Formation of haemozoin/��-haematin under physiological conditions is not spontaneous

Malaria parasite detoxifies free haem, released as a result of haemoglobin digestion, by converting it into an stable, crystalline, black brown pigment known as 'malaria pigment' or 'haemozoin'. Earlier studies have demonstrated the involvement of a parasite-specific enzyme 'haem polymerase' in the formation of haemozoin. However, recently it has been proposed that the polymerization of haem may be a spontaneous process that could take place by incubation of haematin with carboxylic acids (pH 4.2-5.0) even without presence of any parasitic or biological component (FEBS Letters, 352, 54-57 (1994). Here we report that no spontaneous haem polymerization occurs at physiological conditions and the product described in the study mentioned above is not haemozoin/beta-haematin (haem polymer) as characterized by us on the basis of solubility characteristics and thin layer chromatography. The infra-red spectroscopic analysis of the product formed though exhibits the bands corresponding to formation of iron-carboxylate bond, similar to that in haemozoin/beta-haematin, but was identified as haem-acid adduct. Thus polymerization of haem may not occur spontaneously under the reaction conditions corresponding to food vacuoles of the malarial parasite, the physiological site of haemozoin formation.

Temperature-induced sex reversal is not responsible for sex-ratio distortions in grayling Thymallus thymallus or brown trout Salmo trutta

On the basis of the experiments carried out over various years, it was concluded that (1) grayling Thymallus thymallus and brown trout Salmo trutta are resistant to temperature-induced sex reversal at ecologically relevant temperatures, (2) environmental sex reversal is unlikely to cause the persistent sex ratio distortion observed in at least one of the study populations and (3) sex-specific tolerance of temperature-related stress may be the cause of distorted sex ratios in populations of T. thymallus or S. trutta.

ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin

The human insulin gene enhancer-binding protein islet-1 (ISL1) is a transcription factor involved in the differentiation of the neuroendocrine pancreatic cells. Recent studies identified ISL1 as a marker for pancreatic well-differentiated neuroendocrine neoplasms. However, little is known about ISL1 expression in pancreatic poorly differentiated and in extrapancreatic well and poorly differentiated neuroendocrine neoplasms. We studied the immunohistochemical expression of ISL1 in 124 neuroendocrine neoplasms. Among pancreatic neuroendocrine neoplasms, 12/13 with poor differentiation were negative, whereas 5/7 with good differentiation but a Ki67 >20% were positive. In extrapancreatic neuroendocrine neoplasms, strong positivity was found in Merkel cell carcinomas (25/25), pulmonary small cell neuroendocrine carcinomas (21/23), medullary thyroid carcinomas (9/9), paragangliomas/pheochromocytomas (6/6), adrenal neuroblastomas (8/8) and head and neck neuroendocrine carcinomas (4/5), whereas no or only weak staining was recorded in pulmonary carcinoids (3/15), olfactory neuroblastomas (1/4) and basaloid head and neck squamous cell carcinomas (0/15). ISL1 stained the neuroendocrine carcinoma component of 5/8 composite carcinomas and also normal neuroendocrine cells in the thyroid, adrenal medulla, stomach and colorectum. Poorly differentiated neuroendocrine neoplasms, regardless of their ISL1 expression, were usually TP53 positive. Our results show the almost ubiquitous expression of ISL1 in extrapancreatic poorly differentiated neuroendocrine neoplasms and neuroblastic malignancies and its common loss in pancreatic poorly differentiated neuroendocrine neoplasms. These findings modify the role of ISL1 as a marker for pancreatic neuroendocrine neoplasms and suggest that ISL1 has a broader involvement in differentiation and growth of neuroendocrine neoplasms than has so far been assumed.

Naive B-cell trafficking is shaped by local chemokine availability and LFA-1-independent stromal interactions.

It is not known how naive B cells compute divergent chemoattractant signals of the T-cell area and B-cell follicles during in vivo migration. Here, we used two-photon microscopy of peripheral lymph nodes (PLNs) to analyze the prototype G-protein-coupled receptors (GPCRs) CXCR4, CXCR5, and CCR7 during B-cell migration, as well as the integrin LFA-1 for stromal guidance. CXCR4 and CCR7 did not influence parenchymal B-cell motility and distribution, despite their role during B-cell arrest in venules. In contrast, CXCR5 played a nonredundant role in B-cell motility in follicles and in the T-cell area. B-cell migration in the T-cell area followed a random guided walk model, arguing against directed migration in vivo. LFA-1, but not ��4 integrins, contributed to B-cell motility in PLNs. However, stromal network guidance was LFA-1 independent, uncoupling integrin-dependent migration from stromal attachment. Finally, we observed that despite a 20-fold reduction of chemokine expression in virus-challenged PLNs, CXCR5 remained essential for B-cell screening of antigen-presenting cells. Our data provide an overview of the contribution of prototype GPCRs and integrins during naive B-cell migration and shed light on the local chemokine availability that these cells compute.

An orienting response is not enough: Bivalency not infrequency causes the bivalency effect

When switching tasks, occasionally responding to bivalent stimuli (i.e., stimuli with relevant features for two different tasks) slows performance on subsequent univalent stimuli, even when they do not share relevant features with bivalent stimuli. This performance slowing is labelled the bivalency effect here, we investigated whether the bivalency effect results from an orienting response to the infrequent stimuli (i.e., the bivalent stimuli). To this end, we compared the impact of responding to infrequent univalent stimuli to the impact of responding to infrequent bivalent stimuli. For the latter, the results showed a performance slowing for all trials following bivalent stimuli. This indicates a long-lasting bivalency effect, replicating previous findings. For infrequent univalent stimuli, however, the results showed a smaller and shorter-lived performance slowing. These results demonstrate that the bivalency effect does not simply reflect an orienting response to infrequent stimuli. Rather it results from the conflict induced by bivalent stimuli, probably by episodic binding with the more demanding context created by them.

Reading performance is not affected by a prism induced increase of horizontal and vertical vergence demand

PURPOSE Dyslexia is the most common developmental reading disorder that affects language skills. Latent strabismus (heterophoria) has been suspected to be causally involved. Even though phoria correction in dyslexic children is commonly applied, the evidence in support of a benefit is poor. In order to provide experimental evidence on this issue, we simulated phoria in healthy readers by modifying the vergence tone required to maintain binocular alignment. METHODS Vergence tone was altered with prisms that were placed in front of one eye in 16 healthy subjects to induce exophoria, esophoria, or vertical phoria. Subjects were to read one paragraph for each condition, from which reading speed was determined. Text comprehension was tested with a forced multiple choice test. Eye movements were recorded during reading and subsequently analyzed for saccadic amplitudes, saccades per 10 letters, percentage of regressive (backward) saccades, average fixation duration, first fixation duration on a word, and gaze duration. RESULTS Acute change of horizontal and vertical vergence tone does neither significantly affect reading performance nor reading associated eye movements. CONCLUSION Prisms in healthy subjects fail to induce a significant change of reading performance. This finding is not compatible with a role of phoria in dyslexia. Our results contrast the proposal for correcting small angle heterophorias in dyslexic children.

The Initial Slope of the Variogram, Foundation of the Trabecular Bone Score, Is Not or Poorly Associated With Vertebral Strength

Trabecular bone score (TBS) rests on the textural analysis of DXA to reflect the decay in trabecular structure characterising osteoporosis. Yet, its discriminative power in fracture studies remains incomprehensible as prior biomechanical tests found no correlation with vertebral strength. To verify this result possibly due to an unrealistic set-up and to cover a wide range of loading scenarios, the data from three previous biomechanical studies using different experimental settings was used. They involved the compressive failure of 62 human lumbar vertebrae loaded 1) via intervertebral discs to mimic the in vivo situation (���full vertebra���), 2) via the classical endplate embedding (���vertebral body���) or 3) via a ball joint to induce anterior wedge failure (���vertebral section���). HR-pQCT scans acquired prior testing were used to simulate anterior-posterior DXA from which areal bone mineral density (aBMD) and the initial slope of the variogram (ISV), the early definition of TBS, were evaluated. Finally, the relation of aBMD and ISV with failure load (Fexp) and apparent failure stress (��exp) was assessed and their relative contribution to a multi-linear model was quantified via ANOVA. We found that, unlike aBMD, ISV did not significantly correlate with Fexp and ��exp, except for the ���vertebral body��� case (r2���=���0.396, p���=���0.028). Aside from the ���vertebra section��� set-up where it explained only 6.4% of ��exp (p���=���0.037), it brought no significant improvement to aBMD. These results indicate that ISV, a replica of TBS, is a poor surrogate for vertebral strength no matter the testing set-up, which supports the prior observations and raises a fortiori the question of the deterministic factors underlying the statistical relationship between TBS and vertebral fracture risk.

Generosity is a sign of trustworthiness���the punishment of selfishness is not

Peer-punishment is an important determinant of cooperation in human groups. It has been suggested that, at the proximate level of analysis, punitive preferences can explain why humans incur costs to punish their deviant peers. How punitive preferences could have evolved in humans is still not entirely understood. A possible explanation at the ultimate level of analysis comes from signaling theory. It has been argued that the punishment of defectors can be a type-separating signal of the punisher's cooperative intent. As a result, punishers are selected more often as interaction partners in social exchange and are partly compensated for the costs they incur when punishing defectors. A similar argument has been made with regard to acts of generosity. In a laboratory experiment, we investigate whether the punishment of a selfish division of money in a dictator game is a sign of trustworthiness and whether punishers are more trustworthy interaction partners in a trust game than non-punishers. We distinguish between second-party and third-party punishment and compare punitive acts with acts of generosity as signs of trustworthiness. We find that punishers are not more trustworthy than non-punishers and that punishers are not trusted more than non-punishers, both in the second-party and in the third-party punishment condition. To the contrary, second-party punishers are trusted less than their non-punishing counterparts. However, participants who choose a generous division of money are more trustworthy and are trusted more than participants who choose a selfish division or participants about whom no information is available. Our results suggest that, unlike for punitive acts, the signaling benefits of generosity are to be gained in social exchange.

RETINAL LAYER RESPONSE TO RANIBIZUMAB DURING TREATMENT OF DIABETIC MACULAR EDEMA: Thinner is Not Always Better.

PURPOSE To identify individual retinal layer thickness changes associated with visual acuity gain in diabetic macular edema treated with ranibizumab using layer segmentation on high-resolution optical coherence tomography scans. METHODS Retrospective observational case series. Thirty-three treatment-naive eyes with diabetic macular edema were imaged by spectral domain optical coherence tomography at monthly visits while receiving intravitreal ranibizumab treatment as needed, guided by visual acuity. Thickness changes of individual layers after 1 year were quantitatively analyzed and correlated with visual acuity gain. RESULTS The mean best-corrected visual acuity improvement at 1 year was 6.2 (SEM �� 1.5) Early Treatment Diabetic Retinopathy Study letters, and central retinal thickness decreased by 66 �� 18 ��m. In the central subfield, there was a significant decrease of thickness for all layers (P < 0.05) except the outer nuclear layer. Multiple linear regression analysis revealed that thickness decrease of the inner retina was associated with better visual acuity, whereas for the outer retina the opposite was true. The best estimate of final visual acuity (R = 0.817, P < 0.001) was obtained, by including baseline visual acuity and thickness change of the inner and outer plexiform layers in the model. CONCLUSION Whereas thickness decrease of the inner retina was positively associated with visual acuity gain, the opposite was found for the outer retina. This might be indirect evidence for recovery of the outer retina during ranibizumab treatment.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

More Is Not Always Better: An Experimental Individual-Level Validation of the Randomized Response Technique and the Crosswise Model

Social desirability and the fear of sanctions can deter survey respondents from responding truthfully to sensitive questions. Self-reports on norm breaking behavior such as shoplifting, non-voting, or tax evasion may therefore be subject to considerable misreporting. To mitigate such misreporting, various indirect techniques for asking sensitive questions, such as the randomized response technique (RRT), have been proposed in the literature. In our study, we evaluate the viability of several variants of the RRT, including the recently proposed crosswise-model RRT, by comparing respondents��� self-reports on cheating in dice games to actual cheating behavior, thereby distinguishing between false negatives (underreporting) and false positives (overreporting). The study has been implemented as an online survey on Amazon Mechanical Turk (N = 6,505). Our results indicate that the forced-response RRT and the unrelated-question RRT, as implemented in our survey, fail to reduce the level of misreporting compared to conventional direct questioning. For the crosswise-model RRT, we do observe a reduction of false negatives (that is, an increase in the proportion of cheaters who admit having cheated). At the same time, however, there is an increase in false positives (that is, an increase in non-cheaters who falsely admit having cheated). Overall, our findings suggest that none of the implemented sensitive questions techniques substantially outperforms direct questioning. Furthermore, our study demonstrates the importance of distinguishing false negatives and false positives when evaluating the validity of sensitive question techniques.

Bok Is Not Pro-Apoptotic But Suppresses Poly ADP-Ribose Polymerase-Dependent Cell Death Pathways and Protects against Excitotoxic and Seizure-Induced Neuronal Injury.

UNLABELLED Bok (Bcl-2-related ovarian killer) is a Bcl-2 family member that, because of its predicted structural homology to Bax and Bak, has been proposed to be a pro-apoptotic protein. In this study, we demonstrate that Bok is highly expressed in neurons of the mouse brain but thatbokwas not required for staurosporine-, proteasome inhibition-, or excitotoxicity-induced apoptosis of cultured cortical neurons. On the contrary, we found thatbok-deficient neurons were more sensitive to oxygen/glucose deprivation-induced injuryin vitroand seizure-induced neuronal injuryin vivo Deletion ofbokalso increased staurosporine-, excitotoxicity-, and oxygen/glucose deprivation-induced cell death inbax-deficient neurons. Single-cell imaging demonstrated thatbok-deficient neurons failed to maintain their neuronal Ca(2+)homeostasis in response to an excitotoxic stimulus; this was accompanied by a prolonged deregulation of mitochondrial bioenergetics.bokdeficiency led to a specific reduction in neuronal Mcl-1 protein levels, and deregulation of both mitochondrial bioenergetics and Ca(2+)homeostasis was rescued by Mcl-1 overexpression. Detailed analysis of cell death pathways demonstrated the activation of poly ADP-ribose polymerase-dependent cell death inbok-deficient neurons. Collectively, our data demonstrate that Bok acts as a neuroprotective factor rather than a pro-death effector during Ca(2+)- and seizure-induced neuronal injuryin vitroandin vivo SIGNIFICANCE STATEMENT Bcl-2 proteins are essential regulators of the mitochondrial apoptosis pathway. The Bcl-2 protein Bok is highly expressed in the CNS. Because of its sequence similarity to Bax and Bak, Bok has long been considered part of the pro-apoptotic Bax-like subfamily, but no studies have yet been performed in neurons to test this hypothesis. Our study provides important new insights into the functional role of Bok during neuronal apoptosis and specifically in the setting of Ca(2+)- and seizure-mediated neuronal injury. We show that Bok controls neuronal Ca(2+)homeostasis and bioenergetics and, contrary to previous assumptions, exerts neuroprotective activitiesin vitroandin vivo Our results demonstrate that Bok cannot be placed unambiguously into the Bax-like Bcl-2 subfamily of pro-apoptotic proteins.