Brief stimuli cast a persistent long-term trace in visual cortex

Visual processing is strongly influenced by the recent stimulus history - a phenomenon termed adaptation. Prominent theories cast adaptation as a consequence of optimized encoding of visual information, by exploiting the temporal statistics of the world. However, this would require the visual system to track the history of individual briefly experienced events, within a stream of visual input, to build up statistical representations over longer timescales. Here, using an openly available dataset from the Allen Brain Observatory, we show that neurons in the early visual cortex of the mouse indeed maintain long-term traces of individual past stimuli that persist despite the presentation of several intervening stimuli, leading to long-term and stimulus-specific adaptation over dozens of seconds. Long-term adaptation was selectively expressed in cortical, but not in thalamic neurons, which only showed short-term adaptation. Early visual cortex thus maintains concurrent stimulus-specific memory traces of past input, enabling the visual system to build up a statistical representation of the world to optimize the encoding of new information in a changing environment.SIGNIFICANCE STATEMENTIn the natural world, previous sensory input is predictive of current input over multi-second timescales. The visual system could exploit these predictabilities by adapting current visual processing to the long-term history of visual input. However, it is unclear whether the visual system can track the history of individual briefly experienced images, within a stream of input, to build up statistical representations over such long timescales. Here, we show that neurons in early visual cortex of the mouse brain exhibit remarkably long-term adaptation to brief stimuli, persisting over dozens of seconds, and despite the presentation of several intervening stimuli. The visual cortex thus maintains long-term traces of individual briefly experienced past images, enabling the formation of statistical representations over extended timescales

Alternative antibody for the detection of CA125 antigen: a European multicenter study for the evaluation of the analytical and clinical performance of the Access (R) OV Monitor assay on the UniCel (R) Dxl 800 Immunoassay System

Background: Cancer antigen CA125 is known as a valuable marker for the management of ovarian cancer. Methods: The analytical and clinical performance of the Access OV Monitor Immunoassay System (Beckman Coulter) was evaluated at five different European sites and compared with a reference system, defined as CA125 on the Elecsys System (Roche Diagnostics). Results: Total imprecision (%CV) of the OV Monitor ranged between 3.1% and 8.8%, and inter-laboratory reproducibility between 4.7% and 5.0%. Linearity upon dilution showed a mean recovery of 100% (SD+8.1%). Endogenous interferents had no influence on OV Monitor levels (mean recoveries: hemoglobin 107%, bilirubin 103%, triglycericles 103%). There was no high-dose hook effect up to 27,193 kU/L. Clinical performance investigated in sera from 1811 individuals showed a good correlation between the Access OV Monitor and Elecsys CA125 (R = 0.982, slope = 0.921, intercept = + 1.951). OV Monitor serum levels were low in healthy individuals (n = 267, median = 9.7 kU/L, 95th percentile = 30.8 kU/L), higher in individuals with various benign diseases (n = 549, medians = 10.9-16.4 kU/L, 95th percentiles = 44.2-355 kU/L) and even higher in individuals suffering from various cancers (n = 995, medians= 12.4-445 kU/L; 95th percentiles = 53.4-4664 kU/L). Optimal diagnostic accuracy for cancer detection against the relevant benign control group by the OV Monitor was found for ovarian cancer {[}area under the curve (AUC) 0.898]. Results for the reference CA125 assay were comparable (AUC 0.899). Conclusions: The Access OV Monitor provides very good methodological characteristics and demonstrates an excellent analytical and clinical correlation with Elecsys CA125. The best diagnostic accuracy for the OV Monitor was found in ovarian cancer. Our results also suggest a clinical value of the OV Monitor in other cancers

Progression-dependent altered metabolism in osteosarcoma resulting in different nutrient source dependencies

Osteosarcoma (OS) is a primary malignant bone tumor and OS metastases are mostly found in the lung. The limited understanding of the biology of metastatic processes in OS limits the ability for effective treatment. Alterations to the metabolome and its transformation during metastasis aids the understanding of the mechanism and provides information on treatment and prognosis. The current study intended to identify metabolic alterations during OS progression by using a targeted gas chromatography mass spectrometry approach. Using a female OS cell line model, malignant and metastatic cells increased their energy metabolism compared to benign OS cells. The metastatic cell line showed a faster metabolic flux compared to the malignant cell line, leading to reduced metabolite pools. However, inhibiting both glycolysis and glutaminolysis resulted in a reduced proliferation. In contrast, malignant but non-metastatic OS cells showed a resistance to glycolytic inhibition but a strong dependency on glutamine as an energy source. Our in vivo metabolic approach hinted at a potential sex-dependent metabolic alteration in OS patients with lung metastases (LM), although this will require validation with larger sample sizes. In line with the in vitro results, we found that female LM patients showed a decreased central carbon metabolism compared to metastases from male patients

Acromegaly, Mr Punch and caricature.

The origin of Mr Punch from the Italian Pulcinella of the Commedia dell'arte is well known but his feature, large hooked nose, protruding chin, kyphosis and sternal protrusion all in an exaggerated form also suggest the caricature of an acromegalic. This paper looks at the physical characteristics of acromegaly, the origin of Mr Punch and the development of caricature linking them together in the acromegalic caricature that now has a life of its own

The significance of nitrogen fixation to new production during early summer in the Baltic Sea.

Rates of dinitrogen (N2) fixation and primary production were measured during two 9 day transect cruises in the Baltic proper in June–July of 1998 and 1999. Assuming that the early phase of the bloom of cyanobacteria lasted a month, total rates of N2 fixation contributed 15 mmol N m−2 (1998) and 33 mmol N m−2 (1999) to new production (sensu Dugdale and Goering, 1967). This constitutes 12–26% more new N than other annual estimates (mid July–mid October) from the same region. The between-station variability observed in both total N2 fixation and primary productivity greatly emphasizes the need for multiple stations and seasonal sampling strategies in biogeochemical studies of the Baltic Sea. The majority of new N from N2 fixation was contributed by filamentous cyanobacteria. On average, cyanobacterial cells >20 µm were able to supply a major part of their N requirements for growth by N2 fixation in both 1998 (73%) and 1999 (81%). The between-station variability was high however, and ranged from 28–150% of N needed to meet the rate of C incorporation by primary production. The molar C:N rate incorporation ratio (C:NRATE) in filamentous cyanobacterial cells was variable (range 7–28) and the average almost twice as high as the Redfield ratio (6.6) in both years. Since the molar C:N mass ratio (C:NMASS) in filamentous cyanobacterial cells was generally lower than C:NRATE at a number of stations, we suggest that the diazotrophs incorporated excess C on a short term basis (carbohydrate ballasting and buoyancy regulation), released nitrogen or utilized other regenerated sources of N nutrients. Measured rates of total N2 fixation contributed only a minor fraction of 13% (range 4–24) in 1998 and 18% (range 2–45) in 1999 to the amount of N needed for the community primary production. An average of 9 and 15% of total N2 fixation was found in cells <5 µm. Since cells <5 µm did not show any detectable rates of N2 fixation, the 15N-enrichment could be attributed to regenerated incorporation of dissolved organic N (DON) and ammonium generated from larger diazotroph cyanobacteria. Therefore, N excretion from filamentous cyanobacteria may significantly contribute to the pool of regenerated nutrients used by the non-diazotroph community in summer. Higher average concentrations of regenerated N (ammonium) coincided with higher rates of N2 fixation found during the 1999 transect and a higher level of 15N-enrichment in cells <5 µm. A variable but significant fraction of total N2 fixation (1–10%) could be attributed to diazotrophy in cells between 5–20 µm

Acute phase reaction to LPS induced mastitis in early lactation dairy cows fed nitrogenic, glucogenic or lipogenic diets.

The availability of certain macronutrients is likely to influence the capacity of the immune system. Therefore, we investigated the acute phase response to intramammary (i.mam.) LPS in dairy cows fed either a nitrogenic diet (n = 10) high in crude protein, a glucogenic diet (n = 11) high in carbohydrates and glucogenic precursors, or a lipogenic diet (n = 11) high in lipids. Thirty-two dairy cows were fed one of the dietary concentrates directly after calving until the end of trial at 27 ± 3 DIM (mean ± SD). In wk 3 of lactation, 20 µg of LPS was i.mam. injected in one quarter, and sterile NaCl (0.9%) in the contralateral quarter. Milk samples of the LPS challenged and control quarter were taken hourly from before (0 h) until 9 h after LPS challenge, and analyzed for milk amyloid A (MAA), haptoglobin (Hp), and IL-8. In addition, blood samples were taken in the morning, and composite milk samples at morning and evening milkings from 1 d before until 3 d after LPS challenge, and again on d 9 to determine serum amyloid A (SAA) and Hp in blood, and MAA and Hp in milk. The mRNA abundance of various immunological and metabolic factors in blood leukocytes was quantified by RT-qPCR from samples taken at -18 h, -1 h, 6 h, 9 h and 23 h relative to LPS application. The dietary concentrates did not affect any of the parameters in blood, milk, and leukocytes. The IL-8 was increased from 2 h, Hp from 2 to 3 h, and MAA from 6 h relative to the LPS administration in the milk of the challenged quarter and remained elevated until 9 h. The MAA and Hp were also increased at 9 h after LPS challenge in whole udder composite milk, whereas Hp and SAA in blood were increased only after 23 h. All 4 parameters were decreased again on d 9. Similar for all groups, the mRNA abundance of Hp and the heat shock protein family A (HSP70) increased after the LPS challenge, while the mRNA expression of the tumor necrosis factor α (TNF) and the leukocyte integrin β 2 subunit (CD18) were decreased at 6 h after LPS challenge. The glucose transporter (GLUT)1 mRNA abundance decreased after LPS, whereas that of the GLUT3 increased, and that of the GLUT4 was not detectable. The mRNA abundance of GAPDH was increased at 9 h after LPS and remained elevated. The APP response was detected earlier in milk compared with blood indicating mammary production. However, immunological responses to LPS were not affected by the availability of specific macronutrients provided by the different diets

DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity

BACKGROUND: Epigenetic modifications in mammalian DNA are commonly manifested by DNA methylation. In the stomach, altered DNA methylation patterns have been observed following chronic Helicobacter pylori infections and in gastric cancer. In the context of epigenetic regulation, the regional nature of the stomach has been rarely considered in detail. RESULTS: Here, we establish gastric mucosa derived primary cell cultures as a reliable source of native human epithelium. We describe the DNA methylation landscape across the phenotypically different regions of the healthy human stomach, i.e., antrum, corpus, fundus together with the corresponding transcriptomes. We show that stable regional DNA methylation differences translate to a limited extent into regulation of the transcriptomic phenotype, indicating a largely permissive epigenetic regulation. We identify a small number of transcription factors with novel region-specific activity and likely epigenetic impact in the stomach, including GATA4, IRX5, IRX2, PDX1 and CDX2. Detailed analysis of the Wnt pathway reveals differential regulation along the craniocaudal axis, which involves non-canonical Wnt signaling in determining cell fate in the proximal stomach. By extending our analysis to pre-neoplastic lesions and gastric cancers, we conclude that epigenetic dysregulation characterizes intestinal metaplasia as a founding basis for functional changes in gastric cancer. We present insights into the dynamics of DNA methylation across anatomical regions of the healthy stomach and patterns of its change in disease. Finally, our study provides a well-defined resource of regional stomach transcription and epigenetics. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-022-01406-4

Effect of different dietary regimens at dry-off on performance, metabolism, and immune system in dairy cows.

Concentrate withdrawal and feed restriction are commonly used to reduce milk production and to facilitate dry-off, but may impair immune function in dairy cows. We investigated the effect of feed rations providing different amounts of nutrients in combination with feed restriction on performance, endocrine, and metabolic responses, as well as on leukocyte function before and after abrupt dry-off. Forty-three cows were studied from d 12 before until d 6 after dry-off (56 d before scheduled calving). Cows were fed experimental concentrates rich in crude protein (nitrogenic, n = 14), glucogenic precursors (glucogenic, n = 14), or lipids (lipogenic, n = 15). On d 3 before dry-off, total feed allowance was restricted to 50% in half of the animals of each dietary group, whereas feed allowance remained unchanged in the other animals. Performance parameters (milk yield, milk composition, and dry matter intake) were recorded, and daily blood and milk samples were taken and analyzed for various metabolic and endocrine parameters. Additionally, activity and mRNA abundance of several genes in leukocytes were measured at selected time points before and after feed restriction and dry-off, respectively. Feed restriction immediately resulted in a negative energy balance and decreased milk production. Concomitantly, concentrations of nonesterified fatty acids increased, whereas insulin, insulin-like growth factor-1, and glucagon decreased. After dry-off, energy balance turned positive and plasma nonesterified fatty acids decreased. Plasma glucose, insulin, and insulin-like growth factor-1 concentrations increased in all groups after dry-off. Glucose, insulin, and glucagon concentrations in plasma were higher in nonrestricted compared with restricted animals after dry-off. The experimental concentrate types marginally affected the investigated metabolic and endocrine factors, with the exception of elevated milk and plasma urea concentrations in cows fed the nitrogenic concentrate. Chemotactic and phagocytic activity of leukocytes were not affected by diets, feed restriction, or dry-off. Likewise, blood leukocyte mRNA abundance encoding for tumor necrosis factor α (TNF), heat shock protein family A (HSP70), and the glucose transporters (GLUT) 1 and 3 remained unchanged throughout the study period. Overall, the short-term negative energy balance induced by feed restriction was temporarily accompanied by metabolic adaptations, but did not alter the studied factors related to the immune system. Metabolic and endocrine adaptations supporting milk synthesis were continued during the first days after dry-off despite cessation of milking. Thus, the abrupt dry-off resulted in a short-term increase of glucose and triglyceride concentrations, with a delayed endocrine response to re-establish nutrient homeostasis in blood

Development and validation of the ACE tool: Assessing medical trainees' competency in evidence based medicine

BACKGROUND: While a variety of instruments have been developed to assess knowledge and skills in evidence based medicine (EBM), few assess all aspects of EBM - including knowledge, skills attitudes and behaviour - or have been psychometrically evaluated. The aim of this study was to develop and validate an instrument that evaluates medical trainees’ competency in EBM across knowledge, skills and attitude. METHODS: The ‘Assessing Competency in EBM’ (ACE) tool was developed by the authors, with content and face validity assessed by expert opinion. A cross-sectional sample of 342 medical trainees representing ‘novice’, ‘intermediate’ and ‘advanced’ EBM trainees were recruited to complete the ACE tool. Construct validity, item difficulty, internal reliability and item discrimination were analysed. RESULTS: We recruited 98 EBM-novice, 108 EBM-intermediate and 136 EBM-advanced participants. A statistically significant difference in the total ACE score was observed and corresponded to the level of training: on a 0-15-point test, the mean ACE scores were 8.6 for EBM-novice; 9.5 for EBM-intermediate; and 10.4 for EBM-advanced (p < 0.0001). Individual item discrimination was excellent (Item Discrimination Index ranging from 0.37 to 0.84), with internal reliability consistent across all but three items (Item Total Correlations were all positive ranging from 0.14 to 0.20). CONCLUSION: The 15-item ACE tool is a reliable and valid instrument to assess medical trainees’ competency in EBM. The ACE tool provides a novel assessment that measures user performance across the four main steps of EBM. To provide a complete suite of instruments to assess EBM competency across various patient scenarios, future refinement of the ACE instrument should include further scenarios across harm, diagnosis and prognosis

Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research

Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease\u2014secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide\u2014and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future