17β-Estradiol Potentiates the Reinstatement of Cocaine Seeking in Female Rats: Role of the Prelimbic Prefrontal Cortex and Cannabinoid Type-1 Receptors

Clinical observations imply that female cocaine addicts experience enhanced relapse vulnerability compared with males, an effect tied to elevated estrogen phases of the ovarian hormone cycle. Although estrogens can enhance drug-seeking behavior, they do not directly induce reinstatement on their own. To model this phenomenon, we tested whether an estrogen could augment drug-seeking behavior in response to an ordinarily subthreshold reinstatement trigger. Following cocaine self-administration and extinction, female rats were ovariectomized to isolate estrogen effects on reinstatement. Although neither peak proestrus levels of the primary estrogen 17β-estradiol (E2; 10 μg/kg, i.p., 1-h pretreatment) nor a subthreshold cocaine dose (1.25 mg/kg, i.p.) alone were sufficient to reinstate drug-seeking behavior, pretreatment with E2 potentiated reinstatement to the ordinarily subthreshold cocaine dose. Furthermore, E2 microinfusions revealed that E2 (5 μg/0.3 μl, 15-min pretreatment) acts directly within the prelimbic prefrontal cortex (PrL-PFC) to potentiate reinstatement. As E2 has been implicated in endocannabinoid mobilization, which can disinhibit PrL-PFC projection neurons, we investigated whether cannabinoid type-1 receptor (CB1R) activation is necessary for E2 to potentiate reinstatement. The CB1R antagonist AM251 (1 or 3 mg/kg, i.p., 30-min pretreatment) administered prior to E2 and cocaine suppressed reinstatement in a dose-dependent manner. Finally, PrL-PFC AM251 microinfusions (300 ng/side, 15-min pretreatment) also suppressed E2-potentiated reinstatement. Together, these results suggest that E2 can augment reactivity to an ordinarily subthreshold relapse trigger in a PrL-PFC CB1R activation-dependent manner

Development and evaluation of SMART search strategies for PubMed, Embase, and Scopus

Methodological challenges faced by health sciences investigators during the development of evidence-based dynamic treatment regimens are often addressed using sequential multiple assignment randomized trial (SMART) designs. Despite the proliferation of SMART literature, systematic reviews of their methods, reporting practices, and findings remain sparse. This study details the development of two candidate search strategies — one according to common practice and the other strictly using term frequency analysis data — and testing of their performance in three key health sciences databases. Both novel search strategies achieved higher recall relative to a set of known relevant studies than searches reported by extant systematic reviews. In addition to providing a reusable and extensible filter for future evidence synthesis projects, they demonstrate the potential of new methods in term frequency-based search construction to accelerate similar work in the future.Master of Science in Library Scienc

How is digital health suitability measured for communities? A systematic review

Background Digital health services continue growing in usage and popularity, with patients and healthcare organizations benefiting from their use. Despite this, no mechanism exists to measure a patient's and community's suitability to leverage these services. Objective This systematic review aims to evaluate the extent and nature of measuring the overall suitability of individuals and communities within the digital health landscape. Methods Database searches in February 2024 across PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Embase, and IEEE Xplore yielded 1044 unique references. Two screening stages resulted in 10 articles that met all evaluation criteria for review inclusion. Results This systematic review found a gap in the ability to holistically assess a patient's and community's suitability to access digital health services. Myriad indices and tools identify isolated factors contributing to digital health accessibility (e.g., broadband availability); however, no comprehensive mechanism adequately informs providers, policymakers, and researchers. Conclusion A comprehensive index that accurately reflects suitability for digital health services is needed. Index factors should include a combination of indicators related to socioeconomic status, digital accessibility, such as device and internet access, and social determinants of health. Together, these form the predominant driving factors related to one's ability to participate in digital health services

Melanoma-initiating cells exploit M2 macrophage TGFβ and arginase pathway for survival and proliferation

International audienceM2 macrophages promote tumor growth and metastasis, but their interactions with specific tumor cell populations are poorly characterized. Using a mouse model of spontaneous melanoma, we showed that CD34 -but not CD34 + tumor-initiating cells (TICs) depend on M2 macrophages for survival and proliferation. Tumor-associated macrophages (TAMs) and macrophage-conditioned media protected CD34 -TICs from chemotherapy in vitro. In vivo, while inhibition of CD115 suppressed the macrophage-dependent CD34 -TIC population, chemotherapy accelerated its development. The ability of TICs to respond to TAMs was acquired during melanoma progression and immediately preceded a surge in metastatic outgrowth. TAM-derived transforming growth factor-β (TGFβ) and polyamines produced via the Arginase pathway were critical for stimulation of TICs and synergized to promote their growth

Cooperative Roles of CTLA-4 and Regulatory T Cells in Tolerance to an Islet Cell Antigen

Adoptive transfer of ovalbumin (OVA)-specific T cells from the DO.11 TCR transgenic mouse on a Rag−/− background into mice expressing OVA in pancreatic islet cells induces acute insulitis and diabetes only if endogenous lymphocytes, including regulatory T cells, are removed. When wild-type OVA-specific/Rag−/− T cells, which are all CD25−, are transferred into islet antigen–expressing mice, peripheral immunization with OVA in adjuvant is needed to induce diabetes. In contrast, naive CTLA-4−/−/Rag−/− OVA-specific T cells (also CD25−) develop into Th1 effectors and induce disease upon recognition of the self-antigen alone. These results suggest that CTLA-4 functions to increase the activation threshold of autoreactive T cells, because in its absence self-antigen is sufficient to trigger autoimmunity without peripheral immunization. Further, CTLA-4 and regulatory T cells act cooperatively to maintain tolerance, indicating that the function of CTLA-4 is independent of regulatory cells, and deficiency of both is required to induce pathologic immune responses against the islet self-antigen

Mechanochemical Synthesis of a Sodium Anion Complex [Na ⁺(2,2,2-cryptand)Na ^–] and Studies of Its Reactivity:Two-Electron and One-Electron Reductions

Group 1 metal molecular chemistry is dominated by a +1 oxidation state, while a 0 oxidation state is widespread in the metals. A more exotic, yet still available, oxidation state of group 1 metal is −1, i.e., alkalide. Reported as early as the 1970s, the alkalides appear in every modern inorganic chemistry textbook as an iconic chemical curiosity, yet their reactivity remains unexplored. This is due to their synthetic hurdles. In this work, we report the first facile synthesis of the archetypical alkalide complex, [Na+(2,2,2-cryptand)­Na–], which allows us to unveil a versatile reactivity profile of this once exotic species

Mass Determination Method for the Right and Left Selectron Above Production Threshold

The determination of the masses of Supersymmetric particles such as the Selectron for energies above threshold using the energy end-points method is subject to signal deconvolution difficulties and to Standard Model and Supersymmetric backgrounds. The important features of Right and Left Selectron production are used to design an experimentally robust method both for determining the Left and Right Selectron masses, the Neutralino mass and for suppresing backgrounds. The mass resolution is an order of magnitude better than in previous methods. Additional features, such as the determination of the relative leptonic branching ratios of the selectron decay are present in the method.Comment: 4 pages in RevTex (Latex) format and 4 figures in eps forma

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The Transcription Factor GATA3 Is Critical for the Development of All IL-7Rα-Expressing Innate Lymphoid Cells

SummaryInnate lymphoid cells (ILCs) are critical in innate immune responses to pathogens and lymphoid organ development. Similar to CD4+ T helper (Th) cell subsets, ILC subsets positive for interleukin-7 receptor α (IL-7Rα) produce distinct sets of effector cytokines. However, the molecular control of IL-7Rα+ ILC development and maintenance is unclear. Here, we report that GATA3 was indispensable for the development of all IL-7Rα+ ILC subsets and T cells but was not required for the development of classical natural killer cells. Conditionally Gata3-deficient mice had no lymph nodes and were susceptible to Citrobactor rodentium infection. After the ILCs had fully developed, GATA3 remained important for the maintenance and functions of ILC2s. Genome-wide gene expression analyses indicated that GATA3 regulated a similar set of cytokines and receptors in Th2 cells and ILC2s, but not in ILC3s. Thus, GATA3 plays parallel roles in regulating the development and functions of CD4+ T cells and IL-7Rα+ ILCs

Muc5ac: a critical component mediating the rejection of enteric nematodes

The mucin Muc5ac is essential for the expulsion of Trichuris muris and other gut-dwelling nematodes