Body masses,functional responses and predator–prey stability

The stability of ecological communities depends strongly on quantitative characteristics of population interactions (type‐II vs. type‐III functional responses) and the distribution of body masses across species. Until now, these two aspects have almost exclusively been treated separately leaving a substantial gap in our general understanding of food webs. We analysed a large data set of arthropod feeding rates and found that all functional‐response parameters depend on the body masses of predator and prey. Thus, we propose generalised functional responses which predict gradual shifts from type‐II predation of small predators on equally sized prey to type‐III functional‐responses of large predators on small prey. Models including these generalised functional responses predict population dynamics and persistence only depending on predator and prey body masses, and we show that these predictions are strongly supported by empirical data on forest soil food webs. These results help unravelling systematic relationships between quantitative population interactions and large‐scale community patterns.     

The cell death protease Kex1p is essential for hypochlorite-induced apoptosis in yeast

Following microbial pathogen invasion, the human immune system of activated phagocytes generates and releases the potent oxidant hypochlorous acid (HOCl), which contributes to the killing of menacing microorganisms. Though tightly controlled, HOCl generation by the myeloperoxidase-hydrogen peroxide-chloride system of neutrophils/monocytes may occur in excess and lead to tissue damage. It is thus of marked importance to delineate the molecular pathways underlying HOCl cytotoxicity in both microbial and human cells. Here, we show that HOCl induces the generation of reactive oxygen species (ROS), apoptotic cell death and the formation of specific HOCl-modified epitopes in the budding yeast Saccharomyces cerevisiae. Interestingly, HOCl cytotoxicity can be prevented by treatment with ROS scavengers, suggesting oxidative stress to mediate the lethal effect. The executing pathway involves the pro-apoptotic protease Kex1p, since its absence diminishes HOCl-induced production of ROS, apoptosis and protein modification. By characterizing HOCl-induced cell death in yeast and identifying a corresponding central executor, these results pave the way for the use of Saccharomyces cerevisiae in HOCl research, not least given that it combines both being a microorganism as well as a model for programmed cell death in higher eukaryotes.     

Macrophage Specific Caspase-1/11 Deficiency Protects against Cholesterol Crystallization and Hepatic Inflammation in Hyperlipidemic Mice

Background & Aims

While non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis combined with inflammation, the mechanisms triggering hepatic inflammation are unknown. In Ldlr^-/- mice, we have previously shown that lysosomal cholesterol accumulation in Kupffer cells (KCs) correlates with hepatic inflammation and cholesterol crystallization. Previously, cholesterol crystals have been shown to induce the activation of inflammasomes. Inflammasomes are protein complexes that induce the processing and release of pro-inflammatory cytokines IL-1b and IL-18 via caspase-1 activation. Whereas caspase-1 activation is independent of caspase-11 in the canonical pathway of inflammasome activation, caspase-11 was found to trigger caspase-1-dependent IL-1b and IL-18 in response to non-canonical inflammasome activators. So far, it has not been investigated whether inflammasome activation stimulates the formation of cholesterol crystals. We hypothesized that inflammasome activation in KCs stimulates cholesterol crystallization, thereby leading to hepatic inflammation.

Methods

Ldlr ^-/- mice were transplanted (tp) with wild-type (Wt) or caspase-1/11^-/- (dKO) bone marrow and fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 12 weeks. In vitro, bone marrow derived macrophages (BMDM) from wt or caspase-1/11^-/- mice were incubated with oxLDL for 24h and autophagy was assessed.

Results

In line with our hypothesis, caspase-1/11^-/--tp mice had less severe hepatic inflammation than Wt-tp animals, as evident from liver histology and gene expression analysis in isolated KCs. Mechanistically, KCs from caspase-1/11^-/--tp mice showed less cholesterol crystals, enhanced cholesterol efflux and increased autophagy. In wt BMDM, oxLDL incubation led to disturbed autophagy activity whereas BMDM from caspase-1/11^-/- mice had normal autophagy activity.

Conclusion

Altogether, these data suggest a vicious cycle whereby disturbed autophagy and decreased cholesterol efflux leads to newly formed cholesterol crystals and thereby maintain hepatic inflammation during NASH by further activating the inflammasome.     

Complex Patterns of Chromosome 11 Aberrations in Myeloid Malignancies Target CBL,MLL, DDB1 and LMO2

Exome sequencing of primary tumors identifies complex somatic mutation patterns. Assignment of relevance of individual somatic mutations is difficult and poses the next challenge for interpretation of next generation sequencing data. Here we present an approach how exome sequencing in combination with SNP microarray data may identify targets of chromosomal aberrations in myeloid malignancies. The rationale of this approach is that hotspots of chromosomal aberrations might also harbor point mutations in the target genes of deletions, gains or uniparental disomies (UPDs). Chromosome 11 is a frequent target of lesions in myeloid malignancies. Therefore, we studied chromosome 11 in a total of 813 samples from 773 individual patients with different myeloid malignancies by SNP microarrays and complemented the data with exome sequencing in selected cases exhibiting chromosome 11 defects. We found gains, losses and UPDs of chromosome 11 in 52 of the 813 samples (6.4%). Chromosome 11q UPDs frequently associated with mutations of CBL. In one patient the 11qUPD amplified somatic mutations in both CBL and the DNA repair gene DDB1. A duplication within MLL exon 3 was detected in another patient with 11qUPD. We identified several common deleted regions (CDR) on chromosome 11. One of the CDRs associated with de novo acute myeloid leukemia (P=0.013). One patient with a deletion at the LMO2 locus harbored an additional point mutation on the other allele indicating that LMO2 might be a tumor suppressor frequently targeted by 11p deletions. Our chromosome-centered analysis indicates that chromosome 11 contains a number of tumor suppressor genes and that the role of this chromosome in myeloid malignancies is more complex than previously recognized.     

Serum proteomics in amnestic mild cognitive impairment

We have explored proteins related to mild cognitive impairment (MCI). The serum proteome of 35 amnestic MCI patients and 35 cognitively healthy persons was investigated by LC MS. We identified 108 differentially expressed peptides between MCI patients and controls, belonging to 39 proteins. Eight proteins were selected for further investigation by quantitative protein measurements using a MRM assay; apolipoprotein E, carboxypeptidase N subunit 2, complement factor B (CFAB), galectin‐3 binding protein (LG3BP), lumican, serum amyloid A‐4 protein (SAA4), serum amyloid P‐component, and sex hormone binding globulin. Results of the quantitative protein measurements showed significantly decreased levels of carboxypeptidase N subunit 2, CFAB, LG3BP, SAA4, and serum amyloid P‐component in serum from amnestic MCI patients compared with cognitive healthy controls (two‐sided t‐test; p < 0.05). Apolipoprotein E and lumican showed no significant difference in protein levels, sex hormone binding globulin could not be quantified since the MRM assay did not reach the required sensitivity. A model based on the three most significantly decreased proteins (CFAB, LG3BP, and SAA4) showed a sensitivity and specificity of 73 and 66%, respectively, for the initial sample set. A small external validation set yielded 77% sensitivity and 75% specificity.     

Dynamic process conditions in bioprocess development

In this review, we summarise recent studies that purposefully employed dynamic conditions, such as shifts, pulses, ramps and oscillations, for fast physiological strain characterisation and bioprocess development. We show the broad applicability of dynamic conditions and the various objectives that can thereby be investigated in a short time. Dynamic processes reveal information about the analysed system faster than traditional strategies, like continuous cultivations, as process parameters can directly be linked to platform and product parameters. Furthermore, we demonstrate that dynamic operations can result in increased productivity and high product quality, making this strategy a valuable tool for bioprocess development. With this review, we would like to encourage bioprocess engineers to an increased use of dynamic conditions in bioprocess development.     

A9C sensitive Cl? - accumulation in A. thaliana root cells during salt stress is controlled by internal and external calcium

The involvement of chloride in salt stress symptoms and salt tolerance mechanisms in plants has been less investigated in the past. Therefore, we studied the salt-induced chloride influx in Arabidopsis expressing the GFP-based anion indicator Clomeleon. High salt concentrations induce two phases of chloride influx. The fast kinetic phase is likely caused by membrane depolarization, and is assumed to be mediated by channels. This is followed by a slower "saturation" phase, where chloride is accumulated in the cytoplasm. Both phases of chloride uptake are dependent on the presence of external calcium. In general: with high [Ca²⁺] less chloride is accumulated in the cytoplasm. Surprisingly, also the internal calcium availability has an impact on chloride transport. A complete block of the second phase of chloride influx is achieved by the anion channel blocker A9C and trivalent cations (La³⁺, Gd³⁺, and Al³⁺). Other channel blockers and diuretics were found to inhibit the process partially. The results suggest that several transporter species are involved here, including electroneutral cation-chloride-cotransporters, and a part of chloride possibly enters the cells through cation channels after salt application.     

Germline Allele-Specific Expression of DAPK1 in Chronic Lymphocytic Leukemia

We previously reported a rare germline variant (c.1-6531) that resulted in allele–specific expression (ASE) of death-associated protein kinase 1 (DAPK1) and predisposition to chronic lymphocytic leukemia (CLL). We investigated a cohort of CLL patients lacking this mutation for the presence of ASE of DAPK1. We developed a novel strategy that combines single-nucleotide primer extension (SNuPE) with MALDI-TOF mass spectrometry, and detected germline DAPK1 ASE in 17 out of 120 (14.2%) CLL patients associated with a trend towards younger age at diagnosis. ASE was absent in 63 healthy controls. Germline cells of CLL patients with ASE showed increased levels of DNA methylation in the promoter region, however, neither genetic nor further epigenetic aberrations could be identified in the DAPK1 5′ upstream regulatory region, within distinct exons or in the 3′-UTR. We identified B-lymphoid malignancy related cell line models harboring allelic imbalance and found that allele-specific methylation in DAPK1 is associated with ASE. Our data indicate that ASE at the DAPK1 gene locus is a recurrent event, mediated by epigenetic mechanisms and potentially predisposing to CLL.     

Decision-Making in Multiple Sclerosis Consultations in Italy: Third Observer and Patient Assessments

Objective

To assess decision-making in multiple sclerosis (MS) from third observer and patient perspectives.

Method

Audio recordings of first-ever consultations with a participating physician (88 outpatients, 10 physicians) at four tertiary MS care clinics in Italy, were rated by a third observer using the Observing Patient Involvement in Shared Decision Making (OPTION) and by patients using the Perceived Involvement in Care Scale (PICS).

Results

Mean patient age was 37.5, 66% were women, 72% had MS, and 28% had possible MS or other disease. Mean PICS subscale scores (range 0 poor, 100 best possible) were 71.9 (SD 24.3) for "physician facilitation" (PICS-F); 74.6 (SD 22.9) for "patient information exchange" (PICS-I); and only 22.5 (SD 16.2) for "patient decision making" (PICS-DM). Mean OPTION total score (0 poor, 100 best possible) was 29.6 (SD 10.3). Poorest OPTION scores were found for items assessing “preferred patient approach to receiving information” and “preferred patient level of involvement.” Highest scores were for “clinician drawing attention to identified problem”, “indicating need for decision making,” and “need to review the decision.” Consultation time, woman physician, patient-physician gender concordance and PICS-F were associated with higher OPTION total score; older physician and second opinion consultation were associated with lower OPTION score.

Conclusions

In line with findings in other settings, our third observer findings indicated limited patient involvement abilities of MS physicians during first consultations. Patient perceptions of physician skills were better than third observers’, although they correlated. Consultations with women physicians, and younger physicians, were associated with higher third observer and patient-based scores. Our findings reveal a need to empower Italian MS physicians with better communication and shared decision-making skills, and show in particular that attention to MS patient preferences for reception of information and involvement in health decisions, need to be improved.     

Diffusion- and Perfusion-Weighted Imaging in Acute Lacunar Infarction: Is There a Mismatch?

Purpose

Characterization of lacunar infarction (LI) by use of multimodal MRI including diffusion- and perfusion-weighted imaging (DWI, PWI) is difficult because of the small lesion size. Only a few studies evaluated PWI in LI and the results are inconsistent.

Methods

In 16 LI patients who underwent initial MRI within 6 hours after symptom onset and follow-up MRI within 1 week demographics, clinical presentation, and MRI findings were analyzed with special emphasis on DWI and PWI findings. Time to peak maps were classified as showing a normal perfusion pattern or areas of hypoperfusion which were further categorized in mismatch (PWI>DWI), inverse mismatch (PWI<DWI), and match (PWI=DWI). Quantitative perfusion maps were generated and analyzed by use of Signal Processing in NMR-Software (SPIN).

Results

Of the 16 patients (mean age 65.5±12.9 years), 14 (87.5%) were male. Clinical symptoms comprised dysarthria (50%), hemiparesis (81.3%), and hemihypaesthesia (18.8%). Intravenous thrombolysis was performed in 7 (43.8%) patients. Clinical improvement was observed in 12 patients (75 %), while 2 (12.5%) patients showed a deterioration and another 2 (12.5%) a stable course. Acute ischemic lesions (mean volume of 0.46±0.29 cm³) were located in the thalamus (n=8, 50%), internal capsule (n=4, 25%), corona Radiata (n=3, 18.8%) and the mesencephalon (n=1, 6.3%). Circumscribed hypoperfusion (mean volume 0.61±0.48 cm³) was evident in 10 (62.5%) patients. Of these, 3 patients demonstrated a match, 4 an inverse mismatch, and 3 a mismatch between DWI and PWI lesion. Mean CBF and CBV ratios were 0.65±0.28 and 0.84±0.41 respectively. Growth of DWI lesions was observed in 7 (43.8%) and reversal of DWI lesions in 3 (18.8%) patients.

Conclusions

MRI allows identification of different DWI and PWI patterns in LI, including growth and reversal of ischemic lesions. Consequently, it may serve for a better characterization of this stroke subtype and support treatment decisions in daily clinical practice.