A fixed-charge model of the N-protomer of 4-aminobenzoic acid to facilitate the study of the unimolecular and bimolecular chemistry of its "neutral" carboxylic acid group.

RATIONALE: There are a growing number of examples of protomers formed via electrospray ionization (ESI) that do not fragment under mobile proton conditions, giving rise to distinct tandem mass spectra. To model the N-protomer of 4-aminobenzoic acid, here we study the gas-phase unimolecular and bimolecular chemistry of the 4-(carboxyphenyl)trimethylammonium ion. METHODS: 4-(Carboxyphenyl)trimethylammonium iodide was synthesized, purified via recrystallization and transferred to the gas phase via ESI. 4-(Carboxyphenyl)trimethylammonium ion, 7, was mass selected and subjected to collision-induced dissociation and ion-molecule reactions in a linear ion trap mass spectrometer. RESULTS: The major fragmentation channel for the fixed-charge cation 7 is methyl radical loss, whereas loss of trimethylamine and CO2 represents minor pathways. The free carboxylic acid functional group of 7 is unreactive toward a number of neutral reagents (methanol, acetone, acetonitrile, and N,N'-diisopropylcarbodiimide). 7 reacts very slowly with trimethylborate via addition-elimination, consistent with density functional theory (DFT) calculations that show this reaction is slightly endothermic. The deuterated cation 7(D) undergoes slow D/H exchange with ethanol, and DFT calculations reveal that a flip-flop mechanism operates. CONCLUSIONS: The free carboxylic group of 7 is not very reactive toward neutral reagents in the gas phase.

Pelvic Pain in Transgender People Using Testosterone Therapy.

Purpose: This descriptive study aimed to assess the characteristics of pelvic pain and explore predictive factors for pelvic pain in transgender (trans) individuals using testosterone therapy. Methods: An online cross-sectional survey was open between August 28, 2020, and December 31, 2020, to trans people presumed female at birth, using testosterone for gender affirmation, living in Australia, and >16 years of age. The survey explored characteristics of pelvic pain following initiation of testosterone therapy, type and length of testosterone therapy, menstruation history, and relevant sexual, gynecological, and mental health experiences. Logistic regression was applied to estimate the effect size of possible factors contributing to pain after starting testosterone. Results: Among 486 participants (median age = 27 years), 351 (72.2%)* reported experiencing pelvic pain following initiation of testosterone therapy, described most commonly as in the suprapubic region and as "cramping." Median duration of testosterone therapy was 32 months. Persistent menstruation, current or previous history of post-traumatic stress disorder, and experiences of pain with orgasm were associated with higher odds of pelvic pain after testosterone therapy. No association was observed with genital dryness, intrauterine device use, previous pregnancy, penetrative sexual activities, touching external genitalia, or known diagnoses of endometriosis, vulvodynia, vaginismus, depression, anxiety, or obesity. Conclusions: Pelvic pain is frequently reported in trans people following initiation of testosterone therapy. Given the association with persistent menstruation and orgasm, as well as the known androgen sensitivity of the pelvic floor musculature, further research into pelvic floor muscle dysfunction as a contributor is warranted.

Chemistry and biology of the aminosulfonate cysteinolic acid: discovery, distribution, synthesis and metabolism.

D-Cysteinolic acid is a zwitterionic aminosulfonate found in marine (and occasionally freshwater) environments. It is distributed in a wide range of algae (red, green and brown algae and diatoms), and some bacteria and sea animals. It was discovered in 1957 and in spite of its long history, its biosynthesis and degradation is poorly understood. Cysteinolic acid is found conjugated to steroids, lipids and arsenosugars, and the cysteinolic acid motif is found within the structures of various capnoid and sulfoceramide sulfonolipids. This review provides an historical account of the discovery of D-cysteinolic acid and related molecules, its distribution and occurrence within marine and freshwater organisms, routes for its chemical synthesis, and summarizes knowledge and speculations surrounding its biosynthesis, degradation and bioconversions.

Synthesis of the Alkylsulfonate Metabolites Cysteinolic Acid, 3-Amino-2-hydroxypropanesulfonate, and 2,3-Dihydroxypropanesulfonate.

Chiral hydroxy- and aminohydroxysulfonic acids are widespread in the marine and terrestrial environment. Here we report simple methods for the synthesis of d- and l-cysteinolic acid (from (Boc-d-Cys-OH)2 and (Boc-l-Cys-OH)2, respectively), R- and S-3-amino-2-hydroxypropanesulfonate (from S- and R-epichlorohydrin, respectively), and R- and S-2,3-dihydroxypropanesulfonate (from S- and R-epichlorohydrin, respectively). d-Cysteinolate bile salts were generated by coupling with cholic and chenodeoxycholic acids. A series of single-crystal 3D X-ray structures confirmed the absolute configurations of the aminosulfonates. By comparison of optical rotation, we assign naturally occurring 3-amino-2-hydroxypropanesulfonate from Gateloupia livida as possessing the R-configuration. This simple synthetic approach will support future studies of the occurrence, chemotaxonomic distribution, and metabolism of these alkylsulfonates.

From the banal to the bizarre: unravelling immune recognition and response to microbial lipids.

Microbes produce a rich array of lipidic species that through their location in the cell wall and ability to mingle with host lipids represent a privileged class of immune-active molecules. Lipid-sensing immunity recognizes microbial lipids from pathogens and commensals causing immune responses. Yet microbial lipids are often heterogeneous, in limited supply and in some cases their structures are incompletely defined. Total synthesis can assist in structural determination, overcome supply issues, and provide access to high-purity, homogeneous samples and analogues. This account highlights synthetic approaches to lipidic species from pathogenic and commensal bacteria and fungi that have supported immunological studies involving lipid sensing through the pattern recognition receptor Mincle and cell-mediated immunity through the CD1-T cell axis.

Sulfoglycolysis: catabolic pathways for metabolism of sulfoquinovose.

Sulfoquinovose (SQ), a derivative of glucose with a C6-sulfonate, is produced by photosynthetic organisms and is the headgroup of the sulfolipid sulfoquinovosyl diacylglycerol. The degradation of SQ allows recycling of its elemental constituents and is important in the global sulfur and carbon biogeochemical cycles. Degradation of SQ by bacteria is achieved through a range of pathways that fall into two main groups. One group involves scission of the 6-carbon skeleton of SQ into two fragments with metabolic utilization of carbons 1-3 and excretion of carbons 4-6 as dihydroxypropanesulfonate or sulfolactate that is biomineralized to sulfite/sulfate by other members of the microbial community. The other involves the complete metabolism of SQ by desulfonylation involving cleavage of the C-S bond to release sulfite and glucose, the latter of which can enter glycolysis. The discovery of sulfoglycolytic pathways has revealed a wide range of novel enzymes and SQ binding proteins. Biochemical and structural characterization of the proteins and enzymes in these pathways have illuminated how the sulfonate group is recognized by Nature's catalysts, supporting bioinformatic annotation of sulfoglycolytic enzymes, and has identified functional and structural relationships with the pathways of glycolysis.

Biomimetic Total Synthesis of the Rubiginosin Meroterpenoids.

Total synthesis of the Rhododendron meroterpenoids rubiginosins A and G, which both contain unusual 6-6-6-4 ring systems, has been achieved using a bioinspired cascade approach. Stepwise synthesis of these natural products, and the related 6-6-5-4 meroterpenoids fastinoid B and rhodonoid B, from naturally occurring chromene precursors is also reported.

Total Synthesis of Rhodonoids A, B, E, and F, Enabled by Singlet Oxygen Ene Reactions.

Singlet oxygen is a versatile reagent for the selective oxidation of organic compounds under mild reaction conditions. It is frequently invoked in biosynthetic pathways, so it is especially suitable for application in the biomimetic synthesis of natural products. Herein, we show that use of the singlet oxygen ene reaction, combined with [2 + 2] cycloadditions, leads to concise, divergent, and redox-economic total syntheses of several polycyclic members of the rhodonoid family of meroterpenoids.

ortho-Quinone Methide Cyclizations Inspired by the Busseihydroquinone Family of Natural Products.

A series of cascade reactions of o-quinone methides have been developed based on the proposed biosynthesis of busseihydroquinone and parvinaphthol meroterpenoid natural products. The polycyclic framework of the most complex family members, busseihydroquinone E and parvinaphthol C, was assembled by an intramolecular [4 + 2] cycloaddition of an electron-rich chromene substrate. The resultant cyclic enol ether underwent rearrangements under acidic or oxidative conditions, which led to a new total synthesis of rhodonoid D.

Biomimetic Synthesis Enables the Structure Revision of Furoerioaustralasine.

The structure of furoerioaustralasine, a unique Australian alkaloid, has been revised based on a concise, biomimetic synthesis. The key step is a stereospecific, intramolecular ring opening of an epoxide to form a central dihydrofuran fused to a quinoline ring system.

Implementation of a Pelvic Floor Physical Therapy Program for Transgender Women Undergoing Gender-Affirming Vaginoplasty.

OBJECTIVE: To describe the incidence of pelvic floor dysfunction in transgender women undergoing gender-affirming vaginoplasty and outcomes in a program providing pelvic floor physical therapy (PT). METHODS: We conducted a retrospective, single-institution study on vaginoplasty patients between May 1, 2016, and February 28, 2018; all were referred for pelvic floor PT. We reviewed medical records for baseline demographics, medical comorbidities, prior surgeries, insurance data, attendance at pelvic floor PT, and dilation success at 3 and 12 months. RESULTS: Seventy-two of 77 patients (94%) attended pelvic floor PT at least once. Preoperative pelvic floor PT identified a high incidence of potential problems: 42% had pelvic floor dysfunction, 37% had bowel dysfunction. Of those patients found to have dysfunction preoperatively, the rate of resolution by the first postoperative visit of pelvic floor and bowel dysfunction were 69% and 73%, respectively. There were significantly lower rates of pelvic floor dysfunction postoperatively for those patients who attended pelvic floor PT both preoperatively and postoperatively compared with only postoperatively (28% vs 86%, P=.006). Patients reporting a history of abuse had a significantly higher rate of preoperative pelvic floor muscle dysfunction (91% vs 31%, P<.001). Successful dilation at 3 months in all patients was 89%. CONCLUSION: Pelvic floor physical therapists identify and help patients resolve pelvic floor-related problems before and after surgery. We find strong support for pelvic floor PT for patients undergoing gender-affirming vaginoplasty.

Visible-Light Photoredox Catalysis Enables the Biomimetic Synthesis of Nyingchinoids†A, B, and D, and Rasumatranin†D.

The total synthesis of nyingchinoids A and B has been achieved through successive rearrangements of a 1,2-dioxane intermediate that was assembled using a visible-light photoredox-catalysed aerobic [2+2+2] cycloaddition. Nyingchinoid D was synthesised with a competing [2+2] cycloaddition. Based on NMR data and biosynthetic speculation, we proposed a structure revision of the related natural product rasumatranin D, which was confirmed through total synthesis. Under photoredox conditions, we observed the conversion of a cyclobutane into a 1,2-dioxane through retro-[2+2] cycloaddition followed by aerobic [2+2+2] cycloaddition.

Phosphine catalysed (5 + 1) annulation of ynone/cinnamates with primary amines.

The (5 + 1) annulation of ynone/cinnamates and related substrates with protected primary amines gives rise to isoquinolones, pyrrolidinones and pyrrolopiperazines in good to excellent yields under phosphine catalysis. The reaction is viable with chiral phosphines, although the selectivity is poor.

Pregnancy risks in women with pre-existing coronary artery disease, or following acute coronary syndrome.

OBJECTIVE: The objective of this study was to determine outcomes in pregnant women with pre-existing coronary artery disease (CAD) or following an acute coronary syndrome (ACS) including myocardial infarction (MI). BACKGROUND: The physiological changes of pregnancy can contribute to myocardial ischaemia. The pregnancy risk for women with pre-established CAD or a history of ACS/MI is not well studied. METHODS: This was a retrospective multicentre study. Adverse maternal cardiac, obstetric and fetal/neonatal events were examined. The primary outcome was a composite endpoint of cardiac arrest, ACS/MI, ventricular arrhythmia or congestive heart failure. The prevalence of new or progressive angina during pregnancy was also examined. RESULTS: Fifty pregnancies in 43 women (mean age 35±5 years) were included. Coronary atherosclerosis (40%) and coronary thrombus (36%) were the most common underlying diagnoses. The primary outcome occurred in 10% (5/50) of pregnancies and included one maternal death secondary to cardiac arrest. Other events included ACS/MI (3/50) and heart failure (1/50). New or progressive angina occurred in 18% of pregnancies. Ischaemic complications of any type (new or progressive angina, ACS/MI, ventricular arrhythmia, cardiac arrest) occurred more commonly in women with coronary atherosclerosis compared with those without (50% vs 10%, p=0.003). A high rate of adverse obstetric (16%) and fetal/neonatal (30%) events was observed. CONCLUSIONS: Pregnant women with pre-existing CAD or ACS/MI before pregnancy are at increased risk of adverse events during pregnancy. Those with coronary atherosclerosis are at highest risk of adverse maternal cardiac events due to myocardial ischaemia during pregnancy.