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The nucleus of any university is the intellectual life that unfolds among faculty and students. Inevitably, that intellectual life is shaped by the broader university context. Examining that process--in particular, its connection to a Catholic understanding of university mission--offers insight into pressing issues. For instance, what shifting social and academic conditions--both opportunities and challenges--set a context for campus conversations? How might Catholic institutions respond to these conditions? Can Catholic institutions provide a hospitable place for integrating faith and reason at the institutional and personal levels? Can the Catholic intellectual tradition serve as a constructive and creative lens for transforming Catholic higher education? And drawing on ideas that emerged during the Boston College Roundtable seminars, how might change occur?

Studies in tau and Aβ plaque transgenic mouse models demonstrated that brain-penetrant microtubule (MT)-stabilizing compounds, including the 1,2,4-triazolo[1,5-a]pyrimidines, hold promise as candidate treatments for Alzheimer's disease and related neurodegenerative tauopathies. Triazolopyrimidines have already been investigated as anticancer agents; however, the antimitotic activity of these compounds does not always correlate with stabilization of MTs in cells. Indeed, previous studies from our laboratories identified a critical role for the fragment linked at C6 in determining whether triazolopyrimidines promote MT stabilization or, conversely, disrupt MT integrity in cells. To further elucidate the structure-activity relationship (SAR) and to identify potentially improved MT-stabilizing candidates for neurodegenerative disease, a comprehensive set of 68 triazolopyrimidine congeners bearing structural modifications at C6 and/or C7 was designed, synthesized, and evaluated. These studies expand upon prior understanding of triazolopyrimidine SAR and enabled the identification of novel analogues that, relative to the existing lead, exhibit improved physicochemical properties, MT-stabilizing activity, and pharmacokinetics.

BackgroundAlzheimer's disease (AD) and related tauopathies are neurodegenerative diseases that are characterized by the presence of insoluble inclusions of the protein tau within brain neurons and often glia. Tau is normally found associated with axonal microtubules (MTs) in the brain, and in tauopathies this MT binding is diminished due to tau hyperphosphorylation. As MTs play a critical role in the movement of cellular constituents within neurons via axonal transport, it is likely that the dissociation of tau from MTs alters MT structure and axonal transport, and there is evidence of this in tauopathy mouse models as well as in AD brain. We previously demonstrated that different natural products which stabilize MTs by interacting with β-tubulin at the taxane binding site provide significant benefit in transgenic mouse models of tauopathy. More recently, we have reported on a series of MT-stabilizing triazolopyrimidines (TPDs), which interact with β-tubulin at the vinblastine binding site, that exhibit favorable properties including brain penetration and oral bioavailability. Here, we have examined a prototype TPD example, CNDR-51657, in a secondary prevention study utilizing aged tau transgenic mice.Methods9-Month old female PS19 mice with a low amount of existing tau pathology received twice-weekly administration of vehicle, or 3 or 10 mg/kg of CNDR-51657, for 3 months. Mice were examined in the Barnes maze at the end of the dosing period, and brain tissue and optic nerves were examined immunohistochemically or biochemically for changes in MT density, axonal dystrophy, and tau pathology. Mice were also assessed for changes in organ weights and blood cell numbers.ResultsCNDR-51657 caused a significant amelioration of the MT deficit and axonal dystrophy observed in vehicle-treated aged PS19 mice. Moreover, PS19 mice receiving CNDR-51657 had significantly lower tau pathology, with a trend toward improved Barnes maze performance. Importantly, no adverse effects were observed in the compound-treated mice, including no change in white blood cell counts as is often observed in cancer patients receiving high doses of MT-stabilizing drugs.ConclusionsA brain-penetrant MT-stabilizing TPD can safely correct MT and axonal deficits in an established mouse model of tauopathy, resulting in reduced tau pathology.

The availability of l-arginine in tumours is a key determinant of an efficient anti-tumour T cell response.sup.1-4. Consequently, increases of typically low l-arginine concentrations within the tumour may greatly potentiate the anti-tumour responses of immune checkpoint inhibitors, such as programmed death-ligand 1 (PD-L1)-blocking antibodies.sup.5. However, currently no means are available to locally increase intratumoural l-arginine levels. Here we used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumours and continuously converts ammonia, a metabolic waste product that accumulates in tumours.sup.6, to l-arginine. Colonization of tumours with these bacteria increased intratumoural l-arginine concentrations, increased the number of tumour-infiltrating T cells and had marked synergistic effects with PD-L1 blocking antibodies in the clearance of tumours. The anti-tumour effect of these bacteria was mediated by l-arginine and was dependent on T cells. These results show that engineered microbial therapies enable metabolic modulation of the tumour microenvironment leading to enhanced efficacy of immunotherapies. Injection of engineered bacteria that convert ammonia to l-arginine into tumours enhance the anti-tumour response in a mouse model and synergize with anti-PD-L1 treatment to clear tumours., Author(s): Fernando P. Canale [sup.1] , Camilla Basso [sup.1] [sup.5] , Gaia Antonini [sup.1] , Michela Perotti [sup.1] [sup.2] , Ning Li [sup.3] , Anna Sokolovska [sup.3] , Julia Neumann [...]

Alzheimer's disease (AD) is a complex, multifactorial disease in which different neuropathological mechanisms are likely involved, including those associated with pathological tau and Aβ species as well as neuroinflammation. In this context, the development of single multitargeted therapeutics directed against two or more disease mechanisms could be advantageous. Starting from a series of 1,5-diarylimidazoles with microtubule (MT)-stabilizing activity and structural similarities with known NSAIDs, we conducted structure-activity relationship studies that led to the identification of multitargeted prototypes with activities as MT-stabilizing agents and/or inhibitors of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways. Several examples are brain-penetrant and exhibit balanced multitargeted in vitro activity in the low μM range. As brain-penetrant MT-stabilizing agents have proven effective against tau-mediated neurodegeneration in animal models, and because COX- and 5-LOX-derived eicosanoids are thought to contribute to Aβ plaque deposition, these 1,5-diarylimidazoles provide tools to explore novel multitargeted strategies for AD and other neurodegenerative diseases.

A one-step method to convert nitroarenes into aryl sulfones under operationally simple, transition-metal-free conditions is described. A range of nitroarenes were reacted with sodium sulfinates and caesium carbonate in N , N ′-dimethylpropyleneurea to afford aryl sulfones in up to 83% yield. [ABSTRACT FROM AUTHOR]

The replacement of a carboxylic acid with a surrogate structure, or (bio)-isostere, is a classical strategy in medicinal chemistry. The general underlying principle is that by maintaining the features of the carboxylic acid critical for biological activity, but appropriately modifying the physicochemical properties, improved analogs may result. In this context, a systematic assessment of the physicochemical properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure-property relationships (SPR) of 35 phenylpropionic acid derivatives, in which the carboxylic acid moiety is replaced with a series of known isosteres. The data set generated provides an assessment of the relative impact on the physicochemical properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group.

Dialogue about Catholic identity has been taking place at American Catholic colleges and universities since the publication of Ex Corde Ecclesiae in 1990. That student affairs professionals do their work within the context of the mission of the university is a concept that has been accepted from the earliest stages of the establishment of student affairs as an independent profession in the beginning of the twentieth century. For the past 20 years, student affairs professionals at Catholic colleges and universities have been building their capacity for mission integration in a variety of professional development seminars and institutes, largely supported by the work of Catholic higher education associations and sponsoring religious communities, with the intention of increasing the presence and integration of the Catholic mission and religious charism at the institutions in which they work. The Principles of Good Practice for Student Affairs at Catholic Colleges and Universities (The Principles) are the latest mission-driven resource to be developed at a national level in support of the continuing efforts by student affairs professionals and others working at Catholic colleges and universities to build capacity for mission-driven work. This article describes the development of The Principles as a mission-centered resource for student affairs professionals at Catholic colleges and universities. This article further presents the findings of a survey of presidents and senior student affairs officers (SSAOs) at Catholic colleges and universities in the United States and Canada regarding how The Principles are being utilized at their institutions to create mission-driven practices in student affairs work and to form mission-knowledgeable student affairs professionals. This article concludes with a discussion about the efficacy of The Principles to be used in continuing efforts across the diversity of institutions that constitute Catholic higher education in productive and meaningful ways to build a culture of mission integrated institutions.

Since the publication of "Ex Corde Ecclesiae" (John Paul II, 1990), Catholic colleges and universities have become more deliberate and intentional regarding their institutional and Catholic identity. This article continues the conversation about Catholic identity as it relates to student outcomes, and proposes some preliminary strategies for assessment. (Contains 2 tables.)

A series of derivatives of the known thromboxane A2 prostanoid (TP) receptor antagonists, 3-(6-((4-chlorophenyl)sulfonamido)-5,6,7,8-tetrahydronaphthalen-1-yl)propanoic acid and 3-(3-(2-((4-chlorophenyl)sulfonamido)ethyl)phenyl) propanoic acid, were synthesized in which the carboxylic acid functional group was replaced with substituted cyclopentane-1,3-dione (CPD) bioisosteres. Characterization of these molecules led to the discovery of remarkably potent new analogues, some of which were considerably more active than the corresponding parent carboxylic acid compounds. Depending on the choice of the C2 substituent of the CPD unit, these new derivatives can produce either a reversible or an apparent irreversible inhibition of the human TP receptor. Given the potency and the long-lasting inhibition of TP receptor signaling, these novel antagonists may comprise promising leads for the development of antithromboxane therapies.

Microtubule (MT) stabilizing drugs hold promise as potential treatments for Alzheimer's disease (AD) and related tauopathies. However, thus far epothilone D has been the only brain-penetrant MT-stabilizer to be evaluated in tau transgenic mice and in AD patients. Furthermore, this natural product exhibits potential deficiencies as a drug candidate, including an intravenous route of administration and the inhibition of the P-glycoprotein (Pgp) transporter. Thus, the identification of alternative CNS-active MT-stabilizing agents that lack these potential limitations is of interest. Toward this objective, we have evaluated representative compounds from known classes of non-naturally occurring MT-stabilizing small molecules. This led to the identification of selected triazolopyrimidines and phenylpyrimidines that are orally bioavailable and brain-penetrant without disruption of Pgp function. Pharmacodynamic studies confirmed that representative compounds from these series enhance MT-stabilization in the brains of wild-type mice. Thus, these classes of MT-stabilizers hold promise for the development of orally active, CNS-directed MT-stabilizing therapies.

This essay explores the concept of mentoring communities in the context of Christian higher education. It delves into the importance of forming mentoring communities for faculty, administrators, and students that embrace love, empathy, and a shared commitment to justice, particularly in light of systemic injustices within academia and in the broader society. Drawing from the perspectives of scholars, religious leaders, and personal experiences, the essay emphasizes the need for educators, administrators, and students to engage the college experience on a profound level—acknowledging their vulnerabilities and fostering a sense of unity grounded in a shared humanity. In an academic climate too often marked by isolation and individualism, the commitment to forming mentoring communities through the "art of loving" is seen as a countermeasure, fostering interdependence, relational action, dialogue, and reciprocity. The author underscores the significance of forming students, faculty, and institutional leaders with a focus on intellectual, spiritual, and emotional development—nurturing their capacity to recognize the divine love within themselves and in their neighbors. This dual goal of forming individuals and building a supportive community becomes the foundation for mentoring communities rooted in a Christian anthropology, wherein faculty, administrators, and students discover the fullness of their humanity in the love of God. [ABSTRACT FROM AUTHOR]

American Catholic universities and colleges are a large component of the global strength in Christian higher education and scholarship, but they currently do not participate in international collaboration in proportion to their capacity. The Roman Catholic hierarchy looks to the numerical, structural, and curricular strength of Catholic institutions in the USA to bring the wisdom of the Catholic intellectual tradition to bear on the economic, socio/cultural, and political problems of the contemporary world. Admittedly, among all the universities of the world, the Catholic universities do not have a competitive edge in the fields of the natural sciences where huge physical resources are required. However, it is the thesis of this paper that through scholarship in the humanities and a distinct approach to professional school training Catholic colleges and universities could easily have the edge in the areas of comprehensive theory and analysis because we have a commitment to multi-disciplinary approaches to the problems of our contemporary society and an integrating focus on the common good. In this paper I begin with a description of the range and variation in philosophy and practice of the colleges in the United States. Then I offer observations about core values that are shared among these diverse institutions. This is followed by institutional examples in Catholic higher education of the application of principles based on an ethic for the common good in response to the realities of globalization. Finally, I offer a general critique of the academic culture, academic profession, and professional schools in Catholic higher education in light of the challenges presented to us as a result of the outcomes of globalization.

Begins by distinguishing between internal and external forms of assessment. Methods and criteria for internal assessment are determined by the appropriate academic and governance structures within the institution. External assessment criteria usually are determined by an entity outside of an individual institution. Examines the utility of assessment data in the college choice process and offers a list of institutional characteristics that are useful when evaluating Catholic institutions. (RC)