ENU mutagenesis in mice identifies candidate genes for hypogonadism.

Genome-wide mutagenesis was performed in mice to identify candidate genes for male infertility, for which the predominant causes remain idiopathic. Mice were mutagenized using N-ethyl-N-nitrosourea (ENU), bred, and screened for phenotypes associated with the male urogenital system. Fifteen heritable lines were isolated and chromosomal loci were assigned using low-density genome-wide SNP arrays.

3-[4-(10H-Indolo[3,2-b]quinolin-11-yl)piperazin-1-yl]propan-1-ol.

In the title compound, C(22)H(24)N(4)O, the aromatic moiety is essentially planar (r.m.s.

Plasticity of serotonergic innervation of the inferior colliculus in mice following acoustic trauma.

Acoustic trauma often results in permanent damage to the cochlea, triggering changes in processing within central auditory structures such as the inferior colliculus (IC). The serotonergic neuromodulatory system, present in the IC, is responsive to chronic changes in the activity of sensory systems. The current study investigated whether the density of serotonergic innervation in the IC is changed following acoustic trauma.

Timing of adolescent meningococcal conjugate vaccination attitudes and practices of pediatricians and family medicine physicians.

Background: The meningococcal conjugate vaccine (MCV4) was recommended for those aged 11-18 years in 2005. Initial supply issues led to an emphasis on immunizing older adolescents. When supply improved in 2007, routine immunization was recommended for those aged 11-12 years.

The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer.

Background: HER2/neu is an oncogene that facilitates neoplastic transformation due to its ability to transduce growth signals in a ligand-independent manner, is over-expressed in 20-30% of human breast cancers correlating with aggressive disease and has been successfully targeted with trastuzumab (Herceptin®). Because trastuzumab alone achieves only a 15-30% response rate, it is now commonly combined with conventional chemotherapeutic drugs. While the combination of trastuzumab plus chemotherapy has greatly improved response rates and increased survival, these conventional chemotherapy drugs are frequently associated with gastrointestinal and cardiac toxicity, bone marrow and immune suppression.

Effects of captivity and body condition on plasma corticosterone, locomotor behavior, and plasma metabolites in curve-billed thrashers.

The acute stress response involves the secretion of catabolic glucocorticoids, such as corticosterone (CORT) in birds, that mobilize intrinsic energy stores primarily through a gluconeogenic pathway involving fat breakdown, thus linking body condition and stress. We measured changes in CORT and gluconeogenic metabolites (triglycerides, free glycerols, glucose) during handling stress in curve-billed thrashers Toxostoma curvirostre from two habitats (urban vs. desert) that may differ in food abundance in the wild, in captivity, and in response to both food restriction and subsequent recovery.

Adherence to expanded influenza immunization recommendations among primary care providers.

Objective: To assess practices regarding the expanded Advisory Committee on Immunization Practices (ACIP) recommendations for influenza vaccination in children among US pediatricians and family medicine physicians (FMs) and strategies to promote vaccination.

Study Design: We administered a survey between July and October 2009 to 416 pediatricians and 424 FMs from nationally representative networks.

Results: The response rate was 75% (79% pediatricians, 70% FMs).

Solution structure of a 2:1 quindoline-c-MYC G-quadruplex: insights into G-quadruplex-interactive small molecule drug design.

Unimolecular parallel-stranded G-quadruplex structures are found to be prevalent in gene promoters. The nuclease hypersensitivity element III(1) (NHE III(1)) of the c-MYC promoter can form transcriptionally active and silenced forms, and the formation of DNA G-quadruplex structures has been shown to be critical for c-MYC transcriptional silencing. The solution structure of a 2:1 quindoline-G-quadruplex complex has been solved and shows unexpected features, including the drug-induced reorientation of the flanking sequences to form a new binding pocket.

Demonstration that drug-targeted down-regulation of MYC in non-Hodgkins lymphoma is directly mediated through the promoter G-quadruplex.

Most transcription of the MYC proto-oncogene initiates in the near upstream promoter, within which lies the nuclease hypersensitive element (NHE) III(1) region containing the CT-element. This dynamic stretch of DNA can form at least three different topologies: single-stranded DNA, double-stranded DNA, or higher order secondary structures that silence transcription. In the current report, we identify the ellipticine analog GQC-05 (NSC338258) as a high affinity, potent, and selective stabilizer of the MYC G-quadruplex (G4).

Seasonal influenza vaccination in adults: practice and attitudes about collaborative delivery with community vaccinators.

Background: Less than half of adults for whom seasonal influenza vaccine is recommended receive the vaccine. Little is known about physician willingness to collaborate with community vaccinators to improve delivery of vaccine.

Objectives: To assess among general internists and family medicine physicians: (1) seasonal influenza vaccination practices, (2) willingness to collaborate with community vaccinators, (3) barriers to collaboration, and (4) characteristics associated with unwillingness to refer patients to community sites for vaccination.

Positive and negative effects of alcohol and nicotine and their interactions: a mechanistic review.

Nicotine and alcohol are two of the most commonly abused legal substances. Heavy use of one drug can often lead to, or is predictive of, heavy use of the other drug in adolescents and adults. Heavy drinking and smoking alone are of significant health hazard.

Stress-evoked increases in serotonin in the auditory midbrain do not directly result from elevations in serum corticosterone.

Neurochemicals such as serotonin convey information about behavioral context to sensory processing. In the auditory system, serotonin modulates the responses of neurons in the inferior colliculus (IC) to acoustic stimuli, including communication vocalizations. Levels of extracellular serotonin in the IC can change rapidly in response to stressful situations such as social challenge and limited movement.

Social regulation of serotonin in the auditory midbrain.

The neuromodulator serotonin regulates auditory processing and can increase within minutes in response to stimuli like broadband noise as well as nonauditory stressors. Little is known about the serotonergic response in the auditory system to more natural stimuli such as social interactions. Using carbon-fiber voltammetry, we measured extracellular serotonin in the auditory midbrain of resident male mice during encounters with a male intruder.

Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?

G-quadruplexes are four-stranded DNA structures that are over-represented in gene promoter regions and are viewed as emerging therapeutic targets in oncology, as transcriptional repression of oncogenes through stabilization of these structures could be a novel anticancer strategy. Many gene promoter G-quadruplexes have physicochemical properties and structural characteristics that might make them druggable, and their structural diversity suggests that a high degree of selectivity might be possible. Here, we describe the evidence for G-quadruplexes in gene promoters and discuss their potential as therapeutic targets, as well as progress in the development of strategies to harness this potential through intervention with small-molecule ligands.

DNA acting like RNA.

Over the last decade or so, secondary non-B-DNA structures such as G-quadruplexes and i-motifs have come into focus as biologically functioning moieties that are potentially involved in telomeric interactions and the control of gene expression. In the present short review, we first describe the structural and dynamic parallels with complex RNA structures, including the importance of sequence and ions in folding, and then we describe the biological consequences of the folded structures. We conclude that there are considerable parallels between secondary and tertiary structures in RNA and DNA from both the folding and the biological perspectives.

HIV quality performance measures in a large integrated health care system.

HIV quality performance measurements are critical to evaluating a care program's success in areas of testing, access to and retention in care, care processes and outcomes. Kaiser Permanente (KP) provides care to over 8 million Americans and over 19,000 HIV-infected adults. We undertook a quality performance measurement program to assess the care and outcomes for our HIV-positive patient population.

Context-dependent modulation of auditory processing by serotonin.

Context-dependent plasticity in auditory processing is achieved in part by physiological mechanisms that link behavioral state to neural responses to sound. The neuromodulator serotonin has many characteristics suitable for such a role. Serotonergic neurons are extrinsic to the auditory system but send projections to most auditory regions.

Targeting MYC Expression through G-Quadruplexes.

In this review, the authors describe a novel mechanism for control of MYC expression that involves a four-stranded DNA structure, termed a G-quadruplex, amenable to small molecule targeting. The DNA element involved in this mechanism, the nuclease hypersensitive element III(1) (NHE III(1)), is just upstream of the P1 promoter and is subjected to dynamic stress (negative superhelicity) resulting from transcription. This is sufficient to convert the duplex DNA to a G-quadruplex on the purine-rich strand and an i-motif of the pyrimidine-rich strand, which displaces the activating transcription factors to silence gene expression.

A missense mutation in LRR8 of RXFP2 is associated with cryptorchidism.

Using genome-wide mutagenesis with N-ethyl-N-nitrosourea (ENU), a mouse mutant with cryptorchidism was identified. Genome mapping and exon sequencing identified a novel missense mutation (D294G) in Relaxin/insulin-like family peptide receptor 2 (Rxfp2). The mutation impaired testicular descent and resulted in decreased testis weight in Rxfp2 ( DG/DG ) mice compared to Rxfp2 (+/DG ) and Rxfp2 (+/+) mice.

The C-terminus of nucleolin promotes the formation of the c-MYC G-quadruplex and inhibits c-MYC promoter activity.

Nucleolin, the most abundant nucleolar phosphoprotein of eukaryotic cells, is known primarily for its role in ribosome biogenesis and cell proliferation. It is, however, a multifunctional protein that, depending on the cellular context, can drive either cell proliferation or apoptosis. Our laboratory recently demonstrated that nucleolin can function as a repressor of c-MYC transcription by binding to and stabilizing the formation of a G-quadruplex structure in a region of the c-MYC promoter responsible for controlling 85-90% of c-MYC's transcriptional activity.

Acute stress rapidly decreases plasma testosterone in a free-ranging male songbird: potential site of action and mechanism.

We used a free-ranging, seasonally breeding adult male songbird, the rufous-winged sparrow, Aimophila carpalis, to investigate the effects of acute stress-induced by capture followed by restraint, on the hypothalamo-pituitary-testicular axis. Intra- and interindividual comparisons revealed that males decreased their plasma testosterone (T) by 37-52% in response to acute stress. The decrease occurred within 15 min of capture and persisted for at least another 15 min.

Making sense of G-quadruplex and i-motif functions in oncogene promoters.

The presence and biological importance of DNA secondary structures in eukaryotic promoters are becoming increasingly recognized among chemists and biologists as bioinformatics in vitro and in vivo evidence for these structures in the c-Myc, c-Kit, KRAS, PDGF-A, hTERT, Rb, RET and Hif-1alpha promoters accumulates. Nevertheless, the evidence remains largely circumstantial. This minireview differs from previous ones in that here we examine the diversity of G-quadruplex and i-motif structures in promoter elements and attempt to categorize the different types of arrangements in which they are found.

I-motif structures formed in the human c-MYC promoter are highly dynamic--insights into sequence redundancy and I-motif stability.

The GC-rich nuclease hypersensitivity element III1 (NHE III1) of the c-MYC promoter largely controls the transcriptional activity of the c-MYC oncogene. The C-rich strand in this region can form I-motif DNA secondary structures. We determined the folding pattern of the major I-motif formed in the NHE III1, which can be formed at near-neutral pH.

5-HT1A and 5-HT1B receptors differentially modulate rate and timing of auditory responses in the mouse inferior colliculus.

Serotonin (5-hydroxytryptamine; 5-HT) is a physiological signal that translates both internal and external information about behavioral context into changes in sensory processing through a diverse array of receptors. The details of this process, particularly how receptors interact to shape sensory encoding, are poorly understood. In the inferior colliculus, a midbrain auditory nucleus, 5-HT1A receptors have suppressive and 5-HT1B receptors have facilitatory effects on evoked responses of neurons.

The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: a structural analysis of the binding interactions of Gleevec, Nexavar, and BIRB-796.

The majority of kinase inhibitors developed to date are competitive inhibitors that target the ATP binding site; however, recent crystal structures of Gleevec (imatinib mesylate, STI571, PDB: 1IEP), Nexavar (Sorafenib tosylate, BAY 43-9006, PDB: 1UWJ), and BIRB-796 (PDB: 1KV2) have revealed a secondary binding site adjacent to the ATP binding site known as the DFG-out allosteric binding site. The recent successes of Gleevec and Nexavar for the treatment of chronic myeloid leukemia and renal cell carcinoma has generated great interest in the development of other kinase inhibitors that target this secondary binding site. Here, we present a structural comparison of the important and similar interactions necessary for Gleevec(R), Nexavar, and BIRB-796 to bind to their respective DFG-out allosteric binding pockets and the selectivity of each with respect to c-Abl, B-Raf, and p38alpha.