bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Priority Sites to Support Management of Commercially Important Sea Cucumber Species by Applying Infomap and Habitat Filters to Larval Dispersal Data
Authors: Deauna Josephine Dianne L. , Yatco Kevin Matthew B. , Villanoy Cesar L. , Juinio-Meñez Marie Antonette
Published: January 2021

Stocks of commercially valuable sea cucumber species have declined in most tropical countries, which supply majority of the global demand. This work aimed to locate priority sites for the management ofHolothuria scabraandStichopus horrensin the western central Philippines. A passive larval dispersal model was run under four monsoonal regimes (Northeast monsoon, dry-transition, Southwest monsoon, and early Northeast monsoon), and the results subjected to theInfomapnetwork detection algorithm. Three clusters of closely related geographical nodes were identified [southeastern Palawan (Group I), western Panay and eastern Mindoro (Group II), and northern and western Palawan with western Mindoro (Group III)]. Remotely sensed habitat data were used to parameterize the degree of connectivity observed among sites (H. scabraspawning and settlement requires the presence of seagrass and mangrove, whileS. horrensrequires corals and seagrass). Local retention, self-recruitment, settlement success and sink diversity were then calculated for each node with suitable habitat. The locations were ranked according to each metric and those with higher larval export rates, a higher diversity of larval sources and a high degree of successful larval contribution to other sites were deemed crucial for the management of wild populations. Sixteen high-priority sites were identified, distributed mainly along northern Palawan and western Panay. Six sites were common for both species at different seasons, and no single location fulfilled all stated criteria across the four seasons and both sea cucumber species considered. The priority sites for management could serve as broodstock selection and juvenile restocking areas for aquaculture production clusters, which when properly implemented, could lead to an increase in sea cucumber production and contribute to natural populations. On a broader scale, the designation of closely related clusters and incorporation of habitat requirements to dispersal data provided critical input for the delineation of ecologically meaningful management units for sea cucumbers within the region.
Dispersion of Surface Drifters in the Tropical Atlantic
Authors: van Sebille Erik , Zettler Erik , Wienders Nicolas , Amaral-Zettler Linda , Elipot Shane , Lumpkin Rick
Published: January 2021

The Tropical Atlantic Ocean has recently been the source of enormous amounts of floating Sargassum macroalgae that have started to inundate shorelines in the Caribbean, the western coast of Africa and northern Brazil. It is still unclear, however, how the surface currents carry the Sargassum, largely restricted to the upper meter of the ocean, and whether observed surface drifter trajectories and hydrodynamical ocean models can be used to simulate its pathways. Here, we analyze a dataset of two types of surface drifters (38 in total), purposely deployed in the Tropical Atlantic Ocean in July, 2019. Twenty of the surface drifters were undrogued and reached only ∼8 cm into the water, while the other 18 were standard Surface Velocity Program (SVP) drifters that all had a drogue centered around 15 m depth. We show that the undrogued drifters separate more slowly than the drogued SVP drifters, likely because of the suppressed turbulence due to convergence in wind rows, which was stronger right at the surface than at 15 m depth. Undrogued drifters were also more likely to enter the Caribbean Sea. We also show that the novel Surface and Merged Ocean Currents (SMOC) product from the Copernicus Marine Environmental Service (CMEMS) does not clearly simulate one type of drifter better than the other, highlighting the need for further improvements in assimilated hydrodynamic models in the region, for a better understanding and forecasting of Sargassum drift in the Tropical Atlantic.
The Effect of the Source of Deep Water in the Eastern Mediterranean on Western Mediterranean Intermediate and Deep Water
Authors: Amitai Yael , Ashkenazy Yosef , Gildor Hezi
Published: January 2021

The deep water in the western Mediterranean Sea was found to be significantly affected by a climatic event that took place in the eastern Mediterranean during the 1990s. Numerical simulations of the entire Mediterranean Sea showed that multiple equilibria states in the eastern Mediterranean can exist under present-day-like conditions. The two stable states that were found are associated with intermediate water exchange between the eastern Mediterranean's Aegean and Adriatic Basins. In the first state, the Adriatic acts as a source of deep water that flows into the deep layers of the eastern Mediterranean; in the second state, there is no source of deep water in the Adriatic and the eastern Mediterranean intermediate water is warmer and saltier. We studied the water pathways, in both stable states, into the western Mediterranean and found that the eastern Mediterranean water's properties signature can be seen as far as the Gulf of Lion, which is an important open-ocean deep water convection site. Meaning that, the eastern Mediterranean water characteristics are manifested in deep and intermediate water properties all over the Mediterranean Sea. The water propagating from the eastern to the western Mediterranean also has different flow regimes, in both states, through the Sicily Strait and in the Tyrrhenian Basin, as seen from a Lagrangian analysis.
Demographics of Vaccine Hesitancy in Chandigarh, India
Authors: Wagner Abram L. , Shotwell Abigail R. , Boulton Matthew L. , Carlson Bradley F. , Mathew Joseph L.
Published: January 2021

The impact of vaccine hesitancy on childhood immunization in low- and middle-income countries remains largely uncharacterized. This study describes the sociodemographic patterns of vaccine hesitancy in Chandigarh, India. Mothers of children <5 years old were sampled from a two-stage cluster, systematic sample based on Anganwadi child care centers in Chandigarh. Vaccine hesitancy was measured using a 10-item Vaccine Hesitancy Scale, which was dichotomized. A multivariable logistic regression assessed the association between socioeconomic factors and vaccine hesitancy score. Among 305 mothers, >97% of mothers thought childhood vaccines were important, effective, and were a good way to protect against disease. However, many preferred their child to receive fewer co-administered vaccines (69%), and were concerned about side effects (39%). Compared to the “other caste” group, scheduled castes or scheduled tribes had 3.48 times greater odds of vaccine hesitancy (95% CI: 1.52, 7.99). Those with a high school education had 0.10 times the odds of vaccine hesitancy compared to those with less education (95% CI: 0.02, 0.61). Finally, those having more antenatal care visits were less vaccine hesitant (≥4 vs. <4 visits OR: 0.028, 95% CI: 0.1, 0.76). As India adds more vaccines to its Universal Immunization Program, consideration should be given to addressing maternal concerns about vaccination, in particular about adverse events and co-administration of multiple vaccines.
Investigation of Physicochemical Indices and Microbial Communities in Termite Fungus-Combs
Authors: Yang Guiying , Ahmad Farhan , Zhou Qihuan , Guo Meixia , Liang Shiyou , Gaal Hassan Ahmed , Mo Jianchu
Published: January 2021

Termitomyces species are wild edible mushrooms that possess high nutritional value and a wide range of medicinal properties. However, the cultivation of these mushrooms is very difficult because of their symbiotic association with termites. In this study, we aimed to examine the differences in physicochemical indices and microbial communities between combs with Termitomyces basidiomes (CF) and combs without Termitomyces basidiomes (CNF). High-performance liquid chromatography (HPLC), inductively coupled plasma optical emission spectrometry (ICP-OES), gas chromatography equipped with a flame ionization detector (GC-FID), some commercial kits, high-throughput sequencing of the 16s RNA, and internal transcribed spacer (ITS) were used. Humidity, pH, and elements, i.e., Al, Ba, Fe, Mn, Ni, S, Ca, and Mg were higher while amino acids particularly alanine, tyrosine, and isoleucine were lower in CF as compared to CNF. The average contents of fatty acids were not significantly different between the two comb categories. The bacterial genera Alistipes, Burkholderia, Sediminibacterium, and Thermus were dominant in all combs. Brevibacterium, Brevundimonas, and Sediminibacterium were significantly more abundant in CF. Basidiomycota and Ascomycota were also identified in combs. Termitomyces clypeatus, Termitomyces sp. Group3, and Termitomyces sp. were the most dominant species in combs. However, any single Termitomyces species was abundantly present in an individual comb.
Lactic Acid Bacteria in Wine: Technological Advances and Evaluation of Their Functional Role
Authors: Virdis Carla , Sumby Krista , Bartowsky Eveline , Jiranek Vladimir
Published: January 2021

Currently, the main role of Lactic Acid Bacteria (LAB) in wine is to conduct the malolactic fermentation (MLF). This process can increase wine aroma and mouthfeel, improve microbial stability and reduce the acidity of wine. A growing number of studies support the appreciation that LAB can also significantly, positively and negatively, contribute to the sensorial profile of wine through many different enzymatic pathways. This is achieved either through the synthesis of compounds such as diacetyl and esters or by liberating bound aroma compounds such as glycoside-bound primary aromas and volatile thiols which are odorless in their bound form. LAB can also liberate hydroxycinnamic acids from their tartaric esters and have the potential to break down anthocyanin glucosides, thus impacting wine color. LAB can also produce enzymes with the potential to help in the winemaking process and contribute to stabilizing the final product. For example, LAB exhibit peptidolytic and proteolytic activity that could break down the proteins causing wine haze, potentially reducing the need for bentonite addition. Other potential contributions include pectinolytic activity, which could aid juice clarification and the ability to break down acetaldehyde, even when bound to SO2, reducing the need for SO2additions during winemaking. Considering all these findings, this review summarizes the novel enzymatic activities of LAB that positively or negatively affect the quality of wine. Inoculation strategies, LAB improvement strategies, their potential to be used as targeted additions, and technological advances involving their use in wine are highlighted along with suggestions for future research.
Multiplex PCR for the Identification of Pathogenic Listeria in Flammulina velutipes Plant Based on Novel Specific Targets Revealed by Pan-Genome Analysis
Authors: Li Fan , Ye Qinghua , Chen Moutong , Zhang Jumei , Xue Liang , Wang Juan , Wu Shi , Zeng Haiyan , Gu Qihui , Zhang Youxiong , Wei Xianhu , Ding Yu , Wu Qingping
Published: January 2021

Listeria spp. is an important foodborne disease agent, often found in the fresh mushroom (Flammulina velutipes) and its production environment. The aim of this study was to develop multiplex PCR for rapid identification of Listeria monocytogenes and Listeria ivanovii, and nonpathogenic Listeria in F. velutipes plants. Pan-genome analysis was first used to identify five novel Listeria-specific targets: one for the Listeria genus, one for L. monocytogenes, and three for L. ivanovii. Primers for the novel targets were highly specific in individual reactions. The detection limits were 103–104 CFU/mL, meeting the requirements of molecular detection. A mPCR assay for the identification of pathogenic Listeria, with primers targeting the novel genes specific for Listeria genus (LMOSLCC2755_0944), L. monocytogenes (LMOSLCC2755_0090), and L. ivanovii (queT_1) was then designed. The assay specificity was robustly verified by analyzing nonpathogenic Listeria and non-Listeria spp. strains. The determined detection limits were 2.0 × 103 CFU/mL for L. monocytogenes and 3.4 × 103 CFU/mL for L. ivanovii, for pure culture analysis. Further, the assay detected 7.6 × 104 to 7.6 × 100 CFU/10 g of pathogenic Listeria spiked into F. velutipes samples following 4–12 h enrichment. The assay feasibility was evaluated by comparing with a traditional culture-based method, by analyzing 129 samples collected from different F. velutipes plants. The prevalence of Listeria spp. and L. monocytogenes was 58.1% and 41.1%, respectively. The calculated κ factors for Listeria spp., L. monocytogenes, and L. ivanovii were 0.97, 0.97, and 1, respectively. The results of the novel mPCR assay were highly consistent with those of the culture-based method. The new assay thus will allow rapid, specific, and accurate detection and monitoring of pathogenic Listeria in food and its production environment.
The Quest for the Hippocampal Memory Engram: From Theories to Experimental Evidence
Authors: Miry Omid , Li Jie , Chen Lu
Published: January 2021

More than a century after Richard Semon's theoretical proposal of the memory engram, technological advancements have finally enabled experimental access to engram cells and their functional contents. In this review, we summarize theories and their experimental support regarding hippocampal memory engram formation and function. Specifically, we discuss recent advances in the engram field which help to reconcile two main theories for how the hippocampus supports memory formation: The Memory Indexing and Cognitive Map theories. We also highlight the latest evidence for engram allocation mechanisms through which memories can be linked or separately encoded. Finally, we identify unanswered questions for future investigations, through which a more comprehensive understanding of memory formation and retrieval may be achieved.
Gait Optimization Method for Humanoid Robots Based on Parallel Comprehensive Learning Particle Swarm Optimizer Algorithm
Authors: Tao Chongben , Xue Jie , Zhang Zufeng , Cao Feng , Li Chunguang , Gao Hanwen
Published: January 2021

To improve the fast and stable walking ability of a humanoid robot, this paper proposes a gait optimization method based on a parallel comprehensive learning particle swarm optimizer (PCLPSO). Firstly, the key parameters affecting the walking gait of the humanoid robot are selected based on the natural zero-moment point trajectory planning method. Secondly, by changing the slave group structure of the PCLPSO algorithm, the gait training task is decomposed, and a parallel distributed multi-robot gait training environment based on RoboCup3D is built to automatically optimize the speed and stability of bipedal robot walking. Finally, a layered learning approach is used to optimize the turning ability of the humanoid robot. The experimental results show that the PCLPSO algorithm achieves a quickly optimal solution, and the humanoid robot optimized possesses a fast and steady gait and flexible steering ability.
Dentate Granule Cells Recruited in the Home Environment Display Distinctive Properties
Authors: Pléau Claire , Peret Angélique , Pearlstein Edouard , Scalfati Thomas , Vigier Alexandre , Marti Geoffrey , Michel François J. , Marissal Thomas , Crépel Valérie
Published: January 2021

The dentate granule cells (DGCs) play a crucial role in learning and memory. Many studies have described the role and physiological properties of these sparsely active neurons using different behavioral contexts. However, the morpho-functional features of DGCs recruited in mice maintained in their home cage (without training), considered as a baseline condition, have not yet been established. Using fosGFP transgenic mice, we observed ex vivo that DGCs recruited in animals maintained in the home cage condition are mature neurons that display a longer dendritic tree and lower excitability compared with non-activated cells. The higher GABAA receptor-mediated shunting inhibition contributes to the lower excitability of DGCs activated in the home environment by shifting the input resistance towards lower values. Remarkably, that shunting inhibition is neither observed in non-activated DGCs nor in DGCs activated during training in virtual reality. In short, our results suggest that strong shunting inhibition and reduced excitability could constitute a distinctive neural signature of mature DGCs recruited in the context of the home environment.
Alterations of Cerebral Hemodynamics and Network Properties Induced by Newsvendor Problem in the Human Prefrontal Cortex
Authors: Wanniarachchi Hashini , Lang Yan , Wang Xinlong , Pruitt Tyrell , Nerur Sridhar , Chen Kay-Yut , Liu Hanli
Published: January 2021

While many publications have reported brain hemodynamic responses to decision-making under various conditions of risk, no inventory management scenarios, such as the newsvendor problem (NP), have been investigated in conjunction with neuroimaging. In this study, we hypothesized (I) that NP stimulates the dorsolateral prefrontal cortex (DLPFC) and the orbitofrontal cortex (OFC) joined with frontal polar area (FPA) significantly in the human brain, and (II) that local brain network properties are increased when a person transits from rest to the NP decision-making phase. A 77-channel functional near infrared spectroscopy (fNIRS) system with wide field-of-view (FOV) was employed to measure frontal cerebral hemodynamics in response to NP in 27 healthy human subjects. NP-induced changes in oxy-hemoglobin concentration, Δ[HbO], were investigated using a general linear model (GLM) and graph theory analysis (GTA). Significant activation induced by NP was shown in both DLPFC and OFC+FPA across all subjects. Specifically, higher risk NP with low-profit margins (LM) activated left-DLPFC but deactivated right-DLPFC in 14 subjects, while lower risk NP with high-profit margins (HM) stimulated both DLPFC and OFC+FPA in 13 subjects. The local efficiency, clustering coefficient, and path length of the network metrics were significantly enhanced under NP decision making. In summary, multi-channel fNIRS enabled us to identify DLPFC and OFC+FPA as key cortical regions of brain activations when subjects were making inventory-management risk decisions. We demonstrated that challenging NP resulted in the deactivation within right-DLPFC due to higher levels of stress. Also, local brain network properties were increased when a person transitioned from the rest phase to the NP decision-making phase.
The Brain Emotional Systems in Addictions: From Attachment to Dominance/Submission Systems
Authors: Giacolini Teodosio , Conversi David , Alcaro Antonio
Published: January 2021

Human development has become particularly complex during the evolution. In this complexity, adolescence is an extremely important developmental stage. Adolescence is characterized by biological and social changes that create the prerequisites to psychopathological problems, including both substance and non-substance addictive behaviors. Central to the dynamics of the biological changes during adolescence are the synergy between sexual and neurophysiological development, which activates the motivational/emotional systems of Dominance/Submission. The latter are characterized by the interaction between the sexual hormones, the dopaminergic system and the stress axis (HPA). The maturation of these motivational/emotional systems requires the integration with the phylogenetically more recent Attachment/CARE Systems, which primarily have governed the subject’s relationships until puberty. The integration of these systems is particularly complex in the human species, due to the evolution of the process of competition related to sexual selection: from a simple fight between two individuals (of the same genus and species) to a struggle for the acquisition of a position in rank and the competition between groups. The latter is an important evolutionary acquisition and believed to be the variable that has most contributed to enhancing the capacity for cooperation in the human species. The interaction between competition and cooperation, and between competition and attachment, characterizes the entire human relational and emotional structure and the unending work of integration to which the BrainMind is involved. The beginning of the integration of the aforementioned motivational/emotional systems is currently identified in the prepubertal period, during the juvenile stage, with the development of the Adrenarche—the so-called Adrenal Puberty. This latter stage is characterized by a low rate of release of androgens, the hormones released by the adrenal cortex, which activate the same behaviors as those observed in the PLAY system. The Adrenarche and the PLAY system are biological and functional prerequisites of adolescence, a period devoted to learning the difficult task of integrating the phylogenetically ancient Dominance/Submission Systems with the newer Attachment/CARE Systems. These systems accompany very different adaptive goals which can easily give rise to mutual conflict and can in turn make the balance of the BrainMind precarious and vulnerable to mental suffering.
Increased Sestrin3 Contributes to Post-ischemic Seizures in the Diabetic Condition
Authors: Shi Zhongshan , Lei Zhigang , Wu Fan , Xia Luoxing , Ruan Yiwen , Xu Zao C.
Published: January 2021

Seizures are among the most common neurological sequelae of stroke, and diabetes notably increases the incidence of post-ischemic seizures. Recent studies have indicated that Sestrin3 (SESN3) is a regulator of a proconvulsant gene network in human epileptic hippocampus. But the association of SESN3 and post-ischemic seizures in diabetes remains unclear. The present study aimed to reveal the involvement of SESN3 in seizures following transient cerebral ischemia in diabetes. Diabetes was induced in adult male mice and rats via intraperitoneal injection of streptozotocin (STZ). Forebrain ischemia (15 min) was induced by bilateral common carotid artery occlusion, the 2-vessel occlusion (2VO) in mice and 4-vessel occlusion (4VO) in rats. Our results showed that 59% of the diabetic wild-type mice developed seizures after ischemia while no seizures were observed in non-diabetic mice. Although no apparent cell death was detected in the hippocampus of seizure mice within 24 h after the ischemic insult, the expression of SESN3 was significantly increased in seizure diabetic mice after ischemia. The post-ischemic seizure incidence significantly decreased in SESN3 knockout mice. Furthermore, all diabetic rats suffered from post-ischemic seizures and non-diabetic rats have no seizures. Electrophysiological recording showed an increased excitatory synaptic transmission and intrinsic membrane excitability in dentate granule cells of the rat hippocampus, together with decreased IA currents and Kv4.2 expression levels. The above results suggest that SESN3 up-regulation may contribute to neuronal hyperexcitability and seizure generation in diabetic animals after ischemia. Further studies are needed to explore the molecular mechanism of SESN3 in seizure generation after ischemia in diabetic conditions.
The Molecular Mechanism of Chronic High-Dose Corticosterone-Induced Aggravation of Cognitive Impairment in APP/PS1 Transgenic Mice
Authors: Zhang Shen-Qing , Cao Long-Long , Liang Yun-Yue , Wang Pu
Published: January 2021

Clinical studies have found that some Alzheimer’s disease (AD) patients suffer from Cushing’s syndrome (CS). CS is caused by the long-term release of excess glucocorticoids (GCs) from the adrenal gland, which in turn, impair brain function and induce dementia. Thus, we investigated the mechanism of the effect of corticosterone (CORT) on the development and progression of AD in a preclinical model. Specifically, the plasma CORT levels of 9-month-old APP/PS1 Tg mice were abnormally increased, suggesting an association between GCs and AD. Long-term administration of CORT accelerated cognitive dysfunction by increasing the production and deposition of β-amyloid (Aβ). The mechanism of action of CORT treatment involved stimulation of the expression of BACE-1 and presenilin (PS) 1 inin vitroandin vivo. This observation was confirmed in mice with adrenalectomy (ADX), which had lower levels of GCs. Moreover, the glucocorticoid receptor (GR) mediated the effects of CORT on the stimulation of the expression of BACE-1 and PS1viathe PKA and CREB pathways in neuroblastoma N2a cells. In addition to these mechanisms, CORT can induce a cognitive decline in APP/PS1 Tg mice by inducing apoptosis and decreasing the differentiation of neurons.
HEYL Regulates Neoangiogenesis Through Overexpression in Both Breast Tumor Epithelium and Endothelium
Authors: Han Liangfeng , Korangath Preethi , Nguyen Nguyen K. , Diehl Adam , Cho Soonweng , Teo Wei Wen , Cope Leslie , Gessler Manfred , Romer Lewis , Sukumar Saraswati
Published: January 2021

Blocking tumor angiogenesis is an appealing therapeutic strategy, but to date, success has been elusive. We previously identified HEYL, a downstream target of Notch signaling, as an overexpressed gene in both breast cancer cells and as a tumor endothelial marker, suggesting that HEYL overexpression in both compartments may contribute to neoangiogenesis. Carcinomas arising in double transgenic Her2-neu/HeyL mice showed higher tumor vessel density and significantly faster growth than tumors in parental Her2/neu mice. Providing mechanistic insight, microarray-based mRNA profiling of HS578T-tet-off-HEYL human breast cancer cells revealed upregulation of several angiogenic factors including CXCL1/2/3 upon HEYL expression, which was validated by RT-qPCR and protein array analysis. Upregulation of the cytokines CXCL1/2/3 occurred through direct binding of HEYL to their promoter sequences. We found that vessel growth and migration of human vascular endothelial cells (HUVECs) was promoted by conditioned medium from HS578T-tet-off-HEYL carcinoma cells, but was blocked by neutralizing antibodies against CXCL1/2/3. Supporting these findings, suppressing HEYL expression using shRNA in MDA-MB-231 cells significantly reduced tumor growth. In addition, suppressing the action of proangiogenic cytokines induced by HEYL using a small molecule inhibitor of the CXCl1/2/3 receptor, CXCR2, in combination with the anti-VEGF monoclonal antibody, bevacizumab, significantly reduced tumor growth of MDA-MB-231 xenografts. Thus, HEYL expression in tumor epithelium has a profound effect on the vascular microenvironment in promoting neoangiogenesis. Furthermore, we show that lack of HEYL expression in endothelial cells leads to defects in neoangiogenesis, both under normal physiological conditions and in cancer. Thus, HeyL-/- mice showed impaired vessel outgrowth in the neonatal retina, while the growth of mammary tumor cells E0771 was retarded in syngeneic HeyL-/- mice compared to wild type C57/Bl6 mice. Blocking HEYL’s angiogenesis-promoting function in both tumor cells and tumor-associated endothelium may enhance efficacy of therapy targeting the tumor vasculature in breast cancer.
Telomere Dysfunction in Chronic Lymphocytic Leukemia
Authors: Jebaraj Billy Michael Chelliah , Stilgenbauer Stephan
Published: January 2021

Telomeres are nucleprotein structures that cap the chromosomal ends, conferring genomic stability. Alterations in telomere maintenance and function are associated with tumorigenesis. In chronic lymphocytic leukemia (CLL), telomere length is an independent prognostic factor and short telomeres are associated with adverse outcome. Though telomere length associations have been suggested to be only a passive reflection of the cell’s replication history, here, based on published findings, we suggest a more dynamic role of telomere dysfunction in shaping the disease course. Different members of the shelterin complex, which form the telomere structure have deregulated expression and POT1 is recurrently mutated in about 3.5% of CLL. In addition, cases with short telomeres have higher telomerase (TERT) expression and activity. TERT activation and shelterin deregulation thus may be pivotal in maintaining the minimal telomere length necessary to sustain survival and proliferation of CLL cells. On the other hand, activation of DNA damage response and repair signaling at dysfunctional telomeres coupled with checkpoint deregulation, leads to terminal fusions and genomic complexity. In summary, multiple components of the telomere system are affected and they play an important role in CLL pathogenesis, progression, and clonal evolution. However, processes leading to shelterin deregulation as well as cell intrinsic and microenvironmental factors underlying TERT activation are poorly understood. The present review comprehensively summarizes the complex interplay of telomere dysfunction in CLL and underline the mechanisms that are yet to be deciphered.
Long Noncoding RNAs in the Metastasis of Oral Squamous Cell Carcinoma
Authors: Xu Yuming , Jiang Erhui , Shao Zhe , Shang Zhengjun
Published: January 2021

Oral squamous cell carcinoma (OSCC) is a common malignant tumor worldwide. Metastasis is the main cause of the death of OSCC patients. Long noncoding RNAs (lncRNAs), one of the key factors affecting OSCC metastasis, are a subtype of RNA with a length of more than 200 nucleotides that has little or no coding potential. In recent years, the important role played by lncRNAs in biological processes, such as chromatin modification, transcription regulation, RNA stability regulation, and mRNA translation, has been gradually revealed. More and more studies have shown that lncRNAs can regulate the metastasis of various tumors including OSCC at epigenetic, transcriptional, and post-transcriptional levels. In this review, we mainly discussed the role and possible mechanisms of lncRNAs in OSCC metastasis. Most lncRNAs act as oncogenes and only a few lncRNAs have been shown to inhibit OSCC metastasis. Besides, we briefly introduced the research status of cancer-associated fibroblasts-related lncRNAs in OSCC metastasis. Finally, we discussed the research prospects of lncRNAs-mediated crosstalk between OSCC cells and the tumor microenvironment in OSCC metastasis, especially the potential research value of exosomes and lymphangiogenesis. In general, lncRNAs are expected to be used for screening, treatment, and prognosis monitoring of OSCC metastasis, but more work is still required to better understand the biological function of lncRNAs.
Avoidance of Hen's Egg Based on IgE Levels Should Be Avoided for Children With Hen's Egg Allergy
Authors: Miyagi Yoshitsune , Yamamoto-Hanada Kiwako , Ogita Hiroya , Kiguchi Tomoyuki , Inuzuka Yusuke , Toyokuni Kenji , Nishimura Koji , Irahara Makoto , Ishikawa Fumi , Sato Miori , Saito-Abe Mayako , Miyaji Yumiko , Kabashima Shigenori , Fukuie Tatsuki , Nomura Ichiro , Ohya Yukihiro
Published: January 2021

Background: Although hen's egg (HE) allergy was thought to be usually resolved by late childhood, majority of HE allergy patients with a high level of egg white (HEW)-specific IgE could not acquire tolerance for HE by age 8 years.

Objective: The aim is to investigate whether the avoidance of HE until 6 years of age increased the risk of heated HE allergy at age 6 years.

Methods: This was a retrospective case-control study. The HE tolerance children (n = 17) and children with low-dose HE reactor [a positive reaction to ≤ 4 g of heated HEW in oral food challenges (OFCs)] children (n = 26) were included based on the results of OFC at 6 years old. Multivariate logistic regression analysis was applied to examine the associations between HE avoidance until age 6 years and HE allergy status confirmed by OFC, adjusting the level of ovomucoid-specific IgE (OM-sIgE) during early infancy.

Results: A lower proportion of strict avoidance of HE was observed in the HE tolerance group than in the low-dose HE reactor group (6 vs. 46%, p = 0.006). OM-sIgE levels in children younger than 2 years old were significantly higher in the low-dose HE reactor group than those in the HE tolerance group (median [interquartile], 26.7 UA/mL [11.9–53.4] vs. 7.9 UA/mL [0.35–23.4]; p =0.024). The avoidance of HE until 6 years of age increased the risk of heated HE allergy even after adjusting OM-sIgE levels.

Conclusions: The long-term avoidance of HE from infancy increased the risk of heated HE allergy confirmed by OFC at age 6 years.
The Burden of the Serious and Difficult-to-Treat Infections and a New Antibiotic Available: Cefiderocol
Authors: Taheri Yasaman , Joković Nataša , Vitorović Jelena , Grundmann Oliver , Maroyi Alfred , Calina Daniela
Published: January 2021

Background: Infection is a disease that can occur due to the entrance of a virus, bacteria, and other infectious agents. Cefiderocol is innovative cephalosporin drug that belongs to a special class of antibiotics, sideromycins, which are taken up by bacterial cells through active transport. The unique cell entry and stability to β-lactamases allow cefiderocol to overcome the most common resistance mechanisms in Gram-negative bacteria.

Objective: This article aims to highlight the therapeutic efficacy, safety and tolerability of cefiderocol, with a focus on the FDA label.

Methods: The pharmacological properties of cefiderocol are also summarized. In this review, we conducted literature research on the PubMed database using the following keywords: “antimicrobial treatment”, “new antibiotic”, “cefiderocol”, “siderophore cephalosporin”; “multidrug-resistant”, “Gram-negative bacilli”, “critically ill patients”; “severe bacterial infections”.

Results: There were identified the most relevant data about the pathophysiology of serious bacterial infections, antibacterial mechanism of action, microbiology, mechanisms of resistance, pharmacokinetic and pharmacodynamic properties of cefiderocol.

Conclusion: The results highlighted there appeared to be clinical benefit from cefiderocol in the treatment of infections caused by Gram-negative aerobic microorganisms in adult patients with severe infections and limited treatment options.
Pros and Cons of Aspirin for the Primary Prevention of Cardiovascular Events: A Secondary Study of Trial Sequential Analysis
Authors: Zhao Binghao , Wu Qian , Wang Li , Liao Chen , Dong Yifei , Xu Jingsong , Wei Yiping , Zhang Wenxiong
Published: January 2021

Background and Aims: Aspirin leads to substantial benefits for the secondary prevention of cardiovascular disease (CVD). We aimed to cast more light on aspirin’s role for the primary prevention of CVD.

Methods: Databases were searched for clinical trials comparing aspirin vs. no aspirin use in this meta-analysis. Efficacy and safety profiles were rigorously investigated. Trial sequential analysis (TSA) was used to determine the robustness of the results.

Results: Fourteen studies with 163,840 participants were eligible (mean follow-up 6.2 y). Aspirin intake was found to be associated with 9, 13, and 12% reductions in the risk of cardiovascular events (CV events) (relative risk [RR]: 0.91, 95% confidence intervals [CI]: 0.87–0.96; risk difference (RD): 0.29%; absolute risk percentage (AR%): 7.61%; number needed to treat (NNT): 345), myocardial infarction (RR: 0.87, 95% CI: 0.77–0.97; RD: 0.21%; AR%: 11.11%; NNT: 488) and ischemic stroke (RR: 0.88, 95% CI: 0.80–0.96; RD: 0.21%; AR%: 16.14%; NNT: 476), respectively; aspirin intake was also associated with 40%, 30%, and 57% increases in the risk of major bleeding (RR: 1.40, 95% CI: 1.29–1.53; RD: 0.47%; AR%: 27.85; NNT: 214), intracranial bleeding (RR: 1.30, 95% CI: 1.11–1.52; RD: 0.10%; AR%: 22.99%; NNT: 1,000) and major gastrointestinal bleeding (RR: 1.57, 95% CI: 1.38–1.78; RD: 0.32%; AR%: 36.70%; NNT: 315), respectively. Further, populations with low doses of aspirin intake (≤100 mg), populations <65 y old or populations with body mass index (BMI) ≧ 25 experienced more advantages; high-risk (10-y cardiovascular risk ≧10%) and full diabetic individuals reported hardly clinical benefits.

Conclusion: Aspirin intake was associated with a reduced risk of CV events and an increased incidence of bleeding profiles in primary prevention. It is necessary to identify individual’s CVD risk using clear examinations or assessments before aspirin intake, and truly realize individualized prescription.
TLR9 and COVID-19: A Multidisciplinary Theory of a Multifaceted Therapeutic Target
Authors: Bezemer Gillina F. G. , Garssen Johan
Published: January 2021

By mapping the clinical pathophysiology of the novel coronavirus disease 2019 (COVID-19) against insights from virology, immunology, genomics, epidemiology and pharmacology, it is here proposed that the pathogen recognition receptor called toll like receptor 9 (TLR9) might have a pivotal role in the pathogenesis of COVID-19. Severe Acute Respiratory Syndrome Coronavirus 2, is causing the greatest global social and economic disruption since world war II. Lack of a vaccine, lack of successful treatment and limitations of the healthcare workforce and resources needed to safeguard patients with severe COVID-19 on the edge of life, demands radical preventive measures. It is urgently needed to identify biomarkers and drug candidates so that vulnerable individuals can be recognized early and severe multi-organ complications can be prevented or dampened. The TLR9 COVID-19 hypothesis describes a mechanism of action that could explain a wide spectrum of manifestations observed in patients with severe COVID-19. The introduced hypothesis proposes biomarkers for identification of vulnerable individuals and positions TLR9 as a promising multifaceted intervention target for prevention and/or treatment of COVID-19. TLR9 agonists might have value as prophylactic vaccine adjuvants and therapeutic immune stimulators at the early onset of disease. Additionally, in this current manuscript it is proposed for the first time that TLR9 could be considered as a target of “inhibition” aimed to dampen hyperinflammation and thrombotic complications in vulnerable patients that are at risk of developing late stages of COVID-19. The readily availability of TLR9 modulating drug candidates that have reached clinical testing for other disorders could favor a fast track development scenario, an important advantage under the current high unmet medical need circumstances regarding COVID-19.
Machine Learning for Detection of Safety Signals From Spontaneous Reporting System Data: Example of Nivolumab and Docetaxel
Authors: Bae Ji-Hwan , Baek Yeon-Hee , Lee Jeong-Eun , Song Inmyung , Lee Jee-Hyong , Shin Ju-Young
Published: January 2021

Introduction: Various methods have been implemented to detect adverse drug reaction (ADR) signals. However, the applicability of machine learning methods has not yet been fully evaluated.

Objective: To evaluate the feasibility of machine learning algorithms in detecting ADR signals of nivolumab and docetaxel, new and old anticancer agents.

Methods: We conducted a safety surveillance study of nivolumab and docetaxel using the Korea national spontaneous reporting database from 2009 to 2018. We constructed a novel input dataset for each study drug comprised of known ADRs that were listed in the drug labels and unknown ADRs. Given the known ADRs, we trained machine learning algorithms and evaluated predictive performance in generating safety signals of machine learning algorithms (gradient boosting machine [GBM] and random forest [RF]) compared with traditional disproportionality analysis methods (reporting odds ratio [ROR] and information component [IC]) by using the area under the curve (AUC). Each method then was implemented to detect new safety signals from the unknown ADR datasets.

Results: Of all methods implemented, GBM achieved the best average predictive performance (AUC: 0.97 and 0.93 for nivolumab and docetaxel). The AUC achieved by each method was 0.95 and 0.92 (RF), 0.55 and 0.51 (ROR), and 0.49 and 0.48 (IC) for respective drug. GBM detected additional 24 and nine signals for nivolumab and 82 and 76 for docetaxel compared to ROR and IC, respectively, from the unknown ADR datasets.

Conclusion: Machine learning algorithm based on GBM performed better and detected more new ADR signals than traditional disproportionality analysis methods.
Pristimerin Suppresses RANKL-Induced Osteoclastogenesis and Ameliorates Ovariectomy-Induced Bone Loss
Authors: Qi Dahu , Liu Hui , Sun Xuying , Luo Danni , Zhu Meipeng , Tao Tenghui , Gao Chenghao , Zhou Chuankun , Zhou Wei , Xiao Jun
Published: January 2021

Osteoporosis is characterized by bone loss and destruction of trabecular architecture, which greatly increases the burden on the healthcare system. Excessive activation of osteoclasts is an important cause of osteoporosis, and suppression of osteoclastogenesis is helpful for the treatment of osteoporosis. Pristimerin, a natural compound, possesses numerous pharmacological effects via inactivating the NF-κB and MAPK pathways, which are closely related to osteoclastogenesis process. However, the relationship between Pristimerin and osteoclastogenesis requires further investigation. In this research, we examined the effect of Pristimerin on osteoclastogenesis and investigated the related mechanisms. Our results showed Pristimerin inhibited RANKL-induced osteoclast differentiation and osteoclastic bone resorption in vitro, with decreased expression of osteoclastogenesis-related markers including c-Fos, NFATc1, TRAP, Cathepsin K, and MMP-9 at both mRNA and protein levels. Furthermore, Pristimerin suppressed NF-κB and MAPK signaling pathways, reduced reactive oxygen species (ROS) production and activated the nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling during osteoclastogenesis. Our in vivo experiments showed that Pristimerin remarkably ameliorated ovariectomy-induced bone loss, reduced serum levels of TNF-α, IL-1β, IL-6, and RANKL, and increased serum level of osteoprotegerin (OPG). Therefore, our research indicated that Pristimerin is a potential chemical for the treatment of osteoporosis.
Cerebral vs. Cardiovascular Responses to Exercise in Type 2 Diabetic Patients
Authors: Kim Yu-Sok , van der Ster Björn J. P. , Brassard Patrice , Secher Niels H. , van Lieshout Johannes J.
Published: January 2021

The human brain is constantly active and even small limitations to cerebral blood flow (CBF) may be critical for preserving oxygen and substrate supply, e.g., during exercise and hypoxia. Exhaustive exercise evokes a competition for the supply of oxygenated blood between the brain and the working muscles, and inability to increase cardiac output sufficiently during exercise may jeopardize cerebral perfusion of relevance for diabetic patients. The challenge in diabetes care is to optimize metabolic control to slow progression of vascular disease, but likely because of a limited ability to increase cardiac output, these patients perceive aerobic exercise to be more strenuous than healthy subjects and that limits the possibility to apply physical activity as a preventive lifestyle intervention. In this review, we consider the effects of functional activation by exercise on the brain and how it contributes to understanding the control of CBF with the limited exercise tolerance experienced by type 2 diabetic patients. Whether a decline in cerebral oxygenation and thereby reduced neural drive to working muscles plays a role for “central” fatigue during exhaustive exercise is addressed in relation to brain’s attenuated vascular response to exercise in type 2 diabetic subjects.
Utility of Zebrafish Models of Acquired and Inherited Long QT Syndrome
Authors: Simpson Kyle E. , Venkateshappa Ravichandra , Pang Zhao Kai , Faizi Shoaib , Tibbits Glen F. , Claydon Tom W.
Published: January 2021

Long-QT Syndrome (LQTS) is a cardiac electrical disorder, distinguished by irregular heart rates and sudden death. Accounting for ∼40% of cases, LQTS Type 2 (LQTS2), is caused by defects in the Kv11.1 (hERG) potassium channel that is critical for cardiac repolarization. Drug block of hERG channels or dysfunctional channel variants can result in acquired or inherited LQTS2, respectively, which are typified by delayed repolarization and predisposition to lethal arrhythmia. As such, there is significant interest in clear identification of drugs and channel variants that produce clinically meaningful perturbation of hERG channel function. While toxicological screening of hERG channels, and phenotypic assessment of inherited channel variants in heterologous systems is now commonplace, affordable, efficient, and insightful whole organ models for acquired and inherited LQTS2 are lacking. Recent work has shown that zebrafish provide a viablein vivoor whole organ model of cardiac electrophysiology. Characterization of cardiac ion currents and toxicological screening work in intact embryos, as well as adult whole hearts, has demonstrated the utility of the zebrafish model to contribute to the development of therapeutics that lack hERG-blocking off-target effects. Moreover, forward and reverse genetic approaches show zebrafish as a tractable model in which LQTS2 can be studied. With the development of new tools and technologies, zebrafish lines carrying precise channel variants associated with LQTS2 have recently begun to be generated and explored. In this review, we discuss the present knowledge and questions raised related to the use of zebrafish as models of acquired and inherited LQTS2. We focus discussion, in particular, on developments in precise gene-editing approaches in zebrafish to create whole heart inherited LQTS2 models and evidence that zebrafish hearts can be used to study arrhythmogenicity and to identify potential anti-arrhythmic compounds.
Multiple Small-Effect Alleles of Indica Origin Enhance High Iron-Associated Stress Tolerance in Rice Under Field Conditions in West Africa
Authors: Melandri Giovanni , Sikirou Mouritala , Arbelaez Juan D. , Shittu Afeez , Semwal Vimal K. , Konaté Kadougoudiou A. , Maji Alhassan T. , Ngaujah Steven A. , Akintayo Inoussa , Govindaraj Vishnu , Shi Yuxin , Agosto-Peréz Francisco J. , Greenberg Anthony J. , Atlin Gary , Ramaiah Venuprasad , McCouch Susan R.
Published: January 2021

Understanding the genetics of field-based tolerance to high iron-associated (HIA) stress in rice can accelerate the development of new varieties with enhanced yield performance in West African lowland ecosystems. To date, few field-based studies have been undertaken to rigorously evaluate rice yield performance under HIA stress conditions. In this study, two NERICA × O. sativa bi-parental rice populations and one O.sativa diversity panel consisting of 296 rice accessions were evaluated for grain yield and leaf bronzing symptoms over multiple years in four West African HIA stress and control sites. Mapping of these traits identified a large number of QTLs and single nucleotide polymorphisms (SNPs) associated with stress tolerance in the field. Favorable alleles associated with tolerance to high levels of iron in anaerobic rice soils were rare and almost exclusively derived from the indica subpopulation, including the most favorable alleles identified in NERICA varieties. These findings highlight the complex genetic architecture underlying rice response to HIA stress and suggest that a recurrent selection program focusing on an expanded indica genepool could be productively used in combination with genomic selection to increase the efficiency of selection in breeding programs designed to enhance tolerance to this prevalent abiotic stress in West Africa.