Legislative Note: Micigan\u27s Criminal Sexual Assault Law

Under increasing pressure from women\u27s rights groups and other reform organizations, the Michigan legislature has re-evaluated its centenarian rape statute, found it inadequate for the realities of the mid-twentieth century, and enacted a new sexual assault act. While people may refer to the act as the new rape law, it should be noted at the outset that the statute is intended to prohibit a variety of sexual acts which involve criminal assault. Michigan\u27s new criminal sexual assault law was formulated to distinguish among degrees of violence as motivated by hostility rather than passion; rape, like other crimes, is more heinous in certain contexts than others. The new law acknowledges that criminal sexual conduct is generally a premeditated crime of violence rather than a crime provoked by the victim\u27s behavior. The victim is no longer required to resist. Where force is used, it is now presumed that the victim did not consent. Similarly, evidence is limited to that which applies to the specific crime rather than evidence concerning the victim\u27s past sexual behavior. This note will analyze the specific provisions of the new bill and discuss the policies behind the evidentiary changes

Asymmetric organocatalytic synthesis of cyclopentane γ-nitroketones

This paper describes the use of bifunctional thiourea catalysts in the intramolecular reaction of a nitronate with conjugated ketones to generate the corresponding γ-nitroketones. In contrast to our previous studies in this area, we obtained the cis-functionalized systems as the major diastereoisomers in good yields and reasonable selectivities

Asymmetric cyclopropanation of conjugated cyanosulfones using a novel cupreine organocatalyst: rapid access to d3-amino acids

An organocatalytic asymmetric synthesis of a novel, highly functionalised cyclopropane system furnished with versatile substituents and containing a quaternary centre is described. The process utilises a new bifunctional catalyst based on the cinchona alkaloid framework and the products made using this catalyst were obtained as single diastereoisomers, with very high enantioselectivities (up to 96% ee). We have also demonstrated that these resulting cyclopropanes are very useful synthetic intermediates to interesting products, such as the difficult to access d3-amino acids

High potency of lipid conjugated TLR7 agonist requires nanoparticulate or liposomal formulation

Conjugation of small molecule agonists of Toll-like receptor 7 (TLR7) to proteins, lipids, or polymers is known to modulate potency, and the physical form or formulation of these conjugates is likely to have a major effect on their immunostimulatory activity. Here, we studied the effect of formulation on potency of a 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine (DOPE) conjugated TLR7 agonist (DOPE-TLR7a) alongside assessing physical form using Dynamic Light Scattering (DLS), Nanosight Particle Tracking (NTA) analysis and Small Angle X-ray Scattering (SAXS). A very high potency of DOPE-TLR7a conjugate (EC50 around 9 nM) was observed either when prepared by direct dilution from DMSO or when formulated into 400-700 nm large multilamella liposomes containing dimethyldioctadecylammonium bromide salt (DDA) and DOPE. When prepared by dissolution in DMSO followed by dilution in aqueous culture medium, 93 ± 5 nm nanoparticles were formed. Without dilution from solution in DMSO, no nanoparticles were observed, and no immunostimulatory activity could be detected without this formulation step. SAXS analysis of the conjugate after DMSO dissolution/water dilution revealed a lamellar order with a layer spacing of 68.7 Å, which correlates with arrangement in groups of 3 bilayers. The addition of another immunostimulatory glycolipid, trehalose-6,6-dibehenate (TDB), to DOPE:DDA liposomes gave no further increase in immunostimulatory activity beyond that provided by incorporating DOPE-TLR7a. Given the importance of nanoparticle or liposomal formulation for activity, we conclude a major mechanism for increase in potency when TLR7 agonists are conjugated to macromolecules is through alteration of physical form

Synthesis and antiviral properties of spirocyclic [1,2,3]-triazolooxazine nucleosides

An efficient synthesis of spirocyclic triazolooxazine nucleosides is described. This was achieved by the conversion of β-D-psicofuranose to the corresponding azido-derivative, followed by alkylation of the primary alcohol with a range of propargyl bromides - obtained via Sonogashira chemistry. The products of these reactions underwent 1,3-dipolar addition smoothly to generate the protected spirocyclic adducts. These were easily deprotected to give the corresponding ribose nucleosides. The library of compounds obtained was investigated for its antiviral activity, using MHV (Mouse Hepatitis Virus) as a model wherein derivative 3f showed the most promising activity and tolerability

Synthesis of an intriguing steroidal constitutional isomer

We recently described the synthesis of an unusual tricyclic system, whereby a cis-decalin was fused to a cis-hydrindane. Herein, we wish to describe the elaboration of this system towards steroid-like frameworks. This report describes how, en route to an attempted cardiotonic steroid synthesis, we stereoselectively functionalized the leftmost cyclohexyl ring with an ester ready for steroidal A-ring formation. Ultimately however, the required transposition of the cyclohexylketone did not occur as expected and resulted in the subsequent Robinson annulation forming an unusual steroidal constitutional isomer – the saturated cyclopenta[c]phenanthrene. Remarkably, such unusual tetracyclic connectivity has been reported just once in 70 years

Synthesis and antiviral activity of novel spirocyclic nucleosides

The synthesis of a number of spirocyclic ribonucleosides containing either a triazolic or azetidinic system is described, along with two analogous phosphonate derivatives of the former. These systems were constructed from the same β-D-psicofuranose starting material. The triazole spirocyclic nucleosides were constructed using the 1-azido-1-hydroxymethyl derived sugars, where the primary alcohol was alkylated with a range of propargyl bromides, whereas the azetidine systems orginated from the corresponding 1-cyano-1-hydroxymethyl sugars. Owing to their close similarity with ribavirin, the library of compounds were investigated for their antiviral properties using MHV (Murine Hepatitis Virus) as a model

Enantioselective organocatalytic synthesis of bicyclic resorcinols via an intramolecular Friedel-Crafts-type 1,4-addition: access to cannabidiol analogues

The organocatalytic transformation of resorcinols is extremely rare. In this article, we report a highly enantioselective, organocatalytic intramolecular cyclization of these systems by a Friedel–Crafts-type 1,4-addition using a Jørgensen-Hayashi-like organocatalyst with a large silyl protecting group, and show that heat improves reaction yield with virtually no detriment to enantioselectivity. A variety of bicyclic resorcinols were obtained with excellent enantioselectivities (up to 94%). To show the utility of these constructs, and as part of a wider project involving the synthesis of cannabinoid-like compounds, the resorcinol formed was used to generate both ‘normal’ and ‘abnormal’ cannabidiol (CBD) derivatives which were shown to have anticonvulsant activity

Kenneth Lewis Roberts Correspondence

Entries include brief biographical information, a typed biography, typed and handwritten correspondence on personal stationery from Kennebunk Beach, Maine, including a humorous letter in 1933 concerning the Society for Helping Maine Literature, his belief that the author collection was in need of Arnoldiana such as a donated pike head handmade by Arnold\u27s blacksmiths for the attack on Quebec, the manuscript of Arundel sent to be opened after publication and loaned to Leonard for Doubleday Doran and Company and a surprising Western Union telegram requesting permanent loan of the manuscript for MIT, handwritten and typed correspondence from Roberts in Italy including a handwritten artistic postcard from his wife, numerous biographical newspaper review clippings with photographic images, book synopses, and a poem for Theodore Roosevelt who could remember neither the author nor title of the book he was reading, a research question concerning Maine people on cookery, notes through the years concerning his friends, the staff at Doubleday, historians, libraries, and librarians as well as transition at the Maine Development Commission, correspondence with Mary A. Benjamin on Walter R. Benjamin, Autographs, stationery and a postcard concerning the possible sale of a copy of a Maine land grant document, a gift instead from Roberts of his vellum copy of the Trelawny-Goodyear grant of 1631, and the reply of Stubbs from the Maine State Library on receipt of this copy of the Casco Bay land grant

A GWAS Study on Liver Function Test Using eMERGE Network Participants

Introduction: Liver enzyme levels and total serum bilirubin are under genetic control and in recent years genome-wide population-based association studies have identified different susceptibility loci for these traits. We conducted a genome-wide association study in European ancestry participants from the Electronic Medical Records and Genomics (eMERGE) Network dataset of patient medical records with available genotyping data in order to identify genetic contributors to variability in serum bilirubin levels and other liver function tests and to compare the effects between adult and pediatric populations. Methods: The process of whole genome imputation of eMERGE samples with standard quality control measures have been described previously. After removing missing data and outliers based on principal components (PC) analyses, 3294 samples from European ancestry were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and total serum bilirubin and other liver function tests was tested using linear regression, adjusting for age, gender, site, platform and ancestry principal components (PC). Results: Consistent with previous results, a strong association signal has been detected for UGT1A gene cluster (best SNP rs887829, beta = 0.15, p = 1.30x10-118) for total serum bilirubin level. Indeed, in this region more than 176 SNPs (or indels) had p<10−8 spanning 150Kb on the long arm of chromosome 2q37.1. In addition, we found a similar level of magnitude in a pediatric group (p = 8.26x10-47, beta = 0.17). Further imputation using sequencing data as a reference panel revealed association of other markers including known TA7 repeat indels (rs8175347) (p = 9.78x10-117) and rs111741722 (p = 5.41x10-119) which were in proxy (r2 = 0.99) with rs887829. Among rare variants, two Asian subjects homozygous for coding SNP rs4148323 (G71R) were identified. Additional known effects for total serum bilirubin were also confirmed including organic anion transporters SLCO1B1-SLCO1B3, TDRP and ZMYND8 at FDR<0.05 with no gene-gene interaction effects. Phenome-wide association studies (PheWAS) suggest a protective effect of TA7 repeat against cerebrovascular disease in an adult cohort (OR = 0.75, p = 0.0008). Among other liver function tests, we also confirmed the previous effect of the ABO blood group locus for variation in serum alkaline phosphatase (rs579459, p = 9.44x10-15). Conclusions: Taken together, our data present interesting findings with strong confirmation of previous effects by simply using the eMERGE electronic health record phenotyping. In addition, our findings indicate that similar to the adult population, the UGT1A1 is the main locus responsible for normal variation of serum bilirubin in pediatric populations