Interdisciplinary college curriculum and its labor market implications.

This article sheds light on how to capture knowledge integration dynamics in college course content, improves and enriches the definition and measurement of interdisciplinarity, and expands the scope of research on the benefits of interdisciplinarity to postcollege outcomes. We distinguish between what higher education institutions claim regarding interdisciplinarity and what they appear to actually do. We focus on the core academic element of student experience-the courses they take, develop a text-based semantic measure of interdisciplinarity in college curriculum, and test its relationship to average earnings of graduates from different types of schools of higher education. We observe that greater exposure to interdisciplinarity-especially for science majors-is associated with increased earnings after college graduation.

Biallelic ASCC1 variants including a novel intronic variant result in expanded phenotypic spectrum of spinal muscular atrophy with congenital bone fractures 2 (SMABF2).

Spinal muscular atrophy with congenital bone fractures 2 (SMABF2), a type of arthrogryposis multiplex congenita (AMC), is characterized by congenital joint contractures, prenatal fractures of long bones, and respiratory distress and results from biallelic variants in ASCC1. Here, we describe an infant with severe, diffuse hypotonia, congenital contractures, and pulmonary hypoplasia characteristic of SMABF2, with the unique features of cleft palate, small spleen, transverse liver, and pulmonary thromboemboli with chondroid appearance. This infant also had impaired coagulation with diffuse petechiae and ecchymoses which has only been reported in one other infant with AMC. Using trio whole genome sequencing, our proband was identified to have biallelic variants in ASCC1. Using deep next generation sequencing of parental cDNA, we characterized alteration of splicing encoded by the novel, maternally inherited ASCC1 variant (c.297-8 T > G) which provides a mechanism for functional pathogenicity. The paternally inherited ASCC1 variant is a rare nonsense variant (c.466C > T; p.Arg156*) that has been previously identified in one other infant with AMC. This report extends the phenotypic characteristics of ASCC1-associated AMC (SMABF2) and describes a novel intronic variant that partially disrupts RNA splicing.

Local control of 1-5 fraction radiotherapy regimens for spinal metastases: an analysis of the impacts of biologically effective dose and primary histology.

BACKGROUND: This analysis evaluates the impacts of biologically effective dose (BED) and histology on local control (LC) of spinal metastases treated with highly conformal radiotherapy to moderately-escalated doses. MATERIALS AND METHODS: Patients were treated at two institutions from 2010-2020. Treatments with less than 5 Gy per fraction or 8 Gy in 1 fraction were excluded. The dataset was divided into three RPA classes predictive of survival (1). The primary endpoint was LC. RESULTS: 223 patients with 248 treatments met inclusion criteria. Patients had a median Karnofsky Performance Status (KPS ) of 80, and common histologies included breast (29.4%), non-small cell lung cancer (15.7%), and prostate (13.3%). A median 24 Gy was delivered in 3 fractions (BED: 38.4 Gy) to a median planning target volume (PTV) of 37.3 cc. 2-year LC was 75.7%, and 2-year OS was 42.1%. Increased BED was predictive of improved LC for primary prostate cancer (HR = 0.85, 95% CI: 0.74-0.99). Patients with favorable survival (RPA class 1) had improved LC with BED ≥ 40 Gy (p = 0.05), unlike the intermediate and poor survival groups. No grade 3-5 toxicities were reported. CONCLUSIONS: Moderately-escalated treatments were efficacious and well-tolerated. BED ≥ 40 Gy may improve LC, particularly for prostate cancer and patients with favorable survival.

Stereotactic radiosurgery for the treatment of bulky spine metastases.

INTRODUCTION: Stereotactic radiosurgery (SRS) has shown durable local control for the treatment of metastatic diseasespinal metastases. Multilevel disease or epidural or paraspinal involvement present challenges to achieving local control, and this study aims to analyze treatment outcomes for such lesions. METHODS: Patients treated at a single institution with SRS to the spine from 2010-2018 were retrospectively reviewed. Inclusion criteria required clinical follow-up with either a pain assessment or imaging study. Bulky spine metastasis was defined as consisting of multilevel disease or epidural or paraspinal tumor involvement. RESULTS: 54 patients treated for 62 lesions met inclusion criteria. 42 treatments included at least two vertebrae, and 21 and 31 had paraspinal and epidural involvement, respectively. Treatment regimens had a median 24 Gy in 3 fractions to a volume of 37.75 cm3. Median follow-up was 14.36 months, with 5 instances (8%) of local failure. Median overall survival was 13.32 months. Pain improvement was achieved in 47 treatments (76%), and pain improved with treatment (p < 0.0001). Severe pain (HR = 3.08, p = 0.05), additional bone metastases (HR = 4.82, p = 0.05), and paraspinal involvement (HR = 3.93, p < 0.005) were predictive for worse overall survival. Kaplan-Meier analysis demonstrated that prior chemotherapy (p = 0.03) and additional bone metastases (p = 0.02) were predictive of worse overall survival. Grade < 3 toxicity was observed in 19 cases; no grade ≥ 3 side effects were observed. CONCLUSIONS: SRS can effectively treat bulky metastases to the spine, resulting in improvement of pain with minimal toxicity. Severe pain independently predicts for worse overall survival, indicating that treatment prior to worsening of pain is strongly recommended.

Contribution of systemic inflammation to permanence of KATP-induced neonatal diabetes in mice.

Gain-of-function (GOF) mutations in the ATP-sensitive potassium (KATP) channels cause neonatal diabetes. Despite the well-established genetic root of the disease, pathways modulating disease severity and treatment effectiveness remain poorly understood. Patient phenotypes can vary from severe diabetes to remission, even in individuals with the same mutation and within the same family, suggesting that subtle modifiers can influence disease outcome. We have tested the underlying mechanism of transient vs. permanent neonatal diabetes in KATP-GOF mice treated for 14 days with glibenclamide. Some KATP-GOF mice show remission of diabetes and enhanced insulin sensitivity long after diabetes treatment has ended, while others maintain severe insulin-resistance. However, insulin sensitivity is not different between the two groups before or during diabetes induction, suggesting that improved sensitivity is a consequence, rather than the cause of, remission, implicating other factors modulating glucose early in diabetes progression. Leptin, glucagon, insulin, and glucagon-like peptide-1 are not different between remitters and nonremitters. However, liver glucose production is significantly reduced before transgene induction in remitter, relative to nonremitter and nontreated, mice. Surprisingly, while subsequent remitter animals exhibited normal serum cytokines, nonremitter mice showed increased cytokines, which paralleled the divergence in blood glucose. Together, these results suggest that systemic inflammation may play a role in the remitting versus non-remitting outcome. Supporting this conclusion, treatment with the anti-inflammatory meloxicam significantly increased the fraction of remitting animals. Beyond neonatal diabetes, the potential for inflammation and glucose production to exacerbate other forms of diabetes from a compensated state to a glucotoxic state should be considered.

Multiple functions of yeast mitochondrial transcription factor Mtf1p during initiation.

Transcription of the yeast mitochondrial genome is carried out by an RNA polymerase (Rpo41p) that is related to single subunit bacteriophage RNA polymerases but requires an additional factor (Mtf1p) for initiation. In this work we show that Mtf1p is involved in multiple roles during initiation including discrimination of upstream base pairs in the promoter, initial melting of three to four base pairs around the site of transcript initiation, and suppression of nonspecific initiation. It, thus, appears that Mtf1p is functionally analogous to initiation factors of multisubunit RNA polymerases, such as sigma. Photocross-linking experiments reveal close proximity between Mtf1p and the promoter DNA and show that the C-terminal domain makes contacts with the template strand in the vicinity of the start site. Interestingly, Mtf1p is related to a class of RNA methyltransferases, suggesting an early evolutionary link between RNA synthesis and processing.

Rethinking research on forming typologies of homelessness.

In homelessness research and policymaking, it seems to be axiomatic that single adults experience 3 temporally based types of homelessness: chronic, episodic, and transitional. We discuss problems with the theorization of this typology and with the research design, data analysis, and time-aggregated conceptualization and measurement of temporality in the empirical work supporting the typology. To address the latter, we suggest a time-patterned approach to temporality and report a 10-group typology that differs significantly from the more familiar 3-group typology. We argue that which approach is used-and how typologies are developed more generally-should be based on theory and the uses to which typologies are put rather than on claims to being more true.

Neuroscience Near-Peer-Led Flipped Classroom Improves Student Confidence With Clinical Application of Content and Test-Taking Skills.

Introduction: The ability to apply knowledge gained in neuroscience coursework to a clinical scenario is found to be difficult by many medical students. Neuroscience is both important for future clinical practice and an area frequently tested on USMLE Step 1 examinations. Methods: Second-year medical students created a peer-led flipped classroom to help first-year students practice applying medical neuroscience course information to clinical situations and demonstrate how that information might be tested in board-style questions. The second-year students designed a series of board-style questions that included explanations for both the correct and incorrect answers. We divided the first-year students (n = 80) into small groups during the flipped classroom sessions, where they were led by second-year medical students in discussion about the questions and clinical situations. Results: Students reported agreement that the session addressed gaps in their knowledge and provided them with useful critical thinking skills for approaching board-style questions (83% and 81% agreed or strongly agreed, respectively). Discussion: The flipped classroom improved student confidence in both applying neuroscience concepts to clinical scenarios and to board-style vignette questions.

Histone variant H2A.Z inhibits transcription in reconstituted nucleosomes.

The existence of histone nonallelic variants has been known for more than 30 years, but only recently have we acquired significant insights into their functions. Nucleosomes containing histone variants are nonrandomly distributed in genomes and may impart different biological functions to the relevant chromatin regions. We have used the model T7 RNA polymerase to transcribe reconstituted nucleosomes containing either canonical human recombinant histones or two histone variants, H2A.Z or H3.3, whose presence has been associated with active transcription. Remarkably, in contrast to canonical and H3.3-containing nucleosomes, H2A.Z-containing nucleosomes were refractive to transcription, with residual levels of transcription determined by the sequence of the underlying DNA template. To our knowledge, this is the first example of a nucleosome that is intrinsically untranscribable.

A comparison of stereotactic body radiation therapy for metastases to the sacral spine and treatment of the thoracolumbar spine.

Background: This study compares the outcomes of stereotactic body radiation therapy (SBRT) for sacral and thoracolumbar spine metastases. Methods: This analysis considered each sacral spine SBRT treatment at a single institution and a cohort of consecutive thoracolumbar treatments. Results: 28 patients with 35 sacral treatments and 41 patients with 49 thoracolumbar treatments were included. Local control was 63% and 90%, respectively. The sacral cohort contained more lesions with ≥2 vertebrae and epidural and paraspinal involvement. Sacral patients had larger treatment volumes, increased rates of subsequent SBRT, decreased propensity for pain improvement, and decreased local control (p=0.02 on Kaplan-Meier analysis). Multivariate analysis demonstrated that PTV > 50 cc and epidural involvement were correlated with decreased local control. No cases had grade ≥3 toxicity. Conclusion: SBRT for sacral spine metastases is a distinct disease process than metastases to the thoracolumbar spine, resulting in lower rates of local control and pain improvement.

Stereotactic body radiation therapy for spinal metastases: a novel local control stratification by spinal region.

OBJECTIVE: This study evaluated a large cohort of patients treated with stereotactic body radiation therapy for spinal metastases and investigated predictive factors for local control, local progression-free survival (LPFS), overall survival, and pain response between the different spinal regions. METHODS: The study was undertaken via retrospective review at a single institution. Patients with a tumor metastatic to the spine were included, while patients with benign tumors or primary spinal cord cancers were excluded. Statistical analysis involved univariate analysis, Cox proportional hazards analysis, the Kaplan-Meier method, and machine learning techniques (decision-tree analysis). RESULTS: A total of 165 patients with 190 distinct lesions met all inclusion criteria for the study. Lesions were distributed throughout the cervical (19%), thoracic (43%), lumbar (19%), and sacral (18%) spines. The most common treatment regimen was 24 Gy in 3 fractions (44%). Via the Kaplan-Meier method, the 24-month local control was 80%. Sacral spine lesions demonstrated decreased local control (p = 0.01) and LPFS (p < 0.005) compared with those of the thoracolumbar spine. The cervical spine cases had improved local control (p < 0.005) and LPFS (p < 0.005) compared with the sacral spine and trended toward improvement relative to the thoracolumbar spine. The 36-month local control rates for cervical, thoracolumbar, and sacral tumors were 86%, 73%, and 44%, respectively. Comparably, the 36-month LPFS rates for cervical, thoracolumbar, and sacral tumors were 85%, 67%, and 35%, respectively. A planning target volume (PTV) > 50 cm3 was also predictive of local failure (p = 0.04). Fewer cervical spine cases had disease with PTV > 50 cm3 than the thoracolumbar (p = 5.87 × 10-8) and sacral (p = 3.9 × 10-3) cases. Using decision-tree analysis, the highest-fidelity models for predicting pain-free status and local failure demonstrated the first splits as being cervical and sacral location, respectively. CONCLUSIONS: This study presents a novel risk stratification for local failure and LPFS by spinal region. Patients with metastases to the sacral spine may have decreased local control due to increased PTV, especially with a PTV of > 50 cm3. Multidisciplinary care should be emphasized in these patients, and both surgical intervention and radiotherapy should be strongly considered.

Identification of proteins associated with the yeast mitochondrial RNA polymerase by tandem affinity purification.

The abundance of mitochondrial (mt) transcripts varies under different conditions, and is thought to depend upon rates of transcription initiation, transcription termination/attenuation and RNA processing/degradation. The requirement to maintain the balance between RNA synthesis and processing may involve coordination between these processes; however, little is known about factors that regulate the activity of mtRNA polymerase (mtRNAP). Recent attempts to identify mtRNAP-protein interactions in yeast by means of a generalized tandem affinity purification (TAP) protocol were not successful, most likely because they involved a C-terminal mtRNAP-TAP fusion (which is incompatible with mtRNAP function) and because of the use of whole-cell solubilization protocols that did not preserve the integrity of mt protein complexes. Based upon the structure of T7 RNAP (to which mtRNAPs show high sequence similarity), we identified positions in yeast mtRNAP that allow insertion of a small affinity tag, confirmed the mature N-terminus, constructed a functional N-terminal TAP-mtRNAP fusion, pulled down associated proteins, and identified them by LC-MS-MS. Among the proteins found in the pull-down were a DEAD-box protein (Mss116p) and an RNA-binding protein (Pet127p). Previous genetic experiments suggested a role for these proteins in linking transcription and RNA degradation, in that a defect in the mt degradadosome could be suppressed by overexpression of either of these proteins or, independently, by mutations in either mtRNAP or its initiation factor Mtf1p. Further, we found that Mss116p inhibits transcription by mtRNAP in vitro in a steady-state reaction. Our results support the hypothesis that Mss116p and Pet127p are involved in modulation of mtRNAP activity.

A double-blind randomized controlled trial of electromagnetic stimulation of the pelvic floor vs sham therapy in the treatment of women with stress urinary incontinence.

OBJECTIVE: To compare the efficacy of extracorporeal electromagnetic stimulation (ES) of the pelvic floor for treating stress urinary incontinence (SUI) vs sham ES. PATIENTS AND METHODS: In all, 70 women with urodynamically confirmed SUI were randomized to receive active (35) or sham (35) ES. The NeoControl chair (NeoTonus, Marietta, GA, USA) was used, and treatment consisted of three sessions per week for 6 weeks. data were collected before and after treatment on all women, including a 20-min provocative pad-test with a predetermined bladder volume (primary outcome measure), a 3-day bladder diary and 24 h pad-test. Circumvaginal muscle (CVM) rating score, perineometry using two separate instruments and video-urodynamics were also used, and the Urinary Incontinence Quality of Life Scale (I-QOL) and King's Health Questionnaires. Patients were fully re-evaluated 8 weeks after treatment, and the bladder diary, pad-test and questionnaires were repeated at 6 months. The urotherapist and physician were unaware to which treatment group the patient was assigned. RESULTS: In the overall group of 70 patients there were significant improvements in each of the primary and secondary outcome measures at 8 weeks. There were also significant improvements in primary and secondary outcome measures in the active treatment group when compared with baseline measures. At 8 weeks, there were improvements in the mean (sd) values for the 20-min pad-test, of 39.5 (5.1) vs 19.4 (4.6) g (P < 0.001); the 24-h pad-test, of 24.0 (4.7) vs 10.1 (3.1) g (P < 0.01); the number of pads/day, of 0.9 (0.1) vs 0.6 (0.1) (P < 0.01), the I-QOL score, of 63.7 (2.8) vs 71.2 (3.3) (P < 0.001); and King's Health Questionnaire score, of 9.6 (0.8) vs 6.9 (0.7) (P < 0.001). However, these improvements were not statistically significant when compared with the sham-treatment group. In those patients on active treatment who had a poor pelvic floor contraction at the initial assessment (defined by the CVM score and perineometry), there was a significant reduction (P < 0.05) in the 20-min pad-test leakage when compared with the sham-treatment group. CONCLUSIONS: ES was no more effective overall than sham treatment in this patient group. However, in those women who were unable to generate adequate pelvic floor muscle contractions, there was an objective improvement in provocative pad testing when compared to sham treatment.

Single-molecule approaches reveal the idiosyncrasies of RNA polymerases.

Recently developed single-molecule techniques have provided new insights into the function of one of the most complex and highly regulated processes in the cell--the transcription of the DNA template into RNA. This review discusses methods and results from this emerging field, and it puts them in perspective of existing biochemical and structural data.

Effects of substitutions in a conserved DX(2)GR sequence motif, found in many DNA-dependent nucleotide polymerases, on transcription by T7 RNA polymerase.

The region in bacteriophage T7 RNA polymerase (RNAP) comprising residues 421-425 contains a sequence motif (DX(2)GR) that is conserved among many DNA-dependent nucleotide polymerases. We have found that alterations in this motif result in enzymes that display weaker retention of the RNA product during transcript initiation, a decreased ability to make the transition to a stable elongation complex, and changes in substrate binding and catalytic activity. Many of these defects are coupled with an altered response to the presence or absence of the non-template strand. The observed constellation of defects supports a role for the motif in interacting with and stabilizing the RNA:DNA hybrid during the early stages of transcript initiation. This is consistent with the position of the motif in a T7 RNAP initiation complex. Although a conserved DX(2)GR sequence motif is also observed in multisubunit RNAPs, the structural organization of the motif and the manner in which it interacts with the RNA:DNA hybrid in the latter enzymes is different from that in T7 RNAP. However, another element in the multisubunit RNAPs that contains a highly conserved arginine residue may play the same role as R425 in T7 RNAP. (c) 2002 Elsevier Science Ltd.

The global political economy of scheduling: the international-historical context of the Controlled Substances Act.

This article explains the international context of regulation to control addicting substances that gave rise to schedules. It discusses the impact of scheduling decisions on subsequent national drug control legislation and international drug control negotiations, highlighting how the creation of schedules introduced new incentives and rewards into calculations about the national/international commerce in drugs. In particular, the schedules affected the development and clinical application of psychotropic substances, and the 1971 Convention on Psychotropic Substances receives special focus. The roles of governmental representatives, pharmaceutical company interests, medical researchers, physicians, and pharmacists are highlighted. The article illustrates how debates about scheduling in international treaties over the previous 40 years impacted the creation of the 1970 Controlled Substances Act in the United States and how the constituencies that contributed to constructing the Controlled Substances Act viewed their efforts in a global context.

Keeping the lid on: a century of drug regulation and control.

Since the early 1900s, national and international drug control legislation has acted as a key site of contention between important societal actors. Physicians and pharmacists, regulators and drug companies, patients and addicts, and researchers and pharmacologists all attempted to influence formulation and interpretation of the rules that regulate access to addicting but medically useful substances. The 1970 Controlled Substances Act (CSA) consolidated and rationalized previous US domestic legislation and paid careful attention to the international aspects of the issue. Yet the CSA also incorporated long-standing fundamental disputes about who would act as gatekeepers, what criteria would be employed in regulatory decisions, and the basic goals of drug control legislation. Rather than view the CSA as a beginning or an end, it is better conceived as a major milepost in a century-long odyssey of maneuvering among interested parties for advantage in a complex regulatory environment. Instead of providing a definitive authoritative structure to which all parties must adhere, the CSA has served as a vehicle for discernment and continuous renegotiation of essential concepts such as "abuse liability".

The presence of an RNA:DNA hybrid that is prone to slippage promotes termination by T7 RNA polymerase.

Intrinsic termination signals for multisubunit bacterial RNA polymerases (RNAPs) encode a GC-rich stem-loop structure followed by a polyuridine [poly(U)] tract, and it has been proposed that steric clash of the stem-loop with the exit pore of the RNAP imposes a shearing force on the RNA in the downstream RNA:DNA hybrid, resulting in misalignment of the active site. The structurally unrelated T7 RNAP terminates at a similar type of signal (TΦ), suggesting a common mechanism for termination. In the absence of a hairpin (passive conditions), T7 RNAP slips efficiently in both homopolymeric A and U tracts, and we have found that replacement of the U tract in TΦ with a slippage-prone A tract still allows efficient termination. Under passive conditions, incorporation of a single G residue following a poly(U) tract (which is the situation during termination at TΦ) results in a "locked" complex that is unable to extend the transcript. Our results support a model in which transmission of the shearing force generated by steric clash of the hairpin with the exit pore is promoted by the presence of a slippery tracts downstream, resulting in alterations in the active site and the formation of a locked complex that represents an early step in the termination pathway.

Yeast DEAD box protein Mss116p is a transcription elongation factor that modulates the activity of mitochondrial RNA polymerase.

DEAD box proteins have been widely implicated in regulation of gene expression. Here, we show that the yeast Saccharomyces cerevisiae DEAD box protein Mss116p, previously known as a mitochondrial splicing factor, also acts as a transcription factor that modulates the activity of the single-subunit mitochondrial RNA polymerase encoded by RPO41. Binding of Mss116p stabilizes paused mitochondrial RNA polymerase elongation complexes in vitro and favors the posttranslocated state of the enzyme, resulting in a lower concentration of nucleotide substrate required to escape the pause; this mechanism of action is similar to that of elongation factors that enhance the processivity of multisubunit RNA polymerases. In a yeast strain in which the RNA splicing-related functions of Mss116p are dispensable, overexpression of RPO41 or MSS116 increases cell survival from colonies that were exposed to low temperature, suggesting a role for Mss116p in enhancing the efficiency of mitochondrial transcription under stress conditions.

Green Synthesis of Robust, Biocompatible Silver Nanoparticles Using Garlic Extract.

This paper details a facile approach for the synthesis of stable and monodisperse silver nanoparticles performed at ambient/low temperature where Allium sativum (garlic) extract functions as the silver salt reducing agent during nanoparticle synthesis as well as the post-synthesis stabilizing ligands. Varying the synthesis conditions provides control of particle size, size-distribution, and kinetics of particle formation. Infrared spectroscopy, energy dispersive x-ray chemical analysis, and high performance liquid chromatography indicated that the carbohydrates present in the garlic extract are the most likely nanoparticle stabilizing chemistry. The synthesized silver nanoparticles also demonstrate potential for biomeical applications, owing to the 1) enhanced stability in biological media, 2) resistance to oxidation by the addition of H2O2, 3) ease and scalability of synthesis, and 4) lack of harsh chemicals required for synthesis. Cytotoxicity assays indicated no decrease in cellular proliferation for vascular smooth muscle cells and 3T3 fibroblasts at a concentration of 25 µg/ml, confirming that garlic extract prepared silver nanoparticles are ideal candidates for future experimentation and implementation into biomedical applications.