Unfavorable Outcomes Associated With Glucocorticoid Use in Current Standard-of-Care Management of Systemic Lupus Erythematosus in Canada.

OBJECTIVE: Our objective was to describe the administration of glucocorticoids (GCs) and characterize its association with organ damage in a longitudinal systemic lupus erythematosus (SLE) cohort over a time period spanning the introduction of biologics in Canada. METHODS: A retrospective observational study was conducted using data from a large SLE cohort in Canada, including adults without lupus nephritis or central nervous system lupus. Patients were observed from time of entry into the cohort to the last available clinic visit (up to December 31, 2020), with a minimum of 24 months of follow-up. Demographic and clinical characteristics, including average disease activity, treatment administration, and prevalence of organ damage, were examined. Organ damage was stratified by GC administration. RESULTS: A total of 1,255 patients were included. The mean follow-up duration was 10.5 (SD 8.6) years. One hundred eighty-two (15%) patients had organ damage at baseline. More than 80% of patients were prescribed GCs over the follow-up period, almost all patients had long-term GC treatment, and only 5% of patients took any biologics. Organ damage was more frequent in patients with a higher average GC dose and greater years of GC exposure. CONCLUSION: In this large cohort of patients with SLE, the majority of patients continue to rely on GC for SLE symptom management, with limited administration of biologics. GC administration was correlated with increased irreversible organ damage. Access to novel GC-sparing treatment options is critical to improve long-term outcomes for patients with SLE, especially given the continued reliance on GC despite the introduction of biologics.

Cavity-coupled telecom atomic source in silicon.

Novel T centers in silicon hold great promise for quantum networking applications due to their telecom band optical transitions and the long-lived ground state electronic spins. An open challenge for advancing the T center platform is to enhance its weak and slow zero phonon line (ZPL) emission. In this work, by integrating single T centers with a low-loss, small mode-volume silicon photonic crystal cavity, we demonstrate an enhancement of the fluorescence decay rate by a factor of F = 6.89. Efficient photon extraction enables the system to achieve an average ZPL photon outcoupling rate of 73.3 kHz under saturation, which is about two orders of magnitude larger than the previously reported value. The dynamics of the coupled system is well modeled by solving the Lindblad master equation. These results represent a significant step towards building efficient T center spin-photon interfaces for quantum information processing and networking applications.

Costs of breast cancer recurrence after initial treatment for HR+, HER2-, high-risk early breast cancer: estimates from SEER-Medicare linked data.

OBJECTIVE: To assess the costs of treated recurrence and survival in elderly patients with early breast cancer (EBC) at high risk of recurrence using Surveillance Epidemiology and End Results (SEER) registry-Medicare linked claims data. METHODS: This retrospective study included patients aged ≥65 years with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), node-positive EBC at high risk of recurrence. Treated recurrences were defined based on treatment events/procedure codes from claims. Primary outcomes were monthly total extra costs and cumulative extra costs of treated recurrence relative to patients with non/untreated recurrence. Costs were calculated using a Kaplan-Meier sampling average estimator method and inflated to 2021 US$. Secondary outcomes included analysis by recurrence type and overall survival (OS) after recurrence. Subgroup analysis evaluated costs in patients with Medicare Part D coverage. RESULTS: Among 3,081 eligible patients [mean (SD) age at diagnosis was 74.5 (7.1) years], the majority were females (97.4%) and white (87.8%). Treated recurrence was observed in 964 patients (31.3%). The monthly extra cost of treated recurrence was highest at the beginning of the first treated recurrence episode, with 6-year cumulative cost of $117,926. Six-year cumulative extra costs were higher for patients with distant recurrences ($168,656) than for patients with locoregional recurrences ($96,465). Median OS was 4.34 years for all treated recurrences, 1.92 years for distant recurrence, and 6.78 years for locoregional recurrence. Similar cumulative extra cost trends were observed in the subgroup with Part D coverage as in the overall population. LIMITATIONS: This study utilizes claims data to identify treated recurrence. Due to age constraints of the dataset, results may not extrapolate to a younger population where EBC is commonly diagnosed. CONCLUSION: EBC recurrence in this elderly population has substantial costs, particularly in patients with distant recurrences. Therapies that delay or prevent recurrence may reduce long-term costs significantly.

Descriptive study of the real-world, long-term cost estimates and duration of use for hormonal and nonhormonal intrauterine devices using US commercial insurance claims.

BACKGROUND: Intrauterine devices (IUDs) have comparable efficacy to permanent surgical contraceptive methods; however, long-term costs are infrequently considered. Existing estimates inconsistently account for costs outside of IUD insertion or removal, actual duration of use, or differences between hormonal and nonhormonal IUDs. OBJECTIVE: To describe health care resource utilization and commercial payer costs that arise throughout hormonal and nonhormonal IUD use. METHODS: In this retrospective cohort study, paid claims data (Merative, MarketScan) from a large US commercial claims database were evaluated between 2013 and 2019. Claims were included from individuals aged 12 to 45 years who had an IUD inserted in 2014, continuous insurance coverage for 1 year prior to insertion and throughout follow-up, and no insertion, removal, or reinsertion in the previous year. Procedures and services that could be IUD-related were identified using Current Procedural Terminology and International Classification of Diseases, Ninth and Tenth Edition codes. Duration of IUD use was evaluated by Kaplan-Meier analysis of time to IUD removal. Event rates were determined for identified procedures and services; costs were calculated as the sum of payer reimbursements per enrolled individual. All IUD types available during the study period were described: 2 hormonal IUDs (52-mg and 13.5-mg levonorgestrel-releasing [LNG]) and the nonhormonal (380-mm2 copper) IUD. RESULTS: Of 195,009 individuals meeting the age requirement and receiving an IUD in 2014, 63,386 met the inclusion criteria and 53,744 had their IUD type on record-42,777 (67.5%) 52-mg LNG, 2,932 (4.6%) 13.5-mg LNG, and 8,035 (12.7%) nonhormonal IUD users. Despite differences in their indicated duration (13.5-mg LNG, 3 years; 52-mg LNG, 5 years; and nonhormonal, 10 years), most individuals had their IUD removed before its indicated full duration of use (13.5-mg LNG, 56.1%; 52-mg LNG, 61.3%; nonhormonal [at 5 years], 54.6%). The event rate per 100 individuals during the follow-up period was highest for abnormal uterine bleeding (16.2), ovarian cysts (9.3), and surgical management of uterine perforations (4.5). IUD insertion costs (mean ± SE) per enrolled individual for the 13.5-mg LNG, 52-mg LNG, and nonhormonal IUDs were $931 ± $9, $1,107 ± $4, and $897 ± $6, respectively. Cumulative mean ± SE 5-year postinsertion costs for the 13.5-mg LNG, 52-mg LNG, and nonhormonal IUDs were $2,892 ± $232, $1,514 ± $31, and $1,389 ± $97, respectively, among the remaining enrolled individuals. CONCLUSIONS: In this descriptive study of commercially insured IUD users, at least half had their IUD removed before its indicated duration. IUD improvements that reduce the frequency of abnormal uterine bleeding, ovarian cysts, and uterine perforations may help reduce long-term IUD costs.

Identification of underexplored mesenchymal and vascular-related cell populations in human skeletal muscle.

Skeletal muscle repair and maintenance are directly and indirectly supported by interstitial cell populations such as vascular cells and fibro-adipogenic progenitors (FAPs), a subset of which express Twist2 and possess direct myogenic potential. Furthermore, work in rodents has highlighted the potential of pericytes to act as progenitor cells, giving rise to muscle cells and transdifferentiating into endothelial cells. However, less is understood about these populations in human skeletal muscle. Here, we performed single-cell RNA sequencing (scRNAseq) on ∼2,000 cells isolated from the human semitendinosus muscle of young individuals. This demonstrated the presence of a vascular-related cell type that expressed pericyte and pan-endothelial genes that we localized to large blood vessels within skeletal muscle cross sections and termed endothelial-like pericytes (ELPCs). RNA velocity analysis indicated that ELPCs may represent a "transition state" between endothelial cells and pericytes. Analysis of published scRNAseq data sets revealed evidence for ELPCs in trunk and heart musculature, which showed transcriptional similarity. In addition, we identified a subset of FAPs expressing TWIST2 mRNA and protein. Human TWIST2-expressing cells were anatomically and transcriptionally comparable to mouse Twist2 cells as they were restricted to the myofiber interstitium, expressed fibrogenic genes but lacked satellite cell markers, and colocalized with the FAPs marker PDGFRα in human muscle cross sections. Taken together, these results highlight the complexity of stromal cells residing in human skeletal muscle and support the utility of scRNAseq for discovery and characterization of poorly described cell populations.

Twist2-expressing cells reside in human skeletal muscle and are responsive to aging and resistance exercise training.

Skeletal muscle is maintained and repaired by sub-laminar, Pax7-expressing satellite cells. However, recent mouse investigations have described a second myogenic progenitor population that resides within the myofiber interstitium and expresses the transcription factor Twist2. Twist2-expressing cells exclusively repair and maintain type IIx/b muscle fibers. Currently, it is unknown if Twist2-expressing cells are present in human skeletal muscle and if they function as myogenic progenitors. Here, we perform a combination of single-cell RNA sequencing analysis and immunofluorescence staining to demonstrate the identity and localization of Twist2-expressing cells in human skeletal muscle. Twist2-expressing cells were identified to be anatomically and transcriptionally comparable to fibro-adipogenic progenitors (FAPs) and lack expression of typical satellite cell markers such as Pax7. Comparative analysis revealed that human and mouse Twist2-expressing cells were highly transcriptionally analogous and resided within the same anatomical structures in vivo. Examination of young and aged skeletal muscle biopsy samples revealed that Twist2-positive cells are more prevalent in aged muscle and increase following 12-weeks of resistance exercise training (RET) in humans. However, the quantity of Twist2-positive cells was not correlated with indices of muscle mass or muscle fiber cross-sectional area (CSA) in young or older muscle, and their abundance was surprisingly, negatively correlated with CSA and myonuclear domain size following RET. Taken together, we have identified cells expressing Twist2 in human skeletal muscle which are responsive to aging and exercise. Further examination of their myogenic potential is warranted.

Muscle injury induces a transient senescence-like state that is required for myofiber growth during muscle regeneration.

Cellular senescence is the irreversible arrest of normally dividing cells and is driven by the cell cycle inhibitors Cdkn2a, Cdkn1a, and Trp53. Senescent cells are implicated in chronic diseases and tissue repair through their increased secretion of pro-inflammatory factors known as the senescence-associated secretory phenotype (SASP). Here, we use spatial transcriptomics and single-cell RNA sequencing (scRNAseq) to demonstrate that cells displaying senescent characteristics are "transiently" present within regenerating skeletal muscle and within the muscles of D2-mdx mice, a model of Muscular Dystrophy. Following injury, multiple cell types including macrophages and fibrog-adipogenic progenitors (FAPs) upregulate senescent features such as senescence pathway genes, SASP factors, and senescence-associated beta-gal (SA-ß-gal) activity. Importantly, when these cells were removed with ABT-263, a senolytic compound, satellite cells are reduced, and muscle fibers were impaired in growth and myonuclear accretion. These results highlight that an "acute" senescent phenotype facilitates regeneration similar to skin and neonatal myocardium.

Virtual Reality "exergames": A promising countermeasure to improve motivation and restorative effects during long duration spaceflight missions.

Long duration spaceflight missions will require novel exercise systems to protect astronaut crew from the detrimental effects of microgravity exposure. The SPRINT protocol is a novel and promising exercise prescription that combines aerobic and resistive training using a flywheel device, and it was successfully employed in a 70-day bed-rest study as well as onboard the International Space Station. Our team created a VR simulation to further augment the SPRINT protocol when using a flywheel ergometer training device (the Multi-Mode Exercise Device or M-MED). The simulation aspired to maximal realism in a virtual river setting while providing real-time biometric feedback on heart rate performance to subjects. In this pilot study, five healthy, male, physically-active subjects aged 35 ± 9.0 years old underwent 2 weeks of SPRINT protocol, either with or without the VR simulation. After a 1-month washout period, subjects returned for a subsequent 2 weeks in the opposite VR condition. We measured physiological and cognitive variables of stress, performance, and well-being. While physiological effects did not suggest much difference with the VR condition over 2 weeks, metrics of motivation, affect, and mood restoration showed detectable differences, or trended toward more positive outcomes than exercise without VR. These results provide evidence that a well-designed VR "exergaming" simulation with biometric feedback could be a beneficial addition to exercise prescriptions, especially if users are exposed to isolation and confinement.

The Contribution of Innervation to Tissue Repair and Regeneration.

Animals such as amphibians have an incredible capacity for regeneration with some being able to regrow their tail or appendages. Although some mammalian tissues like the skin and bones can repair following injury, there are only a few examples of true multilineage regeneration, including the distal portion of the digit tip. In both amphibians and mammals, however, to achieve successful repair or regeneration, it is now appreciated that intact nerve innervation is a necessity. Here, we review the current state of literature and discuss recent advances that identify axon-derived signals, Schwann cells, and nerve-derived mesenchymal cells as direct and indirect supporters of adult tissue homeostasis and repair. We posit that understanding how nerves positively influence repair and regeneration could lead to targeted regenerative medicine strategies to enhance tissue repair in humans.

Loss of dystrophin expression in skeletal muscle is associated with senescence of macrophages and endothelial cells.

Cellular senescence is the irreversible arrest of normally dividing cells and is driven by cell cycle inhibitory proteins such as p16, p21, and p53. When cells enter senescence, they secrete a host of proinflammatory factors known as the senescence-associated secretory phenotype, which has deleterious effects on surrounding cells and tissues. Little is known of the role of senescence in Duchenne muscular dystrophy (DMD), the fatal X-linked neuromuscular disorder typified by chronic inflammation, extracellular matrix remodeling, and a progressive loss in muscle mass and function. Here, we demonstrate using C57-mdx (8-wk-old) and D2-mdx (4-wk-old and 8-wk-old) mice, two mouse models of DMD, that cells displaying canonical markers of senescence are found within the skeletal muscle. Eight-week-old D2-mdx mice, which display severe muscle pathology, had greater numbers of senescent cells associated with areas of inflammation, which were mostly Cdkn1a-positive macrophages, whereas in C57-mdx muscle, senescent populations were endothelial cells and macrophages localized to newly regenerated myofibers. Interestingly, this pattern was similar to cardiotoxin (CTX)-injured wild-type (WT) muscle, which experienced a transient senescent response. Dystrophic muscle demonstrated significant upregulations in senescence pathway genes [Cdkn1a (p21), Cdkn2a (p16INK4A), and Trp53 (p53)], which correlated with the quantity of senescence-associated ß-galactosidase (SA-ß-Gal)-positive cells. These results highlight an underexplored role for cellular senescence in murine dystrophic muscle.

Repeated Application of a Novel Creatine Cream Improves Muscular Peak and Average Power in Male Subjects.

Whinton, AK, Donahoe, K, Gao, R, Thompson, KMA, Aubry, R, Saunders, TJ, Johnston, A, Chilibeck, PD, and Burr, JF. Repeated application of a novel creatine cream improves muscular peak and average power in male subjects. J Strength Cond Res 34(9): 2482-2491, 2020-Using a multicenter, randomized controlled trial, (N = 123, age 23 ± 4 years) we sought to determine whether administration of a novel, topical creatine supplement could improve muscular performance after acute and repeated (7-day) exposure. To study the acute performance enhancing effects of the supplement, subjects completed 5 sets of 15 maximal concentric single-leg knee extensions with and without the application of a low- (low dose [LD]-3.5 ml) or high-dose (high dose [HD]-7 ml) topical creatine cream. After a wash-out period, subjects had one leg randomized to receive either the creatine or placebo cream, with further randomization into an oral creatine or placebo supplement group. Subjects completed 5 sets of 15 maximal concentric single leg knee extensions before and after the supplementation protocol. After acute application, no significant differences in peak power (LD: 252 ± 93 W, HD: 261 ± 100 W, p = 0.21), average power (LD: 172 ± 65 W, HD: 177 ± 69 W, p = 0.78), or fatigue index (LD: 13.4 ± 10.6%, HD: 14 ± 11.9%, p = 0.79) were observed between experimental and placebo creams (peak power: LD: 244 ± 76 W, HD: 267 ± 109 W; average power: LD: 168 ± 57 W, HD: 177 ± 67 W; fatigue index: LD: 12.4 ± 9.6%, HD: 12.8 ± 10.6%) or when controlling for sex. After the 7-day supplementation protocol, a significant increase in average power (creatine: 203 ± 61-220 ± 65 W, placebo: 224 ± 61-214 ± 61 W) and peak power (creatine: 264 ± 73-281 ± 80 W, placebo: 286 ± 79-271 ± 73 W) in the leg receiving creatine cream was observed in male subjects. No differences were observed in female subjects. The topical creatine cream did not enhance measures of muscle performance after acute application, but was able to improve peak and average power in male subjects after 7 consecutive days of application.

Mesenchymal Precursor Cells in Adult Nerves Contribute to Mammalian Tissue Repair and Regeneration.

Peripheral innervation plays an important role in regulating tissue repair and regeneration. Here we provide evidence that injured peripheral nerves provide a reservoir of mesenchymal precursor cells that can directly contribute to murine digit tip regeneration and skin repair. In particular, using single-cell RNA sequencing and lineage tracing, we identify transcriptionally distinct mesenchymal cell populations within the control and injured adult nerve, including neural crest-derived cells in the endoneurium with characteristics of mesenchymal precursor cells. Culture and transplantation studies show that these nerve-derived mesenchymal cells have the potential to differentiate into non-nerve lineages. Moreover, following digit tip amputation, neural crest-derived nerve mesenchymal cells contribute to the regenerative blastema and, ultimately, to the regenerated bone. Similarly, neural crest-derived nerve mesenchymal cells contribute to the dermis during skin wound healing. These findings support a model where peripheral nerves directly contribute mesenchymal precursor cells to promote repair and regeneration of injured mammalian tissues.

A novel mode of capping protein-regulation by twinfilin.

Cellular actin assembly is controlled at the barbed ends of actin filaments, where capping protein (CP) limits polymerization. Twinfilin is a conserved in vivo binding partner of CP, yet the significance of this interaction has remained a mystery. Here, we discover that the C-terminal tail of Twinfilin harbors a CP-interacting (CPI) motif, identifying it as a novel CPI-motif protein. Twinfilin and the CPI-motif protein CARMIL have overlapping binding sites on CP. Further, Twinfilin binds competitively with CARMIL to CP, protecting CP from barbed-end displacement by CARMIL. Twinfilin also accelerates dissociation of the CP inhibitor V-1, restoring CP to an active capping state. Knockdowns of Twinfilin and CP each cause similar defects in cell morphology, and elevated Twinfilin expression rescues defects caused by CARMIL hyperactivity. Together, these observations define Twinfilin as the first 'pro-capping' ligand of CP and lead us to propose important revisions to our understanding of the CP regulatory cycle.

Species-Specific Functions of Twinfilin in Actin Filament Depolymerization.

Twinfilin is a highly conserved member of the actin depolymerization factor homology (ADF-H) protein superfamily, which also includes ADF/Cofilin, Abp1/Drebrin, GMF, and Coactosin. Twinfilin has a unique molecular architecture consisting of two ADF-H domains joined by a linker and followed by a C-terminal tail. Yeast Twinfilin, in conjunction with yeast cyclase-associated protein (Srv2/CAP), increases the rate of depolymerization at both the barbed and pointed ends of actin filaments. However, it has remained unclear whether these activities extend to Twinfilin homologs in other species. To address this, we purified the three mouse Twinfilin isoforms (mTwf1, mTwf2a, mTwf2b) and mouse CAP1, and used total internal reflection fluorescence microscopy assays to study their effects on filament disassembly. Our results show that all three mouse Twinfilin isoforms accelerate barbed end depolymerization similar to yeast Twinfilin, suggesting that this activity is evolutionarily conserved. In striking contrast, mouse Twinfilin isoforms and CAP1 failed to induce rapid pointed end depolymerization. Using chimeras, we show that the yeast-specific pointed end depolymerization activity is specified by the C-terminal ADF-H domain of yeast Twinfilin. In addition, Tropomyosin decoration of filaments failed to impede depolymerization by yeast and mouse Twinfilin and Srv2/CAP, but inhibited Cofilin severing. Together, our results indicate that Twinfilin has conserved functions in regulating barbed end dynamics, although its ability to drive rapid pointed end depolymerization appears to be species-specific. We discuss the implications of this work, including that pointed end depolymerization may be catalyzed by different ADF-H family members in different species.

Aortic Sca-1+ Progenitor Cells Arise from the Somitic Mesoderm Lineage in Mice.

Sca-1+ progenitor cells in the adult mouse aorta are known to generate vascular smooth muscle cells (VSMCs), but their embryological origins and temporal abundance are not known. Using tamoxifen-inducible Myf5-CreER mice, we demonstrate that Sca-1+ adult aortic cells arise from the somitic mesoderm beginning at E8.5 and continue throughout somitogenesis. Myf5 lineage-derived Sca-1+ cells greatly expand in situ, starting at 4 weeks of age, and become a major source of aortic Sca-1+ cells by 6 weeks of age. Myf5-derived adult aortic cells are capable of forming multicellular sphere-like structures in vitro and express the pluripotency marker Sox2. Exposure to transforming growth factor-ß3 induces these spheres to differentiate into calponin-expressing VSMCs. Pulse-chase experiments using tamoxifen-inducible Sox2-CreERT2 mice at 8 weeks of age demonstrate that ∼35% of all adult aortic Sca-1+ cells are derived from Sox2+ cells. The present study demonstrates that aortic Sca-1+ progenitor cells are derived from the somitic mesoderm formed at the earliest stages of somitogenesis and from Sox2-expressing progenitors in adult mice.

Low-load resistance exercise during inactivity is associated with greater fibre area and satellite cell expression in older skeletal muscle.

BACKGROUND: Age-related sarcopenia is accelerated by physical inactivity. Low-load resistance exercise (LLRE) counters inactivity-induced muscle atrophy in older adults, but changes in muscle fibre morphology are unstudied. We aimed to determine the impact of LLRE during short-term inactivity (step-reduction) on muscle fibre size and capillarity as well as satellite cell (SC) content in older skeletal muscle. METHODS: Fourteen older (~71 years) male adults underwent 14 days of step reduction (<1500 steps/day) while performing six sessions of LLRE (~30% maximal strength) with one leg (SR + EX) while the contralateral leg served as an untrained control (SR). Seven healthy ambulatory age-matched male adults (~69 years) served as a comparator group (COM). Muscle biopsies were taken from the vastus lateralis after 14 days, and immunohistochemical analysis was performed to determine muscle fibre cross-sectional area (CSA), myonuclear content, SC content (PAX7+ cells), and total (C:F) and fibre type-specific (C:Fi) capillary-to-fibre ratios. RESULTS: Type I and II fibre CSA was greater in SR + EX compared with SR. Whereas there were no differences across fibre types between SR + EX and CON, type II fibre CSA was significantly lower in SR compared with COM. Type II myonuclear domain was greater in SR + EX compared with COM and SR. Pax7+ cells associated with type I and II fibres were lower in SR compared with SR + EX. Type II PAX7+ cells were also lower in SR compared with COM with a similar trend for type I fibres. There were trends for a lower C:Fi in SR compared with SR + EX for both fibre types with no differences for each compared with COM. CONCLUSIONS: Minimal LLRE during a period of decreased physical activity is associated with greater muscle fibre CSA, SC content, and capillarization. These results support the use of LLRE as an effective countermeasure to inactivity-induced alterations in muscle morphology with age.

Schwann cells as drivers of tissue repair and regeneration.

Current evidence suggests that peripheral nerve-associated Schwann cells possess the capacity to promote the repair and regeneration of multiple tissue types, in addition to peripheral nervous system axons. These findings shed light on the nerve-dependent nature of regeneration that has been well documented in various organs. This review outlines recent advances in knowledge surrounding endogenous regenerative functions of Schwann cells across species and tissue types, with a specific focus on the role of Sox2+ dedifferentiated Schwann cells in regulating the proliferation of surrounding tissue-resident mesenchymal precursors.

Direct ortho-Arylation of Pyridinecarboxylic Acids: Overcoming the Deactivating Effect of sp2-Nitrogen.

Direct arylations of pyridines are challenging transformations due to the high Lewis basicity of the sp2-nitrogen. The use of carboxylates as directing groups is reported, facilitating the Pd-catalyzed C-H arylation of this difficult class of substrates. This methodology allows regioselective C3/C4 arylation, without the need to use solvent quantities of the pyridine, and using low-cost chloro- and bromoarenes as coupling partners. Furthermore, carboxylates could be employed as traceless directing groups through a one-pot C-H arylation/Cu(I)-mediated decarboxylation sequence, thereby accessing directing-group-free pyridine biaryls.