The Alteration of Intrinsic Excitability and Synaptic Transmission in Lumbar Spinal Motor Neurons and Interneurons of Severe Spinal Muscular Atrophy Mice

Spinal muscular atrophy (SMA) is the leading genetic cause of death in infants. Studies with mouse models have demonstrated increased excitability and loss of afferent proprioceptive synapses on motor neurons (MNs). To further understand functional changes in the motor neural network occurring in SMA, we studied the intrinsic excitability and synaptic transmission of both MNs and interneurons (INs) from ventral horn in the lumbar spinal cord in the survival motor neuron (SMN)Δ7 mouse model. We found significant differences in the membrane properties of MNs in SMA mice compared to littermate controls, including hyperpolarized resting membrane potential, increased input resistance and decreased membrane capacitance. Action potential (AP) properties in MNs from SMA mice were also different from controls, including decreased rheobase current, increased amplitude and an increased afterdepolarization (ADP) potential. The relationship between AP firing frequency and injected current was reduced in MNs, as was the threshold current, while the percentage of MNs showing long-lasting potentiation (LLP) in the intrinsic excitability was higher in SMA mice. INs showed a high rate of spontaneous firing, and those from SMA mice fired at higher frequency. INs from SMA mice showed little difference in their input-output relationship, threshold current, and plasticity in intrinsic excitability. The changes observed in both passive membrane and AP properties suggest greater overall excitability in both MNs and INs in SMA mice, with MNs showing more differences. There were also changes of synaptic currents in SMA mice. The average charge transfer per post-synaptic current of spontaneous excitatory and inhibitory synaptic currents (sEPSCs/sIPSCs) were lower in SMA MNs, while in INs sIPSC frequency was higher. Strikingly in light of the known loss of excitatory synapses on MNs, there was no difference in sEPSC frequency in MNs from SMA mice compared to controls. For miniature synaptic currents, mEPSC frequency was higher in SMA MNs, while for SMA INs, both mEPSC and mIPSC frequencies were higher. In SMA-affected mice we observed alterations of intrinsic and synaptic properties in both MNs and INs in the spinal motor network that may contribute to the pathophysiology, or alternatively, may be a compensatory response to preserve network function

Measuring asymmetric temporal interdependencies in simulated and biological networks

We use a newly developed metric to characterize asymmetric temporal interdependencies in networks of coupled dynamical elements. We studied the formation of temporal ordering in a system of coupled Rössler oscillators for different connectivity ratios and network topologies and also applied the metric to investigate the functional structure of a biological network (cerebral ganglia of Helix snail). In the former example we show how the local ordering evolves to the global one as a function of structural parameters of the network, while in the latter we show spontaneous emergence of functional interdependence between two groups of electrodes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87883/2/043121_1.pd

Closing the Gap: First Year Success in College Mathematics at an HBCU

At our Historically-Black University, about 89% of first-year students place into developmental mathematics, negatively impacting retention and degree completion. In 2012, an NSF-funded learning enrichment project began offering the introductory and developmental mathematics courses on-line over the summer to incoming science, technology, engineering and mathematics (STEM) majors at no cost. Passing rates for the summer on-line classes were around 80%, and students in the on-line classes scored equivalently on the common departmental final exams as students taking the classes in the traditional format. For students who passed the on-line classes, their performance in the following classes (College Algebra and Trigonometry) exceeded that of students who progressed to those courses by taking the traditional series of in-person courses. Three years of data show that students who started college with an on-line mathematics course in a summer bridge program had a higher first year GPA, a better first year retention rate and earned significantly more credits in their first year than the overall population of STEM students. These results suggest that offering introductory mathematics courses on-line as part of a freshman bridge program is an effective, scalable intervention to increase the academic success of students who enter college under-prepared in mathematics. The positive results are particularly exciting since the students in our project were 87% minority

Leucine-rich alpha-2-glycoprotein-1 is upregulated in sera and tumors of ovarian cancer patients

<p>Abstract</p> <p>Background</p> <p>New biomarkers that replace or are used in conjunction with the current ovarian cancer diagnostic antigen, CA125, are needed for detection of ovarian cancer in the presurgical setting, as well as for detection of disease recurrence. We previously demonstrated the upregulation of leucine-rich alpha-2-glycoprotein-1 (LRG1) in the sera of ovarian cancer patients compared to healthy women using quantitative mass spectrometry.</p> <p>Methods</p> <p>LRG1 was quantified by ELISA in serum from two relatively large cohorts of women with ovarian cancer and benign gynecological disease. The expression of LRG1 in ovarian cancer tissues and cell lines was examined by gene microarray, reverse-transcriptase polymerase chain reaction (RT-PCR), Western blot, immunocytochemistry and mass spectrometry.</p> <p>Results</p> <p>Mean serum LRG1 was higher in 58 ovarian cancer patients than in 56 healthy women (89.33 ± 77.90 vs. 42.99 ± 9.88 ug/ml; p = 0.0008) and was highest among stage III/IV patients. In a separate set of 193 pre-surgical samples, LRG1 was higher in patients with serous or clear cell ovarian cancer (145.82 ± 65.99 ug/ml) compared to patients with benign gynecological diseases (82.53 ± 76.67 ug/ml, p < 0.0001). CA125 and LRG1 levels were moderately correlated (r = 0.47, p < 0.0001). <it>LRG1 </it>mRNA levels were higher in ovarian cancer tissues and cell lines compared to their normal counterparts when analyzed by gene microarray and RT-PCR. LRG1 protein was detected in ovarian cancer tissue samples and cell lines by immunocytochemistry and Western blotting. Multiple iosforms of LRG1 were observed by Western blot and were shown to represent different glycosylation states by digestion with glycosidase. LRG1 protein was also detected in the conditioned media of ovarian cancer cell culture by ELISA, Western blotting, and mass spectrometry.</p> <p>Conclusions</p> <p>Serum LRG1 was significantly elevated in women with ovarian cancer compared to healthy women and women with benign gynecological disease, and was only moderately correlated with CA125. Ovarian cancer cells secrete LRG1 and may contribute directly to the elevated levels of LRG1 observed in the serum of ovarian cancer patients. Future studies will determine whether LRG1 may serve as a biomarker for presurgical diagnosis, disease recurrence, and/or as a target for therapy.</p

Urine cadmium and acute myocardial infarction among never smokers in the Danish Diet, Cancer and Health cohort

Cadmium exposure has been associated with cardiovascular disease. Cigarette smoking is a key source of cadmium exposure and thus a potential confounder in observational studies of environmental cadmium and cardiovascular disease that include tobacco smokers. We leveraged up to 20 years of follow-up in the Danish Diet, Cancer and Health cohort to test the hypothesis that cadmium exposure is associated with acute myocardial infarction (AMI) among people who never smoked. Between 1993–1997, 19,394 never-smoking participants (ages 50–64 years) were enrolled and provided a urine sample. From this sample, we randomly selected a subcohort of 600 males and 600 females. We identified 809 AMI cases occurring between baseline and the end of 2015 using the Danish National Patient Registry. We quantified cadmium, creatinine, and osmolality in baseline urine samples. Using an unweighted case-cohort approach, we estimated adjusted hazard ratios (aHR) for AMI in Cox proportional hazards models with age as the time axis. Participants had relatively low concentrations of urinary cadmium, as expected for never smokers (median = 0.20; 25(th), 75(th) = 0.13, 0.32 μg cadmium/g creatinine). We did not find strong evidence to support an association between higher urinary cadmium and AMI when comparing the upper versus lowest quartile (aHR = 1.16; 95% CI: 0.86 – 1.56) and per IQR increment in cadmium concentration (aHR = 1.02; 95% CI: 0.93 – 1.12). Results were not materially different across strata defined by sex. Results were generally similar using creatinine or osmolality to account for differences in urine dilution. While cadmium exposure has been identified as a risk factor for cardiovascular disease, we did not find strong evidence that urinary cadmium at relatively low-levels is associated with AMI among people who have never smoked

Educational Evaluation, Assessment, & Effectiveness Glossary: A Claremont Graduate University EDUC 445 Fall 2021 Course Publication

This glossary is intended to support professionals who are seeking to understand evaluation, assessment, and effectiveness in the context of K-12 and higher education. The definitions in this e-book represent the shared meanings that were co-created by education professionals in EDUC 445 at the Claremont Graduate University during Fall 2021 under the guidance of Dr. Gwen Garrison, PhD

Market Integration and Soil-Transmitted Helminth Infection among the Shuar of Amazonian Ecuador

Background Soil-transmitted helminth (STH) infections have many negative health outcomes (e.g., diarrhea, nutritional deficiencies) that can also exacerbate poverty. These infections are generally highest among low-income populations, many of which are also undergoing market integration (MI; increased participation in a market-based economy). Yet the direct impact of MI-related social and environmental changes on STH infection patterns is poorly understood, making it unclear which lifestyle factors should be targeted to better control disease spread. This cross-sectional study examines if household infrastructure associated with greater MI is associated with lower STH burdens among Indigenous Ecuadorian Shuar. Methods Kato-Katz fecal smears were used to determine STH infection status and intensity (n = 620 participants; 308 females, 312 males, aged 6 months—86 years); Ascaris lumbricoides (ascarid) and Trichuris trichiura (whipworm) were the primary infection types detected. Structured interviews assessing lifestyle patterns (e.g., measures of household infrastructure) measured participant MI. Multilevel regression analyses and zero-inflated negative binomial regression models tested associations between MI measures and STH infection status or intensity, controlling for individual and community characteristics. Results Participants residing in more market-integrated households exhibited lower infection rates and intensities than those in less market integrated households. Parasite infection status and T. trichiura infection intensity were lower among participants living in houses with wood floors than those with dirt floors, while individuals using well or piped water from a spring exhibited lower A. lumbricoides infection intensities compared to those using river or stream water. Unexpectedly, latrine type was not significantly related to STH infection status or intensity. These results suggest that sources of exposure differ between the two helminth species. Conclusions This study documents associations between household measures and STH infection among an Indigenous population undergoing rapid MI. These findings can help healthcare programs better target interventions and reduce STH exposure among at-risk populations

Electrophysiological Properties of Motor Neurons in a Mouse Model of Severe Spinal Muscular Atrophy: In Vitro versus In Vivo Development

We examined the electrophysiological activity of motor neurons from the mouse model of severe spinal muscular atrophy (SMA) using two different methods: whole cell patch clamp of neurons cultured from day 13 embryos; and multi-electrode recording of ventral horns in spinal cord slices from pups on post-natal days 5 and 6. We used the MED64 multi-electrode array to record electrophysiological activity from motor neurons in slices from the lumbar spinal cord of SMA pups and their unaffected littermates. Recording simultaneously from up to 32 sites across the ventral horn, we observed a significant decrease in the number of active neurons in 5–6 day-old SMA pups compared to littermates. Ventral horn activity in control pups is significantly activated by serotonin and depressed by GABA, while these agents had much less effect on SMA slices. In contrast to the large differences observed in spinal cord, neurons cultured from SMA embryos for up to 21 days showed no significant differences in electrophysiological activity compared to littermates. No differences were observed in membrane potential, frequency of spiking and synaptic activity in cells from SMA embryos compared to controls. In addition, we observed no difference in cell survival between cells from SMA embryos and their unaffected littermates. Our results represent the first report on the electrophysiology of SMN-deficient motor neurons, and suggest that motor neuron development in vitro follows a different path than in vivo development, a path in which loss of SMN expression has little effect on motor neuron function and survival

Risk of Arterial and Venous Thrombotic Events Among Patients with COVID-19:A Multi-National Collaboration of Regulatory Agencies from Canada, Europe, and United States

Purpose: Few studies have examined how the absolute risk of thromboembolism with COVID-19 has evolved over time across different countries. Researchers from the European Medicines Agency, Health Canada, and the United States (US) Food and Drug Administration established a collaboration to evaluate the absolute risk of arterial (ATE) and venous thromboembolism (VTE) in the 90 days after diagnosis of COVID-19 in the ambulatory (eg, outpatient, emergency department, nursing facility) setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability. Patients and Methods: We conducted cohort studies of patients initially diagnosed with COVID-19 in the ambulatory setting from the seven specified countries. Patients were followed for 90 days after COVID-19 diagnosis. The primary outcomes were ATE and VTE over 90 days from diagnosis date. We measured country -level estimates of 90 -day absolute risk (with 95% confidence intervals) of ATE and VTE. Results: The seven cohorts included 1,061,565 patients initially diagnosed with COVID-19 in the ambulatory setting before COVID19 vaccines were available (through November 2020). The 90 -day absolute risk of ATE during this period ranged from 0.11% (0.09- 0.13%) in Canada to 1.01% (0.97-1.05%) in the US, and the 90 -day absolute risk of VTE ranged from 0.23% (0.21-0.26%) in Canada to 0.84% (0.80-0.89%) in England. The seven cohorts included 3,544,062 patients with COVID-19 during vaccine availability (beginning December 2020). The 90 -day absolute risk of ATE during this period ranged from 0.06% (0.06-0.07%) in England to 1.04% (1.01-1.06%) in the US, and the 90 -day absolute risk of VTE ranged from 0.25% (0.24-0.26%) in England to 1.02% (0.99- 1.04%) in the US. Conclusion: There was heterogeneity by country in 90 -day absolute risk of ATE and VTE after ambulatory COVID-19 diagnosis both before and during COVID-19 vaccine availability. Plain Language Summary: Cohort studies of patients diagnosed with COVID-19 in both the ambulatory and hospital settings have suggested that SARS-CoV-2 infection promotes hypercoagulability that could lead to arterial or venous thromboembolism. However, few studies have examined how the risk of thromboembolism with COVID-19 has evolved over time across different countries. A new collaboration was established among the regulatory authorities of Canada, Europe, and the US within the International Coalition of Medicines Regulatory Authorities to evaluate the 90 -day risk of both arterial and venous thromboembolism after initial diagnosis of COVID-19 in the ambulatory or hospital setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability. The study found that there was variability in the risk of both arterial and venous thromboembolism by month across the countries among patients initially diagnosed with COVID-19 in the ambulatory or hospital setting. Differences in the healthcare systems, prevalence of comorbidities in the study cohorts, and approaches to the case definitions of thromboembolism likely contributed to the variability in estimates of thromboembolism risk across the countries