Ribosome Profiling and Mass Spectrometry Reveal Widespread Mitochondrial Translation Defects in a Striatal Cell Model of Huntington Disease.

Huntington disease (HD) is caused by an expanded polyglutamine mutation in huntingtin (mHTT) that promotes prominent atrophy in the striatum and subsequent psychiatric, cognitive deficits, and choreiform movements. Multiple lines of evidence point to an association between HD and aberrant striatal mitochondrial functions; however, the present knowledge about whether (or how) mitochondrial mRNA translation is differentially regulated in HD remains unclear. We found that protein synthesis is diminished in HD mitochondria compared to healthy control striatal cell models. We utilized ribosome profiling (Ribo-Seq) to analyze detailed snapshots of ribosome occupancy of the mitochondrial mRNA transcripts in control and HD striatal cell models. The Ribo-Seq data revealed almost unaltered ribosome occupancy on the nuclear-encoded mitochondrial transcripts involved in oxidative phosphorylation (SDHA, Ndufv1, Timm23, Tomm5, Mrps22) in HD cells. By contrast, ribosome occupancy was dramatically increased for mitochondrially encoded oxidative phosphorylation mRNAs (mt-Nd1, mt-Nd2, mt-Nd4, mt-Nd4l, mt-Nd5, mt-Nd6, mt-Co1, mt-Cytb, and mt-ATP8). We also applied tandem mass tag-based mass spectrometry identification of mitochondrial proteins to derive correlations between ribosome occupancy and actual mature mitochondrial protein products. We found many mitochondrial transcripts with comparable or higher ribosome occupancy, but diminished mitochondrial protein products, in HD. Thus, our study provides the first evidence of a widespread dichotomous effect on ribosome occupancy and protein abundance of mitochondria-related genes in HD.

Notch signaling determines cell-fate specification of the two main types of vomeronasal neurons of rodents.

The ability of terrestrial vertebrates to find food and mating partners, and to avoid predators, relies on the detection of chemosensory information. Semiochemicals responsible for social and sexual behaviors are detected by chemosensory neurons of the vomeronasal organ (VNO), which transmits information to the accessory olfactory bulb. The vomeronasal sensory epithelium of most mammalian species contains a uniform vomeronasal system; however, rodents and marsupials have developed a more complex binary vomeronasal system, containing vomeronasal sensory neurons (VSNs) expressing receptors of either the V1R or V2R family. In rodents, V1R/apical and V2R/basal VSNs originate from a common pool of progenitors. Using single cell RNA-sequencing, we identified differential expression of Notch1 receptor and Dll4 ligand between the neuronal precursors at the VSN differentiation dichotomy. Our experiments show that Notch signaling is required for effective differentiation of V2R/basal VSNs. In fact, Notch1 loss of function in neuronal progenitors diverts them to the V1R/apical fate, whereas Notch1 gain of function redirects precursors to V2R/basal. Our results indicate that Notch signaling plays a pivotal role in triggering the binary differentiation dichotomy in the VNO of rodents.

Cell cycle perturbation uncouples mitotic progression and invasive behavior in a post-mitotic cell.

The acquisition of the post-mitotic state is crucial for the execution of many terminally differentiated cell behaviors during organismal development. However, the mechanisms that maintain the post-mitotic state in this context remain poorly understood. To gain insight into these mechanisms, we used the genetically and visually accessible model of C. elegans anchor cell (AC) invasion into the vulval epithelium. The AC is a terminally differentiated uterine cell that normally exits the cell cycle and enters a post-mitotic state before initiating contact between the uterus and vulva through a cell invasion event. Here, we set out to identify the set of negative cell cycle regulators that maintain the AC in this post-mitotic, invasive state. Our findings revealed a critical role for CKI-1 (p21CIP1/p27KIP1) in redundantly maintaining the post-mitotic state of the AC, as loss of CKI-1 in combination with other negative cell cycle regulators-including CKI-2 (p21CIP1/p27KIP1), LIN-35 (pRb/p107/p130), FZR-1 (Cdh1/Hct1), and LIN-23 (ß-TrCP)-resulted in proliferating ACs. Remarkably, time-lapse imaging revealed that these ACs retain their ability to invade. Upon examination of a node in the gene regulatory network controlling AC invasion, we determined that proliferating, invasive ACs do so by maintaining aspects of pro-invasive gene expression. We therefore report that the requirement for a post-mitotic state for invasive cell behavior can be bypassed following direct cell cycle perturbation.

A tale of two functions: C-reactive protein complement-ary structures and their role in rheumatoid arthritis.

C-reactive protein (CRP) is an inflammatory biomarker with associated clinical utility in a wide number of inflammatory disorders, including rheumatoid arthritis (RA). The interaction of CRP with pro-inflammatory cytokines has been explored before, however its role in complement regulation is more subtle, where CRP is capable of both up and downregulating the complement cascade. CRP is produced in a pentameric form and can dissociate to a monomeric form in circulation which has significant implications for its ability to interact with receptors and binding partners. This dichotomy of CRP structure could have relevance in patients with RA who have significant dysfunction in their complement cascade and also widely varying CRP levels including at the time of flare. This review aims to bring together current knowledge of CRP in its various forms, its effects on complement function and how this could influence pathology in the context of RA.

Lateral root branching: evolutionary innovations and mechanistic divergence in land plants.

The root system architecture in plants is a result of multiple evolutionary innovations over time in response to changing environmental cues. Dichotomy and endogenous lateral branching in the roots evolved in lycophytes lineage but extant seed plants use lateral branching instead. This has led to the development of complex and adaptive root systems, with lateral roots playing a key role in this process exhibiting conserved and divergent features in different plant species. The study of lateral root branching in diverse plant species can shed light on the orderly yet distinct nature of postembryonic organogenesis in plants. This insight provides an overview of the diversity in lateral root (LR) development in various plant species during the evolution of root system in plants.

The sialyl-Tn antigen synthase genes regulates migration-proliferation dichotomy in prostate cancer cells under hypoxia.

A low-oxygen (hypoxia) tumor microenvironment can facilitate chemotherapy and radiation therapy resistance in tumors and is associated with a poor prognosis. Hypoxia also affects PCa (prostate cancer) phenotype transformation and causes therapeutic resistance. Although O-glycans are known to be involved in the malignancy of various cancers under hypoxia, the expression and function of O-glycans in PCa are not well understood. In this study, the saccharide primer method was employed to analyze O-glycan expression in PCa cells. Results showed that the expression of sTn antigens was increased in PCa cells under hypoxia. Furthermore, it was found that ST6GalNAc1, the sTn antigen synthase gene, was involved in the migration-proliferation dichotomy and drug resistance in PCa cells under hypoxia. The results of this study will contribute to the development of novel diagnostic markers and drug targets for PCa under hypoxia.

A Comprehensive Approach for Detecting Brake Pad Defects Using Histogram and Wavelet Features with Nested Dichotomy Family Classifiers.

The brake system requires careful attention for continuous monitoring as a vital module. This study specifically focuses on monitoring the hydraulic brake system using vibration signals through experimentation. Vibration signals from the brake pad assembly of commercial vehicles were captured under both good and defective conditions. Relevant histograms and wavelet features were extracted from these signals. The selected features were then categorized using Nested dichotomy family classifiers. The accuracy of all the algorithms during categorization was evaluated. Among the algorithms tested, the class-balanced nested dichotomy algorithm with a wavelet filter achieved a maximum accuracy of 99.45%. This indicates a highly effective method for accurately categorizing the brake system based on vibration signals. By implementing such a monitoring system, the reliability of the hydraulic brake system can be ensured, which is crucial for the safe and efficient operation of commercial vehicles in the market.

Two-Eyed Seeing as a strategic dichotomy for decolonial nursing knowledge development and practice.

The profession of nursing has recognized the need for contextual and relational frameworks to inform knowledge development. Two-Eyed Seeing is a framework developed by Mi'kmaw Elders to respectfully engage with Indigenous and non-Indigenous knowledges. Some scholars and practitioners, however, are concerned that Two-Eyed Seeing re-instantiates dichotomized notions regarding Western and Indigenous knowledges. As dichotomies and binaries are often viewed as polarizing devices for nursing knowledge development, this paper explores the local worldviews in which Two-Eyed Seeing emerged, proposing that the onto-epistemological and axiological 'roots' of the framework are antithetical to divisiveness, paradoxically asserting space for the dichotomy to stand. Two-Eyed Seeing, if understood as a relational, decolonial praxis, could fundamentally change the way nursing scholarship and practice operate by facilitating space for diverse knowledges, ways of being, doing and relating. In this paper, considerations for nursing scholarship and practice, as well as recommendations to support the uptake of Two-Eyed Seeing are explored. The authors assert that conceptual divisiveness, dichotomization and exclusion can be mitigated if nursing is informed by contextual knowledge, seeks to enact accountable partnerships with Indigenous knowledge holders, and holds the Mi'kmaq worldview upon which the concept developed in positive regard.

Multituberculate Mammals Show Evidence of a Life History Strategy Similar to That of Placentals, Not Marsupials.

AbstractThe remarkable evolutionary success of placental mammals has been partly attributed to their reproductive strategy of prolonged gestation and birthing of relatively precocial, quickly weaned neonates. Although this strategy was conventionally considered derived relative to that of marsupials with highly altricial neonates and long lactation periods, mounting evidence has challenged this view. Until now the fossil record has been relatively silent on this debate, but here we find that proportions of different bone tissue microstructures in the femoral cortices of small extant marsupials and placentals correlate with length of lactation period, allowing us to apply this histological correlate of reproductive strategies to Late Cretaceous and Paleocene members of Multituberculata, an extinct mammalian clade that is phylogenetically stemward of Theria. Multituberculate bone histology closely resembles that of placentals, suggesting that they had similar life history strategies. A stem-therian clade exhibiting evidence of placental-like life histories supports the hypothesis that intense maternal-fetal contact characteristic of placentals is ancestral for therians. Alternatively, multituberculates and placentals may have independently evolved prolonged gestation and abbreviated lactation periods. Our results challenge the hypothesis that the rise of placental mammals was driven by unique life history innovations and shed new light on early mammalian diversification.

Dichotomy in Growth and Invasion from Low- to High-Grade Glioma Cellular Variants.

Glial dysfunction outraging CNS plasticity and integrity results in one of the most dangerous cancers, namely glioma, featuring little median survival period and high recurrence. The hallmark properties of proliferation, invasion and angiogenesis with the infiltrated macrophages in glioma are expected to be tightly coupled or cross-linked, but not properly related so far. The present study is aimed to find a relationship between this featured quadrangle from lower to higher grades (HG) of post-operative glioma tissues and their invading subsets. Elevated Ki67-associated proliferation in lower grades (LG) was supported with VEGF dependent angiogenic maintenance which found a decrease unlikely in HG. In contrast, MMP 2 and 9-associated invasions augmented high in HG with the dominant presence of CD204+ M2 polarized macrophages and a general increase in global DNMT1-associated methylation. Marked differences found in ECM invading cellular subsets of HG showing high proliferative capacity indicating rationally for recurrence, contrasting the nature of gross tumor tissue of the same grade. Thus in LG, the neoplastic lesion is more inclined to its growth while in higher grade more disposed towards tissue wreckage in support with cellular environmental milieu whereas the cellular variants and subsets of invaded cells showed different trends. Therefore, some operational dichotomy or coupling among cellular variants in glioma is active in determining its low- to high-grade transition and aggressive progression.

Find extra options or reason badly: An investigation of children's reasoning with incompatibility statements.

The false dilemma or dichotomy is a logical fallacy that occurs when interlocuters accept the premises in an incompatibility statement as being jointly exhaustive (i.e., leaving no third option), whereas that is in fact not the case. Brisson et al. [Memory & Cognition (2018), Vol. 46, pp. 657-670] investigated this fallacy in an adult sample and discovered a content effect that influenced participants' performance. The current study aimed to elaborate on these findings by establishing whether similar patterns could be observed with children. A number of age-appropriate incompatibility premises were constructed. For every item, four different inferential problems were presented (Affirm First, Affirm Second, Deny First, and Deny Second) with three potential answers to choose from (X, not X, or uncertainty regarding X). A sample of 192 volunteer children, with ages ranging from 8 to 13 years, was collected. Statistical analysis showed no significant effect for participants' age but did reveal main effects for premise validity and the amount of available "third options" (possibilities outside of the presented dichotomy). These results are a clear replication of the general effects on adults found by Brisson et al. Affirm inferences were also easy for children, Deny inferences were difficult (even more so than for adults), and content had a profound effect on participants' performance. Whenever more third options could be generated, children were less likely to fall into the false dilemma fallacy. Our findings thus further support the idea that reasoning with incompatibilities is influenced by the same semantic retrieval processes that have been previously related to human conditional reasoning.

Beyond clinical trials: Extending the role of the clinical research nurse into social care and homeless research.

AIM: Clinical research nurses work at the fulcrum of clinical trials with clearly defined roles and responsibilities. In England, the National Institute for Health Research (the main funder of health research) has broadened its scope to encompass social care research. The expectation is that clinical research nurses will expand their skill set to support these new studies, many of which will employ qualitative and mixed methods. This discussion paper explores the challenges of facilitating this clinical academic workforce development through a case study of a homeless health and social care research project. This was one of the first studies to engage clinical research nurses in this new and expanded role. BACKGROUND: Much of what is known about the research nurse workforce has been generated through studies of clinical trials in oncology. The 'caring-recruiting' dichotomy has been used as a heuristic device for identifying workforce issues that can impact on study delivery such as how intense pressure to recruit study participants leads to low job satisfaction. DESIGN: This case study reflects on the authors' experiences of employing a clinical research nurse in a social care research project concerned with the discharge of homeless people from hospital. The 'caring-recruiting' dichotomy is used to generate new information about the relationship between workforce development and the successful delivery of social care research. CONCLUSION: The case study illuminates how social care research can generate different pressures and ethical challenges for research nurses. The time and skill it took to recruit study participants identified as 'hard to reach' was suggestive of the need to move beyond performance measures that prioritise recruitment metrics. The need for different types of staff supervision and training was also warranted as supporting study participants who were homeless was often distressing, leading to professional boundary issues. RELEVANCE TO WORKFORCE DEVELOPMENT: This study highlights that performance management, training and supervisory arrangements must be tailored to the characteristics of each new study coming onto the portfolio to ensure research nurses are fully supported in this new and expanded role.

Stress-Inducible Gene Atf3 Dictates a Dichotomous Macrophage Activity in Chemotherapy-Enhanced Lung Colonization.

Previously, we showed that chemotherapy paradoxically exacerbated cancer cell colonization at the secondary site in a manner dependent on Atf3, a stress-inducible gene, in the non-cancer host cells. Here, we present evidence that this phenotype is established at an early stage of colonization within days of cancer cell arrival. Using mouse breast cancer models, we showed that, in the wild-type (WT) lung, cyclophosphamide (CTX) increased the ability of the lung to retain cancer cells in the vascular bed. Although CTX did not change the WT lung to affect cancer cell extravasation or proliferation, it changed the lung macrophage to be pro-cancer, protecting cancer cells from death. This, combined with the initial increase in cell retention, resulted in higher lung colonization in CTX-treated than control-treated mice. In the Atf3 knockout (KO) lung, CTX also increased the ability of lung to retain cancer cells. However, the CTX-treated KO macrophage was highly cytotoxic to cancer cells, resulting in no increase in lung colonization-despite the initial increase in cell retention. In summary, the status of Atf3 dictates the dichotomous activity of macrophage: pro-cancer for CTX-treated WT macrophage but anti-cancer for the KO counterpart. This dichotomy provides a mechanistic explanation for CTX to exacerbate lung colonization in the WT but not Atf3 KO lung.

Interannual variation in riparian vegetation cover and its relationship with river flow under a high level of human intervention: an example from the Yongding River Basin.

Riparian vegetation cover is significantly affected by a river's hydrological conditions. Especially in arid and semiarid areas, low flow will degrade riparian vegetation, and recent, intensive human activities in the Yongding River Basin have caused a sharp decrease in river flow. We analyzed interannual change in riparian vegetation, river flow effects, and land use on vegetation coverage using the 40 years (1977-2016) of remote sensing images and river flow, combined with 38 years (1980-2018) of land use data. The normalized difference vegetation index (NDVI) was used to determine vegetation cover in five different categories: extremely low, low, medium, high, and extremely high based on the pixel dichotomy model. The weighted average was calculated to obtain vegetation cover trends. We show that riparian vegetation cover from four rivers increased. Compared with 1977, in 2016, combined high and extremely high vegetation covers at the Dongyang, Yang, Sanggan, and Yongding Rivers increased by 20.3%, 26.7%, 50.0%, and 39.2%, respectively. High (R = -0.976, P < 0.01) and extremely high (R = -0.762, P < 0.05) vegetation covers are negatively correlated with flow in the Yongding River. The high vegetation cover of the Sanggan River riparian zone is negatively correlated with river flow (R = -0.683, P < 0.05). In the Dongyang and Sanggan Rivers, land use analysis in the riparian zone showed that change in cultivated land, grassland, and forest were significantly correlated with high and extremely high vegetation cover. The abundant cultivated land and restoration activities are likely responsible for the increase of riparian vegetation cover as river flows decline.

Copper-Mediated Dichotomic Borylation of Alkyne Carbonates: Stereoselective Access to (E)-1,2-Diborylated 1,3-Dienes versus Traceless Monoborylation Affording α-Hydroxyallenes.

A mild copper-mediated protocol has been developed for borylation of alkynyl cyclic carbonates. Depending on the nature of the borylating reaction partner, either stereoselective diborylation of the propargylic surrogate takes place, providing convenient access to (E)-1,2-borylated 1,3-dienes, or traceless monoborylation occurs, which leads to α-hydroxyallenes as the principal product. The dichotomy in this borylation protocol has been scrutinized by several control experiments, illustrating that a relatively small change in the diboron(4) reagent allows for competitive alcohol-assisted protodemetalation to forge an α-hydroxyallene product under ambient conditions.

Prevalence of placental dichotomy, fetal cardiomegaly and starry-sky liver in twin anemia-polycythemia sequence.

OBJECTIVE: To investigate the prevalence of three additional ultrasound markers, placental dichotomy, cardiomegaly and 'starry-sky' liver, in monochorionic twin pregnancy with twin anemia-polycythemia sequence (TAPS). METHODS: All monochorionic twin pregnancies, diagnosed antenatally with TAPS at our center between 2006 and 2019, were reviewed retrospectively for the presence of placental dichotomy, cardiomegaly in the donor twin and a starry-sky liver in the recipient twin. TAPS was diagnosed based on delta middle cerebral artery (MCA) peak systolic velocity (PSV) > 0.5 multiples of the median. The primary outcome was the prevalence of placental dichotomy, cardiomegaly, starry-sky liver and at least one of these markers in both spontaneous and post-laser TAPS. The secondary outcome was the prevalence of these ultrasound markers according to the antenatal stage of TAPS. RESULTS: A total of 91 monochorionic twin pregnancies with TAPS were eligible for analysis. Placental dichotomy was observed in 44% (40/91) of TAPS cases. A total of 70% (64/91) of the TAPS donors developed cardiomegaly and a starry-sky liver was identified in 66% (53/80) of the TAPS recipients. The prevalence of cardiomegaly and starry-sky liver was roughly comparable between spontaneous and post-laser TAPS (69% (33/48) vs 72% (31/43) and 64% (25/39) vs 68% (28/41), respectively). Pregnancies with spontaneous TAPS showed a higher prevalence of placental dichotomy compared with post-laser TAPS (63% (30/48) vs 23% (10/43)). At least one of the three ultrasound markers was detected in 86% (78/91) of TAPS cases, meaning that 14% (13/91) of cases presented solely with discordant MCA-PSV values. There was a trend towards increased prevalence of all three ultrasound markers with increasing antenatal TAPS stage. CONCLUSIONS: Placental dichotomy, fetal cardiomegaly and a starry-sky liver are commonly found in TAPS pregnancy. Investigating the presence of these ultrasound markers can be of additional help in improving antenatal detection of TAPS in monochorionic twin pregnancy. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Simple nuclear C*-algebras not isomorphic to their opposites.

We show that it is consistent with Zermelo-Fraenkel set theory with the axiom of choice (ZFC) that there is a simple nuclear nonseparable [Formula: see text]-algebra, which is not isomorphic to its opposite algebra. We can furthermore guarantee that this example is an inductive limit of unital copies of the Cuntz algebra [Formula: see text] or of the canonical anticommutation relations (CAR) algebra.

The P Value Line Dance: When Does the Music Stop?

When should a trial stop? Such a seemingly innocent question evokes concerns of type I and II errors among those who believe that certainty can be the product of uncertainty and among researchers who have been told that they need to carefully calculate sample sizes, consider multiplicity, and not spend P values on interim analyses. However, the endeavor to dichotomize evidence into significant and nonsignificant has led to the basic driving force of science, namely uncertainty, to take a back seat. In this viewpoint we discuss that if testing the null hypothesis is the ultimate goal of science, then we need not worry about writing protocols, consider ethics, apply for funding, or run any experiments at all-all null hypotheses will be rejected at some point-everything has an effect. The job of science should be to unearth the uncertainties of the effects of treatments, not to test their difference from zero. We also show the fickleness of P values, how they may one day point to statistically significant results; and after a few more participants have been recruited, the once statistically significant effect suddenly disappears. We show plots which we hope would intuitively highlight that all assessments of evidence will fluctuate over time. Finally, we discuss the remedy in the form of Bayesian methods, where uncertainty leads; and which allows for continuous decision making to stop or continue recruitment, as new data from a trial is accumulated.

Beyond the state/market dichotomy: Institutional innovations in China's electricity industry reform.

China's electricity industry has gone through three decades of market-oriented reform, and this process is often interpreted as a tug of war between marketization and state control. However, this paper argues that a dichotomous conception of the state-market relationship cannot explain the evolution and complexity of China's electricity governance. By systematically analyzing the institutions of China's electricity reform, this paper identifies a sequence of innovations that align well with both the history of China's economic transition and the institutional underpinnings of China's economic governance. Also, by interpreting the respective roles of state and market in China's reformed electricity industry, this paper shows that state control and marketization are complementary rather than contradictory, and that their complementarity is best exercised in addressing issues like market fragmentation and renewable energy curtailment. Moreover, this paper presents two case studies - both on China's most recent electricity market experimentation - to elaborate how state and market jointly serve sectoral functions as well as broader economic and political goals.

120th Anniversary of the Kraepelinian Dichotomy of Psychiatric Disorders.

PURPOSE OF REVIEW: Emil Kraepelin, in 1899, proposed a dichotomy of psychiatric disorders into "dementia praecox," further called schizophrenia, and "manisch-depressives Irresein," now conceptualized as a bipolar disorder. The purpose of the review is to show both similarities and differences between disorders involved in this dichotomy, speaking for and against the idea. RECENT FINDINGS: On the molecular genetic side, there are data for both a genetic overlap and genetic differences between these two illnesses. Among pharmacological treatment, lithium, valproates, and carbamazepine present evidence for Kraepelinian dichotomy while atypical antipsychotics speak against this. The recent results for similarities and differences in the immune system, cognitive functions, and neurodevelopmental mechanisms have also been presented and discussed. As of 2019, the Kraepelinian dichotomy has been still partly valid although the results of recent clinical, neurobiological, and pharmacological studies provided a large number of data for an intermediate space between schizophrenia and bipolar disorder.