Elements heavier than helium are produced in the lives and deaths of stars. This Review discusses when and how the process of nucleosynthesis made elements. High-mass stars fuse elements much faster, ...fuse heavier nuclei, and die more catastrophically than low-mass stars. The explosions of high-mass stars as supernovae release elements into their surroundings. Supernovae can leave behind neutron stars, which may later merge to produce additional heavy elements. Dying low-mass stars throw off their enriched outer layers, leaving behind white dwarfs. These white dwarfs may also later merge and synthesize elements as well. Because these processes occur on different time scales and produce a different pattern of elements, the composition of the Universe changes over time as stars populate the periodic table.
Triple-negative breast cancer (TNBC) is a heterogeneous disease that can be classified into distinct molecular subtypes by gene expression profiling. Considered a difficult-to-treat cancer, a ...fraction of TNBC patients benefit significantly from neoadjuvant chemotherapy and have far better overall survival. Outside of BRCA1/2 mutation status, biomarkers do not exist to identify patients most likely to respond to current chemotherapy; and, to date, no FDA-approved targeted therapies are available for TNBC patients. Previously, we developed an approach to identify six molecular subtypes TNBC (TNBCtype), with each subtype displaying unique ontologies and differential response to standard-of-care chemotherapy. Given the complexity of the varying histological landscape of tumor specimens, we used histopathological quantification and laser-capture microdissection to determine that transcripts in the previously described immunomodulatory (IM) and mesenchymal stem-like (MSL) subtypes were contributed from infiltrating lymphocytes and tumor-associated stromal cells, respectively. Therefore, we refined TNBC molecular subtypes from six (TNBCtype) into four (TNBCtype-4) tumor-specific subtypes (BL1, BL2, M and LAR) and demonstrate differences in diagnosis age, grade, local and distant disease progression and histopathology. Using five publicly available, neoadjuvant chemotherapy breast cancer gene expression datasets, we retrospectively evaluated chemotherapy response of over 300 TNBC patients from pretreatment biopsies subtyped using either the intrinsic (PAM50) or TNBCtype approaches. Combined analysis of TNBC patients demonstrated that TNBC subtypes significantly differ in response to similar neoadjuvant chemotherapy with 41% of BL1 patients achieving a pathological complete response compared to 18% for BL2 and 29% for LAR with 95% confidence intervals (CIs; 33, 51, 9, 28, 17, 41, respectively). Collectively, we provide pre-clinical data that could inform clinical trials designed to test the hypothesis that improved outcomes can be achieved for TNBC patients, if selection and combination of existing chemotherapies is directed by knowledge of molecular TNBC subtypes.
The efficacy of antiretroviral therapy depends on patient adherence to a daily medication regimen, yet many patients fail to adhere at high enough rates to maintain health and reduce the risk of ...transmitting HIV. Given the explosive global growth of cellular-mobile phone use, text-messaging interventions to promote adherence are especially appropriate. This meta-analysis synthesized available text messaging interventions to promote antiretroviral therapy adherence in people living with HIV.
We performed Boolean searches of electronic databases, hand searches of recent year conference abstracts and reverse searches. Included studies (1) targeted antiretroviral therapy adherence in a sample of people living with HIV, (2) used a randomized-controlled trial design to examine a text messaging intervention, and (3) reported at least one adherence measurement or clinical outcome.
Eight studies, including 9 interventions, met inclusion criteria. Text-messaging interventions yielded significantly higher adherence than control conditions (OR = 1.39; 95% CI = 1.18, 1.64). Sensitivity analyses of intervention characteristics suggested that studies had larger effects when interventions (1) were sent less frequently than daily, (2) supported bidirectional communication, (3) included personalized message content, and (4) were matched to participants' antiretroviral therapy dosing schedule. Interventions were also associated with improved viral load and/or CD4+ count (k = 3; OR = 1.56; 95% CI = 1.11, 2.20).
Text-messaging can support antiretroviral therapy adherence. Researchers should consider the adoption of less frequent messaging interventions with content and timing that is individually tailored and designed to evoke a reply from the recipient. Future research is needed in order to determine how best to optimize efficacy.
Chemical evolution models are powerful tools for interpreting stellar abundance surveys and understanding galaxy evolution. However, their predictions depend heavily on the treatment of inflow, ...outflow, star formation efficiency (SFE), the stellar initial mass function, the SN Ia delay time distribution, stellar yields, and stellar population mixing. Using flexCE, a flexible one-zone chemical evolution code, we investigate the effects of and trade-offs between parameters. Two critical parameters are SFE and the outflow mass-loading parameter, which shift the knee in O/Fe-Fe/H and the equilibrium abundances that the simulations asymptotically approach, respectively. One-zone models with simple star formation histories follow narrow tracks in O/Fe-Fe/H unlike the observed bimodality (separate high- and low- sequences) in this plane. A mix of one-zone models with inflow timescale and outflow mass-loading parameter variations, motivated by the inside-out galaxy formation scenario with radial mixing, reproduces the two sequences better than a one-zone model with two infall epochs. We present X/Fe-Fe/H tracks for 20 elements assuming three different supernova yield models and find some significant discrepancies with solar neighborhood observations, especially for elements with strongly metallicity-dependent yields. We apply principal component abundance analysis to the simulations and existing data to reveal the main correlations among abundances and quantify their contributions to variation in abundance space. For the stellar population mixing scenario, the abundances of -elements and elements with metallicity-dependent yields dominate the first and second principal components, respectively, and collectively explain 99% of the variance in the model. flexCE is a python package available at https://github.com/bretthandrews/flexCE.
Targeted therapy with imatinib and other selective tyrosine kinase inhibitors has transformed the treatment of chronic myeloid leukemia. Unlike chronic myeloid leukemia, chronic lymphocytic leukemia ...(CLL) lacks a common genetic aberration amenable to therapeutic targeting. However, our understanding of normal B-cell versus CLL biology points to differences in properties of B-cell receptor (BCR) signaling that may be amenable to selective therapeutic targeting. The applica-tion of mouse models has further expanded this understanding and provides information about targets in the BCR signaling pathway that may have other important functions in cell development or long-term health. In addition, overexpression or knockout of selected targets offers the potential to validate targets genetically using new mouse models of CLL. The initial success of BCR-targeted therapies has promoted much excitement in the field of CLL. At the present time, GS-1101, which reversibly inhibits PI3Kδ, and ibrutinib (PCI-32765), an irreversible inhibitor of Bruton tyrosine kinase, have generated the most promising early results in clinical trials including predominately refractory CLL where durable disease control has been observed. This review provides a summary of BCR signaling, tools for studying this pathway relevant to drug development in CLL, and early progress made with therapeutics targeting BCR-related kinases.
The coronavirus disease 2019 (COVID-19) pandemic has led to accelerated efforts to develop therapeutics and vaccines. A key target of these efforts is the spike (S) protein, which is metastable and ...difficult to produce recombinantly. We characterized 100 structure-guided spike designs and identified 26 individual substitutions that increased protein yields and stability. Testing combinations of beneficial substitutions resulted in the identification of HexaPro, a variant with six beneficial proline substitutions exhibiting higher expression than its parental construct (by a factor of 10) as well as the ability to withstand heat stress, storage at room temperature, and three freeze-thaw cycles. A cryo-electron microscopy structure of HexaPro at a resolution of 3.2 angstroms confirmed that it retains the prefusion spike conformation. High-yield production of a stabilized prefusion spike protein will accelerate the development of vaccines and serological diagnostics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Inhibition of Bruton’s tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has emerged as a transformative treatment option for patients with chronic lymphocytic leukemia (CLL) and other ...B-cell malignancies, yet >80% of CLL patients develop resistance due to a cysteine to serine mutation at the site covalently bound by ibrutinib (C481S). Currently, an effective treatment option for C481S patients exhibiting relapse to ibrutinib does not exist, and these patients have poor outcomes. To address this, we have developed a PROteolysis TArgeting Chimera (PROTAC) that induces degradation of both wild-type and C481S mutant BTK. We selected a lead PROTAC, MT-802, from several candidates on the basis of its potency to induce BTK knockdown. MT-802 recruits BTK to the cereblon E3 ubiquitin ligase complex to trigger BTK ubiquitination and degradation via the proteasome. MT-802 binds fewer off-target kinases than ibrutinib does and retains an equivalent potency (>99% degradation at nanomolar concentrations) against wild-type and C481S BTK. In cells isolated from CLL patients with the C481S mutation, MT-802 is able to reduce the pool of active, phosphorylated BTK whereas ibrutinib cannot. Collectively, these data provide a basis for further preclinical study of BTK PROTACs as a novel strategy for treatment of C481S mutant CLL.
Pornography has become a primary source of sexual education. At the same time, mainstream commercial pornography has coalesced around a relatively homogenous script involving violence and female ...degradation. Yet, little work has been done exploring the associations between pornography and dyadic sexual encounters: What role does pornography play inside real-world sexual encounters between a man and a woman? Cognitive script theory argues media scripts create a readily accessible heuristic model for decision-making. The more a user watches a particular media script, the more embedded those codes of behavior become in their worldview and the more likely they are to use those scripts to act upon real life experiences. We argue pornography creates a sexual script that then guides sexual experiences. To test this, we surveyed 487 college men (ages 18–29 years) in the United States to compare their rate of pornography use with sexual preferences and concerns. Results showed the more pornography a man watches, the more likely he was to use it during sex, request particular pornographic sex acts of his partner, deliberately conjure images of pornography during sex to maintain arousal, and have concerns over his own sexual performance and body image. Further, higher pornography use was negatively associated with enjoying sexually intimate behaviors with a partner. We conclude that pornography provides a powerful heuristic model which is implicated in men’s expectations and behaviors during sexual encounters.
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