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"Snyder, Mary H"
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Spiritual questions for the twenty-first century
The result for questing Catholics is a modern treasure, a resource for now and the future: the seminal thinking of such spiritual/political leaders as Tissa Balasuriya of Sri Lanka, Bishop Thomas Gumbleton of Detroit, theologians Ivone Gebara of Brazil, [Mary Hembrow Snyder] John Mananzan of the Philippines and Elizabeth Johnson of Fordham, and geologian Thomas Berry of New York. [Joan Chittister] herself says in the afterword, \"great questions themselves have the power to propel.\" These may be the most creative religious voices of our tradition in one volume. The quality of the contributors is a signal tribute to the woman. The range of voices is wide. Rembert Weakland, OSB, of Milwaukee writes that the most pressing spiritual question of the time is the urgent need to develop a global relational spirituality. Ivone Gebara wonders why the human has so little confidence in the human. Lutheran pastor and writer Martin E. Marty discusses a \"dwelling spirituality\" where one is rooted, and a \"seeking spirituality\" leading to a life of meaningful action. Bishop Gumbleton writes of his lifelong work confronting American nuclear madness.
Book Review
Saturday Diarist is mistaken in thinking that gender is pure and
I didn't realize just how many obstacles women have yet to overturn until 15 months after my daughter was born. I was raped while taking a walk on a beach, trying to get a brief respite from motherhood and wifehood. People's reactions to my being raped were ignorant, unjustified, and hurtful, more damaging to my psyche than the rape itself. And I was raped by a stranger; women who are date-raped don't stand a chance of escaping the blame of others. The images she receives from movies like \"The Little Mermaid\" and \"The Lion King\" negate almost all that I say. But Mom, she must think, girls live their lives in the shadows of boys, women live their lives in the shadows of men. Ms. [Diana Nelson Jones], even if I wanted to believe gender is pure and simple, my daughter would scare me right out of my ignorance. I do like her idea of genders as not opposite. We all talk about the other gender as the opposite sex and that is harmful to our view of each other. But, Ms. Jones, women and men are different. Our major biological difference, our reproductive systems, causes each gender to experience the world in different ways.
Newspaper Article
Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses
Macrophages are activated during microbial infection to coordinate inflammatory responses and host defense. Here we find that in macrophages activated by bacterial lipopolysaccharide (LPS), mitochondrial glycerol 3-phosphate dehydrogenase (GPD2) regulates glucose oxidation to drive inflammatory responses. GPD2, a component of the glycerol phosphate shuttle, boosts glucose oxidation to fuel the production of acetyl coenzyme A, acetylation of histones and induction of genes encoding inflammatory mediators. While acute exposure to LPS drives macrophage activation, prolonged exposure to LPS triggers tolerance to LPS, where macrophages induce immunosuppression to limit the detrimental effects of sustained inflammation. The shift in the inflammatory response is modulated by GPD2, which coordinates a shutdown of oxidative metabolism; this limits the availability of acetyl coenzyme A for histone acetylation at genes encoding inflammatory mediators and thus contributes to the suppression of inflammatory responses. Therefore, GPD2 and the glycerol phosphate shuttle integrate the extent of microbial stimulation with glucose oxidation to balance the beneficial and detrimental effects of the inflammatory response.
Horng and colleagues show that mitochondrial glycerol-3-phosphate dehydrogenase, a component of the glycerol phosphate shuttle, modulates a shift from inflammation to immunosuppression in activated macrophages.
Journal Article
Predictors of mesh explantation after incisional hernia repair
Prosthetic mesh used for incisional hernia repair (IHR) reduces hernia recurrence. Mesh infection results in significant morbidity and challenges for subsequent abdominal wall reconstruction. The risk factors that lead to mesh explantation are not well known.
This is a multisite cohort study of patients undergoing IHR at 16 Veterans Affairs hospitals from 1998 to 2002.
Of the 1,071 mesh repairs, 55 (5.1%) had subsequent mesh explantation at a median of 7.3 months (interquartile range 1.4–22.2) after IHR with permanent mesh prosthesis. Infection was the most common reason for explantation (69%). No differences were observed by the type of repair. Adjusting for covariates, same-site concomitant surgery (hazard ratio [HR] = 6.3) and postoperative surgical site infection (HR = 6.5) were associated with mesh explantation.
Patients undergoing IHR with concomitant intra-abdominal procedures have a greater than 6-fold increased hazard of subsequent mesh explantation. Permanent prosthetic mesh should be used with caution in this setting.
Journal Article
O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation
Glioblastomas (GBMs) preferentially generate acetyl-CoA from acetate as a fuel source to promote tumor growth. O-GlcNAcylation has been shown to be elevated by increasing O-GlcNAc transferase (OGT) in many cancers and reduced O-GlcNAcylation can block cancer growth. Here, we identify a novel mechanism whereby OGT regulates acetate-dependent acetyl-CoA and lipid production by regulating phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5). OGT is required and sufficient for GBM cell growth and regulates acetate conversion to acetyl-CoA and lipids. Elevating O-GlcNAcylation in GBM cells increases phosphorylation of ACSS2 on Ser-267 in a CDK5-dependent manner. Importantly, we show that ACSS2 Ser-267 phosphorylation regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Importantly, we show that pharmacologically targeting OGT and CDK5 reduces GBM growth ex vivo. Thus, the OGT/CDK5/ACSS2 pathway may be a way to target altered metabolic dependencies in brain tumors.
Journal Article
The deacylase SIRT5 supports melanoma viability by influencing chromatin dynamics
Cutaneous melanoma remains the most lethal skin cancer, and ranks third among all malignancies in terms of years of life lost. Despite the advent of immune checkpoint and targeted therapies, only roughly half of patients with advanced melanoma achieve a durable remission. Sirtuin 5 (SIRT5) is a member of the sirtuin family of protein deacylases that regulates metabolism and other biological processes. Germline Sirt5 deficiency is associated with mild phenotypes in mice. Here we showed that SIRT5 was required for proliferation and survival across all cutaneous melanoma genotypes tested, as well as uveal melanoma, a genetically distinct melanoma subtype that arises in the eye and is incurable once metastatic. Likewise, SIRT5 was required for efficient tumor formation by melanoma xenografts and in an autochthonous mouse Braf Pten-driven melanoma model. Via metabolite and transcriptomic analyses, we found that SIRT5 was required to maintain histone acetylation and methylation levels in melanoma cells, thereby promoting proper gene expression. SIRT5-dependent genes notably included MITF, a key lineage-specific survival oncogene in melanoma, and the c-MYC proto-oncogene. SIRT5 may represent a druggable genotype-independent addiction in melanoma.
Journal Article
Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease
A child with a neuronal ceroid lipofuscinosis was found to carry loss-of-function mutations in the gene
MFSD8
(
CLN7
). A year after genetic diagnosis, the child began treatment with an oligonucleotide drug that was designed to correct the aberrant pre–messenger RNA splicing caused by one of these mutations.
Journal Article