Cyclin-dependent kinase 5 has been implicated in Alzheimer's disease pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a (...) targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis. (shrink)

PURPOSE:To report the localization of a gene causing drusen and macular degeneration in a previously undescribed North American family. METHODS:Genetic mapping studies were performed using linkage analysis in a single family with drusen and atrophic macular degeneration. RESULTS:The clinical manifestations in this family ranged from fine macular drusen in asymptomatic middle-aged individuals to atrophic macular lesions in two children and two elderly patients. We mapped the gene to chromosome 6q14 between markers D6S2258 and D6S1644. CONCLUSIONS:In a family with autosomal dominant (...) drusen and atrophic macular degeneration, the gene maps to a 3.2-cM region on chromosome 6q14. This locus appears to be distinct from, but adjacent to, the loci for cone-rod dystrophy 7 (CORD7) and North Carolina macular dystrophy (MCDR1). Future identification of the gene responsible for the disease in this family will provide a better understanding of macular degeneration. (shrink)

The technical literature actively discusses ideas for creating digital twins to solve a wide range of problems that arise for enterprises of various kinds. Advances in the areas of information technology and the development of the necessary software really make it possible to obtain important new results through the creation of digital twins. This paper proposes the concept of building a network of digital twins, used to solve a number of actual problems in complex telecommunication systems. Two applications are considered (...) examples of such tasks. The first application is the organization of information feedback for enterprises involved in the life cycle of a telecommunication network: “elaboration of modernization principles, development of equipment, design, construction, and operation.” The second application is monitoring traffic, including its atypical behavior, in order to avoid the recurrence of erroneous actions in case of emergency situations. Another important feature of the digital twin network is that it will become an effective tool for conducting interdisciplinary research. (shrink)

Haydar el-Herevî Horasan’dan Osmanlı topraklarına gelen önemli âlimlerdendir. Teftâzânî’nin şeçkin bir talebesi olan bu âlim I. Mehmed’ten büyük saygı görerek onun tarafından himaye edilmiştir. Herevî, Zemahşerî’nin el-Keşşâf’ı üzerine yazdığı şerhi büyük övgü ifadeleriyle I. Mehmed’e ithaf etmiş, ithafın yer aldığı mukaddimede hayat hikayesiyle ilgili önemli ayrıntılar vermiştir. Osmanlı topraklarında geçirdiği uzun yıllar sonra Timur’un oğlu Şahruh ile irtibat kuran Herevî, el-Keşşâf şerhi mukaddimesini tekrardan kaleme alarak aynı eseri bu sefer Şahruh’a ithaf etmiştir. Herevî’nin bu yeni patronaj ilişkisi mukaddimenin ikinci versiyonundan (...) öğrenilmektedir. İkinci versiyonda sadece ithaf kısmı değiştirilmemiş, yeni haminin kimliğiyle irtibatlı olarak muhteva da yeni- den kurgulanmıştır. İlk versiyonda bulunmayan önemli biyografik ayrıntılar ikinci versiyonda yer almaktadır. Mukaddimenin iki versiyonu Herevî biyografisinin neredeyse yegâne kaynağıdır. Bu makalede mukaddimenin ikinci versiyonu ilk defa gün yüzüne çıkarılmış ve her iki versiyonda verilen bilgiler bir araya getirilerek Herevî’nin biyografisi inşa edilmiştir. İki versiyonda herhangi bir tarih verilmemiş, sadece bazı şehirlerdeki ikamet süreleri belirtilmiştir. Biyografi inşa edilirken anlatıda oluşan boşluklar tarihi olaylardan hareketle doldurulmuş ve tarihlendirme yapılmıştır. Bahsedilen olaylar, yapılan nitelemeler ve verilen ikamet süreleri itibara alınarak Herevî’nin hayatının yaklaşık kırk yıllık bölümü tam olarak tarihlendirilmiş, Serahs’tan başlayarak sırasıyla Şîraz, Tebriz, Şirvan, Bursa, Edirne ve tekrar Horasan’a uzanan yıllara dair bütünlüklü bir tablo ortaya konulmuştur. Bu hayat hikayesi ulema-sultan ilişkileri, siyasî gelişmelerin ilim hayatına yansımaları ve hayatını ilim yolculuklarında geçiren bir âlimin zihin dünyası hakkında eşsiz bilgiler sunmaktadır. (shrink)

Recent years have seen a significant increase in stakeholder pressure on firms to be not only economically sustainable but also from an environmental and social perspective. Besides operational changes in practices and products companies have reacted toward this increased pressure from a strategic perspective through structural changes of their top management team. A recent addition to the TMT has been the appointment of the chief officer of corporate social responsibility. In this paper, we take a behavioral perspective and investigate how (...) the employment of a chief officer of CSR to the TMT impact on firm performance. Specifically, we explore how certain characteristics of the newly appointed chief executive of CSR impact on a firm’s financial performance. We collected secondary, longitudinal data of listed companies in the United States. Results indicate that appointing a chief executive of CSR does under certain conditions and characteristics result in financial performance benefits. Furthermore, the greatest financial performance benefits can be achieved if the appointee is female and has a CSR functional background. (shrink)

The article is devoted to the communicative competence of a doctor as a component of professional ethics. Knowledge of norms of the modern Russian literary language, compliance with these standards in the oral and written speech of a medical worker helps to establish contact between doctor and a patient. To identify the level of knowledge of Russian language norms, readiness for professional speech a scientific research was made, during which the most typical mistakes were revealed:orthoepic, morphological, lexical, stylistic. Following the (...) norms of the language and ethics of communication contributes to the achievement of the main aim of a medical activity – recovering of a patient. (shrink)

Reorienting the Political examines the reception of two controversial German philosophers, Carl Schmitt and Leo Strauss, in the Chinese-speaking world. This volume explores the powerful resonance of both thinkers in Chinese political thought from a cross-cultural and interdisciplinary perspective.

In recent years, society has come to recognize that the work performed by scientists, like that of journalists and politicians, may be influenced by the interests they serve. As a result, scientists' research is increasingly contested as a source of reliable knowledge. Such has been the case in issues concerning the climate debate, for example, where research results are at times perceived to comfortably fit in with the viewpoints of interested parties outside science. In medicine, governmental as well as commercial (...) organizations influence the public health research agenda (McGarity and Wagner 2008). Also, studies sponsored by pharmaceutical companies, for example, often yield biased, favorable results for .. (shrink)

In the seminiferous tubule of the mammalian testis, one type A1 spermatogonium (diploid, 2n) divides and differentiates into 256 spermatozoa (haploid, n) during spermatogenesis. To complete spermatogenesis and produce ∼150 × 106 spermatozoa each day in a healthy man, germ cells must migrate progressively across the seminiferous epithelium yet remain attach to the nourishing Sertoli cells. This active cell migration process involves precisely controlled restructuring events at the tight (TJ) and anchoring junctions at the cell–cell interface. While the hormonal events (...) that regulate spermatogenesis by follicle‐stimulating hormone and testosterone from the pituitary gland and Leydig cells, respectively, are known, less is known about the mechanism(s) that regulates junction restructuring during germ cell movement in the seminiferous epithelium. The relative position of tight (TJs) and anchoring junctions in the testis is of interest. Sertoli cell TJs that constitute the blood–testis barrier (BTB) are present side by side with anchoring junctions and are adjacent to the basement membrane. This intimate physical association with the TJs, the anchoring junctions and the basement membrane (a modified form of extracellular matrix, ECM) suggests a role for the ECM in the junction dynamics of the testis. Indeed, evidence is accumulating that ECM proteins are crucial to Sertoli cell TJ dynamics. In this review, we discuss the pivotal role of tumor necrosis factor α (TNFα) on BTB dynamics via its effects on the homeostasis of ECM proteins. In addition, discussion will also be focused on the novel findings regarding the role of non‐basement‐membrane‐associated ECM proteins and components of focal adhesion (a cell–matrix anchoring junction type) in the regulation of junction dynamics in the testis. BioEssays 26:978–992, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Artificial intelligence tools used in employment decision-making cut across the multiple stages of job advertisements, shortlisting, interviews and hiring, and actual and potential bias can arise in each of these stages. One major challenge is to mitigate AI bias and promote fairness in opaque AI systems. This paper argues that the equal opportunity merit principle is an ethical approach for fair AI employment decision-making. Further, explainable AI can mitigate the opacity problem by placing greater emphasis on enhancing the understanding of (...) reasonable users and affected persons as to the AI output. Both the equal opportunity merit principle and explainable AI should be integrated in the design and implementation of AI employment decision-making systems so as to ensure, as far as possible, that the AI output is arrived at through a fair process. (shrink)

COVID-19 often manifests with different outcomes in different patients, highlighting the complexity of the host-pathogen interactions involved in manifestations of the disease at the molecular and cellular levels. In this paper, we propose a set of postulates and a framework for systematically understanding complex molecular host-pathogen interaction networks. Specifically, we first propose four host-pathogen interaction (HPI) postulates as the basis for understanding molecular and cellular host-pathogen interactions and their relations to disease outcomes. These four postulates cover the evolutionary dispositions involved (...) in HPIs, the dynamic nature of HPI outcomes, roles that HPI components may occupy leading to such outcomes, and HPI checkpoints that are critical for specific disease outcomes. Based on these postulates, an HPI Postulate and Ontology (HPIPO) framework is proposed to apply interoperable ontologies to systematically model and represent various granular details and knowledge within the scope of the HPI postulates, in a way that will support AI-ready data standardization, sharing, integration, and analysis. As a demonstration, the HPI postulates and the HPIPO framework were applied to study COVID-19 with the Coronavirus Infectious Disease Ontology (CIDO), leading to a novel approach to rational design of drug/vaccine cocktails aimed at interrupting processes occurring at critical host-coronavirus interaction checkpoints. Furthermore, the host-coronavirus protein-protein interactions (PPIs) relevant to COVID-19 were predicted and evaluated based on prior knowledge of curated PPIs and domain-domain interactions, and how such studies can be further explored with the HPI postulates and the HPIPO framework is discussed. (shrink)

We give two new characterizations of K-triviality. We show that if for all Y such that Ω is Y-random, Ω is -random, then A is K-trivial. The other direction was proved by Stephan and Yu, giving us the first titular characterization of K-triviality and answering a question of Yu. We also prove that if A is K-trivial, then for all Y such that Ω is Y-random, ≡LRY. This answers a question of Merkle and Yu. The other direction is immediate, so (...) we have the second characterization of K-triviality.The proof of the first characterization uses a new cupping result. We prove that if A≰LRB, then for every set X there is a B-random set Y such that X is computable from Y⊕A. (shrink)

Adaptation to climate change impacts is a key research topic in business ethics that poses substantial implications on the good lives of human beings. The commercial port sector is a highly relevant study focus with its pivotal roles in supply chains and international trade. Hence, it is important to investigate whether the port planning system and practice is appropriate in tackling climate change impacts. But beforehand, we must thoroughly understand the attitude and behaviors of port planners and operators on ports’ (...) climate adaptation planning. Through a survey towards 21 ports in Canada, the paper investigates the attitude and behaviors of port planners and operators on ports’ climate adaptation planning. Towards the end, we propose a new approach so as to enable port stakeholders to carry out climate adaptation planning effectively. The paper offers important insight to researchers to investigate the ways in developing effective climate adaptation plans and practice for ports and other business sectors. (shrink)

The present article allows to explore, analyze and reflect on the consequences and problems posed by biobanks and attempts to prove the need of social and humanitarian support in establishing and functioning of biobanks as a new type of scientific institutions. The basis of the article is the latest publications devoted to social and humanitarian aspects of biobanking and Russian experience of the initial formation of this subject domain. The article marks and classifies different aspects of biobanking that objectively demands (...) the participation of specialists in ethics and social sciences. The cases of biobanking development and risks are estimated; the objective need of applied ethics and social sciences specialists’ participation in biobanking is proved. (shrink)

Hand function improvement in stroke survivors in the chronic stage usually plateaus by 6 months. Brain-computer interface (BCI)-guided robot-assisted training has been shown to be effective for facilitating upper-limb motor function recovery in chronic stroke. However, the underlying neuroplasticity change is not well understood. This study aimed to investigate the whole-brain neuroplasticity changes after 20-session BCI-guided robot hand training, and whether the changes could be maintained at the 6-month follow-up. Therefore, the clinical improvement and the neurological changes before, immediately after, (...) and 6 months after training were explored in 14 chronic stroke subjects. The upper-limb motor function was assessed by Action Research Arm Test (ARAT) and Fugl-Meyer Assessment for Upper-Limb (FMA), and the neurological changes were assessed using resting-state functional magnetic resonance imaging. Repeated-measure ANOVAs indicated that long-term motor improvement was found by both FMA (F[2,26]= 6.367,p= 0.006) and ARAT (F[2,26]= 7.230,p= 0.003). Seed-based functional connectivity analysis exhibited that significantly modulated FC was observed between ipsilesional motor regions (primary motor cortex and supplementary motor area) and contralesional areas (supplementary motor area, premotor cortex, and superior parietal lobule), and the effects were sustained after 6 months. The fALFF analysis showed that local neuronal activities significantly increased in central, frontal and parietal regions, and the effects were also sustained after 6 months. Consistent results in FC and fALFF analyses demonstrated the increase of neural activities in sensorimotor and fronto-parietal regions, which were highly involved in the BCI-guided training.Clinical Trial Registration:This study has been registered atClinicalTrials.govwith clinical trial registration number NCT02323061. (shrink)

With postmodern societies placing a strong emphasis on making full use of one’s time, it is increasingly common to extol busy individuals as more achieving. In this context, although feeling a social expectation to be busy might imply that individuals are regarded as competent and desirable, its accompanying stressors may also detrimentally impact their mental health. Utilising data from a seven-day diary study, the current research examined the relationship between people’s daily perceived pressure to be busy and their daily emotional (...) wellbeing. Multilevel modelling revealed that daily social pressure to be busy was a significant predictor of daily negative affect, anxiety, and depressive symptoms at the within-person level. Of import, individuals’ trait emotional complexity acceptance moderated these relationships, with those lower on emotional complexity acceptance reporting significantly higher negative affect, anxiety, and depressive symptoms on days they felt greater social pressure to be busy. These effects were not observed among those higher on emotional complexity acceptance. Together, the current findings suggest that social pressure to feel busy is generally related to poorer daily emotional wellbeing, and that those with higher trait emotional complexity acceptance have an advantage of maintaining their emotional wellbeing in the face of such a social pressure. (shrink)

Biology incorporated into other disciplines is often distorted, alarmingly so in some areas of medicine. Together with other forms of bias, this may have detrimental effects for patients depending on medical research for their health. A case study concerning omeprazole (Losec), one of the acid-suppressive drugs against gastric ulcers, and NSAIDs, non-steroid anti-inflammatory drugs, confirms that distorted biology together with biased health care policies foster disasters in current biomedicine and medical practice. In our country, The Netherlands, omeprazole is presumably the (...) most commonly used medication. NSAIDs are also used in large quantities, increasingly since they have become available as analgesic over-the-counter drugs. Unofficial and official sources tend to inform the general public that the drugs promote human health. We argue that their being used on a massive scale is actually a medical disaster. The health of many patients would be served better if the drugs they take were replaced by proper forms of diet, but the pharmaceutical industry, the most potent force affecting medication policies, appears to prevent a shift in the balance from over-medicalization towards healthy life styles. The shift should come from government agencies responsible for regulation in the medication market. Policies of these agencies are now a dismal failure. (shrink)

Autoimmune diseases such as rheumatoid arthritis and gastrointestinal disorders such as stomach ulcers are often treated with drugs. NSAIDs, a common treatment in rheumatoid arthritis, may cause stomach ulcers which call for additional medications, notably antacids in the sense of drugs that suppress acid secretion by the stomach. Infection with Helicobacter pylori also plays a role in the ulcers. The infection is typically treated with antibiotics added to antacids. Considering NSAIDs and antacids, we suspect that overmedication is common to the (...) extent that particular diets are a better option. Current research and current treatments with these drugs are also problematic since circadian rhythms are mostly disregarded. All the processes involved in the disorders treated show marked variations in the course of the day. Hence experiments conforming to the guidelines of evidence-based medicine, and treatments in line with them, have outcomes strongly depending on the time factor. This calls for reforms in medicine with fresh inputs from biology. (shrink)

Editor's Note: Over a long period of time, the evil bourgeois reactionary line has created antagonism between two groups of students in schools—antagonism on the basis of one's family background. This antagonism became very obvious during the initial stage of the Cultural Revolution, and has lasted to this day. It has prevented further criticism of the bourgeois reactionary line and hindered further development of the Cultural Revolution.

In December of last year, a few clowns appeared on the grand and spectacular stage of the Great Proletarian Cultural Revolution. These clowns were the reincarnated ghosts from the Capital Red Guard West City, East City, and Haidian Districts Pickets. They viciously attacked Chairman Mao's revolutionary line, engaged in slander on the Central Cultural Revolution Group, called dear Comrade Jiang Qing names, and sabotaged the organizations under the proletarian dictatorship. They provoked violence, created chaos, searched and confiscated the possessions of (...) revolutionary organizations, and spread reactionary declarations. The crimes they committed are simply too numerous to mention. These clowns were none other than the "Capital Red Guards United Action Committee.". (shrink)

The existence of the Language Familiarity Effect (LFE), where talkers of a familiar language are easier to identify than talkers of an unfamiliar language, is well‐documented and uncontroversial. However, a closely related phenomenon known as the Other Accent Effect (OAE), where accented talkers are more difficult to recognize, is less well understood. There are several possible explanations for why the OAE exists, but to date, little data exist to adjudicate differences between them. Here, we begin to address this issue by (...) directly comparing listeners’ recognition of talkers who speak in different types of accents, and by examining both the LFE and OAE in the same set of listeners. Specifically, Canadian English listeners were tested on their ability to recognize talkers within four types of voice line‐ups: Canadian English talkers, Australian English talkers, Mandarin‐accented English talkers, and Mandarin talkers. We predicted that the OAE would be present for talkers of Mandarin‐accented English but not for talkers of Australian English—which is precisely what we observed. We also observed a disconnect between listeners’ confidence and performance across different types of accents; that is, listeners performed equally poorly with Mandarin and Mandarin‐accented talkers, but they were more confident with their performance with the latter group of talkers. The present findings set the stage for further investigation into the nature of the OAE by exploring a range of potential explanations for the effect, and introducing important implications for forensic scientists’ evaluation of ear witness testimony. (shrink)