Accumulation of C-terminal fragments of transactive response DNA-binding protein 43 leads to synaptic loss and cognitive deficits in human TDP-43 transgenic mice

Accumulation of the transactive response DNA-binding protein 43 (TDP-43) is a major hallmark of several neurodegenerative disorders, collectively known as TDP-43 proteinopathies. The most common TDP-43 proteinopathies, frontotemporal lobar degeneration with TDP–43-positive inclusions, and amyotrophic lateral sclerosis, share overlapping neuropathological and clinical phenotypes. The development and detailed analysis of animal models of TDP-43 proteinopathies are critical for understanding the pathogenesis of these disorders. Transgenic mice overexpressing mutant human TDP-43 (herein referred to as hTDP-43) are characterized by neurodegeneration and reduced life span. However, little is known about the behavioral phenotype of these mice. Here we report the novel finding that hTDP-43 mice develop deficits in cognition, motor performance, and coordination. We show that these behavioral deficits are associated with the accumulation of nuclear and cytosolic TDP-43 C-terminal fragments, a decrease in endogenous TDP-43 levels, and synaptic loss. Our findings provide critical insights into disease pathology, and will help guide future preclinical studies aimed at testing the effects of potential therapeutic agents on the onset and progression of TDP-43 proteinopathies.     

The Impact of COVID-19 on Orthopedic Surgery Fellowship Training: A Survey of Fellowship Program Directors

Background: The COVID-19 pandemic has had a wide-reaching impact. Graduate medical education of orthopedic surgeons was not spared from the jarring changes. Purpose: We sought to survey fellowship program directors in the field of orthopedic surgery about how the COVID-19 pandemic affected the education of the 2019 to 2020 and 2020 to 2021 fellowship classes and the future of their programs. Methods: In October 2020, an 18-item survey was distributed by an official of the American Academy of Orthopedic Surgeons (AAOS) to the specialty societies that govern fellowship training. Each specialty society then distributed the survey to its respective program directors. A reminder email was sent during the enrollment period. Each respondent was able to complete the survey once. Survey questions were grouped into 3 sections: general information about the fellowship training programs, the impact of COVID-19 on the 2019 to 2020 fellowship class, and the future impact of COVID-19 on the fellowship training programs. Results: Of the 564 accredited orthopedic surgery fellowship programs in the United States, 190 directors responded. Of these, 73.59% reported COVID-19 had a negative impact on the 2019 to 2020 fellowship class. A normal distribution of responses was found regarding didactic and academic learning, research, and mentorship opportunities. A majority of respondents said they believe that there will be no negative impact on patient care the fellows provide in the years to come. Conclusion: Orthopedic surgery fellowship program directors acknowledged that while there were negative effects to training in the pandemic, they did not think these would negatively affect patient care provided by 2019 to 2020 fellows in the short and medium term. They also reported positive outcomes from the experience of the pandemic, including new ways to educate fellows.     

Antimicrobial Therapy of Experimental Enterococcal Endocarditis

The successful therapy of enterococcal endocarditis requires prolonged administration of synergistic antibiotic combinations. Controversy has arisen regarding optimal therapy (i) when the organism possesses high-level streptomycin resistance, and (ii) when the patient is allergic to penicillin. This study examines these questions in vitro and in a rabbit model of enterococcal endocarditis. The combination of penicillin with either streptomycin or gentamicin increased the rate of bacterial killing in vitro and in vivo when compared with penicillin alone (P < 0.05) when the test strain was relatively susceptible to streptomycin (minimal inhibitory concentration, 128 mug/ml). Only the combination of penicillin and gentamicin was consistently more effective than penicillin alone (P < 0.01) when the test strain was highly resistant to streptomycin (minimal inhibitory concentration > 150,000 mug/ml). The combination of vancomycin and streptomycin was more rapidly bactericidal than vancomycin alone in vitro and in the animal model against the streptomycin-susceptible strain (P < 0.01). The relative rate of in vitro bacterial killing by various antibiotics and combinations was predictive of the efficacy of these drugs in eradicating enterococci from cardiac vegetation in experimental endocarditis.     

Digestion of the fifth component of complement by leukocyte enzymes. Sequential generation of chemotactic activities for leukocytes and for tumor cells.

Leukocytes contain within their lysosomal granules enzymatic activity that will generate from C5 chemotactic activity for leukocytes (neutrophils) and tumor (Walker carcinosarcoma) cells. Similar activity has been found in phagocytic supernatant fluids from neutrophils and in purified preparations of the leukocyte neutral proteases elastase and cathepsin G. White leukotactic activities can be generated from either the third (C3) or the fifth (C5) components of complement, only C5 serves as a source for generation of the chemotactic activity for tumor cells. As has been previously shown with trypsin, the C5-related chemotactic activities generated by leukocyte proteases are time-dependent: leukotactic activity appears early, then disappears, and is replaced by chemotactic activity for tumor cells. The generation of these chemotactic activities from C5 is blocked by prior treatment of leukocyte preparations with the neutral protease inhibitor Trasylol. The demonstration that enzyme activities from leukocytes have the ability to generate tumor cell chemotactic factors from C5 suggests a possible mechanism by which the development of metastatic lesions may be promoted at sites of tissue injury or inflammation.     

Mastery,Intimacy, and Stress Resistance during War

The relationship between war-related stressors and emotional and behavioral adjustment during the Israel-Lebanon war was studied on a sample of 220 Israeli students, many of whom had been in combat. Mastery had direct effects on the well-being of both sexes. There was limited support for the stress-buffering effect of intimacy for men, such that those who had less intimate ties were increasingly negatively affected by greater exposure to war-related stressors, whereas those with more intimate relationships were relatively unaffected; the buffering effect applied both to emotions and behavior. No stress-buffering effect of intimate ties was found for women, but women were not affected by war-related stress at this time. The diagnosis post-traumatic stress disorder is examined in terms of the fact that normally healthy populations may be at increased risk of long-term adjustment difficulties following exposure to extreme stress if the threat of recurrence of the stressor continues. Implications for Vietnam veterans are also discussed.     

Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1

Many neurodegenerative disorders are caused by abnormal accumulation of misfolded proteins. In spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded (polyQ-expanded) ataxin-1 (ATXN1) causes neuronal toxicity. Lowering total ATXN1, especially the polyQ-expanded form, alleviates disease phenotypes in mice, but the molecular mechanism by which the mutant ATXN1 is specifically modulated is not understood. Here, we identified 22 mutant ATXN1 regulators by performing a cross-species screen of 7787 and 2144 genes in human cells and Drosophila eyes, respectively. Among them, transglutaminase 5 (TG5) preferentially regulated mutant ATXN1 over the WT protein. TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length–dependent manner, thereby preferentially modulating mutant ATXN1 stability and oligomerization. Perturbing Tg in Drosophila SCA1 models modulated mutant ATXN1 toxicity. Moreover, TG5 was enriched in the nuclei of SCA1-affected neurons and colocalized with nuclear ATXN1 inclusions in brain tissue from patients with SCA1. Our work provides a molecular insight into SCA1 pathogenesis and an opportunity for allele-specific targeting for neurodegenerative disorders.