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Electrophysiological biomarkers of behavioral dimensions from cross-species paradigms.

Transl Psychiatry 2021 Sep 17;11(1):482. Epub 2021 Sep 17.

Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.

There has been a fundamental failure to translate preclinically supported research into clinically efficacious treatments for psychiatric disorders. One of the greatest impediments toward improving this species gap has been the difficulty of identifying translatable neurophysiological signals that are related to specific behavioral constructs. Here, we present evidence from three paradigms that were completed by humans and mice using analogous procedures, with each task eliciting candidate a priori defined electrophysiological signals underlying effortful motivation, reinforcement learning, and cognitive control. Read More

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September 2021

Enhancing plant growth and biomass production by overexpression of GA20ox gene under control of a root preferential promoter.

Transgenic Res 2021 Sep 13. Epub 2021 Sep 13.

Institute of Biotechnology, Vietnam Academy of Science and Technology, A10 building, 18 Hoang Quoc Viet, Hanoi, Vietnam.

Overexpression of GA20 oxidase gene has been a recent trend for improving plant growth and biomass. Constitutive expression of GA20ox has successfully improved plant growth and biomass in several plant species. However, the constitutive expression of this gene causes side-effects, such as reduced leaf size and stem diameter, etc. Read More

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September 2021

R-Ras subfamily proteins elicit distinct physiologic effects and phosphoproteome alterations in neurofibromin-null MPNST cells.

Cell Commun Signal 2021 Sep 16;19(1):95. Epub 2021 Sep 16.

Department of Pathology and Laboratory Medicine (SMW, AP, JFL, SLC), MUSC Medical Scientist Training Program (SMW), Medical University of South Carolina, 171 Ashley Avenue, MSC 908, Charleston, SC, 29425-9080, USA.

Background: Loss of the Ras GTPase-activating protein neurofibromin promotes nervous system tumor pathogenesis in patients with neurofibromatosis type 1 (NF1). Neurofibromin loss potentially hyperactivates classic Ras (H-Ras, N-Ras, K-Ras), M-Ras, and R-Ras (R-Ras, R-Ras2/TC21) subfamily proteins. We have shown that classic Ras proteins promote proliferation and survival, but not migration, in malignant peripheral nerve sheath tumor (MPNST) cells. Read More

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September 2021

A high-frequency single nucleotide polymorphism in the MtrB sensor kinase in clinical strains of Mycobacterium tuberculosis alters its biochemical and physiological properties.

PLoS One 2021 16;16(9):e0256664. Epub 2021 Sep 16.

Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India.

The DNA polymorphisms found in clinical strains of Mycobacterium tuberculosis drive altered physiology, virulence, and pathogenesis in them. Although the lineages of these clinical strains can be traced back to common ancestor/s, there exists a plethora of difference between them, compared to those that have evolved in the laboratory. We identify a mutation present in ~80% of clinical strains, which maps in the HATPase domain of the sensor kinase MtrB and alters kinase and phosphatase activities, and affects its physiological role. Read More

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September 2021

Secondary predation constrains DNA-based diet reconstruction in two threatened shark species.

Sci Rep 2021 Sep 15;11(1):18350. Epub 2021 Sep 15.

NSW Department of Primary Industries, Fisheries Conservation Technology Unit, National Marine Science Centre, Southern Cross University, 2 Bay Drive, Coffs Harbour, NSW, 2450, Australia.

Increasing fishing effort, including bycatch and discard practices, are impacting marine biodiversity, particularly among slow-to-reproduce taxa such as elasmobranchs, and specifically sharks. While some fisheries involving sharks are sustainably managed, collateral mortalities continue, contributing towards > 35% of species being threatened with extinction. To effectively manage shark stocks, life-history information, including resource use and feeding ecologies is pivotal, especially among those species with wide-ranging distributions. Read More

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September 2021

Reduced TREM2 activation in microglia of patients with Alzheimer's disease.

FEBS Open Bio 2021 Sep 15. Epub 2021 Sep 15.

Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, 26-Muraoka-higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.

Loss-of-function variants of triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of developing Alzheimer's disease (AD). The mechanism through which TREM2 contributes to the disease (TREM2 activation vs inactivation) is largely unknown. Here, we analyzed changes in a gene set downstream of TREM2 to determine whether TREM2 signaling is modified by AD progression. Read More

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September 2021

Mechanistic insights into dopaminergic and serotonergic neurotransmission - concerted interactions with helices 5 and 6 drive the functional outcome.

Chem Sci 2021 Aug 2;12(33):10990-11003. Epub 2021 Jul 2.

Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Medical Research Institute (IMIM) - Pompeu Fabra University (UPF) Dr Aiguader 88 Barcelona E-08003 Spain

Brain functions rely on neurotransmitters that mediate communication between billions of neurons. Disruption of this communication can result in a plethora of psychiatric and neurological disorders. In this work, we combine molecular dynamics simulations, live-cell biosensor and electrophysiological assays to investigate the action of the neurotransmitter dopamine at the dopaminergic D receptor (DR). Read More

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Development of a Mobile Mitochondrial Physiology Laboratory for Measuring Mitochondrial Energetics in the Field.

J Vis Exp 2021 Aug 27(174). Epub 2021 Aug 27.

School of Kinesiology, Auburn University.

Mitochondrial energetics is a central theme in animal biochemistry and physiology, with researchers using mitochondrial respiration as a metric to investigate metabolic capability. To obtain the measures of mitochondrial respiration, fresh biological samples must be used, and the entire laboratory procedure must be completed within approximately 2 h. Furthermore, multiple pieces of specialized equipment are required to perform these laboratory assays. Read More

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Binary and ternary complexes of FLNa-Ig21 with cytosolic tails of αMß2 integrin reveal dual role of filamin mediated regulation.

Biochim Biophys Acta Gen Subj 2021 Sep 9;1865(12):130005. Epub 2021 Sep 9.

School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore. Electronic address:

Background: Cytoskeletal protein filamin A is critical for the outside-in signaling of integrins. Although molecular mechanisms of filamin-integrin interactions are not fully understood. Mostly, the membrane distal (MD) part of the cytosolic tail (CT) of β subunit of integrin is known to interact with filamin A domain 21 (FLNa-Ig2). Read More

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September 2021

Pro-pigmentary action of 5-fluorouracil through the stimulated secretion of CXCL12 by dermal fibroblasts.

Chin Med J (Engl) 2021 Sep 9. Epub 2021 Sep 9.

Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.

Background: There is growing evidence that 5-fluorouracil (5-FU) combined with therapeutic trauma can effectively induce skin repigmentation in vitiligo patients who are unresponsive to conventional treatments. Previous studies have mainly focused on identifying the antimitotic activity of 5-FU for the treatment of skin cancer, but few studies have investigated its extra-genotoxic actions favoring melanocyte recruitment.

Methods: We utilized the full thickness excisional skin wound model in Dct-LacZ transgenic mice to dynamically assess the migration of melanocytes in the margins of wounds treated with or without 5-FU. Read More

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September 2021

Integrating Reverse Transcription Recombinase Polymerase Amplification with CRISPR Technology for the One-Tube Assay of RNA.

Anal Chem 2021 Sep 10. Epub 2021 Sep 10.

Division of Analytical and Environmental Toxicology, Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2G3, Canada.

CRISPR-Cas systems integrated with nucleic acid amplification techniques improve both analytical specificity and sensitivity. We describe here issues and solutions for the successful integration of reverse transcription (RT), recombinase polymerase amplification (RPA), and CRISPR-Cas12a nuclease reactions into a single tube under an isothermal condition (40 °C). Specific detection of a few copies of a viral DNA sequence was achieved in less than 20 min. Read More

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September 2021

Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates.

Sci Rep 2021 Sep 9;11(1):17977. Epub 2021 Sep 9.

CHDI Management/CHDI Foundation, 6080 Center Drive, Suite 700, Los Angeles, CA, 90045, USA.

Huntington's disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of HTT led us to consider the development of high-affinity small-molecule binders of HTT oligomerized/amyloid-containing species that could serve as either cellular and in vivo imaging tools or potential therapeutic agents. Read More

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September 2021

A barbed end interference mechanism reveals how capping protein promotes nucleation in branched actin networks.

Nat Commun 2021 Sep 9;12(1):5329. Epub 2021 Sep 9.

Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany.

Heterodimeric capping protein (CP/CapZ) is an essential factor for the assembly of branched actin networks, which push against cellular membranes to drive a large variety of cellular processes. Aside from terminating filament growth, CP potentiates the nucleation of actin filaments by the Arp2/3 complex in branched actin networks through an unclear mechanism. Here, we combine structural biology with in vitro reconstitution to demonstrate that CP not only terminates filament elongation, but indirectly stimulates the activity of Arp2/3 activating nucleation promoting factors (NPFs) by preventing their association to filament barbed ends. Read More

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September 2021

ATP Inhibits Breast Cancer Migration and Bone Metastasis through Down-Regulation of CXCR4 and Purinergic Receptor P2Y11.

Cancers (Basel) 2021 Aug 26;13(17). Epub 2021 Aug 26.

Department of Biochemistry and Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.

ATP released by bone osteocytes is shown to activate purinergic signaling and inhibit the metastasis of breast cancer cells into the bone. However, the underlying molecular mechanism is not well understood. Here, we demonstrate the important roles of the CXCR4 and P2Y11 purinergic receptors in mediating the inhibitory effect of ATP on breast cancer cell migration and bone metastasis. Read More

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Complement Factor B Mediates Ocular Angiogenesis through Regulating the VEGF Signaling Pathway.

Int J Mol Sci 2021 Sep 3;22(17). Epub 2021 Sep 3.

Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Proteos, 61 Biopolis Dr., Singapore 138673, Singapore.

Complement factor B (CFB), a 95-kDa protein, is a crucial catalytic element of the alternative pathway (AP) of complement. After binding of CFB to C3b, activation of the AP depends on the proteolytic cleavage of CFB by factor D to generate the C3 convertase (C3bBb). The C3 convertase contains the catalytic subunit of CFB (Bb), the enzymatic site for the cleavage of a new molecule of C3 into C3b. Read More

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September 2021

Mathematical modelling of SARS-CoV-2 infection of human and animal host cells reveals differences in the infection rates and delays in viral particle production by infected cells.

J Theor Biol 2021 Sep 6:110895. Epub 2021 Sep 6.

Institut Pasteur, Viral Populations and Pathogenesis Unit, Department of Virology, CNRS UMR 3569, Paris F-75015, France.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of COVID-19 disease, poses a significant threat to public health. Since its outbreak in December 2019, Wuhan, China, extensive collection of diverse data from cell culture and animal infections as well as population level data from an ongoing pandemic, has been vital in assessing strategies to battle its spread. Mathematical modelling plays a key role in quantifying determinants that drive virus infection dynamics, especially those relevant for epidemiological investigations and predictions as well as for proposing efficient mitigation strategies. Read More

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September 2021

extract kills pre-malignant and malignant oral squamous cell carcinoma cells.

J Herb Med 2021 Oct 21;29. Epub 2021 May 21.

University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR 72205.

In this study, the potential of was evaluated in the management of oral cancer through assays designed to mimic conditions expected when chewing the whole seeds or use of a seed extract. For this purpose, a water-based extract of seeds was prepared, mimicking the chewing process. This extract demonstrated significant cytotoxic effect on oral cancer and pre-cancerous leukoplakia cells at a much lower concentration than the predicted oral concentration that could be achieved upon seed chewing. Read More

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October 2021

Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental mouse model of sepsis.

Blood 2021 Sep;138(9):806-810

Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China.

PD-L1 is a ligand for PD-1, and its expression has been shown to be upregulated in neutrophils harvested from septic patients. However, the effect of PD-L1 on neutrophil survival and sepsis-induced lung injury remains largely unknown. In this study, PD-L1 expression correlated negatively with rates of apoptosis in human neutrophils harvested from patients with sepsis. Read More

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September 2021

Minimal Residual Disease in Multiple Myeloma: Potential for Blood-Based Methods to Monitor Disease.

Clin Lymphoma Myeloma Leuk 2021 Aug 2. Epub 2021 Aug 2.

Dept. of Haematology, Cork University Hospital, Cork, Ireland; Dept. of Medicine, University College Cork, Cork, Ireland.

In recent years, the life expectancy of Multiple Myeloma (MM) patients has substantially improved, but this cancer remains incurable with increasing incidence in the developed world. Most MM patients will eventually relapse due to residual drug-resistant cancerous cells that survive treatment, commonly referred to as minimal residual disease (MRD). Methods to improve MRD detection in MM patients are generating considerable interest as a means of monitoring patients' response to treatment. Read More

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Multiple signals in the gut contract the mouse norovirus capsid to block antibody binding while enhancing receptor affinity.

J Virol 2021 Sep 1:JVI0147121. Epub 2021 Sep 1.

University of Texas Medical Branch at Galveston, Department of Biochemistry and Molecular Biology, 301 University Boulevard, Route 0645, Galveston, TX, 77555.

Human norovirus is the leading cause of gastroenteritis world-wide, with no approved vaccine or antiviral treatment to mitigate infection. These plus-strand RNA viruses have T=3 icosahedral protein capsids with 90 pronounced protruding (P) domain dimers to which antibodies and cellular receptors bind. We previously demonstrated that bile binding to the capsid of mouse norovirus (MNV) causes several major conformational changes; the entire P domain rotates by ∼90° and contracts onto the shell, the P domain dimers rotate about each other, and the structural equilibrium of the epitopes at the top of the P domain shift towards the 'closed' conformation that favors receptor binding while blocking antibody binding. Read More

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September 2021

Synthesis of Fluorescent Proanthocyanidin-Cinnamaldehydes Pyrylium Products for Microscopic Detection of Interactions with Extra-Intestinal Pathogenic .

J Agric Food Chem 2021 Sep 31;69(36):10700-10708. Epub 2021 Aug 31.

Department of Animal Sciences, Reed Research Group, University of Wisconsin-Madison, 1675 Observatory Drive, Madison, Wisconsin 53706, United States.

Synthesis of proanthocyanidin-cinnamaldehydes pyrylium products (PCPP) was achieved by the condensation reaction of proanthocyanidins (PAC) with cinnamaldehyde and four cinnamaldehyde derivatives. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) spectra of PCPP show masses that correspond to (epi)catechin oligomers attached to single, double, or triple moieties of cinnamaldehydes. Synthesized PCPP exhibited fluorescence at higher excitation and emission wavelengths than PAC. Read More

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September 2021

Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold.

J Med Chem 2021 Aug 31. Epub 2021 Aug 31.

Structural Genomics Consortium, University of Campinas (UNICAMP), Av. Dr. André Tosello, 550, Barão Geraldo, Campinas, SP 13083-886, Brazil.

SLK (STE20-like kinase) and STK10 (serine/threonine kinase 10) are closely related kinases whose enzymatic activity is linked to the regulation of ezrin, radixin, and moesin function and to the regulation of lymphocyte migration and the cell cycle. We identified a series of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10 with good kinome-wide selectivity. Optimization of this series led to multiple SLK/STK10 inhibitors with nanomolar potency. Read More

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Atmospheric conditions and composition that influence PM oxidative potential in Beijing, China.

Atmos Chem Phys 2021 Apr;21(7):5549-5573

Department of Environmental Sciences, University of Basel, Basel, Switzerland.

Epidemiological studies have consistently linked exposure to PM with adverse health effects. The oxidative potential (OP) of aerosol particles has been widely suggested as a measure of their potential toxicity. Several acellular chemical assays are now readily employed to measure OP; however, uncertainty remains regarding the atmospheric conditions and specific chemical components of PM that drive OP. Read More

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Nanoparticle shell structural cues drive in vitro transport properties, tissue distribution and brain accessibility in zebrafish.

Biomaterials 2021 Aug 24;277:121085. Epub 2021 Aug 24.

INRS Centre Armand-Frappier Santé Biotechnologie, 531 Boulevard des Prairies, Laval, Québec, H7V 1B7, Canada. Electronic address:

Zwitterion polymers with strong antifouling properties have been suggested as the prime alternative to polyethylene glycol (PEG) for drug nanocarriers surface coating. It is believed that PEG coating shortcomings, such as immune responses and incomplete protein repellency, could be overcome by zwitterionic polymers. However, no systematic study has been conducted so far to complete a comparative appraisal of PEG and zwitterionic-coating effects on nanoparticles (NPs) stealthness, cell uptake, cell barrier translocation and biodistribution in the context of nanocarriers brain targeting. Read More

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Spontaneous Mutants of with Defects in the Glucose-PTS Show Enhanced Post-Exponential Phase Fitness.

J Bacteriol 2021 Aug 30:JB0037521. Epub 2021 Aug 30.

Department of Oral Biology, University of Florida College of Dentistry, 1395 Center Drive, Gainesville, Florida, USA.

Genetic truncations in a gene encoding a putative glucose-PTS protein (, EIIAB) were identified in subpopulations of two separate laboratory stocks of SK36; the mutants had reduced PTS activities on glucose and other monosaccharides. To understand the emergence of these mutants, we engineered deletion mutants of and showed that the ManL-deficient strain had improved bacterial viability in stationary phase and was better able to inhibit the growth of the dental caries pathogen . Transcriptional analysis and biochemical assays suggested that the mutant underwent reprograming of central carbon metabolism that directed pyruvate away from production of lactate, increasing production of hydrogen peroxide (HO) and excretion of pyruvate. Read More

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A STING-based fluorescent polarization assay for monitoring activities of cyclic dinucleotide metabolizing enzymes.

RSC Chem Biol 2021 Feb 17;2(1):206-214. Epub 2020 Dec 17.

Department of Chemistry 560 Oval Drive West Lafayette Indiana 47907-2084 USA.

Cyclic dinucleoties, such as cGAMP, c-di-GMP and c-di-AMP, are fascinating second messengers with diverse roles in both prokaryotes and eukaryotes. Consequently there is a need for simple and inexpensive methods for profiling these compounds in biological media, monitoring their synthesis or degradation by enzymes and for identifying inhibitors of proteins that metabolize or bind to these dinucleotides. Since 2011, when we reported the first simple method to detect c-di-GMP (S. Read More

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February 2021

The role of molecular tests for adjuvant and post-surgical treatment in gynaecological cancers.

Best Pract Res Clin Obstet Gynaecol 2021 Aug 4. Epub 2021 Aug 4.

Department of Haematology-Oncology, National University Cancer Institute, 1E Kent Ridge Road, National University Health System Tower Block Level 7, 119228, Singapore; Cancer Science Institute, National University of Singapore, 14 Medical Drive, 117599, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, 117597, Singapore. Electronic address:

The adjuvant and post-surgical treatment of gynaecological cancers has historically been guided by the estimation of relapse risk based on clinicopathological factors determined at the time of cancer diagnosis. The recent advancement of genomic and molecular characterisation of gynaecological cancers has begun to shift paradigms in the selection of adjuvant treatment strategy. Recent data regarding the predictive and/or prognostic value of molecular tests in the treatment of advanced ovarian cancer as well as early stage endometrial cancer have been the first such examples to enter adjuvant treatment guidelines for these diseases. Read More

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Overcoming the acquired resistance to gefitinib in lung cancer brain metastasis in vitro and in vivo.

Arch Toxicol 2021 Aug 28. Epub 2021 Aug 28.

Department of Occupational and Environmental Health Sciences, School of Public Health, West Virginia University, 64 Medical Center Drive, Morgantown, WV, 26505, USA.

In our previous work, PC-9-Br, a PC-9 brain seeking line established via a preclinical animal model of lung cancer brain metastasis (LCBM), exhibited not only resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib in vitro, but also chemotherapy regimens of cisplatin plus etoposide in vivo. Using this cell line, we investigated novel potential targeted therapeutics for treating LCBM in vitro and in vivo to combat drug resistance. Significant increases in mRNA and protein expression levels of Bcl-2 were found in PC-9-Br compared with parental PC-9 (PC-9-P), but no significant changes of Bcl-XL were observed. Read More

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Long noncoding RNA LINC00261 upregulates ITIH5 to impair tumorigenic ability of pancreatic cancer stem cells.

Cell Death Discov 2021 Aug 26;7(1):220. Epub 2021 Aug 26.

Clinical Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110000, P. R. China.

Long noncoding RNAs (lncRNAs) are implicated tumor development in a range of different cancers, including pancreatic cancer (PC). Cancer stem cells (CSCs), a drug-resistant cancer cell subset, drive tumor progression in PC. In this work, we aimed to investigate the mechanism by which lncRNA LINC00261 affects the biological functions of CSCs during the progression of PC. Read More

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An Energy Efficient Thermally Regulated Optical Spectroscopy Cell for Lab-on-Chip Devices: Applied to Nitrate Detection.

Micromachines (Basel) 2021 Jul 22;12(8). Epub 2021 Jul 22.

Department of Electrical and Computer Engineering, Dalhousie University, 1360 Barrington Street, Halifax, NS B3H 4R2, Canada.

Reagent-based colorimetric analyzers often heat the fluid under analysis for improved reaction kinetics, whilst also aiming to minimize energy use per measurement. Here, a novel method of conserving heat energy on such microfluidic systems is presented. Our design reduces heat transfer to the environment by surrounding the heated optical cell on four sides with integral air pockets, thereby realizing an insulated and suspended bridge structure. Read More

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