Mitigation of TDP-43 toxic phenotype by an RGNEF fragment in amyotrophic lateral sclerosis models.

Aggregation of the RNA-binding protein TAR DNA binding protein (TDP-43) is a hallmark of TDP-proteinopathies including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As TDP-43 aggregation and dysregulation are causative of neuronal death, there is a special interest in targeting this protein as a therapeutic approach. Previously, we found that TDP-43 extensively co-aggregated with the dual function protein GEF (guanine exchange factor) and RNA-binding protein rho guanine nucleotide exchange factor (RGNEF) in ALS patients. Here, we show that an N-terminal fragment of RGNEF (NF242) interacts directly with the RNA recognition motifs of TDP-43 competing with RNA and that the IPT/TIG domain of NF242 is essential for this interaction. Genetic expression of NF242 in a fruit fly ALS model overexpressing TDP-43 suppressed the neuropathological phenotype increasing lifespan, abolishing motor defects and preventing neurodegeneration. Intracerebroventricular injections of AAV9/NF242 in a severe TDP-43 murine model (rNLS8) improved lifespan and motor phenotype, and decreased neuroinflammation markers. Our results demonstrate an innovative way to target TDP-43 proteinopathies using a protein fragment with a strong affinity for TDP-43 aggregates and a mechanism that includes competition with RNA sequestration, suggesting a promising therapeutic strategy for TDP-43 proteinopathies such as ALS and FTD.

Rigorous Bounds on Transport from Causality.

We use causality to derive a number of simple and universal constraints on dispersion relations, which describe the location of singularities of retarded two-point functions in relativistic quantum field theories. We prove that all causal dissipative dispersion relations have a finite radius of convergence in cases where stochastic fluctuations are negligible. We then give two-sided bounds on all transport coefficients in units of this radius, including an upper bound on diffusivity.

Hydrodynamic Gradient Expansion Diverges beyond Bjorken Flow.

The gradient expansion is the fundamental organizing principle underlying relativistic hydrodynamics, yet understanding its convergence properties for general nonlinear flows has posed a major challenge. We introduce a simple method to address this question in a class of fluids modeled by Israel-Stewart-type relaxation equations. We apply it to (1+1)-dimensional flows and provide numerical evidence for factorially divergent gradient expansions. This generalizes results previously only obtained for (0+1)-dimensional comoving flows, notably Bjorken flow. We also demonstrate that the only known nontrivial case of a convergent hydrodynamic gradient expansion at the nonlinear level relies on Bjorken flow symmetries and becomes factorially divergent as soon as these are relaxed. Finally, we show that factorial divergence can be removed using a momentum space cutoff, which generalizes a result obtained earlier in the context of linear response.

Undergraduate Teaching During COVID-19.

Introduction: Universities were challenged during the COVID-19 pandemic to continue providing quality education for their students while navigating the uncertainties of the SARS-CoV-2 virus. Objectives: The goal of this article is to describe strategies used by Colorado State University (CSU) to mitigate SARS-CoV-2 transmission among faculty, staff, and students and to describe procedures used in microbiology teaching laboratories. Methods: Information concerning CSU's pandemic response was gathered via email communications to the CSU community, town hall meetings, and interviews with leaders, researchers, and staff who spearheaded public health initiatives. Results: To date, there have been no known cases of transmission of SARS-CoV-2 in the classroom. Early strategies that contributed to this success included social norming of safe public health behaviors, development of low-cost, rapid screening and surveillance methods, an online COVID-19 reporting system, contact tracing and quarantine, rearranging classrooms to reduce the capacity by 50%, increasing air flow, enhanced cleaning and production of sanitizer, and flexible instructors who quickly changed their courses for remote delivery or launched extra risk management procedures for face-to-face delivery of laboratory, performance, or studio classes. Conclusion: Intense collaboration among the CSU community, open and frequent communication, coordination of efforts, flexible instructors, and the willingness to follow safe public health behaviors allowed CSU to continue face-to-face teaching in courses that required hands-on learning or demanded in-person instruction. It is the hope of the authors that this information can provide both a historical account and useful information for others dealing with the COVID-19 pandemic.

Universal Spatial Structure of Nonequilibrium Steady States.

We describe a large family of nonequilibrium steady states (NESS) corresponding to forced flows over obstacles. The spatial structure at large distances from the obstacle is shown to be universal, and can be quantitatively characterized in terms of certain collective modes of the strongly coupled many body system, which we define in this work. In holography, these modes are spatial analogues of quasinormal modes, which are known to be responsible for universal aspects of relaxation of time dependent systems. These modes can be both hydrodynamical or nonhydrodynamical in origin. The decay lengths of the hydrodynamic modes are set by η/s, the shear viscosity over entropy density ratio, suggesting a new route to experimentally measuring this ratio. We also point out a new class of nonequilibrium phase transitions, across which the spatial structure of the NESS undergoes a dramatic change, characterized by the properties of the spectrum of these spatial collective modes.

Rho guanine nucleotide exchange factor (RGNEF) is a prosurvival factor under stress conditions.

Rho guanine nucleotide exchange factor (RGNEF) is a 190kDa RNA binding protein (RBP) that also contains a Dbl/PH domain capable of RhoA activation. Consistent with a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS), RGNEF forms pathological neuronal cytoplasmic inclusions in degenerating spinal motor neurons. To further understand the role of RGNEF in the stress response, we first observed that the expression of RGNEF is upregulated in murine spinal motor neurons following distal sciatic nerve injury. Secondly, in response to in vitro cellular stress (500µM sodium arsenite for 1h; or 400mM sorbitol 1 hour exposure; as an oxidative or osmotic stress, respectively), we observed a significant survival benefit in RGNEF-transfected HEK293T cells. Using deletion constructs, we found that the NH2-terminus domain is essential for this protective effect. Interestingly, we observed that under stress conditions RGNEF associates with Staufen1 positive granules but not TIA-1-positive stress granules. These findings support the hypothesis that RGNEF plays a critical role both in RNA homeostasis and in the response to cell stress.

Ephrin-A5 Is Required for Optimal Fertility and a Complete Ovulatory Response to Gonadotropins in the Female Mouse.

Follicle growth and ovulation involve the coordinated expression of many genes, driven by FSH and LH. Reports indicate that Eph receptors and ephrins are expressed in the ovary, suggesting roles in follicle growth and/or ovulation. We previously reported FSH-induced expression of ephrin-A5 (EFNA5) and 4 of its cognate Eph receptors in mouse granulosa cells. We now report that female mice lacking EFNA5 are subfertile, exhibit a compromised response to LH, and display abnormal ovarian histology after superovulation. Efna5(-/-) females litters were 40% smaller than controls, although no difference in litter frequency was detected. The ovarian response to superovulation was also compromised in Efna5(-/-) females, with 37% fewer oocytes ovulated than controls. These results corresponded with a reduction in ovarian mRNA levels of several LH-responsive genes, including Pgr, Ptgs2, Tnfaip6, Ereg, Btc, and Adamts4, suggesting that Efna5(-/-) ovaries exhibit a partially attenuated response to LH. Histopathological analysis indicated that superovulated Efna5(-/-) females exhibited numerous ovarian defects, including intraovarian release of cumulus oocyte complexes, increased incidence of oocytes trapped within luteinized follicles, granulosa cell and follicular fluid emboli, fibrin thrombi, and interstitial hemorrhage. In addition, adult Efna5(-/-) ovaries exhibited a 4-fold increase in multioocyte follicles compared with controls, although no difference was detected in 3-week-old mice, suggesting the possibility of follicle merging. Our observations indicate that loss of EFNA5 in female mice results in subfertility and imply that Eph-ephrin signaling may also play a previously unidentified role in the regulation of fertility in women.