bluuebunny/crossref_metadata_2025 huggingface dataset:
Fiber Derived Microbial Metabolites Prevent Acute Kidney Injury Through G-Protein Coupled Receptors and HDAC Inhibition
Authors: Liu Yunzi , Li Yan J. , Loh Yik W. , Singer Julian , Zhu Weiping , Macia Laurence , Mackay Charles R. , Wang Weiming , Chadban Steven J. , Wu Huiling
Published: April 2021

Short-chain fatty acids (SCFA) derived from gut microbial fermentation of fiber have been shown to exert anti-inflammatory and immune-modulatory properties in acute kidney injury (AKI). However the direct mechanistic link between SCFAs, diet and the gut microbiome is yet to be established. Using the murine model of folic-acid nephropathy (FAN), we examined the effect of dietary fiber on development of AKI (day 2) and subsequent chronic kidney disease (CKD) (day 28). FAN was induced in wild-type and knockout mice lacking G protein–coupled receptors GPR41, GPR43, or GPR109A. Mice were randomized to high-fiber or normal-chow diets, or SCFAs in drinking water. We used 16S rRNA sequencing to assess the gut microbiome and 1H-NMR spectroscopy for metabolic profiles. Mice fed high-fiber were partially protected against development of AKI and subsequent CKD, exhibiting better kidney function throughout, less tubular injury at day 2 and less interstitial fibrosis and chronic inflammation at day 28 vs controls. Fiber modified the gut microbiome and alleviated dysbiosis induced by AKI, promoting expansion of SCFA-producing bacteria Bifidobacterium and Prevotella, which increased fecal and serum SCFA concentrations. SCFA treatment achieved similar protection, but not in the absence of GPR41 or GPR109A. Histone deacetylase activity (HDAC) was inhibited in kidneys of high-fiber fed mice. We conclude that dietary manipulation of the gut microbiome protects against AKI and subsequent CKD, mediated by HDAC inhibition and activation of GPR41 and GPR109A by SCFAs. This study highlights the potential of the gut microbiome as a modifiable target in the prevention of AKI.
Saltwater Intrusion and Submarine Groundwater Discharge: Acceleration of Biogeochemical Reactions in Changing Coastal Aquifers
Authors: Moore Willard S. , Joye Samantha B.
Published: April 2021

Intrusion of saltwater into freshwater coastal aquifers poisons an essential resource. Such intrusions are occurring along coastlines worldwide due largely to the over-pumping of freshwater and sea level rise. Saltwater intrusion impacts drinking water, agriculture and industry, and causes profound changes in the biogeochemistry of the affected aquifers, the dynamic systems called subterranean estuaries. Subterranean estuaries receive freshwater from land and saltwater from the ocean and expose this fluid mixture to intense biogeochemical dynamics as it interacts with the aquifer and aquiclude solids. Increased saltwater intrusion alters the ionic strength and oxidative capacity of these systems, resulting in elevated concentrations of certain chemical species in the groundwater, which flows from subterranean estuaries into the ocean as submarine groundwater discharge (SGD). These highly altered fluids are enriched in nutrients, carbon, trace gases, sulfide, metals, and radionuclides. Seawater intrusion expands the subterranean estuary. Climate change amplifies sea level variations on short and seasonal time scales. These changes may result in higher SGD fluxes, further accelerating release of nutrients and thus promoting biological productivity in nutrient-depleted waters. But this process may also adversely affect the environment and alter the local ecology. Research on saltwater intrusion and SGD has largely been undertaken by different groups. We demonstrate that these two processes are linked in ways that neither group has articulated effectively to date.
Roughness Effects of Crack Surfaces on the Elastic Moduli of Cracked Rocks
Authors: Fu Bo-Ye , Fu Li-Yun , Han Tongcheng , Cao Chenghao
Published: April 2021

Crack surfaces are usually rough on various scales, and are sensitive to loading stresses and hence significantly affecting the mechanical properties of cracked rocks. We design a number of dry- and fluid-saturated numerical cracked samples to investigate the roughness influence of crack surfaces on the elastic stiffness. The fracture surface roughness is characterized by non-uniform fracture radii. We calculate the elastic moduli of cracked samples by finite-element simulation. Comparisons with the theoretical predictions by Gassmann and C&S (Ciz and Shapiro) (Ciz and Shapiro, Geophysics, 2007, 72(6), A75–A79) substitution equations demonstrate that the rough crack surfaces for both dry- and fluid-saturated samples can induce a stress concentration around the crack that reduces the elastic moduli and decreases the stiffness of rocks. For the fluid/solid-saturated cracks under the normal (shear) loading stresses, because the stress-concentration can induce shear (normal) strains around fracture, shear (bulk) modulus of the filling material will have contributions to the effective bulk (shear) modulus of rocks. The extra contribution, however, makes the Gassmann equation and C&S equation invalid.
The Interrelation Between Language Anxiety and Self-Determined Motivation; A Mixed Methods Approach
Authors: Alamer Abdullah , Almulhim Fahad
Published: April 2021

The relationship between language anxiety and self-determined motivation has been examined from various aspects in the applied linguistics domain. However, the direction of the relationship tend to disagree. Some studies report positive correlation whereas others (and in most cases) show negative correlation. To address this issue, the present study attempted to evaluate in depth the relationship between these two variables. We first qualitatively examined the types of language anxiety students face during learning, and then assessed how motivational variables based on self-determination theory can predict these identified types of anxiety. The results showed that sense of competence and relatedness negatively predicted certain types of anxiety while controlled motivation positively predicted only the general language anxiety. However, perception of autonomy and autonomous motivation did not predict any sub-types of language anxiety while sense of relatedness positively predicted psychological anxiety. The findings are discussed in terms of their theoretical and educational implications for language learning.
Comparative Transcriptome Analysis of Key Genes and Pathways Activated in Response to Fat Deposition in Two Sheep Breeds With Distinct Tail Phenotype
Authors: Zhang Wei , Xu Mengsi , Wang Juanjuan , Wang Shiyin , Wang Xinhua , Yang Jingquan , Gao Lei , Gan Shangquan
Published: April 2021

Fat tail in sheep presents a valuable energy reserve that has historically facilitated adaptation to harsh environments. However, in modern intensive and semi-intensive sheep industry systems, breeds with leaner tails are more desirable. In the present study, RNA sequencing (RNA-Seq) was applied to determine the transcriptome profiles of tail fat tissues in two Chinese sheep breeds, fat-rumped Altay sheep and thin-tailed Xinjiang fine wool (XFW) sheep, with extreme fat tail phenotype difference. Then the differentially expressed genes (DEGs) and their sequence variations were further analyzed. In total, 21,527 genes were detected, among which 3,965 displayed significant expression variations in tail fat tissues of the two sheep breeds (P< 0.05), including 707 upregulated and 3,258 downregulated genes. Gene Ontology (GO) analysis disclosed that 198 DEGs were related to fat metabolism. In Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, the majority of DEGs were significantly enriched in “adipocytokine signaling,” “PPAR signaling,” and “metabolic pathways” (P< 0.05); moreover, some genes were involved in multiple pathways. Among the 198 DEGs, 22 genes were markedly up- or downregulated in tail fat tissue of Altay sheep, indicating that these genes might be closely related to the fat tail trait of this breed. A total of 41,724 and 42,193 SNPs were detected in the transcriptomic data of tail fat tissues obtained from Altay and XFW sheep, respectively. The distribution of seven SNPs in the coding regions of the 22 candidate genes was further investigated in populations of three sheep breeds with distinct tail phenotypes. In particular, the g.18167532T/C (Oar_v3.1) mutation of the ATP-binding cassette transporter A1 (ABCA1) gene and g.57036072G/T (Oar_v3.1) mutation of the solute carrier family 27 member 2 (SLC27A2) gene showed significantly different distributions and were closely associated with tail phenotype (P< 0.05). The present study provides transcriptomic evidence explaining the differences in fat- and thin-tailed sheep breeds and reveals numerous DEGs and SNPs associated with tail phenotype. Our data provide a valuable theoretical basis for selection of lean-tailed sheep breeds.
The Impact of COVID-19 on Immigration Detention
Authors: Marouf Fatma E.
Published: April 2021

COVID-19 has spread quickly through immigration detention facilities in the United States. As of December 2, 2020, there have been over 7,500 confirmed COVID-19 cases among detained noncitizens. This Article examines why COVID-19 spread rapidly in immigration detention facilities, how it has transformed detention and deportation proceedings, and what can be done to improve the situation for detained noncitizens. Part I identifies key factors that contributed to the rapid spread of COVID-19 in immigration detention. While these factors are not an exhaustive list, they highlight important weaknesses in the immigration detention system. Part II then examines how the pandemic changed the size of the population in detention, the length of detention, and the nature of removal proceedings. In Part III, the Article offers recommendations for mitigating the impact of COVID-19 on detained noncitizens. These recommendations include using more alternatives to detention, curtailing transfers between detention facilities, establishing a better tracking system for medically vulnerable detainees, prioritizing bond hearings and habeas petitions, and including immigration detainees among the groups to be offered COVID-19 vaccine in the initial phase of the vaccination program. The lessons learned from the spread of COVID-19 in immigration detention will hopefully lead to a better response to any future pandemics. In discussing these issues, the Article draws on national data from January 2019 through November 2020 published by Immigration and Customs Enforcement (ICE) and Customs and Border Protection (CBP), two agencies within DHS. The main datasets used are detention statistics published by ICE for FY 2019 (Oct. 2018-Sep. 2019), FY 2020 (Oct. 2019-Sep. 2020), and the first two months of FY 2021 (Oct. 2020-Nov. 2020). These datasets include detention statistics about individuals arrested by ICE in the interior of the country, as well as by CBP at or near the border. Additionally, the Article draws on separate data published by CBP regarding the total number of apprehensions at the border based on its immigration authority under Title 8 of the United States Code, as well as the number of expulsions at the border based on its public health authority under Title 42 of the United States Code.
Surface Topography, Bacterial Carrying Capacity, and the Prospect of Microbiome Manipulation in the Sea Anemone Coral Model Aiptasia
Authors: Costa Rúben M. , Cárdenas Anny , Loussert-Fonta Céline , Toullec Gaëlle , Meibom Anders , Voolstra Christian R.
Published: April 2021

Aiptasia is an emerging model organism to study cnidarian symbioses due to its taxonomic relatedness to other anthozoans such as stony corals and similarities of its microalgal and bacterial partners, complementing the existing Hydra (Hydrozoa) and Nematostella (Anthozoa) model systems. Despite the availability of studies characterizing the microbiomes of several natural Aiptasia populations and laboratory strains, knowledge on basic information, such as surface topography, bacterial carrying capacity, or the prospect of microbiome manipulation is lacking. Here we address these knowledge gaps. Our results show that the surface topographies of the model hydrozoan Hydra and anthozoans differ substantially, whereas the ultrastructural surface architecture of Aiptasia and stony corals is highly similar. Further, we determined a bacterial carrying capacity of ∼104 and ∼105 bacteria (i.e., colony forming units, CFUs) per polyp for aposymbiotic and symbiotic Aiptasia anemones, respectively, suggesting that the symbiotic status changes bacterial association/density. Microbiome transplants from Acropora humilis and Porites sp. to gnotobiotic Aiptasia showed that only a few foreign bacterial taxa were effective colonizers. Our results shed light on the putative difficulties of transplanting microbiomes between cnidarians in a manner that consistently changes microbial host association at large. At the same time, our study provides an avenue to identify bacterial taxa that exhibit broad ability to colonize different hosts as a starting point for cross-species microbiome manipulation. Our work is relevant in the context of microbial therapy (probiotics) and microbiome manipulation in corals and answers to the need of having cnidarian model systems to test the function of bacteria and their effect on holobiont biology. Taken together, we provide important foundation data to extend Aiptasia as a coral model for bacterial functional studies.
Enhanced Glutamate Synthesis and Export by the Thermotolerant Emerging Industrial Workhorse Bacillus methanolicus in Response to High Osmolarity
Authors: Frank Christine , Hoffmann Tamara , Zelder Oskar , Felle Max F. , Bremer Erhard
Published: April 2021

The thermotolerant methylotroph Bacillus methanolicus MGA3 was originally isolated from freshwater marsh soil. Due to its ability to use methanol as sole carbon and energy source, B. methanolicus is increasingly explored as a cell factory for the production of amino acids, fine chemicals, and proteins of biotechnological interest. During high cell density fermentation in industrial settings with the membrane-permeable methanol as the feed, the excretion of low molecular weight products synthesized from it will increase the osmotic pressure of the medium. This in turn will impair cell growth and productivity of the overall biotechnological production process. With this in mind, we have analyzed the core of the physiological adjustment process of B. methanolicus MGA3 to sustained high osmolarity surroundings. Through growth assays, we found that B. methanolicus MGA3 possesses only a restricted ability to cope with sustained osmotic stress. This finding is consistent with the ecophysiological conditions in the habitat from which it was originally isolated. None of the externally provided compatible solutes and proline-containing peptides affording osmostress protection for Bacillus subtilis were able to stimulate growth of B. methanolicus MGA3 at high salinity. B. methanolicus MGA3 synthesized the moderately effective compatible solute L-glutamate in a pattern such that the cellular pool increased concomitantly with increases in the external osmolarity. Counterintuitively, a large portion of the newly synthesized L-glutamate was excreted. The expression of the genes (gltAB and gltA2) for two L-glutamate synthases were upregulated in response to high salinity along with that of the gltC regulatory gene. Such a regulatory pattern of the system(s) for L-glutamate synthesis in Bacilli is new. Our findings might thus be generally relevant to understand the production of the osmostress protectant L-glutamate by those Bacilli that exclusively rely on this compatible solute for their physiological adjustment to high osmolarity surroundings.
Effect of Divalent Cations (Cu, Zn, Pb, Cd, and Sr) on Microbially Induced Calcium Carbonate Precipitation and Mineralogical Properties
Authors: Kim Yumi , Kwon Sunki , Roh Yul
Published: April 2021

Microbially induced calcium carbonate precipitation (MICP) is a bio-geochemical process involving calcium carbonate precipitation and possible co-precipitation of other metals. The study investigated the extent to which a urease-positive bacterium, Sporosarcina pasteurii, can tolerate a range of metals (e.g., Cu, Zn, Pb, Cd, and Sr), and analyzed the role of calcium carbonate bioprecipitation in eliminating these divalent toxicants from aqueous solutions. The experiments using S. pasteurii were performed aerobically in growth media including urea, CaCl2 (30 mM) and different metals such Cu, Zn, Pb, and Cd (0.01 ∼ 1 mM), and Sr (1 ∼ 30 mM). Microbial growth and urea degradation led to an increase in pH and OD600, facilitating the precipitation of calcium carbonate. The metal types and concentrations contributed to the mineralogy of various calcium carbonates precipitated and differences in metal removal rates. Pb and Sr showed more than 99% removal efficiency, whereas Cu, Zn, and Cd showed a low removal efficiency of 30∼60% at a low concentration of 0.05 mM or less. Thus the removal efficiency of metal ions during MICP varied with the types and concentrations of divalent cations. The MICP in the presence of divalent metals also affected the mineralogical properties such as carbonate mineralogy, shape, and crystallinity.
Development and Validation of a Prognostic Gene Signature in Clear Cell Renal Cell Carcinoma
Authors: Zhan Chuanchuan , Wang Zichu , Xu Chao , Huang Xiao , Su Junzhou , Chen Bisheng , Wang Mingshan , Qi Zhihong , Bai Peiming
Published: April 2021

Clear cell renal cell carcinoma (ccRCC), one of the most common urologic cancer types, has a relatively good prognosis. However, clinical diagnoses are mostly done during the medium or late stages, when mortality and recurrence rates are quite high. Therefore, it is important to perform real-time information tracking and dynamic prognosis analysis for these patients. We downloaded the RNA-seq data and corresponding clinical information of ccRCC from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A total of 3,238 differentially expressed genes were identified between normal and ccRCC tissues. Through a series of Weighted Gene Co-expression Network, overall survival, immunohistochemical and the least absolute shrinkage selection operator (LASSO) analyses, seven prognosis-associated genes (AURKB, FOXM1, PTTG1, TOP2A, TACC3, CCNA2, and MELK) were screened. Their risk score signature was then constructed. Survival analysis showed that high-risk scores exhibited significantly worse overall survival outcomes than low-risk patients. Accuracy of this prognostic signature was confirmed by the receiver operating characteristic curve and was further validated using another cohort. Gene set enrichment analysis showed that some cancer-associated phenotypes were significantly prevalent in the high-risk group. Overall, these findings prove that this risk model can potentially improve individualized diagnostic and therapeutic strategies.
Exercise Training-Related Changes in Cortical Gray Matter Diffusivity and Cognitive Function in Mild Cognitive Impairment and Healthy Older Adults
Authors: Callow Daniel D. , Won Junyeon , Pena Gabriel S. , Jordan Leslie S. , Arnold-Nedimala Naomi A. , Kommula Yash , Nielson Kristy A. , Smith J. Carson
Published: April 2021

Individuals with Mild Cognitive Impairment (MCI) are at an elevated risk of dementia and exhibit deficits in cognition and cortical gray matter (GM) volume, thickness, and microstructure. Meanwhile, exercise training appears to preserve brain function and macrostructure may help delay or prevent the onset of dementia in individuals with MCI. Yet, our understanding of the neurophysiological effects of exercise training in individuals with MCI remains limited. Recent work suggests that the measures of gray matter microstructure using diffusion imaging may be sensitive to early cognitive and neurophysiological changes in the aging brain. Therefore, this study is aimed to determine the effects of exercise training in cognition and cortical gray matter microstructure in individuals with MCI vs. cognitively healthy older adults. Fifteen MCI participants and 17 cognitively intact controls (HC) volunteered for a 12-week supervised walking intervention. Following the intervention, MCI and HC saw improvements in cardiorespiratory fitness, performance on Trial 1 of the Rey Auditory Verbal Learning Test (RAVLT), a measure of verbal memory, and the Controlled Oral Word Association Test (COWAT), a measure of verbal fluency. After controlling for age, a voxel-wise analysis of cortical gray matter diffusivity showed individuals with MCI exhibited greater increases in mean diffusivity (MD) in the left insular cortex than HC. This increase in MD was positively associated with improvements in COWAT performance. Additionally, after controlling for age, the voxel-wise analysis indicated a main effect of Time with both groups experiencing an increase in left insular and left and right cerebellar MD. Increases in left insular diffusivity were similarly found to be positively associated with improvements in COWAT performance in both groups, while increases in cerebellar MD were related to gains in episodic memory performance. These findings suggest that exercise training may be related to improvements in neural circuits that govern verbal fluency performance in older adults through the microstructural remodeling of cortical gray matter. Furthermore, changes in left insular cortex microstructure may be particularly relevant to improvements in verbal fluency among individuals diagnosed with MCI.
ASD-SAENet: A Sparse Autoencoder, and Deep-Neural Network Model for Detecting Autism Spectrum Disorder (ASD) Using fMRI Data
Authors: Almuqhim Fahad , Saeed Fahad
Published: April 2021

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder which is characterized by impaired communication, and limited social interactions. The shortcomings of current clinical approaches which are based exclusively on behavioral observation of symptomology, and poor understanding of the neurological mechanisms underlying ASD necessitates the identification of new biomarkers that can aid in study of brain development, and functioning, and can lead to accurate and early detection of ASD. In this paper, we developed a deep-learning model called ASD-SAENet for classifying patients with ASD from typical control subjects using fMRI data. We designed and implemented a sparse autoencoder (SAE) which results in optimized extraction of features that can be used for classification. These features are then fed into a deep neural network (DNN) which results in superior classification of fMRI brain scans more prone to ASD. Our proposed model is trained to optimize the classifier while improving extracted features based on both reconstructed data error and the classifier error. We evaluated our proposed deep-learning model using publicly available Autism Brain Imaging Data Exchange (ABIDE) dataset collected from 17 different research centers, and include more than 1,035 subjects. Our extensive experimentation demonstrate that ASD-SAENet exhibits comparable accuracy (70.8%), and superior specificity (79.1%) for the whole dataset as compared to other methods. Further, our experiments demonstrate superior results as compared to other state-of-the-art methods on 12 out of the 17 imaging centers exhibiting superior generalizability across different data acquisition sites and protocols. The implemented code is available on GitHub portal of our lab at: https://github.com/pcdslab/ASD-SAENet.
A Validated Nomogram That Predicts Prognosis of Autoimmune Encephalitis: A Multicenter Study in China
Authors: Sun Yueqian , Ren Guoping , Ren Jiechuan , Shan Wei , Han Xiong , Lian Yajun , Wang Tiancheng , Wang Qun
Published: April 2021

The aim of this retrospective study was to derive and validate a reliable nomogram for predicting prognosis of autoimmune encephalitis (AE). A multi-center retrospective study was conducted in four hospitals in China, using a random split-sample method to allocate 173 patients into either a training (n = 126) or validation (n = 47) dataset. Demographic, radiographic and therapeutic presentation, combined with clinical features were collected. A modified Rankin Scale (mRS) at discharge was the principal outcome variable. A backward-stepwise approach based on the Akaike information criterion was used to test predictors and construct the final, parsimonious model. Multivariable analysis was conducted using logistic regression to develop a prognosis model and validate a nomogram using an independent dataset. The performance of the model was assessed using receiver operating characteristic curves and a Hosmer-Lemeshow test. The final nomogram model considered age, viral prodrome, consciousness impairment, memory dysfunction and autonomic dysfunction as predictors. Model validations displayed a good level of discrimination in the validation set: area under the Receiver operator characteristic curve = 0.72 (95% Confidence Interval: 0.56–0.88), Hosmer–Lemeshow analysis suggesting good calibration (chi-square: 10.33; p = 0.41). The proposed nomogram demonstrated considerable potential for clinical utility in prediction of prognosis in autoimmune encephalitis.
Status of Immunotherapy Acceptance in Chinese Patients With Multiple Sclerosis: Analysis of Multiple Sclerosis Patient Survival Report 2018
Authors: Zhou Ran , Zeng Qiuming , Yang Huan , Xu Yan , Tan Guojun , Liu Hongbo , Wang Lihua , Zhou Hongyu , Zhang Meini , Feng Jinzhou , Jin Tao , Zhang Xinghu , Wang Jiawei , Zhang Xu , Gao Feng , Yang Chunsheng , Bu Bitao , Li Chunyang , Zhang Min , Dong Huiqing , Lin Aiyu , Liu Weibin , Wu Lei , Wang Manxia , Tang Yulan , Wang Honghao , Long Youming , Wang Zhe , Zheng Weihong
Published: April 2021

Objective: The prevalence of multiple sclerosis (MS) in China is low, although it has been increasing recently. Owing to the paucity of data on immunotherapy acceptance in the Chinese population, we conducted this study to analyze factors affecting the acceptance of immunotherapy and selection of disease-modifying therapies (DMTs) based on personal and clinical data of patients with MS.

Methods: In this study, data were obtained from the Multiple Sclerosis Patient Survival Report 2018, which was the first national survey of patients with MS in China. There were 1,212 patients with MS from 31 provinces who were treated at 49 Chinese hospitals over a 4-month period from May 2018 to August 2018, and the patients were asked to complete online questionnaires to assess their understanding of the disease.

Results: In general, highly educated patients with frequent relapses were more willing to receive treatment regardless of DMTs or other immunotherapy, and patients with more understanding of the disease opted to be treated. Younger patient population, patients with severe disease course, and those with more symptoms were likely to choose the treatment. Moreover, a higher proportion of women chose to be treated with DMTs than with other immunotherapies.

Conclusions: Education status and patient awareness of the disease impact the treatment acceptance in Chinese patients with MS. Therefore, we call for improving the awareness of MS disease and social security to help patients to improve their quality of life.
Suppression of Circadian Timing and Its Impact on the Hippocampus
Authors: Ruby Norman F.
Published: April 2021

In this article, I describe the development of the disruptive phase shift (DPS) protocol and its utility for studying how circadian dysfunction impacts memory processing in the hippocampus. The suprachiasmatic nucleus (SCN) of the Siberian hamster is a labile circadian pacemaker that is easily rendered arrhythmic (ARR) by a simple manipulation of ambient lighting. The DPS protocol uses room lighting to administer a phase-advancing signal followed by a phase-delaying signal within one circadian cycle to suppress clock gene rhythms in the SCN. The main advantage of this model for inducing arrhythmia is that the DPS protocol is non-invasive; circadian rhythms are eliminated while leaving the animals neurologically and genetically intact. In the area of learning and memory, DPS arrhythmia produces much different results than arrhythmia by surgical ablation of the SCN. As I show, SCN ablation has little to no effect on memory. By contrast, DPS hamsters have an intact, but arrhythmic, SCN which produces severe deficits in memory tasks that are accompanied by fragmentation of electroencephalographic theta oscillations, increased synaptic inhibition in hippocampal circuits, and diminished responsiveness to cholinergic signaling in the dentate gyrus of the hippocampus. The studies reviewed here show that DPS hamsters are a promising model for translational studies of adult onset circadian dysfunction in humans.
Determinants of Junk Food Consumption Among Adolescents in Pokhara Valley, Nepal
Authors: Bohara Suraj Sujan , Thapa Kanchan , Bhatt Laxman Datt , Dhami Shankar Singh , Wagle Shreejana
Published: April 2021

Background: Junk food consumption and its consequences has become a major public health concern globally because of its deteriorating health consequences and surging prevalence. Though its adverse health consequences are widely prevalent in all age groups, children and adolescents are more at risk. It may lead to obesity and act as a risk factor for different non-communicable diseases (NCD's) like heart diseases, cardiovascular disease, cancer, hypertension, diabetes, etc. This study was carried out to explore the junk food consumption and its associated factors among adolescent students.

Methods: A cross-sectional study was conducted among 538 adolescent students of Kaski district, Nepal. We used a stratified proportionate sampling technique to recruit the participants. A self-administered questionnaire was used for data collection. Descriptive and bivariate statistical analysis was performed. The odds ratio was computed to test the association.

Results: The study found that more than half of the participants (60.30%) consumed junk foods over the last 30 days, more prevalent among public school participants (65.1%) followed by participants of private school (56.3%). More than half of the participants consumed salty snacks (58.7%) followed by sweets (57.5%). The time of consumption was found to be higher together with friends (83.9%). Similarly, it was consumed more while the participants were on a trip (70.1%). Consumption of junk foods was significantly associated with public school (OR: 1.44, CI = 1.01–2.06), single family (OR: 1.46, CI = 1.01–2.10), living with parents (OR: 1.64, CI = 1.03–2.63), while on travel (OR: 1.99, CI = 1.33–2.98), while reading (OR: 2.01, CI = 1.16–3.47), at home (OR: 2.20, CI = 1.53–3.16), at school (OR: 2.86, CI = 1.98–4.12), friends' influence (OR: 2.01, CI = 1.37–2.94), and junk food availability at home (OR: 1.92, CI = 1.33–2.76).

Conclusion: Consumption of junk foods among adolescent students was remarkably high in both public school and private school adolescents. Regardless of adequate knowledge on harmful consequences of junk foods, school-going adolescents are consuming junk foods due to its easy availability and ready-to-use packaging. The government of Nepal should strictly standardize and regulate advertising policies and extravagant health claims advertised by junk food manufacturers. An appropriate intervention targeted to adolescents to improve food behaviors is recommended.
GZ17-6.02 Interacts With [MEK1/2 and B-RAF Inhibitors] to Kill Melanoma Cells
Authors: Booth Laurence , West Cameron , Von Hoff Daniel , Kirkwood John M. , Dent Paul
Published: April 2021

We defined the lethal interaction between the novel therapeutic GZ17-6.02 and the standard of care combination of the MEK1/2 inhibitor trametinib and the B-RAF inhibitor dabrafenib in PDX isolates of cutaneous melanoma expressing a mutant B-RAF V600E protein. GZ17-6.02 interacted with trametinib/dabrafenib in an additive fashion to kill melanoma cells. Regardless of prior vemurafenib resistance, the drugs when combined interacted to prolong ATM S1981/AMPK T172 and eIF2α S51 phosphorylation and prolong the reduced phosphorylation of JAK2 Y1007, STAT3 Y705 and STAT5 Y694. In vemurafenib-resistant cells GZ17-6.02 caused a prolonged reduction in mTORC1 S2448, mTORC2 S2481 and ULK1 S757 phosphorylation; regardless of vemurafenib resistance, GZ17-6.02 caused a prolonged elevation in CD95 and FAS-L expression. Knock down of eIF2α, Beclin1, ATG5, ATM, AMPKα, CD95 or FADD significantly reduced the ability of GZ17-6.02 to kill as a single agent or when combined with the kinase inhibitors. Expression of activated mTOR, activated STAT3, activated MEK1 or activated AKT significantly reduced the ability of GZ17-6.02 to kill as a single agent or when combined with kinase inhibitors; protective effects that were significantly less pronounced in cells treated with trametinib/dabrafenib. Regardless of vemurafenib resistance, the drugs alone or in combination all reduced the expression of PD-L1 and increased the levels of MHCA, which was linked to degradation of multiple HDAC proteins. Our findings support the use of GZ17-6.02 in combination with trametinib/dabrafenib in the treatment of melanomas expressing mutant B-RAF V600E proteins.
Off-Label Use of Antineoplastic Drugs to Treat Malignancies: Evidence From China Based on a Nationwide Medical Insurance Data Analysis
Authors: Wei Guoxu , Wu Min , Zhu He , Han Sheng , Chen Jing , Zhai Chenchen , Shi Luwen
Published: April 2021

Purpose: Cancer is a leading cause of morbidity and mortality worldwide. Off-label (OL) use of antineoplastic drugs to treat malignancies is prevalent. In this study, we quantified and characterized OL use of antineoplastic drugs to treat malignancies in China.

Methods: This was a retrospective study using nationwide data collected from 2008 to 2010. Use of antineoplastic drugs was considered OL if they were used for indications not reflected in the package insert published by the National Medical Products Administration at the time of prescription. Descriptive analysis and Spearman rank correlation were used to evaluate the frequency and pattern of OL drug use.

Results: In total, 51,382 patients with malignancies, 24 categories of antineoplastic drugs, and 77 types of malignancies treated with OL drugs were included in this study. Twenty commonly used antineoplastic drugs (ICD encoded as L01) were used OL in 10–61% of cases, and four commonly used endocrine therapy antineoplastic drugs (ICD encoded as L02) were used OL in 10–19% of cases. There was a significant negative correlation between the disease constituent ratio and the average OL use rate of antineoplastic drugs for various malignancies. In contrast, there was a significant positive correlation between the average OL use rate of antineoplastic drugs and the number of malignancies treated with OL drugs.

Conclusion: This study provided information regarding OL use of antineoplastic drugs for treatment of malignancies, and showed that OL use was prevalent. In addition, uncommon malignancies were more likely to be treated with OL antineoplastic drugs. Furthermore, more commonly used antineoplastic drugs were more likely to be used OL.
A Nudibranch Marine Extract Selectively Chemosensitizes Colorectal Cancer Cells by Inducing ROS-Mediated Endoplasmic Reticulum Stress
Authors: Ruiz-Torres Verónica , Forsythe Nicholas , Pérez-Sánchez Almudena , Van Schaeybroeck Sandra , Barrajón-Catalán Enrique , Micol Vicente
Published: April 2021

The present study shows the putative antiproliferative mechanism of action of the previously analytically characterized nudibranch extract (Dolabella auricularia, NB) and its different effects in colon cancer cells vs. nontumor colon cells. NB extract increased the accumulation of reactive oxygen species (ROS) and increased endoplasmic reticulum (ER) stress via stimulation of the unfolded protein response. Stress scavengers, N-acetylcysteine (NAC) and 4-phenylbutyric acid (4-PBA), decreased the stress induced by NB. The results showed that NB extract increased ER stress through overproduction of ROS in superinvasive colon cancer cells, decreased their resistance threshold, and produced a nonreturn level of ER stress, causing DNA damage and cell cycle arrest, which prevented them from achieving hyperproliferative capacity and migrating to and invading other tissues. On the contrary, NB extract had a considerably lower effect on nontumor human colon cells, suggesting a selective effect related to stress balance homeostasis. In conclusion, our results confirm that the growth and malignancy of colon cancer cells can be decreased by marine compounds through the modification of one of the most potent resistance mechanisms present in tumor cells; this characteristic differentiates cancer cells from nontumor cells in terms of stress balance.
The Calcium-Activated Chloride Channel TMEM16A is Inhibitied by Liquiritigenin
Authors: Kato Mami , Takayama Yasunori , Sunagawa Masataka
Published: April 2021

The transmembrane 16 (TMEM16) family contains 10 subtypes, and the function of each protein is different. TMEM16A is a calcium-activated chloride channel involved in physiological and pathological situations. Liquiritigenin is an aglycone derived from Glycyrrhiza glabra, and it is generated via the metabolism of enterobacterial flora. It has been known that liquiritigenin reduces pain sensation involving TMEM16A activation in primary sensory neurons. In addition, other pharmacological effects of liquiritigenin in physiological functions involving TMEM16A have been reported. However, the relationship between TMEM16A and liquiritigenin is still unknown. Therefore, we hypothesized that TMEM16A is inhibited by liquiritigenin. To confirm this hypothesis, we investigated the effect of liquiritigenin on TMEM16A currents evoked by intracellular free calcium in HEK293T cells transfected with TMEM16A. In this study, we found that liquiritigenin inhibited the mouse and human TMEM16A currents. To further confirm its selectivity, we also investigated its pharmacological effects on other ion channels, including transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1), which are non-selective cation channels involved in pain sensation. However, liquiritigenin did not inhibit the currents of TRPV1 and TRPA1 induced by capsaicin and allyl isothiocyanate, respectively. Therefore, our findings indicate that selective TMEM16A inhibition could be one molecular mechanism that explains liquiritigenin-induced pain reduction. Additionally, we also investigated the inhibitory effects of estrogens on TMEM16A because liquiritigenin reportedly binds to the estrogen receptor. In this study, a pregnancy-dependent estrogen, estriol, significantly inhibited TMEM16A. However, the efficacy was weak. Although there is a possibility that TMEM16A activity could be suppressed during pregnancy, the physiological significance seems to be small. Thus, the inhibitory effect of estrogen might not be significant under physiological conditions. Furthermore, we investigated the effect of dihydrodaidzein, which is an analog of liquiritigenin that has a hydroxyphenyl at different carbon atom of pyranose. Dihydrodaidzein also inhibited mouse and human TMEM16A. However, the inhibitory effects were weaker than those of liquiritigenin. This suggests that the efficacy of TMEM16A antagonists depends on the hydroxyl group positions. Our finding of liquiritigenin-dependent TMEM16A inhibition could connect the current fragmented knowledge of the physiological and pathological mechanisms involving TMEM16A and liquiritigenin.
PDE9 Inhibitor PF-04447943 Attenuates DSS-Induced Colitis by Suppressing Oxidative Stress, Inflammation, and Regulating T-Cell Polarization
Authors: Rana Mohammad Nasiruddin , Lu Jie , Xue Enfu , Ruan Jingjing , Liu Yuting , Zhang Lejun , Dhar Rana , Li Yajun , Hu Zhengqiang , Zhou Jie , Ma Wangqian , Tang Huifang
Published: April 2021

Ulcerative colitis (UC) is a form of inflammatory bowel disease, which manifests as irritation or swelling and sores in the large intestine in a relapsing and remitting manner. In a dextran sulfate sodium sulfate (DSS)-induced UC model in female mice, we found that the levels of cyclic guanosine monophosphate (cGMP) are reduced, while the expression of phosphodiesterase 9A (PDE9A) is highest among all phosphodiesterase (PDEs). Since PDE9 has the highest affinity toward cGMP, we evaluated the selective PDE9 inhibitor PF-04447943 (PF) as a potential candidate for UC treatment. PF has been extensively studies in cognitive function and in sickle cell disease, but not in models for inflammatory bowel disease (IBD). Therefore, we used female C57BL/6 mice treated with 3% DSS alone or co-treated with PF or sulfasalazine (SASP) to study the body weight, colon length, histopathology, and measure superoxide dismutase (SOD), malondialdehyde (MDA), and cGMP level, as well as cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-12/23 (IL-12/23), interleukin-10 (IL-10), and pathways including nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and inflammasome activation. In addition, the number of dendritic cells (DC) and regulatory T cells (Treg cell) was assessed in the spleen, lymph node, and colon using flow cytometry. DSS reduced the number of goblet cells, decreased colon lengths and body weights, all of them were attenuated by PF treatment. It also suppressed the elevated level of inflammatory cytokines and increased level the anti-inflammatory cytokine, IL-10. PF treatment also reduced the DSS-induced inflammation by suppressing oxidative stress, NF-κB, STAT3, and inflammasome activation, by upregulating nuclear factor erythroid 2-related factor 2 (Nrf-2) and its downstream proteins via extracellular signal-regulated kinase (ERK) phosphorylation. Importantly, PF reversed imbalance in Treg/T helper 17 cells (Th17) cells ratio, possibly by regulating dendritic cells and Treg developmental process. In summary, this study shows the protective effect of a PDE9A inhibitor in ulcerative colitis by suppressing oxidative stress and inflammation as well as reversing the Treg/Th17 cells imbalance.
Functional Polymorphisms in Oxytocin and Dopamine Pathway Genes and the Development of Dispositional Compassion Over Time: The Young Finns Study
Authors: Dobewall Henrik , Saarinen Aino , Lyytikäinen Leo-Pekka , Keltikangas-Järvinen Liisa , Lehtimäki Terho , Hintsanen Mirka
Published: April 2021

Background:We define compassion as an enduring disposition that centers upon empathetic concern for another person's suffering and the motivation to act to alleviate it. The contribution of specific candidate genes to the development of dispositional compassion for others is currently unknown. We examine candidate genes in the oxytocin and dopamine signaling pathways.

Methods:In a 32-year follow-up of the Young Finns Study (N= 2,130, 44.0% men), we examined with multiple indicators latent growth curve modeling the molecular genetic underpinnings of dispositional compassion for others across the life span. We selected five single nucleotide polymorphisms (SNPs) whose functions are known in humans: rs2268498 (OXTR), rs3796863 (CD38) (related to lower oxytocin levels), rs1800497 (ANKK1/DRD2), rs4680 (COMT), and rs1611115 (DBH) (related to higher dopamine levels). Compassion was measured with Cloninger's Temperament and Character Inventory on three repeated observations spanning 15 years (1997–2012). Differences between gender were tested.

Results:We did not find an effect of the five SNPs in oxytocin and dopamine pathway genes on the initial levels of dispositional compassion for others. Individuals who carry one or two copies of the T-allele of DBH rs1611115, however, tend to increase faster in compassion over time than those homozygotes for the C-allele, b = 0.063 (SE = 0.027;p= 0.018). This effect was largely driven by male participants, 0.206 (SE = 0.046;p< 0.001), and was not significant in female participants when analyzed separately.

Conclusions:Men who are known to have, on average, lower compassion than women seem to reduce this difference over time if they carry the T-allele of DBH rs1611115. The direction of the association indicates that dopamine signaling activity rather than overall dopamine levels might drive the development of compassion.
Art Therapy in the Digital World: An Integrative Review of Current Practice and Future Directions
Authors: Zubala Ania , Kennell Nicola , Hackett Simon
Published: April 2021

Background

Psychotherapy interventions increasingly utilize digital technologies to improve access to therapy and its acceptability. Opportunities that digital technology potentially creates for art therapy reach beyond increased access to include new possibilities of adaptation and extension of therapy tool box. Given growing interest in practice and research in this area, it is important to investigate how art therapists engage with digital technology or how (and whether) practice might be safely adapted to include new potential modes of delivery and new arts media.

Methods

An integrative review of peer-reviewed literature on the use of digital technology in art therapy was conducted. The methodology used is particularly well suited for early stage exploratory inquiries, allowing for close examination of papers from a variety of methodological paradigms. Only studies that presented empirical outcomes were included in the formal analysis.

Findings

Over 400 records were screened and 12 studies were included in the synthesis, pertaining to both the use of digital technology for remote delivery and as a medium for art making. Included studies, adopting predominantly qualitative and mixed methods, are grouped according to their focus on: art therapists’ views and experiences, online/distance art therapy, and the use of digital arts media. Recurring themes are discussed, including potential benefits and risks of incorporating digital technology in sessions with clients, concerns relating to ethics, resistance toward digital arts media, technological limitations and implications for therapeutic relationship and therapy process. Propositions for best practice and technological innovations that could make some of the challenges redundant are also reviewed. Future directions in research are indicated and cautious openness is recommended in both research and practice.

Conclusion

The review documents growing research illustrating increased use of digital technology by art therapists for both online delivery and digital art making. Potentially immense opportunities that technology brings for art therapy should be considered alongside limitations and challenges of clinical, pragmatic and ethical nature. The review aims to invite conversations and further research to explore ways in which technology could increase relevance and reach of art therapy without compromising clients’ safety and key principles of the profession.