OBJECTIVES/GOALS: Motoric cognitive risk (MCR) is a pre-dementia syndrome characterized by slow gait and subjective cognitive complaints. In the Atherosclerosis Risk in Communities (ARIC) study, we aim to (1) identify plasma proteins and protein modules associated with MCR and (2) compare the proteomic signature of MCR to that of mild cognitive impairment (MCI). METHODS/STUDY POPULATION: Nondemented ARIC participants were classified by MCR status (yes/no) according to a memory questionnaire and 4-meter walk. MCI status (yes/no) was classified by expert diagnosis using standardized criteria. We measured 4,877 proteins in plasma collected at ARIC Visit 5 (late-life) and Visit 2 (midlife) utilizing the SomaScan4 proteomic assay. Multivariable logistic regression”adjusted for demographic variables, kidney function, cardiovascular risk factors, and APOE4 status”related each protein to MCR at late-life. An FDR corrected P RESULTS/ANTICIPATED RESULTS: Proteome-wide association study among 4076 ARIC participants (mean age=75; 58% women, 17% Black, 4% MCR+, 21% MCI+; MCR+ and MCI+ groups overlapped) at late-life identified 26 MCR-associated proteins involved in metabolism, vascular/visceral smooth muscle, and extracellular matrix organization. At an uncorrected P DISCUSSION/SIGNIFICANCE: This proteomic characterization of MCR identifies novel plasma proteins and networks, both distinct from and overlapping with those of MCI, thus highlighting the partially divergent mechanisms underlying these pre-dementia syndromes. These findings may be leveraged toward dementia prognostication and targeted therapeutic approaches.

ABSTRACT IMPACT: Urine tumor DNA non-invasively detects minimal residual disease and infers tumor mutational burden in locally advanced bladder cancer prior to radical cystectomy, which may potentially enable the selection of patients for bladder-sparing treatment or facilitate personalized adjuvant immunotherapy. OBJECTIVES/GOALS: Standard-of-care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy. The inability to assess minimal residual disease (MRD) non-invasively limits our ability to offer bladder-sparing treatment. We sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. METHODS/STUDY POPULATION: We applied uCAPP-Seq, a targeted sequencing method for detecting utDNA, to urine cell-free DNA samples acquired on the day of radical cystectomy from 42 patients with bladder cancer. utDNA variant-calling was performed non-invasively without prior tumor mutational knowledge. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. Tumor mutational burden (TMB) was inferred from the number of non-silent mutations detected in urine cell-free DNA by applying a linear relationship derived from TCGA whole exome sequencing of 409 MIBC tumors. RESULTS/ANTICIPATED RESULTS: utDNA levels were significantly higher in patients with residual disease detected in their surgical pathology compared to those who achieved a pathologic complete response (P = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD significantly predicted the absence of pathologic complete response with a sensitivity of 81% and specificity of 81%. Positive utDNA MRD also portended significantly worse progression-free survival (HR = 7.4; P = 0.03) compared to negative utDNA MRD. Furthermore, we applied a linear relationship (Pearson r = 0.84; P < 0.0001) to identify patients with high inferred TMB who may have been candidates for early immune checkpoint blockade. DISCUSSION/SIGNIFICANCE OF FINDINGS: utDNA MRD analysis prior to surgery correlated significantly with pathologic response and progression-free survival, which may help select patients for bladder-sparing treatment. utDNA can also non-invasively infer TMB, which could facilitate personalized adjuvant therapy for patients in the future.

Prior research has examined the firm-level performance implications of “busy” boards. Firm-level analysis, however, masks important heterogeneity in the time constraints and expertise of individual busy directors. We develop and validate shareholder voting as a proxy for shareholders’ satisfaction. Our director-specific tests provide compelling evidence that the potential costs of busy directors outweigh their benefits. At the same time, we uncover new sources of heterogeneity among busy directors. For example, the downsides are more pronounced for directors who sit on boards where fiscal year ends cluster in the same month. Our analysis highlights the role of shareholder voting in board composition research.

Periodontitis, or conventionally “Gum Disease,” is the infection and inflammation of gingival tissue, and is currently the leading cause of tooth loss in the United States. One of the most effective treatments of periodontitis is guided bone regeneration (GBR); however, current GBR barrier membranes lack high biocompatibility and cell impermeability. The authors of this study evaluated the in vitro viability of previously synthesized Gelatin-Pluronic® F127 hybrid hydrogels as potential GBR barrier membranes through a novel three-partition test involving migration of fluorescent-dyed human dermal fibroblasts. Results showed that cells were unable to migrate across the Gelatin-Pluronic® F127 hybrid hydrogel barrier, whereas control setups with gelatin hydrogel barriers showed cell permeability. In addition, cytotoxicity tests were conducted with fibroblasts plated in both cell mediums that had been incubated while in contact hybrid gels and cell mediums suspended on the surface of hybrid gels during swelling procedures. Fluorescence cell plate readings showed similar cell viability across data from both tests, indicating that Gelatin-Pluronic® F127 hybrid hydrogels are not toxic to cells, and thus biocompatible.

We solve two problems in representation theory for the periplectic Lie superalgebra $\mathfrak{p}\mathfrak{e}(n)$, namely, the description of the primitive spectrum in terms of functorial realisations of the braid group and the decomposition of category ${\mathcal{O}}$ into indecomposable blocks.

To solve the first problem, we establish a new type of equivalence between category ${\mathcal{O}}$ for all (not just simple or basic) classical Lie superalgebras and a category of Harish-Chandra bimodules. The latter bimodules have a left action of the Lie superalgebra but a right action of the underlying Lie algebra. To solve the second problem, we establish a BGG reciprocity result for the periplectic Lie superalgebra.

What are the consequences of nationalist unrest? This paper utilizes two original datasets, which cover 377 city-level anti-Japanese protests during the 2012 Senkaku/Diaoyu Island crisis and the careers of municipal leaders, to analyse the downstream effects of nationalist unrest at the subnational level. We find both political and economic consequences of China's 2012 protest demonstrations against Japan. Specifically, top Party leaders in cities that saw relatively spontaneous, early protests were less likely to be promoted to higher office, a finding that is consistent with the widely held but rarely tested expectation that social instability is punished in the Chinese Communist Party's cadre evaluation system. We also see a negative effect of nationalist protest on foreign direct investment (FDI) growth at the city level. However, the lower promotion rates associated with relatively spontaneous protests appear to arise through political rather than economic channels. By taking into account data on social unrest in addition to economic performance, these results add to existing evidence that systematic evaluation of leaders’ performance plays a major role in the Chinese political system. These findings also illuminate the dilemma that local leaders face in managing popular nationalism amid shifting national priorities.

The main objective of this study was to investigate the relationships between motivation and readiness levels for physical activity and exercise behaviour among persons with chronic musculoskeletal pain. Participants were 211 U.S. adults with chronic musculoskeletal pain from online support groups as well as specialty and primary care clinics (females = 86.7%; mean age = 43.4 years, SD = 14.4 years). The participants completed an online survey on their engagement in physical activity and exercise behaviour. Multiple one-way analyses of variance with post-hoc comparisons using the Tukey HSD test revealed significant differences between the readiness stages of change groups of preintenders, intenders, and actors in their motivation for physical activity and exercise behaviour. Specifically, the actor group of behavioural change reported higher levels of motivation beliefs for physical activity and exercise behaviour compared to preintenders and intenders. These findings suggest that people with chronic musculoskeletal pain experiencing increased motivation for physical activity and exercise behaviour are more engaged in desired behaviours than the persons with chronic pain reporting varying degrees of behavioural intentions.

Many China scholars have explored shirking by local officials and “effective implementation,” but fewer have examined polices that are implemented with great enthusiasm. The Microfinance for Women Programme fits in this last category. Especially in Sichuan, targets for lending were set by the province, exceeded, raised by cities and counties, and then exceeded again. The immediate reason that lending took off in 2012 was the relaxation of collateral requirements that shifted the risk of defaults away from local authorities. But the surge in lending also had deeper roots in the policy's vagueness, institutional incentives, bureaucratic pressure, and local fiscal and organizational interests. Although enthusiastic implementation occurred (and generated much-needed revenues for local governments), the history of the programme also shows that it can be halted, as was the case when instability loomed and the authorities reversed bureaucratic pressure by calling for local cost-sharing and introducing uncertainty over whether interest subsidies would continue.

Most marine creatures exhibit remarkable flow sensing abilities. Their task of discerning hydrodynamic cues from local sensory information is particularly challenging because it relies on local and partial measurements to accurately characterize the ambient flow. This is in contrast to classical flow characterization methods, which invariably depend on the ability of an external observer to reconstruct the flow field globally and identify its topological structures. In this paper, we develop a mathematical framework in which a local sensory array is used to identify select flow features. Our approach consists of linearizing the flow field around the sensory array and providing a frame-independent parameterization of the velocity gradient tensor which reveals both the local flow ‘type’ and ‘intensity’. We show that a simple bioinspired sensory system that measures differences in flow velocities is capable of locally characterizing the flow type and intensity. We discuss the conditions under which such flow characterization is possible. Then, to demonstrate the effectiveness of this sensory system, we apply it in the canonical problem of a circular cylinder in uniform flow. We find excellent agreement between the sensed and actual flow properties. These findings will serve to direct future research on optimal sensory layouts and dynamic deployment of sensory arrays.

Solutions are presented for both laminar developing flow in a curved pipe with a parabolic inlet velocity and laminar transitional flow downstream of a curved pipe into a straight outlet. Scalings and linearized analyses about appropriate base states are used to show that both cases obey the same governing equations and boundary conditions. In particular, the governing equations in the two cases are linearized about fully developed Poiseuille flow in cylindrical coordinates and about Dean’s velocity profile for curved pipe flow in toroidal coordinates respectively. Subsequently, we identify appropriate scalings of the axial coordinate and disturbance velocities that eliminate dependence on the Reynolds number $Re$ and dimensionless pipe curvature $\unicode[STIX]{x1D6FC}$ from the governing equations and boundary conditions in the limit of small $\unicode[STIX]{x1D6FC}$ and large $Re$. Direct numerical simulations confirm the scaling arguments and theoretical solutions for a range of $Re$ and $\unicode[STIX]{x1D6FC}$. Maximum values of the axial velocity, secondary velocity and pressure perturbations are determined along the curved pipe section. Results collapse when the scalings are applied, and the theoretical solutions are shown to be valid up to Dean numbers of $D=Re^{2}\unicode[STIX]{x1D6FC}=O(100)$. The developing flows are shown numerically and analytically to contain spatial oscillations. The numerically determined decay of the velocity perturbations is also used to determine entrance/development lengths for both flows, which are shown to scale linearly with the Reynolds number, but with a prefactor ${\sim}60\,\%$ larger than the textbook case of developing flow in a straight pipe.

Pipe bifurcations are common flow configurations in both natural and man-made systems. This study follows our previous report (Chen et al., Phys. Fluids, vol. 27, 2015, 034107) by describing three aspects of flows through junction angles of $70^{\circ }$, $90^{\circ }$ and $110^{\circ }$, with a square cross-section. First, the inflow creates tightly spiralling vortices in four quadrants of the junction. For sufficiently large Reynolds number $Re$, these vortices undergo behaviour resembling steady near-axisymmetric breakdown. With increasing $Re$, the flow through the $90^{\circ }$ junction remains steady and stable until the first Hopf bifurcation. Beyond the Hopf bifurcation, the vortices undergo a helical instability. The $70^{\circ }$ and $110^{\circ }$ junctions, however, first exhibit pitchfork bifurcations leading to asymmetric solutions. Second, the direct eigenmodes of the linearised flow are large in vortices in the outlet pipes, whereas the adjoint eigenmodes primarily reside in a small region in the inlet and the junction, near the front and back walls. Third, the sensitivities of the eigenvalues to spatially localised feedback and base flow modifications are greatest in and near the junction vortices. We highlight the regions of high growth rate and frequency sensitivity, as well as regions where the production and transport of perturbations by modifications of the base flow contribute most to the base flow sensitivity. The flow separation at the corners of the junction does not coincide with the eigenmodes or sensitivity regions.

For the Boussinesq equations, we present a theory of linear stability sensitivity to base flow density and velocity modifications. Given a steady-state flow with small density variations, the sensitivity of the stability eigenvalues is computed from the direct and adjoint global modes of the linearised Boussinesq equations, similarly to Marquet et al. (J. Fluid Mech., vol. 615, 2008, pp. 221–252). Combinations of the density and velocity components of these modes reveal multiple production and transport mechanisms that contribute to the eigenvalue sensitivity. We present an application of the sensitivity theory to a stably linearly density-stratified flow around a thin plate at a $90^{\circ }$ angle of attack, a Reynolds number of 30 and Froude numbers of 1, 8 and $\infty$. The global mode analysis reveals lightly damped undulations pervading through the entire domain, which are predicted by both inviscid uniform base flow theory and Orr–Sommerfeld theory. The sensitivity to base flow velocity modifications is primarily concentrated just downstream of the bluff body. On the other hand, the sensitivity to base flow density modifications is concentrated in regions both immediately upstream and immediately downstream of the plate. Both sensitivities have a greater upstream presence for lower Froude numbers.