First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B.

Zinc-finger nuclease (ZFN)-based in vivo genome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivo editing therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events.

Approaches toward Atropisomerically Stable and Conformationally Pure Diarylamines.

Diarylamines possess two potentially atropisomeric C-N axes; however, there are few examples of atropisomerically stable diarylamines in the literature, as the contiguous axes can allow for low energy racemization pathways via concerted bond rotations. Herein, we describe highly atropisomerically stable diarylamines that possess barriers to racemization of 30-36 kcal/mol, corresponding to half-lives to racemization on the decade to century time scale at room temperature. Investigation of the factors that led to the high stereochemical stability suggests that increased conjugation of the aniline lone pair of electrons into a more electron-deficient aryl ring, coupled with intramolecular hydrogen-bonding, locked the corresponding axis into a defined planar conformation, disfavoring the lower energy racemization pathways.

Characterizing the bacterial consortium ASDF capable of catabolic degradation of fluoranthene and other mono- and poly-aromatic hydrocarbons.

In this study, a bacterial consortium ASDF was developed, capable of degrading fluoranthene (a non-alternant poly-aromatic hydrocarbon). It comprised of three bacterial strains: sp. ASDF1, sp.

Catalyst-Controlled Regioselective Chlorination of Phenols and Anilines through a Lewis Basic Selenoether Catalyst.

We report a highly efficient ortho-selective electrophilic chlorination of phenols utilizing a Lewis basic selenoether catalyst. The selenoether catalyst resulted in comparable selectivities to our previously reported bis-thiourea ortho-selective catalyst, with a catalyst loading as low as 1%. The new catalytic system also allowed us to extend this chemistry to obtain excellent ortho-selectivities for unprotected anilines.

Catalytic Atroposelective Synthesis of -Aryl Quinoid Compounds.

Diarylamines and related scaffolds are among the most common chemotypes in modern drug discovery. While they can potentially possess two chiral axes, there are no studies on their enantioselective synthesis, as these axes typically possess lower stereochemical stabilities. Herein, we report a chiral phosphoric acid catalyzed atroposelective electrophilic halogenation of -aryl quinoids, a class of compounds that are analogous to diarylamines.

Degradation of Chrysene by Enriched Bacterial Consortium.

Chrysene is a high molecular weight (HMW), polycyclic aromatic hydrocarbon (PAH) known for its recalcitrance and carcinogenic properties and sparsely soluble (0.003 mg/L) in aqueous medium. Due to these refractory properties, bioavailability of chrysene is very low and therefore is persistence in the environment escaping the metabolism by microorganisms.

Metabolism of pyrene through phthalic acid pathway by enriched bacterial consortium composed of Pseudomonas, Burkholderia, and Rhodococcus (PBR).

Polycyclic aromatic hydrocarbons (PAHs) are highly recalcitrant compounds due to their high hydrophobicity and tendency to partition in organic phase of soils. Pyrene is a high-molecular weight PAH, which has human health concerns. In the present study, a bacterial consortium, PBR, was developed from a long-term polluted site, viz.

A Biomimetic Synthesis of Phaitanthrin E Involving a Fragmentation of sp(3) Carbon-Carbon Bond: Synthesis and Rearrangement of Phaitanthrin D to Phaitanthrin E.

A biogenetic type total synthesis of alkaloids phaitanthrin D and phaitanthrin E has been described. The Csp(3)-Csp(3) bond cleavage with the release of several heteroatoms bearing unexpected leaving groups in intramolecular substitution reactions on an iminium double bond in the quinazolinones has been demonstrated using HMDS/ZnCl2 or NaHMDS. The mechanistic aspects have been supported by isolation and characterization of appropriate intermediates.

Increased frequency and function of KIR2DL1-3⁺ NK cells in primary HIV-1 infection are determined by HLA-C group haplotypes.

The acquisition and maintenance of NK-cell function is mediated by inhibitory killer-cell immunoglobulin-like receptors (KIRs) through their interaction with HLA class I molecules. Recently, HLA-C expression levels were shown to be correlated with protection against multiple outcomes of HIV-1 infection; however, the underlying mechanisms are poorly understood. As HLA-C is the natural ligand for the inhibitory receptors KIR2DL1 and KIR2DL2/3, we sought to determine whether HLA-C group haplotypes affect NK-cell responses during primary HIV-1 infection.

Tumor necrosis factor α is associated with viral control and early disease progression in patients with HIV type 1 infection.

Inflammation in early human immunodeficiency virus type 1 (HIV-1) disease progression is not well characterized. Ninety patients with untreated primary HIV-1 infection were studied to determine associations of inflammatory proteins with early disease progression. High plasma tumor necrosis factor α (TNF-α) levels (≥8.

Temporal effect of HLA-B*57 on viral control during primary HIV-1 infection.

Background: HLA-B alleles are associated with viral control in chronic HIV-1 infection, however, their role in primary HIV-1 disease is unclear. This study sought to determine the role of HLA-B alleles in viral control during the acute phase of HIV-1 infection and establishment of the early viral load set point (VLSP).

Findings: Individuals identified during primary HIV-1 infection were HLA class I typed and followed longitudinally.

Aryne insertion reactions leading to bioactive fused quinazolinones: diastereoselective total synthesis of cruciferane.

Insertion reactions of an in situ generated arynes to a variety of suitably substituted 1,3-quinazolin-4-ones have been demonstrated for a new efficient one-step approach to a diverse range of fused quinazolinone architectures. The present protocol has been effectively utilized to accomplish the concise total synthesis of recently isolated bioactive natural products tryptanthrin, phaitanthrins A-C, and cruciferane.

Estimating the risk of rabies transmission to humans in the U.S.: a Delphi analysis.

Background: In the United States, the risk of rabies transmission to humans in most situations of possible exposure is unknown. Controlled studies on rabies are clearly not possible. Thus, the limited data on risk has led to the frequent administration of rabies post-exposure prophylaxis (PEP), often in inappropriate circumstances.

Cost effectiveness of rabies post exposure prophylaxis in the United States.

There is growing concern in the United States about the excessive use of rabies post exposure prophylaxis (PEP) treatment. In this paper we have estimated the cost effectiveness of rabies PEP treatment under various scenarios of rabies transmission. When the risk of a patient getting rabies is deemed greater than 0.

Human rabies prevention--United States, 2008: recommendations of the Advisory Committee on Immunization Practices.

These recommendations of the Advisory Committee on Immunization Practices (ACIP) update the previous recommendations on human rabies prevention (CDC. Human rabies prevention--United States, 1999: recommendations of the Advisory Committee on Immunization Practices. MMWR 1999;48 [No.

In vitro activity of 11 antibiotics against 74 anaerobes isolated from pediatric intra-abdominal infections.

The in vitro activity of 11 antimicrobials was tested against 74 recent anaerobic isolates obtained from pretreatment cultures in pediatric patients with complicated intra-abdominal infections using the CLSI M11-A-6 agar dilution method. Carbapenems, beta-lactamase inhibitor combinations and metronidazole retained good activity, while all Bacteroides fragilis group species produced beta-lactamase and were penicillin resistant and 43% were either intermediately susceptible or resistant to clindamycin. Cefoxitin had moderate activity against B.

Pelvic abscess due to Ochrobactrum intermedium [corrected] in an immunocompetent host: case report and review of the literature.

Ochrobactrum intermedium [corrected] infection is rare in humans and is generally associated with immunocompromised hosts with indwelling foreign bodies. We report a case of pelvic abscess with O. intermedium [corrected] after a routine appendectomy in an immunocompetent patient and review the literature on O.

Immune activation of type I IFNs by Listeria monocytogenes occurs independently of TLR4, TLR2, and receptor interacting protein 2 but involves TNFR-associated NF kappa B kinase-binding kinase 1.

Type I IFNs are well established antiviral cytokines that have also been shown to be induced by bacteria. However, the signaling mechanisms regulating the activation of these cytokines during bacterial infections remain poorly defined. We show that although Gram-negative bacteria can activate the type I IFN pathway through TLR4, the intracellular Gram-positive bacterium Listeria monocytogenes (LM) can do so independently of TLR4 and TLR2.

Type I interferon production enhances susceptibility to Listeria monocytogenes infection.

Numerous bacterial products such as lipopolysaccharide potently induce type I interferons (IFNs); however, the contribution of this innate response to host defense against bacterial infection remains unclear. Although mice deficient in either IFN regulatory factor (IRF)3 or the type I IFN receptor (IFNAR)1 are highly susceptible to viral infection, we show that these mice exhibit a profound resistance to infection caused by the Gram-positive intracellular bacterium Listeria monocytogenes compared with wild-type controls. Furthermore, this enhanced bacterial clearance is accompanied by a block in L.

Toll-like receptors induce a phagocytic gene program through p38.

Toll-like receptor (TLR) signaling and phagocytosis are hallmarks of macrophage-mediated innate immune responses to bacterial infection. However, the relationship between these two processes is not well established. Our data indicate that TLR ligands specifically promote bacterial phagocytosis, in both murine and human cells, through induction of a phagocytic gene program.

Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism.

The liver X receptors (LXR) alpha and beta are regulators of cholesterol metabolism and determinants of atherosclerosis susceptibility. Viral and bacterial pathogens have long been suspected to be modulators of atherogenesis; however, mechanisms linking innate immunity to cholesterol metabolism are poorly defined. We demonstrate here that pathogens interfere with macrophage cholesterol metabolism through inhibition of the LXR signaling pathway.

Toll-like receptors and innate antiviral responses.

Toll-like receptors (TLRs) have a unique and important role in detecting the presence of pathogenic infection. TLRs can recognize conserved structures from a wide variety of microorganisms, such as bacteria, mycobacteria, spirochetes and yeast. However, they are generally not thought to play a major role in viral infection.

Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4.

We have recently described an IFN regulatory factor 3-mediated antiviral gene program that is induced by both Toll-like receptor (TLR)3 and TLR4 ligands. In our current study, we show that activation of IFN/viral response gene expression in primary macrophage cells is stronger and prolonged with TLR3 stimulation compared with that of TLR4. Our data also reveal that the cytoplasmic tails of both TLR3 and TLR4 can directly interact with myeloid differentiation factor 88 (MyD88).

IRF3 mediates a TLR3/TLR4-specific antiviral gene program.

We have identified a subset of genes that is specifically induced by stimulation of TLR3 or TLR4 but not by TLR2 or TLR9. Further gene expression analyses established that upregulation of several primary response genes was dependent on NF-kappaB, commonly activated by several TLRs, and interferon regulatory factor 3 (IRF3), which was found to confer TLR3/TLR4 specificity. Also identified was a group of secondary response genes which are part of an autocrine/paracrine loop activated by the primary response gene product, interferon beta (IFNbeta).