Preparing Humanities Students for Employment: Reimagining Career Exploration and Education through Ignatian Spirituality and Discernment

Graduate students in the humanities are hungry for career exploration as they face limited academic career options and feel called to work beyond the academy. Career preparation is typically left to graduate advisors, and then, the focus tends to be on academic career preparation. This article details how a required, introductory graduate class was reimagined to integrate career exploration using a framework at the heart of Ignatian spirituality and education: discernment. The authors outline the course and two assignments that can be adapted and applied to any graduate course. The authors share reflections on how the class has impacted their own professional and personal formation, and they end with heuristics for educators to use when preparing to teach similar graduate courses

Microbial Biocatalysis within Us: The Underexplored Xenobiotic Biotransformation Potential of the Urinary Tract Microbiota

Enzymatic biotransformation of xenobiotics by the human microbiota mediates diet-drug-microbe-host interactions and affects human health. Most research on xenobiotics has focused on the gut microbiota while neglecting other body sites, yet over two-thirds of pharmaceuticals are primarily excreted in urine. As a result, the urinary microbiota is exposed to many xenobiotics in much higher concentrations than in the gut. Microbial xenobiotic biocatalysis in the bladder has implications for urinary tract infections and the emergence of antibiotic resistance. However, we have limited knowledge of biotransformations catalyzed by the urinary microbiota. In this perspective, we investigated differences in physicochemical conditions and microbial community composition between the gut and urinary tract. We used a comparative enzyme class mining approach to profile the distribution of xenobiotic-transforming enzyme homologs in genomes of urinary bacteria. Our analysis revealed a discontinuous distribution of enzyme classes even among closely related organisms. We detected diverse amidase homologs involved in pharmaceutical and dietary additive biotransformation pathways, pinpointing microbial candidates to validate for their involvement in xenobiotic transformations in urine. Overall, we highlight the biocatalytic potential of urinary tract bacteria as a lens to study how the human microbiota may respond and adapt to xenobiotic inputs

Normalization of clonal diversity in gene therapy studies using shape constrained splines

Viral vectors are used to insert genetic material into semirandom genomic positions of hematopoietic stem cells which, after reinfusion into patients, regenerate the entire hematopoietic system. Hematopoietic cells originating from genetically modified stem cells will harbor insertions in specific genomic positions called integration sites, which represent unique genetic marks of clonal identity. Therefore, the analysis of vector integration sites present in the genomic DNA of circulating cells allows to determine the number of clones in the blood ecosystem. Shannon diversity index is adopted to evaluate the heterogeneity of the transduced population of gene corrected cells. However, this measure can be affected by several technical variables such as the DNA amount used and the sequencing depth of the library analyzed and therefore the comparison across samples may be affected by these confounding factors. We developed an advanced spline-regression approach that leverages on confounding effects to provide a normalized entropy index. Our proposed method was first validated and compared with two state of the art approaches in a specifically designed in vitro assay. Subsequently our approach allowed to observe the expected impact of vector genotoxicity on entropy level decay in an in vivo model of hematopoietic stem cell gene therapy based on tumor prone mice

The paradox of verbal autopsy in cause of death assignment: symptom question unreliability but predictive accuracy

Background: We believe that it is important that governments understand the reliability of the mortality data which they have at their disposable to guide policy debates. In many instances, verbal autopsy (VA) will be the only source of mortality data for populations, yet little is known about how the accuracy of VA diagnoses is affected by the reliability of the symptom responses. We previously described the effect of the duration of time between death and VA administration on VA validity. In this paper, using the same dataset, we assess the relationship between the reliability and completeness of symptom responses and the reliability and accuracy of cause of death (COD) prediction. Methods: The study was based on VAs in the Population Health Metrics Research Consortium (PHMRC) VA Validation Dataset from study sites in Bohol and Manila, Philippines and Andhra Pradesh, India. The initial interview was repeated within 3-52 months of death. Question responses were assessed for reliability and completeness between the two survey rounds. COD was predicted by Tariff Method. Results: A sample of 4226 VAs was collected for 2113 decedents, including 1394 adults, 349 children, and 370 neonates. Mean question reliability was unexpectedly low (kappa = 0.447): 42.5 % of responses positive at the first interview were negative at the second, and 47.9 % of responses positive at the second had been negative at the first. Question reliability was greater for the short form of the PHMRC instrument (kappa = 0.497) and when analyzed at the level of the individual decedent (kappa = 0.610). Reliability at the level of the individual decedent was associated with COD predictive reliability and predictive accuracy. Conclusions: Families give coherent accounts of events leading to death but the details vary from interview to interview for the same case. Accounts are accurate but inconsistent; different subsets of symptoms are identified on each occasion. However, there are sufficient accurate and consistent subsets of symptoms to enable the Tariff Method to assign a COD. Questions which contributed most to COD prediction were also the most reliable and consistent across repeat interviews; these have been included in the short form VA questionnaire. Accuracy and reliability of diagnosis for an individual death depend on the quality of interview. This has considerable implications for the progressive roll out of VAs into civil registration and vital statistics (CRVS) systems

Repurposing Itraconazole as a Treatment for Advanced Prostate Cancer: A Noncomparative Randomized Phase II Trial in Men With Metastatic Castration‐Resistant Prostate Cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139926/1/onco0163-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139926/2/onco0163.pd

Insights into the Regulatory Characteristics of the Mycobacterial Dephosphocoenzyme A Kinase: Implications for the Universal CoA Biosynthesis Pathway

Being vastly different from the human counterpart, we suggest that the last enzyme of the Mycobacterium tuberculosis Coenzyme A biosynthetic pathway, dephosphocoenzyme A kinase (CoaE) could be a good anti-tubercular target. Here we describe detailed investigations into the regulatory features of the enzyme, affected via two mechanisms. Enzymatic activity is regulated by CTP which strongly binds the enzyme at a site overlapping that of the leading substrate, dephosphocoenzyme A (DCoA), thereby obscuring the binding site and limiting catalysis. The organism has evolved a second layer of regulation by employing a dynamic equilibrium between the trimeric and monomeric forms of CoaE as a means of regulating the effective concentration of active enzyme. We show that the monomer is the active form of the enzyme and the interplay between the regulator, CTP and the substrate, DCoA, affects enzymatic activity. Detailed kinetic data have been corroborated by size exclusion chromatography, dynamic light scattering, glutaraldehyde crosslinking, limited proteolysis and fluorescence investigations on the enzyme all of which corroborate the effects of the ligands on the enzyme oligomeric status and activity. Cysteine mutagenesis and the effects of reducing agents on mycobacterial CoaE oligomerization further validate that the latter is not cysteine-mediated or reduction-sensitive. These studies thus shed light on the novel regulatory features employed to regulate metabolite flow through the last step of a critical biosynthetic pathway by keeping the latter catalytically dormant till the need arises, the transition to the active form affected by a delicate crosstalk between an essential cellular metabolite (CTP) and the precursor to the pathway end-product (DCoA)

Time-dynamic effects on the global temperature when harvesting logging residues for bioenergy

The climate mitigation potential of using logging residues (tree tops and branches) for bioenergy has been debated. In this study, a time-dependent life cycle assessment (LCA) was performed using a single-stand perspective. Three forest stands located in different Swedish climate zones were studied in order to assess the global temperature change when using logging residues for producing district heating. These systems were compared with two fossil reference systems in which the logging residues were assumed to remain in the forest to decompose over time, while coal or natural gas was used for energy. The results showed that replacing coal with logging residues gave a direct climate benefit from a single-stand perspective, while replacing natural gas gave a delayed climate benefit of around 8-12 years depending on climate zone. A sensitivity analysis showed that the time was strongly dependent on the assumptions for extraction and combustion of natural gas. The LCA showed that from a single-stand perspective, harvesting logging residues for bioenergy in the south of Sweden would give the highest temperature change mitigation potential per energy unit. However, the differences between the three climate zones studied per energy unit were relatively small. On a hectare basis, the southern forest stand would generate more biomass compared to the central and northern locations, which thereby could replace more fossil fuel and give larger climate benefits

Using verbal autopsy to measure causes of death: the comparative performance of existing methods

Background: Monitoring progress with disease and injury reduction in many populations will require widespread use of verbal autopsy (VA). Multiple methods have been developed for assigning cause of death from a VA but their application is restricted by uncertainty about their reliability. Methods: We investigated the validity of five automated VA methods for assigning cause of death: InterVA-4, Random Forest (RF), Simplified Symptom Pattern (SSP), Tariff method (Tariff), and King-Lu (KL), in addition to physician review of VA forms (PCVA), based on 12,535 cases from diverse populations for which the true cause of death had been reliably established. For adults, children, neonates and stillbirths, performance was assessed separately for individuals using sensitivity, specificity, Kappa, and chance-corrected concordance (CCC) and for populations using cause specific mortality fraction (CSMF) accuracy, with and without additional diagnostic information from prior contact with health services. A total of 500 train-test splits were used to ensure that results are robust to variation in the underlying cause of death distribution. Results: Three automated diagnostic methods, Tariff, SSP, and RF, but not InterVA-4, performed better than physician review in all age groups, study sites, and for the majority of causes of death studied. For adults, CSMF accuracy ranged from 0.764 to 0.770, compared with 0.680 for PCVA and 0.625 for InterVA; CCC varied from 49.2% to 54.1%, compared with 42.2% for PCVA, and 23.8% for InterVA. For children, CSMF accuracy was 0.783 for Tariff, 0.678 for PCVA, and 0.520 for InterVA; CCC was 52.5% for Tariff, 44.5% for PCVA, and 30.3% for InterVA. For neonates, CSMF accuracy was 0.817 for Tariff, 0.719 for PCVA, and 0.629 for InterVA; CCC varied from 47.3% to 50.3% for the three automated methods, 29.3% for PCVA, and 19.4% for InterVA. The method with the highest sensitivity for a specific cause varied by cause. Conclusions: Physician review of verbal autopsy questionnaires is less accurate than automated methods in determining both individual and population causes of death. Overall, Tariff performs as well or better than other methods and should be widely applied in routine mortality surveillance systems with poor cause of death certification practices. © 2014 Murray et al.; licensee BioMed Central Ltd