Phosphorylation of p66Shc and forkhead proteins mediates Aβ toxicity

Excessive accumulation of amyloid β-peptide (Aβ) plays an early and critical role in synapse and neuronal loss in Alzheimer's Disease (AD). Increased oxidative stress is one of the mechanisms whereby Aβ induces neuronal death. Given the lessened susceptibility to oxidative stress exhibited by mice lacking p66Shc, we investigated the role of p66Shc in Aβ toxicity. Treatment of cells and primary neuronal cultures with Aβ caused apoptotic death and induced p66Shc phosphorylation at Ser36. Ectopic expression of a dominant-negative SEK1 mutant or chemical JNK inhibition reduced Aβ-induced JNK activation and p66Shc phosphorylation (Ser36), suggesting that JNK phosphorylates p66Shc. Aβ induced the phosphorylation and hence inactivation of forkhead transcription factors in a p66Shc-dependent manner. Ectopic expression of p66ShcS36A or antioxidant treatment protected cells against Aβ-induced death and reduced forkhead phosphorylation, suggesting that p66Shc phosphorylation critically influences the redox regulation of forkhead proteins and underlies Aβ toxicity. These findings underscore the potential usefulness of JNK, p66Shc, and forkhead proteins as therapeutic targets for AD

Electronic structure investigation of CeB6 by means of soft X-ray scattering

The electronic structure of the heavy fermion compound CeB6 is probed by resonant inelastic soft X-ray scattering using photon energies across the Ce 3d and 4d absorption edges. The hybridization between the localized 4f orbitals and the delocalized valence-band states is studied by identifying the different spectral contributions from inelastic Raman scattering and normal fluorescence. Pronounced energy-loss structures are observed below the elastic peak at both the 3d and 4d thresholds. The origin and character of the inelastic scattering structures are discussed in terms of charge-transfer excitations in connection to the dipole allowed transitions with 4f character. Calculations within the single impurity Anderson model with full multiplet effects are found to yield consistent spectral functions to the experimental data.Comment: 9 pages, 4 figures, 1 table, http://link.aps.org/doi/10.1103/PhysRevB.63.07510

Neuropathology of COVID-19 (neuro-COVID): clinicopathological update

Coronavirus disease 2019 (COVID-19) is emerging as the greatest public health crisis in the early 21st century. Its causative agent, Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), is an enveloped single-stranded positive-sense ribonucleic acid virus that enters cells via the angiotensin converting enzyme 2 receptor or several other receptors. While COVID-19 primarily affects the respiratory system, other organs including the brain can be involved. In Western clinical studies, relatively mild neurological dysfunction such as anosmia and dysgeusia is frequent (~70-84%) while severe neurologic disorders such as stroke (~1-6%) and meningoencephalitis are less common. It is unclear how much SARS-CoV-2 infection contributes to the incidence of stroke given co-morbidities in the affected patient population. Rarely, clinically-defined cases of acute disseminated encephalomyelitis, Guillain-Barré syndrome and acute necrotizing encephalopathy have been reported in COVID-19 patients. Common neuropathological findings in the 184 patients reviewed include microglial activation (42.9%) with microglial nodules in a subset (33.3%), lymphoid inflammation (37.5%), acute hypoxic-ischemic changes (29.9%), astrogliosis (27.7%), acute/subacute brain infarcts (21.2%), spontaneous hemorrhage (15.8%), and microthrombi (15.2%). In our institutional cases, we also note occasional anterior pituitary infarcts. COVID-19 coagulopathy, sepsis, and acute respiratory distress likely contribute to a number of these findings. When present, central nervous system lymphoid inflammation is often minimal to mild, is detected best by immunohistochemistry and, in one study, indistinguishable from control sepsis cases. Some cases evince microglial nodules or neuronophagy, strongly supporting viral meningoencephalitis, with a proclivity for involvement of the medulla oblongata. The virus is detectable by reverse transcriptase polymerase chain reaction, immunohistochemistry, or electron microscopy in human cerebrum, cerebellum, cranial nerves, olfactory bulb, as well as in the olfactory epithelium; neurons and endothelium can also be infected. Review of the extant cases has limitations including selection bias and limited clinical information in some cases. Much remains to be learned about the effects of direct viral infection of brain cells and whether SARS-CoV-2 persists long-term contributing to chronic symptomatology

BMC Public Health

Background Failure to retain HIV-positive pregnant women on antiretroviral therapy (ART) leads to increased mortality for the mother and her child. This study evaluated different retention measures for women’s engagement along the continuum of care for prevention of mother-to-child transmission (PMTCT) option B+ services in Mozambique. Methods We compared ‘point’ retention (patient’s presence in care 12-month post-ART initiation or any time thereafter) with the following definitions: alive and in care 12 month post-ART initiation (Ministry of Health; MOH); attendance at a health facility up to 15-month post-ART initiation (World Health Organization; WHO); alive and in treatment at 1-, 2-, 3-, 6-, 9-, and 12-month post-ART initiation (Inter-Agency Task Team; IATT); and alive and in care 12-month post-ART initiation with ≥75% appointment adherence during follow-up (i.e. ‘appointment adherence’ retention) or with ≥75% of appointments met on time during follow-up (i.e. ‘on-time adherence’ retention). Kaplan-Meier survival curves were produced to assess variability in retention rates. We used ‘on-time adherence’ retention as our reference to estimate sensitivity, specificity, and proportion of misclassified patients. Results Considering the ‘point’ retention definition, 16,840 HIV-positive pregnant women enrolled in option B+ PMTCT services were identified as ‘retained in care’ 12-month post-ART initiation. Of these, 60.3% (95% CI 59.6–61.1), 84.8% (95% CI 84.2–85.3), and 16.4% (95% CI 15.8–17.0) were classified as ‘retained in care’ using MOH, WHO, and IATT definitions, respectively, and 1.2% (95% CI 1.0–1.4) were classified as ‘retained in care’ using the ‘≥75% on-time adherence’ definition. All definitions provided specificity rates of ≥98%. The sensitivity rates were 3.0% with 78% of patients misclassified according to the WHO definition and 4.3% with 54% of patients misclassified according to the MOH definition. The ‘point’ retention definition misclassified 97.6% of patients. Using IATT and ‘appointment adherence’ retention definitions, sensitivity rates (9.0 and 11.7%, respectively) were also low; however, the proportion of misclassified patients was smaller (15.9 and 18.3%, respectively). Conclusion More stringent definitions indicated lower retention rates for PMTCT programs. Policy makers and program managers should include attendance at follow-up visits when measuring retention in care to better guide planning, scale-up, and monitoring of interventions

Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein.

Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies

The mortality rates and the space-time patterns of John Snow’s cholera epidemic map

Background Snow’s work on the Broad Street map is widely known as a pioneering example of spatial epidemiology. It lacks, however, two significant attributes required in contemporary analyses of disease incidence: population at risk and the progression of the epidemic over time. Despite this has been repeatedly suggested in the literature, no systematic investigation of these two aspects was previously carried out. Using a series of historical documents, this study constructs own data to revisit Snow’s study to examine the mortality rate at each street location and the space-time pattern of the cholera outbreak. Methods This study brings together records from a series of historical documents, and prepares own data on the estimated number of residents at each house location as well as the space-time data of the victims, and these are processed in GIS to facilitate the spatial-temporal analysis. Mortality rates and the space-time pattern in the victims’ records are explored using Kernel Density Estimation and network-based Scan Statistic, a recently developed method that detects significant concentrations of records such as the date and place of victims with respect to their distance from others along the street network. The results are visualised in a map form using a GIS platform. Results Data on mortality rates and space-time distribution of the victims were collected from various sources and were successfully merged and digitised, thus allowing the production of new map outputs and new interpretation of the 1854 cholera outbreak in London, covering more cases than Snow’s original report and also adding new insights into their space-time distribution. They confirmed that areas in the immediate vicinity of the Broad Street pump indeed suffered from excessively high mortality rates, which has been suspected for the past 160 years but remained unconfirmed. No distinctive pattern was found in the space-time distribution of victims’ locations. Conclusions The high mortality rates identified around the Broad Street pump are consistent with Snow’s theory about cholera being transmitted through contaminated water. The absence of a clear space-time pattern also indicates the water-bourne, rather than the then popular belief of air bourne, nature of cholera. The GIS data constructed in this study has an academic value and would cater for further research on Snow’s map

Brain arteriolosclerosis

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer’s disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g. hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that include consideration of comorbid diseases, B-ASC is independently associated with impairments in global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability

Repeated freeze–thaw cycles reduce the survival rate of osteocytes in bone-tendon constructs without affecting the mechanical properties of tendons

Frozen bone-patellar tendon bone allografts are useful in anterior cruciate ligament reconstruction as the freezing procedure kills tissue cells, thereby reducing immunogenicity of the grafts. However, a small portion of cells in human femoral heads treated by standard bone-bank freezing procedures survive, thus limiting the effectiveness of allografts. Here, we characterized the survival rates and mechanisms of cells isolated from rat bones and tendons that were subjected to freeze–thaw treatments, and evaluated the influence of these treatments on the mechanical properties of tendons. After a single freeze–thaw cycle, most cells isolated from frozen bone appeared morphologically as osteocytes and expressed both osteoblast- and osteocyte-related genes. Transmission electron microscopic observation of frozen cells using freeze-substitution revealed that a small number of osteocytes maintained large nuclei with intact double membranes, indicating that these osteocytes in bone matrix were resistant to ice crystal formation. We found that tendon cells were completely killed by a single freeze–thaw cycle, whereas bone cells exhibited a relatively high survival rate, although survival was significantly reduced after three freeze–thaw cycles. In patella tendons, the ultimate stress, Young’s modulus, and strain at failure showed no significant differences between untreated tendons and those subjected to five freeze–thaw cycles. In conclusion, we identified that cells surviving after freeze–thaw treatment of rat bones were predominantly osteocytes. We propose that repeated freeze–thaw cycles could be applied for processing bone-tendon constructs prior to grafting as the treatment did not affect the mechanical property of tendons and drastically reduced surviving osteocytes, thereby potentially decreasing allograft immunogenecity

On the Experimental Analysis of Integral Sliding Modes for Yaw Rate and Sideslip Control of an Electric Vehicle with Multiple Motors

With the advent of electric vehicles with multiple motors, the steady-state and transient cornering responses can be designed and implemented through the continuous torque control of the individual wheels, i.e., torque-vectoring or direct yaw moment control. The literature includes several papers on sliding mode control theory for torque-vectoring, but the experimental investigation is so far limited. More importantly, to the knowledge of the authors, the experimental comparison of direct yaw moment control based on sliding modes and typical controllers used for stability control in production vehicles is missing. This paper aims to reduce this gap by presenting and analyzing an integral sliding mode controller for concurrent yaw rate and sideslip control. A new driving mode, the Enhanced Sport mode, is proposed, inducing sustained high values of sideslip angle, which can be limited to a specified threshold. The system is experimentally assessed on a four-wheel-drive electric vehicle. The performance of the integral sliding mode controller is compared with that of a linear quadratic regulator during step steer tests. The results show that the integral sliding mode controller significantly enhances the tracking performance and yaw damping compared to the more conventional linear quadratic regulator based on an augmented singletrack vehicle model formulation. © 2018, The Korean Society of Automotive Engineers and Springer-Verlag GmbH Germany, part of Springer Natur