A study of biomolecular interactions using three biological complexes to explore structure, dynamics and method development

The protein, RDE-4 in C. elegans, served as a model for studying how double stranded RNA binding proteins that bind to dsRNA molecules are critical for RNAi cellular processes. NMR spectroscopy confirms that the RDE-4 construct has characteristic protein domains that bind to. dsRNA and that RNA binding causes a significant global change of the protein structure. SAXS analysis indicates that the two binding domains in the RDE-4 protein do not interact with one another, but instead forms a continuous interface onto which long target dsRNA can bind. Gel shift assay experiments reveal that multiple RDE-4 molecules bind to a non-sequence specific RNA substrate with positive cooperativity. RNA binding occurs with micromolar affinity and a second binding event occurs with millimolar affinity. The binding of E. coli dihydrofolate reductase (DHFR) to inhibitors methotrexate (MTX) and 1,4-Bis-{[ N-(1-imino-1-guanidino-methyl)]sulfanylmethyl}-3,6-dimethyl-benzene (inhibitor 1) has been studied to investigate the dynamics involved in the catalytic mechanism of DHFR. NMR relaxation methods show that in the presence of inhibitor 1, the catalytic domain of DHFR binds 1 in the substrate-binding pocket and an occluded conformation is assumed. In both the DHFR:NADPH and DHFR:NADPH:1 complexes, motion is exhibited on the microsecond-millisecond timescale. The heat capacity change of DHFR upon binding to 1 and MTX are 43 ± 10 cal/mol-K and -120 ± 109 cal/mol-K respectively. Differences in ΔCp of DHFR binding to inhibitor 1 compared to that of MTX indicate that the mode of binding to 1 is different from what is observed in the crystal structure of the complex. An affinity electrophoresis method to screen for RNA-small molecule ligand interactions has been developed. This method is made quantifiable by cross-linking the ligand into the gel matrix and gauging binding by RNA mobility. The utility of this method is demonstrated using the known interaction between different aminoglycoside ligands with the E. coli ribosomal A-site RNA and with an RNA molecule containing a C-C mismatch. Average apparent dissociation constants are determined. This method allows an easy quantitative comparison between different nucleic acid molecules for a small molecule ligand

Balancing Human Rights and the Use of Artificial Intelligence in Border Security in Africa

In a continent marked by its historical pursuit of secure borders, Africa now stands at a pivotal juncture, transitioning from traditional physical barriers to harnessing the transformative potential of Artificial Intelligence (AI) technologies. This transformation signifies the continent’s unwavering commitment to efficiency and innovation, yet it unveils a formidable challenge – striking a harmonious balance between the imperative of security and safeguarding of fundamental human rights and freedoms. The integration of AI in border security, with its utilization of biometric data, facial recognition, iris scanning, and more, has given rise to a host of intricate concerns, including ethical considerations such as transparency and accountability. Privacy emerges as a paramount issue as the data reservoirs amassed at border crossings raise questions about storage, accessibility, and potential misuse. The complexities of personal information management take centre stage, necessitating scrutiny over data handling, security, and safeguards against abuse. Through an examination of historical trends and a detailed analysis of past and present border security practices in Africa, this paper reviews the evolution of strategies and challenges in Africa’s border security. This investigation spotlights the continent’s adoption of AI as a cornerstone in safeguarding its borders. However, it underscores that while advancements are evident, a delicate equilibrium must be achieved. This paper argues that achieving a harmonious balance between bolstering security measures and safeguarding individual rights and freedoms, all within the framework of ethical principles is an attainable endeavor

Mind the Gap: Student Researchers Use Secondary Data to Explore Disparities in STEM Education

Large data sets offer opportunities for graduate students to become involved in meaningful research, but also comes with a unique set of challenges. This paper seeks to examine that relationship through utilizing the High School Longitudinal Study 2009 – representative of US ninth graders in 2009 (n = 21,444) – to examine a set of research questions about STEM interest and preparation amongst secondary students. Student researchers identified gaps in plans and outcomes with regards to race, gender, exceptionalities, and socioeconomic status. Findings indicated inequities that affect STEM outcomes. A significant interaction was found between students education expectations by gender on science self-efficacy [F(4,1264) = 2.797, p =.025]. This interaction was not observed for math self-efficacy. Females and underrepresented minorities were less likely to pursue computer science courses and computer science careers [Females: Χ2 (2, N = 20,594) = 111.500, p \u3c .0001; Minorities: Χ2 (2, N = 13,069) = 6.455, p = .040]. Students’ expectations for post-secondary education differed by IEP status and socioeconomic status [Χ2 (3, n =165,684) = 26.886, p = 0.001]. Finally, time spent in extracurricular activities impacted academic achievement and students in lower socioeconomic groups were less involved in extracurricular activities [Χ2 (4, n = 20,598) = 132.298, p \u3c .0001]

Small Schools: Great Strides, A Study of New Schools in Chicago

This book documents a two-year study and analysis of small schools in Chicago. Using a mixed-method study, gathering both quantitative and qualitative data, the research serves to compare results to previous studies of small urban schools.The study examines the effects of small schools on students, parents, teachers, and community members. Both previous and current research suggest that small school size is correlated with an increase in student attendance, performance, and better sense of community overall.https://educate.bankstreet.edu/books/1022/thumbnail.jp

The Effects of Electric Power Lines on the Breeding Ecology of Greater Sage-Grouse

Anthropogenic infrastructure can negatively affect wildlife through direct mortality and/or displacement behaviors. Some tetranoids (grouse spp.) species are particularly vulnerable to tall anthropogenic structures because they evolved in ecosystems void of vertical structures. In western North America, electric power transmission and distribution lines (power lines) occur in sagebrush (Artemisia spp.) landscapes within the range of the greater sage-grouse (Centrocercus urophasianus; sage-grouse). The U.S. Fish and Wildlife Service recommended using buffer zones near leks to mitigate the potential impacts of power lines on sage-grouse. However, recommended buffer distances are inconsistent across state and federal agencies because data are lacking. To address this, we evaluated the effects of power lines on sage-grouse breeding ecology within Utah, portions of southeastern Idaho, and southwestern Wyoming from 1998–2013. Overall, power lines negatively affected lek trends up to a distance of 2.7 and 2.8 km, respectively. Power lines died not affect lek persistence. Female sage-grouse avoided transmission lines during the nesting and brooding seasons at distances up to 1.1 and 0.8 km, respectively. Nest and brood success were negatively affected by transmission lines up to distances of 2.6 and 1.1 km, respectively. Distribution lines did not appear to affect sage-grouse habitat selection or reproductive fitness. Our analyses demonstrated the value of sagebrush cover in mitigating potential power line impacts. Managers can minimize the effects of new transmission power lines by placing them in existing anthropogenic corridors and/or incorporating buffers at least 2.8 km from active leks. Given the uncertainty we observed in our analyses regarding sage-grouse response to distribution lines coupled with their role in providing electric power service directly to individual consumers, we recommend that buffers for these power lines be considered on a case-by-case basis. Micrositing to avoid important habitats and habitat reclamation may reduce the potential impacts of new power line construction

OR30-1 Safety and Efficacy of Recombinant Human Parathyroid Hormone 1-84 for the Treatment of Adults with Chronic Hypoparathyroidism: Six-Year Results of the RACE Study

RACE is an open-label study that assessed the long-term safety and efficacy of recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) for the treatment of hypoparathyroidism in adults (ClinicalTrials.gov identifier NCT01297309). Patients initially received 25 or 50 µg/day of rhPTH(1-84) subcutaneously, once daily, with stepwise dose adjustments of 25 µg (up or down) to a maximum of 100 µg/day. rhPTH(1-84) could be titrated and oral calcium (Ca) and calcitriol doses adjusted at any time during the study to maintain albumin-corrected serum Ca levels in the target range of 8.0-9.0 mg/dL. A composite efficacy endpoint was the proportion of patients who achieved at least a 50% reduction from baseline (BL) in oral Ca dose (or Ca ≤500 mg/day) and at least a 50% reduction from BL in calcitriol dose (or calcitriol ≤0.25 µg/day), while normalizing or maintaining albumin-corrected serum Ca compared with BL value and not exceeding the upper limit of normal for the central laboratory. Here, we present 6-year safety and efficacy data with descriptive summary statistics (mean ± SD). The study cohort consisted of 49 patients enrolled at 12 US centers (mean age, 48.1±9.78 years; 81.6% female); data from 34 patients (69.4%) who completed 72 months (M72) of treatment with rhPTH(1-84) as of July 17, 2018 are presented here. Oral Ca and calcitriol doses were reduced by 40.4% and 72.2% at M72, respectively, and albumin-corrected serum Ca levels were maintained within the target range (BL, 8.4±0.70 mg/dL; M72, 8.4±0.68 mg/dL). At M72, 22 of 34 patients (64.7%) achieved the composite efficacy endpoint. Urinary Ca excretion declined from above-normal at BL to within the normal range (BL, 356.7±200.37 mg/24 h; M72, 213.2±128.82 mg/24 h). Mean serum creatinine levels remained stable (BL, 1.0±0.21 mg/dL; M72, 0.9±0.21 mg/dL), as did estimated glomerular filtration rate (eGFR; BL, 77.7±17.67 mL/min/1.73 m2; M72, 79.4±18.39 mL/min/1.73 m2). Serum phosphorus levels declined from above-normal at BL to within normal range (BL, 4.8±0.58 mg/dL; M72, 4.0±0.62 mg/dL); calcium-phosphorus product levels also declined (BL, 42.1±6.35 mg2/dL2; M72, 33.7±5.01 mg2/dL2). Treatment-emergent adverse events and treatment-emergent serious adverse events were reported in 98.0% and 26.5% of patients, respectively; no new safety concerns were identified. Continuous use of rhPTH(1-84) over 6 years resulted in a favorable safety profile, was effective, and improved key measurements of mineral homeostasis, notably normalization of urinary calcium. Disclosures: All of the authors disclose a relationship with Shire: advisory board member, JPB, MAL, MM, DMS, TJV; consultant, JPB, BLC, MAL, MM, DMS, TJV; grant recipient, JPB, DD, MM, MP, DMS, MLW; employee, H-ML, NS; research investigator, JPB, HB, JR, DMS, TJV, MLW, NBW; speaker, JPB, HB, MLW, NBW. Funding: Shir

Safety and Efficacy of 5 Years of Treatment With Recombinant Human Parathyroid Hormone in Adults With Hypoparathyroidism

CONTEXT: Conventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency. OBJECTIVE: To evaluate long-term safety and tolerability of recombinant human PTH (1-84) [rhPTH(1-84)]. DESIGN: Open-label extension study; 5-year interim analysis. SETTING: 12 US centers. PATIENTS: Adults (N = 49) with chronic hypoparathyroidism. INTERVENTION(S): rhPTH(1-84) 25 or 50 µg/d initially, with 25-µg adjustments permitted to a 100 µg/d maximum. MAIN OUTCOME MEASURE(S): Safety parameters; composite efficacy outcome was the proportion of patients with ≥50% reduction in oral calcium (or ≤500 mg/d) and calcitriol (or ≤0.25 µg/d) doses, and albumin-corrected serum calcium normalized or maintained compared with baseline, not exceeding upper limit of normal. RESULTS: Forty patients completed 60 months of treatment. Mean albumin-corrected serum calcium levels remained between 8.2 and 8.7 mg/dL. Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively. Serum creatinine level and estimated glomerular filtration rate were unchanged. Treatment-emergent adverse events (AEs) were reported in 48 patients (98.0%; hypocalcemia, 36.7%; muscle spasms, 32.7%; paresthesia, 30.6%; sinusitis, 30.6%; nausea, 30.6%) and serious AEs in 13 (26.5%). At month 60, 28 patients (70.0%) achieved the composite efficacy outcome. Bone turnover markers increased, peaked at ∼12 months, and then declined to values that remained above baseline. CONCLUSION: Treatment with rhPTH(1-84) for 5 years demonstrated a safety profile consistent with previous studies and improved key biochemical parameters

Establishing a process to translate and adapt health education materials for natives and immigrants: The case of Mandarin adaptations of cardiac rehabilitation education

Background: Cardiac rehabilitation (CR) is a proven model of secondary prevention in which patient education is a core component. Objectives: to translate and culturally-adapt CR patient education for Mandarin-speaking patients living in China as well as immigrants, and offer recommendation for best practices in adaptation for both. Methods: these steps were undertaken in China and Canada: (1) preparation; (2) translation and adaptation; (3) review by healthcare providers based on PEMAT-P; (4) think-aloud review by patients; and (5) finalization. Results: Two independent Mandarin translations were undertaken using best practices: one domestic (China) and one international (immigrants). Input by 23 experts instigated revisions. Experts rated the language and content as culturally-appropriate, and perceived the materials would benefit their patients. A revised version was then administered to 36 patients, based on which a few edits were made to optimize understandability. Conclusions: some important differences emerged between translations adapted for native versus immigrant settings.This project has received funds from Toronto Rehab Foundation for the translation of materials (international version)