The elusive nature of the blocking effect: 15 failures to replicate

With the discovery of the blocking effect, learning theory took a huge leap forward, because blocking provided a crucial clue that surprise is what drives learning. This in turn stimulated the development of novel association-formation theories of learning. Eventually, the ability to explain blocking became nothing short of a touchstone for the validity of any theory of learning, including propositional and other nonassociative theories. The abundance of publications reporting a blocking effect and the importance attributed to it suggest that it is a robust phenomenon. Yet, in the current article we report 15 failures to observe a blocking effect despite the use of procedures that are highly similar or identical to those used in published studies. Those failures raise doubts regarding the canonical nature of the blocking effect and call for a reevaluation of the central status of blocking in theories of learning. They may also illustrate how publication bias influences our perspective toward the robustness and reliability of seemingly established effects in the psychological literature

A Periaxonal Net in the Zebrafish Central Nervous System

We produced a monoclonal antibody, named A20, which specifically recognizes a 35 kDa protein and stains myelinated axons in zebrafish brain. The A20 antigen is located at the outside of the myelin layer of large axons, and comprises a fine meshwork composed of thin unit fibers about 1–2 μm in length and about 100–200 nm in thickness. The unit fibers form pentagonal and hexagonal structures, which further polymerize into an envelope structure on the axons. The A20 monoclonal antibody did not stain neuronal cell bodies nor synapses. Instead, the distribution of the A20 antigen was along axons, practically coincident with the distribution of myelin basic protein. The monoclonal antibody stained only axons in the central nervous system (CNS), and not the extracellular matrix surrounding Schwann cells. These results suggest that this antigenic meshwork (which we call the periaxonal net) is synthesized by oligodendrocytes. During the development of the zebrafish brain, the periaxonal net appeared after the formation of myelin on the axons. The periaxonal net developed first at the brain stem, then gradually appeared at the caudal end of the spinal cord. The thickness of the periaxonal net around the Mauthner axon changed during development. Although the thickness of the Mauthner axon continues to grow throughout life, the thickness of periaxonal net stopped growing at 6 months after fertilization

Failures to replicate blocking are surprising and informative : reply to Soto

The blocking effect has inspired numerous associative learning theories and is widely cited in the literature. We recently reported a series of 15 experiments that failed to obtain a blocking effect in rodents. Based on those consistent failures, we claimed that there is a lack of insight into the boundary conditions for blocking. In his commentary, Soto (in press) argues that contemporary associative learning theory does provide a specific boundary condition for the occurrence of blocking, namely the use of same- versus different-modality stimuli. Given that in ten of our 15 experiments same-modality stimuli were used, he claims that our failure to observe a blocking effect is unsurprising. We cannot but disagree with that claim, because of theoretical, empirical, and statistical problems with his analysis. We also address two other possible reasons for a lack of blocking that are referred to in Soto's (in press) analysis, related to generalization and salience, and dissect the potential importance of both. While Soto's (in press) analyses raises a number of interesting points, we see more merit in an empirically guided analysis and call for empirical testing of boundary conditions on blocking

Shp-2 Is Dispensable for Establishing T Cell Exhaustion and for PD-1 Signaling In Vivo.

In chronic infection and cancer, T cells acquire a dysfunctional state characterized by the expression of inhibitory receptors. In vitro studies implicated the phosphatase Shp-2 downstream of these receptors, including PD-1. However, whether Shp-2 is responsible in vivo for such dysfunctional responses remains elusive. To address this, we generated T cell-specific Shp-2-deficient mice. These mice did not show differences in controlling chronic viral infections. In this context, Shp-2-deleted CD8 <sup>+</sup> T lymphocytes expanded moderately better but were less polyfunctional than control cells. Mice with Shp-2-deficient T cells also showed no significant improvement in controlling immunogenic tumors and responded similarly to controls to α-PD-1 treatment. We therefore showed that Shp-2 is dispensable in T cells for globally establishing exhaustion and for PD-1 signaling in vivo. These results reveal the existence of redundant mechanisms downstream of inhibitory receptors and represent the foundation for defining these relevant molecular events

Finn Malmgren and polar exploration

The research aims to reconstruct a transnational history of Finn Malmgren’s contribution to the exploration of the Arctic, with a specific focus on the polar air expeditions of Norge (1926) and Italia (1928). The analysis of archive sources consulted in Italy, Norway, and Sweden sheds light on some key aspects of these two expeditions. In particular, the study of numerous unpublished documents – from the correspondence with personalities such as Umberto Nobile and Anna Nordenskjöld to the contemporary testimonies of Adalberto Mariano and Filippo Zappi – offers new insights into issues such as the international meteorological cooperation during the preparation of the Norge expedition and the march on the pack of Malmgren, Mariano and Zappi

Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production

open2The increasing emergence of bacteria producing β-lactamases enzymes (BLEs), able to inactivate the available β-lactam antibiotics (BLAs), causing the hydrolytic opening of their β-lactam ring, is one of the global major warnings. According to Ambler classification, BLEs are grouped in serine-BLEs (SBLEs) of class A, C, and D, and metal-BLEs (MBLEs) of class B. A current strategy to restore no longer functioning BLAs consists of associating them to β-lactamase enzymes inhibitors (BLEsIs), which, interacting with BLEs, prevent them hydrolyzing to the associated antibiotic. Worryingly, the inhibitors that are clinically approved are very few and inhibit only most of class A and C SBLEs, leaving several class D and all MBLEs of class B untouched. Numerous non-clinically approved new molecules are in development, which have shown broad and ultra-broad spectrum of action, some of them also being active on the New Delhi metal-β-lactamase-1 (NDM-1), which can hydrolyze all available BLAs except for aztreonam. To not duplicate the existing review concerning this topic, we have herein examined BLEsIs by a chemistry approach. To this end, we have reviewed both the long-established synthesis adopted to prepare the old BLEsIs, those proposed to achieve the BLEsIs that are newly approved, and those recently reported to prepare the most relevant molecules yet in development, which have shown high potency, providing for each synthesis the related reaction scheme.openAlfei, Silvana; Zuccari, GuendalinaAlfei, Silvana; Zuccari, Guendalin

N,N,N-Tris(tert-butoxycarbonyl)-l-arginine: five isoforms whose obtainment depends on procedure and scrupulous NMR confirmation of their structures

L-arginine is often covalently linked to vectors for gene or drug delivery as a means of increasing their transfection activity and reducing toxicity. This strategy relies on the protection of basic nitrogen atoms, for example, by employing the tert-butoxycarbonyl group. Our aim in the present work was to prepare the widely described\uce\ub1N,\ucf\u89N,\ucf\u89\ue2\u80\ub2N-tris(tert-butyloxycarbonyl)-l-arginine as a single isomer in high yield and with high levels of purity for use in the esterification of dendrimers with several peripheral hydroxyl groups. Following three reported protocols which assured this goal, we observed the unexpected formation of four additional isomers. Using the first procedure,\uce\ub1N,\ucf\u89N,\ucf\u89\ue2\u80\ub2N-tris(tert-butyloxycarbonyl)-l-arginine was never obtained. The second procedure delivered the desired compound as a mixture of geometric isomers (E/Z), while the third protocol led to a single isomer in high yield and purity, but with an unreported symmetrical structure. Since Boc protection is transient, this discovery would seem to be of little interest, but preliminary results from an ongoing investigation of the behavior of each of the isomers obtained in the esterification reactions of interest has shown that their reactivity depends on their structure. Although this research is ongoing, here we report a detailed description of these unexpected results, along with an NMR investigation focusing on the double-bond geometry and position which enabled confirmation of the structures

An optimized and very detailed, grams scale synthesis of CTEP, through a complete characterization of all the isolated and purified intermediates

Glutamate is the major excitatory neurotransmitter in the brain. 2-Chloro-4-[2,5-dimethyl-1-(4-trifluoromethoxyphenyl)-1H-imidazol-4-ylethynyl]pyridine (5) (CTEP) is the first reported negative allosteric modulator of the metabotropic glutamate receptor 5 (mGlu5NAM) with a biological half-life of 48 hours in rodents and therefore considered an ideal tool for chronic studies in rats and mice. In this work an optimized protocol for the synthesis and purification of CTEP is reported. Through the developed new work up scrupulously described in detail, CTEP was obtained in 63 % yield, with a significant improvement in comparison with the methods reported in literature (27%) and in a tripled overall yield (27% versus 9%). Furthermore, all the intermediates between which the unreported multifunctional and appealing compound 8 as well as the final compound 5 were isolated, purified and fully characterized by IR, NMR (1H NMR and 13C NMR), melting point, except for the oily 7, and Elemental analysis

DCision-making in tumors governs T cell anti-tumor immunity.

The exploitation of T cell-based immunotherapies and immune checkpoint blockade for cancer treatment has dramatically shifted oncological treatment paradigms and broadened the horizons of cancer immunology. Dendritic cells have emerged as the critical tailors of T cell immune responses, which initiate and coordinate anti-tumor immunity. Importantly, genetic alterations in cancer cells, cytokines and chemokines produced by cancer and stromal cells, and the process of tumor microenvironmental regulation can compromise dendritic cell-T cell cross-talk, thereby disrupting anti-tumor T cell responses. This review summarizes how T cell activation is controlled by dendritic cells and how the tumor microenvironment alters dendritic cell properties in the context of the anti-tumor immune cycle. Furthermore, we will highlight therapeutic options for tailoring dendritic cell-mediated decision-making in T cells for cancer treatment