3,4-Diarylpiperidines as potent renin inhibitors

The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species.     

The nature of lemming cycles on Wrangel: an island without small mustelids

Lemming cycles are a key process in the functioning of tundra ecosystems. Although it is agreed that trophic interactions are important in causing the cycles, the actual mechanism is disputed. Some researchers attribute a major role to predation by small mustelids such as stoats and least weasels. Here we present a 40-year time series of lemming dynamics from Wrangel Island and show statistically that lemmings do exhibit population cycles in the absence of small mustelids. The observed density fluctuations differed, however, from those observed elsewhere, with long cycles and possibly higher densities of lemmings during the low phase. These differences in the shape of the population cycles may be related to the unique species assemblage of Wrangel Island, where arctic foxes are the only year-round resident lemming predator, and to the high diversity of landscapes, microclimatic conditions, and plants on the island. Both spectral analysis and wavelet analysis show a change in period length from five?years in the 1970s to nearly eight?years in the 1990s and 2000s. This change in dynamics coincides with reports of dampening or fading out of lemming cycles that have been observed in several regions of the Arctic in recent decades. As in the other cases, the changed lemming dynamics on Wrangel Island may be related to ground icing in winter, which could delay peak years.     

Is plant genetic control of ectomycorrhizal fungal communities an untapped source of stable soil carbon in managed forests?

Background

Ectomycorrhizal (ECM) fungi provide one of the main pathways for carbon (C) to move from trees into soils, where these fungi make significant contributions to microbial biomass and soil respiration.

Scope

ECM fungal species vary significantly in traits that likely influence C sequestration, such that forest C sequestration potential may be driven in part by the existing community composition of ECM fungi. Moreover, accumulating experimental data show that tree genotypes differ in their compatibility with particular ECM fungal species, i.e. mycorrhizal traits of forest trees are heritable. Those traits are genetically correlated with other traits for which tree breeders commonly select, suggesting that selection for traits of interest, such as disease resistance or growth rate, could lead to indirect selection for or against particular mycorrhizal traits of trees in forest plantations.

Conclusions

Altogether, these observations suggest that selection of particular tree genotypes could alter the community composition of symbiotic ECM fungi in managed forests, with cascading effects on soil functioning and soil C sequestration.     

Prenatal stress and balance of the child's cardiac autonomic nervous system at age 5-6 years

Objective

Autonomic nervous system (ANS) misbalance is a potential causal factor in the development of cardiovascular disease. The ANS may be programmed during pregnancy due to various maternal factors. Our aim is to study maternal prenatal psychosocial stress as a potential disruptor of cardiac ANS balance in the child.

Methods

Mothers from a prospective birth cohort (ABCD study) filled out a questionnaire at gestational week 16 [IQR 12–20], that included validated instruments for state anxiety, depressive symptoms, pregnancy-related anxiety, parenting daily hassles and job strain. A cumulative stress score was also calculated (based on 80^th percentiles). Indicators of cardiac ANS in the offspring at age 5–6 years are: pre-ejection period (PEP), heart rate (HR), respiratory sinus arrhythmia (RSA) and cardiac autonomic balance (CAB), measured with electrocardiography and impedance cardiography in resting supine and sitting positions.

Results

2,624 mother-child pairs, only single births, were available for analysis. The stress scales were not significantly associated with HR, PEP, RSA and CAB (p≥0.17). Accumulation of maternal stress was also not associated with HR, PEP, RSA and CAB (p≥0.07).

Conclusion

Results did not support the hypothesis that prenatal maternal psychosocial stress deregulates cardiac ANS balance in the offspring, at least in rest, and at the age of five-six years.     

Evaluation of MCM-2 expression in TMA cervical specimens

Background

Minichromosome maintenance proteins (MCM) are highly expressed in actively replicating cells. The need for biological markers for cervical carcinoma and its precursor lesions is emerging. Our main aim was to determine the immunohistochemical expression of MCM-2 in HIV-positive and -negative dysplastic cervical specimens.

Methods

Immunohistochemical analysis of MCM-2 was performed in a total of 352 cervical TMA specimens of normal control, low-grade CIN, high-grade CIN and invasive tumor. 38 specimens were from HIV-positive women. A receiver operating characteristic (ROC) curve was constructed to determine the best cutoff to diagnose high-grade CIN and invasive cervical cancer.

Results

In the progression from normal epithelium to high-grade CIN and invasive tumor we found significant differences in the MCM-2 expression (p<0.05). Based on the ROC curve of 80% with an area under the curve (AUC) of 0.78, expression of MCM-2 to diagnose high-grade CIN and invasive tumor resulted in sensitivity of 81%, specificity of 66%, a positive predictive value (PPV) of 86% and a negative predictive value (NPV) of 57%. HIV-positive cervices revealed a decreasing expression of MCM-2 in both LGCIN and HGCIN compared with HIV-negative specimens (p<0.0001).

Conclusions

The present study suggests that immunohistochemical MCM-2 may not be a promising biomarker for diagnosing high-grade CIN and invasive cancer.     

The neural substrates of memory suppression: a FMRI exploration of directed forgetting

The directed forgetting paradigm is frequently used to determine the ability to voluntarily suppress information. However, little is known about brain areas associated with information to forget. The present study used functional magnetic resonance imaging to determine brain activity during the encoding and retrieval phases of an item-method directed forgetting recognition task with neutral verbal material in order to apprehend all processing stages that information to forget and to remember undergoes. We hypothesized that regions supporting few selective processes, namely recollection and familiarity memory processes, working memory, inhibitory and selection processes should be differentially activated during the processing of to-be-remembered and to-be-forgotten items. Successful encoding and retrieval of items to remember engaged the entorhinal cortex, the hippocampus, the anterior medial prefrontal cortex, the left inferior parietal cortex, the posterior cingulate cortex and the precuneus; this set of regions is well known to support deep and associative encoding and retrieval processes in episodic memory. For items to forget, encoding was associated with higher activation in the right middle frontal and posterior parietal cortex, regions known to intervene in attentional control. Items to forget but nevertheless correctly recognized at retrieval yielded activation in the dorsomedial thalamus, associated with familiarity-based memory processes and in the posterior intraparietal sulcus and the anterior cingulate cortex, involved in attentional processes.     

Empathy manipulation impacts music-induced emotions: a psychophysiological study on opera

This study investigated the effects of voluntarily empathizing with a musical performer (i.e., cognitive empathy) on music-induced emotions and their underlying physiological activity. N = 56 participants watched video-clips of two operatic compositions performed in concerts, with low or high empathy instructions. Heart rate and heart rate variability, skin conductance level (SCL), and respiration rate (RR) were measured during music listening, and music-induced emotions were quantified using the Geneva Emotional Music Scale immediately after music listening. Listening to the aria with sad content in a high empathy condition facilitated the emotion of nostalgia and decreased SCL, in comparison to the low empathy condition. Listening to the song with happy content in a high empathy condition also facilitated the emotion of power and increased RR, in comparison to the low empathy condition. To our knowledge, this study offers the first experimental evidence that cognitive empathy influences emotion psychophysiology during music listening.     

Effect of insecticide resistance on development, longevity and reproduction of field or laboratory selected Aedes aegypti populations

Aedes aegypti dispersion is the major reason for the increase in dengue transmission in South America. In Brazil, control of this mosquito strongly relies on the use of pyrethroids and organophosphates against adults and larvae, respectively. In consequence, many Ae. aegypti field populations are resistant to these compounds. Resistance has a significant adaptive value in the presence of insecticide treatment. However some selected mechanisms can influence important biological processes, leading to a high fitness cost in the absence of insecticide pressure. We investigated the dynamics of insecticide resistance and its potential fitness cost in five field populations and in a lineage selected for deltamethrin resistance in the laboratory, for nine generations. For all populations the life-trait parameters investigated were larval development, sex ratio, adult longevity, relative amount of ingested blood, rate of ovipositing females, size of egglaying and eggs viability. In the five natural populations, the effects on the life-trait parameters were discrete but directly proportional to resistance level. In addition, several viability parameters were strongly affected in the laboratory selected population compared to its unselected control. Our results suggest that mechanisms selected for organophosphate and pyrethroid resistance caused the accumulation of alleles with negative effects on different life-traits and corroborate the hypothesis that insecticide resistance is associated with a high fitness cost.     

Caregiver burden in amyotrophic lateral sclerosis is more dependent on patients’ behavioral changes than physical disability: a comparative study

Background

Behavioral changes in patients with amyotrophic lateral sclerosis (ALS) mirror those found in frontotemporal dementia (FTD). Considering the high rate of neuropsychiatric symptoms found in ALS patients, this paper examines whether caregiver burden is associated with behavioral changes over and above the physical disability of patients with ALS, and if the presence of caregivers’ depression, anxiety and stress also impacts on caregiver burden.

Methods

140 caregivers of patients with ALS participated in a postal survey investigating patients’ neuropsychiatric symptoms (Cambridge Behaviour Inventory Revised CBI-R), motor function (Amyotrophic Lateral Sclerosis Functional Rating Scale Revised - ALSFRS-R), caregiver burden (Zarit Burden Interview), and caregiver mood (Depression, Anxiety and Stress Scale- DASS21). Seventy four percent of them were caregivers of patients with limb onset and 25.7% were caregivers of patients with bulbar onset.

Results

Moderate to severe behavioral changes were reported in 10-40% of patients with ALS. The levels of depression, anxiety and stress in the caregivers reached 20%. Burden was high in 48% of the caregivers. The strongest predictor of high caregiver burden was ALS patients’ abnormal behavior rather than physical disability, with an odds ratio of 1.4, followed by caregivers’ stress.

Conclusions

Our study has identified that behavioral changes (e.g. disinhibition, impulsivity) and caregiver stress have greater impact on caregiver burden than level and pattern of physical disability.

     

Impact of adrenal versus ovarian androgen ratio on signs and symptoms of polycystic ovarian syndrome

The aim of this study was to examine the effect of adrenal versus ovarian androgen (dehydroepiandrosterone sulfate/total testosterone [DHEAS/TT]) on clinical presentation and related metabolic disturbances in Turkish women with polycystic ovarian syndrome (PCOS). Two hundred eighty PCOS cases were taken into the study. For all cases, the DHEAS/TT ratio was calculated. The median value of this ratio was 4.40. Patients with an androgen ratio lower than 4.40 were included in Group 1 and cases with a ratio higher than 4.40 were Group 2. The two groups were compared in terms of hormonal, biochemical and clinical parameters. Body mass index and waist circumference were lower, the Ferriman-Gallwey score was higher and the cycle length was shorter in Group 2. High DHEAS level was associated with better lipid profiles and lower levels of inflammatory markers, meaning good metabolic control in these women, in spite of increased hirsutism rates. In patients with PCOS, both androgens are usually high in proportion to each other. Therefore, it would be more meaningful to use the DHEAS/TT ratio for an assessment of the metabolic and phenotypic effects of PCOS.