Spatiotemporal modeling of chemoresistance evolution in breast tumors uncovers dependencies on SLC38A7 and SLC46A1.

In solid tumors, drug concentrations decrease with distance from blood vessels. However, cellular adaptations accompanying the gradated exposure of cancer cells to drugs are largely unknown. Here, we modeled the spatiotemporal changes promoting chemotherapy resistance in breast cancer. Using pairwise cell competition assays at each step during the acquisition of chemoresistance, we reveal an important priming phase that renders cancer cells previously exposed to sublethal drug concentrations refractory to dose escalation. Therapy-resistant cells throughout the concentration gradient display higher expression of the solute carriers SLC38A7 and SLC46A1 and elevated intracellular concentrations of their associated metabolites. Reduced levels of SLC38A7 and SLC46A1 diminish the proliferative potential of cancer cells, and elevated expression of these SLCs in breast tumors from patients correlates with reduced survival. Our work provides mechanistic evidence to support dose-intensive treatment modalities for patients with solid tumors and reveals two members of the SLC family as potential actionable targets.

C3-Alkylation of furfural derivatives by continuous flow homogeneous catalysis.

The C3-functionalization of furfural using homogeneous ruthenium catalysts requires the preinstallation of an ortho-directing imine group, as well as high temperatures, which did not allow scaling up, at least under batch conditions. In order to design a safer process, we set out to develop a continuous flow process specifically for the C3-alkylation of furfural (Murai reaction). The transposition of a batch process to a continuous flow process is often costly in terms of time and reagents. Therefore, we chose to proceed in two steps: the reaction conditions were first optimized using a laboratory-built pulsed-flow system to save reagents. The optimized conditions in this pulsed-flow mode were then successfully transferred to a continuous flow reactor. In addition, the versatility of this continuous flow device allowed both steps of the reaction to be carried out, namely the formation of the imine directing group and the C3-functionalization with some vinylsilanes and norbonene.

PGC-1s shape epidermal physiology by modulating keratinocyte proliferation and terminal differentiation.

Skin plays central roles in systemic physiology, and it undergoes significant functional changes during aging. Members of the peroxisome proliferator-activated receptor-gamma coactivator (PGC-1) family (PGC-1s) are key regulators of the biology of numerous tissues, yet we know very little about their impact on skin functions. Global gene expression profiling and gene silencing in keratinocytes uncovered that PGC-1s control the expression of metabolic genes as well as that of terminal differentiation programs. Glutamine emerged as a key substrate promoting mitochondrial respiration, keratinocyte proliferation, and the expression of PGC-1s and terminal differentiation programs. Importantly, gene silencing of PGC-1s reduced the thickness of a reconstructed living human epidermal equivalent. Exposure of keratinocytes to a salicylic acid derivative potentiated the expression of PGC-1s and terminal differentiation genes and increased mitochondrial respiration. Overall, our results show that the PGC-1s are essential effectors of epidermal physiology, revealing an axis that could be targeted in skin conditions and aging.

The mitochondrial pyruvate carrier complex potentiates the efficacy of proteasome inhibitors in multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy that emerges from antibody-producing plasma B cells. Proteasome inhibitors, including the US Food and Drug Administration-approved bortezomib (BTZ) and carfilzomib (CFZ), are frequently used for the treatment of patients with MM. Nevertheless, a significant proportion of patients with MM are refractory or develop resistance to this class of inhibitors, which represents a significant challenge in the clinic. Thus, identifying factors that determine the potency of proteasome inhibitors in MM is of paramount importance to bolster their efficacy in the clinic. Using genome-wide CRISPR-based screening, we identified a subunit of the mitochondrial pyruvate carrier (MPC) complex, MPC1, as a common modulator of BTZ response in 2 distinct human MM cell lines in vitro. We noticed that CRISPR-mediated deletion or pharmacological inhibition of the MPC complex enhanced BTZ/CFZ-induced MM cell death with minimal impact on cell cycle progression. In fact, targeting the MPC complex compromised the bioenergetic capacity of MM cells, which is accompanied by reduced proteasomal activity, thereby exacerbating BTZ-induced cytotoxicity in vitro. Importantly, we observed that the RNA expression levels of several regulators of pyruvate metabolism were altered in advanced stages of MM for which they correlated with poor patient prognosis. Collectively, this study highlights the importance of the MPC complex for the survival of MM cells and their responses to proteasome inhibitors. These findings establish mitochondrial pyruvate metabolism as a potential target for the treatment of MM and an unappreciated strategy to increase the efficacy of proteasome inhibitors in the clinic.

Rape Crisis Victim Advocacy: A Systematic Review.

While rape crisis center (RCC) advocacy is generally regarded as valuable, there are no prior systematic reviews of the advocacy literature. This review examined RCC advocacy service provision, perceptions and impact of advocacy, and challenges and facilitators to effective service provision. Databases related to health and social sciences were searched including Academic Search Complete, PsychINFO, PubMed, CINAHL, ProQuest, Science Direct, OAlster, WorldCat, and MEDLINE. Empirical articles written in English that examined RCC advocacy service provision and/or impact in the US were included. The researchers reviewed abstracts and titles, and then full texts. Forty-five articles met criteria, were summarized, and double checked. Findings demonstrate advocacy is multi-faceted, beneficial, and challenging. Advocates work directly with survivors and interact with other responders on behalf of survivors. Specifically, advocates provide emotional support, safety plan, support survivors in making decisions, and assist them in navigating other systems. While advocates are generally regarded positively by survivors and responders, some responders have concerns about advocates. In addition, advocates sometimes report victim-blaming and being ill-equipped to meet survivors' needs. Finally, advocates face specific challenges in their work with survivors and responders. Future research using diverse methodological approaches is needed to understand advocacy utilization and reach; survivors' perceptions of advocacy; marginalized survivors' experiences; connections between specific services, implementation, and outcomes; and effective strategies for advocates' interactions with other responders. Additional resources to help advocates serve all survivors effectively and equitably; to support evaluator-practitioner partnerships; and to share unpublished data on advocacy may help contribute to improvements in advocacy practice.

Graduate student workload: Pandemic challenges and recommendations for accommodations.

The COVID-19 pandemic has had a significant impact on the lives of graduate student workers within university settings. At a large Midwestern private university, a Psychology Graduate Student Association (PsychGSA) identified that, in response to the pandemic, different levels of accommodations were being provided by faculty to graduate students. The PsychGSA conducted an evaluative survey that captured the experiences of 50 graduate students in the psychology department. The results highlight the inequitable challenges graduate students are currently facing. Recommendations to faculty to appropriately accommodate students during this unprecedented time, and beyond, are reported.

Revealing Size Dependent Structural Transitions in Supported Gold Nanoparticles in Hydrogen at Atmospheric Pressure.

The enhancement of the catalytic activity of gold nanoparticles with their decreasing size is often attributed to the increasing proportion of low-coordinated surface sites. This correlation is based on the paradigmatic picture of working gold nanoparticles as perfect crystal forms having complete and static outer surface layers whatever their size. This picture is incomplete as catalysts can dynamically change their structure according to the reaction conditions and as such changes can be eventually size-dependent. In this work, using aberration-corrected environmental electron microscopy, size-dependent crystal structure and morphological evolution in gold nanoparticles exposed to hydrogen at atmospheric pressure, with loss of the face-centered cubic crystal structure of gold for particle size below 4 nm, are revealed for the first time. Theoretical calculations highlight the role of mobile gold atoms in the observed symmetry changes and particle reshaping in the critical size regime. An unprecedented stable surface molecular structure of hydrogenated gold decorating a highly distorted core is identified. By combining atomic scale in situ observations and modeling of nanoparticle structure under relevant reaction conditions, this work provides a fundamental understanding of the size-dependent reactivity of gold nanoparticles with a precise picture of their surface at working conditions.

A selective and stable Fe/TiO2 catalyst for selective hydrogenation of butadiene in alkene-rich stream.

The replacement of precious metals by more abundant and therefore much less expensive metals remains a very important challenge in catalysis. A Fe/TiO2 catalyst prepared by deposition-precipitation with urea showed very high selectivity to alkenes (>99%), even at high conversion (>90%), in selective hydrogenation of butadiene in an excess of propene. Its activity is very stable at 175 °C whereas the catalyst deactivates at 50 °C, although it is also initially very active. The presence of metallic iron seems to be necessary to ensure these excellent performances.

Resistance to different anthracycline chemotherapeutics elicits distinct and actionable primary metabolic dependencies in breast cancer.

Chemotherapy resistance is a critical barrier in cancer treatment. Metabolic adaptations have been shown to fuel therapy resistance; however, little is known regarding the generality of these changes and whether specific therapies elicit unique metabolic alterations. Using a combination of metabolomics, transcriptomics, and functional genomics, we show that two anthracyclines, doxorubicin and epirubicin, elicit distinct primary metabolic vulnerabilities in human breast cancer cells. Doxorubicin-resistant cells rely on glutamine to drive oxidative phosphorylation and de novo glutathione synthesis, while epirubicin-resistant cells display markedly increased bioenergetic capacity and mitochondrial ATP production. The dependence on these distinct metabolic adaptations is revealed by the increased sensitivity of doxorubicin-resistant cells and tumor xenografts to buthionine sulfoximine (BSO), a drug that interferes with glutathione synthesis, compared with epirubicin-resistant counterparts that are more sensitive to the biguanide phenformin. Overall, our work reveals that metabolic adaptations can vary with therapeutics and that these metabolic dependencies can be exploited as a targeted approach to treat chemotherapy-resistant breast cancer.

Unlocking synergy in bimetallic catalysts by core-shell design.

Extending the toolbox from mono- to bimetallic catalysts is key in realizing efficient chemical processes1. Traditionally, the performance of bimetallic catalysts featuring one active and one selective metal is optimized by varying the metal composition1-3, often resulting in a compromise between the catalytic properties of the two metals4-6. Here we show that by designing the atomic distribution of bimetallic Au-Pd nanocatalysts, we obtain a synergistic catalytic performance in the industrially relevant selective hydrogenation of butadiene. Our single-crystalline Au-core Pd-shell nanorods were up to 50 times more active than their alloyed and monometallic counterparts, while retaining high selectivity. We find a shell-thickness-dependent catalytic activity, indicating that not only the nature of the surface but also several subsurface layers play a crucial role in the catalytic performance, and rationalize this finding using density functional theory calculations. Our results open up an alternative avenue for the structural design of bimetallic catalysts.

Supported Cu Nanoparticles as Selective and Stable Catalysts for the Gas Phase Hydrogenation of 1,3-Butadiene in Alkene-Rich Feeds.

Supported copper nanoparticles are a promising alternative to supported noble metal catalysts, in particular for the selective gas phase hydrogenation of polyunsaturated molecules. In this article, the catalytic performance of copper nanoparticles (3 and 7 nm) supported on either silica gel or graphitic carbon is discussed in the selective hydrogenation of 1,3-butadiene in the presence of a 100-fold excess of propene. We demonstrate that the routinely used temperature ramp-up method is not suitable in this case to reliably measure catalyst activity, and we present an alternative measurement method. The catalysts exhibited selectivity to butenes as high as 99% at nearly complete 1,3-butadiene conversion (95%). Kinetic analysis showed that the high selectivity can be explained by considering H2 activation as the rate-limiting step and the occurrence of a strong adsorption of 1,3-butadiene with respect to mono-olefins on the Cu surface. The 7 nm Cu nanoparticles on SiO2 were found to be a very stable catalyst, with almost full retention of its initial activity over 60 h of time on stream at 140 °C. This remarkable long-term stability and high selectivity toward alkenes indicate that Cu nanoparticles are a promising alternative to replace precious-metal-based catalysts in selective hydrogenation.

Synthesis of small Ni-core-Au-shell catalytic nanoparticles on TiO2 by galvanic replacement reaction.

We report the first preparation of small gold-nickel (AuNi) bimetallic nanoparticles (<5 nm) supported on titania by the method of galvanic replacement reaction (GRR), evidenced by the replacement of Ni atoms by Au atoms according to the stoichiometry of the reaction. We showed that this preparation method allowed not only the control of the gold and nickel contents in the samples, but also the formation of small bimetallic nanoparticles with strained core-shell structures, as revealed by aberration-corrected scanning transmission electron microscopy in combination with energy-dispersive X-ray spectroscopy mapping. The catalytic characterization by the probe reaction of semi-hydrogenation of butadiene showed that the resulting nickel-based nanocatalysts containing a small amount of gold exhibited higher selectivity to butenes than pure nickel catalysts and a high level of activity, closer to that of pure nickel catalysts than to that of pure gold catalysts. These improved catalytic performances could not be explained by a mere structural model of simple core-shell structure of the nanoparticles. Instead, they could come from the incorporation of Ni within the gold surface and/or from surface lattice relaxation and subsurface misfit defects.

Metal-organic framework-based nanomaterials for photocatalytic hydrogen peroxide production.

As an environmentally friendly and renewable energy source, hydrogen peroxide (H2O2) could be produced photocatalytically through selective two-electron reduction of O2 using effective photocatalysts. Metal organic frameworks (MOFs), as hybrid porous materials consisting of organic linkers and metal oxide clusters, have aroused great interest in the design of effective catalysts for photocatalysis under visible light irradiation due to their unique properties, such as large surface area, good chemical stability, and diverse and tunable chemical components. In this perspective, we highlight our recent progress in the application of various MOF-based nanomaterials for photocatalytic H2O2 production from the selective two-electron reduction of O2 in a single-phase system (acetonitrile) and two-phase system (water/benzyl alcohol). Photocatalytic H2O2 production in the single-phase system achieved a higher activity using NiO as a cocatalyst of the MOF rather than Pt. Photocatalytic H2O2 production in the two-phase system using various hydrophobic MOFs showed further improved activity compared to the single-phase system. It has been possible to design a hydrophobic MOF-based photocatalyst with high activity and stability under recycling conditions. These studies gathered in this perspective revealed the novel application of MOFs in the field of energy production.

Hybrid phase 1T/2H-MoS2 with controllable 1T concentration and its promoted hydrogen evolution reaction.

MoS2 has been investigated as a low-cost alternative to Pt in the electrochemical hydrogen evolution reaction. One of the promising methods to further activate MoS2 is phase engineering. MoS2 generally exhibits two kinds of crystalline phases: hexagonal 2H phase and octahedral 1T phase. 1T-MoS2 exhibits much better chemical/physical properties than natural semiconductor 2H-MoS2. However, 1T-MoS2 is metastable and its synthesis is still a challenge. Hybrid 1T/2H-MoS2 has been synthesized under relatively mild conditions, but controlling the 1T/2H ratio is still an issue which has not been discussed in detail. In this study, the synthesis methods of hybrid phase 1T/2H-MoS2 with controllable 1T concentration are investigated. The electrochemical hydrogen evolution reaction is then evaluated for 1T/2H-MoS2 with different 1T concentrations by performing both experiments and theoretical calculations.

Design of Advanced Functional Materials Using Nanoporous Single-Site Photocatalysts.

Nanoporous silica solids can offer opportunities for hosting photocatalytic components such as various tetra-coordinated transition metal ions to form systems referred to as "single-site photocatalysts". Under UV/visible-light irradiation, they form charge transfer excited states, which exhibit a localized charge separation and thus behave differently from those of bulk semiconductor photocatalysts exemplified by TiO2 . This account presents an overview of the design of advanced functional materials based on the unique photo-excited mechanisms of single-site photocatalysts. Firstly, the incorporation of single-site photocatalysts within transparent porous silica films will be introduced, which exhibit not only unique photocatalytic properties, but also high surface hydrophilicity with self-cleaning and antifogging applications. Secondary, photo-assisted deposition (PAD) of metal precursors on single-site photocatalysts opens up a new route to prepare nanoparticles. Thirdly, visible light sensitive photocatalysts with single and/or binary oxides moieties can be prepared so as to use solar light, the ideal energy source.

Effects of syndemic psychiatric diagnoses on health indicators in men who have sex with men.

OBJECTIVE: Syndemic theory posits that co-occurring problems (e.g., substance use, depression, and trauma) synergistically increase HIV risk in men who have sex with men (MSM). However, most investigations have assessed these problems additively using self-report. METHOD: In a sample of HIV-negative MSM with trauma histories (n = 290), we test bivariate relationships between four clinical diagnoses (substance use disorder [SUD]); major depressive disorder [MDD], posttraumatic stress disorder [PTSD], and anxiety disorders) and their additive and interactive effects on three health indicators (i.e., high-risk sex, visiting the emergency room [ER], and sexually transmitted infections [STIs]). RESULTS: We found significant bivariate relationships between SUD and MDD (χ² = 4.85, p = .028) and between PTSD and MDD (χ² = 35.38, p = .028, p < .001) but did not find a significant relationship between SUD and PTSD (χ² = 3.64, p = .056). Number of diagnoses were associated with episodes of high-risk sex (incidence rate ratio [IRR] = 1.14, 95% CI [1.03, 1.26], p = .009) and visiting the ER (odds ratio = 1.27; 95% CI [1.01, 1.60], p = .040) but not with STIs. No interactions were found between diagnoses and health-related indicators. CONCLUSIONS: This is the first study to demonstrate additive effects of clinical diagnoses on risk behavior and health care utilization among MSM with developmental trauma histories. Results indicate the need to prioritize empirically supported treatments for SUD and MDD, in addition to trauma treatment, for this population. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Reshaping Dynamics of Gold Nanoparticles under H2 and O2 at Atmospheric Pressure.

Despite intensive research efforts, the nature of the active sites for O2 and H2 adsorption/dissociation by supported gold nanoparticles (NPs) is still an unresolved issue in heterogeneous catalysis. This stems from the absence of a clear picture of the structural evolution of Au NPs at near reaction conditions, i. e., at high pressures and high temperatures. We hereby report real-space observations of the equilibrium shapes of titania-supported Au NPs under O2 and H2 at atmospheric pressure using gas transmission electron microscopy. In situ TEM observations show instantaneous changes in the equilibrium shape of Au NPs during cooling under O2 from 400 °C to room temperature. In comparison, no instant change in equilibrium shape is observed under a H2 environment. To interpret these experimental observations, the equilibrium shape of Au NPs under O2, atomic oxygen, and H2 is predicted using a multiscale structure reconstruction model. Excellent agreement between TEM observations and theoretical modeling of Au NPs under O2 provides strong evidence for the molecular adsorption of oxygen on the Au NPs below 120 °C on specific Au facets, which are identified in this work. In the case of H2, theoretical modeling predicts no interaction with gold atoms that explain their high morphological stability under this gas. This work provides atomic structural information for the fundamental understanding of the O2 and H2 adsorption properties of Au NPs under real working conditions and shows a way to identify the active sites of heterogeneous nanocatalysts under reaction conditions by monitoring the structure reconstruction.

In Situ Observation of Atomic Redistribution in Alloying Gold-Silver Nanorods.

The catalytic performance and optical properties of bimetallic nanoparticles critically depend on the atomic distribution of the two metals in the nanoparticles. However, at elevated temperatures, during light-induced heating, or during catalysis, atomic redistribution can occur. Measuring such metal redistribution in situ is challenging, and a single experimental technique does not suffice. Furthermore, the availability of a well-defined nanoparticle system has been an obstacle for a systematic investigation of the key factors governing the atomic redistribution. In this study, we follow metal redistribution in precisely tunable, single-crystalline Au-core, Ag-shell nanorods in situ, both at a single particle and an ensemble-averaged level, by combining in situ transmission electron spectroscopy with in situ extended X-ray absorption fine structure validated by ex situ measurements. We show that the kinetics of atomic redistribution in Au-Ag nanoparticles depend on the metal composition and particle volume, such that a higher Ag content or a larger particle size led to significantly slower metal redistribution. We developed a simple theoretical model based on Fick's first law that can correctly predict the composition- and size-dependent alloying behavior in Au-Ag nanoparticles, as observed experimentally.

Challenges associated with parenting youth with neurofibromatosis: A qualitative investigation.

Parents of children with the neurofibromatoses (NF; neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis) are at an increased risk for emotional and physical health problems. This study aimed to determine parents' perceptions of stressors associated with parenting a child with NF in order to inform the development of a resiliency intervention. We conducted three live video semi structured focus groups with parents of youth with NF (N = 30), which were subsequently transcribed and coded using qualitative content analysis. Parents reported heightened stress associated with the child's educational, medical, and social needs, as well as concerns about their child's physical and mental health. They also reported stress associated with managing finances, multiple medical appointments, role challenges (i.e., being a parent or partner), and managing the uncertainty/unpredictability of their child's NF diagnosis. These stressors reportedly affected employment status (i.e., work scale backs), relationships (i.e., social, familial, with partner, other children), and the parents' physical and mental health. All participants expressed interest in a mind body program aimed at improving resiliency by teaching coping skills (e.g., mindfulness, adaptive thinking, positive psychology skills) and enhancing social support. Results show parents' enthusiasm for a resiliency intervention targeting stress associated with parenting a child with NF, and provide valuable information for the content of the intervention and its delivery modality.