bluuebunny/crossref_metadata_2025 huggingface dataset:
Determination of caveolin-1 in renal caveolar and non-caveolar fractions in experimental type 1 diabetes
Authors: Demová H , Komers R
Published: February 2021

Caveolin-1 (CAV-1) is the main structural component of caveolae,
acting as a modulator of signal transduction. CAV-1 might be
involved in the pathophysiology of microvascular complications in
Type 1 diabetes (DM). We sought to determine whether
fractionation on sucrose gradient (SF), a method routinely
utilized for isolation of caveolar fractions in homogenous cell
lines, is applicable for CAV-1-related studies in tissues with
multiple cell types, such as the normal rat kidney cortex (C).
Using this method, we also determined whether streptozotocininduced DM in rats (4-week duration) leads to changes in renal
subcellular targeting of CAV-1, and evaluated the effects of tight
metabolic control (insulin, 12 IU/day) and angiotensin receptor
blocker, losartan (4 weeks, 20 mg/kg/day). Immunoblotting of
individual fractions obtained from C revealed CAV-1 expression in
fractions 4-6 that corresponded to light scattering band that
typically forms after separating cellular fractions on SF. These
fractions were considered to be caveolar fractions. In C, CAV-1
was also detectable in fractions 8-10. These and all other
fractions except caveolar fractions were considered to be noncaveolar fractions. A ratio of caveolar/non-caveolar expression of
CAV-1 (CNCR) was computed for each renal cortex allowing
comparisons of CAV-1 subcellular distribution in C and DM rats,
and effects of treatments. Using this approach, DM was
characterized by marked increases in CNCR as compared to C
(5.54±1.56 vs. 2.65±1.33, p<0.05) that were reduced by
treatment with insulin (0.78±0.24, p<0.01 vs. DM) or losartan
(0.84±0.06, p<0.01 vs. DM). In summary, analysis of CAV-1
following the SF of renal cortex detected similar distribution of
the protein as in homogenous cell lines, DM-induced changes in
CAV-1 targeting, and the effects of pharmacological treatments.
This suggests applicability of SF in studies focusing on CAV-1
targeting in organs with various cell lines in vivo.
Further evidence for the role of nitric oxide in maternal aggression: effects of L-NAME on maternal aggression towards female intruders in Wistar rats
Authors: Ankarali S , Ankarali HC , Marangoz C
Published: February 2021

It has been shown that nitric oxide (NO) increases aggression in
male mice, whereas it decreases aggression in lactating female
mice and prairie voles. It is also known that aggression can be
exhibited at different levels in rodent species, strain or subtypes.
The aims of this study were to investigate the proportion of
aggressiveness in Wistar rats, the effect of intraperitoneally
administered nonspecific nitric oxide synthase (NOS) inhibitor
L-NAME (NG-nitro L-arginine methyl ester) on maternal aggression
towards female intruders, and whether these effects are due to NO
production or not. Rats were given saline intraperitoneally on the
postpartum Day 2 and aggression levels were recorded. The same
rats were given 60 mg/kg L-NAME or D-NAME (NG
-nitro D-arginine methyl ester) on the postpartum Day 3 and their effects on
aggression levels were compared to saline. While L-NAME
administration did not cause any differences in the total number of
aggressive behavior, aggression duration and aggression intensity,
it reduced the proportion of animals showing aggressive behavior.
In addition, the latency of the first aggression was significantly
increased by L-NAME. In the D-NAME group, however, no
significant change was found. Our results have shown that L-NAME
reduces maternal aggression towards female intruders in Wistar
rats through inhibition of NO production. These results suggest that
the role of NO in offensive and defensive maternal aggression
shares neural mechanisms.
PENGARUH MIND MAPPING TERHADAP PENGUASAAN KONSEP KIMIA PADA MATERI HIDROKARBON SISWA KELAS XI MAN 1 KOTA BIMA
Authors: Fitrah Elfi , Annafi Nurfidianty , Mutmainnah Putri Ayu
Published: February 2021

Penelitian ini bertujuan untuk mengetahui ada atau tidaknya pengaruh mind mapping terhadap penguasaan konsep kimia pada materi hidrokarbon siswa kelas XI MAN 1 Kota Bima yang terbagi dari 5  kelas dan terdiri dari 115 siswa dengan kelas XI IPA 5 (eksperimen ) dan kelas XI IPA 4 ( kelas kontrol). Pada kelas eksperimen diterapkan mind mapping  sebagai sampel setelah sebelumnya pemilihan sampel ini menggunakan teknik non probality sampling dengan jenis purposiv sampling. Jenis penelitian ini adalah quasi eksperiment. Dari hasil pengolahan data dapat dilihat pengaruh mind mapping  terhadap penguasaan konsep siswa. pengolahan data hasil penelitian menggunakan uji Mann Whitney U. Data nilai posttest penguasaan konsep siswa dapat dilihat dari nilai Asym sig. (2-tailed), yaitu 0,000 sehingga hipotesis H0 yang diajukan  ditolak karena jika nilai asymp sig <0.05  Ha diterima. Dari hasil pengolahan data dapat disimpulkan bahwa terdapat pengaruh mind mapping terhadap penguasaan konsep kimia pada materi hidrokarbon siswa kelas XI MAN 1 Kota Bima.
Yüksek Çözünürlüklü ERA-Interim ve HadGEM2-CC Model Verilerine Göre Türkiye’nin Güncel ve Gelecekteki Holdridge Ekolojik Bölgeleri
Authors: YILMAZ Erkan
Published: February 2021

Holdridge ekolojik bölgeleri (HEB), iklim sınıflandırma amacıyla kullanılmakta, ayrıca biyom tanımlaması sunmaktadır. Bu çalışmada yüksek çözünürlüklü ERA-Interim ve gelecek durumu yansıtan HadGEM2-CC modeli verileri kullanılarak, Türkiye’nin güncel, 2041-2060 ve 2061-2080 dönemleri içi HEB ve bu dönemlere ait tümleşik HEB sınırları oluşturulmuştur. Elde edilen sonuçlara göre 2041-2080 döneminde Türkiye’de alçak irtifa ve dağönü kuşakları genişlerken dağlık, yarı alpin ve alpin sahaların daralmakta karlı sahalar ise neredeyse ortadan kalkmaktadır. Türkiye’de 2041-2060 döneminde kurak sahalar ortaya çıkmakta, yarı kurak ve yarı nemli sahalar artmakta, nemli, çok nemli, aşırı nemli ve yarı doygun sahalar ise daralmaktadır. Günümüzde Türkiye’de çöl çalılıkları, dikenli çalılıklar, dikenli stepler, stepler, kurak ormanlar, nemli ormanlar, ıslak ormanlar, yağmur ormanları, tundralar ve soğuk çöl biyomları ile buzul alanları bulunmaktadır. 2041-2060 döneminde çok kurak orman biyomu ortaya çıkarken, 2061-2080 döneminde buzul alanları ortadan kalkmaktadır. Çalışmada ayrıca HEB sınıflarının belirlenmesi pratik hale getiren bir yöntem geliştirilmiştir.
Capitalism(s) and the future of adult education policy
Authors: Marcella Milana  , Martin Kopecký  , Fergal Finnegan
Published: February 2021

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Aptamer Functionalized Upconversion Nanotheranostic Agent With Nuclear Targeting as the Highly Localized Drug-Delivery System of Doxorubicin
Authors: Song Xinyue , Yan Tao , Tian Feng , Li Fengyan , Ren Linlin , Li Qiong , Zhang Shusheng
Published: February 2021

As a widely used anticancer drug, doxorubicin (DOX) could induce cell death mainly via interfering with DNA activity; thus, DOX could perform therapeutic effects mainly in the cell nucleus. However, most of the reported drug delivery systems lacked the well localization in the nucleus and released DOX molecules into the cytoplasm. Due to formidable barriers formed in the nuclear envelope, only around 1% of DOX could reach the nucleus and keep active. Therefore, DOX molecules were inevitably overloaded to achieve the desired therapeutic efficacy, which would induce serious side effects. Herein, we developed a highly localized drug nanocarrier for in situ release of DOX molecules to their action site where they could directly interfere with the DNA activity. In this work, we used cationic polymer-modified upconversion nanoparticles (UCNPs) as the luminescence core and gene carrier, while aptamers served as the DNA nanotrain to load DOX. Finally, the prepared nanotheranostic agent displayed good targetability, high cell apoptosis ratio (93.04%) with quite lower concentration than the LC50 of DOX, and obvious inhibition on tumor growth.
Extraction and Application of Natural Rutin From Sophora japonica to Prepare the Novel Fluorescent Sensor for Detection of Copper Ions
Authors: Yang Shilong , Sun Lu , Song Zhiwen , Xu Li
Published: February 2021

Rutin (R), a representative flavonoid found in various biomasses, can be used to prepare different fluorescent sensors for environmental, biological and medical fields. In this work, the natural R in Sophora japonica was extracted and purified to prepare fluorescent-responding sensor systems intended to recognize copper ions with both strong selectivity as well as appropriate sensitivity. Results showed that neat R had no obvious fluorescent emission peak in PBS buffer solution. However, when R and (2-hydroxypropyl)-β-cyclodextrin (CD) were introduced within buffer solution, fluorescent emission intensity was significantly increased due to the resultant R-CD inclusion complex. In addition, the formed R-CD inclusion complex was shown to behave as the aforementioned fluorescent sensor for copper ions through a mechanism of quenched fluorescent emission intensity when R-CD became bound with copper ions. The binding constant value for R-CD with copper ions was 1.33 × 106, allowing for quantification of copper ions between the concentration range of 1.0 × 10–7–4.2 × 10–6mol⋅L–1. Furthermore, the minimum detection limit was found to be 3.5 × 10–8mol⋅L–1. This work showed the prepared R-CD inclusion complex was both highly selective and strongly sensitive toward copper ions, indicating that this system could be applied into various fields where copper ions are of concern.
Achieving Residential Coastal Communities Resilient to Tropical Cyclones and Climate Change
Authors: Adhikari Pramodit , Abdelhafez Mohamed A. , Dong Yue , Guo Yanlin , Mahmoud Hussam N. , Ellingwood Bruce R.
Published: February 2021

Coastal cities in the Southeast and Gulf Coast of the United States are at an increased risk of tropical cyclones (hurricanes) due to the combined effects of urbanization, rapid economic development, and climate change. Current building codes and standards focus on minimum performance criteria for individual buildings exposed to severe hazard events to ensure occupant safety. However, they do not consider the resilience of buildings and building portfolios, which are key factors in determining whether a community can respond to and recover from a severe natural hazard event. Light-frame wood residential buildings dominate the residential market in the US, represent a significant percentage of the investment in the built environment, and are especially vulnerable to hurricane winds and storm surge in coastal areas. Our study of the impact of various hurricane and climate change scenarios on the performance of coastal residential communities reveals that decision-making at the community level is needed to develop rational engineering and urban planning policies, to mitigate the impact of hurricane wind and storm surge, and to adapt to climate change. The results suggest that fundamental changes in the current building regulatory process may be necessary.
SIN3A Regulates Porcine Early Embryonic Development by Modulating CCNB1 Expression
Authors: Luo Lei , Dang Yanna , Shi Yan , Zhao Panpan , Zhang Yunhai , Zhang Kun
Published: February 2021

SIN3A is the central scaffold protein of the SIN3/histone deacetylase (HDAC) transcriptional repressor complex. SIN3A participates in the mouse preimplantation development by fine-tuning HDAC1 expression. However, it remains unresolved if this functional significance of SIN3A was conserved in other mammals. Herein, RNA-seq results show a large amount of SIN3A mRNA is present in oocytes and early embryos prior to embryonic genome activation and a low amount thereafter, suggesting a maternal origin of SIN3A in pigs, cattle, mice, and humans. Interestingly, immunofluorescence data show that SIN3A protein level peaks at four-cell stage in pigs compared with morula stage in cattle. SIN3A depletion in early embryos causes a developmental arrest at two-cell stage in pigs but does not affect bovine early embryonic development. In contrast with mouse data, SIN3A depletion results in only a slight decrease and even no difference in HDAC1 expression in porcine and bovine early embryos, respectively. In addition, HDAC1 knockdown does not cause two-cell block but leads to a reduced blastocyst rate. By using unbiased RNA-seq approach, we found that Cyclin B1 (CCNB1) transcript level is dramatically reduced. Moreover, CCNB1 knockdown results in a similar phenotype as SIN3A depletion. Injection of exogenous CCNB1 mRNA into SIN3A-depleted embryos could partly rescue embryonic development to pass two-cell stage. In conclusion, our results indicate SIN3A plays an essential role in porcine early embryonic development, which probably involves the regulation of CCNB1 expression.
Upregulating the Expression of LncRNA ANRIL Promotes Osteogenesis via the miR-7-5p/IGF-1R Axis in the Inflamed Periodontal Ligament Stem Cells
Authors: Bian Minxia , Yu Yan , Li Yuzhi , Zhou Zhou , Wu Xiao , Ye Xiaying , Yu Jinhua
Published: February 2021

Background

Long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) is a base length of about 3.8 kb lncRNA, which plays an important role in several biological functions including cell proliferation, migration, and senescence. This study ascertained the role of lncRNA ANRIL in the senescence and osteogenic differentiation of inflamed periodontal ligament stem cells (iPDLSCs).

Methods

Healthy periodontal ligament stem cells (hPDLSCs) and iPDLSCs were isolated from healthy/inflamed periodontal ligament tissues, respectively. The proliferation abilities were determined by CCK-8, EdU assay, and flow cytometry (FCM). The methods of Western blot assay (WB), quantitative real-time polymerase chain reaction (qRT-PCR), alizarin red staining, alkaline phosphatase (ALP) staining, ALP activity detection, and immunofluorescence staining were described to determine the biological influences of lncRNA ANRIL on iPDLSCs. Senescence-associated (SA)-β-galactosidase (gal) staining, Western blot analysis, and qRT-PCR were performed to determine cell senescence. Dual-luciferase reporter assays were conducted to confirm the binding of lncRNA ANRIL and miR-7-5-p, as well as miR-7-5p and insulin-like growth factor receptor (IGF-1R).

Results

HPDLSCs and iPDLSCs were isolated and cultured successfully. LncRNA ANRIL and IGF-1R were declined, while miR-7-5p was upregulated in iPDLSCs compared with hPDLSCs. Overexpression of ANRIL enhanced the osteogenic protein expressions of OSX, RUNX2, ALP, and knocked down the aging protein expressions of p16, p21, p53. LncRNA ANRIL could promote the committed differentiation of iPDLSCs by sponging miR-7-5p. Upregulating miR-7-5p inhibited the osteogenic differentiation of iPDLSCs. Further analysis identified IGF-1R as a direct target of miR-7-5p. The direct binding of lncRNA ANRIL and miR-7-5p, miR-7-5p and the 3′-UTR of IGF-1R were verified by dual-luciferase reporter assay. Besides, rescue experiments showed that knockdown of miR-7-5p reversed the inhibitory effect of lncRNA ANRIL deficiency on osteogenesis of iPDLSCs.

Conclusion

This study disclosed that lncRNA ANRIL promotes osteogenic differentiation of iPDLSCs by regulating the miR-7-5p/IGF-1R axis.
Dysregulation of Leukocyte Trafficking in Type 2 Diabetes: Mechanisms and Potential Therapeutic Avenues
Authors: Pezhman Laleh , Tahrani Abd , Chimen Myriam
Published: February 2021

Type 2 Diabetes Mellitus (T2DM) is a chronic inflammatory disorder that is characterized by chronic hyperglycemia and impaired insulin signaling which in addition to be caused by common metabolic dysregulations, have also been associated to changes in various immune cell number, function and activation phenotype. Obesity plays a central role in the development of T2DM. The inflammation originating from obese adipose tissue develops systemically and contributes to insulin resistance, beta cell dysfunction and hyperglycemia. Hyperglycemia can also contribute to chronic, low-grade inflammation resulting in compromised immune function. In this review, we explore how the trafficking of innate and adaptive immune cells under inflammatory condition is dysregulated in T2DM. We particularly highlight the obesity-related accumulation of leukocytes in the adipose tissue leading to insulin resistance and beta-cell dysfunction and resulting in hyperglycemia and consequent changes of adhesion and migratory behavior of leukocytes in different vascular beds. Thus, here we discuss how potential therapeutic targeting of leukocyte trafficking could be an efficient way to control inflammation as well as diabetes and its vascular complications.
The Emerging Role of Exosomes in Oral Squamous Cell Carcinoma
Authors: Lu Yanhui , Zheng Zhichao , Yuan Yunyi , Pathak Janak L. , Yang Xuechao , Wang Lijing , Ye Zhitong , Cho William C. , Zeng Mingtao , Wu Lihong
Published: February 2021

Oral cancer constitutes approximately 2% of all cancers, while the most common type, oral squamous cell carcinoma (OSCC) represents 90% of oral cancers. Although the treatment of OSCC has improved recently, it still has a high rate of local recurrence and poor prognosis, with a 5-year survival rate of only 50%. Advanced stage OSCC tends to metastasize to lymph nodes. Thus, exploring new therapeutic strategies for OSCC is therefore an urgent priority. Exosomes, the small membrane vesicles derived from endosomes, have been detected in a wide array of bodily fluids. Exosomes contain a diversity of proteins, mRNAs, and non-coding RNAs, including microRNAs, long non-coding RNAs, piRNAs, circular RNAs, tsRNAs, and ribosomal RNAs, which are delivered to neighboring cells or even transported to distant sites. Exosomes have been associated with the tumorigenesis of OSCC, promote the proliferation, colonization, and metastasis of OSCC by transferring their contents to the target cells. Furthermore, exosomes are involved in the regulation of the tumor microenvironment to transform conditions favoring cancer progression in vivo. In this review, we summarize the crucial role of exosomes in the tumorigenesis and progression of OSCC and discuss the potential clinical application of exosomes in OSCC treatment.
Cell-Free DNA: Hope and Potential Application in Cancer
Authors: Yan Yan-yan , Guo Qiao-ru , Wang Feng-hua , Adhikari Rameshwar , Zhu Zhuang-yan , Zhang Hai-yan , Zhou Wen-min , Yu Hua , Li Jing-quan , Zhang Jian-ye
Published: February 2021

Cell-free DNA (cfDNA) is easily accessible in peripheral blood and can be used as biomarkers for cancer diagnostics, prognostics, and therapeutics. The applications of cfDNA in various areas of cancer management are attracting attention. In this review article, we discuss the potential relevance of using cfDNA analysis in clinical oncology, particularly in cancer screening, early diagnosis, therapeutic evaluation, monitoring disease progression; and determining disease prognosis.
Electroacupuncture Reduces Oocyte Number and Maintains Vascular Barrier Against Ovarian Hyperstimulation Syndrome by Regulating CD200
Authors: Chen Li , Huang Xuan , Wang Li , Wang Cencen , Tang Xu , Gu Minghui , Jing Jun , Ma Rujun , Ge Xie , Yao Bing
Published: February 2021

Ovarian hyperstimulation syndrome (OHSS) is a common complication caused by ovulatory stimulation therapy, which manifests as an increase in ovarian volume, an increase in the number of oocytes retrieved, and increased vascular permeability throughout the body and especially in ovarian tissue. In our previous study, we found that electroacupuncture (EA) could prevent the progression of OHSS, by mainly affecting ovary. However, the specific molecules and the mechanism of this process were still unknown. In order to explore the underlying mechanism, OHSS rat model was established and EA treatment was performed, which was followed by proteomic analysis of ovaries. Results showed a significant increase in the expression level of CD200 in the ovaries of OHSS group treated with EA than those of OHSS group. Clinical data showed that the level of CD200 in follicular fluid was negatively correlated with the number of oocytes retrieved and serum E2 level. Further in vitro experiments showed a concentration-dependent role of human chorionic gonadotropin (hCG) in reducing CD200 and CD200R levels, and increasing inflammatory cytokine levels in cultured KGN cells. In human umbilical vein endothelial cells (HUVECs), the vascular barrier function was improved by CM (cultural medium from KGN cell) which treated with CD200Fc (CD200R agonist). Meanwhile, the results of in vivo experiments indicated that EA reduced the number of ovarian corpora lutea, decreased inflammatory response, and improved the vascular barrier function by increasing the expression of CD200 and CD200R in rat ovaries. These findings suggest that EA treatment may reduce oocyte number and maintain vascular barrier against OHSS through ovarian anti-inflammatory response mediated by CD200. Therefore, this study is the first to identify CD200 as a main of EA in the ovary and elucidate the possible mechanism of EA on preventing and treating OHSS, which provide a scientific basis for CD200 as an effector and indicator in EA treatment.
Donor Microbiota Composition and Housing Affect Recapitulation of Obese Phenotypes in a Human Microbiota-Associated Murine Model
Authors: Kaiser Thomas , Nalluri Harika , Zhu Zhigang , Staley Christopher
Published: February 2021

Human microbiota-associated (HMA) mouse models offer a valuable approach to study the role of intestinal microbiota in the development of obesity. In this study, we used an HMA model to evaluate whether engraftment of human obese or lean microbiota, from each of three donors, could recapitulate host phenotypes under conventional and specific-pathogen-free housing. Microbiota engraftment was correlated with donor relative abundances of the class Bacteroidia (Spearman’s ρ = 0.73, P ≤ 0.001), and one obese donor resulted in significant weight gain (P ≤ 0.003) and compromised insulin sensitivity under conventional housing. SPF housing partially blunted phenotypic response. Results of this study indicate that our HMA model partially recapitulates obese phenotypes under conventional housing and highlights a need to consider donor-specific effects as well as housing conditions when studying the role of the microbiota in obesity.
Rock My World: Rewind to a Better Transition to Remote Learning
Authors: Garland Michelle E. , Violanti Michelle T.
Published: February 2021

Students and faculty alike found themselves in tumultuous times as they made the transition from face-to-face to remote learning. As faculty and administrators worked hard to overcommunicate with students in the hopes of keeping them engaged and focused on their academic pursuits, students found their attentions split among school, the Covid-19 health pandemic, and paying bills as many lost their employment. In some cases, the overcommunication led to students ignoring messages as they were completely overwhelmed; at the same time, some students found themselves reverting back to looking for the days of someone telling them what to do every minute of the day. Because faculty, and administrators, were not well prepared to handle the situation, an unevenness in how faculty communicated with students occurred. That is, some faculty withdrew in the same way that students did, and the term essentially ended with students turning in remaining assignments even though no further instruction occurred. Other faculty tried to move their face-to-face class online without taking into consideration the differences between these two channels. Still others tried to create an online course as they went from week to week. The inconsistencies across classes combined with the additional stress students were already experiencing became a recipe for exactly what the administration was trying to avoid—unsuccessful completion of courses and/or students unprepared for the courses that would come after the ones in which they were enrolled that term. The purpose of this study is to examine the experiences and perceptions of students when their classes pivoted from face-to-face to mediated, usually through video conferencing for synchronous or learning management systems for asynchronous. More specifically, we have collected qualitative data that addresses the communication students received from their instructors, what they believed instructors did successfully, what instructors could have done better, and the advice they would offer to instructors who found themselves in a similar crisis situation in the future.
Deep Multi-Modal Transfer Learning for Augmented Patient Acuity Assessment in the Intelligent ICU
Authors: Shickel Benjamin , Davoudi Anis , Ozrazgat-Baslanti Tezcan , Ruppert Matthew , Bihorac Azra , Rashidi Parisa
Published: February 2021

Accurate prediction and monitoring of patient health in the intensive care unit can inform shared decisions regarding appropriateness of care delivery, risk-reduction strategies, and intensive care resource use. Traditionally, algorithmic solutions for patient outcome prediction rely solely on data available from electronic health records (EHR). In this pilot study, we explore the benefits of augmenting existing EHR data with novel measurements from wrist-worn activity sensors as part of a clinical environment known as the Intelligent ICU. We implemented temporal deep learning models based on two distinct sources of patient data: (1) routinely measured vital signs from electronic health records, and (2) activity data collected from wearable sensors. As a proxy for illness severity, our models predicted whether patients leaving the intensive care unit would be successfully or unsuccessfully discharged from the hospital. We overcome the challenge of small sample size in our prospective cohort by applying deep transfer learning using EHR data from a much larger cohort of traditional ICU patients. Our experiments quantify added utility of non-traditional measurements for predicting patient health, especially when applying a transfer learning procedure to small novel Intelligent ICU cohorts of critically ill patients.
Distinguishing Late Holocene Storm Deposit From Shore-normal Beach Sediments From the Gulf of Thailand
Authors: Kongsen Stapana , Phantuwongraj Sumet , Choowong Montri
Published: February 2021

Grain size, as one of sedimentological proxies, coupled with a detailed description of the sedimentary structures and luminescence dating were used to unveil the sediment sources and transport process of the Holocene ancient coastal storm events recorded in the beach ridge plain, wet swale and muddy environments at Prachuap Khiri Khan, in the Southern Peninsula of Thailand. In this study, a total of 141 sand samples were collected from the shore-normal ridge-swale topography and analyzed for layers of candidate storm deposits, revealing at least 21 candidate coastal storm events. The grain size distribution of beach sediments was, in general, unimodal, while the candidate storm sediments revealed a mixed combination of multimodal, bimodal and unimodal distributions. Plots of mean grain size against skewness and kurtosis and of skewness against kurtosis could differentiate storm deposits from shore-normal beach sediments. Sedimentary structures preserved in the ancient coastal storm deposits included parallel and inclined landward laminations, mud rip-up clasts, layers of shell fragments, a pebble grain, normal and reverse grading and sharp lower and upper contacts. Candidate storm layers overlain on a dry beach ridge intervened with mud in a swale showed a finer and thinner landward deposit. Marine shell fragments, smaller foraminifers, ostracod and scaphopod (tusk shell), were well preserved. Based on optically stimulated luminescence dating and a correlated accelerator mass spectrometry age, multiple layers of sand derived from different frequencies of coastal storms were deposited over the middle to late Holocene.
High Diagnostic Yield of Targeted Next-Generation Sequencing in a Cohort of Patients With Congenital Hypothyroidism Due to Dyshormonogenesis
Authors: Stoupa Athanasia , Al Hage Chehade Ghada , Chaabane Rim , Kariyawasam Dulanjalee , Szinnai Gabor , Hanein Sylvain , Bole-Feysot Christine , Fourrage Cécile , Nitschke Patrick , Thalassinos Caroline , Pinto Graziella , Mnif Mouna , Baron Sabine , De Kerdanet Marc , Reynaud Rachel , Barat Pascal , Hachicha Mongia , Belguith Neila , Polak Michel , Carré Aurore
Published: February 2021

Objective

To elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS).

Study design

We studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature.

Results

TNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis.

Conclusions

In a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.
Circulating microRNA Expression in Cushing’s Syndrome
Authors: Vetrivel Sharmilee , Zhang Ru , Engel Mareen , Altieri Barbara , Braun Leah , Osswald Andrea , Bidlingmaier Martin , Fassnacht Martin , Beuschlein Felix , Reincke Martin , Chen Alon , Sbiera Silviu , Riester Anna
Published: February 2021

Context

Cushing’s syndrome (CS) is a rare disease of endogenous hypercortisolism associated with high morbidity and mortality. Diagnosis and classification of CS is still challenging.

Objective

Circulating microRNAs (miRNAs) are minimally invasive diagnostic markers. Our aim was to characterize the circulating miRNA profiles of CS patients and to identify distinct profiles between the two major CS subtypes.

Methods

We included three groups of patients from the German Cushing’s registry: ACTH-independent CS (Cortisol-Producing-Adenoma; CPA), ACTH-dependent pituitary CS (Cushing’s Disease; CD), and patients in whom CS had been ruled out (controls). Profiling of miRNAs was performed by next-generation-sequencing (NGS) in serum samples of 15 CS patients (each before and after curative surgery) and 10 controls. Significant miRNAs were first validated by qPCR in the discovery cohort and then in an independent validation cohort of 20 CS patients and 11 controls.

Results

NGS identified 411 circulating miRNAs. Differential expression of 14 miRNAs were found in the pre- and postoperative groups. qPCR in the discovery cohort validated 5 of the significant miRNAs from the preoperative group analyses. Only, miR-182-5p was found to be significantly upregulated in the CD group of the validation cohort. Comparing all CS samples as a group with the controls did not reveal any significant differences in expression.

Outcome

In conclusion, our study identified miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort. Furthermore, our results suggest that presence or absence of ACTH might be at least as relevant for miRNA expression as hypercortisolism itself.
Modeling Maturity Onset Diabetes of the Young in Pluripotent Stem Cells: Challenges and Achievements
Authors: Braverman-Gross Carmel , Benvenisty Nissim
Published: February 2021

Maturity onset diabetes of the young (MODY), is a group of monogenic diabetes disorders. Rodent models for MODY do not fully recapitulate the human phenotypes, calling for models generated in human cells. Human pluripotent stem cells (hPSCs), capable of differentiation towards pancreatic cells, possess a great opportunity to model MODY disorders in vitro. Here, we review the models for MODY diseases in hPSCs to date and the molecular lessons learnt from them. We also discuss the limitations and challenges that these types of models are still facing.
Prospects of Germline Nuclear Transfer in Women With Diminished Ovarian Reserve
Authors: Christodoulaki Antonia , Boel Annekatrien , Tang Maoxing , De Roo Chloë , Stoop Dominic , Heindryckx Björn
Published: February 2021

Diminished ovarian reserve (DOR) is associated with a reduced quantity and quality of the retrieved oocytes, usually leading to poor reproductive outcomes which remain a great challenge for assisted reproduction technology (ART). Women with DOR often have to seek for oocyte donation, precluding genetically related offspring. Germline nuclear transfer (NT) is a novel technology in ART that involves the transfer of the nuclear genome from an affected oocyte/zygote of the patient to the cytoplast of an enucleated donor oocyte/zygote. Therefore, it offers opportunities for the generation of genetically related embryos. Currently, although NT is clinically applied only in women with serious mitochondrial DNA disorders, this technology has also been proposed to overcome certain forms of female infertility, such as advanced maternal age and embryo developmental arrest. In this review, we are proposing the NT technology as a future treatment option for DOR patients. Strikingly, the application of different NT strategies will result in an increase of the total number of available reconstituted embryos for DOR patients.
Genetic Parameters and Genome-Wide Association Studies of Quality Traits Characterised Using Imaging Technologies in Rainbow Trout, Oncorhynchus mykiss
Authors: Blay Carole , Haffray Pierrick , Bugeon Jérôme , D’Ambrosio Jonathan , Dechamp Nicolas , Collewet Guylaine , Enez Florian , Petit Vincent , Cousin Xavier , Corraze Geneviève , Phocas Florence , Dupont-Nivet Mathilde
Published: February 2021

One of the top priorities of the aquaculture industry is the genetic improvement of economically important traits in fish, such as those related to processing and quality. However, the accuracy of genetic evaluations has been hindered by a lack of data on such traits from a sufficiently large population of animals. The objectives of this study were thus threefold: (i) to estimate genetic parameters of growth-, yield-, and quality-related traits in rainbow trout (Oncorhynchus mykiss) using three different phenotyping technologies [invasive and non-invasive: microwave-based, digital image analysis, and magnetic resonance imaging (MRI)], (ii) to detect quantitative trait loci (QTLs) associated with these traits, and (iii) to identify candidate genes present within these QTL regions. Our study collected data from 1,379 fish on growth, yield-related traits (body weight, condition coefficient, head yield, carcass yield, headless gutted carcass yield), and quality-related traits (total fat, percentage of fat in subcutaneous adipose tissue, percentage of fat in flesh, flesh colour); genotypic data were then obtained for all fish using the 57K SNP Axiom® Trout Genotyping array. Heritability estimates for most of the 14 traits examined were moderate to strong, varying from 0.12 to 0.67. Most traits were clearly polygenic, but our genome-wide association studies (GWASs) identified two genomic regions on chromosome 8 that explained up to 10% of the genetic variance (cumulative effects of two QTLs) for several traits (weight, condition coefficient, subcutaneous and total fat content, carcass and headless gutted carcass yields). For flesh colour traits, six QTLs explained 1–4% of the genetic variance. Within these regions, we identified several genes (htr1, gnpat, ephx1, bcmo1, and cyp2x) that have been implicated in adipogenesis or carotenoid metabolism, and thus represent good candidates for further functional validation. Finally, of the three techniques used for phenotyping, MRI demonstrated particular promise for measurements of fat content and distribution, while the digital image analysis-based approach was very useful in quantifying colour-related traits. This work provides new insights that may aid the development of commercial breeding programmes in rainbow trout, specifically with regard to the genetic improvement of yield and flesh-quality traits as well as the use of invasive and/or non-invasive technologies to predict such traits.
Hyperactive Behavior and Altered Brain Morphology in Adult Complement C3a Receptor Deficient Mice
Authors: Pozo-Rodrigálvarez Andrea , Ollaranta Roosa , Skoog Jenny , Pekny Milos , Pekna Marcela
Published: February 2021

The C3a receptor (C3aR) is a seven trans-membrane domain G-protein coupled receptor with a range of immune modulatory functions. C3aR is activated by the third complement component (C3) activation derived peptide C3a and a neuropeptide TLQP-21. In the central nervous system (CNS), C3aR is expressed by neural progenitors, neurons as well as glial cells. The non-immune functions of C3aR in the adult CNS include regulation of basal neurogenesis, injury-induced neural plasticity, and modulation of glial cell activation. In the developing brain, C3aR and C3 have been shown to play a role in neural progenitor cell proliferation and neuronal migration with potential implications for autism spectrum disorder, and adult C3aR deficient (C3aR−/−) mice were reported to exhibit subtle deficit in recall memory. Here, we subjected 3 months old male C3aR−/− mice to a battery of behavioral tests and examined their brain morphology. We found that the C3aR−/− mice exhibit a short-term memory deficit and increased locomotor activity, but do not show any signs of autistic behavior as assessed by self-grooming behavior. We also found regional differences between the C3aR−/− and wild-type (WT) mice in the morphology of motor and somatosensory cortex, as well as amygdala and hippocampus. In summary, constitutive absence of C3aR signaling in mice leads to neurodevelopmental abnormalities that persist into adulthood and are associated with locomotive hyperactivity and altered cognitive functions.
Mesenchymal Stromal Cells Rapidly Suppress TCR Signaling-Mediated Cytokine Transcription in Activated T Cells Through the ICAM-1/CD43 Interaction
Authors: Zheng Shuwei , Huang Ke , Xia Wenjie , Shi Jiahao , Liu Qiuli , Zhang Xiaoran , Li Gang , Chen Jieying , Wang Tao , Chen Xiaoyong , Xiang Andy Peng
Published: February 2021

Cell-cell contact participates in the process of mesenchymal stromal cell (MSC)-mediated T cell modulation and thus contributes to MSC-based therapies for various inflammatory diseases, especially T cell-mediated diseases. However, the mechanisms underlying the adhesion interactions between MSCs and T cells are still poorly understood. In this study, we explored the interaction between MSCs and T cells and found that activated T cells could rapidly adhere to MSCs, leading to significant reduction of TNF-α and IFN-γ mRNA expression. Furthermore, TCR-proximal signaling in activated T cells was also dramatically suppressed in the MSC co-culture, resulting in weakened Ca2+signaling. MSCs rapidly suppressed TCR signaling and its downstream signaling in a cell-cell contact-dependent manner, partially through the ICAM-1/CD43 adhesion interaction. Blockade of either ICAM-1 on MSCs or CD43 on T cells significantly reversed this rapid suppression of proinflammatory cytokine expression in T cells. Mechanistically, MSC-derived ICAM-1 likely disrupts CD43-mediated TCR microcluster formation to limit T cell activation. Taken together, our results reveal a fast mechanism of activated T cell inhibition by MSCs, which provides new clues to unravel the MSC-mediated immunoregulatory mechanism for aGVHD and other severe acute T cell-related diseases.
Epinephrine Production in Th17 Cells and Experimental Autoimmune Encephalitis
Authors: Yang Pinguang , Tian Hong , Zou Yong-Rui , Chambon Pierre , Ichinose Hiroshi , Honig Gerard , Diamond Betty , Kim Sun Jung
Published: February 2021

Epinephrine is a hormone secreted primarily by medullary cells of the adrenal glands which regulates permeability of blood–brain barrier (BBB). Recent studies showed signaling by epinephrine/epinephrine receptor in T cells is involved in autoimmune diseases. Nevertheless, the production of epinephrine by T cells and its pathogenic function in T cells are not well investigated. Our results show that phenylethanol N-methyltransferase (PNMT), a rate-limiting enzyme of epinephrine synthesis, is specifically expressed in vitro in differentiated TH17 cells and in tissue-resident TH17 cells. Indeed, expression levels of enzymes involved in epinephrine production are higher in TH17 cells from animals after EAE induction. The induction of PNMT was not observed in other effector T cell subsets or regulatory T cells. Epinephrine producing TH17 cells exhibit co-expression of GM-CSF, suggesting they are pathogenic TH17 cells. To delineate the function of epinephrine-production in TH17 cells, we generated a TH17-specific knockout of tyrosine hydroxylase (Th) by breeding a Th-flox and a ROR-gt-CRE mouse (Th-CKO). Th-CKO mice are developmentally normal with an equivalent T lymphocyte number in peripheral lymphoid organs. Th-CKO mice also show an equivalent number of TH17 cells in vivo and following in vitro differentiation. To test whether epinephrine-producing TH17 cells are key for breaching the BBB, migration of T cells through mouse brain endothelial cells was investigated in vitro. Both epi+ wild-type and epi- TH17 cells migrate through an endothelial cell barrier. Mice were immunized with MOG peptide to induce experimental autoimmune encephalitis (EAE) and disease progression was monitored. Although there is a reduced infiltration of CD4+ T cells in Th-CKO mice, no difference in clinical score was observed between Th-CKO and wild-type control mice. Increased neutrophils were observed in the central nervous system of Th-CKO mice, suggesting an alternative pathway to EAE progression in the absence of TH17 derived epinephrine.
Amino Acid Metabolism in Lupus
Authors: Kono Michihito , Yoshida Nobuya , Tsokos George C.
Published: February 2021

T cell metabolism is central to cell proliferation, survival, differentiation, and aberrations have been linked to the pathophysiology of systemic autoimmune diseases. Besides glycolysis and fatty acid oxidation/synthesis, amino acid metabolism is also crucial in T cell metabolism. It appears that each T cell subset favors a unique metabolic process and that metabolic reprogramming changes cell fate. Here, we review the mechanisms whereby amino acid transport and metabolism affects T cell activation, differentiation and function in T cells in the prototype systemic autoimmune disease systemic lupus erythematosus. New insights in amino acid handling by T cells should guide approaches to correct T cell abnormalities and disease pathology.
Circ_0088194 Promotes the Invasion and Migration of Rheumatoid Arthritis Fibroblast-Like Synoviocytes via the miR-766-3p/MMP2 Axis
Authors: Cai Yujie , Liang Renge , Xiao Shibai , Huang Qin , Zhu Dingji , Shi Guo-Ping , Ouyang Qingqing , Yang Min
Published: February 2021

Dysregulation of circular RNAs (circRNAs) is involved in various human diseases. Fibroblast-like synoviocytes (FLSs), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype and contribute to joint destruction in rheumatoid arthritis (RA). In the present study, we identified a novel circRNA, Circ_0088194, which was upregulated in RA fibroblast-like synoviocytes (RA-FLSs) and correlated with the disease activity score in 28 joints. Overexpression of Circ_0088194 promoted RA-FLS migration and invasion, while inhibition of Circ_0088194 had the opposite effect. Mechanistically, Circ_0088194 acted as a miR-766-3p sponge to relieve the repressive effect of miR-766-3p on its target, MMP2 (encoding matrix metalloproteinase 2), thereby promoting migration and invasion. The expression level of Circ_0088194 was inversely correlated with that of miR-766-3p in RA-FLSs. Importantly, overexpression of miR-766-3p partially blocked the migration and invasion induced by Circ_0088194 overexpression. Collectively, this study identified a novel circRNA Circ_0088194 that promotes RA-FLS invasion and migration via the miR-766-3p/MMP2 axis. Circ_0088194 might represent a novel therapeutic target to prevent and treat RA.
A Two-Gene Signature for Tuberculosis Diagnosis in Persons With Advanced HIV
Authors: Kulkarni Vandana , Queiroz Artur T. L. , Sangle Shashi , Kagal Anju , Salvi Sonali , Gupta Amita , Ellner Jerrold , Kadam Dileep , Rolla Valeria C. , Andrade Bruno B. , Salgame Padmini , Mave Vidya
Published: February 2021

Background: Transcriptomic signatures for tuberculosis (TB) have been proposed and represent a promising diagnostic tool. Data remain limited in persons with advanced HIV.

Methods: We enrolled 30 patients with advanced HIV (CD4 <100 cells/mm3) in India; 16 with active TB and 14 without. Whole-blood RNA sequencing was performed; these data were merged with a publicly available dataset from Uganda (n = 33; 18 with TB and 15 without). Transcriptomic profiling and machine learning algorithms identified an optimal gene signature for TB classification. Receiver operating characteristic analysis was used to assess performance.

Results: Among 565 differentially expressed genes identified for TB, 40 were shared across India and Uganda cohorts. Common upregulated pathways reflect Toll-like receptor cascades and neutrophil degranulation. The machine-learning decision-tree algorithm selected gene expression values from RAB20 and INSL3 as most informative for TB classification. The signature accurately classified TB in discovery cohorts (India AUC 0.95 and Uganda AUC 1.0; p < 0.001); accuracy was fair in external validation cohorts.

Conclusions: Expression values of RAB20 and INSL3 genes in peripheral blood compose a biosignature that accurately classified TB status among patients with advanced HIV in two geographically distinct cohorts. The functional analysis suggests pathways previously reported in TB pathogenesis.