Drosophila CENP-A Mutations Cause a BubR1- Dependent Early Mitotic Delay without Normal Localization of Kinetochore Components

The centromere/kinetochore complex plays an essential role in cell and organismal viability by ensuring chromosome movements during mitosis and meiosis. The kinetochore also mediates the spindle attachment checkpoint (SAC), which delays anaphase initiation until all chromosomes have achieved bipolar attachment of kinetochores to the mitotic spindle. CENP-A proteins are centromere-specific chromatin components that provide both a structural and a functional foundation for kinetochore formation. Here we show that cells in Drosophila embryos homozygous for null mutations in CENP-A (CID) display an early mitotic delay. This mitotic delay is not suppressed by inactivation of the DNA damage checkpoint and is unlikely to be the result of DNA damage. Surprisingly, mutation of the SAC component BUBR1 partially suppresses this mitotic delay. Furthermore, cid mutants retain an intact SAC response to spindle disruption despite the inability of many kinetochore proteins, including SAC components, to target to kinetochores. We propose that SAC components are able to monitor spindle assembly and inhibit cell cycle progression in the absence of sustained kinetochore localization

The Genetic Basis of Individual-Recognition Signals in the Mouse

SummaryThe major histocompatibility complex (MHC) is widely assumed to be a primary determinant of individual-recognition scents in many vertebrates [1–6], but there has been no functional test of this in animals with normal levels of genetic variation. Mice have evolved another polygenic and highly polymorphic set of proteins for scent communication, the major urinary proteins (MUPs) [7–12], which may provide a more reliable identity signature ([13, 14] and A.L. Sherborne, M.D.T., S. Paterson, F.J., W.E.R.O., P. Stockley, R.J.B., and J.L.H., unpublished data). We used female preference for males that countermark competitor male scents [15–17] to test the ability of wild-derived mice to recognize individual males differing in MHC or MUP type on a variable genetic background. Differences in MHC type were not used for individual recognition. Instead, recognition depended on a difference in MUP type, regardless of other genetic differences between individuals. Recognition also required scent contact, consistent with detection of involatile components through the vomeronasal system [6, 18]. Other differences in individual scent stimulated investigation but did not result in individual recognition. Contrary to untested assumptions of a vertebrate-wide mechanism based largely on MHC variation, mice use a species-specific [12] individual identity signature that can be recognized reliably despite the complex internal and external factors that influence scents [2]. Specific signals for genetic identity recognition in other species now need to be investigated

Differing effects of age and starvation on reproductive performance in Drosophila melanogaster

Successful reproduction requires the completion of many, often condition-dependent, stages, from mate searching and courtship through to sperm transfer, fertilisation and offspring production. Animals can plastically adjust their investment in each stage according to the physical and social environment, their own condition, their future reproductive potential, and the condition of their partner. Here we manipulate age and condition, through a nutritional challenge early or late in life, of both male and female Drosophila melanogaster and measure the effects on courtship, mating, and fitness when paired with a standardized (unmanipulated) partner. Older males were slower to start courting and mating, and courted at a slower rate, but males were indifferent to female age or condition despite older females laying and hatching fewer eggs. Female condition had a substantial effect on mating acceptance rate, which dropped dramatically after starvation, and particularly recent starvation experience. In contrast, male condition had little effect on any of the components of reproductive performance we measured. Intriguingly, we found no evidence for additive or multiplicative effects of ageing and starvation: the only significant interaction between these variables was on male latency to initiate courtship - older males were slower to start courting unless they had experienced starvation early in life. These results indicate that the immediate costs of mating differ between males and females, and that the sexes differ in their perception of the opportunity cost sustained by refusing a mating opportunity. Our results support the idea that ageing has more wide-ranging impact on reproductive behaviours than does nutritional challenge

The Nature of the Warm/Hot Intergalactic Medium I. Numerical Methods, Convergence, and OVI Absorption

We perform a series of cosmological simulations using Enzo, an Eulerian adaptive-mesh refinement, N-body + hydrodynamical code, applied to study the warm/hot intergalactic medium. The WHIM may be an important component of the baryons missing observationally at low redshift. We investigate the dependence of the global star formation rate and mass fraction in various baryonic phases on spatial resolution and methods of incorporating stellar feedback. Although both resolution and feedback significantly affect the total mass in the WHIM, all of our simulations find that the WHIM fraction peaks at z ~ 0.5, declining to 35-40% at z = 0. We construct samples of synthetic OVI absorption lines from our highest-resolution simulations, using several models of oxygen ionization balance. Models that include both collisional ionization and photoionization provide excellent fits to the observed number density of absorbers per unit redshift over the full range of column densities (10^13 cm-2 <= N_OVI <= 10^15 cm^-2). Models that include only collisional ionization provide better fits for high column density absorbers (N_OVI > 10^14 cm^-2). The distribution of OVI in density and temperature exhibits two populations: one at T ~ 10^5.5 K (collisionally ionized, 55% of total OVI) and one at T ~ 10^4.5 K (photoionized, 37%) with the remainder located in dense gas near galaxies. While not a perfect tracer of hot gas, OVI provides an important tool for a WHIM baryon census.Comment: 22 pages, 21 figures, emulateapj, accepted for publication in Ap

Identification of Specific Circular RNA Expression Patterns and MicroRNA Interaction Networks in Mesial Temporal Lobe Epilepsy

Circular RNAs (circRNAs) regulate mRNA translation by binding to microRNAs (miRNAs), and their expression is altered in diverse disorders, including cancer, cardiovascular disease, and Parkinson’s disease. Here, we compare circRNA expression patterns in the temporal cortex and hippocampus of patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) and healthy controls. Nine circRNAs showed significant differential expression, including circRNA-HOMER1, which is expressed in synapses. Further, we identified miRNA binding sites within the sequences of differentially expressed (DE) circRNAs; expression levels of mRNAs correlated with changes in complementary miRNAs. Gene set enrichment analysis of mRNA targets revealed functions in heterocyclic compound binding, regulation of transcription, and signal transduction, which maintain the structure and function of hippocampal neurons. The circRNA–miRNA–mRNA interaction networks illuminate the molecular changes in MTLE, which may be pathogenic or an effect of the disease or treatments and suggests that DE circRNAs and associated miRNAs may be novel therapeutic target

Improving psychological science: further thoughts, reflections and ways forward

Cogent Psychology is a pioneering and dynamic Open Access journal for the psychology community, publishing original research, reviews, and replications that span the full spectrum of psychological inquiry. In 2021, it relaunched with a new Editor-in-Chief and Section Editors with an exciting vision to combine open access publishing with open research practices. As such, the journal welcomes traditional and new article formats, including Registered Reports, Brief Replication Reports, Review Articles, and Brief Reports. This broader range of formats is designed to reflect the evolving nature of psychological research and open science approaches. To the best of our knowledge, no other psychology journal offers such a distinctive combination of article publishing formats. Moreover, we welcome submissions in nine key areas of psychological science: Clinical Psychology, Cognitive & Experimental Psychology, Developmental Psychology, Educational Psychology, Health Psychology, Neuropsychology, Personality & Individual Differences, Social Psychology and Work, Industrial & Organisational Psychology

Differences in trajectories of quality of life according to type of dementia: 6-year longitudinal findings from the IDEAL programme

Background: People with different types of dementia may have distinct symptoms and experiences that affect their quality of life. This study investigated whether quality of life varied across types of dementia and over time. Methods: The participants were 1555 people with mild-to-moderate dementia and 1327 carers from the IDEAL longitudinal cohort study, recruited from clinical services. As many as possible were followed for up to 6 years. Diagnoses included were Alzheimer’s disease, vascular dementia, mixed Alzheimer’s and vascular dementia, Parkinson’s disease dementia, dementia with Lewy bodies, and frontotemporal dementia. Self- and informant-rated versions of the Quality of Life in Alzheimer’s Disease scale were used. A joint model, incorporating a mixed effects model with random effects and a survival model to account for dropout, was used to examine whether quality of life varied by dementia type at the time of diagnosis and how trajectories changed over time. Results: The strongest associations between dementia type and quality of life were seen around the time of diagnosis. For both self-ratings and informant ratings, people with Parkinson’s disease dementia or dementia with Lewy bodies had lower quality of life scores. Over time there was little change in self-rated scores across all dementia types (− 0.15 points per year). Informant-rated scores declined over time (− 1.63 points per year), with the greatest decline seen in ratings by informants for people with dementia with Lewy bodies (− 2.18 points per year). Conclusions: Self-rated quality of life scores were relatively stable over time whilst informant ratings showed a steeper decline. People with Parkinson’s disease dementia or dementia with Lewy bodies report particularly low levels of quality of life, indicating the importance of greater attention to the needs of these groups

Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8-10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy

Cosmic Origins Spectrograph and FUSE Observations of T ~ 10^5 K Gas In A Nearby Galaxy Filament

We present a detection of a broad Ly-alpha absorber (BLA) with a matching O VI line in the nearby universe. The BLA is detected at z = 0.01028 in the high S/N spectrum of Mrk 290 obtained using the Cosmic Origins Spectrograph. The Ly-alpha absorption has two components, with b(HI) = 55 +/- 1 km/s and b(HI) = 33 +/- 1 km/s, separated in velocity by v ~ 115 km/s. The O VI, detected by FUSE at z = 0.01027, has a b(OVI) = 29 +/- 3 km/s and is kinematically well aligned with the broader HI component. The different line widths of the BLA and OVI suggest a temperature of T = 1.4 x 10^5 K in the absorber. The observed line strength ratios and line widths favor an ionization scenario in which both ion-electron collisions and UV photons contribute to the ionization in the gas. Such a model requires a low-metallicity of -1.7 dex, ionization parameter of log U ~ -1.4, a large total hydrogen column density of N(H) ~ 4 x 10^19 cm^-2, and a path length of 400 kpc. The line of sight to Mrk 290 intercepts at the redshift of the absorber, a megaparsec scale filamentary structure extending over 20 deg in the sky, with several luminous galaxies distributed within 1.5 Mpc projected distance from the absorber. The collisionally ionized gas in this absorber is likely tracing a shock-heated gaseous structure, consistent with a few different scenarios for the origin, including an over-dense region of the WHIM in the galaxy filament or highly ionized gas in the extended halo of one of the galaxies in the filament. In general, BLAs with metals provide an efficient means to study T ~ 10^5 - 10^6 K gas in galaxy halos and in the intergalactic medium. A substantial fraction of the baryons "missing" from the present universe is predicted to be in such environments in the form of highly ionized plasma.Comment: Astrophysical Journal Accepte