Expanding the bandwidth of fluorescence-detected two-dimensional electronic spectroscopy using a broadband continuum probe pulse pair.

We demonstrate fluorescence-detected two-dimensional electronic spectroscopy (F-2DES) with a broadband, continuum probe pulse pair in the pump-probe geometry. The approach combines a pump pulse pair generated by an acousto-optic pulse-shaper with precise control of the relative pump pulse phase and time delay with a broadband, continuum probe pulse pair created using the Translating Wedge-based Identical pulses eNcoding System (TWINS). The continuum probe expands the spectral range of the detection axis and lengthens the waiting times that can be accessed in comparison to implementations of F-2DES using a single pulse-shaper. We employ phase-cycling of the pump pulse pair and take advantage of the separation of signals in the frequency domain to isolate rephasing and non-rephasing signals and optimize the signal-to-noise ratio. As proof of principle, we demonstrate broadband F-2DES on a laser dye and bacteriochlorophyll a.

Commentary on "Same-Sex Marriage and Common Mental Health Diagnoses: A Sibling Comparison and Adoption Approach".

This is a commentary on "Same-sex Marriage and Common Mental Health Diagnoses: A Sibling Comparison and Adoption Approach" by Xu, Rahman, Hiyoshi, and Montgomery. It considers the advantages and disadvantages of the study design and the contribution the study makes to the scientific literature. Discussed are issues of phenotype accuracy especially with respect to sexual orientation and other potential confounds, and some comments on common misunderstandings of the meaning and implications of findings of genetic correlations to human behavior.

On the Trail of Molecular Hydrophilicity and Hydrophobicity at Aqueous Interfaces.

Uncovering microscopic hydrophilicity and hydrophobicity at heterogeneous aqueous interfaces is essential as it dictates physico/chemical properties such as wetting, the electrical double layer, and reactivity. Several molecular and spectroscopic descriptors were proposed, but a major limitation is the lack of connections between them. Here, we combine density functional theory-based MD simulations (DFT-MD) and SFG spectroscopy to explore how interfacial water responds in contact with self-assembled monolayers (SAM) of tunable hydrophilicity. We introduce a microscopic metric to track the transition from hydrophobic to hydrophilic interfaces. This metric combines the H/V descriptor, a structural descriptor based on the preferential orientation within the water network in the topmost binding interfacial layer (BIL) and spectroscopic fingerprints of H-bonded and dangling OH groups of water carried by BIL-resolved SFG spectra. This metric builds a bridge between molecular descriptors of hydrophilicity/hydrophobicity and spectroscopically measured quantities and provides a recipe to quantitatively or qualitatively interpret experimental SFG signals.

Wedge-Based Design for Phase Stable and Phase Accurate Heterodyne-Detected Sum-Frequency Generation Spectroscopy.

Phase sensitive and heterodyne-detected (HD) sum-frequency generation (SFG) spectroscopy offers the ability to separate the nonlinear susceptibility into its real and imaginary components. This provides information about the absolute orientation of molecules at interfaces while also producing an absorptive spectrum that is linear in spectral composition and can easily be decomposed into different spectral components. However, simultaneously obtaining phase accuracy and phase stability remains a challenge in SFG. Here we present a new experimental design for HD-SFG spectroscopy that incorporates a wedge pair to accurately control the timing between the local oscillator and the sample signal. This experimental approach provides high phase accuracy and long-time phase stability in a compact and flexible configuration.

An exploratory test of a couples-based condom-use intervention designed to promote pleasurable and safer penile-vaginal sex among university students.

Objective: Dual use of male condoms and female contraceptives is widely advocated for unplanned pregnancy prevention, yet college students often neglect condoms. This feasibility and acceptability study assessed the efficacy of a self-guided home-based condom-promotion intervention among college students in heterosexual relationships. Participants: Fifty-nine couples who had been together at least 30 days and had penile-vaginal sex at least twice weekly. Methods: Assessments were done at baseline and 6 months later. Outcomes were frequency of condom-unprotected penile-vaginal sex and four psychosocial mediators of condom use. Results: Frequency of unprotected penile-vaginal sex decreased over time. Several corresponding psychosocial mediators showed change, particularly among women. Using actor-partner interdependence modeling, men's increase in condom use was associated with an increase in women's sexual pleasure. Conclusion: Findings support implementation of a brief, self-guided, home-based condom-use intervention that could lower incidence of unplanned pregnancy and STIs among heterosexually active college students.

The Presence and Potential Role of ALDH1A2 in the Glioblastoma Microenvironment.

Glioblastoma (GBM) is the most aggressive malignant glioma. Therapeutic targeting of GBM is made more difficult due to its heterogeneity, resistance to treatment, and diffuse infiltration into the brain parenchyma. Better understanding of the tumor microenvironment should aid in finding more effective management of GBM. GBM-associated macrophages (GAM) comprise up to 30% of the GBM microenvironment. Therefore, exploration of GAM activity/function and their specific markers are important for developing new therapeutic agents. In this study, we identified and evaluated the expression of ALDH1A2 in the GBM microenvironment, and especially in M2 GAM, though it is also expressed in reactive astrocytes and multinucleated tumor cells. We demonstrated that M2 GAM highly express ALDH1A2 when compared to other ALDH1 family proteins. Additionally, GBM samples showed higher expression of ALDH1A2 when compared to low-grade gliomas (LGG), and this expression was increased upon tumor recurrence both at the gene and protein levels. We demonstrated that the enzymatic product of ALDH1A2, retinoic acid (RA), modulated the expression and activity of MMP-2 and MMP-9 in macrophages, but not in GBM tumor cells. Thus, the expression of ALDH1A2 may promote the progressive phenotype of GBM.

Comment on "Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior".

The phenotypic measures used by Ganna et al (Research Articles, 30 August 2019, p. 882) lump together predominantly heterosexual, bisexual, and homosexual individuals, including those who have experimented with a same-sex partner only once. This may have resulted in misleading associations to personality traits unrelated to understood categories of human sexuality. Scientific studies of human sexuality should use validated and reliable measures of sexual behaviors, attractions, and identities that capture the full spectrum of complexity.

Attenuating hypoxia driven malignant behavior in glioblastoma with a novel hypoxia-inducible factor 2 alpha inhibitor.

Hypoxia inducible factor (HIFs) signaling contributes to malignant cell behavior in glioblastoma (GBM). We investigated a novel HIF2α inhibitor, PT2385, both in vitro, with low-passage patient-derived cell lines, and in vivo, using orthotopic models of glioblastoma. We focused on analysis of HIF2α expression in situ, cell survival/proliferation, and survival in brain tumor-bearing mice treated with PT2385 alone and in combination with standard of care chemoradiotherapy. HIF2α expression increased with glioma grade, with over half of GBM specimens HIF2α positive. Staining clustered in perivascular and perinecrotic tumor regions. Cellular phenotype including proliferation, viability, migration/invasion, and also gene expression were not altered after PT2385 treatment. In the animal model, PT2385 single-agent treatment did improve median overall survival compared to placebo (p = 0.04, n = 21) without a bioluminescence correlate (t = 0.67, p = 0.52). No difference in animal survival was seen in combination treatment with radiation (RT)/temozolomide (TMZ)/PT2385 (p = 0.44, n = 10) or mean tumor bioluminescence (t 1.13, p = 0.32). We conclude that HIF2α is a reasonable novel therapeutic target as expressed in the majority of glioblastomas in our cohort. PT2385 as a single-agent was efficacious in vivo, however, an increase in animal survival was not seen with PT2385 in combination with RT/TMZ. Further study for targeting HIF2α as a therapeutic approach in GBM is warranted.

A home-practice intervention for increasing condom use among university undergraduates.

The consistently high rate of sexually transmitted infections among people 18-24 years old warrants novel strategies promoting condom use among large segments of this population. Ample opportunity exits to employ such strategies in university settings. This study evaluated a sex-positive, home-practice intervention designed to promote condom use among university undergraduates engaging in penile-vaginal intercourse (PVI). A sample of 29 opposite-sex undergraduate couples, engaging in PVI, was recruited from a large university. After teaching couples about condom use, a health educator helped couples select condoms/lubricants from options comprising various sizes, fits, shapes, textures, and other features. A 30-day 'homework assignment' was made to use these products while reducing condom use errors/problems and enhancing sexual pleasure. A repeated measures design, with a six-month observation period, was used to evaluate the program. Over the six-month period, the mean frequency of condomless PVI decreased from 26.4 to 3.9 times (P < .001). Significant and favorable changes were also found relative to attitudes toward condom use (P = .027) and in condom use self-efficacy (P < .001). Most students completing the follow-up assessment indicated the intervention would favorably impact their future condom use. Findings suggest this intervention program may be important to promoting condom use among university couples engaging in PVI.

Challenges to Successful Implementation of the Immune Checkpoint Inhibitors for Treatment of Glioblastoma.

Glioblastoma (GBM) is the most common and aggressive malignant glioma, treatment of which has not improved significantly in many years. This is due to the unique challenges that GBM tumors present when designing and implementing therapies. Recently, immunotherapy in the form of immune checkpoint inhibition (ICI) has revolutionized the treatment of various malignancies. The application of immune checkpoint inhibition in GBM treatment has shown promising preclinical results. Unfortunately, this has met with little to no success in the clinic thus far. In this review, we will discuss the challenges presented by GBM tumors that likely limit the effect of ICI and discuss the approaches being tested to overcome these challenges.

A first-in-human proof-of-concept trial of intravaginal artesunate to treat cervical intraepithelial neoplasia 2/3 (CIN2/3).

OBJECTIVE: Most treatment options for cervical intraepithelial neoplasia 2/3 (CIN2/3) are either excisional or ablative, and require sequential visits to health care providers. Artesunate, a compound that is WHO-approved for treatment of acute malaria, also has cytotoxic effect on squamous cells transformed by HPV. We conducted a first-in-human Phase I dose-escalation study to assess the safety and efficacy of self-administered artesunate vaginal inserts in biopsy-confirmed CIN2/3. METHODS: Safety analyses were based on patients who received at least one dose, and were assessed by the severity, frequency, and duration of reported adverse events. Tolerability was assessed as the percentage of subjects able to complete their designated dosing regimen. Modified intention-to-treat analyses for efficacy and viral clearance were based on patients who received at least one dose for whom endpoint data were available. Efficacy was defined as histologic regression to CIN1 or less. Viral clearance was defined as absence of HPV genotoype (s) detected at baseline. RESULTS: A total of 28 patients received 1, 2, or 3 five-day treatment cycles at study weeks 0, 2, and 4, respectively, prior to a planned, standard-of-care resection at study week 15. Reported adverse events were mild, and self-limited. In the modified intention-to-treat analysis, histologic regression was observed in 19/28 (67.9%) subjects. Clearance of HPV genotypes detected at baseline occurred in 9 of the 19 (47.4%) subjects whose lesions underwent histologic regression. CONCLUSIONS: Self-administered vaginal artesunate inserts were safe and well-tolerated, at clinically effective doses to treat CIN2/3. These findings support proceeding with Phase II clinical studies.

"Sex" and the Ace Spectrum: Definitions of Sex, Behavioral Histories, and Future Interest for Individuals Who Identify as Asexual, Graysexual, or Demisexual.

This paper explores how people (n = 1,093) who identify as asexual or on the ace spectrum (i.e., graysexual, demisexual) define sex behaviorally using a list of 22 specific behaviors and assesses their lifetime behavioral histories and interest in future engagement in these activities. Lifetime behavioral history was also compared to each individual's personal definition of sex. Asexual, demisexual, and graysexual groups defined sex similarly. Although there were significant group differences in behavioral histories, almost all had engaged in behaviors included in their personal definition of sex. There was little interest in engaging in "sex" in the future (~4% asexual and graysexual groups, ~12% demisexuals, p < .004). Reasons for or against engaging in these behaviors in the future were explored qualitatively. The most common reasons were classified as "Emotional connection," "Partner interest," and "Disinterest-Disgust," with significant group differences noted. Disinterest-Disgust was the most frequently cited reason for the asexual group (43%). Emotional Connection was the most frequent reason for the graysexual (40%) and demisexual (69.3%) groups. Findings highlight the heterogeneity of the ace community with regard to history of and interest in sexual behaviors and the importance of distinguishing between wanting and being willing to engage in sexual behaviors across the ace spectrum.

Women's Sexual Satisfaction, Communication, and Reasons for (No Longer) Faking Orgasm: Findings from a U.S. Probability Sample.

We aimed to assess, among a U.S. probability sample of adult women: (1) the prevalence of, and reasons given for, faking and no longer faking orgasm, (2) women's histories of sexual non-communication and reasons for non-communication, (3) associations between sexual non-communication and sexual satisfaction and faking orgasm, (4) associations between specific sexual communication and recent sexual satisfaction, and (5) associations between specific sexual communication and faking orgasm. Respondents were 1008 adult women ages 18-94 from the GfK KnowledgePanel (a nationally representative probability sample of non-institutionalized and English-speaking adults), who completed a confidential Internet-based survey. Although 58.8% of female respondents reported having ever faked/pretended orgasm, 67.3% of those who had ever faked orgasm no longer did. Women who continued to fake orgasms were more likely to indicate embarrassment talking about sex with their partner in explicit ways and were less likely to agree that they and their partner are able to talk specifically about what makes sex more pleasurable for them. More than half (55.4%) of women reported they had wanted to communicate with a partner regarding sex but decided not to; the most common reasons were not wanting to hurt a partner's feelings (42.4%), not feeling comfortable going into detail (40.2%), and embarrassment (37.7%). Greater self-reported sexual satisfaction was associated with more comfortable sexual communication. Study findings and implications for professionals are discussed in the context of adult sexual development and learning. This includes growing more comfortable talking with a partner about sexual preferences and sexual pleasure.

Heterodyne-detected sum frequency generation of water at surfaces with varying hydrophobicity.

Aqueous surfaces mediate many atmospheric, biological, and technological processes. At the interface, the bulk hydrogen-bonding network is terminated and the interfacial water molecules restructure according to the surface chemistry of the interface. Given the complexity of both natural and technical aqueous interfaces, self-assembled monolayers provide a platform for controllably tuning the chemical composition of the surface and thus the water restructuring. Here, we study a hydrophobic monolayer, a hydrophilic monolayer, and a mixed hydrophobic/hydrophilic monolayer in contact with water. Monolayers composed of both hydrophilic and hydrophobic chains mimic the complex and heterogeneous chemical composition of natural and technological surfaces. By employing heterodyne-detected sum frequency generation, the purely absorptive vibrational line shape of interfacial water is measured experimentally. We examined the structure of the interfacial water in contact with each of the monolayers by analyzing the relative dipole moment orientations and fitting the imaginary component of χ(2) with a combination of Lorentzian and Gaussian line shapes. For all of the monolayers, the hydrogen-bonded water points toward the monolayer, which is opposite of the orientation of the hydrogen-bonded water at the air-water interface. Additionally, a strongly hydrogen-bonded water species exists for the monolayers containing hydrophilic chains. The spectroscopic results suggest that the microscopic water structure in contact with the mixed monolayer is dominated by the hydrophilic parts of the monolayer, while the contact angle shows that at the macroscopic level the surface properties lie closer to the pure hydrophobic monolayer.

HTLV-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of Heme Oxygenase I.

Adult T-cell Leukemia (ATL) is a lymphoproliferative disease of CD4+ T-cells infected with Human T-cell Leukemia Virus type I (HTLV-1). With the exception of allogeneic hematopoietic stem cell transplantation, there are no effective treatments to cure ATL, and ATL cells often acquire resistance to conventional chemotherapeutic agents. Accumulating evidence shows that development and maintenance of ATL requires key contributions from the viral protein, HTLV-1 basic leucine zipper factor (HBZ). In this study we found that HBZ activates expression of Heme Oxygenase 1 (HMOX-1), a component of the oxidative stress response that functions to detoxify free heme. Transcription of HMOX1 and other antioxidant genes is regulated by the small Mafs. These cellular basic leucine zipper (bZIP) factors control transcription by forming homo- or heterodimers among themselves or with other cellular bZIP factors that then bind Maf responsive elements (MAREs) in promoters or enhancers of antioxidant genes. Our data support a model in which HBZ activates HMOX1 transcription by forming heterodimers with the small Mafs that bind MAREs located in an upstream enhancer region. Consistent with this model, we found that HMOX-1 is upregulated in HTLV-1-transformed T-cell lines and confers these cells with resistance to heme-induced cytotoxicity. In this context, HBZ-mediated activation of HMOX-1 expression may contribute to resistance of ATL cells to certain chemotherapeutic agents. We also provide evidence that HBZ counteracts oxidative stress caused by two other HTLV-1-encoded proteins, Tax and p13. Tax induces oxidative stress as a byproduct of driving mitotic expansion of infected cells, and p13 is believed to induce oxidative stress to eliminate infected cells that have become transformed. Therefore, in this context, HBZ-mediated activation of HMOX-1 expression may facilitate transformation. Overall, this study characterizes a novel function of HBZ that may support the development and maintenance of ATL.

Corrigendum to: Decision making over condom use during menses to avert sexually transmissible infections.

Background:The aim of this study was to test the hypothesis that receptive partners in penile-vaginal intercourse (PVI) who exercise independent decision making over condom use during menses do so to avert sexually transmissible infection (STI) transmission or acquisition. Methods: Data were collected through a partnership with Clue, the industry-leading female health app. A brief web-based questionnaire was developed, translated into 10 languages, and made accessible via a URL link sent to Clue users and posted on social media. Inclusion criteria were: age ≥14 years, not being currently pregnant and engaging in PVI and condom use during menses in the past 3 months. The analytical subsample comprised 12889 respondents residing in 146 countries. Results: Twenty per cent indicated independent decision making about condom use during menses. Independent decision making was associated with lower odds of reporting that condoms were used for contraception (adjusted odds ratio (aOR) 0.65; 99% confidence interval (CI) 0.57-0.73) and higher odds that they were used for the prevention of STIs (aOR 1.44; 99% CI 1.28-1.61). A third significant finding pertained to always using condoms during menses; this was less likely among those indicating independent (female only) decision making (aOR 0.69; 99% CI 0.62-0.78). Non-significant associations with another two outcomes were found: protecting the partner against menstrual blood and protecting themselves against semen. Conclusions: Findings from people in 146 countries strongly support the hypothesis that those exercising independent decision making over condom use during menses do so to avert STI transmission or acquisition. That only one-fifth of this global sample reported this type of independent decision making suggests that empowerment-oriented (structural-level) interventions may be advantageous for individuals who are the receptive partner in PVI that occurs during menses.

Decision making over condom use during menses to avert sexually transmissible infections.

Background The aim of this study was to test the hypothesis that receptive partners in penile-vaginal intercourse (PVI) who exercise independent decision making over condom use during menses do so to avert sexually transmissible infection (STI) transmission or acquisition. METHODS: Data were collected through a partnership with Clue, the industry-leading female health app. A brief web-based questionnaire was developed, translated into 10 languages, and made accessible via a URL link sent to Clue users and posted on social media. Inclusion criteria were: age ≥14 years, not being currently pregnant and engaging in PVI and condom use during menses in the past 3 months. The analytical subsample comprised 12889 respondents residing in 146 countries. RESULTS: Twenty per cent indicated independent decision making about condom use during menses. Independent decision making was associated with lower odds of reporting that condoms were used for contraception (adjusted odds ratio (aOR) 0.65; 99% confidence interval (CI) 0.57-0.73) and higher odds that they were used for the prevention of STIs (aOR 1.44; 99% CI 1.28-1.61). A third significant finding pertained to always using condoms during menses; this was less likely among those indicating independent (female only) decision making (aOR 0.69; 99% CI 0.62-0.78). Non-significant associations with another two outcomes were found: protecting the partner against menstrual blood and protecting themselves against semen. CONCLUSIONS: Findings from people in 146 countries strongly support the hypothesis that those exercising independent decision making over condom use during menses do so to avert STI transmission or acquisition. That only one-fifth of this global sample reported this type of independent decision making suggests that empowerment-oriented (structural-level) interventions may be advantageous for individuals who are the receptive partner in PVI that occurs during menses.

Relationships Among Sexual Identity, Sexual Attraction, and Sexual Behavior: Results from a Nationally Representative Probability Sample of Adults in the United States.

Sexual orientation is a multi-dimensional concept, at a minimum comprised of sexual identity, sexual attraction, and sexual behavior. Our study aimed to assess relationships among self-identified sexual identity, sexual attraction, and sexual behaviors in a probability sample of adults in the U.S. and to identify associated factors with diverse patterns. We collected data from adults in the 2015 National Survey of Sexual Health and Behavior, an Internet-based nationally representative probability survey of the general U.S. population. Concordance between sexual identity versus sexual attraction and sexual behaviors was assessed using percent agreement. We identified correlates of discordance using logistic regression. Concordance between sexual identity versus sexual attraction and past-year sexual behaviors was 94% and 96%, respectively, though our sample was predominately composed of heterosexual individuals. Women and sexual minority individuals reported greater discordance across sexuality-related measures than men and heterosexual individuals. Younger adults (aged 18-24 years) were more likely to report sexual behaviors discordant with sexual identity compared with older adults (including those ages 25-34 years). Higher levels of educational attainment were significantly associated with less discordance of reported recent sexual activity and sexual identity. Measures of sexual identity, attraction, and behaviors are not interchangeable. Future research should consider multiple sexuality-related measures in order to capture the complexity and variability of sexualities.

Loss of XIST in Breast Cancer Activates MSN-c-Met and Reprograms Microglia via Exosomal miRNA to Promote Brain Metastasis.

Up to 30% of patients with metastatic breast cancer eventually develop brain metastasis, yet the pathologic mechanism behind this development remains poorly understood. Here, we profiled long noncoding RNAs in brain metastatic tumors from patients with breast cancer and found that the X-inactive-specific transcript (XIST) was significantly downregulated in these tissues. XIST expression levels inversely correlated with brain metastasis, but not with bone metastasis in patients. Silencing of XIST preferentially promoted brain metastatic growth of XISThigh cells in our xenograft models. Moreover, knockout of XIST in mice mammary glands accelerated primary tumor growth as well as metastases in the brain. Decreased expression of XIST stimulated epithelial-mesenchymal transition and activated c-Met via MSN-mediated protein stabilization, which resulted in the promotion of stemness in the tumor cells. Loss of XIST also augmented secretion of exosomal miRNA-503, which triggered M1-M2 polarization of microglia. This M1-M2 conversion upregulated immune suppressive cytokines in microglia that suppressed T-cell proliferation. Furthermore, we screened an FDA-approved drug library and identified fludarabine as a synthetic lethal drug for XISTlow breast tumor cells and found that fludarabine blocked brain metastasis in our animal model. Our results indicate that XIST plays a critical role in brain metastasis in breast cancer by affecting both tumor cells and the tumor microenvironment and that the XIST-mediated pathway may serve as an effective target for treating brain metastasis.Significance: These findings describe mechanisms of how loss of the lncRNA XIST promotes brain metastasis in breast cancer and identify fludarabine as a potential therapeutic agent that specifically eliminates XISTlow tumor cells in the brain. Cancer Res; 78(15); 4316-30. ©2018 AACR.