Miracle-dz/UniFAR-FTUs huggingface dataset:
Recent advances in acetylcholinesterase Inhibitors and Reactivators: an update on the patent literature (2012-2015)

ABSTRACT Introduction: Acetylcholinesterase (AChE) is the major enzyme that hydrolyzes acetylcholine, a key neurotransmitter for synaptic transmission, into acetic acid and choline. Mild inhibition of AChE has been shown to have therapeutic relevance in Alzheimer’s disease (AD), myasthenia gravis, and glaucoma among others. In contrast, strong inhibition of AChE can lead to cholinergic poisoning. To combat this, AChE reactivators have to be developed to remove the offending AChE inhibitor, restoring acetylcholine levels to normal. Areas covered: This article covers recent advances in the development of acetylcholinesterase modulators, including both inhibitors of acetylcholinesterase for the efforts in development of new chemical entities for treatment of AD, as well as re-activators for resurrection of organophosphate bound acetylcholinesterase. Expert opinion: Over the past three years, research efforts have continued to identify novel small molecules as AChE inhibitors for both CNS and peripheral diseases. The more recent patent activity has focused on three AChE ligand design areas: derivatives of known AChE ligands, natural product based scaffolds and multifunctional ligands, all of which have produced some unique chemical matter with AChE inhibition activities in the mid picomolar to low micromolar ranges. New AChE inhibitors with polypharmacology or dual inhibitory activity have also emerged as highlighted by new AChE inhibitors with dual activity at L-type calcium channels, GSK-3, BACE1 and H3, although most only show low micromolar activity, thus further research is warranted. New small molecule reactivators of organophosphate-inhibited AChE have also been disclosed, which focused on the design of neutral ligands with improved pharmaceutical properties and blood-brain barrier (BBB) penetration. Gratifyingly, some research in this area is moving away from the traditional quaternary pyridinium oximes AChE reactivators, while still employing the necessary reactivation group (oximes). However, selectivity over inhibition of native AChE enzyme, effectiveness of reactivation, broad-spectrum reactivation against multiple organophosphates and reactivation of aged-enzyme continue to be hurdles for this area of research.
Are sigma modulators an effective opportunity for cancer treatment? A patent overview (1996-2016)

ABSTRACT Introduction: Although several molecular targets against cancer have been identified, there is a continuous need for new therapeutic strategies. Sigma Receptors (SRs) overexpression has been recently associated with different cancer conditions. Therefore, novel anticancer agents targeting SRs may increase the specificity of therapies, overcoming some of the common drawbacks of conventional chemotherapy. Areas covered: The present review focuses on patent documents disclosing SR modulators with possible application in cancer therapy and diagnosis. The analysis reviews patents of the last two decades (1996–2016); patents were grouped according to target subtypes (S1R, S2R, pan-SRs) and relevant Applicants. The literature was searched through Espacenet, ISI Web, PatentScope and PubMed databases. Expert opinion: The number of patents related to SRs and cancer has increased in the last twenty years, confirming the importance of this receptor family as valuable target against neoplasias. Despite their short history in the cancer scenario, many SR modulators are at pre-clinical stage and one is undergoing a phase II clinical trial. SRs ligands may represent a powerful source of innovative antitumor therapeutics. Further investigation is needed for validating SR modulators as anti-cancer drugs. We strongly hope that this review could stimulate the interest of both Academia and pharmaceutical companies.
The knockdown of maternal glucocorticoid receptor mRNA alters embryo development in zebrafish

In zebrafish, ovulated oocytes contain both maternal cortisol and the mRNA for the glucocorticoid receptor (gr), which is spread as granular structures throughout the ooplasm. At 0.2 hpf, this transcript is relocated in the blastodisc area and partitioned among blastomeres. At 6–8 hpf, it is replaced by zygotic transcript. We used morpholinos to block translation of both maternal and zygotic gr transcripts, and a missplicing morpholino to block post‐transcriptionally the zygotic transcript alone. Only knockdown of translation produced an increase of apoptosis and subsequent craniofacial and caudal deformities with severe malformations of neural, vascular, and visceral organs in embryos and 5‐dpf larvae. Such defects were rescued with trout gr2 mRNA. Microarray analysis revealed that 114 and 37 highly expressed transcripts were up‐ and down‐regulated, respectively, by maternal Gr protein deficiency in 5‐hpf embryos. These results indicate that the maternal gr transcript and protein participate in the maternal programming of zebrafish development. Developmental Dynamics 240:874–889, 2011. © 2011 Wiley‐Liss, Inc.
Detection of isoform‐specific fibroblast growth factor receptors by whole‐mount in situ hybridization in early chick embryos

We have developed “b” and “c” isoform‐specific chicken fibroblast growth factor (FGF) receptor 1–3 probes for in situ hybridization. We rigorously demonstrate the specificity of these probes by using both dot blot hybridization and whole‐mount in situ hybridization during neurulation and early postneurulation stages, and we compare expression patterns of each of the three isoform‐specific probes to one another and to generic probes to each of the three (non–isoform‐specific) FGF receptors. We show that the expression pattern of each receptor is represented by the collective expression of each of its two isoforms, with the expression of each FGF receptor being most similar to that of its “c” isoform at two of the three stages studied, and that tissue and stage differences exist in the patterns of expression of the six isoforms. We demonstrate the usefulness of these probes for defining the differential tissue expression of FGF receptor 1–3 isoforms. Developmental Dynamics 240:1537–1547, 2011. © 2011 Wiley‐Liss, Inc.
Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia

ABSTRACT Introduction: Frontline chemotherapy is successful against chronic lymphocytic leukemia (CLL), but results in untoward toxicity. Further, prognostic factors, cytogenetic anomalies, and compensatory cellular signaling lead to therapy resistance or disease relapse. Therefore, for the past few years, development of targeted therapies is on the rise. PI3K is a major player in the B-cell receptor (BCR) signaling axis, which is critical for the survival and maintenance of B cells. Duvelisib, a PI3K δ/γ dual isoform specific inhibitor that induces apoptosis and reduces cytokine and chemokine levels in vitro, holds promise for CLL. Areas covered: Herein, we review PI3K isoforms and their inhibitors in general, and duvelisib in particular; examine literature on preclinical investigations, pharmacokinetics and clinical studies of duvelisib either as single agent or in combination, for patients with CLL and other lymphoid malignancies. Expert opinion: Duvelisib targets the PI3K δ isoform, which is necessary for cell proliferation and survival, and γ isoform, which is critical for cytokine signaling and pro-inflammatory responses from the microenvironment. In phase I clinical trials, duvelisib as a single agent showed promise for CLL and other lymphoid malignancies. Phase II and III trials of duvelisib alone or in combination with other agents are ongoing.
Avian intervertebral disc arises from rostral sclerotome and lacks a nucleus pulposus: Implications for evolution of the vertebrate disc

Deterioration of the intervertebral discs is an unfortunate consequence of aging. The intervertebral disc in mammals is composed of three parts: a jelly‐like center called the nucleus pulposus, the cartilaginous annulus fibrosus, and anterior and posterior endplates that attach the discs to vertebrae. To understand the origin of the disc, we have investigated the intervertebral region of chickens. Surprisingly, our comparison of mouse and chicken discs revealed that chicken discs lack nuclei pulposi. In addition, the notochord, which in mice forms nuclei pulposi, was found to persist as a rod‐like structure and express Shh throughout chicken embryogenesis. Our fate mapping data indicate that cells originating from the rostral half of each somite are responsible for forming the avian disc while cells in the caudal region of each somite form vertebrae. A histological analysis of mammalian and nonmammalian organisms suggests that nuclei pulposi are only present in mammals. Developmental Dynamics 241:675–683, 2012. © 2012 Wiley Periodicals, Inc.
Optic tectum morphogenesis: A step‐by‐step model based on the temporal–spatial organization of the cell proliferation. Significance of deterministic and stochastic components subsumed in the spatial organization

Background: Cell proliferation plays an important morphogenetic role. This work analyzes the temporal–spatial organization of cell proliferation as an attempt to understand its contribution to the chick optic tectum (OT) morphogenesis. Results: A morphogenetic model based on space‐dependent differences in cell proliferation is presented. Step1: a medial zone of high mitotic density (mZHMD) appears at the caudal zone. Step2: the mZHMD expands cephalically forming the dorsal curvature and then duplicates into two bilateral ZHMDs (bZHMD). Step3: the bZHMDs move toward the central region of each hemitectum. Step4: the planar expansion of both bZHMD and a relative decrement in the dorsal midline growth produces a dorsal medial groove separating the tectal hemispheres. Step5: a relative caudal displacement of the bZHMDs produces the OT caudal curvature. Numerical sequences derived from records of mitotic cells spatial coordinates, analyzed as stochastic point processes, show that they correspond to 1/f(β) processes. The spatial organization subsumes deterministic and stochastic components. Conclusions: The deterministic component describes the presence of a long‐range influence that installs an asymmetric distribution of cell proliferation, i.e., an asymmetrically located ZHMD that print space‐dependent differences onto the tectal corticogenesis. The stochastic component reveals short‐range anti‐correlations reflecting spatial clusterization and synchronization between neighboring cells. Developmental Dynamics 241:1043–1061, 2012. © 2012 Wiley Periodicals, Inc.
Lineage tracing of the endoderm during oral development

Background: The contribution of the endoderm to the oral tissues of the head has been debated for many years. With the arrival of Cre/LoxP technology endoderm progenitor cells can now be genetically labeled and tissues derived from the endoderm traced. Using Sox17‐2A‐iCre/Rosa26 reporter mice we have followed the fate of the endoderm in the teeth, glands, and taste papillae of the oral cavity. Results: No contribution of the endoderm was observed at any stage of tooth development, or in development of the major salivary glands, in the reporter mouse during development. In contrast, the minor mucous glands of the tongue were found to be of endodermal origin, along with the circumvallate papilla and foliate papillae. The mucous minor salivary glands of the palate, however, were of mixed ectodermal and endodermal origin. Conclusions: In contrast to urodele studies, the epithelium of murine teeth is derived solely from the ectoderm. The border between the ectoderm‐ and endoderm‐derived epithelium may play a role in determining the position of the lingual glands and taste buds, and may explain differences observed between taste buds in the anterior and posterior part of the tongue. Developmental Dynamics 241:1183–1191, 2012. © 2012 Wiley Periodicals, Inc.
Slits affect the timely migration of neural crest cells via robo receptor

Background: Neural crest cells emerge by delamination from the dorsal neural tube and give rise to various components of the peripheral nervous system in vertebrate embryos. These cells change from non‐motile into highly motile cells migrating to distant areas before further differentiation. Mechanisms controlling delamination and subsequent migration of neural crest cells are not fully understood. Slit2, a chemorepellant for axonal guidance that repels and stimulates motility of trunk neural crest cells away from the gut has recently been suggested to be a tumor suppressor molecule. The goal of this study was to further investigate the role of Slit2 in trunk neural crest cell migration by constitutive expression in neural crest cells. Results: We found that Slit gain‐of‐function significantly impaired neural crest cell migration while Slit loss‐of‐function favored migration. In addition, we observed that the distribution of key cytoskeletal markers was disrupted in both gain and loss of function instances. Conclusions: These findings suggest that Slit molecules might be involved in the processes that allow neural crest cells to begin migrating and transitioning to a mesenchymal type. Developmental Dynamics 241:1274–1288, 2012. © 2012 Wiley Periodicals, Inc.
In vitro oocyte culture‐based manipulation of zebrafish maternal genes

In animals, females deposit gene products into developing oocytes, which drive early cellular events in embryos immediately after fertilization. As maternal gene products are present before fertilization, the functional manipulation of maternal genes is often challenging to implement, requiring gene expression or targeting during oogenesis. Maternal expression can be achieved through transgenesis, but transgenic approaches are time consuming and subject to undesired epigenetic effects. Here, we have implemented in vitro culturing of experimentally manipulated immature oocytes to study maternal gene contribution to early embryonic development in the zebrafish. We demonstrate phenotypic rescue of a maternal‐effect mutation by expressing wild‐type product in cultured oocytes. We also generate loss‐of‐function phenotypes in embryos through either the expression of a dominant‐negative transcript or injection of translation‐blocking morpholino oligonucleotides. Finally, we demonstrate subcellular localization during the early cell divisions immediately after fertilization of an exogenously provided maternal product fused to a fluorescent protein. These manipulations extend the potential to carry out genetic and imaging studies of zebrafish maternal genes during the egg‐to‐embryo transition. Developmental Dynamics 242:44–52, 2013. © 2012 Wiley Periodicals, Inc.
Spatiotemporal expression pattern of Myt/NZF family zinc finger transcription factors during mouse nervous system development

Three members of the Myt/NZF family of transcription factors are involved in many processes of vertebrate development. Several studies have reported that Myt1/NZF‐2 has a regulatory function in the development of cultured oligodendrocyte progenitors or in neuronal differentiation during Xenopus primary neurogenesis. However, little is known about the proper function of Myt/NZF family proteins during mammalian nervous system development. To assess the possible function of Myt/NZF transcription factors in mammalian neuronal differentiation, we determined the comparative spatial and temporal expression patterns of all three types of Myt/NZF family genes in the embryonic mouse nervous system using quantitative reverse transcriptase polymerase chain reaction and in situ hybridization. Results: All three Myt/NZF family genes were extensively expressed in developing mouse nervous tissues, and their expression was transient. NZF‐1 was expressed later in post‐mitotic neurons. NZF‐2 was initially expressed in neuronal cells a little earlier than NZF‐3. NZF‐3 was initially expressed in neuronal cells, just after proliferation was complete. Conclusion: These expression patterns suggest that the expression of NZF family genes is spatially and temporally regulated, and each Myt/NZF family gene may have a regulatory function in a specific phase during neuronal differentiation. Developmental Dynamics 243:588–600, 2014. © 2013 Wiley Periodicals, Inc.
The role of attention processes in facial affect recognition in schizophrenia

Introduction: Studies investigating the involvement of attention processes in facial affect recognition (FAR) have been contradictory, with some suggesting a generalised cognitive deficit, whereas others a specialised deficit in affect recognition. Given the ubiquity of both attention and emotion perception deficits in schizophrenia, we examined whether specific attentional processes, in fact, mediate FAR. Methods: Patients with schizophrenia (n = 38) and healthy controls (n = 24) performed tests assessing FAR and attention processes, specifically, visual attention (Trail Making Test A), sustained attention/inhibition (Rapid Visual Processing subtest; Cambridge Automated Neuropsychological Test Battery), and attention to details in facial features (AFF). AFF and FAR were assessed with newly devised experimental procedures. Results: Hierarchical multiple regression analyses showed a similar pattern of association between attention processes and FAR in both participant groups with respect to all attention processes investigated, predicting FAR accuracy. Additionally, visual attention predicted accuracy in happiness, disgust and surprise, whereas AFF predicted accuracy in anger and fear. Regarding FAR processing speed, no attention process predicted participants' performance on correct responses; AFF response speed predicted participants' FAR response speed, but only on incorrect responses. Discussion: The present findings highlight the role of attentional processes in emotion recognition, as deficits in the former were predictive of impairments in the latter. Furthermore, AFF appears to be involved in the discrimination of negatively valenced facial expressions. The lack of association between attentional processes and FAR processing speed, particularly regarding correct responses, might reflect the differential pattern of activation of cortical and subcortical structures involved in these cognitive processes.
Embryological manipulations in the developing Xenopus inner ear reveal an intrinsic role for Wnt signaling in dorsal–ventral patterning

Background: The inner ear develops from an ectodermal thickening known as the otic placode into a complex structure that is asymmetrical along both the anterior–posterior (A‐P) and dorsal–ventral (D‐V) axes. Embryological manipulations in Xenopus allow us to test regenerative potential along specific axes and timing of axis determination. We explore the role of Wnt signaling with gain and loss of function experiments. Results: In contrast to A or P half ablations, D or V half ablations almost never result in mirror duplications or normal ears. Instead there is a loss of structures, especially those associated with the ablated region. Rotation experiments inverting the D‐V axis reveal that it is determined by stage 24–26 which is just before expression of the dorsal otic marker Wnt3a. Conditional blocking of canonical Wnt signaling results in reductions in the number of sensory organs and semicircular canals which could be placed in one of three categories, the most common phenotypes being similar to those seen after dorsal ablations. Conclusions: There is less regenerative potential along the D‐V axis. Wnt3a protein alone is sufficient to rescue the severe loss of inner ear structures resulting from dorsal but not ventral half ablations. Developmental Dynamics 243:1262–1274, 2014. © 2014 Wiley Periodicals, Inc.
Sonic hedgehog–expressing basal cells are general post‐mitotic precursors of functional taste receptor cells

Background: Taste buds contain ∼60 elongate cells and several basal cells. Elongate cells comprise three functional taste cell types: I, glial cells; II, bitter/sweet/umami receptor cells; and III, sour detectors. Although taste cells are continuously renewed, lineage relationships among cell types are ill‐defined. Basal cells have been proposed as taste bud stem cells, a subset of which express Sonic hedgehog (Shh). However, Shh+ basal cells turn over rapidly suggesting that Shh+ cells are post‐mitotic precursors of some or all taste cell types. Results: To fate map Shh‐expressing cells, mice carrying ShhCreERT2 and a high (CAG‐CAT‐EGFP) or low (R26RLacZ) efficiency reporter allele were given tamoxifen to activate Cre in Shh+ cells. Using R26RLacZ, lineage‐labeled cells occur singly within buds, supporting a post‐mitotic state for Shh+ cells. Using either reporter, we show that Shh+ cells differentiate into all three taste cell types, in proportions reflecting cell type ratios in taste buds (I > II > III). Conclusions: Shh+ cells are not stem cells, but are post‐mitotic, immediate precursors of taste cells. Shh+ cells differentiate into each of the three taste cell types, and the choice of a specific taste cell fate is regulated to maintain the proper ratio within buds. Developmental Dynamics 243:1286–1297, 2014. © 2014 Wiley Periodicals, Inc.
The effect of self-monitoring on Wisconsin Card Sorting Test performance in euthymic patients with bipolar disorder: a pilot study

ABSTRACT Objectives: Euthymic patients with bipolar disorder (BD) show executive impairment. Assisting cognitive function with non-pharmacological strategies has not been widely explored in BD. In schizophrenia, concomitant verbalisation (self-monitoring) during executive tests improved performance. The present pilot study assesses the effects of self-monitoring whilst completing the Wisconsin Card Sorting Test (WCST) in BD patients. Methods: Thirty-six euthymic BD patients and 42 healthy controls participated. Twenty patients with BD and 20 controls received standard administration and 16 patients and 22 controls used self-monitoring during the test. Results: ANCOVA revealed a significant “group by administration” interaction. Patients who received the standard administration were significantly worse than healthy controls (trials administered: p = .012, η p 2 = 0.17; trials to first category: p = .046, η p 2 = 0.11; failure to maintain set: p = .003, η p 2 = 0.23). BD patients who self-monitored performed significantly better than patients receiving the standard administration (trials to first category: p = .020, η p 2 = 0.17) and showed no significant differences in performance compared to controls. Conclusion: Self-monitoring deserves further investigation as a tool that may be helpful for patients with BD. Further exploration of the utility, generalisability, and stability of the effects of self-monitoring is needed.