Cipes: The Crime War

A Review of The Crime War by Robert M. Cipe

Miller: The Assault on Privacy

A Review of The Assault on Privacy by Arthur R. Mille

Contributions of VLDLR and LRP8 in the establishment of retinogeniculate projections

Background Retinal ganglion cells (RGCs), the output neurons of the retina, project to over 20 distinct brain nuclei, including the lateral geniculate nucleus (LGN), a thalamic region comprised of three functionally distinct subnuclei: the ventral LGN (vLGN), the dorsal LGN (dLGN) and the intergeniculate leaflet (IGL). We previously identified reelin, an extracellular glycoprotein, as a critical factor that directs class-specific targeting of these subnuclei. Reelin is known to bind to two receptors: very-low-density lipoprotein receptor (VLDLR) and low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2). Here we examined the roles of these canonical reelin receptors in retinogeniculate targeting. Results To assess the roles of VLDLR and LRP8 in retinogeniculate targeting, we used intraocular injections of fluorescently conjugated cholera toxin B subunit (CTB) to label all RGC axons in vivo. Retinogeniculate projections in mutant mice lacking either VLDLR or LRP8 appeared similar to controls; however, deletion of both receptors resulted in dramatic defects in the pattern of retinal innervation in LGN. Surprisingly, defects in vldlr−/−;lrp8−/− double mutant mice were remarkably different than those observed in mice lacking reelin. First, we failed to observe retinal axons exiting the medial border of the vLGN and IGL to invade distant regions of non-retino-recipient thalamus. Second, an ectopic region of binocular innervation emerged in the dorsomedial pole of vldlr−/−;lrp8−/− mutant dLGN. Analysis of retinal projection development, retinal terminal sizes and LGN cytoarchitecture in vldlr−/−;lrp8−/− mutants, all suggest that a subset of retinal axons destined for the IGL are misrouted to the dorsomedial pole of dLGN in the absence of VLDLR and LRP8. Such mistargeting is likely the result of abnormal migration of IGL neurons into the dorsomedial pole of dLGN in vldlr−/−;lrp8−/− mutants. Conclusions In contrast to our expectations, the development of both the LGN and retinogeniculate projections appeared dramatically different in mutants lacking either reelin or both canonical reelin receptors. These results suggest that there are reelin-independent functions of VLDLR and LRP8 in LGN development, and VLDLR- and LRP8-independent functions of reelin in class-specific axonal targeting

Universal point contact resistance between thin-film superconductors

A system comprising two superconducting thin films connected by a point contact is considered. The contact resistance is calculated as a function of temperature and film geometry, and is found to vanish rapidly with temperature, according to a universal, nearly activated form, becoming strictly zero only at zero temperature. At the lowest temperatures, the activation barrier is set primarily by the superfluid stiffness in the films, and displays only a weak (i.e., logarithmic) temperature dependence. The Josephson effect is thus destroyed, albeit only weakly, as a consequence of the power-law-correlated superconducting fluctuations present in the films below the Berezinskii-Kosterlitz-Thouless transition temperature. The behavior of the resistance is discussed, both in various limiting regimes and as it crosses over between these regimes. Details are presented of a minimal model of the films and the contact, and of the calculation of the resistance. A formulation in terms of quantum phase-slip events is employed, which is natural and effective in the limit of a good contact. However, it is also shown to be effective even when the contact is poor and is, indeed, indispensable, as the system always behaves as if it were in the good-contact limit at low enough temperature. A simple mechanical analogy is introduced to provide some heuristic understanding of the nearly-activated temperature dependence of the resistance. Prospects for experimental tests of the predicted behavior are discussed, and numerical estimates relevant to anticipated experimental settings are provided.Comment: 29 pages (single column format), 7 figure

Latent NOTCH3 epitopes unmasked in CADASIL and regulated by protein redox state

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy CADASIL is caused by more than a hundred NOTCH3 mutations. Virtually all encoded mutant proteins contain an odd number of cysteines. As such, structural changes in NOTCH3 may be the primary molecular abnormality in CADASIL. Thus, we sought evidence for structurally altered NOTCH3 protein in CADASIL tissue. Four antibodies were raised in rabbits against two non-overlapping N-terminal NOTCH3 sequences. These reagents were used in immunohistochemical experiments to detect epitopes in post-mortem CADASIL brains (n=8), control brains, and cells overexpressing NOTCH3. To determine the biochemical nature of NOTCH3 epitopes, we used these antibodies to probe pure NOTCH3-Fc fusion proteins treated with acid, urea, guanidinium, ionic detergents, acrylamide, and thiol- and phosphorus-based reductants. All antibodies avidly stained arteries in 8 of 8 CADASIL brain samples. The most prominent staining was in degenerating media of leptomeningeal arteries and sclerotic penetrating vessels. Normal appearing vessels from control brains were not reactive. Antibodies did not react with cultured cells overexpressing NOTCH3 or with purified NOTCH3-Fc protein. Furthermore, treatment of pure protein with acid, chaotropic denaturants, alkylators, and detergents failed to unmask N-terminal NOTCH3 epitopes. Antibodies, however, recognized novel N-terminal epitopes in purified NOTCH3-Fc protein treated with three different reductants (DTT, beta-mercaptoethanol, and TCEP). We conclude that CADASIL arteries feature latent N-terminal NOTCH3 epitopes, suggesting the first evidence in vivo of NOTCH3 structural alterations

Fate of the Josephson effect in thin-film superconductors

The dc Josephson effect refers to the dissipationless electrical current -- the supercurrent -- that can be sustained across a weak link connecting two bulk superconductors. This effect is a probe of the fundamental nature of the superconducting state. Here, we analyze the case of two superconducting thin films connected by a point contact. Remarkably, the Josephson effect is absent at nonzero temperature, and the resistance across the contact is nonzero. Moreover, the point contact resistance is found to vary with temperature in a nearly activated fashion, with a UNIVERSAL energy barrier determined only by the superfluid stiffness characterizing the films, an angle characterizing the geometry, and whether or not the Coulomb interaction between Cooper pairs is screened. This behavior reflects the subtle nature of the superconductivity in two-dimensional thin films, and should be testable in detail by future experiments.Comment: 16 + 8 pages. 1 figure, 1 tabl

Cardiovascular fitness associated with cognitive performance in heart failure patients enrolled in cardiac rehabilitation

Abstract Background Reduced cognitive function is common in persons with heart failure (HF). Cardiovascular fitness is a known contributor to cognitive function in many patient populations, but has only been linked to cognition based on estimates of fitness in HF. The current study examined the relationship between fitness as measured by metabolic equivalents (METs) from a standardized stress test and cognition in persons with HF, as well as the validity of office-based predictors of fitness in this population. Methods Forty-one HF patients enrolled in cardiac rehabilitation completed a standardized exercise stress test protocol, a brief neuropsychological battery, the 2-minute step test (2MST), and a series of medical history and self-report questionnaires. Results Maximum METs from stress testing demonstrated incremental predictive validity for attention (β = .41,p = .03), executive function (β = .37,p = .04), and memory domains (β = .46,p = .04). Partial correlations accounting for key medical and demographic characteristics revealed greater METs was associated with the 2MST (r(32) = .41,p = .02) but not with the Duke Activity Status Index (DASI) (r(32) = .24,p = .17). Conclusion The current findings indicate that better fitness levels measured by METs is independently associated with better cognitive function in older adults with HF. Results also showed that METs was closely associated with one office-based measure of fitness (2MST), but not another (DASI). Prospective studies are needed to clarify the mechanisms linking fitness and cognitive function in HF

Sleep Apnea and Cognitive Function in Heart Failure

Background. Prior research indicates that heart failure (HF) patients exhibit significant cognitive deficits on neuropsychological testing. Sleep apnea is associated with both HF and reduced cognitive function, but the combined impact of these conditions on cognitive function is unknown. Methods. In the current study, 172 older adults with a dual diagnosis of HF and sleep apnea or HF alone completed a battery of cognitive tests measuring attention, executive functioning, and memory. Results. Relative to patients with HF alone, persons with both HF and sleep apnea performed worse on measures of attention after adjusting for demographic and medical variables. Conclusions. The current findings suggest that HF patients with comorbid sleep apnea may be at greater risk for cognitive impairment relative to HF patient without such history. Further work is needed to clarify mechanisms for these findings and to determine whether the interactive effects on cognitive function lead to poorer patient outcomes

The Additive Effects of Type-2 Diabetes on Cognitive Function in Older Adults with Heart Failure

Background. Medical comorbidity has been theorized to contribute to cognitive impairment in heart failure (HF) patients. Specifically, type-2 diabetes mellitus (T2DM), a common coexisting condition among HF patients, may be an independent predictor of cognitive impairment. Nonetheless, the relationships between T2DM and other risk factors for cognitive impairment among persons with HF are unclear. Methods. Persons with HF (N = 169, 34.3% women, age 68.57 ± 10.28 years) completed neuropsychological testing within a framework of an ongoing study. History of T2DM, along with other medical characteristics, was ascertained through a review of participants' medical charts and self-report. Results. Many participants (34.9%) had a comorbid T2DM diagnosis. After adjustment for demographic and medical characteristics, HF patients with T2DM evidenced significantly greater impairments across multiple cognitive domains than HF patients without T2DM: λ = .92, F(5, 156) = 2.82, P = .018. Post hoc tests revealed significant associations between T2DM and attention (P = .003), executive function (P = .032), and motor functioning (P = .008). Conclusion. The findings suggest additive contributions of T2DM and HF to impairments in attention, executive function, and motor function. Future work is needed to elucidate the mechanisms by which T2DM exacerbates cognitive impairment in HF