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Meng-Wong Taing,1,2 Felicity J Rose,1,3 Jonathan P Whitehead11Metabolic Medicine, Mater Research Institute, University of Queensland, 2School of Pharmacy, University of Queensland, Brisbane, QLD, Australia; 3University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, AustraliaAbstract: The glucagon-like peptide-1 (GLP-1) axis has emerged as a major therapeutic target for the treatment of type 2 diabetes. GLP-1 mediates its key insulinotropic effects via a G-protein coupled receptor expressed on β-cells and other pancreatic cell types. The insulinotropic activity of GLP-1 is terminated via enzymatic cleavage by dipeptidyl peptidase-4. Until recently, GLP-1-derived metabolites were generally considered metabolically inactive; however, accumulating evidence indicates some have biological activity that may contribute to the pleiotropic effects of GLP-1 independent of the GLP-1 receptor. Recent reports describing the putative effects of one such metabolite, the GLP-1-derived nonapeptide GLP-1(28-36)amide, are the focus of this review. Administration of the nonapeptide elevates cyclic adenosine monophosphate (cAMP) and activates protein kinase A, β-catenin, and cAMP response-element binding protein in pancreatic β-cells and hepatocytes. In stressed cells, the nonapeptide targets the mitochondria and, via poorly defined mechanisms, helps to maintain mitochondrial membrane potential and cellular adenosine triphosphate levels and to reduce cytotoxicity and apoptosis. In mouse models of diet-induced obesity, treatment with the nonapeptide reduces weight gain and ameliorates associated pathophysiology, including hyperglycemia, hyperinsulinemia, and hepatic steatosis. Nonapeptide administration in a streptozotocin-induced model of type 1 diabetes also improves glucose disposal concomitant with elevated insulin levels and increased β-cell mass and proliferation. Collectively, these results suggest some of the beneficial effects of GLP-1 receptor analogs may be mediated by the nonapeptide. However, the concentrations required to elicit some of these effects are in the micromolar range, leading to reservations about potentially related therapeutic benefits. Moreover, although controversial, concerns have been raised about the potential for incretin-based therapies to promote pancreatitis and pancreatic and thyroid cancers. The effects ascribed to the nonapeptide make it a potential contributor to such outcomes, raising additional questions about its therapeutic suitability. Notwithstanding, the nonapeptide, like other GLP-1 metabolites, appears to be biologically active. Increasing understanding of such noncanonical GLP-1 activities should help to improve future incretin-based therapeutics.Keywords: diabetes, incretins, metabolites, insulinotropism

Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: This study evaluated the use of evidence-based practices (EBPs) for smoking cessation in centers providing behavioral healthcare for patient populations that included some proportion of sexual and gender minorities (SGMs)., Methods: Healthcare providers from 75 healthcare centers across Texas serving SGMs with behavioral health needs participated in a survey assessing their center's tobacco control policies and practices., Results: Nearly half (N = 36) of participating centers had a comprehensive tobacco-free workplace policy, 30.67% employed ≥1 tobacco treatment specialist, 73.91% employed ≥1 prescriber, 80.82% mandated screening for patient tobacco use at intake, and 57.53% provided a template for tobacco use assessments. Overall, 70.67% of providers asked patients about smoking status, 69.33% advised patients to quit, 64.00% assessed patients' interest in quitting, 58.67% assisted patients with quit attempts, and 36.00% arranged follow-up. Providers' ability to tailor interventions for special populations like SGMs ranged from very low/0 to very high/10 (M = 4.63 ± 2.59)., Conclusions: There are opportunities to improve policy implementation, standardization and usage of evidence-based interventions, and intervention tailoring within settings providing care to SGM patients in Texas to better address their tobacco use inequities.

Introduction: Individuals experiencing homelessness have elevated smoking rates in addition to chronic and acute physical and mental health conditions, which may increase chances for complications associated with COVID-19 recovery. Unfortunately, there is underuse of tobacco cessation services in many agencies (e.g., substance use treatment centers, mental health treatment centers) providing care to these individuals. The purpose of the current study was to evaluate the feasibility of providing tobacco cessation treatment alongside local COVID-19 emergency response efforts., Method: Taking Texas Tobacco Free (TTTF) partnered with relevant emergency response teams at 5 isolation centers (repurposed hotels) in Austin, Texas, to address tobacco use among presumed or confirmed COVID-19 positive individuals who had nowhere else to seek care and shelter. TTTF trained staff on tobacco cessation treatment; specifically, the 5A's and use of nicotine replacement therapy., Results: Over 5 months in 2020; 170 of 379 (44.9%) isolation center residents were reached and assessed for cigarette or vape use. Smoking/vaping prevalence was 70.6%, and 41.7% of tobacco users accepted cessation treatment., Discussion: Results suggest the feasibility and potential acceptability of providing tobacco treatment services in similar care settings during local emergency response efforts, including but potentially not limited to the COVID-19 pandemic. Further, this initiates a call to action for health care providers to deliver tobacco use cessation services for typically hard-to-reach groups (e.g., individuals/families experiencing homelessness) who may have increased contact with service agencies and health providers during times of crisis. Limitations and suggestions for future implementation are also provided. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Tobacco use is exceedingly high among individuals receiving care for opioid addiction, but not commonly addressed by clinicians in treatment settings. Taking Texas Tobacco Free (TTTF) is a comprehensive tobacco-free workplace (TFW) program that builds treatment centers' capacity to address tobacco use with evidence-based tobacco cessation policies and practices. Here, we examine the process and outcomes of TTTF's implementation within 7 opioid addiction centers. Program goals were structured according to the RE-AIM framework. Pre- and post-implementation data were collected from client facing and non-client facing employees to assess changes in education, training receipt, knowledge, and intervention behaviors, relative to program goals. Centers reported tobacco screenings conducted and nicotine replacement therapy (NRT) delivered through 6 months post-implementation. Overall, 64.56% of employees participated in TTTF-delivered tobacco education, with a 54.9% gain in tobacco control and treatment knowledge ( p < 0.0001), and significant increases in exposure to education about tobacco use and harms among individuals with opioid use disorder ( p = 0.0401). There were significant gains in clinicians' receipt of training in 9/9 tobacco education areas ( ps ≤ 0.0118). From pre- to post-implementation, there were mean increases in the use of the 5A's (ask, advise, assess, assist, and arrange) and other evidence-based interventions for tobacco cessation, with statistically significant gains seen in NRT provision/referral ( p < 0.0001). Several program goals were achieved or exceeded; however, 100% center participation in specialized clinical trainings was among notable exceptions. One program withdrew due to competing pandemic concerns; all others implemented comprehensive TFW policies. Overall, TTTF may have improved participating opioid treatment centers' capacity to address tobacco use, although study limitations, including lower post-implementation evaluation response rates, suggest that results require replication in other opioid addiction treatment settings.

Nucleobase mimicking small molecules able to reconfigure DNA are a recently discovered strategy that promises to extend the structural and functional diversity of nucleic acids. However, only simple, unfunctionalized molecules such as cyanuric acid and melamine have so far been used in this approach. In this work, we show that the addition of substituted cyanuric acid molecules can successfully program polyadenine strands to assemble into supramolecular fibers. Unlike conventional DNA nanostructure functionalization, which typically end-labels DNA strands, our approach incorporates functional groups into DNA with high density using small molecules and results in new DNA triple helices coated with alkylamine or alcohol units that grow into micrometer-long fibers. We find that small changes in the small molecule functional group can result in large structural and energetic variation in the overall assembly. A combination of circular dichroism, atomic force microscopy, molecular dynamics simulations, and a new thermodynamic method, transient equilibrium mapping, elucidated the molecular factors behind these large changes. In particular, we identify substantial DNA sugar and phosphate group deformations to accommodate a hydrogen bond between the phosphate and the small-molecule functional groups, as well as a critical chain length of the functional group which switches this interaction from intra- to interfiber. These parameters allow the controlled formation of hierarchical, hybrid DNA assemblies simply through the addition and variation of small, functionalized molecules.

Although tobacco use is the leading preventable cause of death and is elevated among patients with substance use disorders, many substance use treatment centers (SUTCs) do not offer tobacco use interventions (i.e., screening and treatment). This study examined a key outcome of the implementation of a tobacco-free workplace program that provided education and specialized training to employees; namely, changes in clinician provision of the five As (Asking about tobacco use; Advising to quit; Assessing willingness to quit; Assisting with quitting; Arranging follow-up) from before to after the larger program implementation. The five As are a brief tobacco screening and treatment protocol that was taught as part of the program and that formed the basis for further intervention (e.g., provision of nicotine replacement therapies, Motivational Interviewing to enhance desire and willingness to make a quit attempt). Moreover, we also examined organizational moderators that may have impacted changes in the delivery of the five As over time among clinicians from 15 participating SUTCs. The number of the centers' total and unique annual patient visits; full-time employees; and organizational readiness for implementing change were assessed as potential moderators of change in clinicians' behaviors over time. Clinicians completed pre- and post-program implementation surveys assessing their provision of the five As. Results demonstrated significant increases in Asking ( p = 0.0036), Advising ( p = 0.0176), Assisting ( p < 0.0001), and Arranging ( p < 0.0001). SUTCs with higher Change Efficacy ( p = 0.025) and lower Resource Availability ( p = 0.019) had greater increases in Asking. SUTCs with lower Resource Availability had greater increases in Assessing ( p = 0.010). These results help guide tobacco control program implementation to increase the provision of tobacco use interventions (i.e., the five As) to SUTC patients and elucidate Change Efficacy and Resource Availability as organizational factors promoting this clinician behavior change.

Intersecting socially marginalized identities and unique biopsychosocial factors place women with substance use disorders (SUDs) experiencing myriad disadvantages at higher risk for smoking and stigmatization. Here, based on our work with women receiving care for SUDs in four participating treatment/women-serving centers (N = 6 individual clinics), we: (1) describe the functions of smoking for women with SUDs; and (2) explore participants' experiences of a comprehensive tobacco-free workplace (TFW) program, Taking Texas Tobacco-Free (TTTF), that was implemented during their SUD treatment. Ultimately, information gleaned was intended to inform the development of women-tailored tobacco interventions. Data collection occurred pre- and post-TTTF implementation and entailed conducting client (7) and clinician (5) focus groups. Using thematic analysis, we identified four main themes: "the social context of smoking," "challenges to finding support and better coping methods," "addressing underlying conditions: building inner and outer supportive environments," and "sustaining support: TFW program experiences." Women reported that: smoking served as a "coping mechanism" for stress and facilitated socialization; stigmatization hindered quitting; non-stigmatizing counseling cessation support provided alternative coping strategies; and, with clinicians, the cessation opportunities TTTF presented are valuable. Clinicians reported organizational support, or lack thereof, and tobacco-related misconceptions as the main facilitator/barriers to treating tobacco addiction. Effective tobacco cessation interventions for women with SUDs should be informed by, and tailored to, their gendered experiences, needs, and recommendations. Participants recommended replacing smoking with healthy stress alleviating strategies; the importance of adopting non-judgmental, supportive, cessation interventions; and the support of TFW programs and nicotine replacement therapy to aid in quitting.

Background: Cigarette smoking disproportionately affects homeless individuals, who have a higher smoking prevalence, fewer resources, and increased stressors compared to domiciled smokers. Little is known about how to facilitate smoking cessation among this population although some findings support focusing efforts on affective variables as well as alternate outcomes in order to optimize interventions for this group., Methods: Participants were homeless adults recruited from a Dallas, TX, shelter (N = 57, 61.4% male, M age  = 48.8 ± 9.0) to participate in tobacco cessation classes using an American Cancer Society-based therapy and support group with nicotine replacement therapy. Moment-to-moment changes in affect [e.g., negative affect (NA), positive affect (PA), and stress] were recorded via Ecological Momentary Assessments to assess whether they were associated with concurrent changes in cigarettes smoked per day (CPD) following a specific quit attempt. Separate generalized linear models (GLM) were evaluated for each predictor to examine the associations between affective variables and CPD in covariate-adjusted analyses., Results: Significant interaction effects of time and affect were found for all variables (NA: p = 0.0011, PA: p = 0.0006, stress: p = 0.0259), whereby the association of affect and CPD were significant in the early part of the week but the effects faded as time progressed. With regard to main effects, only increases in PA during the post-quit week significantly predicted fewer CPD (adjusted incidence rate ratio = 0.924, SE = 0.027, p = 0.0032)., Conclusions: Homeless smokers may be more likely to decrease their cigarette consumption during periods of greater PA throughout the post-quit week. Relationship between positive affect and reduction in CPD suggest focus on affective variables with homeless smokers may be an effective avenue for change in smoking behaviors, particularly in the days immediately following a quit attempt. Time effects should be further investigated to determine when these interventions might best be implemented., (Copyright © 2020. Published by Elsevier Ltd.)

DNA polymerases have revolutionized the biotechnology field due to their ability to precisely replicate stored genetic information. Screening variants of these enzymes for specific properties gives the opportunity to identify polymerases with different features. We have previously developed a single-molecule DNA sequencing platform by coupling a DNA polymerase to an α-hemolysin pore on a nanopore array. Here, we use this approach to demonstrate a single-molecule method that enables rapid screening of polymerase variants in a multiplex manner. In this approach, barcoded DNA strands are complexed with polymerase variants and serve as templates for nanopore sequencing. Nanopore sequencing of the barcoded DNA reveals both the barcode identity and kinetic properties of the polymerase variant associated with the cognate barcode, allowing for multiplexed investigation of many polymerase variants in parallel on a single nanopore array. Further, we develop a robust classification algorithm that discriminates kinetic characteristics of the different polymerase mutants. As a proof of concept, we demonstrate the utility of our approach by screening a library of ∼100 polymerases to identify variants for potential applications of biotechnological interest. We anticipate our screening method to be broadly useful for applications that require polymerases with altered physical properties.

Individuals experiencing homelessness smoke cigarettes at high rates, suffer a disproportionate incidence of lung cancer, but are unlikely to be screened to enhance early detection. Understanding correlates of lung cancer screening (LCS) interest within this vulnerable group may lend insight into prevention and treatment efforts and reduce their smoking-related morbidity and mortality. This study sought to understand how risk perception and interest in quitting smoking relate to LCS interest among homeless adults. Participants comprised a convenience sample of CO-verified current smokers ( N = 310; 72.6% men, M age = 43 + 11.7) from a homeless shelter in Dallas, TX. Participants self-reported risk perception, interest in quitting smoking, and interest in LCS. The average risk perception was 6.7 + 3.2 (range 0-10), 74.8% ( n = 232) agreed or strongly agreed with interest in LCS, and 65.8% ( n = 204) were interested in quitting smoking. Greater interest in quitting smoking, but not greater risk perception, was associated with greater interest in LCS (adjusted OR: 1.968, (95% CI: 1.213, 3.191), p = 0.006). Risk perception and interest in quitting smoking did not interact in their association with interest in LCS. Results suggest that homeless smokers with an interest in quitting may be receptive to LCS: a diagnostic tool by which cancers can be caught at earlier stages and prior to metastasis. However, few in the current sample would be eligible for LCS based on current guidelines; results have implications for altered screening practices among chronic smokers experiencing homelessness.

Tobacco use is exceedingly high among those who are homeless or at risk of homelessness but not commonly addressed by clinicians. Taking Texas Tobacco Free (TTTF) is a tobacco control program that addresses known clinician barriers to intervention (e.g., low training receipt, limited resources). Here, we examine the process and outcomes of TTTF's adaptation within four agencies that provide housing or other services to individuals who are homeless or vulnerably housed. Pre- and post-implementation data were collected from clinicians ( N = 68) to assess changes in training receipt, knowledge, and intervention behaviors, relative to program goals. Results indicated significant gains in clinicians' receipt of training in 9 (of 9) target areas ( p 's ≤ 0.0042) and a 53% knowledge gain ( p < 0.0001). From pre- to post-implementation, there were mean increases in the use of the 5As (ask, advise, assess, assist, and arrange) and other evidence-based interventions for tobacco cessation, with significant gains seen in assisting residents/clients to quit, arranging follow-ups, and providing or referring for non-nicotine medications ( p 's ≤ 0.0491). All program goals, except gains related to advising smokers to quit and the use of specific interventions (behavioral counseling), were met. Overall, TTTF improved clinicians' capacity to address tobacco use among homeless and vulnerably housed individuals and can serve as a model for tobacco control efforts in similar agencies.

Background: Whiplash associated disorder (WAD), a common and disabling condition, incurs huge burden and costs to Australia. Yet, current treatments for whiplash are not very effective; improved outcomes are urgently needed. Clinical guidelines recommend simple analgesia (paracetamol and non-steroidal anti-inflammatory drugs) but there have been no trials of guideline-recommended drugs. This study will investigate the effectiveness of evidence-based advice (EBA), paracetamol, naproxen, and both paracetamol and naproxen, in reducing daily neck pain and preventing chronic neck pain after whiplash injury., Methods: This study is a pilot series of multi-cycle, double-blinded, randomised N-of-1 trials, nested in a multiple baseline design. The design will comprise three baselines of 5, 8 or 11 days duration. Post enrolment, participants will be randomly assigned to one of the baselines. Fifteen participants with acute (<2 weeks) Grade II WAD, experiencing at least moderate pain (NRS: ≥ 5/10), and at risk of poor recovery will be recruited from hospitals in Queensland, Australia, and through local physiotherapists. Patients will receive EBA plus a randomised sequence of three cycles of ten day treatment triplets (paracetamol designated as a C phase, naproxen, designated as a D phase, and both paracetamol and naproxen, designated as an E phase)., Discussion: We will test the effects of different treatments on the primary outcome of average neck pain intensity collected daily and at 4 and 7 months post-injury. Secondary outcomes, including disability, depression, post-traumatic stress symptoms, pain catastrophizing, and feasibility of study procedures, will also be evaluated. The results of this study will inform a larger trial aiming to strengthen the evidence on EBA and simple analgesics for WAD., Trial Registration: Clinical Trials Primary Registry: Australian and New Zealand Clinical Trials Registry., Clinical Trial Registration Number: ACTRN12618001291279., Date of Registration: 31/07/2018., Primary Trial Sponsor: The University of Queensland, Brisbane QLD 4072 Australia., Funding: The University of Queensland., Competing Interests: Nil declared., (© 2019 Published by Elsevier Inc.)

Background: Many psychotropic medications affect oral health. This review identified oral side effects for antidepressant, antipsychotic, anticonvulsant, antianxiety and sedative drugs that are recommended in Australia for the management of common mental illnesses and provides recommendations to manage these side-effects., Methods: The Australian Therapeutic Guidelines and the Australian Medicines Handbook were searched for medications used to treat common mental health conditions. For each medication, the generic name, class, and drug company reported side-effects were extracted from the online Monthly Index of Medical Specialties (eMIMs) and UpToDate databases. Meyler's Side Effect of Drugs Encyclopaedia was used to identify additional oral adverse reactions to these medications., Results: Fifty-seven drugs were identified: 23 antidepressants, 22 antipsychotics or mood stabilisers, and 12 anxiolytic or sedative medications. Xerostomia (91%) the most commonly reported side effect among all classes of medications of the 28 identified symptoms. Other commonly reported adverse effects included dysguesia (65%) for antidepressants, and tardive dyskinesia (94%) or increased salivation (78%) for antipsychotic medications., Conclusions: While xerostomia has often been reported as a common adverse effect of psychotropic drugs, this review has identified additional side effects including dysguesia from antidepressants and tardive dyskinesia and increased salivation from antipsychotics. Clinicians should consider oral consequences of psychotropic medication in addition to other side-effects when prescribing. For antidepressants, this would mean choosing duloxetine, agomelatine and any of the serotonin re-uptake inhibitors except sertraline. In the case of antipsychotics and mood stabilisers, atypical agents have less oral side effects than older alternatives., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Many medications used to manage multiple sclerosis (MS) affect oral health. This review aimed to identify the oral side-effects of the current drugs recommended in Australia to treat MS and make dental practitioners aware of the range of symptoms., Methods: The Australian Therapeutic Guidelines and the Australian Medicines Handbook were searched for medications used to treat MS. For each medication, the generic name, class, route of administration, dosage and drug company reported side-effects were extracted from the online Monthly Index of Medical Specialties (MIMs) database. Meyler's Side-effect of Drugs Encyclopaedia was used to identify any additional oral adverse reactions to medications used to treat MS., Results: Fourteen drugs were identified for the treatment of MS progression and 13 drugs for the treatment of MS symptoms. For these medications, 18 oral side-effects were documented: xerostomia was the most common, followed by dysgeusia, dysphagia, mouth ulceration and sinusitis. Anticholinergic drugs caused xerostomia while immunosuppressants resulted in more infection-related side-effects., Conclusions: Dental practitioners should be aware of the range of symptoms likely to be reported by this population. Clinicians are encouraged to continue providing dental care for their patients who develop MS and refer complex cases to specialists., (© 2017 Australian Dental Association.)

Purpose: To examine the microtensile bond strengths (microTBS) of six 1-step and one 2-step self-etch systems to dentin and ground enamel., Methods: Resin composite buildups were bonded to buccal and lingual ground enamel surfaces, and to occlusal dentin of third molars using the following 1-step adhesives: Xeno IV (XE), GBond (GB), Clearfil S3 Bond (CS3); Adper Prompt L-Pop (AD); Go (GO) and All Bond SE (1-step; ABSE), in comparison to the 2-steps (All Bond SE; (2-step ABSE) and Clearfil SE Bond (CSE). After storage in water (24 hour/37 degrees C), the bonded specimens were sectioned into beams approximately 0.9 mm2. These beams were tested until failure at a crosshead speed of 0.5 mm/minute. Data were subjected to appropriate statistical analysis (alpha = 0.05)., Results: The total number of specimens/premature debonding specimens (PDS) for each adhesive were, respectively, in enamel: XE (59/36), GB (63/33), CS3 (62/29), AD (47/19), GO (53/14), 1-step ABSE (61/29), 2-step ABSE (57/14) and CSE (58/13); and in dentin: XE (51/24), GB (50/7), CS3 (53/13), ADP (51/1), GO (43/8), 1-step ABSE (59/2), 1-step ABSE (56/0) and CSE (47/0). The fracture pattern was predominantly adhesive/mixture for all adhesives in dentin (51.5 to 99%) and in enamel (34.8 to 75.4%), however XE (61.2) and GB (52.5) had more than 50% PDS. For ground enamel, no significant difference was detected among materials in the same subgroup (with or without PDS). However, there was a significant difference for all adhesives when subgroups (with and without PDS, respectively) were tested against each other: XE (7.9/10.5 double dagger 19.7/5.5), GB (8.6/10.5 double dagger 17.2/7.4), CS3 (8.8/10.3 double dagger 15.7/5.6), AD (13.0/12.0 = 20.3/8.9), Go (18.2/13.8 = 25.1/10.0), 1-step ABSE (15.9/11.4 = 16.2/5.4), 2-step ABSE (8.4/9.1 double dagger 25.3/7.9) and CSE (17.6/16.3 = 19.9/7.8). For dentin, no difference was found when subgroups for the same adhesive were tested against each other (with or without PDS). However, significantly higher resin-dentin bond strength was observed for adhesives in the following order: CSE (38.5/6.5 = 38.5/6.5) > or = 2-step ABSE (41.4/16.3 double dagger 42.4/19.3) = 1-step ABSE (43.9/17.7 = 44.2/17.1) = AD (34.4/14.2 = 35.2/13.3) < or = CS3 (31.9/19.4 = 40.1/13.4) double dagger GB (14.3/6.3 = 16.3/5.9) = Go (14.2/13.9 = 22.4/12.6) double dagger XE (7.1/5.4 = 9.5/5.1), respectively for with PDS and without PDS. All materials showed similar performance on ground enamel. The performance of one-step self-etch systems to dentin appears to be material-dependent. Adper Prompt L-Pop, Clearfil S3 Bond and the 1-step All Bond SE had microTBS similar to Clearfil SE Bond and the 2-step All Bond SE, while Xeno IV and GBond had significantly lower microTBS values. Go had an intermediate performance.

Several protein tyrosine phosphatases (PTPases) have been implicated as regulatory agents in the insulin-stimulated signal transduction pathway, including PTP1B, PTPalpha, and LAR. Furthermore, since all three enzymes are suggested to serve as negative regulators of insulin signaling, one or more may play a pivotal role in the pathogenesis of insulin resistance. We report herein the acquisition of highly selective PTP1B-targeted inhibitors. We recently demonstrated that PTP1B contains two proximal aromatic phosphate binding sites [Puius, Y. A., Zhao, Y., Sullivan, M., Lawrence, D. S., Almo S. C., and Zhang, Z. Y. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 13420-5], and we have now employed this structural feature to design and synthesize an array of bis(aryldifluorophosphonates). Not only do the lead compounds serve as potent inhibitors of PTP1B but, in addition, several exhibit selectivities for PTP1B versus PTPalpha, LAR, and VHR that are greater than 2 orders in magnitude.