Evaluation of omadacycline against intracellular in an infection model in human macrophages.

Background: Omadacycline is an aminomethylcycline antibiotic in the tetracycline class that was approved by the US FDA in 2018 for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It is available in both IV and oral formulations. Omadacycline has broad-spectrum activity and clinical efficacy against infections caused by Gram-positive and Gram-negative pathogens.

Evaluation of Dilution Susceptibility Testing Methods for Aztreonam in Combination with Avibactam against Enterobacterales.

As multidrug and pan-resistance among Enterobacterales continue to increase, there is an urgent need for more therapeutic options to treat these infections. New β-lactam and β-lactam inhibitor (BLI) combinations have a broad spectrum of activity, but those currently approved do not provide coverage against isolates harboring metallo-β-lactamases (MBL). Aztreonam (ATM) and avibactam (AVI) in combination (ATM/AVI; AVI at 4 μg/mL fixed concentration) provides a similarly broad range of activity while maintaining activity against MBL-producing isolates.

1,3-Dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Expanding Structural Diversity and the Antibacterial Spectrum.

Antibacterial resistance continues its devastation of available therapies. Novel bacterial topoisomerase inhibitors (NBTIs) offer one solution to this critical issue. Two series of amine NBTIs bearing tricyclic DNA-binding moieties as well as amide NBTIs with a bicyclic DNA-binding moiety were synthesized and evaluated against methicillin-resistant (MRSA).

Potent LpxC Inhibitors with Activity against Multidrug-Resistant Pseudomonas aeruginosa.

New drugs with novel mechanisms of resistance are desperately needed to address both community and nosocomial infections due to Gram-negative bacteria. One such potential target is LpxC, an essential enzyme that catalyzes the first committed step of lipid A biosynthesis. Achaogen conducted an extensive research campaign to discover novel LpxC inhibitors with activity against We report here the antibacterial activity and pharmacodynamics of ACHN-975, the only molecule from these efforts and the first ever LpxC inhibitor to be evaluated in phase 1 clinical trials.

Context dependent roles for RB-E2F transcriptional regulation in tumor suppression.

RB-E2F transcriptional control plays a key role in regulating the timing of cell cycle progression from G1 to S-phase in response to growth factor stimulation. Despite this role, it is genetically dispensable for cell cycle exit in primary fibroblasts in response to growth arrest signals. Mice engineered to be defective for RB-E2F transcriptional control at cell cycle genes were also found to live a full lifespan with no susceptibility to cancer.

Activity of plazomicin in combination with other antibiotics against multidrug-resistant Enterobacteriaceae.

Plazomicin is a next-generation aminoglycoside that was approved by the US FDA in June 2018 for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis due to Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Proteus mirabilis. Plazomicin is active against multi-drug resistant (MDR) Enterobacteriaceae, where combination therapy is often used to treat infections caused by these pathogens. To determine synergy with other antibiotics, plazomicin was combined with antibiotics in checkerboard assays against MDR Enterobacteriaceae, including isolates with resistance to aminoglycosides and β-lactams; 10 Escherichia coli isolates, 8 Klebsiella spp.

Evaluation of the Bactericidal Activity of Plazomicin and Comparators against Multidrug-Resistant Enterobacteriaceae.

The next-generation aminoglycoside plazomicin, in development for infections due to multidrug-resistant (MDR) , was evaluated alongside comparators for bactericidal activity in minimum bactericidal concentration (MBC) and time-kill (TK) assays against MDR isolates with characterized aminoglycoside and β-lactam resistance mechanisms. Overall, plazomicin and colistin were the most potent, with plazomicin demonstrating an MBC of 0.5/4 μg/ml and sustained 3-log kill against MDR , , and spp.

In vitro potency and fungicidal activity of CD101, a novel echinocandin, against recent clinical isolates of Candida spp.

Candida infections vary in severity and manifestation. Common infections include invasive bloodstream infections among hospitalized/immunocompromised patients and vulvovaginal candidiasis among women. Echinocandins and azoles are commonly utilized to treat Candida infections, although echinocandin use has been restricted to indications amenable to once-daily IV administration.

Multiple molecular interactions redundantly contribute to RB-mediated cell cycle control.

Background: The G1-S phase transition is critical to maintaining proliferative control and preventing carcinogenesis. The retinoblastoma tumor suppressor is a key regulator of this step in the cell cycle.

Results: Here we use a structure-function approach to evaluate the contributions of multiple protein interaction surfaces on pRB towards cell cycle regulation.

Interchangeable Roles for E2F Transcriptional Repression by the Retinoblastoma Protein and p27KIP1-Cyclin-Dependent Kinase Regulation in Cell Cycle Control and Tumor Suppression.

The mammalian G-S phase transition is controlled by the opposing forces of cyclin-dependent kinases (CDK) and the retinoblastoma protein (pRB). Here, we present evidence for systems-level control of cell cycle arrest by pRB-E2F and p27-CDK regulation. By introducing a point mutant allele of pRB that is defective for E2F repression (Rb1) into a p27 null background (Cdkn1b), both E2F transcriptional repression and CDK regulation are compromised.

Structural Conservation and E2F Binding Specificity within the Retinoblastoma Pocket Protein Family.

The human pocket proteins retinoblastoma (Rb), p107, and p130 are critical negative regulators of the cell cycle and contribute to tumor suppression. While strong structural conservation within the pocket protein family provides for some functional redundancy, important differences have been observed and may underlie the reason that Rb is a uniquely potent tumor suppressor. It has been proposed that distinct pocket protein activities are mediated by their different E2F transcription factor binding partners.

Cell Synchronization of Mouse Embryonic Fibroblasts.

A fundamental need in the analysis of the cell cycle is the ability to isolate relatively homogeneous populations of cells in different phases. This is complicated by the variable proliferative properties and responses to synchronizing methods of different cancer-derived cell lines. Paradoxically, cell lines with genetic defects in cell cycle control are sometimes chosen because they are amenable to chemical synchronization.

Analyzing RB and E2F during the G1-S transition.

The G1/S-phase restriction point is an important landmark in the mammalian cell division cycle. The key regulator of the G1/S transition is the retinoblastoma gene product (pRB). It prevents the transcription of genes required for S-phase progression by repressing E2F transcription factors.

Loss of the mammalian DREAM complex deregulates chondrocyte proliferation.

Mammalian DREAM is a conserved protein complex that functions in cellular quiescence. DREAM contains an E2F, a retinoblastoma (RB)-family protein, and the MuvB core (LIN9, LIN37, LIN52, LIN54, and RBBP4). In mammals, MuvB can alternatively bind to BMYB to form a complex that promotes mitotic gene expression.

A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene-targeted mice.

The retinoblastoma protein (pRB) is best known for regulating cell proliferation through E2F transcription factors. In this report, we investigate the properties of a targeted mutation that disrupts pRB interactions with the transactivation domain of E2Fs. Mice that carry this mutation endogenously (Rb1(ΔG)) are defective for pRB-dependent repression of E2F target genes.

Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia.

Background: Although the induction of behavioural unconsciousness during sleep and general anaesthesia has been shown to involve overlapping brain mechanisms, sleep involves cyclic fluctuations between different brain states known as active (paradoxical or rapid eye movement: REM) and quiet (slow-wave or non-REM: nREM) stages whereas commonly used general anaesthetics induce a unitary slow-wave brain state.

Methodology/principal Findings: Long-duration, multi-site forebrain field recordings were performed in urethane-anaesthetized rats. A spontaneous and rhythmic alternation of brain state between activated and deactivated electroencephalographic (EEG) patterns was observed.

Inflammatory papillary hyperplasia: review of literature and case report involving a 10-year-old child.

Inflammatory papillary hyperplasia is a benign lesion of the palate seen most often in patients with a history of ill-fitting dentures or poor oral hygiene. The specific cause is unknown. Inflammatory papillary hyperplasia can occur at any age.

Complex odontoma: report of case.

This is a case report of a six-year-old boy with a complex odontoma, associated with an unerupted central incisor with a hypoplastic defect in the enamel and a malocclusion. Expedient removal provided an unobstructed path for the eruption of the central incisor.

The psychosocial aspects of adolescent pregnancy: a dental perspective.

This paper presents some of the psychological and social aspects of the adolescent who is pregnant, and how the combination of adolescence and pregnancy affect the dental management of these patients.