Search

Hyperphosphorylation of the neuronal tau protein is a hallmark of neurodegenerative tauopathies such as Alzheimer’s disease. A central unanswered question is why tau becomes progressively hyperphosphorylated. Here, we show that tau phosphorylation is governed by interdependence— a mechanistic link between initial site-specific and subsequent multi-site phosphorylation. Systematic assessment of site interdependence identified distinct residues (threonine-50, threonine-69, and threonine-181) as master sites that determine propagation of phosphorylation at multiple epitopes. CRISPR point mutation and expression of human tau in Alzheimer’s mice showed that site interdependence governs physiologic and amyloid-associated multi-site phosphorylation and cognitive deficits, respectively. Combined targeting of master sites and p38α, the most central tau kinase linked to interdependence, synergistically ablated hyperphosphorylation. In summary, our work delineates how complex tau phosphorylation arises to inform therapeutic and biomarker design for tauopathies.

L. T. Hobhouse (1864–1929) is most familiar today as a leading theorist of British new liberalism. This article recovers and examines his overlooked commentary on the concept and rhetoric of race, which constituted part of his better-known project of advancing an authoritative account of liberal doctrine. His writings during and after the South African War, I argue, represent a prominent effort to cast liberalism as compatible with both imperial rule and what he called ‘the idea of racial equality’. A properly liberal empire, he asserted, would dissolve the colour line. This article traces the arguments Hobhouse advanced to make this claim, and explores his motivations for doing so. I contend that Hobhouse drew on the idiom of race as a form of exclusionary rhetoric, to delegitimise rival accounts of liberal empire and to cast his own as properly cosmopolitan. This recovery, I suggest, offers payoffs for our understanding of both Hobhouse's political thought and, more broadly, the uses of ‘race’ in twentieth-century liberalism.

Objective: To reassess reliability and validity of the Submental Nasal Appearance Scale (SNAS) compared to the preliminary pilot study, for assessment of patient photographs with repaired unilateral cleft lip and palate (UCLP). When utilizing the SNAS, 3 nasal features (1. nasal outline; 2. alar base position; 3. nostril axis) must be graded according to symmetry between the cleft and noncleft side using a 5-point scale with reference photographs for each feature. The mean score calculated from the graded features reflects the overall degree of nasal symmetry, which is considered an important goal when repairing UCLP. Design: Fifty patient photographs were selected and cropped, displaying the submental view. Six raters assessed these photographs using the SNAS and a separate 5-point scale to assess the overall submental appearance. Interrater reliability was determined for both methods and correlation was calculated between these as an indication of construct validity. Setting: Amsterdam UMC, location VUmc, Amsterdam, The Netherlands. Patients: Six- to 9-year-old patients with repaired UCLP. Results: Interrater reliability of 0.73 and 0.48 was found for the SNAS and overall appearance assessment, respectively, while in the pilot study values of 0.79 and 0.69 were found. Correlation of 0.59 and 0.74 was found in the current and pilot study, respectively, between the SNAS and overall appearance assessment. Conclusions: The SNAS is a reliable tool to assess nasal symmetry from the submental perspective. Reliability of the SNAS is higher compared to grading overall appearance, but validity of the SNAS was less well supported.

A significant body of literature has demonstrated that infants demonstrate a decline in sensitivity to nonnative sound contrasts by their first birthday, a transition often thought to be adaptive for later word learning. The present study investigated infants' sensitivity to these contrasts in a habituation-based discrimination and word learning task (total N = 168, 78 males and 90 females). All infants were native to Singapore and were of Chinese origin. Family socioeconomic status (SES) was measured by parental education. The mean number of years of parental education was 4.02 years after high school. Using a habituation-based discrimination paradigm, monolingual, and bilingual infants' sensitivity to the Hindi dental/retroflex voiceless stop was investigated at 14 months (Experiment 1). Neither group discriminated the contrast. Using the Switch paradigm, we assessed sensitivity to the same contrast in a word learning task. Monolingual and bilingual infants were tested at 14- and 19 months (Experiment 2a) and subsequently, an older group of bilingual infants was tested at 24 months (Experiment 2b). Results demonstrated an overall sensitivity to the Hindi contrast in Experiment 2a. Bilingual infants tested in Experiment 2b were not sensitive to the Hindi contrast. Findings are discussed with reference to discontinuities in the growth of a phonological lexicon as well as possible mechanisms elicit nonnative sensitivity in word learning. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

We investigate the intensity and phase noise properties of GaAs-based 1060 nm oxide-confined single-mode vertical-cavity surface-emitting lasers (VCSELs) and their dependence on slope efficiency and current spreading, parameters that control the achievable output power. We find strong dependence of the linewidth on slope efficiency because it affects the optical resonator loss and therefore the spontaneous emission rate and the photon density. Likewise, we find strong dependence of the relative intensity noise on the slope efficiency since the optical resonator loss controls the photon lifetime, and therefore the damping of the relaxation oscillations. There is no noticeable dependence on transverse current confinement and current spreading. We measure linewidths as small as 6 MHz which we attribute to a small linewidth enhancement factor. This assumption is supported by calculations of the linewidth enhancement factor from optical resonator and optical gain simulations. The dependencies of noise on design parameters are general and therefore valid for single-mode VCSELs at other wavelengths and in other material systems.

Au nanoparticles (NPs) prepared under different molar ratio (concentration) of polyoxometalate Na10SiW9O34 ⋅ 18H2O (SiW9) at definite concentrations of AuIII (0.15 mM), NaOH (1.5 mM), and ascorbic acid (0.225 mM) have been investigated systematically and quantitatively. The size of Au NPs decreases from 81.5 nm to 30.0 nm when the molar ratio of SiW9 increases from 1 to 22, which is related to the activity of Auric precursor in reaction solution. It has been identified that the introduction of SiW9 generates a new complex (expressed as AuIII−SiW9) which is more active than the precursor of Auric hydroxide. Therefore, there is a competing equilibrium between Auric hydroxide and AuIII–SiW9 complex in the reaction system. The increasing AuIII–SiW9 complex results in increasing reaction rate and decreasing Au nanoparticle size, while the increasing Auric hydroxide provides a contrary result. This work represents an approach to tune the size of Au NPs by changing the molar ratio of polyoxometalate SiW9 at a stationary AuIII concentration (0.15 mM) in the ascorbic acid reduction method. The resulting NPs capped by SiW9 are expected a functionalized prospect due to not only the synergism of POM and Au NPs but also the strong coordination ability of POM which makes it continue to be modified.

Hyperphosphorylation of the neuronal tau protein contributes to Alzheimer's disease (AD) by promoting tau pathology and neuronal and cognitive deficits. In contrast, we have previously shown that site-specific tau phosphorylation can inhibit toxic signals induced by amyloid-β (Aβ) in mouse models. The post-synaptic mitogen-activated protein (MAP) kinase p38γ mediates this site-specific phosphorylation on tau at Threonine-205 (T205). Using a gene therapeutic approach, we draw on this neuroprotective mechanism to improve memory in two Aβ-dependent mouse models of AD at stages when advanced memory deficits are present. Increasing activity of post-synaptic kinase p38γ that targets T205 in tau reduced memory deficits in symptomatic Aβ-induced AD models. Reconstitution experiments with wildtype human tau or phosphorylation-deficient tauT205A showed that T205 modification is critical for downstream effects of p38γ that prevent memory impairment in APP-transgenic mice. Furthermore, genome editing of the T205 codon in the murine Mapt gene showed that this single side chain in endogenous tau critically modulates memory deficits in APP-transgenic Alzheimer's mice. Ablating the protective effect of p38γ activity by genetic p38γ deletion in a tau transgenic mouse model that expresses non-pathogenic tau rendered tau toxic and resulted in impaired memory function in the absence of human Aβ. Thus, we propose that modulating neuronal p38γ activity serves as an intrinsic tau-dependent therapeutic approach to augment compromised cognition in advanced dementia.

We discuss the design and demonstration of 4-channel coarse wavelength-division (de-)multiplexers based on cascaded Mach–Zehnder interferometer (MZI) lattice filters and arrayed waveguide gratings (AWG) on a 150 nm silicon nitride (Si3N4) platform. The 1 × 4 (de-)multiplexers are designed for a channel separation of 25 nm and operate within 990–1065 nm for bottom emitting vertical cavity surface emitting lasers (VCSEL)-based optical links. For Si3N4 Gaussian AWGs, we demonstrate crosstalk

Delayed post-operative spinal epidural haematoma (DPSEH) is diagnosed when the onset of symptoms is more than three days from the index surgery. DPSEH is a rare but serious complication of spinal surgery. Missed diagnosis will result in irreversible neurological deficit which may lead to permanent disabilities. We report two cases of DPSEH who presented with worsening neurological deficit four days after the index surgery. Magnetic resonance imaging (MRI) showed the presence of an epidural haematoma compressing the spinal cord. Surgical evacuation of haematoma were performed for both patients. Both patients experienced neurological improvement. Surgeons should have high index of suspicion to identify delayed onset of spinal epidural haematoma (SEH) and timely intervention should be taken to avoid irreversible neurological damage.

The intensification of drought and unsustainable management of water resources has caused increasing demand for water resources. Interbasin water transfer has been implemented as an alternative solution method to this demand in last decades. This study presented the statistical investigation regarding hydrological effects of interbasin water transfer for karst areas in southern part of Turkey. In order to maintain water level above the critical level at Beysehir Lake (BL), the largest fresh water resource of Turkey, the water of Gembos Closed Basin (GCB), located at the south of the BL, has been diverted to the BL via Gembos Diversion Canal (GDC) since 2008. The main reason for diverting water to the BL was to save water level influenced by severe fluctuations due to irrigation water transferring to the Konya Plain. It was supposed that the GCB was feeding the Manavgat River (MR) in the south by way to dolines that the transfer zone located at densely karst area. Statistical analysis applied to the hydrometeorological data of adjacent basins showed a significant relation between flow of the MR and adjacent basins. The cross-correlation functions between high correlation values of + 1 lag time indicates that precipitation occurring throughout the GCB affects the baseflow at the MR about a month later. The GDC caused 0.84 m increase in the level of the BL; however, it does not create a statistically significant change on the MR. The results also demonstrated that the GDC contributed positively to water level of the Lake despite irrigation water.

This case report presents the diagnosis and treatment of a case with subcutaneous sparganosis.

Gastrointestinal pathology leading to the death in paediatric age group is uncommon. The diseases that encountered were mostly intestinal obstruction, peritonitis and gastrointestinal bleeding. Due to the severe symptoms, most of the patients presented to hospital in time and were treated appropriately. However, with the presence of contributing factors, certain gastrointestinal pathology can progress rapidly leading to the death. We report a rare case of intestinal volvulus in a 3 years old girl where the deceased presented with one day short history of vomiting before her demise. The contributing factors were bronchopneumonia sepsis and underlying intestinal malrotation identified via post-mortem examination.

Rhabdomyolysis is characterized by the breakdown of muscle tissue, and release of intracellular muscle constituents into the blood circulation. The severity of the illness may range from asymptomatic elevation in serum muscle enzymes to a life-threatening disease. One disease may behave differently in different way in different individuals. The first patient was involved in a motor vehicle accident and developed acute kidney injury on the third day of admission. The second patient complained of lower limb weakness, and was discharged with vitamin D supplements. Both patients’ conditions were not properly diagnosed or treated, and succumbed to death. Autopsies were conducted in both cases, in which rhabdomyolysis were diagnosed. This case report emphasizes the importance of making a correct diagnosis of rhabdomyolysis Progression of the disease and its complications should be monitored closely. Timely management may save life in high risk patients.

Mitogen-activated protein (MAP) kinases are a central component in signaling networks in a multitude of mammalian cell types. This review covers recent advances on specific functions of p38 MAP kinases in cells of the central nervous system. Unique and specific functions of the four mammalian p38 kinases are found in all major cell types in the brain. Mechanisms of p38 activation and downstream phosphorylation substrates in these different contexts are outlined and how they contribute to functions of p38 in physiological and under disease conditions. Results in different model organisms demonstrated that p38 kinases are involved in cognitive functions, including functions related to anxiety, addiction behavior, neurotoxicity, neurodegeneration, and decision making. Finally, the role of p38 kinases in psychiatric and neurological conditions and the current progress on therapeutic inhibitors targeting p38 kinases are covered and implicate p38 kinases in a multitude of CNS-related physiological and disease states.

Hyperphosphorylation of the neuronal tau protein contributes to Alzheimer's disease (AD) by promoting tau pathology and neuronal and cognitive deficits. In contrast, we have previously shown that site-specific tau phosphorylation can inhibit toxic signals induced by amyloid-β (Aβ) in mouse models. The post-synaptic mitogen-activated protein (MAP) kinase p38γ mediates this site-specific phosphorylation on tau at Threonine-205 (T205). Using a gene therapeutic approach, we draw on this neuroprotective mechanism to improve memory in two Aβ-dependent mouse models of AD at stages when advanced memory deficits are present. Increasing activity of post-synaptic kinase p38γ that targets T205 in tau reduced memory deficits in symptomatic Aβ-induced AD models. Reconstitution experiments with wildtype human tau or phosphorylation-deficient tauT205A showed that T205 modification is critical for downstream effects of p38γ that prevent memory impairment in APP-transgenic mice. Furthermore, genome editing of the T205 codon in the murine Mapt gene showed that this single side chain in endogenous tau critically modulates memory deficits in APP-transgenic Alzheimer's mice. Ablating the protective effect of p38γ activity by genetic p38γ deletion in a tau transgenic mouse model that expresses non-pathogenic tau rendered tau toxic and resulted in impaired memory function in the absence of human Aβ. Thus, we propose that modulating neuronal p38γ activity serves as an intrinsic tau-dependent therapeutic approach to augment compromised cognition in advanced dementia.

Past studies suggest that monolingual and bilingual infants respond differently to race information in face discrimination and social learning tasks. In particular, bilingual infants have been shown to respond more similarly to own- and other-race individuals, in contrast to monolingual infants, who respond preferentially to own-race individuals. In the current study, we investigated monolingual and bilingual sensitivity to speaker race in spoken word recognition. Two-year-old infants were presented with spoken words in association with visual targets. Words were presented in association with own- or other-race actors and were either correctly pronounced or mispronounced. Measuring speech-responsive eye movements to visual targets, we analyzed fixation to visual targets for correct and mispronounced words in relation to speaker race for each group. When presented with own-race speakers, both monolingual and bilingual infants associated correctly pronounced labels, but not mispronounced labels, with visual targets. When presented with other-race speakers, bilingual infants responded similarly. In contrast, monolingual infants did not fixate visual targets regardless of whether words were correctly pronounced or mispronounced by an other-race speaker. Results are discussed in terms of the sensitivities of bilingual and monolingual infants to novelty, learned associations between race and language, and prior social experiences.

Financial exclusion prevents the poor and disadvantaged from accessing formal financial systems . The unbanked and underbanked use alternate channels to meet their financial needs but face exorbitant pricing. The inability of banks to respond to the needs of the unbanked and underbanked because of government regulations and legacy IT systems, and inherent organizational friction have created opportunities for Fintech firms. The widespread adoption of mobile phones, the advancement of technology infrastructure, the harvesting of big data, financial education and technological education have escalated financial innovation and financial deepening.

Melioidosis is an infectious disease caused by Burkholderia pseudomallei, a gram-negative intracellular bacillus. Tuberculosis, also an infectious disease, is caused by Mycobacterium tuberculosis, an acid fast bacillus. In both diseases, patients commonly present with fever and respiratory symptoms due to sepsis which might lead to respiratory failure or sudden death if left untreated. Not only are these two entities similar in clinical presentation, but the autopsy findings may mimic each other, giving rise to difficulties in determining the cause of death. We report a case of melioidosis and compare it to a typical case of miliary tuberculosis. Similarities between the cases on gross and histopathological examinations are discussed. In such circumstances, microbiological culture of bodily fluids and internal organs should be performed to ascertain the correct cause of death.

In this study, the scour induced by a propeller jet around a single pile was examined experimentally on four different non-cohesive sediment beds. The initiation of scour formation was found to be related to the densimetric Froude number (Frd), propeller diameter (Dp), and the gap of the propeller (G), which is defined as the vertical distance between the centerline of the propeller and the undisturbed sand bed. Three types of scour profiles were defined that can be classified according to a) the scour depth at the upstream toe of the pile (So), and b) the scour at the downstream section of the pile (Sd). Scour profiles were also found to be highly dependent on the densimetric Froude number (Frd) and pile diameter (do). Scour profiles and scour depths at the toe of the pile (So) were investigated at different distances between pile locations and propeller face (X), pile diameter, sediment bed material size, propeller diameter, speed, and gap. New empirical equations were proposed for the estimation of scour depth at the toe of the pile. The locations of the pile (X) were also investigated to assess whether the predominant scouring mechanism was the propeller jet or the pile mechanism.

Background Coronary artery aneurysm can be defined as an abnormal dilatation of the coronaries. In recent years, the disease has been frequently encountered during surgical procedures such as percutaneous coronary intervention (PCI) and coronary computed tomography angiography (CCTA). Case presentation We reported a case of cardiac tamponade due to spontaneous rupture of coronary artery aneurysm in a 53-year-old Chinese man, who had collapsed and died at home after returning from work. Autopsy revealed a cardiac tamponade with ruptured aneurysm of the left circumflex artery. Conclusion This case highlights the need to consider ruptured coronary aneurysm as a differential diagnosis when cardiac tamponade is encountered during autopsy.

Tb/s class, copackaged coarse wavelength division multiplexing optical engine based on four wavelength vertical cavity surface emitting lasers (VCSELs) around 1 $\mu$ m is presented. The capability to scale bandwidth of 64 Gb/s using equalization and advanced modulation scheme, e.g., four-level pulse amplitude modulation (PAM4) is demonstrated. The capability to scale link distance of 2 km using single-mode VCSELs and standard SMF-28 fiber is demonstrated. Single-mode VCSELs error-free transmission at 25 Gb/s NRZ over 2 km of SMF-28 is achieved. Using forward-error-correction error-free transmission is possible for the PAM4 modulation over 2 km of SMF-28.

A P-graph model was recently developed for direct reuse/recycle scheme for both in-plant resource conservation networks (RCNs) and inter-plant RCNs (IPRCNs). The proposed P-graph model allows visualization which expedites the assessment of optimal and near-optimal solutions. In this paper, the P-graph model will be extended to material interception schemes, i.e., material regeneration and pre-treatment. Material regeneration involves the use of purification unit for quality improvement of the process sources before they are reused/recycled to the sinks. Pre-treatment processes, on the other hand, involve the purification of fresh resources for use in processes with stringent quality requirement. Two literature case studies are solved to demonstrate the newly extended model.

The need for climate change adaptation in industry has led to intensified research in industrial resource conservation, as well as waste reduction, to enable sustainable operations to be achieved even under conditions of declining water resources. Such sustainability initiatives can be facilitated using the systematic approach of process integration (PI). Of particular interest are resource conservation network (RCN) problems, which have been solved using pinch analysis or mathematical programming methods. On the other hand, other process system engineering (PSE) tools such as the process graph (or P-graph) framework offers potential alternative approaches to RCN problems. To date, P-graph methodology has been used for various process network synthesis (PNS) problems; however, no RCN synthesis applications have been reported thus far. This paper presents a novel implementation of P-graph for RCN synthesis. In addition to the inherent computational efficiency of its algorithms, P-graph allows the elucidation of optimal and near-optimal solutions, a feature which is potentially useful for practical decision-making. Capital and operating cost considerations can be incorporated easily. In this paper, direct reuse/recycle scheme is applied for in-plant RCN and inter-plant RCN (IPRCN).

This study provides new evidence about short sellers' trading strategies by showing that short sellers exploit firm information in combination with industry information in their trades. In industries with the highest aggregate shorted values, the most-shorted stocks earn about 1.535% lower abnormal returns than other highly shorted stocks in less shorted industries over the next six months. These results are likely driven by short sellers’ preference for complex industries with the highest profit potential. We also show that the aggregate shorted value at the industry level is able to predict important industry shifts, such as declines in sales and increased competition. Overall, our results suggest that short sellers help to reduce information complexity and improve economic efficiency at the industry level.

Background/Introduction Classic electrocardiographic (ECG) criteria for left ventricular hypertrophy (LVH) have been well studied in Western populations, particularly in hypertensive patients. However, their utility in Asian populations is not well studied, and their applicability to young pre-participation cohorts is unclear. We sought to evaluate the performance of classical criteria against that of machine learning models. Aims We sought to evaluate the performance of classical criteria against the performance of novel machine learning models in the identification of LVH. Methodology Between November 2009 and December 2014, pre-participation screening ECG and subsequent echocardiographic data was collected from 13,954 males aged 16 to 22, who reported for medical screening prior to military conscription. Final diagnosis of LVH was made on echocardiography, with LVH defined as a left ventricular mass index >115g/m2. The continuous and binary forms of classical criteria were compared against machine learning models using receiver-operating characteristics (ROC) curve analysis. An 80:20 split was used to divide the data into training and test sets for the machine learning models, and three fold cross validation was used in training the models. We also compared the important variables identified by machine learning models with the input variables of classical criteria. Results Prevalence of echocardiographic LVH in this population was 0.91% (127 cases). Classical ECG criteria had poor performance in predicting LVH, with the best predictions achieved by the continuous Sokolow-Lyon (AUC = 0.63, 95% CI = 0.58–0.68) and the continuous Modified Cornell (AUC = 0.63, 95% CI = 0.58–0.68). Machine learning methods achieved superior performance – Random Forest (AUC = 0.74, 95% CI = 0.66–0.82), Gradient Boosting Machines (AUC = 0.70, 95% CI = 0.61–0.79), GLMNet (AUC = 0.78, 95% CI = 0.70–0.86). Novel and less recognized ECG parameters identified by the machine learning models as being predictive of LVH included mean QT interval, mean QRS interval, R in V4, and R in I. ROC curves of models studies Conclusion The prevalence of LVH in our population is lower than that previously reported in other similar populations. Classical ECG criteria perform poorly in this context. Machine learning methods show superior predictive performance and demonstrate non-traditional predictors of LVH from ECG data. Further research is required to improve the predictive ability of machine learning models, and to understand the underlying pathology of the novel ECG predictors identified.