bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum adipocyte fatty acid binding protein levels in patients with type 2 diabetes mellitus and obesity: the influence of fenofibrate treatment
Authors: Haluzík M , Anderlová K , Doležalová R , Adamíková A , Haluzíková D , Housová J , Svačina Š , Haluzík M
Published: February 2021

Recent studies have demonstrated that adipocyte fatty acid
binding proteins (FABP) may play a role in the etiopathogenesis
of insulin resistance. The aim of our study was to assess serum
FABP levels in obese patients with type 2 diabetes mellitus
(T2DM) before and after 3 months of treatment with PPAR-α
agonist fenofibrate (F) and to explore the relationship of FABP to
biochemical parameters and measures of insulin sensitivity
assessed by hyperinsulinemic-isoglycemic clamp. We measured
biochemical parameters by standard laboratory methods, insulin
sensitivity by hyperinsulinemic-isoglycemic clamp and serum
concentrations of FABP by commercial ELISA kit in 11 obese
females with T2DM before and after three months of treatment
with PPAR-α agonist fenofibrate and in 10 lean healthy control
women (C). Serum FABP levels were 2.5-fold higher in T2DM
group relative to C and were not affected by fenofibrate
treatment (C: 20.6±2.1 μg/l, T2DM before F: 55.6±5.7 μg/l,
T2DM after F: 54.2±5.4 μg/l, p<0.0001 for C vs. T2DM before F).
Hyperinsulinemia during the clamp significantly suppressed FABP
levels in both C and T2DM group. FABP levels positively
correlated with BMI, triglyceride levels, blood glucose, glycated
hemoglobin, atherogenic index and insulin levels. An inverse
relationship was found between FABP and HDL levels, metabolic
clearance rate of glucose, M/I and MCRglc/I sensitivity indexes.
We conclude that FABP levels are closely related to BMI,
parameters of insulin sensitivity, HDL levels and measures of
diabetes compensation. This combination makes FABP a valuable
marker of metabolic disturbances in patients with type 2 diabetes
mellitus.
Different sensitivity of miniature endplate currents in rat external and internal intercostal muscles to the acetylcholinesterase inhibitor C-547 as compared with diaphragm and extensor digitorum longus
Authors: Petrov K , Kovyazina I , Zobov V , Bukharaeva E , Nikolsky EE , Vyskočil F
Published: February 2021

Derivative of 6-methyluracil, selective cholinesterase inhibitor C547 potentiates miniature endplate currents (MEPCs) in rat
external intercostal muscles (external ICM) more effectively than
in internal intercostal muscles (internal ICM). Effect of the C-547
on intercostal muscles was compared with those on extensor
digitorum longus (EDL) and diaphragm muscles. Half-effective
concentrations for τ of MEPC decay arranged in increasing order
were as follows: EDL, locomotor muscle, most sensitive = 1.3
nM, external ICM, inspiration muscle = 6.8 nM, diaphragm, main
inspiration muscle = 28 nM, internal ICM, expiration muscle =
71 nM. External ICM might therefore be inhibited, similarly as the
limb muscles, by nanomolar concentrations of the drug and do
not participate in inspiration in the presence of the C-547.
Moreover, internal ICM inhibition can hinder the expiration during
exercise-induced fast breathing of C-547- treated experimental
animals.
Analisis Kesiapan Dalam Penerapan SIMPUS dengan Metode TRI di Puskesmas Jenggawah Jember
Authors: Roziqin Mochammad Choirur , Darmawan Dirga Putra
Published: February 2021

Puskesmas Jenggawah Kabupaten Jember menerapkan Sistem Informasi Manajemen Puskesmas (SIMPUS) sejak awal tahun 2017, namun dalam penerapannya tidak berjalan dengan optimal. Berdasarkan studi pendahuluan ditemukan masalah diantaranya kurangnya minat pengguna, petugas kurang yakin dalam menggunakan sistem dan petugas masih khawatir dalam menggunakan sistem. Penelitian ini bertujuan untuk mengidentifikasi kesiapan puskesmas dalam menerapkan SIMPUS berdasarkan teori Technology Readiness Index (TRI). Jenis penelitian ini adalah penelitian deskriptif dengan pendekatan kuantitatif. Metode pengumpulan data dilakukan menggunakan kuesioner guna memperoleh data tingkat kesiapan pengguna. Jumlah sampel 31 responden yaitu seluruh petugas yang terlibat dalam penggunaan SIMPUS di puskesmas. Adopsi TIK dalam organisasi tidak selalu berjalan dengan mudah karena adanya berbagai kendala, maka dari itu peneliti berasalan perlu dilakukan pengukuran tingkat kesiapan pengguna dalam mengadopsi SIMPUS, karena kesuksesan adopsi TIK di suatu organinsasi juga ditentukan dari kesiapan dan kemampuan penggunanya. Berdasarkan hasil penelitian dapat disimpulkan kesiapan pengguna SIMPUS di puskesmas jenggawah secara umum memiliki tingkat kesiapan yang sedang yaitu sebesar 70%. Sebagian besar petugas berada pada tingkat kesiapan Pioneers yaitu sebesar 58%, artinya memiliki sikap optimis dan inovasi diatas rata-rata, akan tetapi sebagian kecil masih rentan dalam menggunakan sistem.
Analisis Error Terhadap Peramalan Data Penjualan
Authors: Hajjah Alyauma , Marlim Yulvia Nora
Published: February 2021

Tujuan penelitian ini membahas tentang peramalan permintaan lampu LED bermerk Sanyo. Penelitian ini menggunakan metode Moving Average dan Exponential Smoothing. Pada Metode Moving Average digunakan untuk peramalan periode 3 bulan dan 5 bulan, sedangkan metode Exponential Smoothing menggunakan parameter  = 0,1; 0,5; 0,7 dan 0,9. Dari hasil peramalan setiap metode dibandingkan nilai dari error, adapun nilai error yang dibahas adalah Mean Absolut Deviation (MAD), Mean Squared Error (MSE), dan Mean Absolute Percentage Error (MAPE). Berdasarkan hasil penelitian ini metode yang memiliki tingkat kesalahan terkecil adalah metode Exponential Smoothing dengan parameter , yang memiliki nilai MAD= 1.214,54; MSE = 2.758.993 dan MAPE = 9,17%. Dapat disimpulkan bahwa metode yang paling optimal digunakan untuk meramalkan jumlah permintaan lampu pada bulan berikutnya adalah metode Exponential Smoothing dengan parameter . Hasil peramalan permintaan lampu pada bulan Januari 2020 dengan menggunakan metode Exponential Smoothing dengan  adalah 15.800,88. Sehingga untuk peramalan permintaan untuk bulan berikutnya peneliti merekomendasikan menggunakan metode Exponential Smoothing dengan perameter .
Otomatisasi Pemberian Air dan Keamanan Kandang pada Ternak ayam petelur dengan komunikasi LoRa
Authors: Angriawan Randy , Anugraha Nurhajar
Published: February 2021

Ayam petelur merupakan ayam yang rentan dengan resiko stres. Stres pada ayam petelur sering terjadi karena kekurangan cairan atau air minum. Hal ini dapat menyebabkan menurunnya produksi telur bahkan sampai kematian ayam petelur. Pemberian air harus dilakukan secara rutin dan tepat waktu. Selain resiko stres, keamanan kandang menjadi salah satu kendala dalam pengembangan usaha ayam petelur. Jenis kandang terbuka (open house) sangat berpotensi terjadinya pencurian. Peternak membutuhkan sistem pemantauan jarak jauh untuk dapat mengetahui kondisi kandang meskipun tidak berada pada lokasi. Untuk mengatasi masalah yang telah diuraikan, dalam paper ini dikembangkan sistem otomatisasi pemberian air dan pemantauan keamanan pada ternak ayam petelur dengan komunikasi LoRa. Hasil Pengujian otomatisasi pemberian air menunjukkan bahwa sensor ultrasonik dan solenoid valve dapat bekerja dengan biak dengan variasi debit air. Debit air 1.5 liter/menit membutuhkan waktu sekitar 6 menit 59 detik untuk mencapai batas air maksimal dan debit 3 liter/menit membutuhkan waktu sekitar 3 menit 12 detik. Hasil pengujian keamanan kandang dengan sensor proximity dan limit switch dapat mendeteksi buka tutup pintu dan lalu lalang pada kandang. Untuk hasil pengujian pemantauan keamanan menggunakan komunikasi LoRa mununjukkan persentase keberhasilan pengiriman data sebesar 96%
Optimasi Parameter K Pada Algoritma K-NN Untuk Klasifikasi Prioritas Bantuan Pembangunan Desa
Authors: Ulya Saiful , Soeleman M Arief , Budiman Fikri
Published: February 2021

Klasifikasi adalah proses menemukan model atau fungsi yang menggambarkan dan membedakan kelas atau konsep data. Algoritma k-NN (k Nearest Neighbors) merupakan algoritma klasifikasi berdasarkan pembelajaran dari data yang sudah terklasifiasi sebelumnya. Algoritma k-NN (k Nearest Neighbors) merupakan algoritma yang sangat bagus dalam menangani beberapa kasus, salah satu kelebihan k-NN diantaranya adalah tangguh terhadap data training yang noisy dan sangat efektif apabila data trainingnya besar. Namun terdapat beberapa masalah pada algoritma k-NN diantaranya adalah penentuan nilai k untuk pemilihan jumlah tetangga terdekatnya sangat sulit, karena nilai k sangat peka atau sensitif terhadap hasil klasifikasi. Pada penelitian ini, akan dilakukan pemodelan klasifiasi dengan menggunakan algoritma k-NN yang difokuskan pada proses penentuan nilai k terbaik pada dataset IKG (Indeks Kesulitas Geografis) desa. Pada penelitian ini akan melakukan integrasi algoritma k-NN dengan menentukan nilai k optimal dengan optimize parameters berdasar algoritma genetika.
Convolutional Neural Network untuk Metode Klasifikasi Multi-Label pada Motif Batik
Authors: Bariyah Taufiqotul , Rasyidi Mohammad Arif , Ngatini Ngatini
Published: February 2021

Salah satu warisan budaya Indonesia yang diakui dunia adalah kain batik. Beragamnya motif batik di Indonesia membuat masyarakat awam sulit membedakan motif-motif yang ada. Penelitian ini menggunakan convolutional neural network (CNN) dalam melakukan klasifikasi multi-label citra motif batik. CNN merupakan salah satu algoritma deep learning pengembangan multi-layer perceptron (MLP) yang telah banyak digunakan dalam klasifikasi data, khususnya klasifikasi citra.  Hasil penelitian menunjukkan akurasi penggunaan arsitektur CNN dalam melakukan klasifikasi multi-label pada 15 motif batik mencapai 91.41% dengan penggunaan epoch 100.
A Voice From Heaven: Could The Study Of Glossolalia Both Benefit Linguistic Theory And Improve Communication During the COVID-19 Pandemic?
Authors: Campbell Junior
Published: February 2021

My 2005 Linguistics bachelor of arts thesis argues for an "open minded" approach to scientific inquiry. It not only addresses the possible role of science in the exploration of supposed "supernatural" or spiritual phenomena but also asks if science itself may be enriched by such exploration. It suggests that conventional Western scientific enquiry, is the poorer for its traditional aversion toward enquiry beyond empirically reducible matters. I believe it is apparent that in the current COVID-19 environment, the answer to the fundamental question my thesis asks about the compatibility of science and religion could mean life or death for some people.  The precise area of scientific inquiry with which I am concerned is the field of Linguistics. The supposed "supernatural" or spiritual phenomenon that I would subject to linguistic analysis is glossolalia, known more widely in Western society as the Christian practice of "speaking in tongues".
���������� ��������� ������������: �� ����� �������� �� ����������
Authors: Rohozha Maria
Published: February 2021

������� ��������, ��������� �� ������������� ����� ����� ��������� � �������� ����������� ����������� ������������ ��������� ������������ �� 20-� � �� ���� 80-� ��. �� ��. ������� ������� ������� ���� ������� ��������� �� ����� �� ������ ���������� ��������, ����� ������������ ���������� � ����� ����������� ����������. ��������� ��������� ������� ��������� ���� ������� ���������� ������ �� �������� ��������� ��������. ϳ��������� ������������� ������������� ������� �� ����������� ����� ��� ������� ���������� ��������� ������������. ������� ������� �������� �������� ����������� �������� � �������� ������������� �����������.
�������� �������� �����-��������������� ��������: ����� ��������� � ���������� � �VIII � �� ������� �� ��.
Authors: Kravchenko Inna
Published: February 2021

� ����� ����������� ����� ��������� � ���������� ��������� ��������� �����-���������������� ��������� �������� ����� ���� ��������� (1748-1926 ��.). ������� �� ��������� ���� ��� ��� ��� ���������� � ����� ����� ������� ����������� ���������������� �� �����-���������������� ���������.
�������� ���� ��������� � �������� ������ �����
Authors: Tarasenko Olha
Published: February 2021

� ����� ��������� ���������� ��������� ��������� ����� ����������� ��. ���������� ����� ����������� ���������� (1845-1918) ����� ������� ���� ������ ³��������� ����� (1874-1955). ��������� ����� ������� �� ����. ������ ���������� ����� �� �������� ���� ������ � �������� � ����������� ������������ ����� �������� ����������� ��. ����������.
������� ������� �� ������� ��������� ������������ ����������� ��������� � ���� �������
Authors: Savchenko Andrii
Published: February 2021

��������� ��������� ��������� ������� �� ��������� ����������� ����������� ����������� ��������� � ���� �������. ������������� ������ ������� � �������� ������� ����������� �������� ��������� ����������� ����������� ���� ����������� �. ������� �� ����������� ����� ���� �� �������. ǒ�������, �� ����� ������ ������������ ����� ������, �� ���� ������ �� ����������� ���� ������ ����� ������� �������, ����������� ���������� (1953 �.) �������� �� ����. ��������, �� ������� ��������� ������ ������� ��������� ��������� �������� ����������� ��������� ����������� �������������-����������� ��������.
����� ������������ ���������� � ������ �������� ���������� �������
Authors: Mykhtunenko Viktoriia , Motsak Svitlana
Published: February 2021

� ����� ������������ ��������� � ���� ������ 1991 �. ������� ���������� ������������ �� �������, �������� �� ͳ�������� � ������������ ���������� ������. ³� ������� ����� ������������� ���������� � ���� �������� ����� ���� �������� ���������� ������ � ������������� ���������. � ����� ����������� ���������� ��������� �� �������� ������ ������� �������� ���� �� ����������� ���������� �� ������� ������ � ���� ���� ������������� � ����� �� ����� ��-�ղ ��.
���������� �. ����������: ��������� ������� �� ������, ������������ �� �������������
Authors: Fayda Oleh
Published: February 2021

� ����� ��������� �������-������������ �������� �������� � ������ �� ���������� ������� ��� ���������� ���������. ���������� ���� ����� ����������� ����������, �� ��������� �������� ���������� � ����� ����� � ����� ���. ǒ������� ������������� ��� ���������-��������� ��� ������� ����� � ����������� �������� ������-����䳿������� ��������. ��������������� ����������� � ������ ������������ ������� �� ������������������� ������, �������� �������� �������� ����. ��������, �� ���� ��������� �� ���������� �������� ��������������� � �����糿, ������������ ���� �� ��������� �������� �. �����������.
����� ������� ������������ �.�. ����������: ���������� ������������ (����� ղ� � ������� �� ��.)
Authors: Korzun Dmytro
Published: February 2021

���������, �� ����� ��� �������� � ���������� ������������ ������, ���� ��������� ��������� (1856-1910), �������-�������, ����� ����� ������� ������������, ������������� �������� ������, �� �������� �� ���������� ���� �������� ����. ������ ��������� ������������� �����, ��������� ����� �������� ����� ����������� ��������� ��������� ������������� �� �������� �������� �������� ������� �������� �� �������� ���������� �������� ����������. �� ������� �������� ���������� ���������� ����������� ��������� �ᒺ����� (������� �� ���������� ���������� ��������� ������������) ������������ ������� ���������� ���������� ����� ���� ������������ ���� �.�. ����������.
Successful Enzyme Colocalization Strategies in Yeast for Increased Synthesis of Non-native Products
Authors: Yocum Hannah C. , Pham Anhuy , Da Silva Nancy A.
Published: February 2021

Yeast cell factories, particularly Saccharomyces cerevisiae, have proven valuable for the synthesis of non-native compounds, ranging from commodity chemicals to complex natural products. One significant challenge has been ensuring sufficient carbon flux to the desired product. Traditionally, this has been addressed by strategies involving “pushing” and “pulling” the carbon flux toward the products by overexpression while “blocking” competing pathways via downregulation or gene deletion. Colocalization of enzymes is an alternate and complementary metabolic engineering strategy to control flux and increase pathway efficiency toward the synthesis of non-native products. Spatially controlling the pathway enzymes of interest, and thus positioning them in close proximity, increases the likelihood of reaction along that pathway. This mini-review focuses on the recent developments and applications of colocalization strategies, including enzyme scaffolding, construction of synthetic organelles, and organelle targeting, in both S. cerevisiae and non-conventional yeast hosts. Challenges with these techniques and future directions will also be discussed.
Nitric Oxide in the Control of the in vitro Proliferation and Differentiation of Human Hematopoietic Stem and Progenitor Cells
Authors: Hümmer Julia , Kraus Saskia , Brändle Katharina , Lee-Thedieck Cornelia
Published: February 2021

Hematopoietic stem and progenitor cell (HSPC) transplantation is the best-studied cellular therapy and successfulin vitrocontrol of HSPCs has wide clinical implications. Nitric oxide (NO) is a central signaling moleculein vivoand has been implicated in HSPC mobilization to the blood stream in mice. The influence of NO on HSPC behaviorin vitrois, however, largely obscure due to the variety of employed cell types, NO administration systems, and used concentration ranges in the literature. Additionally, most studies are based on murine cells, which do not necessarily mimic human HSPC behavior. Thus, the aim of the present study was the systematic, concentration-dependent evaluation of NO-mediated effects on human HSPC behaviorin vitro. By culture in the presence of the long-term NO donor diethylenetriamine/nitric oxide adduct (DETA/NO) in a nontoxic concentration window, a biphasic role of NO in the regulation of HSPC behavior was identified: Low DETA/NO concentrations activated classical NO signaling, identified via increased intracellular cyclic guanosine monophosphate (cGMP) levels and proteinkinases G (PKG)-dependent vasodilator-stimulated phosphoprotein (VASP) phosphorylation and mediated a pro-proliferative response of HSPCs. In contrast, elevated NO concentrations slowed cell proliferation and induced HSPC differentiation. At high concentrations, s-nitrosylation levels were elevated, and myeloid differentiation was increased at the expense of lymphoid progenitors. Together, these findings hint at a central role of NO in regulating human HSPC behavior and stress the importance and the potential of the use of adequate NO concentrations forin vitrocultures of HSPCs, with possible implications for clinical application ofin vitroexpanded or differentiated HSPCs for cellular therapies.
Human Bile Contains Cholangiocyte Organoid-Initiating Cells Which Expand as Functional Cholangiocytes in Non-canonical Wnt Stimulating Conditions
Authors: Roos Floris J. M. , Verstegen Monique M. A. , Muñoz Albarinos Laura , Roest Henk P. , Poley Jan-Werner , Tetteroo Geert W. M. , IJzermans Jan N. M. , van der Laan Luc J. W.
Published: February 2021

Diseases of the bile duct (cholangiopathies) remain a common indication for liver transplantation, while little progress has been made over the last decade in understanding the underlying pathophysiology. This is largely due to lack of properin vitromodel systems to study cholangiopathies. Recently, a culture method has been developed that allows for expansion of human bile duct epithelial cells grown as extrahepatic cholangiocyte organoids (ncECOs) in non-canonical Wnt-stimulating conditions. These ncECOs closely resemble cholangiocytes in culture and have shown to efficiently repopulate collagen scaffolds that could act as functional biliary tissue in mice. Thus far, initiation of ncECOs required tissue samples, thereby limiting broad patient-specific applications. Here, we report that bile fluid, which can be less invasively obtained and with low risk for the patients, is an alternative source for culturing ncECOs. Further characterization showed that bile-derived cholangiocyte organoids (ncBCOs) are highly similar to ncECOs obtained from bile duct tissue biopsies. Compared to the previously reported bile-cholangiocyte organoids cultured in canonical Wnt-stimulation conditions, ncBCOs have superior function of cholangiocyte ion channels and are able to respond to secretin and somatostatin. In conclusion, bile is a new, less invasive, source for patient-derived cholangiocyte organoids and makes their regenerative medicine applications more safe and feasible.
Identification of Specific Trafficking Defects of Naturally Occurring Variants of the Human ABCG2 Transporter
Authors: Bartos Zsuzsa , Homolya László
Published: February 2021

Proper targeting of the urate and xenobiotic transporter ATP-binding transporter subfamily G member 2 (ABCG2) to the plasma membrane (PM) is essential for its normal function. The naturally occurring Q141K and M71V polymorphisms in ABCG2, associated with gout and hyperuricemia, affect the cellular routing of the transporter, rather than its transport function. The cellular localization of ABCG2 variants was formerly studied by immunolabeling, which provides information only on the steady-state distribution of the protein, leaving the dynamics of its cellular routing unexplored. In the present study, we assessed in detail the trafficking of the wild-type, M71V-, and Q141K-ABCG2 variants from the endoplasmic reticulum (ER) to the cell surface using a dynamic approach, the so-called Retention Using Selective Hooks (RUSH) system. This method also allowed us to study the kinetics of glycosylation of these variants. We found that the fraction of Q141K- and M71V-ABCG2 that passes the ER quality control system is only partially targeted to the PM; a subfraction is immobile and retained in the ER. Surprisingly, the transit of these variants through the Golgi apparatus (either the appearance or the exit) was unaffected; however, their PM delivery beyond the Golgi was delayed. In addition to identifying the specific defects in the trafficking of these ABCG2 variants, our study provides a novel experimental tool for studying the effect of drugs that potentially promote the cell surface delivery of mutant or polymorphic ABCG2 variants with impaired trafficking.
Differential Thresholds of Proteasome Activation Reveal Two Separable Mechanisms of Sensory Organ Polarization in C. elegans
Authors: Kunz Patricia , Lehmann Christina , Pohl Christian
Published: February 2021

Cephalization is a major innovation of animal evolution and implies a synchronization of nervous system, mouth, and foregut polarization to align alimentary tract and sensomotoric system for effective foraging. However, the underlying integration of morphogenetic programs is poorly understood. Here, we show that invagination of neuroectoderm through de novo polarization and apical constriction creates the mouth opening in the Caenorhabditis elegans embryo. Simultaneously, all 18 juxta-oral sensory organ dendritic tips become symmetrically positioned around the mouth: While the two bilaterally symmetric amphid sensilla endings are towed to the mouth opening, labial and cephalic sensilla become positioned independently. Dendrite towing is enabled by the pre-polarized sensory amphid pores intercalating into the leading edge of the anteriorly migrating epidermal sheet, while apical constriction-mediated cell–cell re-arrangements mediate positioning of all other sensory organs. These two processes can be separated by gradual inactivation of the 26S proteasome activator, RPN-6.1. Moreover, RPN-6.1 also shows a dose-dependent requirement for maintenance of coordinated apical polarization of other organs with apical lumen, the pharynx, and the intestine. Thus, our data unveil integration of morphogenetic programs during the coordination of alimentary tract and sensory organ formation and suggest that this process requires tight control of ubiquitin-dependent protein degradation.
Flotillin-1 Interacts With and Sustains the Surface Levels of TRPV2 Channel
Authors: Hu Juan , Gao Yue , Huang Qian , Wang Yuanyuan , Mo Xiaoyi , Wang Peiyu , Zhang Youjing , Xie Chang , Li Dongdong , Yao Jing
Published: February 2021

Transient receptor potential vanilloid subtype 2 (TRPV2) channel is a polymodal receptor regulating neuronal development, cardiac function, immunity and oncogenesis. The activity of TRPV2 is regulated by the molecular interactions in the subplasmalemmel signaling complex. Here by yeast two-hybrid screening of a cDNA library of mouse dorsal root ganglia (DRG) and patch clamp electrophysiology, we identified that flotillin-1, the lipid raft-associated protein, interacts with TRPV2 channel and regulates its function. The interaction between TRPV2 and flotillin-1 was validated through co-immuoprecipitationin situusing endogenous DRG neurons and the recombinant expression model in HEK 293T cells. Fluorescent imaging and bimolecular fluorescence complementation (BiFC) further revealed that flotillin-1 and TRPV2 formed a functional complex on the cell membrane. The presence of flotillin-1 enhanced the whole-cell current density of TRPV2 via increasing its surface expression levels. Using site-specific mapping, we also uncovered that the SPFH (stomatin, prohibitin, flotillin, and HflK/C) domain of flotillin-1 interacted with TRPV2 N-termini and transmembrane domains 1–4, respectively. Our findings therefore demonstrate that flotillin-1 is a key element in TRPV2 signaling complex and modulates its cellular response.
Immunomodulatory Properties of Mesenchymal Stromal Cells: An Update
Authors: Müller Luise , Tunger Antje , Wobus Manja , von Bonin Malte , Towers Russell , Bornhäuser Martin , Dazzi Francesco , Wehner Rebekka , Schmitz Marc
Published: February 2021

Mesenchymal stromal cells (MSCs) are characterized by an extraordinary capacity to modulate the phenotype and functional properties of various immune cells that play an essential role in the pathogenesis of inflammatory disorders. Thus, MSCs efficiently impair the phagocytic and antigen-presenting capacity of monocytes/macrophages and promote the expression of immunosuppressive molecules such as interleukin (IL)-10 and programmed cell death 1 ligand 1 by these cells. They also effectively inhibit the maturation of dendritic cells and their ability to produce proinflammatory cytokines and to stimulate potent T-cell responses. Furthermore, MSCs inhibit the generation and proinflammatory properties of CD4+ T helper (Th)1 and Th17 cells, while they promote the proliferation of regulatory T cells and their inhibitory capabilities. MSCs also impair the expansion, cytokine secretion, and cytotoxic activity of proinflammatory CD8+ T cells. Moreover, MSCs inhibit the differentiation, proliferation, and antibody secretion of B cells, and foster the generation of IL-10-producing regulatory B cells. Various cell membrane-associated and soluble molecules essentially contribute to these MSC-mediated effects on important cellular components of innate and adaptive immunity. Due to their immunosuppressive properties, MSCs have emerged as promising tools for the treatment of inflammatory disorders such as acute graft-versus-host disease, graft rejection in patients undergoing organ/cell transplantation, and autoimmune diseases.
Abnormal Glucose Metabolism in Male Mice Offspring Conceived by in vitro Fertilization and Frozen-Thawed Embryo Transfer
Authors: Qin Ningxin , Zhou Zhiyang , Zhao Wenlong , Zou Kexin , Shi Weihui , Yu Chuanjin , Liu Xia , Dong Zehan , Mao Yiting , Liu Xinmei , Sheng Jianzhong , Ding Guolian , Wu Yanting , Huang Hefeng
Published: February 2021

Frozen and thawed embryo transfer (FET) is currently widely applied in routine assisted reproductive technology (ART) procedure. It is of great necessity to assess the safety of FET and investigate the long-term effect including glucose metabolism on FET-conceived offspring. The mouse model is a highly efficient method to figure out the relationship between the process of FET and offspring health. In this study, we obtained mouse offspring of natural conception (NC), in vitro fertilization (IVF), and FET. Glucose and insulin tolerance test (GTT/ITT) were performed on both chow fed or high fat diet (HFD) fed offspring to examine the glucose metabolism status. We detected hepatic PI3K/AKT pathway by western blotting and transcriptome status by RNA-sequencing. Impaired glucose tolerance (IGT) and decreased insulin tolerance were occurred in FET conceived male offspring. After challenged with the HFD-fed, male offspring in FET group performed earlier and severer IGT than IVF group. Furthermore, higher HOMA-IR index and higher serum insulin level post glucose injected in FET-chow group suggested the insulin resistance status. The PI3K/AKT signaling pathway, the major pathway of insulin in the liver, were also disrupted in FET group. Transcriptomics of the liver reveals significantly downregulated in glucose metabolic process and insulin resistance in the FET-chow group. In our study, FET-conceived male mouse offspring presented glucose metabolism dysfunction mainly manifesting insulin resistance. The hepatic insulin signaling pathway were in concordance with reduced glycogen synthesis, increased glycolysis and enhanced gluconeogenesis status in FET-conceived male offspring.
Prognostic Value of Right Ventricular Ejection Fraction Assessed by 3D Echocardiography in COVID-19 Patients
Authors: Zhang Yanting , Sun Wei , Wu Chun , Zhang Yiwei , Cui Li , Xie Yuji , Wang Bin , He Lin , Yuan Hongliang , Zhang Yongxing , Cai Yu , Li Meng , Zhang Yu , Yang Yun , Li Yuman , Wang Jing , Yang Yali , Lv Qing , Zhang Li , Xie Mingxing
Published: February 2021

Background: RVEF (right ventricular ejection fraction) measured by three-dimensional echocardiography (3DE) has been used in evaluating right ventricular (RV) function and can provide useful prognostic information in other various cardiovascular diseases. However, the prognostic value of 3D-RVEF in coronavirus disease 2019 (COVID-19) remains unknown. We aimed to investigate whether 3D-RVEF can predict the mortality of COVID-19 patients.

Methods: A cohort of 128 COVID-19-confirmed patients who had undergone echocardiography were studied. Thirty-one healthy volunteers were also enrolled as controls. COVID-19 patients were divided into three subgroups (general, severe, and critical) according to COVID-19 severity-of-illness. Conventional RV structure and function parameters, RV free wall longitudinal strain (FWLS) and 3D-RVEF were acquired. RVFWLS was measured by two-dimensional speckle tracking echocardiography. RVEF was acquired by 3DE.

Results: Compared with controls, 2D-RVFWLS and 3D-RVEF were both significantly decreased in COVID-19 patients (−27.2 ± 4.4% vs. −22.9 ± 4.8%, P < 0.001; 53.7 ± 4.5% vs. 48.5 ± 5.8%, P < 0.001). Critical patients were more likely to have a higher incidence of acute cardiac injury and acute respiratory distress syndrome (ARDS), and worse prognosis than general and severe patients. The critical patients exhibited larger right-heart chambers, worse RV fractional area change (RVFAC), 2D-RVFWLS, and 3D-RVEF and higher proportion of pulmonary hypertension than general and severe patients. Eighteen patients died during a median follow-up of 91 days. The multivariate Cox regression analysis revealed the acute cardiac injury, ARDS, RVFAC, RVFWLS, and 3D-RVEF were independent predictors of death. 3D-RVEF (chi-square to improve 18.3; P < 0.001), RVFAC (chi-square to improve 4.5; P = 0.034) and 2D-RVFWLS (chi-square to improve 5.1; P = 0.024) all provided additional prognostic value of higher mortality over clinical risk factors. Moreover, the incremental predictive value of 3D-RVEF was significantly (P < 0.05) higher than RVFAC and RVFWLS.

Conclusion: 3D-RVEF was the most robust independent predictor of mortality in COVID-19 patients and provided a higher predictive value over conventional RV function parameters and RVFWLS, which may be helpful to identify COVID-19 patients at a higher risk of death.
The Effects of Multi-Scale Climate Variability on Biodiversity Patterns of Chinese Evergreen Broad-Leaved Woody Plants: Growth Form Matters
Authors: Xu Yue , Shen Zehao , Zhang Jinlong , Zang Runguo , Jiang Youxu
Published: February 2021

Large-scale patterns of species diversity are thought to be linked to contemporary climate variability and Quaternary glacial–interglacial climate change. For plants, growth forms integrate traits related to competition or migration capacity, which determine their abilities to deal with the climate variability they face. Evergreen broad-leaved woody plants (EBWPs) are major components of numerous biomes in the subtropical and tropical regions. Hence, incorporating phylogenetic (temporal) and biogeographic (spatial) approaches, we assessed the relative importance of short- and long-term climate variability for biodiversity patterns of different growth forms (i.e., tree, shrub, liana, and bamboo) in EBWPs. We used a dated phylogeny and the distribution records for 6,265 EBWP species which are naturally occurred in China, and computed the corrected weighted endemism, standardized phylogenetic diversity and net relatedness index for the four growth forms, respectively. Ordinary least squares linear regressions, spatial error simultaneous autoregressive models, partial regression and hierarchical variation partitioning were employed to estimate the explanatory power of contemporary climate variability and climate-change velocity from the Last Glacial Maximum to the present. Our results showed that short- and long-term climate variability play complementary role in the biogeographic patterns of Chinese EBWPs. The former had larger effects, but the legacy effects of past climate changes were also remarkable. There were also differences in the effects of historical and current climate among the four growth forms, which support growth forms as a critical plant trait in predicting vegetation response to climate change. Compared to the glacial-interglacial climate fluctuation, seasonality as a unique feature of mid-latitude monsoon climate played a dominant role in the diversification and distribution of EBWP species at the macroscale. The results indicated that the relative importance of climate variability at different temporal scales may relate to distinct mechanisms. To understand effects of future climate change on species distribution more thoroughly, climate conditions in different time scales should be incorporated.
Identification and Validation of Efficacy of Immunological Therapy for Lung Cancer From Histopathological Images Based on Deep Learning
Authors: Yang Yachao , Yang Jialiang , Liang Yuebin , Liao Bo , Zhu Wen , Mo Xiaofei , Huang Kaimei
Published: February 2021

Cancer immunotherapy, as a novel treatment against cancer metastasis and recurrence, has brought a significantly promising and effective therapy for cancer treatments. At present, programmed death 1 (PD-1) and programmed cell death-Ligand 1 (PD-L1) treatment for lung cancer is primarily recognized as an immune checkpoint inhibitor (ICI) to play an anti-tumor effect; however, it remains uncertain regarding of its efficacy though. Thereafter, tumor mutation burden (TMB) was recognized as a high-potential to be a predictive marker for the immune therapy, but it is invasive and costly. Therefore, discovering more immune-related biomarkers that have a guiding role in immunotherapy is a crucial step in the development of immunotherapy. In our study, we proposed a deep convolutional neural network (CNN)-based framework, DeepLRHE, which can efficiently analyze immunological stained pathological images of lung cancer tissues, as well as to identify and explore pathogenesis which can be used for immunological treatment in clinical field. In this study, we used 180 whole slice images (WSIs) of lung cancer downloaded from TCGA which was model training and validation. After two cross-validation used for this model, we compared with the area under the curve (AUC) of multiple mutant genes, TP53 had highest AUC, which reached 0.87, and EGFR, DNMT3A, PBRM1, STK11 also reached ranged from 0.71 to 0.84. The study results showed that the deep learning can used to assist health professionals for target-therapy as well as immunotherapies, therefore to improve the disease prognosis.
Metabolic Regulation of Immune Responses to Mycobacterium tuberculosis: A Spotlight on L-Arginine and L-Tryptophan Metabolism
Authors: Crowther Rebecca R. , Qualls Joseph E.
Published: February 2021

Mycobacterium tuberculosis(Mtb), the causative agent of tuberculosis (TB), is a leading cause of death worldwide. Despite decades of research, there is still much to be uncovered regarding the immune response toMtbinfection. Here, we summarize the current knowledge on anti-Mtbimmunity, with a spotlight on immune cell amino acid metabolism. Specifically, we discuss L-arginine and L-tryptophan, focusing on their requirements, regulatory roles, and potential use as adjunctive therapy in TB patients. By continuing to uncover the immune cell contribution duringMtbinfection and how amino acid utilization regulates their functions, it is anticipated that novel host-directed therapies may be developed and/or refined, helping to eradicate TB.
Clarifying Water Column Respiration and Sedimentary Oxygen Respiration Under Oxygen Depletion Off the Changjiang Estuary and Adjacent East China Sea
Authors: Zhou Jun , Zhu Zhuo-Yi , Hu Huan-Ting , Zhang Gui-Ling , Wang Qian-Qian
Published: February 2021

The Changjiang Estuary and its adjacent East China Sea are among the largest coastal hypoxic sites in the world. The oxygen depletion in the near-bottom waters (e.g., meters above the seabed) off the Changjiang Estuary is caused by water column respiration (WCR) and sedimentary oxygen respiration (SOR). It is essential to quantify the contributions of WCR and SOR to total apparent oxygen utilization (AOU) to understand the occurrence of hypoxia off the Changjiang Estuary. In this work, we analyzed the δ18O and O2/Ar values of marine dissolved gas samples collected during a field investigation in July 2018. We observed that the δ18O values of dissolved oxygen in near-bottom waters ranged from 1.039 to 8.457‰ (vs. air), generally higher than those of surface waters (−5.366 to 2.336‰). For all the sub-pycnocline samples, the δ18O values were negatively related to O2 concentrations (r2 = 0.97), indicating apparent fractionation of δ18O during oxygen depletion in the water column. Based on two independent isotope fractionation models that quantified the isotopic distillation of dissolved oxygen concentration and its δ18O, the mean contributions of WCR and SOR to total near-bottom AOU were calculated as 53 and 47%, respectively. Beneath the pycnocline, the WCR contribution to the total AOU varied from 24 to 69%, and the SOR contribution varied from 31 to 76%. The pooled samples beneath both the pycnocline and upper mixed layer indicated that WCR contributions (%) to total AOU increased with increasing AOU (μmol/L), whereas SOR% – AOU had the reverse trend. We propose that the WCR% and SOR% contributions to the total AOU of the sub-pycnocline waters are dynamic, not stationary, with changes in ambient environmental factors. Under hypoxic conditions, we observed that up to 70% of the total AOU was contributed by WCR, indicating that WCR is the major oxygen consumption mechanism under hypoxia; that is, WCR plays a vital role in driving the dissolved oxygen to become hypoxic off the Changjiang Estuary.
DHA Accumulation in the Polar Lipids of the Euryhaline Copepod Pseudodiaptomus inopinus and Its Transfer to Red Sea Bream Pagrus major Larvae
Authors: Matsui Hideaki , Sasaki Taku , Kobari Toru , Waqalevu Viliame , Kikuchi Kazuma , Ishikawa Manabu , Kotani Tomonari
Published: February 2021

The euryhaline copepodPseudodiaptomus inopinusplay important roles in coastal waters as vectors of docosahexanoic (DHA) and eicosapentaenoic (EPA) acids for larval fish. While DHA and EPA in polar lipids (PLs) are more effective for fish larval development than non-polar lipid forms (NLs), there is little knowledge how much these lipids are accumulated in copepods from microalgae and are effective for early development of fish larvae. We report PLs fatty acid profiles ofP. inopinusfed DHA-poor microalgae and evaluate its significance as a food source for larvae development ofPagrus major, compared with DHA-enriched rotifers. Copepods and rotifers were fed a mixed diet of three algal species (Phaeodactylum tricornutum,Tisochrysis lutea, andPavlova lutheri), in addition of DHA-supplemented Super Fresh Chlorella (SFC) for rotifers. Compared with SFC, the algal mixture had higher EPA but lower DHA. Copepods had higher DHA and EPA in total lipids than rotifers fed each diet. Copepod PLs were specifically enriched with DHA and their contents were higher than both rotifers. On the other hand, PLs EPA contents were comparable between preys, indicating that copepods selectively fortified the PLs. Fish culture experiment showed that larvae fed copepods had higher growth than those fed SFC-enriched rotifers. Principal component analysis for each organism fatty acid composition emphasized trophic modification of DHA by copepods toward larval fish. This study highlighted thatP. inopinuscontribute to enhanced growth of coastal larval fish by efficiently transferring DHA via copepod fatty acid metabolism.
How to Work on a Non-endangered Species and Contribute to Cetacean Conservation: An Example by the Sarasota Dolphin Research Program
Authors: Gulland Frances M. D.
Published: February 2021

The world’s most endangered small cetaceans are found in countries many miles from Sarasota Bay and its common bottlenose dolphins (Tursiops truncatus). Information on the ecology and threats to many of these endangered cetaceans is often far more limited than that on bottlenose dolphins, with the IUCN Red Data List describing many species as “data deficient.” In many developing nations where these rare species occur, resources for research and monitoring are scant, and logistical challenges further limit research into marine mammal health and population status and their threats. The Sarasota Dolphin Research Program (SDRP) has tackled this problem by using the bottlenose dolphin as a model for cetacean species in other parts of the world and using its resources to assist scientists working with more endangered species of cetacean. The celebration of 50 years of study by the SDRP exemplifies how using long-term data on known individuals can advance the fields of cetacean behavior, ecology, life history, physiology, toxicology, and medicine, all providing information for informing certain conservation actions. The Sarasota team has used their work to inform conservation policy both home and abroad.
Adverse Outcomes Associated With Corticosteroid Use in Critical COVID-19: A Retrospective Multicenter Cohort Study
Authors: Li Yichen , Li Jie , Ke Jia , Jiao Na , Zhu Lixin , Shen Lihan , Chen Lei , Jiang Zhiqiang , Cheng Sijing , Huang Yibo , Zou Yifeng , Zhu Ruixin , Yan Guangjun
Published: February 2021

Corticosteroid is commonly used to reduce damage from inflammatory reactions in coronavirus disease 2019 (COVID-19). We aim to determine the outcomes of corticosteroid use in critically ill COVID-19 patients. Ninety six critically ill patients, hospitalized in 14 hospitals outside Wuhan from January 16 to March 30, 2020 were enrolled in this study. Among 96 critical patients, 68 were treated with corticosteroid (CS group), while 28 were not treated with corticosteroids (non-CS group). Multivariable logistic regression were performed to determine the possible correlation between corticosteroid use and the treatment outcomes. Forty-six (68%) patients in the CS group died compared to six (21%) of the non-CS group. Corticosteroid use was also associated with the development of ARDS, exacerbation of pulmonary fibrosis, longer hospital stay and virus clearance time. On admission, no difference in laboratory findings between the CS and the non-CS group was observed. After corticosteroid treatment, patients treated with corticosteroids were associated with higher counts of white blood cells, neutrophils, neutrophil-to-lymphocyte ratio, alanine aminotransferase level and Sequential Organ Failure Assessment score. In conclusion, corticosteroid use in critically ill COVID-19 patients was associated with a much higher case fatality rate. Frequent incidence of liver injury and multi-organ failure in corticosteroid treated patients may have contributed to the adverse outcomes. The multi-organ failure is likely caused by more persistent SARS-CoV-2 infection and higher viral load, due to the inhibition of immune surveillance by corticosteroid.
Acute Kidney Injury in COVID-19: 90 Days of the Pandemic in a Brazilian Public Hospital
Authors: Zamoner Welder , Santos Camilla Andrade da Silva , Magalhães Luís Eduardo , Oliveira Paula Gabriela Sousa de , Balbi André Luis , Ponce Daniela
Published: February 2021

Renal involvement is frequent in COVID-19 (4–37%). This study evaluated the incidence and risk factors of acute kidney injury (AKI) in hospitalized patients with COVID-19.

Methodology: This study represents a prospective cohort in a public and tertiary university hospital in São Paulo, Brazil, during the first 90 days of the COVID-19 pandemic, with patients followed up until the clinical outcome (discharge or death).

Results: There were 101 patients hospitalized with COVID-19, of which 51.9% were admitted to the intensive care unit (ICU). The overall AKI incidence was 50%; 36.8% had hematuria or proteinuria (66.6% of those with AKI), 10.2% had rhabdomyolysis, and mortality was 36.6%. Of the ICU patients, AKI occurred in 77.3% and the mortality was 65.4%. The mean time for the AKI diagnosis was 6 ± 2 days, and Kidney Disease Improving Global Outcomes (KDIGO) stage 3 AKI was the most frequent (58.9%). Acute renal replacement therapy was indicated in 61.5% of patients. The factors associated with AKI were obesity [odds ratio (OR) 1.98, 95% confidence interval (CI) 1.04–2.76, p < 0.05] and the APACHE II score (OR 1.97, 95% CI 1.08–2.64, p < 0.05). Mortality was higher in the elderly (OR 1.03, 95% CI 1.01–1.66, p < 0.05), in those with the highest APACHE II score (OR 1.08, 95% CI 1.02–1.98, p < 0.05), and in the presence of KDIGO stage 3 AKI (OR 1.11, 95% CI 1.05–2.57, p < 0.05).

Conclusion: AKI associated with severe COVID-19 in this Brazilian cohort was more frequent than Chinese, European, and North American data, and the risk factors associated with its development were obesity and higher APACHE II scores. Mortality was high, mainly in elderly patients, in those with a more severe disease manifestation, and in those who developed KDIGO stage 3 AKI.
Causes of Pruritus in Patients Treated With Immune Checkpoint Inhibitors for Melanomas or Skin Carcinomas
Authors: Salinas Nadia , Nowak Emmanuel , Etienne Maxime , Legoupil Delphine , Fouchard Maxime , Brenaut Emilie , Misery Laurent
Published: February 2021

Background: Pruritus is a frequent adverse event during the use of immune checkpoint inhibitors (ICIs), with a frequency estimated to be between 11 and 47%. The underlying causes remain poorly understood.

Objectives: The main goal was to search for putative causes of pruritus occurring in patients treated with ICIs for melanomas and cutaneous carcinomas. Other objectives were to assess the association between the occurrence of pruritus and survival and between the occurrence of pruritus and other adverse events.

Methods: A monocentric retrospective descriptive study was performed using data for patients treated with ICIs (nivolumab, pembrolizumab, ipilimumab, and cemiplimab) between August 2010 and November 2019.

Results: A total of 181 patients were included (mean age: 69 years). Pruritus was reported by 25 patients (13.8%). We were able to determine three subgroups of pruritus causes under ICI use: pruritus directly related to immunotherapy, pruritus indirectly related through other pruritus-inducing side effects and pruritus unrelated to ICIs. In 6/25 patients, no more specific cause of pruritus was found at the onset of pruritus or in their backgrounds, other than ICI use.

Limitations: The study has some limitations due to unicentric and retrospective design.

Conclusion: Pruritus was found in 25/181 patients in this series; only in 6/25 patients no potential cause other than ICI could be found, and pruritus was not associated with differences in survival.