Targeting STAT3 in Cancer with Nucleotide Therapeutics.

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting the proliferation and survival of tumor cells. As a ubiquitously-expressed transcription factor, STAT3 has commonly been considered an "undruggable" target for therapy; thus, much research has focused on targeting upstream pathways to reduce the expression or phosphorylation/activation of STAT3 in tumor cells. Recently, however, novel approaches have been developed to directly inhibit STAT3 in human cancers, in the hope of reducing the survival and proliferation of tumor cells. Several of these agents are nucleic acid-based, including the antisense molecule AZD9150, CpG-coupled STAT3 siRNA, G-quartet oligodeoxynucleotides (GQ-ODNs), and STAT3 decoys. While the AZD9150 and CpG-STAT3 siRNA interfere with STAT3 expression, STAT3 decoys and GQ-ODNs target constitutively activated STAT3 and modulate its ability to bind to target genes. Both STAT3 decoy and AZD9150 have advanced to clinical testing in humans. Here we will review the current understanding of the structures, mechanisms, and potential clinical utilities of the nucleic acid-based STAT3 inhibitors

Live calcium imaging of Aedes aegypti neuronal tissues reveals differential importance of chemosensory systems for life-history-specific foraging strategies.

BackgroundThe mosquito Aedes aegypti has a wide variety of sensory pathways that have supported its success as a species as well as a highly competent vector of numerous debilitating infectious pathogens. Investigations into mosquito sensory systems and their effects on behavior are valuable resources for the advancement of mosquito control strategies. Numerous studies have elucidated key aspects of mosquito sensory systems, however there remains critical gaps within the field. In particular, compared to that of the adult form, there has been a lack of studies directed towards the immature life stages. Additionally, although numerous studies have pinpointed specific sensory receptors as well as responding motor outputs, there has been a lack of studies able to monitor both concurrently.ResultsTo begin filling aforementioned gaps, here we engineered Ae. aegypti to ubiquitously express a genetically encoded calcium indicator, GCaMP6s. Using this strain, combined with advanced microscopy, we simultaneously measured live stimulus-evoked calcium responses in both neuronal and muscle cells with a wide spatial range and resolution.ConclusionsBy coupling in vivo live calcium imaging with behavioral assays we were able to gain functional insights into how stimulus-evoked neural and muscle activities are represented, modulated, and transformed in mosquito larvae enabling us to elucidate mosquito sensorimotor properties important for life-history-specific foraging strategies

Factors Affecting Speech Discrimination in Children with Cochlear Implants: Evidence from Early-Implanted Infants

Background To learn words and acquire language, children must be able to discriminate and correctly perceive phonemes. Although there has been much research on the general language outcomes of children with cochlear implants (CIs), little is known about the development of speech perception with regard to specific speech processes, such as speech discrimination. Purpose The purpose of this study was to investigate the development of speech discrimination in infants with CIs and identify factors that might correlate with speech discrimination skills. Research Design Using a Hybrid Visual Habituation procedure, we tested infants with CIs on their ability to discriminate the vowel contrast /i/-/u/. We also gathered demographic and audiological information about each infant. Study Sample Children who had received CIs before 2 yr of age served as participants. We tested the children at two post cochlear implantation intervals: 2–4 weeks post CI stimulation (N = 17) and 6–9 mo post CI stimulation (N = 10). Data Collection and Analysis The infants’ mean looking times during the novel versus old trials of the experiment were measured. A linear regression model was used to evaluate the relationship between the normalized looking time difference and the following variables: chronological age, age at CI stimulation, gender, communication mode, and best unaided pure-tone average. Results We found that the best unaided pure-tone average predicted speech discrimination at the early interval. In contrast to some previous speech perception studies that included children implanted before 3 yr of age, age at CI stimulation did not predict speech discrimination performance. Conclusions The results suggest that residual acoustic hearing before implantation might facilitate speech discrimination during the early period post cochlear implantation; with more hearing experience, communication mode might have a greater influence on the ability to discriminate speech. This and other studies on age at cochlear implantation suggest that earlier implantation might not have as large an effect on speech perception as it does on other language skills

Northern Hemisphere winter snow anomalies: ENSO, NAO and the winter of 2009/10

Winter 2009/10 had anomalously large snowfall in the central parts of the United States and in northwestern Europe. Connections between seasonal snow anomalies and the large scale atmospheric circulation are explored. An El Niño state is associated with positive snowfall anomalies in the southern and central United States and along the eastern seaboard and negative anomalies to the north. A negative NAO causes positive snow anomalies across eastern North America and in northern Europe. It is argued that increased snowfall in the southern U.S. is contributed to by a southward displaced storm track but further north, in the eastern U.S. and northern Europe, positive snow anomalies arise from the cold temperature anomalies of a negative NAO. These relations are used with observed values of NINO3 and the NAO to conclude that the negative NAO and El Niño event were responsible for the northern hemisphere snow anomalies of winter 2009/10

Goal-Focused Emotion-Regulation Therapy (GET) for young adult survivors of testicular cancer: a pilot randomized controlled trial of a biobehavioral intervention protocol.

BackgroundTesticular cancer diagnosis and treatment, especially given its threat to sexuality and reproductive health, can be distressing in the formative period of young adulthood and the majority of young survivors experience impairing, distressing, and modifiable adverse outcomes that can persist long after medical treatment. These include psychological distress, impairment in pursuit of life goals, persistent physical side effects, elevated risk of secondary malignancies and chronic illness, and biobehavioral burden (e.g., enhanced inflammation, dysregulated diurnal stress hormones). However, few targeted interventions exist to assist young survivors in renegotiating life goals and regulating cancer-related emotions, and none focus on reducing the burden of morbidity via biobehavioral mechanisms. This paper describes the methodology of a randomized controlled biobehavioral trial designed to investigate the feasibility and preliminary impact of a novel intervention, Goal-focused Emotion-Regulation Therapy (GET), aimed at improving distress symptoms, emotion regulation, goal navigation skills, and stress-sensitive biomarkers in young adult testicular cancer patients.MethodsParticipants will be randomized to receive six sessions of GET or Individual Supportive Therapy (ISP) delivered over 8 weeks. In addition to indicators of intervention feasibility, we will measure primary (depressive and anxiety symptoms) and secondary (emotion regulation and goal navigation skills, career confusion) psychological outcomes prior to (T0), immediately after (T1), and 12 weeks after (T2) intervention. Additionally, identified biomarkers will be measured at baseline and at T2.DiscussionGET may have the potential to improve self-regulation across biobehavioral domains, improve overall cancer adjustment, and address the need for targeted supportive care interventions for young adult cancer survivors.Trial registrationClinicaltrials.gov, NCT04150848. Registered on 28 October 2019

Exploring Halo Substructure with Giant Stars. XV. Discovery of a Connection between the Monoceros Ring and the Triangulum-Andromeda Overdensity?

Thanks to modern sky surveys, over twenty stellar streams and overdensity structures have been discovered in the halo of the Milky Way. In this paper, we present an analysis of spectroscopic observations of individual stars from one such structure, "A13", first identified as an overdensity using the M giant catalog from the Two Micron All-Sky Survey. Our spectroscopic observations show that stars identified with A13 have a velocity dispersion of $\lesssim$ 40 $\mathrm{km~s^{-1}}$, implying that it is a genuine coherent structure rather than a chance super-position of random halo stars. From its position on the sky, distance ($\sim$15~kpc heliocentric), and kinematical properties, A13 is likely to be an extension of another low Galactic latitude substructure -- the Galactic Anticenter Stellar Structure (also known as the Monoceros Ring) -- towards smaller Galactic longitude and farther distance. Furthermore, the kinematics of A13 also connect it with another structure in the southern Galactic hemisphere -- the Triangulum-Andromeda overdensity. We discuss these three connected structures within the context of a previously proposed scenario that one or all of these features originate from the disk of the Milky Way.Comment: 12 pages, 9 figures. Accepted for publication in Ap

Shell Neurons of the Master Circadian Clock Coordinate the Phase of Tissue Clocks Throughout the Brain and Body

Background: Daily rhythms in mammals are programmed by a master clock in the suprachiasmatic nucleus (SCN). The SCN contains two main compartments (shell and core), but the role of each region in system-level coordination remains ill defined. Herein, we use a functional assay to investigate how downstream tissues interpret region-specific outputs by using in vivo exposure to long day photoperiods to temporally dissociate the SCN. We then analyze resulting changes in the rhythms of clocks located throughout the brain and body to examine whether they maintain phase synchrony with the SCN shell or core. Results: Nearly all of the 17 tissues examined in the brain and body maintain phase synchrony with the SCN shell, but not the SCN core, which indicates that downstream oscillators are set by cues controlled specifically by the SCN shell. Interestingly, we also found that SCN dissociation diminished the amplitude of rhythms in core clock gene and protein expression in brain tissues by 50–75 %, which suggests that light-driven changes in the functional organization of the SCN markedly influence the strength of rhythms in downstream tissues. Conclusions: Overall, our results reveal that body clocks receive time-of-day cues specifically from the SCN shell, which may be an adaptive design principle that serves to maintain system-level phase relationships in a changing environment. Further, we demonstrate that lighting conditions alter the amplitude of the molecular clock in downstream tissues, which uncovers a new form of plasticity that may contribute to seasonal changes in physiology and behavior

Near-infrared H2 and continuum survey of extended green objects. II. Complete census for the northern Galactic plane

We discuss 94 Extended Green Objects (EGOs) in the northern Galactic plane cataloged by Cyganowski et al., based on near-infrared narrow H2 (2.122 μm) and continuum observations from the United Kingdom Infrared Telescope. This data set is three times larger than the one in our previous study and is unbiased by preselection. As discussed in the previous paper, the morphologies of the 4.5 μm emission generally resemble those of the near-infrared continuum, but are different from those of the H2 emission. Of our sample, only 28% of EGOs with H2 emission show similar morphologies between 4.5 μm and H2 emission. These results suggest that the 4.5 μm emission mainly comes from scattered continuum from the embedded young stellar objects, and partially from H2 emission. About half of EGOs are associated with H2 outflows, if the H 2 outflow incompleteness is considered. The H2 outflow detection rate for EGOs with K-band detections (61%) is significantly higher than for those without K-band detections (36%). This difference may be due to the fact that both H2 and K-band emissions are associated with outflows, i.e., H2 emission and K-band continuum are associated with shocks and outflow cavities, respectively. We also compared the correlation between the H2 outflows and Class I 44 GHz methanol masers from the literature. The methanol masers can be located upstream or downstream of the H2 outflows and some bright H2 spots or outflows are not associated with methanol masers, suggesting that methanol masers and H 2 emission trace different excitation conditions. © 2013. The American Astronomical Society. All rights reserved.

Genome maps across 26 human populations reveal population-specific patterns of structural variation.

Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one can identify large SVs (>2 kb) across the genome in one experiment. Analyzing optical genome maps of 154 individuals from the 26 populations sequenced in the 1000 Genomes Project, we find that phylogenetic population patterns of large SVs are similar to those of single nucleotide variations in 86% of the human genome, while ~2% of the genome has high structural complexity. We are able to characterize SVs in many intractable regions of the genome, including segmental duplications and subtelomeric, pericentromeric, and acrocentric areas. In addition, we discover ~60 Mb of non-redundant genome content missing in the reference genome sequence assembly. Our results highlight the need for a comprehensive set of alternate haplotypes from different populations to represent SV patterns in the genome