Evidence for a lipochaperonin: Association of active proteinfolding GroESL oligomers with lipids can stabilize membranes under heat shock conditions

During heat shock, structural changes in proteins and membranes may lead to cell death. While GroE and other chaperone proteins are involved in the prevention of stress-induced protein aggregation and in the recovery of protein structures, a mechanism for short-term membrane stabilization during stress remains to be established. We found that GroEL chaperonin can associate with model lipid membranes. Binding was apparently governed by the composition and the physical state of the host bilayer. Limited proteolysis of GroEL oligomers by proteinase K, which removes selectively the conserved glycine- and methionine-rich C terminus, leaving the chaperonin oligomer intact, prevented chaperonin association with lipid membranes. GroEL increased the lipid order in the liquid crystalline state, yet remained functional as a protein-folding chaperonin. This suggests that, during stress, chaperonins can assume the functions of assisting the folding of both soluble and membrane-associated proteins while concomitantly stabilizing lipid membranes.     

Outcomes of pancreatoduodenectomy in the cirrhotic patient: risk stratification and meta-analysis

Background

Cirrhosis increases the risk of perioperative mortality in gastrointestinal surgery. Though cirrhosis is sometimes considered a contraindication to pancreatoduodenectomy (PD), few data are available in this patient population. The aim of the present study is to identify predictors of outcome in cirrhotic patients undergoing PD.

Expanding the chemical diversity of an endophytic fungus Bulgaria inquinans,an ascomycete associated with mistletoe,through an OSMAC approach

An endophytic fungus Bulgaria inquinans (isolate MSp3-1), isolated from mistletoe (Viscum album), was subjected to fermentation on solid Czapek medium. Chromatographic workup of the crude EtOAc extract yielded five new natural products (1–5). Subsequent application of the “One Strain, MAny Compounds” (OSMAC) strategy on this strain by the addition of a mixture of salts (MgSO₄, NaNO₃ and NaCl) to solid Czapek medium induced the accumulation of nine additional new secondary metabolites (6–13, 16), with most of them (8, 10–12) not detectable in cultures lacking the salt mixture. The structures of the new compounds were established on the basis of the 1D/2D NMR and HRESIMS data. The TDDFT-ECD method was applied to determine the absolute configurations of the new compounds 1, 4 and 6 as well as of the previously reported bulgarialactone B (14), for which the absolute configuration was unknown so far. The modified Mosher''s method was performed to assign the absolute configurations of 12 and 13. TDDFT-ECD analysis also allowed determining the absolute configuration of (+)-epicocconone, which had an enantiomeric absolute configuration in the tricyclic moiety compared to that of bulgarialactone B (14). All the isolated metabolites were evaluated for their cytotoxic activity. Compound 2 was found to possess strong cytotoxic activity against the murine lymphoma cell line L5178Y with an IC₅₀ value of 1.8 μM, while the remaining metabolites were shown to be inactive.

OSMAC approach on endophytic Bulgaria inquinans by addition of a mixture of salts (MgSO₄, NaNO₃ and NaCl) to solid Czapek medium induced the accumulation of new secondary metabolites.     

Wear Pattern,Dental Function,and Jaw Mechanism in the Late Cretaceous Ankylosaur Hungarosaurus

Feeding in thyreophoran dinosaurs is poorly understood. Although the group existed for over 130 million years, only the Early Jurassic basal thyreophoran Scelidosaurus harrisonii and the Late Cretaceous ankylosaurid Euoplocephalus tutus have been studied from this perspective in detail. In contrast to the earlier, conservative hypothesis of a simple “orthal pulping” feeding mode with no or limited tooth–tooth contact, recent studies have demonstrated precise dental occlusion with differing jaw mechanisms in these two species. Here, we describe the first detailed study of feeding related characters in a nodosaurid ankylosaur, Hungarosaurus tormai, from the Late Cretaceous of Hungary. Dental wear patterns comprising small, apical, and low‐angled facets on the maxillary and steep, extended, and bowl‐like facets on the dentary teeth reveal sophisticated tooth–tooth contact in this basal nodosaurid. The presence of two different scratch generations (vertical and low‐angled) on the dentary teeth unambiguously demonstrate a multiphasic powerstroke, which is further supported by the morphology of the quadrate‐articular and mandibular symphyseal joints and by the architecture of the reconstructed jaw adductors. Chewing started with an initial slicing phase associated with orthal movement that was followed by a retractive powerstroke with significant occlusal contact. Because of the curved tooth rows, these movements were probably facilitated by some mediolateral translation and/or axial rotation of the mandibles to produce precise shearing along the whole tooth row. These results demonstrate that complex jaw mechanisms and dental occlusion were more widespread among thyreophorans than thought previously and that palinal movement was present in at least two ankylosaurian lineages. Anat Rec, 297:1165–1180, 2014. © 2014 Wiley Periodicals, Inc.     

Colorectal cancer extracellular acidosis decreases immune cell killing and is partially ameliorated by pH-modulating agents that modify tumor cell cytokine profiles

Tumor cells upregulate myriad proteins that are important for pH regulation, resulting in the acidification of the extracellular tumor microenvironment (TME). Abnormal pH is known to dampen immune function, resulting in a worsened anti-tumor immune response. Understanding how extrinsic alterations in pH modulate the interactions between immune cells and tumors cells will help elucidate opportunities for new therapeutic approaches. We observed that pH impacts the function of immune cells, both natural killer (NK) and T cells, which is relevant in the context of a highly acidic TME. Decreased NK and T cell activity was correlated with decreasing pH in a co-culture immune cell-mediated tumor cell-killing assay. The addition of pH-modulating drugs cariporide, lansoprazole, and acetazolamide to the co-culture assay was able to partially mitigate this dampened immune cell function. Treatment of colorectal cancer (CRC) cells with NHE1 inhibitor cariporide increased CRC cell-secreted cytokines involved in immune cell recruitment and activation and decreased cytokines involved in epithelial-mesenchymal transition (EMT). Cariporide treatment also decreased CRC cell shed TRAIL-R2, TRAIL-R3, and PD-L1 which is relevant in the context of immunotherapy. These experiments can help inform future investigations into how the pH of the tumor microenvironment may be extrinsically modulated to improve anti-tumor immune response in solid tumors such as colorectal cancer.     

Suicide attempt and melancholic depression in a male with erotomania: case report.

Erotomania is a delusional disorder, which is more common among women. A case of erotomania in a 34-year-old male associated with depression and suicidal behavior is presented. At the time he attempted suicide his erotomania fulfilled the diagnostic criteria of "pure" erotomania, described by de Clérambault. A depressive picture with melancholic features emerged four months later. Antidepressant medication was given and two months later he became euthymic. The erotomanic delusion disappeared in the third month of the euthymic state. In this case primary erotomania was associated with a depressive illness, presumably unipolar depression. The patient developed delusional guilt and suicidal ideation before the unequivocal change in his mood. To the authors' knowledge this is the first reported case where the erotomanic symptomatology led to suicidal attempt.     

Mechanism of aminopyridine-induced ictal seizure activity in the cat neocortex

Intracellular recordings were obtained from neurons in the motor cortex of anesthetized cats in order to examine membrane and synaptic processes involved in aminopyridine (AP)-induced ictal seizure activity. Depolarizing and hyperpolarizing membrane potential sequences which behaved as large, synchronized excitatory and inhibitory postsynaptic potentials, were found to accompany the ictal seizure potentials. After several repetitions of the seizure attack, partial responses, bursts and depolarizing plateaus with spike inactivation occurred. In layers IV and V we found non-pyramidal tract neurons showing endogenous bursting ability activated by AP. These neurons seemed to be the initiators of the rhythmic synchronous activity of the epileptic neuron population. Our results suggest that AP-induced epileptogenesis represents an adequate model of ictal events in the neocortex.     

Number and size of stones in patients with asymptomatic and symptomatic gallstones and gallbladder carcinoma: A prospective study of 592 cases

The development of gallbladder carcinoma has been correlated with the presence of a single large gallstone in two retrospective studies. The objective of the present study was to determine the number and size of gallstones in patients with gallbladder carcinoma compared to asymptomatic and symptomatic female patients with gallstones. The following three groups of patients were included in this prospective trial: (A) 78 asymptomatic patients with gallstones; (B) 365 symptomatic patients with gallstones; and (C) 149 patients with gallbladder carcinoma. At the end of the operation, the resected gallbladder was opened and the number of stones counted. The maximum size of the stones was determined using calipers. Patients with gallbladder carcinoma were significantly older than patients in the other two groups (P <0.001). In the group with asymptomatic gallstones, there were significantly more patients with one single stone, whereas in the group with gallbladder carcinoma there were significantly more patients with multiple stones (more than 11; P <0.01). Patients with gallbladder carcinoma had significantly larger stones, regardless of the number of stones present (P <0.001). We postulate that the increase in the number and size of the stones among patients with gallbladder carcinoma could simply be an effect of aging or it could be a reflection of the long-term presence of stones in the gallbladder rather than some particular chemical or physical influence.