Role of alternative polyadenylation dynamics in acute myeloid leukaemia at single-cell resolution.

Alternative polyadenylation (APA) has been discovered to play regulatory roles in the development of many cancer cells through preferential addition of a poly(A) tail at specific sites of pre-mRNA. A recent study found that APA was involved in the mediation of acute myeloid leukaemia (AML). However, unlike gene expression heterogeneity, little attention has been directed toward variations in single-cell APA for different cell types during AML development.

Nociceptin/orphanin FQ modulates energy homeostasis through inhibition of neurotransmission at VMN SF-1/ARC POMC synapses in a sex- and diet-dependent manner.

Background: Orphanin FQ (aka nociceptin; N/OFQ) binds to its nociceptin opioid peptide (NOP) receptor expressed in proopiomelanocortin (POMC) neurons within the arcuate nucleus (ARC), a critical anorexigenic component of the hypothalamic energy balance circuitry. It inhibits POMC neurons by modifying neuronal excitability both pre- and postsynaptically. We tested the hypothesis that N/OFQ inhibits neurotransmission at synapses involving steroidogenic factor (SF)-1 neurons in the ventromedial nucleus (VMN) and ARC POMC neurons in a sex- and diet-dependent fashion.

Investigating the Role of Everolimus in mTOR Inhibition and Autophagy Promotion as a Potential Host-Directed Therapeutic Target in Infection.

Tuberculosis (TB) is a serious infectious disease caused by the pathogen (). The current therapy consists of a combination of antibiotics over the course of four months. Current treatment protocols run into problems due to the growing antibiotic resistance of and poor compliance to the multi-drug-resistant TB treatment protocol.

Impaired cerebellar plasticity and eye-blink conditioning in calpain-1 knock-out mice.

Calpain-1 and calpain-2 are involved in the regulation of several signaling pathways and neuronal functions in the brain. Our recent studies indicate that calpain-1 is required for hippocampal synaptic plasticity, including long-term depression (LTD) and long-term potentiation (LTP) in field CA1. However, little is known regarding the contributions of calpain-1 to cerebellar synaptic plasticity.

Recent Development of Wnt Signaling Pathway Inhibitors for Cancer Therapeutics.

Purpose Of Review: Review current understanding of both canonical and non-canonical Wnt signaling in cancer and provide updated knowledge in current clinical trials of Wnt signaling drugs.

Recent Findings: Important roles of both canonical and non-canonical Wnt signaling in cancer have been increasingly recognized. Recent clinical trials of several Wnt-signaling drugs have showed promising outcomes.

Multiplexing Focused Ultrasound Stimulation with Fluorescence Microscopy.

By focusing low-intensity ultrasound pulses that penetrate soft tissues, LIPUS represents a promising biomedical technology to remotely and safely manipulate neural firing, hormonal secretion and genetically-reprogrammed cells. However, the translation of this technology for medical applications is currently hampered by a lack of biophysical mechanisms by which targeted tissues sense and respond to LIPUS. A suitable approach to identify these mechanisms would be to use optical biosensors in combination with LIPUS to determine underlying signaling pathways.

Differential alternative polyadenylation contributes to the developmental divergence between two rice subspecies, japonica and indica.

Alternative polyadenylation (APA) is a widespread post-transcriptional mechanism that regulates gene expression through mRNA metabolism, playing a pivotal role in modulating phenotypic traits in rice (Oryza sativa L.). However, little is known about the APA-mediated regulation underlying the distinct characteristics between two major rice subspecies, indica and japonica.

The most complete enantiornithine from North America and a phylogenetic analysis of the Avisauridae.

The most complete known North American enantiornithine was collected in 1992 but never formally described. The so-called "Kaiparowits avisaurid" remains one of the most exceptional Late Cretaceous enantiornithine fossils. We recognize this specimen as a new taxon, (gen.

Assessing the Professional Identity of Dental School Faculty: An Exploratory Study.

Experts have argued that dental education needs to shift from a teacher-centered paradigm to a learner-centered paradigm. Assisting faculty members to self-identify as educators may be a key to reaching that goal. The aim of this exploratory study was to assess how dental faculty members described their professional identity (educator or clinician) and the effect of their self-defined identity on their motivation to pursue professional development as educators.

Glutathione as a Marker for Human Disease.

Glutathione (GSH), often referred to as "the master antioxidant," participates not only in antioxidant defense systems, but many metabolic processes, and therefore its role cannot be overstated. GSH deficiency causes cellular risk for oxidative damage and thus as expected, GSH imbalance is observed in a wide range of pathological conditions including tuberculosis (TB), HIV, diabetes, cancer, and aging. Consequently, it is not surprising that GSH has attracted the attention of biological researchers and pharmacologists alike as a possible target for medical intervention.

The Synergistic Effects of the Glutathione Precursor, NAC and First-Line Antibiotics in the Granulomatous Response Against .

(), the causative bacterial agent responsible for tuberculosis (TB) continues to afflict millions of people worldwide. Although the human immune system plays a critical role in containing infection, elimination proves immensely more challenging. Consequently, there has been a worldwide effort to eradicate, and limit the spread of through the conventional use of first-line antibiotics.

Characterizing the Effects of Glutathione as an Immunoadjuvant in the Treatment of Tuberculosis.

is the etiological agent that is responsible for causing tuberculosis (TB), which continues to affect millions of people worldwide, and the rate of resistance of to antibiotics is ever increasing. We tested the synergistic effects of -acetyl cysteine (NAC; the precursor molecule for the synthesis of glutathione [GSH]) and individual first-line antibiotics typically given for the treatment of TB, such as isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA), to improve the ability of macrophages to control intracellular infection. GSH, a pleiotropic antioxidant molecule, has previously been shown to display both antimycobacterial and immune-enhancing effects.

Detection by a Sensitive and Specific PCR Platform.

is an emerging zoonotic pathogen present in the United States, South America, and Europe. The molecular detection of frequently relies on polymerase chain reaction (PCR) assays that target the genus coupled with DNA sequencing for species determination. However, the presence of other spp.

UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity.

Accumulating evidence indicates that the lysosomal Ragulator complex is essential for full activation of the mechanistic target of rapamycin complex 1 (mTORC1). Abnormal mTORC1 activation has been implicated in several developmental neurological disorders, including Angelman syndrome (AS), which is caused by maternal deficiency of the ubiquitin E3 ligase UBE3A. Here we report that Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator.

Endocannabinoid Signaling at Hypothalamic Steroidogenic Factor-1/Proopiomelanocortin Synapses Is Sex- and Diet-Sensitive.

We tested the hypotheses that steroidogenic factor (SF)-1 neurons in the hypothalamic ventromedial nucleus (VMN) provide sexually disparate, endocannabinoid (EC)- and diet-sensitive glutamatergic input onto proopiomelanocortin (POMC) neurons. Electrophysiological recordings were performed in hypothalamic slices from intact and castrated guinea pigs, along with optogenetic experiments in intact male as well as cycling and ovariectomized female NR5A1-Cre mice. In slices from castrated male and female guinea pigs, depolarized-induced suppression of excitation (DSE) time-dependently reduced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) in POMC neurons generated by electrically stimulating the dorsomedial VMN.

Molecular Characterization of Tandem Repeat Protein 36 Gene of Detected in Naturally Infected Dogs from Peru.

spp. are emerging infectious pathogens, especially in the Americas. Although is primarily a parasite of dogs, polymerase chain reaction-confirmed human infections have been reported from Mexico, Venezuela, and Costa Rica.

Application of pharmacogenetics in clinical practice: problems and solutions.

This paper discusses difficulties of pharmacogenomic data integration into clinical practice. It emphasizes the need for developing simple and easy to use bioinformatics tools to help prescribers to rapidly access and use genetic data in clinical decision-making at the point of encounter.

Probing the gating mechanism of the mechanosensitive channel Piezo1 with the small molecule Yoda1.

Piezo proteins are transmembrane ion channels which transduce many forms of mechanical stimuli into electrochemical signals. Their pore, formed by the assembly of three identical subunits, opens by an unknown mechanism. Here, to probe this mechanism, we investigate the interaction of Piezo1 with the small molecule agonist Yoda1.

Calpain inhibition reduces NMDA receptor rundown in rat substantia nigra dopamine neurons.

Repeated activation of N-Methyl-d-aspartate receptors (NMDARs) causes a Ca-dependent reduction in NMDAR-mediated current in dopamine (DA) neurons of the substantia nigra pars compacta (SNc) in one week old rats; however, a Ca-dependent regulatory protein has not been identified. The role of the Ca-dependent cysteine protease, calpain, in mediating NMDAR current rundown was investigated. In brain slices from rats aged postnatal day 7-9 ('P7'), bath application of either of the membrane permeable calpain inhibitors, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN, 20 μM) or MDL-28170 (30 μM) significantly reduced whole-cell NMDAR current rundown.

Immunotherapies: Exploiting the Immune System for Cancer Treatment.

Cancer is a condition that has plagued humanity for thousands of years, with the first depictions dating back to ancient Egyptian times. However, not until recent decades have biological therapeutics been developed and refined enough to safely and effectively combat cancer. Three unique immunotherapies have gained traction in recent decades: adoptive T cell transfer, checkpoint inhibitors, and bivalent antibodies.

Biological effects of Ni(II) on monocytes and macrophages in normal and hyperglycemic environments.

Corrosion and release of nickel ions from biomedical alloys are well documented, but little is still known about the effects of released nickel ions on cellular function with recurrent inflammatory challenges. Evidence suggests Ni(II) ions amplify LPS-induced secretion of several pro-inflammatory cytokines from monocytes. Exacerbating the inflammatory response, hyperglycemic conditions also affect monocytic function.

Daptomycin Proliposomes for Oral Delivery: Formulation, Characterization, and In Vivo Pharmacokinetics.

The aim of this study was to develop a proliposomal formulation of lipopeptide antibiotic drug daptomycin (DAP) for oral delivery. Thin film hydration was the selected method for preparation of proliposomes. Different phospholipids including soy-phosphatidylcholine (SPC), hydrogenated egg-phosphatidylcholine (HEPC), and distearoyl-phosphatidylcholine (DSPC) were evaluated in combination with cholesterol.

Prescribing Bioidentical Menopausal Hormone Therapy: A Survey of Physician Views and Practices.

Background: It is estimated that 1-2.5 million U.S.