Aversive Conditioning of Spatial Position Sharpens Neural Population-Level Tuning in Visual Cortex and Selectively Alters Alpha-Band Activity

Processing capabilities for many low-level visual features are experientially malleable, aiding sighted organisms in adapting to dynamic environments. Explicit instructions to attend a specific visual field location influence retinotopic visuocortical activity, amplifying responses to stimuli appearing at cued spatial positions. It remains undetermined both how such prioritization affects surrounding nonprioritized locations, and if a given retinotopic spatial position can attain enhanced cortical representation through experience rather than instruction. The current report examined visuocortical response changes as human observers (N = 51, 19 male) learned, through differential classical conditioning, to associate specific screen locations with aversive outcomes. Using dense-array EEG and pupillometry, we tested the preregistered hypotheses of either sharpening or generalization around an aversively associated location following a single conditioning session. Competing hypotheses tested whether mean response changes would take the form of a Gaussian (generalization) or difference-of-Gaussian (sharpening) distribution over spatial positions, peaking at the viewing location paired with a noxious noise. Occipital 15 Hz steady-state visual evoked potential responses were selectively heightened when viewing aversively paired locations and displayed a nonlinear, difference-of-Gaussian profile across neighboring locations, consistent with suppressive surround modulation of nonprioritized positions. Measures of alpha-band (8–12 Hz) activity were differentially altered in anterior versus posterior locations, while pupil diameter exhibited selectively heightened responses to noise-paired locations but did not evince differences across the nonpaired locations. These results indicate that visuocortical spatial representations are sharpened in response to location-specific aversive conditioning, while top-down influences indexed by alpha-power reduction exhibit posterior generalization and anterior sharpening.SIGNIFICANCE STATEMENT It is increasingly recognized that early visual cortex is not a static processor of physical features, but is instead constantly shaped by perceptual experience. It remains unclear, however, to what extent the cortical representation of many fundamental features, including visual field location, is malleable by experience. Using EEG and an aversive classical conditioning paradigm, we observed sharpening of visuocortical responses to stimuli appearing at aversively associated locations along with location-selective facilitation of response systems indexed by pupil diameter and EEG alpha power. These findings highlight the experience-dependent flexibility of retinotopic spatial representations in visual cortex, opening avenues toward novel treatment targets in disorders of attention and spatial cognition.     

UV-induced DNA damage disrupts the coordination between replication initiation,elongation and completion

Replication initiation, elongation and completion are tightly coordinated to ensure that all sequences replicate precisely once each generation. UV-induced DNA damage disrupts replication and delays elongation, which may compromise this coordination leading to genome instability and cell death. Here, we profiled the Escherichia coli genome as it recovers from UV irradiation to determine how these replicational processes respond. We show that oriC initiations continue to occur, leading to copy number enrichments in this region. At late times, the combination of new oriC initiations and delayed elongating forks converging in the terminus appear to stress or impair the completion reaction, leading to a transient over-replication in this region of the chromosome. In mutants impaired for restoring elongation, including recA, recF and uvrA, the genome degrades or remains static, suggesting that cell death occurs early after replication is disrupted, leaving partially duplicated genomes. In mutants impaired for completing replication, including recBC, sbcCD xonA and recG, the recovery of elongation and initiation leads to a bottleneck, where the nonterminus region of the genome is amplified and accumulates, indicating that a delayed cell death occurs in these mutants, likely resulting from mis-segregation of unbalanced or unresolved chromosomes when cells divide.     

A novel xanthine derivative counteracting in vivo tumor necrosis factor alpha toxicity in mice.

The xanthine derivative A 802715 (1-(5-hydroxy-5-methyl)hexyl-3-methyl-7- propyl-xanthine, Hoechst AG) caused dose-dependent protection against lipopolysaccharide (LPS)-induced lethal shock in mice. In animals which had received the compound, the LPS-induced increase of serum tumor necrosis factor (TNF alpha) levels was not significantly affected. Protection against LPS-induced lethality was observed not only when A 802715 was given 1 hr before or simultaneously with LPS but also when administered 1 hr after LPS challenge. Administration of 200 mg/kg of the compound 1 hr before challenge also fully protected against lethal shock induced by intravenous administration of recombinant murine TNF alpha. It is concluded that A 802715 counteracts TNF alpha toxicity and that the drug bears the potential of therapeutic intervention in septic shock.     

Relationship between leptin levels and bone mineral density in the elderly

OBJECTIVE: To assess the relationship between circulating leptin levels, bone mineral content and density in the elderly. DESIGN: A cross-sectional study. PATIENTS: A cohort of 92 men and 171 women, with ages ranging from 68 to 75 years, selected as a healthy and normal functioning group, in the city centre of Verona. MEASUREMENTS: Plasma leptin levels were determined in each participant. Body composition was evaluated with dual energy X-ray absorptiometry (DXA). Bone mineral content (BMC) and bone mineral density (BMD) were measured at whole-body, hip and femoral neck level in all subjects. RESULTS: In both men and women a significant relationship between fat mass and whole-body BMC or BMD was found. The strength of this association was consistently reduced after adjustment for plasma leptin. A significant association between circulating leptin levels, whole-body, total hip and femoral neck BMC and BMD was found in both sexes. This association retained the statistical significance after adjustment for fat mass percentage, especially in women. In stepwise multiple linear regression analyses, leptin was shown to be a significant predictor of whole-body, total hip and femoral neck BMC and BMD, independently of age and the percentage of body fat in both sexes. The circulating levels of leptin accounted for a variance in whole-body BMC of 8.9% in men and 18.2% in women, and in whole-body BMD of 10.6% in women. CONCLUSION: Our data show a significant relationship between leptin, bone mineral mass and density in healthy elderly men and women.     

Molecular genetic characterization and urinary excretion pattern of metabolites in two families with MCAD deficiency due to compound heterozygosity with a 13 base pair insertion in one allele

Summary Two families with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency due to compound heterozygosity are described. All patients have a 13 bp insertion in exon 11 of one allele at the MCAD gene locus. In the other allele patients in one of the families harbour the prevalent G985 mutation, and the other family possess an unidentified mutation causing reduced levels of MCAD mRNA. We demonstrate that the disease in these families is inherited as an autosomal recessive trait. Individuals heterozygous for the mutations show heterozygous/control levels of -oxidation activities in cultured fibroblasts (9.1–16.3 pmol/min per mg protein; control 10–17 pmol/min per mg protein), and in the excretion of the -oxidation metabolites, hexanoylglycine (<2 µmol/mmol creatinine), suberylglycine (<2 µmol/mmol creatinine) and phenylpropionylglycine (<2 µmol/mmol creatinine). This shows that there is no negative dominance from the mutant monomeric protein onto the normal ones, in accordance with the finding of low levels of MCAD mRNA from the allele harbouring the 13 bp insertion as well as the allele with the unidentified mutation, and the low steady-state level of enzyme protein expressed from the G985-bearing allele. In the family possessing the G985 and the 13 bp insertion mutations, two asymptomatic compound heterozygous individuals were detected. They exhibited elevated excretion of hexanoylglycine (5–15 µmol/mmol creatinine) and suberylglycine (4–13 µmol/mmol creatinine), together with -oxidation activity in fibroblasts in the homozygous range (2.9 pmol/min per mg protein), showing a lack of correlation between the genotype, some biochemical parameters and the clinical phenotype.     

Impact of joint status on contraction steadiness of m. quadriceps femoris in people with severe haemophilia

Impaired contraction steadiness of lower limb muscles affects functional performance and may increase injury risk. We hypothesize that haemophilic arthropathy of the knee and the strength status of quadriceps are relevant factors which compromise a steady contraction. This study addresses the questions if impaired steadiness of the quadriceps is verifiable in people with haemophilia (PWH) and whether a connection between the status of the knee joint and quadriceps strength exists. A total of 157 PWH and 85 controls (C) performed a strength test with a knee extensor device to evaluate their bilateral and unilateral maximal quadriceps strength and steadiness. Isometric steadiness was measured by the coefficient of variation of maximum peak torque (CV‐MVIC in %). For classification of the knee joint status the World Federation of Haemophilia (WFH) score was used. Lower steadiness (higher CV values) was found in PWH compared with C during bilateral [PWH vs. C; 0.63 (0.36/1.13) vs. 0.35 (0.15/0.72), median (Q25/Q75) P < 0.001] and unilateral trials [left leg: 0.70 (0.32/1.64) vs. 0.50 (0.23/1.04), P < 0.05; right leg: 0.68 (0.29/1.51) vs. 0.39 (0.18/0.68), P < 0.001]. PWH with a WFH score difference (≥1) between their extremities showed a less steady contraction in the more affected extremity (P < 0.05). More unsteady contractions have also been found in extremities with lower quadriceps strength compared with the contralateral stronger extremities (P < 0.001), whereby the weaker extremities were associated with a worse joint status (P < 0.001). The results of this study verify an impaired ability to realize a steady contraction of quadriceps in PWH and the influence of joint damage and strength on its manifestation.     

A prospective study on survival in cancer patients with and without venous thromboembolism

Retrospective population-based studies showed that in cancer patients venous thromboembolism (VTE) is associated with reduced survival. Master Oncology is a multicenter study in patients with solid advanced cancer aimed at assessing (1) risk factors for VTE using a case–control design, and (2) survival in cases (patients with VTE) and controls (patients without VTE). Survival data were prospectively collected for at least 10 months. Overall, 237 cases and 339 controls were included in the analysis. The following factors were found to be associated with an increased risk of VTE: body mass index (BMI; OR 2.02; 95 % CI 1.31–3.12 for ≥26 vs. <23 kg/m²), ECOG score (OR 2.14; 95 % CI 1.47–3.11 for grade 1, and 3.32; 95 % CI 1.64–6.00 for grade 2–3, compared to grade 0) and recent diagnosis of cancer (OR 1.90; 95 % CI 1.33–2.71 for <12 vs. ≥12 months). After an average prospective observation of 8.3 months, 136 cases (57.4 %) and 127 controls (37.5 %) died with a median survival of 8.7 (95 % CI 7.5–10.9) and 14.3 months (95 % CI 12.2–18.7), respectively, (Wilcoxon = 27.72, p < 0.001; multivariate hazard ratio 1.55; 95 % CI 1.21–2.00). Median survival time was reduced for both patients with symptomatic (Wilcoxon = 35.22, p < 0.001) and asymptomatic VTE (Wilcoxon = 4.63, p = 0.031). Patients with advanced solid cancer, high BMI, high ECOG score, and recent diagnosis of cancer are associated with an increased risk for VTE. Patients with both symptomatic and asymptomatic VTE have a reduced survival compared to those without VTE.