exercise.
The Role of Inositol in Thyroid Physiology and in Subclinical Hypothyroidism Management
Authors: Benvenga Salvatore , Nordio Maurizio , Laganà Antonio Simone , Unfer Vittorio
Published: May 2021

Myo-Inositol (MYO) is the most abundant stereoisomer of inositols’ family, cyclic polyols with 6 hydroxyl groups. Myo-Inositol has a relevant role in thyroid function and autoimmune diseases, as a precursor of phosphoinositides that takes part in the phosphatidylinositol (PI) signal transduction pathway. Among phosphoinositides, phosphatidylinositol 4,5- bisphosphate (PIP2) is the precursor of inositol triphosphates (IP3), second messenger of several hormones including thyroid-stimulating hormone (TSH). As a second messenger in the phospholipase C (PLC)-dependent inositol phosphate Ca2+/DAG pathway, Myo-Inositol is essential to produce H2O2 required for the synthesis of thyroid hormones. Consequently, depletion of Myo-Inositol or impaired inositol dependent TSH signaling pathway may predispose to the development of some thyroid diseases, such as hypothyroidism. Many clinical studies have shown that after treatment with Myo-Inositol plus Selenium (MYO+Se), TSH levels significantly decreased in patients with subclinical hypothyroidism with or without autoimmune thyroiditis. The TSH reduction was accompanied by a decline of antithyroid autoantibodies. Moreover, Myo-Inositol supplementation seemed to be involved also in the management of thyroidal benign nodules, with a possible effect in the size reduction. This review proposes a summary of the role of inositol, especially of Myo-Inositol, in the thyroidal physiology and its contribution on the management of some thyroid diseases.
Gene-Environmental Interactions as Metabolic Drivers of Nonalcoholic Steatohepatitis
Authors: Albhaisi Somaya , Sanyal Arun J.
Published: May 2021

Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide in the past few decades as a consequence of the global obesity epidemic and is associated with significant morbidity and mortality. NAFLD is closely associated with components of the metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease, suggesting a plausible metabolic mechanistic basis. Metabolic inflexibility is considered a nidus for NAFLD pathogenesis, causing lipotoxicity, mitochondrial dysfunction and cellular stress leading to inflammation, apoptosis and fibrogenesis, thus mediating disease progression into nonalcoholic steatohepatitis (NASH) and ultimately cirrhosis. In this review, we describe they key metabolic drivers that contribute to development of NAFLD and NASH, and we explain how NASH is a metabolic disease. Understanding the metabolic basis of NASH is crucial for the prevention and treatment of this disease.
Metastasis of cN0 Papillary Thyroid Carcinoma of the Isthmus to the Lymph Node Posterior to the Right Recurrent Laryngeal Nerve
Authors: Du Wei , Fang Qigen , Zhang Xu , Dai Liyuan
Published: May 2021

Objective

The association between metastasis to the lymph node posterior to the right recurrent laryngeal nerve (LN-prRLN) and cN0 papillary thyroid carcinoma (PTC) located in the thyroid isthmus remains unknown; therefore, our goal was to analyze the characteristics of LN-prRLN metastasis of cN0 PTCs of the thyroid isthmus and determine its potential predictors.

Patients and methods

This retrospective study included patients who underwent bilateral central neck dissection between January 2018 and January 2021. The specimen was divided into five groups of prelaryngeal lymph node (LN), pretracheal LN, left paratracheal LN, lymph node anterior to the right recurrent laryngeal nerve (LN-arRLN), and LN-prRLN. Univariate and multivariate analyses were used to assess the association between the clinical pathologic variables and LN-prRLN metastases. Surgical complications were presented descriptively.

Results

A total of 357 patients were included, LN-prRLN metastasis occurred in 23 (6.4%) patients, and LN-prRLN was positive only when there were other LN metastases, especially LN-arRLN metastases. Other independent risk factors for LN-prRLN included foci numbers ≥2, tumor size ≥5.0 mm, and extrathyroidal extensions. The rates of permanent hypoparathyroidism and vocal cord paralysis were 1.1% and 2.0%, respectively.

Conclusion

LN-prRLN metastases should not be ignored in cN0 PTC located in the thyroid isthmus; however, its dissection is a safe procedure, and the status of LN-arRLN can be a reliable predictor for LN-prRLN metastases.
Clinical Efficiency of Non-invasive Prenatal Screening for Common Trisomies in Low-Risk and Twin Pregnancies
Authors: Xu Yanfei , Jin Pengzhen , Lei Yu , Qian Yeqing , Xu Yuqing , Wang Miaomiao , Jin Jinglei , Yin Yixuan , Dong Minyue
Published: May 2021

To evaluate the clinical efficiency of non-invasive prenatal screening (NIPS) for fetal aneuploidies in low-risk and twin pregnancies, patients who received NIPS in a tertiary university hospital were enrolled, and their clinical data, NIPS results and pregnancy outcomes were collected. Patients were divided into singleton and twin pregnancies, and then those with singleton pregnancies were divided into low- and high-risk pregnancies. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were estimated. Comparisons were made on the clinical efficiency of NIPS between singleton and twin pregnancies, as well as between low- and high-risk pregnancies. Of 66,172 patients enrolled, 59,962 were eligible for analysis. The sensitivity, specificity and NPV were ≥ 99% in singleton and twin pregnancies. The PPVs were 90.4, 56.6, and 13.0% in singleton pregnancies, while 100, 33.3, and 0% in twin pregnancies for trisomy 21 (T21), trisomy 18 (T18) and trisomy 13 (T13), respectively (P> 0.05 for all). The PPVs were 97.4 and 90.0% in high-risk pregnancies, while 78.6 and 16.7% in low-risk pregnancies for T21 and T18, respectively (P< 0.05 for all). In summary, the performance of NIPS in singleton pregnancies was similar to that in twin pregnancies. NIPS can be recommended for all pregnancies regardless of the risks.
Dynamic Regulation of the Molecular Mechanisms of Regulatory T Cell Migration in Inflamed Skin
Authors: Norman M. Ursula , Chow Zachary , Snelgrove Sarah L. , Prakongtham Peemapat , Hickey Michael J.
Published: May 2021

The presence of regulatory T cells (Tregs) in skin is important in controlling inflammatory responses in this peripheral tissue. Uninflamed skin contains a population of relatively immotile Tregs often located in clusters around hair follicles. Inflammation induces a significant increase both in the abundance of Tregs within the dermis, and in the proportion of Tregs that are highly migratory. The molecular mechanisms underpinning Treg migration in the dermis are unclear. In this study we used multiphoton intravital microscopy to examine the role of RGD-binding integrins and signalling through phosphoinositide 3-kinase P110δ (PI3K p110δ) in intradermal Treg migration in resting and inflamed skin. We found that inflammation induced Treg migration was dependent on RGD-binding integrins in a context-dependent manner. αv integrin was important for Treg migration 24 hours after induction of inflammation, but contributed to Treg retention at 48 hours, while β1 integrin played a role in Treg retention at the later time point but not during the peak of inflammation. In contrast, inhibition of signalling through PI3K p110δ reduced Treg migration throughout the entire inflammatory response, and also in the absence of inflammation. Together these observations demonstrate that the molecular mechanisms controlling intradermal Treg migration vary markedly according to the phase of the inflammatory response.
Over-Generalizing About GC (Hypoxia): Pitfalls of Limiting Breadth of Experimental Systems and Analyses in Framing Informatics Conclusions
Authors: Boothby Mark R. , Raybuck Ariel , Cho Sung Hoon , Stengel Kristy R. , Haase Volker H. , Hiebert Scott , Li Jingxin
Published: May 2021

Accumulating evidence suggests that many immune responses are influenced by local nutrient concentrations in addition to the programming of intermediary metabolism within immune cells. Humoral immunity and germinal centers (GC) are settings in which these factors are under active investigation. Hypoxia is an example of how a particular nutrient is distributed in lymphoid follicles during an antibody response, and how oxygen sensors may impact the qualities of antibody output after immunization. Using exclusively a bio-informatic analysis of mRNA levels in GC and other B cells, recent work challenged the concept that there is any hypoxia or that it has any influence. To explore this proposition, we performed new analyses of published genomics data, explored potential sources of disparity, and elucidated aspects of the apparently conflicting conclusions. Specifically, replicability and variance among data sets derived from different naïve as well as GC B cells were considered. The results highlight broader issues that merit consideration, especially at a time of heightened focus on scientific reports in the realm of immunity and antibody responses. Based on these analyses, a standard is proposed under which the relationship of new data sets should be compared to prior “fingerprints” of cell types and reported transparently to referees and readers. In light of independent evidence of diversity within and among GC elicited by protein immunization, avoidance of overly broad conclusions about germinal centers in general when experimental systems are subject to substantial constraints imposed by technical features also is warranted.
Design of a Trispecific Checkpoint Inhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common Light Chain Antibody Architecture
Authors: Bogen Jan P. , Carrara Stefania C. , Fiebig David , Grzeschik Julius , Hock Björn , Kolmar Harald
Published: May 2021

Natural killer cell engagers gained enormous interest in recent years due to their potent anti-tumor activity and favorable safety profile. Simultaneously, chicken-derived antibodies entered clinical studies paving the way for avian-derived therapeutics. In this study, we describe the affinity maturation of a common light chain (cLC)-based, chicken-derived antibody targeting EGFR, followed by utilization of the same light chain for the isolation of CD16a- and PD-L1-specific monoclonal antibodies. The resulting binders target their respective antigen with single-digit nanomolar affinity while blocking the ligand binding of all three respective receptors. Following library-based humanization, bispecific and trispecific variants in a standard 1 + 1 or a 2 + 1 common light chain format were generated, simultaneously targeting EGFR, CD16a, and PD-L1. The trispecific antibody mediated an elevated antibody-dependent cellular cytotoxicity (ADCC) in comparison to the EGFR×CD16a bispecific variant by effectively bridging EGFR/PD-L1 double-positive cancer cells with CD16a-positive effector cells. These findings represent, to our knowledge, the first detailed report on the generation of a trispecific 2 + 1 antibodies exhibiting a common light chain and illustrate synergistic effects of trispecific antigen binding. Overall, this generic procedure paves the way for the engineering of tri- and oligospecific therapeutic antibodies derived from avian immunizations.
Multi-Site Tumour Sampling Improves the Detection of Intra-Tumour Heterogeneity in Oral and Oropharyngeal Squamous Cell Carcinoma
Authors: Jie Weiping , Bai Jiaying , Yan Jing , Chi Yanting , Li Bin-bin
Published: May 2021

Background: Oral squamous cell carcinoma (OSCC) and oropharyngeal squamous cell carcinoma (OPSCC) are very common in head and neck malignancy. Intratumour heterogeneity (ITH) may hamper their responses to treatment. Hence, novel tumour sampling methods that reflect ITH are required. In this study, we investigated the clinical significance of multi-site tumour sampling (MSTS) to detect ITH in OSCC and OPSCC.

Methods: One hundred eighty-two paired specimens were sampled by routine sampling (RS) or MSTS, respectively. Histologically, tumour grade, peri-tumoural vascular and lymphatic growth, perineural permeation, tumour necrosis, and muscle invasion were assessed. Immunohistochemically, the positive and average detection rates of P53(mutant), ki67 and CyclinD1 were detected. The exon 9 and exon 20 mutations of PIK3CA gene and the methylation status of the CDKN2A promoter were analysed.

Results: Microscopically, the detection rate of perineural permeation, the detection density of peri-tumoural vascular and lymphatic growth, necrosis and muscle invasion in MSTS were significantly more frequent than those in RP (P < 0.05, P < 0.05, P < 0.01, P < 0.01). MSTS resulted in a higher detection rate of P53 (mutant), ki67, and CyclinD1 expression than did RS, but the difference was not significant. MSTS's detection rates in PIK3CA gene mutation and gene methylation sequencing in CDKN2A gene promoter region were both higher than RP (P < 0.05, P < 0.01). To be emphasised, the hotspot mutation H1047Rwas detected in one MSTS specimen (case 24M5) but in no RS specimens.

Conclusions: This study verified that MSTS's advantage in the reflection of morphological and molecular characteristics of OSCC and OPSCC. MSTS was more representative than RP. Therefore, MSTS can compensate the RP limitations in ITH detection especially in large tumours.
Whole-Genome Analysis of Mycobacterium avium subsp. paratuberculosis IS900Insertions Reveals Strain Type-Specific Modalities
Authors: Conde Cyril , Price-Carter Marian , Cochard Thierry , Branger Maxime , Stevenson Karen , Whittington Richard , Bannantine John P. , Biet Franck
Published: May 2021

Mycobacterium avium subsp. paratuberculosis (Map) is the etiological agent of Johne’s disease in ruminants. The IS900 insertion sequence (IS) has been used widely as an epidemiological marker and target for PCR diagnosis. Updated DNA sequencing technologies have led to a rapid increase in available Map genomes, which makes it possible to analyze the distribution of IS900 in this slow-growing bacterium. The objective of this study is to characterize the distribution of the IS900 element and how it affects genomic evolution and gene function of Map. A secondary goal is to develop automated in silico restriction fragment length polymorphism (RFLP) analysis using IS900. Complete genomes from the major phylogenetic lineages known as C-type and S-type (including subtypes I and III), were chosen to represent the genetic diversity of Map. IS900 elements were located in these genomes using BLAST software and the relevant fragments extracted. An in silico RFLP analysis using the BstEII restriction site was performed to obtain exact sizes of the DNA fragments carrying a copy of IS900 and the resulting RFLP profiles were analyzed and compared by digital visualization of the separated restriction fragments. The program developed for this study allowed automated localization of IS900 sequences to identify their position within each genome along with the exact number of copies per genome. The number of IS900 copies ranged from 16 in the C-type isolate to 22 in the S-type subtype I isolate. A loci-by-loci sequence alignment of all IS900 copies within the three genomes revealed new sequence polymorphisms that define three sequevars distinguishing the subtypes. Nine IS900 insertion site locations were conserved across all genomes studied while smaller subsets were unique to a particular lineage. Preferential insertion motif sequences were identified for IS900 along with genes bordering all IS900 insertions. Rarely did IS900 insert within coding sequences as only three genes were disrupted in this way. This study makes it possible to automate IS900 distribution in Map genomes to enrich knowledge on the distribution dynamics of this IS for epidemiological purposes, for understanding Map evolution and for studying the biological implications of IS900 insertions.
Leveraging Pseudomonas Stress Response Mechanisms for Industrial Applications
Authors: Craig Kelly , Johnson Brant R. , Grunden Amy
Published: May 2021

Members of the genus Pseudomonas are metabolically versatile and capable of adapting to a wide variety of environments. Stress physiology of Pseudomonas strains has been extensively studied because of their biotechnological potential in agriculture as well as their medical importance with regards to pathogenicity and antibiotic resistance. This versatility and scientific relevance led to a substantial amount of information regarding the stress response of a diverse set of species such as Pseudomonas chlororaphis, P. fluorescens, P. putida, P. aeruginosa, and P. syringae. In this review, environmental and industrial stressors including desiccation, heat, and cold stress, are cataloged along with their corresponding mechanisms of survival in Pseudomonas. Mechanisms of survival are grouped by the type of inducing stress with a focus on adaptations such as synthesis of protective substances, biofilm formation, entering a non-culturable state, enlisting chaperones, transcription and translation regulation, and altering membrane composition. The strategies Pseudomonas strains utilize for survival can be leveraged during the development of beneficial strains to increase viability and product efficacy.
Saliva Neurofilament Light Chain Is Not a Diagnostic Biomarker for Neurodegeneration in a Mixed Memory Clinic Population
Authors: Gleerup Helena Sophia , Sanna Federica , Høgh Peter , Simrén Joel , Blennow Kaj , Zetterberg Henrik , Hasselbalch Steen Gregers , Ashton Nicholas J. , Simonsen Anja Hviid
Published: May 2021

Neurodegeneration and axonal injury result in an increasing release of neurofilament light chain (NfL) into bodily fluids, including cerebrospinal fluid (CSF) and blood. Numerous studies have shown that NfL levels in CSF and blood are increased in neurodegenerative disorders and monitor neurodegeneration. Saliva is an easily accessible biofluid that could be utilized as a biofluid measurement of Alzheimer’s disease (AD) biomarkers. In this study, for the first time, salivary NfL was measured and compared to plasma NfL in a consecutive cohort of patients referred to cognitive assessments. In two mixed memory clinic cohorts, saliva samples were taken from 152 patients, AD (n = 49), mild cognitive impairment (MCI) (n = 47), non-AD (n = 56), and also 17 healthy controls. In addition, 135 also had a matching plasma sample. All saliva and plasma samples were analyzed for NfL, and the association between saliva and plasma NfL and CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and beta amyloid 1–42 (Aβ42) were investigated. In total, 162/169 had quantifiable levels of salivary NfL by single molecule array (Simoa). No statistically significant differences were found in salivary NfL concentration across the diagnostic groups, but as expected, significant increases were found for plasma NfL in dementia cases (P < 0.0001). There was no association between saliva and plasma NfL levels. Furthermore, saliva NfL did not correlate with CSF Aβ42, p-tau, or tau concentrations. In conclusion, NfL is detectable in saliva but does not reflect neurodegeneration in the brain.
The Role of NF-κB Triggered Inflammation in Cerebral Ischemia
Authors: Jover-Mengual Teresa , Hwang Jee-Yeon , Byun Hyae-Ran , Court-Vazquez Brenda L. , Centeno José M. , Burguete María C. , Zukin R. Suzanne
Published: May 2021

Cerebral ischemia is a devastating disease that affects many people worldwide every year. The neurodegenerative damage as a consequence of oxygen and energy deprivation, to date, has no known effective treatment. The ischemic insult is followed by an inflammatory response that involves a complex interaction between inflammatory cells and molecules which play a role in the progression towards cell death. However, there is presently a matter of controversy over whether inflammation could either be involved in brain damage or be a necessary part of brain repair. The inflammatory response is triggered by inflammasomes, key multiprotein complexes that promote secretion of pro-inflammatory cytokines. An early event in post-ischemic brain tissue is the release of certain molecules and reactive oxygen species (ROS) from injured neurons which induce the expression of the nuclear factor-kappaB (NF-κB), a transcription factor involved in the activation of the inflammasome. There are conflicting observations related to the role of NF-κB. While some observe that NF-κB plays a damaging role, others suggest it to be neuroprotective in the context of cerebral ischemia, indicating the need for additional investigation. Here we discuss the dual role of the major inflammatory signaling pathways and provide a review of the latest research aiming to clarify the relationship between NF-κB mediated inflammation and neuronal death in cerebral ischemia.
Amaranthus spinosus Attenuated Obesity-Induced Metabolic Disorders in High-Carbohydrate-High-Fat Diet-Fed Obese Rats
Authors: Prince Md. Raihan Uzzaman , Zihad S. M. Neamul Kabir , Ghosh Puja , Sifat Nazifa , Rouf Razina , Al Shajib Gazi Mohammad , Alam Md. Ashraful , Shilpi Jamil A. , Uddin Shaikh J.
Published: May 2021

Amaranthus spinosus is a common vegetable of Bangladesh and well-known for its ethnomedicinal uses. In this study, we have evaluated the ability of powdered supplementation, methanol extract, and aqueous extract of A. spinosus in attenuating in high-carbohydrate-high-fat (HCHF) diet-induced obesity and associated metabolic disorders in female obese rates. Several parameters have been analyzed in this study including body weight, organ weight, fat deposition, glycemic status, lipid levels, hepatic and renal biomarkers, hepatic antioxidant status, and hepatosteatosis. All three samples of A. spinosus significantly reduced weight gain, organ weight, and abdominal fat deposition. Improved glucose tolerance and lipid parameters were seen in obese rats administered with A. spinosus powder, methanol extract, and aqueous extract. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and creatine kinase levels were normalized by the test samples. A. spinosus boosted hepatic antioxidant levels including reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Histopathology of liver tissue revealed increased fat infiltration and higher steatosis score in HCHF diet-fed obese rats which was brought down by A. spinosus. Analyzing all the results it can be concluded that this medicinal herb is beneficial in the management of obesity and obesity-induced metabolic disorders, making it a prospective food supplement.
Immunotherapy Combined With Radiation Therapy for Genitourinary Malignancies
Authors: Ukleja Jacob , Kusaka Erika , Miyamoto David T.
Published: May 2021

Immunotherapy drugs have recently been approved by the Food and Drug Administration for the treatment of several genitourinary malignancies, including bladder cancer, renal cancer, and prostate cancer. Preclinical data and early clinical trial results suggest that immune checkpoint inhibitors can act synergistically with radiation therapy to enhance tumor cell killing at local irradiated sites and in some cases at distant sites through an abscopal effect. Because radiation therapy is commonly used in the treatment of genitourinary malignancies, there is great interest in testing the combination of immunotherapy with radiation therapy in these cancers to further improve treatment efficacy. In this review, we discuss the current evidence and biological rationale for combining immunotherapy with radiation therapy, as well as emerging data from ongoing and planned clinical trials testing the efficacy and tolerability of this combination in the treatment of genitourinary malignancies. We also outline outstanding questions regarding sequencing, dose fractionation, and biomarkers that remain to be addressed for the optimal delivery of this promising treatment approach.
Developmental Trajectories in Very Preterm Born Children Up to 8 Years: A Longitudinal Cohort Study
Authors: van Beek Pauline E. , van der Horst Iris E. , Wetzer Josse , van Baar Anneloes L. , Vugs Brigitte , Andriessen Peter
Published: May 2021

Aim: Long-term outcome data in preterm children is often limited to cross-sectional measurement of neurodevelopmental impairment (NDI) at the corrected age of 24-36 months. However, impairments may only become overt during childhood or resolve with time, and individual trajectories in outcome over time may vary. The primary aim of this study was to describe NDI in very preterm born children at three subsequent ages of 2, 5, and 8 years of age. As a secondary aim, a longitudinal analysis was performed on the individual longitudinal trajectories in NDI from 2 to 8 years of age.

Methods: Single-center prospective cohort study including children born between 1990 and 2011 below 30 weeks' gestation and followed into 2019. The outcome measurement was NDI assessed at 2, 5, and 8 years of age. NDI is a composite score that includes cognitive, neurological, visual, and auditory functions, in which problems were categorized as none, mild, moderate, or severe. Cognitive function measured as total DQ/IQ score was assessed by standardized psychometric tests. Neurological, visual, and auditory functions were assessed by the neonatologist.

Results: In total, 921 children were eligible for follow-up, of whom 726 (79%) children were assessed. No NDI was seen in 54, 54, and 62%, mild NDI was seen in 31, 36, and 30%, and moderate-to-severe NDI was seen in 15, 9.2, and 8.6% of the children at 2, 5, and 8 years, respectively. From 2 to 8 years, 63% of the children remained in the same NDI category, 20% of the children improved to a better NDI category, and 17% deteriorated toward a worse NDI category. No differences were found in baseline characteristics of infants that improved or deteriorated. Extreme prematurity, male gender and low parental education were associated with worse NDI status at all time points. Although we observed considerable individual variation over time in NDI status, the course of the trajectories in NDI were not associated with gestation, gender, and parental education.

Conclusions: Continued follow-up until school life is essential in order to provide optimal and individually focused referrals and care when needed.
Exploring the Mechanism of Zhibai Dihuang Decoction in the Treatment of Ureaplasma Urealyticum-Induced Orchitis Based on Integrated Pharmacology
Authors: Bin Dong-hua , Zhang Shi-ying , Zhan Min , Li Ling , Li Ying-qiu , Zhou Xing , Lu Fang-guo , Zhou Qing , He Qing-hu
Published: May 2021

Background: Ureaplasma urealyticum (UU) infection is the most common cause of male infertility. Zhibai Dihuang Decoction (ZBDHD) can improve the rate of forwarding motility sperm, sperm deformity rate, seminal plasma zinc and refined berry sugar levels.

Methods: The potential targets of ZBDHD are obtained from The Encyclopedia of Traditional Chinese Medicine (ETCM). Orchitis-related targets were collected from the Genecards and OMIM databases. The Cytoscape and the Database for Annotation, Visualization and Integrated Discovery (DAVID) were utilized to construct and analyzed the networks. Finally, a rat model of orchitis caused by UU infection was used to detect related indicators of mitochondrial energy metabolism using TUNEL apoptosis detection technology, loss cytometry, Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) and Western Blot.

Results: A total of 795 ZBDHD targets and 242 orchitis-related targets were obtained. The “ZBDHD- orchitis PPI network” was constructed and analyzed. ZBDHD can regulate signaling pathways and biological processes related to mitochondrial energy metabolism. The results of experimental studies have shown that ZBDHD maintains the integrity of sperm mitochondrial respiratory chain function by enhancing mitochondrial Na+-K+-ATPase and Ca2+-Mg2+-ATPase activities, promotes the synthesis of mitochondrial ATP, and improves sperm energy supply, thereby improving the motility, vitality and survival rate of sperm, and effectively improving the quality of semen in UU-infected rats (p < 0.05).

Conclusion:This study discovered the multi-pathway mechanism of ZBDHD intervention in UU-induced orchitis through integrated pharmacological strategies, which provides a reference for further research on the mechanism of ZBDHD intervention in orchitis in the direction of mitochondrial energy metabolism.
FMS-Related Tyrosine Kinase 3 Ligand Promotes Radioresistance in Esophageal Squamous Cell Carcinoma
Authors: Zhu Zuoquan , Song Jiahang , Gu Junjie , Xu Bing , Sun Xinchen , Zhang Shu
Published: May 2021

Aim: The FMS-related tyrosine kinase 3 ligand (FL) has an important role in regulating FMS-related tyrosine kinase 3 (Flt-3) activity. Serum FL levels are markedly increased among patients with hematopoietic disease. However, its role in radiation treatment remains unclear. In this study, we investigated the effects of FL on radiotherapy for esophageal squamous cell carcinoma (ESCC).

Methods: KYSE150 and KYSE450 cells were stimulated with FL (200 ng/ml). mRNA expression was analyzed using qRT-PCR. Cell viability was checked using CCK-8 assay kits. Proliferation was determined using the EdU assay. Radiosensitivity was detected through a colony-forming assay. Flow cytometry was used to evaluate cell apoptosis. The number of γH2AX foci was verified using an immunofluorescence assay. The change in relative proteins was determined by western blot analysis. The growth of transplanted tumors was demonstrated in nude mice.

Results: Our results showed that FL increased the radiation resistance of ESCC cells by promoting clone formation, increasing EdU incorporation, enhancing DNA damage repair, and inhibiting apoptosis. Moreover, the Flt-3 receptor expression significantly increased in ESCC cells after radiation, which may have been an important factor in their radioresistance.

Conclusion: Our results suggest that FL increases the radioresistance of esophageal cancer cells and that FL-Flt-3 could be a potential target for enhancing radiosensitivity in ESCC.
The Role of Chinese Herbal Therapy in Methamphetamine Abuse and its Induced Psychiatric Symptoms
Authors: Chen Lin , Ru Qin , Xiong Qi , Zhou Mei , Yue Kai , Wu Yuxiang
Published: May 2021

Repeated intake of methamphetamine (METH) leads to drug addiction, the inability to control intake, and strong drug cravings. It is also likely to cause psychiatric impairments, such as cognitive impairment, depression, and anxiety. Because the specific neurobiological mechanisms involved are complex and have not been fully and systematically elucidated, there is no established pharmacotherapy for METH abuse. Studies have found that a variety of Chinese herbal medicines have significant therapeutic effects on neuropsychiatric symptoms and have the advantage of multitarget comprehensive treatment. We conducted a systematic review, from neurobiological mechanisms to candidate Chinese herbal medicines, hoping to provide new perspectives and ideas for the prevention and treatment of METH abuse.
Long-Term Bed Rest Delays the Circadian Phase of Core Body Temperature
Authors: Mendt Stefan , Brauns Katharina , Friedl-Werner Anika , Belavy Daniel L. , Steinach Mathias , Schlabs Thomas , Werner Andreas , Gunga Hanns-Christian , Stahn Alexander C.
Published: May 2021

Spaceflight can be associated with sleep loss and circadian misalignment as a result of non-24 h light-dark cycles, operational shifts in work/rest cycles, high workload under pressure, and psychological factors. Head-down tilt bed rest (HDBR) is an established model to mimic some of the physiological and psychological adaptions observed in spaceflight. Data on the effects of HDBR on circadian rhythms are scarce. To address this gap, we analyzed the change in the circadian rhythm of core body temperature (CBT) in two 60-day HDBR studies sponsored by the European Space Agency [n = 13 men, age: 31.1 ± 8.2 years (M ± SD)]. CBT was recorded for 36 h using a non-invasive and validated dual-sensor heatflux technology during the 3rd and the 8th week of HDBR. Bed rest induced a significant phase delay from the 3rd to the 8th week of HDBR (16.23 vs. 16.68 h, p = 0.005, g = 0.85) irrespective of the study site (p = 0.416, g = −0.46), corresponding to an average phase delay of about 0.9 min per day of HDBR. In conclusion, long-term bed rest weakens the entrainment of the circadian system to the 24-h day. We attribute this effect to the immobilization and reduced physical activity levels associated with HDBR. Given the critical role of diurnal rhythms for various physiological functions and behavior, our findings highlight the importance of monitoring circadian rhythms in circumstances in which gravity or physical activity levels are altered.
Telemonitored Human Circadian Temperature Dynamics During Daily Routine
Authors: Huang Qi , Komarzynski Sandra , Bolborea Matei , Finkenstädt Barbel , Lévi Francis Albert
Published: May 2021

Background

Circadian rhythms in body temperature coordinate peripheral molecular clocks, hence they could potentially predict optimal treatment timing (chronotherapy) in individual patients. Circadian parameters in chest surface body temperature (Chesttemp) were recorded remotely and in real time through the use of wearable sensors.

Methods

The dynamics of circadian oscillations in Chesttemp and core body temperature (Coretemp) and their moderation by sex and age were analysed in 38 men and 50 women, aged 21–78 years. In two studies (ST1 and ST2), Chesttemp was measured every minute and teletransmitted using a BLE-connected sensor for 3.6–28.3 days. Additionally, in ST2, Coretemp was recorded per minute in 33 age- and sex-stratified subjects using electronic ingestible pills with radio-frequency transmissions. Circadian parameters were computed using spectral analysis and cosinor modelling. The temporal relations between Chesttemp and Coretemp cosinor parameters were summarised with principal component (PC) analysis. The effect of sex and age was analysed through multivariate regression.

Results

Using spectral analysis, a dominant period of 24- or 12-h was identified in 93.2% of the Chesttemp and in 100% of the Coretemp time series. The circadian parameters varied largely between-subjects both for Chesttemp (ranges: mesors, 33.2–36.6°C; amplitudes, 0.2–2.5°C; acrophases, 14:05–7:40), and Coretemp (mesors, 36.6–37.5°C; amplitudes, 0.2–0.7°C; bathyphases, 23:50–6:50). Higher PC loadings mainly corresponded to (i) large Chesttemp amplitudes, and phase advance of both temperature rhythms for the first PC (PC1, 27.2% of variance var.), (ii) high mesors in both temperature rhythms for PC2 (22.4% var.), and (iii) large Coretemp amplitudes for PC3 (12.9% var.). Chesttemp and Coretemp mesors and PC2 loadings decreased in females, while remaining quite stable in males as a function of age. In contrast, Coretemp amplitude and PC3 loadings increased with age in females, but decreased in males. Finally, older subjects, both female and male, displayed a reduction in ultradian variabilities, and an increase in both Chesttemp circadian amplitude and PC1 loadings.

Interpretation

The dynamics relations between Chesttemp and Coretemp rhythms were largely moderated by age and sex, with results suggesting that treatment timing could be most critical for therapeutic index in women and in order people.
Overexpression of GmGAMYB Accelerates the Transition to Flowering and Increases Plant Height in Soybean
Authors: Yang Xue , Li Xin , Shan Jinming , Li Yinghua , Zhang Yuntong , Wang Yuhe , Li Wenbin , Zhao Lin
Published: May 2021

The flowering time and plant height of soybean are important agronomic characters, which control the adaptability and yield of soybean. R2R3 MYB transcription factor plays an important regulatory role in plant growth and development. In this study, soybean GmGAMYB gene of R2R3-MYB type was induced by long-days (LDs). GmGAMYB showed higher transcriptional levels in the flowers, leaves and pods of soybean. Overexpression of GmGAMYB in transgenic soybean showed earlier flowering time and maturity in LDs and short-days (SDs). GmGAMYB interacted with GmGBP1 and might promote flowering time by up-regulating the expression of GmFULc gene in soybean. Moreover, the expression level of GmGAMYB was also induced by gibberellins (GAs) and the plant height of GmGAMYB-ox plants was significantly increased, which was caused by the enlargement of internode cell in stem. Furthermore, GmGAMYB overexpression led to increased GA sensitivity in the hypocotyl of soybean seedlings compared with WT. GmGAMYB may be a positive regulator of GA response of promoting plant height by up-regulating the expression of GmGA20ox gene in soybean. Together, our studies preliminarily showed that the partial functions of GmGAMYB in regulating flowering time and GA pathway.
Emotional State and Feedback-Related Negativity Induced by Positive, Negative, and Combined Reinforcement
Authors: Xu Shuyuan , Sun Yuyan , Huang Min , Huang Yanhong , Han Jing , Tang Xuemei , Ren Wei
Published: May 2021

Reinforcement learning relies on the reward prediction error (RPE) signals conveyed by the midbrain dopamine system. Previous studies showed that dopamine plays an important role in both positive and negative reinforcement. However, whether various reinforcement processes will induce distinct learning signals is still unclear. In a probabilistic learning task, we examined RPE signals in different reinforcement types using an electrophysiology index, namely, the feedback-related negativity (FRN). Ninety-four participants were randomly assigned into four groups: base (no money incentive), positive reinforcement (presentation of money rewards), negative reinforcement (removal of money losses), and combined reinforcement (money rewards and removal of money losses) groups. In addition, in order to evaluate the engagement of emotional activity in the different reinforcement processes, Positive and Negative Affect Schedule-Expanded Form (PANAS-X) scales were applied before and after the experiment to detect the emotional changes. The results showed that there was no difference between groups in the dopamine-related learning bias. However, compared to the other three groups, negative reinforcement elicited smaller FRN (the difference-wave measure) during the learning, stronger positive affect and joviality, and less fatigue after the learning, in which the difference between the negative and positive reinforcement groups was smaller. The results indicated that pure avoidance motivation may induce distinct emotional fluctuations, which influence the feedback processing.