Miracle-dz/UniFAR-FTUs huggingface dataset:
Application of human pancreatic carcinoid BON cells for receptor-targeted drug development

In our previous study, we found that several tumor cell lines displayed high receptor-specific binding affinity, one of which, the human pancreatic carcinoid BON cell line, demonstrates high affinity binding of the bombesin (BN) and somatostatin (SST) receptor-specific ligands. In the present study, BON cells, as a representative model, were further applied to evaluate various peptide analogs and cytotoxic receptor-targeted peptide conjugates. We observed quick ligand–receptor internalization in BON cells as well as high binding affinity. Furthermore, BON cells have high expression of multidrug resistance-associated genes (MDR1) and show camptothecin (CPT) resistance. Various receptor-specific cytotoxic conjugates were synthesized and evaluated in the BON cell model via in vitro and in vivo studies. We found that all the tested conjugates displayed potent antitumor ability in xenografts. Especially, the CPT conjugates, CPT-SST, and CPT-BN, are most likely to increase sensitivity to CPT-resistant BON cells. Our findings suggest that appropriately defined tumor cell lines may provide physiologically relevant cell-based evaluations of novel peptide analogs and receptor-targeted chemotherapeutics.
Neto2 Assembles with Kainate Receptors in DRG Neurons during Development and Modulates Neurite Outgrowth in Adult Sensory Neurons

Peripheral sensory neurons in the dorsal root ganglia (DRG) are the initial transducers of sensory stimuli, including painful stimuli, from the periphery to central sensory and pain-processing centers. Small- to medium-diameter non-peptidergic neurons in the neonatal DRG express functional kainate receptors (KARs), one of three subfamilies of ionotropic glutamate receptors, as well as the putative KAR auxiliary subunit Neuropilin- and tolloid-like 2 (Neto2). Neto2 alters recombinant KAR function markedly but has yet to be confirmed as an auxiliary subunit that assembles with and alters the function of endogenous KARs. KARs in neonatal DRG require the GluK1 subunit as a necessary constituent, but it is unclear to what extent other KAR subunits contribute to the function and proposed roles of KARs in sensory ganglia, which include promotion of neurite outgrowth and modulation of glutamate release at the DRG–dorsal horn synapse. In addition, KARs containing the GluK1 subunit are implicated in modes of persistent but not acute pain signaling. We show here that the Neto2 protein is highly expressed in neonatal DRG and modifies KAR gating in DRG neurons in a developmentally regulated fashion in mice. Although normally at very low levels in adult DRG neurons, Neto2 protein expression can be upregulated via MEK/ERK signaling and after sciatic nerve crush and Neto2−/− neurons from adult mice have stunted neurite outgrowth. These data confirm that Neto2 is a bona fide KAR auxiliary subunit that is an important constituent of KARs early in sensory neuron development and suggest that Neto2 assembly is critical to KAR modulation of DRG neuron process outgrowth. SIGNIFICANCE STATEMENT Pain-transducing peripheral sensory neurons of the dorsal root ganglia (DRG) express kainate receptors (KARs), a subfamily of glutamate receptors that modulate neurite outgrowth and regulate glutamate release at the DRG–dorsal horn synapse. The putative KAR auxiliary subunit Neuropilin- and tolloid-like 2 (Neto2) is also expressed in DRG. We show here that it is a developmentally downregulated but dynamic component of KARs in these neurons, that it contributes to regulated neurite regrowth in adult neurons, and that it is increased in adult mice after nerve injury. Our data confirm Neto2 as a KAR auxiliary subunit and expand our knowledge of the molecular composition of KARs in nociceptive neurons, a key piece in understanding the mechanistic contribution of KAR signaling to pain-processing circuits.
Media coverage of mental health care in the UK, USA and Australia

AIMS AND METHOD We aimed to assess the contents and tone of articles on mental health care in the UK print media by comparing them with reporting in the USA and Australia. Two broadsheets from each country were analysed using the Internet for a random 4 months over a 1-year period. The number of articles, their content and the views expressed in them were identified and compared. RESULTS A total of 118 articles on mental health care issues were found. The predominant tone of the articles in all three countries was negative, though there were slightly more positive articles in the USA and Australian media. Positive articles highlighted in the UK media covered mostly medical conferences and research findings. CLINICAL IMPLICATIONS Efforts to achieve a more positive attitude towards people with mental illnesses in the public, such as anti-stigma campaigns, operate against a background of predominantly negative coverage of mental health care issues in broadsheets. The coverage in the UK may tend to be even less positive than in the USA and Australia. Medical conferences and research findings can, however, be used to promote positive views of mental health care in the media.
Advanced glycation end products

Aging is the progressive accumulation of damage to an organism over time leading to disease and death. Aging research has been very intensive in the last years aiming at characterizing the pathophysiology of aging and finding possibilities to fight age-related diseases. Various theories of aging have been proposed. In the last years advanced glycation end products (AGEs) have received particular attention in this context. AGEs are formed in high amounts in diabetes but also in the physiological organism during aging. They have been etiologically implicated in numerous diabetes- and age-related diseases. Strategies inhibiting AGE accumulation and signaling seem to possess a therapeutic potential in these pathologies. However, still little is known on the precise role of AGEs during skin aging. In this review the existing literature on AGEs and skin aging will be reviewed. In addition, existing and potential anti-AGE strategies that may be beneficial on skin aging will be discussed.
Cannabinoids Activate Monoaminergic Signaling to Modulate Key C. elegans Behaviors

Cannabis sativa, or marijuana, a popular recreational drug, alters sensory perception and exerts a range of potential medicinal benefits. The present study demonstrates that the endogenous cannabinoid receptor agonists 2-arachidonoylglycerol (2-AG) and anandamide (AEA) activate a canonical cannabinoid receptor in Caenorhabditis elegans and also modulate monoaminergic signaling at multiple levels. 2-AG or AEA inhibit nociception and feeding through a pathway requiring the cannabinoid-like receptor NPR-19. 2-AG or AEA activate NPR-19 directly and cannabinoid-dependent inhibition can be rescued in npr-19-null animals by the expression of a human cannabinoid receptor, CB1, highlighting the orthology of the receptors. Cannabinoids also modulate nociception and locomotion through an NPR-19-independent pathway requiring an α2A-adrenergic-like octopamine (OA) receptor, OCTR-1, and a 5-HT1A-like serotonin (5-HT) receptor, SER-4, that involves a complex interaction among cannabinoid, octopaminergic, and serotonergic signaling. 2-AG activates OCTR-1 directly. In contrast, 2-AG does not activate SER-4 directly, but appears to enhance SER-4-dependent serotonergic signaling by increasing endogenous 5-HT. This study defines a conserved cannabinoid signaling system in C. elegans, demonstrates the cannabinoid-dependent activation of monoaminergic signaling, and highlights the advantages of studying cannabinoid signaling in a genetically tractable whole-animal model. SIGNIFICANCE STATEMENT Cannabis sativa, or marijuana, causes euphoria and exerts a wide range of medicinal benefits. For years, cannabinoids have been studied at the cellular level using tissue explants with conflicting results. To better understand cannabinoid signaling, we have used the Caenorhabditis elegans model to examine the effects of cannabinoids on behavior. The present study demonstrates that mammalian cannabinoid receptor ligands activate a conserved cannabinoid signaling system in C. elegans and also modulate monoaminergic signaling, potentially affecting an array of disorders, including anxiety and depression. This study highlights the potential role of cannabinoids in modulating monoaminergic signaling and the advantages of studying cannabinoid signaling in a genetically tractable, whole-animal model.
The Gliotransmitter d-Serine Promotes Synapse Maturation and Axonal Stabilization In Vivo

The NMDAR is thought to play a key role in the refinement of connectivity in developing neural circuits. Pharmacological blockade or genetic loss-of-function manipulations that prevent NMDAR function during development result in the disorganization of topographic axonal projections. However, because NMDARs contribute to overall glutamatergic neurotransmission, such loss-of-function experiments fail to adequately distinguish between the roles played by NMDARs and neural activity in general. The gliotransmitter d-serine is a coagonist of the NMDAR that is required for NMDAR channel opening, but which cannot mediate neurotransmission on its own. Here we demonstrate that acute administration of d-serine has no immediate effect on glutamate release or AMPA-mediated neurotransmission. We show that endogenous d-serine is normally present below saturating levels in the developing visual system of the Xenopus tadpole. Using an amperometric enzymatic biosensor, we demonstrate that glutamatergic activation elevates ambient endogenous d-serine levels in the optic tectum. Chronically elevating levels of d-serine promoted synaptic maturation and resulted in the hyperstabilization of developing axon branches in the tadpole visual system. Conversely, treatment with an enzyme that degrades endogenous d-serine resulted in impaired synaptic maturation. Despite the reduction in axon arbor complexity seen in d-serine-treated animals, tectal neuron visual receptive fields were expanded, suggesting a failure to prune divergent retinal inputs. Together, these findings positively implicate NMDAR-mediated neurotransmission in developmental synapse maturation and the stabilization of axonal inputs and reveal a potential role for d-serine as an endogenous modulator of circuit refinement. SIGNIFICANCE STATEMENT Activation of NMDARs is critical for the activity-dependent development and maintenance of highly organized topographic maps. d-Serine, a coagonist of the NMDAR, plays a significant role in modulating NMDAR-mediated synaptic transmission and plasticity in many brain areas. However, it remains unknown whether d-serine participates in the establishment of precise neuronal connections during development. Using an in vivo model, we show that glutamate receptor activation can evoke endogenous d-serine release, which promotes glutamatergic synapse maturation and stabilizes axonal structural and functional inputs. These results reveal a pivotal modulatory role for d-serine in neurodevelopment.
Idiopathic chronic urticaria and thyroid autoimmunity

Urticaria is one of the most frequent dermatosis, being its prevalence in general population estimated about 20%. This prospective case-control study was aimed at determining the prevalence of thyroid autoimmune disorders in a cohort of patients with chronic urticaria (CU), all living within an area with mild-to-moderate iodine deficiency. Fifty four consecutive patients affected by CU were recruited and compared to 108 healthy controls. Assessment of the thyroid function included measurement of serum concentrations of TSH, FT3, FT4, anti-thyreoglobulin (anti-TG) and anti-peroxidase (anti-TPO) antibodies. Ultrasound scan of the thyroid gland was performed in all subjects using a 7.5 MHz linear transducer. All subjects were followed up for 6 months. The prevalence of thyroid antibodies was significantly higher in our cohort of patients with CU than in controls (22% vs. 6.5 %). Hashimoto’s thyroiditis was also more frequent in patients than controls (18.5% vs. 1.8%). These frequencies do not differ from those previously reported by some other authors and confirm the association between CU and thyroid autoimmunity also in the area of iodine deficiency. However, presence of antibodies or thyroiditis does not seem to influence clinical course of CU. These results suggest that screening for thyroid function may be useful in all the patients with CU.
The emergency supply of prescription‐only medicines: a survey of requests to community pharmacists and their views on the procedures

Objectives — The provisions of the Medicines Act for the emergency supply of prescription‐only medicines (POMs) represent circumstances in which pharmacists in the UK may lawfully supply a patient with a POM without having a prescription. The objectives of this research were to establish the frequency of requests for emergency supplies from doctors and patients, and the characteristics of the requests, to investigate the procedures for emergency supply from the perspective of community pharmacists and to survey their views on the subject.
Noisy Spiking in Visual Area V2 of Amblyopic Monkeys

Interocular decorrelation of input signals in developing visual cortex can cause impaired binocular vision and amblyopia. Although increased intrinsic noise is thought to be responsible for a range of perceptual deficits in amblyopic humans, the neural basis for the elevated perceptual noise in amblyopic primates is not known. Here, we tested the idea that perceptual noise is linked to the neuronal spiking noise (variability) resulting from developmental alterations in cortical circuitry. To assess spiking noise, we analyzed the contrast-dependent dynamics of spike counts and spiking irregularity by calculating the square of the coefficient of variation in interspike intervals (CV2) and the trial-to-trial fluctuations in spiking, or mean matched Fano factor (m-FF) in visual area V2 of monkeys reared with chronic monocular defocus. In amblyopic neurons, the contrast versus response functions and the spike count dynamics exhibited significant deviations from comparable data for normal monkeys. The CV2 was pronounced in amblyopic neurons for high-contrast stimuli and the m-FF was abnormally high in amblyopic neurons for low-contrast gratings. The spike count, CV2, and m-FF of spontaneous activity were also elevated in amblyopic neurons. These contrast-dependent spiking irregularities were correlated with the level of binocular suppression in these V2 neurons and with the severity of perceptual loss for individual monkeys. Our results suggest that the developmental alterations in normalization mechanisms resulting from early binocular suppression can explain much of these contrast-dependent spiking abnormalities in V2 neurons and the perceptual performance of our amblyopic monkeys. SIGNIFICANCE STATEMENT Amblyopia is a common developmental vision disorder in humans. Despite the extensive animal studies on how amblyopia emerges, we know surprisingly little about the neural basis of amblyopia in humans and nonhuman primates. Although the vision of amblyopic humans is often described as being noisy by perceptual and modeling studies, the exact nature or origin of this elevated perceptual noise is not known. We show that elevated and noisy spontaneous activity and contrast-dependent noisy spiking (spiking irregularity and trial-to-trial fluctuations in spiking) in neurons of visual area V2 could limit the visual performance of amblyopic primates. Moreover, we discovered that the noisy spiking is linked to a high level of binocular suppression in visual cortex during development.
Complex carriers of affibody-displaying bio-nanocapsules and composition-varied liposomes for HER2-expressing breast cancer cell-specific protein delivery

A bio-nanocapsule (BNC), a hollow particle composed of hepatitis B virus (HBV) surface antigen (HBsAg), and liposome (LP) conjugation method (BNC/LP) has been recently developed by . The BNC/LP complex carrier could successfully deliver fluorescence-labeled beads (100 nm) into liver cells. In this study, we report the promising delivery of proteins incorporated in the complex carriers, which were prepared by the BNC/LP conjugation method with specificity-altered BNC and composition-varied LPs. The specificity-altered BNC, ZHER2-BNC was developed by replacing the hepatocyte recognition site of BNC with ZHER2 binding to HER2 receptor specifically. Using green fluorescent protein (GFP; 27 kDa) and cellular cytotoxic protein (exotoxin A; 66 kDa) for the delivery, we herein present the impact of different charges attributed to the composition of the LP on specific cell targeting and cellular uptake of the complex carriers. In addition, we demonstrate that the mixture prepared by mixing LPs with helper lipid possessing endosomal escaping ability boosts the functional expression of the cellular cytotoxic exotoxin A activity specifically. Finally, we further show the blending ratio of the LP mixture and ZHER2-BNC is a critical factor in determining the highly-efficient expression of the cytotoxic activity of exotoxin A.
Genetic and epigenetic analysis of non-small cell lung cancer with NotI-microarrays

This study aimed to clarify genetic and epigenetic alterations that occur during lung carcinogenesis and to design perspective sets of newly identified biomarkers. The original method includes chromosome 3 specific NotI-microarrays containing 180 NotI clones associated with genes for hybridization with 40 paired normal/tumor DNA samples of primary lung tumors: 28 squamous cell carcinomas (SCC) and 12 adenocarcinomas (ADC). The NotI-microarray data were confirmed by qPCR and bisulfite sequencing analyses. Forty-four genes showed methylation and/or deletions in more than 15% of non–small cell lung cancer (NSCLC) samples. In general, SCC samples were more frequently methylated/deleted than ADC. Moreover, the SCC alterations were observed already at stage I of tumor development, whereas in ADC many genes showed tumor progression specific methylation/deletions. Among genes frequently methylated/deleted in NSCLC, only a few were already known tumor suppressor genes: RBSP3 (CTDSPL), VHL and THRB. The RPL32, LOC285205, FGD5 and other genes were previously not shown to be involved in lung carcinogenesis. Ten methylated genes, i.e., IQSEC1, RBSP3, ITGA9, FOXP1, LRRN1, GNAI2, VHL, FGD5, ALDH1L1 and BCL6 were tested for expression by qPCR and were found downregulated in the majority of cases. Three genes (RBSP3, FBLN2 and ITGA9) demonstrated strong cell growth inhibition activity. A comprehensive statistical analysis suggested the set of 19 gene markers, ANKRD28, BHLHE40, CGGBP1, RBSP3, EPHB1, FGD5, FOXP1, GORASP1/TTC21, IQSEC1, ITGA9, LOC285375, LRRC3B, LRRN1, MITF, NKIRAS1/RPL15, TRH, UBE2E2, VHL, WNT7A, to allow early detection, tumor progression, metastases and to discriminate between SCC and ADC with sensitivity and specificity of 80–100%.
The Hierarchical Cortical Organization of Human Speech Processing

Speech comprehension requires that the brain extract semantic meaning from the spectral features represented at the cochlea. To investigate this process, we performed an fMRI experiment in which five men and two women passively listened to several hours of natural narrative speech. We then used voxelwise modeling to predict BOLD responses based on three different feature spaces that represent the spectral, articulatory, and semantic properties of speech. The amount of variance explained by each feature space was then assessed using a separate validation dataset. Because some responses might be explained equally well by more than one feature space, we used a variance partitioning analysis to determine the fraction of the variance that was uniquely explained by each feature space. Consistent with previous studies, we found that speech comprehension involves hierarchical representations starting in primary auditory areas and moving laterally on the temporal lobe: spectral features are found in the core of A1, mixtures of spectral and articulatory in STG, mixtures of articulatory and semantic in STS, and semantic in STS and beyond. Our data also show that both hemispheres are equally and actively involved in speech perception and interpretation. Further, responses as early in the auditory hierarchy as in STS are more correlated with semantic than spectral representations. These results illustrate the importance of using natural speech in neurolinguistic research. Our methodology also provides an efficient way to simultaneously test multiple specific hypotheses about the representations of speech without using block designs and segmented or synthetic speech. SIGNIFICANCE STATEMENT To investigate the processing steps performed by the human brain to transform natural speech sound into meaningful language, we used models based on a hierarchical set of speech features to predict BOLD responses of individual voxels recorded in an fMRI experiment while subjects listened to natural speech. Both cerebral hemispheres were actively involved in speech processing in large and equal amounts. Also, the transformation from spectral features to semantic elements occurs early in the cortical speech-processing stream. Our experimental and analytical approaches are important alternatives and complements to standard approaches that use segmented speech and block designs, which report more laterality in speech processing and associated semantic processing to higher levels of cortex than reported here.