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Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons.

Abstract There have been over 769 million cases of COVID-19, and up to 50% of infected individuals are asymptomatic. The purpose of this study aimed to assess the use of a clinical-grade physiological wearable monitoring system, ANNE One, to develop an artificial intelligence algorithm for (1) cough detection and (2) early detection of COVID-19, through the retrospective analysis of prospectively collected physiological data from longitudinal wear of ANNE sensors in a multicenter single arm study of subjects at high risk for COVID-19 due to occupational or home exposures. The study employed a two-fold approach: cough detection algorithm development and COVID-19 detection algorithm development. For cough detection, healthy individuals wore an ANNE One chest sensor during scripted activity. The final performance of the algorithm achieved an F-1 score of 83.3% in twenty-seven healthy subjects during biomarker validation. In the COVID-19 detection algorithm, individuals at high-risk for developing COVID-19 because of recent exposures received ANNE One sensors and completed daily symptom surveys. An algorithm analyzing vital parameters (heart rate, respiratory rate, cough count, etc.) for early COVID-19 detection was developed. The COVID-19 detection algorithm exhibited a sensitivity of 0.47 and specificity of 0.72 for detecting COVID-19 in 325 individuals with recent exposures. Participants demonstrated high adherence (≥ 4 days of wear per week). ANNE One shows promise for detection of COVID-19. Inclusion of respiratory biomarkers (e.g., cough count) enhanced the algorithm's predictive ability. These findings highlight the potential value of wearable devices in early disease detection and monitoring.

Abstract Background A previously healthy young male of Southeast Asian descent presented with 6 weeks of fevers, cough, mucocutaneous ulcers, arthritis, and myalgias. Initial workup revealed positive Mycoplasma pneumoniae immunoglobulin M, and the patient was treated with antibiotics without relief of symptoms. Rheumatologic workup revealed highly positive melanoma differentiation-associated gene 5 antibody. Viral infections are thought to potentially trigger loss of self tolerance, and prompt the autoimmunity cascade that can result in conditions such as dermatomyositis. To our knowledge, this is the first case report demonstrating a non-viral infection, specifically Mycoplasma pneumoniae, as the inciting infectious trigger for the anti-melanoma differentiation-associated gene 5 dermatomyositis subtype. Case presentation A 20-year-old southeast Asian–American male with no significant past medical history presented with symptoms of intermittent fevers, nonproductive cough, dry eyes, oral ulcers, rash, arthritis, and myalgias. The patient was noted to have erythematous papules across the bilateral hands along the lateral digits and palms, as well as synovitis involving the bilateral hands and feet. Immunoglobulin M antibodies were positive for Mycoplasma pneumoniae. The patient was diagnosed with mycoplasma pneumonia. The patient did not respond to a course of antibiotics, leading to rheumatological testing that found highly positive melanoma differentiation-associated gene 5 autoantibody. Muscle enzyme and electromyography testing were normal, indicating clinically amyopathic disease. Methylprednisolone was initiated, with resolution of fevers and improvement of arthritis and myalgias. The cutaneous lesions on the digits and palms improved. Conclusions This patient presented with symptoms of fever, cough, oral ulcers, rashes, and arthritis, and blood work demonstrated the presence of immunoglobulin M antibodies to Mycoplasma pneumoniae. Despite antibiotic treatment for the presumed diagnosis of Mycoplasma pneumoniae infection, the patient did not improve, prompting rheumatological workup and revealing melanoma differentiation-associated gene 5 autoantibodies. This case suggests that infections, other than viral, can trigger the autoinflammatory cascade, leading to the development of amyopathic melanoma differentiation-associated gene 5 dermatomyositis.

We investigated the effects of a major revision of the differential and integral calculus curriculum, the primary goal of which was to improve STEM retention. The revamped curriculum has greater emphasis on the power of computing to help visualize patterns and gain insights to better prepare students for STEM majors, and less emphasis on traditional and theoretical calculus content, such as the limit definition of the derivative. We investigated a comparison between 338 students who had taken the traditional sequence and 328 who had taken the revamped sequence during the Fall 2020 and Spring 2021 semesters. STEM retention, i.e., following through with the initial intent to major in a STEM field, was enhanced by 7% in the revamped group. STEM majors in the traditional group were found to over-perform in their other STEM classes by a 0.18 GPA margin, while non-STEM majors in the revamped group over-performed in their other STEM classes by a 0.17 GPA margin. Both differences are statistically significant. Focus groups were also conducted to gather and synthesize student perceptions. Results may encourage similar innovations to core math curricula in other universities to foster enhanced STEM retention.

Tissue plasminogen activator (tPA) is the only FDA-approved drug for the treatment of ischemic stroke. Delayed tPA administration is associated with increased risks of blood-brain barrier (BBB) disruption and hemorrhagic transformation. Studies have shown that interferon beta (IFNβ) or type I IFN receptor (IFNAR1) signaling confers protection against ischemic stroke in preclinical models. In addition, we have previously demonstrated that IFNβ can be co-administered with tPA to alleviate delayed tPA-induced adverse effects in ischemic stroke. In this study, we investigated the time limit of IFNβ treatment on the extension of tPA therapeutic window and assessed the effect of IFNβ on modulating microglia (MG) phenotypes in ischemic stroke with delayed tPA treatment. Mice were subjected to 40 minutes transient middle cerebral artery occlusion (MCAO) followed by delayed tPA treatment in the presence or absence of IFNβ at 3h, 4.5h or 6h post-reperfusion. In addition, mice with MG-specific IFNAR1 knockdown were generated to validate the effects of IFNβ on modulating MG phenotypes, ameliorating brain injury, and lessening BBB disruption in delayed tPA-treated MCAO mice. Our results showed that IFNβ extended tPA therapeutic window to 4.5h post-reperfusion in MCAO mice, and that was accompanied with attenuated brain injury and lessened BBB disruption. Mechanistically, our findings revealed that IFNβ modulated MG polarization, leading to the suppression of inflammatory MG and the promotion of anti-inflammatory MG, in delayed tPA-treated MCAO mice. Notably, these effects were abolished in MG-specific IFNAR1 knockdown MCAO mice. Furthermore, the protective effect of IFNβ on the amelioration of delayed tPA-exacerbated ischemic brain injury was also abolished in these mice. Finally, we identified that IFNβ-mediated modulation of MG phenotypes played a role in maintaining BBB integrity, because the knockdown of IFNAR1 in MG partly reversed the protective effect of IFNβ on lessening BBB disruption in delayed tPA-treated MCAO mice. In summary, our study reveals a novel function of IFNβ in modulating MG phenotypes, and that may subsequently confer protection against delayed tPA-exacerbated brain injury in ischemic stroke.