High accuracy theoretical investigations of CaF, SrF, and BaF and implications for laser-cooling

The NL-eEDM collaboration is building an experimental setup to search for the permanent electric dipole moment of the electron in a slow beam of cold barium fluoride molecules [Eur. Phys. J. D, 72, 197 (2018)]. Knowledge of molecular properties of BaF is thus needed to plan the measurements and in particular to determine an optimal laser-cooling scheme. Accurate and reliable theoretical predictions of these properties require incorporation of both high-order correlation and relativistic effects in the calculations. In this work theoretical investigations of the ground and the lowest excited states of BaF and its lighter homologues, CaF and SrF, are carried out in the framework of the relativistic Fock-space coupled cluster (FSCC) and multireference configuration interaction (MRCI) methods. Using the calculated molecular properties, we determine the Franck-Condon factors (FCFs) for the $A^2\Pi_{1/2} \rightarrow X^2\Sigma^{+}_{1/2}$ transition, which was successfully used for cooling CaF and SrF and is now considered for BaF. For all three species, the FCFs are found to be highly diagonal. Calculations are also performed for the $B^2\Sigma^{+}_{1/2} \rightarrow X^2\Sigma^{+}_{1/2}$ transition recently exploited for laser-cooling of CaF; it is shown that this transition is not suitable for laser-cooling of BaF, due to the non-diagonal nature of the FCFs in this system. Special attention is given to the properties of the $A'^2\Delta$ state, which in the case of BaF causes a leak channel, in contrast to CaF and SrF species where this state is energetically above the excited states used in laser-cooling. We also present the dipole moments of the ground and the excited states of the three molecules and the transition dipole moments (TDMs) between the different states.Comment: Minor changes; The following article has been submitted to the Journal of Chemical Physics. After it is published, it will be found at https://publishing.aip.org/resources/librarians/products/journals

Systematic study and uncertainty evaluation of P, T-odd molecular enhancement factors in BaF

A measurement of the magnitude of the electric dipole moment of the electron (eEDM) larger than that predicted by the Standard Model (SM) of particle physics is expected to have a huge impact on the search for physics beyond the SM. Polar diatomic molecules containing heavy elements experience enhanced sensitivity to parity (P) and time-reversal (T)-violating phenomena, such as the eEDM and the scalar-pseudoscalar (S-PS) interaction between the nucleons and the electrons, and are thus promising candidates for measurements. The NL-eEDM collaboration is preparing an experiment to measure the eEDM and S-PS interaction in a slow beam of cold BaF molecules [P. Aggarwal et al., Eur. Phys. J. D 72, 197 (2018)]. Accurate knowledge of the electronic structure parameters, Wd and Ws, connecting the eEDM and the S-PS interaction to the measurable energy shifts is crucial for the interpretation of these measurements. In this work, we use the finite field relativistic coupled cluster approach to calculate the Wd and Ws parameters in the ground state of the BaF molecule. Special attention was paid to providing a reliable theoretical uncertainty estimate based on investigations of the basis set, electron correlation, relativistic effects, and geometry. Our recommended values of the two parameters, including conservative uncertainty estimates, are 3.13 ±0.12×1024Hzecm for Wd and 8.29 ± 0.12 kHz for W

Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity

Several trypanosomatid cyclic nucleotide phosphodiesterases (PDEs) possess a unique, parasite-specific cavity near the ligand-binding region that is referred to as the P-pocket. One of these enzymes, Trypanosoma brucei PDE B1 (TbrPDEB1), is considered a drug target for the treatment of African sleeping sickness. Here, we elucidate the molecular determinants of inhibitor binding and reveal that the P-pocket is amenable to directed design. By iterative cycles of design, synthesis, and pharmacological evaluation and by elucidating the structures of inhibitor-bound TbrPDEB1, hPDE4B, and hPDE4D complexes, we have developed 4a,5,8,8a-tetrahydrophthalazinones as the first selective TbrPDEB1 inhibitor series. Two of these, 8 (NPD-008) and 9 (NPD-039), were potent (Ki = 100 nM) TbrPDEB1 inhibitors with antitrypanosomal effects (IC50 = 5.5 and 6.7 ?M, respectively). Treatment of parasites with 8 caused an increase in intracellular cyclic adenosine monophosphate (cAMP) levels and severe disruption of T. brucei cellular organization, chemically validating trypanosomal PDEs as therapeutic targets in trypanosomiasis

HPV and anal cancer in HIV-infected individuals: a review

HIV infection is one of the strongest risk factors for anal squamous cell cancer (ASCC). Most ASCC are caused by HPV, and most HPV-associated ASCC are caused by HPV-16. Anal HPV infections are very common in men who have sex with men (MSM), and nearly universal among HIV-infected MSM. High-grade anal intraepithelial neoplasia (HGAIN), the precursor for ASCC, is present in about 30 % of HIV+ MSM, but neither the progression rate to ASCC nor the regression rate are known. The incidence rate of ASCC among HIV-infected people has risen in the first decade after cART became available, but appears to be plateauing recently. Anal cytology has poor sensitivity and specificity. High resolution anoscopy (HRA) is advocated by some as a screening tool in high-risk groups, but is cumbersome and time-consuming and it is unknown whether HRA followed by treatment of HGAIN prevents ASCC. More research is needed on progression and regression rates of HGAIN, on effective therapy of HGAIN, and on biomarkers that predict HGAIN or anal cancer. HPV vaccination and earlier start of cART may prevent most anal cancers in the long ru

HPV and anal cancer in HIV-infected individuals: a review

HIV infection is one of the strongest risk factors for anal squamous cell cancer (ASCC). Most ASCC are caused by HPV, and most HPV-associated ASCC are caused by HPV-16. Anal HPV infections are very common in men who have sex with men (MSM), and nearly universal among HIV-infected MSM. High-grade anal intraepithelial neoplasia (HGAIN), the precursor for ASCC, is present in about 30 % of HIV+ MSM, but neither the progression rate to ASCC nor the regression rate are known. The incidence rate of ASCC among HIV-infected people has risen in the first decade after cART became available, but appears to be plateauing recently. Anal cytology has poor sensitivity and specificity. High resolution anoscopy (HRA) is advocated by some as a screening tool in high-risk groups, but is cumbersome and time-consuming and it is unknown whether HRA followed by treatment of HGAIN prevents ASCC. More research is needed on progression and regression rates of HGAIN, on effective therapy of HGAIN, and on biomarkers that predict HGAIN or anal cancer. HPV vaccination and earlier start of cART may prevent most anal cancers in the long ru

Diagnostic performance of PET/computed tomography versus PET/MRI and diffusion-weighted imaging in the N- and M-staging of breast cancer patients

Objective To provide a systematic review regarding the diagnostic performance of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) and diffusion-weighted imaging (DWI) compared to 18F-FDG PET/computed tomography (CT) focused on nodal and distant staging in breast cancer patients. Methods ThePubMedandEmbasedatabases were searched for relevant publications until April 2020. Two independent reviewers searched for eligible articles based on predefined in- and exclusion criteria, assessed quality and extracted data. Results Eleven eligible studies were selected from 561 publications identified by the search. In seven studies, PET/CT was compared with PET/MRI, and in five, PET/CT with DWI. Significantly higher sensitivity for PET/MRI compared to PET/CT in a lesion-based analysis was reported for all lesions together (77% versus 89%) in one study, osseous metastases (69-99% versus 92-98%) in two studies and hepatic metastases (70-75% versus 80-100%) in one study. Moreover, PET/MRI revealed a significantly higher amount of osseous metastases (90 versus 141) than PET/CT. PET/CT is associated with a statistically higher specificity than PET/MRI in the lesion detection of all lesions together (98% versus 96%) and of osseous metastases (100% versus 95%), both in one study. None of the reviewed studies reported significant differences between PET/CT and DWI for any of the evaluated sites. There is a trend toward higher specificity for PET/CT. Conclusion In general, there is a trend toward higher sensitivity and lower specificity of PET/MRI when compared to PET/CT. Results on the diagnostic performance of DWI are conflicting. Rather than evaluating it separate, it seems to have complementary value when combined with other MR sequences

Anal and penile high-risk human papillomavirus prevalence in HIV-negative and HIV-infected MSM

Anal and penile high-risk human papillomavirus (HPV) infection is associated with anogenital cancer, which is especially common in HIV-infected MSM. We assessed HPV prevalence and determinants in MSM. Analysis of baseline data from a prospective cohort study. MSM aged 18 years or older were recruited in Amsterdam, the Netherlands. Participants completed risk-factor questionnaires. HPV DNA was analyzed in anal and penile shaft self-swabs and genotyped using a sensitive PCR and reverse line blot assay (SPF10-PCR-DEIA-LiPA25-system). Multivariable logistic regression analyses were performed to assess determinants of high-risk HPV infection. MSM (n = 778) were recruited in 2010-2011, of whom 317 (41%) were HIV-infected. Prevalence of anal high-risk HPV infection was 45% in HIV-negative versus 65% in HIV-infected MSM (P  <0.001). HPV-16 was the most frequently detected type and was more common in HIV-infected MSM (13% in HIV-negative and 22% in HIV-infected MSM; P = 0.001). Prevalence of penile high-risk HPV infection was 16% in HIV-negative and 32% in HIV-infected MSM (P  <0.001). In multivariable analyses, HIV infection remained associated with anal [adjusted odds ratio (aOR) 2.2; 1.8-2.7] and penile (aOR 2.0; 1.4-2.9) high-risk HPV infection. Higher number of lifetime male sex partners was significantly associated with anal and penile high-risk HPV in HIV-negative, but not HIV-infected MSM. Receptive anal intercourse was associated with anal high-risk HPV in HIV-infected MSM. Anal and penile high-risk HPV infections are very common in MSM. HIV infection is a strong and independent determinant for anal and penile high-risk HPV infection. Determinants for HPV infection appear to differ between HIV-negative and HIV-infected MS

Seroepidemiology of high-risk HPV in HIV-negative and HIV-infected MSM: the H2M study

Men who have sex with men (MSM), in particular HIV-infected MSM, are at increased risk for diseases related to human papilloma virus (HPV). Our goal was to assess the effect of HIV status on the presence of type-specific antibodies against seven high-risk HPV types in HPV-unvaccinated MSM. Moreover, we compared determinants of HPV seropositivity between HIV-negative and HIV-infected MSM. MSM ≥18 years of age were recruited from the Amsterdam Cohort Studies, a sexually transmitted infection clinic, and an HIV-treatment center in Amsterdam, the Netherlands. Participants completed a risk-factor questionnaire; serum samples were analyzed using a fluorescent bead-based multiplex assay. MSM (n = 795) were recruited in 2010 to 2011; 758 MSM were included in this analysis. Median age was 40.1 years (interquartile range 34.8-47.5) and 308 MSM (40.6%) were HIV-infected. Seroprevalence of HPV-16 was 37.1% in HIV-negative and 62.7% in HIV-infected MSM (P < 0.001); seroprevalence of HPV-18 was 29.1% in HIV-negative MSM and 42.5% in HIV-infected MSM (P < 0.001). Similar patterns of seroprevalence were observed for HPV types 31, 33, 45, 52, and 58. In multivariable analyses, HPV seropositivity was associated with HIV infection [adjusted OR = 2.1; 95% confidence interval, 1.6-2.6]. In multivariable analyses stratified by HIV status, increasing age and number of lifetime male sex partners were significantly associated with HPV seropositivity in HIV-negative, but not HIV-infected MSM. Seroprevalence of high-risk HPV types is high among unvaccinated MSM. HIV infection is a strong and independent determinant for HPV seropositivity, which we hypothesize is because of increased persistence of HPV infection in HIV-infected MS

Measuring the electric dipole moment of the electron in BaF

Abstract: We investigate the merits of a measurement of the permanent electric dipole moment of the electron (eEDM) with barium monofluoride molecules, thereby searching for phenomena of CP violation beyond those incorporated in the standard model (SM) of particle physics. Although the BaF molecule has a smaller enhancement factor in terms of the effective electric field than other molecules used in current studies (YbF, ThO and ThF+), we show that a competitive measurement is possible by combining Stark-deceleration, laser-cooling and an intense primary cold source of BaF molecules. With the long coherent interaction times obtainable in a cold beam of BaF, a sensitivity of 5 × 10−30 e⋅cm for an eEDM is feasible. We describe the rationale, the challenges and the experimental methods envisioned to achieve this target. Graphical abstract: [Figure not available: see fulltext.]