Miracle-dz/UniFAR-FTUs huggingface dataset:
Loss of Piccolo Function in Rats Induces Cerebellar Network Dysfunction and Pontocerebellar Hypoplasia Type 3-like Phenotypes

Piccolo, a presynaptic active zone protein, is best known for its role in the regulated assembly and function of vertebrate synapses. Genetic studies suggest a further link to several psychiatric disorders as well as Pontocerebellar Hypoplasia type 3 (PCH3). We have characterized recently generated Piccolo KO (Pclogt/gt) rats. Piccolo, a presynaptic active zone protein, is best known for its role in the regulated assembly and function of vertebrate synapses. Genetic studies suggest a further link to several psychiatric disorders as well as Pontocerebellar Hypoplasia type 3 (PCH3). We have characterized recently generated Piccolo KO (Pclogt/gt) rats. Analysis of rats of both sexes revealed a dramatic reduction in brain size compared with WT (Pclowt/wt) animals, attributed to a decrease in the size of the cerebral cortical, cerebellar, and pontine regions. Analysis of the cerebellum and brainstem revealed a reduced granule cell layer and a reduction in size of pontine nuclei. Moreover, the maturation of mossy fiber afferents from pontine neurons and the expression of the α6 GABAA receptor subunit at the mossy fiber-granule cell synapse are perturbed, as well as the innervation of Purkinje cells by cerebellar climbing fibers. Ultrastructural and functional studies revealed a reduced size of mossy fiber boutons, with fewer synaptic vesicles and altered synaptic transmission. These data imply that Piccolo is required for the normal development, maturation, and function of neuronal networks formed between the brainstem and cerebellum. Consistently, behavioral studies demonstrated that adult Pclogt/gt rats display impaired motor coordination, despite adequate performance in tasks that reflect muscle strength and locomotion. Together, these data suggest that loss of Piccolo function in patients with PCH3 could be involved in many of the observed anatomical and behavioral symptoms, and that the further analysis of these animals could provide fundamental mechanistic insights into this devastating disorder. SIGNIFICANCE STATEMENT Pontocerebellar Hypoplasia Type 3 is a devastating developmental disorder associated with severe developmental delay, progressive microcephaly with brachycephaly, optic atrophy, seizures, and hypertonia with hyperreflexia. Recent genetic studies have identified non-sense mutations in the coding region of the PCLO gene, suggesting a functional link between this disorder and the presynaptic active zone. Our analysis of Piccolo KO rats supports this hypothesis, formally demonstrating that anatomical and behavioral phenotypes seen in patients with Pontocerebellar Hypoplasia Type 3 are also exhibited by these Piccolo deficient animals.
The Determination of Immunomodulation and Its Impact on Survival of Rectal Cancer Patients Depends on the Area Comprising a Tissue Microarray

Background: T cell density in colorectal cancer (CRC) has proven to be of high prognostic importance. Here, we evaluated the influence of a hyperfractionated preoperative short-term radiation protocol (25 Gy) on immune cell density in tumor samples of rectal cancer (RC) patients and on patient survival. In addition, we assessed spatial tumor heterogeneity by comparison of analogue T cell quantification on full tissue sections with digital T cell quantification on a virtually established tissue microarray (TMA). Methods: A total of 75 RC patients (60 irradiated, 15 treatment-naïve) were defined for retrospective analysis. RC samples were processed for immunohistochemistry (CD3, CD8, PD-1, PD-L1). Analogue (score 0–3) as well as digital quantification (TMA: 2 cores vs. 6 cores, mean T cell count) of marker expression in 2 areas (central tumor, CT; invasive margin, IM) was performed. Survival was estimated on the basis of analogue as well as digital marker densities calculated from 2 cores (Immunoscore: CD3/CD8 ratio) and 6 cores per tumor area. Results: Irradiated RC samples showed a significant decrease in CD3 and CD8 positive T cells, independent of quantification mode. T cell densities of 6 virtual cores approximated to T cell densities of full tissue sections, independent of individual core density or location. Survival analysis based on full tissue section quantification demonstrated that CD3 and CD8 positive T cells as well as PD-1 positive tumor infiltrating leucocytes (TILs) in the CT and the IM had a significant impact on disease-free survival (DFS) as well as overall survival (OS). In addition, CD3 and CD8 positive T cells as well as PD-1 positive TILs in the IM proved as independent prognostic factors for DFS and OS; in the CT, PD-1 positive TILs predicted DFS and CD3 and CD8 positive T cells as well as PD-1 positive TILs predicted OS. Survival analysis based on virtual TMA showed no impact on DFS or OS. Conclusion: Spatial tumor heterogeneity might result in inadequate quantification of immune marker expression; however, if using a TMA, 6 cores per tumor area and patient sample represent comparable amounts of T cell densities to those quantified on full tissue sections. Consistently, the tissue area used for immune marker quantification represents a crucial factor for the evaluation of prognostic and predictive biomarker potential.
Physical interactions between Gsx2 and Ascl1 balance progenitor expansion versus neurogenesis in the mouse lateral ganglionic eminence

ABSTRACT The Gsx2 homeodomain transcription factor promotes neural progenitor identity in the lateral ganglionic eminence (LGE), despite upregulating the neurogenic factor Ascl1. How this balance in maturation is maintained is unclear. Here, we show that Gsx2 and Ascl1 are co-expressed in subapical progenitors that have unique transcriptional signatures in LGE ventricular zone (VZ) cells. Moreover, whereas Ascl1 misexpression promotes neurogenesis in dorsal telencephalic progenitors, the co-expression of Gsx2 with Ascl1 inhibits neurogenesis. Using luciferase assays, we found that Gsx2 reduces the ability of Ascl1 to activate gene expression in a dose-dependent and DNA binding-independent manner. Furthermore, Gsx2 physically interacts with the basic helix-loop-helix (bHLH) domain of Ascl1, and DNA-binding assays demonstrated that this interaction interferes with the ability of Ascl1 to bind DNA. Finally, we modified a proximity ligation assay for tissue sections and found that Ascl1-Gsx2 interactions are enriched within LGE VZ progenitors, whereas Ascl1-Tcf3 (E-protein) interactions predominate in the subventricular zone. Thus, Gsx2 contributes to the balance between progenitor maintenance and neurogenesis by physically interacting with Ascl1, interfering with its DNA binding and limiting neurogenesis within LGE progenitors. Summary: This study demonstrates that Gsx2 physically interacts with the proneural factor Ascl1 in LGE progenitors and interferes with the DNA binding capacity of Ascl1, thus priming progenitors for neurogenesis while allowing for further expansion.
Crosstalk among Indoleamines, Neuropeptides and JH/20E in Regulation of Reproduction in the American Cockroach, Periplaneta americana

Although the regulation of vitellogenesis in insects has been mainly discussed in terms of ‘classical’ lipid hormones, juvenile hormone (JH), and 20-hydroxyecdysone (20E), recent data support the notion that this process must be adjusted in harmony with a nutritional input/reservoir and involvement of certain indoleamines and neuropeptides in regulation of such process. This study focuses on crosstalks among these axes, lipid hormones, monoamines, and neuropeptides in regulation of vitellogenesis in the American cockroach Periplaneta americana with novel aspects in the roles of arylalkylamine N-acetyltransferase (aaNAT), a key enzyme in indoleamine metabolism, and the enteroendocrine peptides; crustacean cardioactive peptide (CCAP) and short neuropeptide F (sNPF). Double-stranded RNA against aaNAT (dsRNAaaNAT) was injected into designated-aged females and the effects were monitored including the expressions of aaNAT itself, vitellogenin 1 and 2 (Vg1 and Vg2) and the vitellogenin receptor (VgR) mRNAs, oocyte maturation and changes in the hemolymph peptide concentrations. Effects of peptides application and 20E were also investigated. Injection of dsRNAaaNAT strongly suppressed oocyte maturation, transcription of Vg1, Vg2, VgR, and genes encoding JH acid- and farnesoate O-methyltransferases (JHAMT and FAMeT, respectively) acting in the JH biosynthetic pathway. However, it did not affect hemolymph concentrations of CCAP and sNPF. Injection of CCAP stimulated, while sNPF suppressed oocyte maturation and Vgs/VgR transcription, i.e., acting as allatomedins. Injection of CCAP promoted, while sNPF repressed ecdysteroid (20E) synthesis, particularly at the second step of Vg uptake. 20E also affected the JH biosynthetic pathway and Vg/VgR synthesis. The results revealed that on the course of vitellogenesis, JH- and 20E-mediated regulation occurs downstream to indoleamines- and peptides-mediated regulations. Intricate mutual interactions of these regulatory routes must orchestrate reproduction in this species at the highest potency.
Cognitive Interpersonal Model for Anorexia Nervosa Revisited: The Perpetuating Factors that Contribute to the Development of the Severe and Enduring Illness

The cognitive interpersonal model was outlined initially in 2006 in a paper describing the valued and visible aspects of anorexia nervosa (Schmidt and Treasure, 2006). In 2013, we summarised many of the cognitive and emotional traits underpinning the model (Treasure and Schmidt, 2013). In this paper, we describe in more detail the perpetuating aspects of the model, which include the inter- and intrapersonal related consequences of isolation, depression, and chronic stress that accumulate in the severe and enduring stage of the illness. Since we developed the model, we have been using it to frame research and development at the Maudsley. We have developed and tested interventions for both patients and close others, refining the model through iterative cycles of model/intervention development in line with the Medical Research Council (MRC) framework for complex interventions. For example, we have defined the consequences of living with the illness on close others (including medical professionals) and characterised the intense emotional reactions and behaviours that follow. For the individual with an eating disorder, these counter-reactions can allow the eating disorder to become entrenched. In addition, the consequent chronic stress from starvation and social pain set in motion processes such as depression, neuroprogression, and neuroadaptation. Thus, anorexia nervosa develops a life of its own that is resistant to treatment. In this paper, we describe the underpinnings of the model and how this can be targeted into treatment.
Designing Efficient Sinkhole Attack Detection Mechanism in Edge-Based IoT Deployment

The sinkhole attack in an edge-based Internet of Things (IoT) environment (EIoT) can devastate and ruin the whole functioning of the communication. The sinkhole attacker nodes (SHAs) have some properties (for example, they first attract the other normal nodes for the shortest path to the destination and when normal nodes initiate the process of sending their packets through that path (i.e., via SHA), the attacker nodes start disrupting the traffic flow of the network). In the presence of SHAs, the destination (for example, sink node i.e., gateway/base station) does not receive the required information or it may receive partial or modified information. This results in reduction of the network performance and degradation in efficiency and reliability of the communication. In the presence of such an attack, the throughput decreases, end-to-end delay increases and packet delivery ratio decreases. Moreover, it may harm other network performance parameters. Hence, it becomes extremely essential to provide an effective and competent scheme to mitigate this attack in EIoT. In this paper, an intrusion detection scheme to protect EIoT environment against sinkhole attack is proposed, which is named as SAD-EIoT. In SAD-EIoT, the resource rich edge nodes (edge servers) perform the detection of different types of sinkhole attacker nodes with the help of exchanging messages. The practical demonstration of SAD-EIoT is also provided using the well known NS2 simulator to compute the various performance parameters. Additionally, the security analysis of SAD-EIoT is conducted to prove its resiliency against various types of SHAs. SAD-EIoT achieves around 95.83% detection rate and 1.03% false positive rate, which are considerably better than other related existing schemes. Apart from those, SAD-EIoT is proficient with respect to computation and communication costs. Eventually, SAD-EIoT will be a suitable match for those applications which can be used in critical and sensitive operations (for example, surveillance, security and monitoring systems).
Energy Restriction Enhances Adult Hippocampal Neurogenesis-Associated Memory after Four Weeks in an Adult Human Population with Central Obesity; a Randomized Controlled Trial

Adult neurogenesis, the generation of new neurons throughout life, occurs in the subventricular zone of the dentate gyrus in the human hippocampal formation. It has been shown in rodents that adult hippocampal neurogenesis is needed for pattern separation, the ability to differentially encode small changes derived from similar inputs, and recognition memory, as well as the ability to recognize previously encountered stimuli. Improved hippocampus-dependent cognition and cellular readouts of adult hippocampal neurogenesis have been reported in daily energy restricted and intermittent fasting adult mice. Evidence that nutrition can significantly affect brain structure and function is increasing substantially. This randomized intervention study investigated the effects of intermittent and continuous energy restriction on human hippocampal neurogenesis-related cognition, which has not been reported previously. Pattern separation and recognition memory were measured in 43 individuals with central obesity aged 35–75 years, before and after a four-week dietary intervention using the mnemonic similarity task. Both groups significantly improved pattern separation (P = 0.0005), but only the intermittent energy restriction group had a significant deterioration in recognition memory. There were no significant differences in cognitive improvement between the two diets. This is the first human study to investigate the association between energy restriction with neurogenesis-associated cognitive function. Energy restriction may enhance hippocampus-dependent memory and could benefit those in an ageing population with declining cognition. This study was registered on ClinicalTrials.gov (NCT02679989) on 11 February 2016.
The Connection Project: Changing the peer environment to improve outcomes for marginalized adolescents

Abstract This study evaluated a school-based intervention to enhance adolescent peer relationships and improve functional outcomes, building upon Ed Zigler’s seminal contribution in recognizing the potential of academic contexts to enhance social and emotional development. Adolescents (N = 610) primarily from economically or racially/ethnically marginalized groups were assessed preintervention, postintervention, and at 4-month follow-up in a randomized controlled trial. At program completion, intervention participants reported significantly increased quality of peer relationships; by 4-month follow-up, this increased quality was also observable by peers outside of the program, and program participants also displayed higher levels of academic engagement and lower levels of depressive symptoms. These latter effects appear to have potentially been mediated via participants’ increased use of social support. The potential of the Connection Project intervention specifically, and of broader efforts to activate adolescent peer relationships as potent sources of social support and growth more generally within the secondary school context, is discussed.
SMAD7 enhances adult β-cell proliferation without significantly affecting β-cell function in mice

The interplay between the transforming growth factor β (TGF-β) signaling proteins, SMAD family member 2 (SMAD2) and 3 (SMAD3), and the TGF-β–inhibiting SMAD, SMAD7, seems to play a vital role in proper pancreatic endocrine development and also in normal β-cell function in adult pancreatic islets. Here, we generated conditional SMAD7 knockout mice by crossing insulin1Cre mice with SMAD7fx/fx mice. We also created a β cell–specific SMAD7-overexpressing mouse line by crossing insulin1Dre mice with HPRT-SMAD7/RosaGFP mice. We analyzed β-cell function in adult islets when SMAD7 was either absent or overexpressed in β cells. Loss of SMAD7 in β cells inhibited proliferation, and SMAD7 overexpression enhanced cell proliferation. However, alterations in basic glucose homeostasis were not detectable following either SMAD7 deletion or overexpression in β cells. Our results show that both the absence and overexpression of SMAD7 affect TGF-β signaling and modulates β-cell proliferation but does not appear to alter β-cell function. Reversible SMAD7 overexpression may represent an attractive therapeutic option to enhance β-cell proliferation without negative effects on β-cell function.
LiDAR-Based System and Optical VHR Data for Building Detection and Mapping

The aim of this paper is to highlight how the employment of Light Detection and Ranging (LiDAR) technique can enhance greatly the performance and reliability of many monitoring systems applied to the Earth Observation (EO) and Environmental Monitoring. A short presentation of LiDAR systems, underlying their peculiarities, is first given. References to some review papers are highlighted, as they can be regarded as useful guidelines for researchers interested in using LiDARs. Two case studies are then presented and discussed, based on the use of 2D and 3D LiDAR data. Some considerations are done on the performance achieved through the use of LiDAR data combined with data from other sources. The case studies show how the LiDAR-based systems, combined with optical Very High Resolution (VHR) data, succeed in improving the analysis and monitoring of specific areas of interest, specifically how LiDAR data help in exploring external environment and extracting building features from urban areas. Moreover the discussed Case Studies demonstrate that the use of the LiDAR data, even with a low density of points, allows the development of an automatic procedure for accurate building features extraction, through object-oriented classification techniques, therefore by underlying the importance that even simple LiDAR-based systems play in EO and Environmental Monitoring.
Consistent altered internal capsule white matter microstructure in insomnia disorder

Abstract Study Objectives Suggested neural correlates of insomnia disorder have been hard to replicate. Even the most consistent finding, altered white matter microstructure in the anterior limb of the internal capsule, is based on handful studies. The urge for replicable targets to understand the underlying mechanisms of insomnia made us study white matter fractional anisotropy (FA) across three samples of cases and controls. Methods 3-Tesla MRI diffusion tensor imaging data of three independent samples were combined for analysis, resulting in n = 137 participants, of whom 73 were diagnosed with insomnia disorder and 64 were matched controls without sleep complaints. Insomnia severity was measured with the Insomnia Severity Index (ISI). White matter microstructure was assessed with FA. White matter tracts were skeletonized and analyzed using tract-based spatial statistics. We performed a region-of-interest analysis using linear mixed-effect models to evaluate case–control differences in internal capsule FA as well as associations between internal capsule FA and insomnia severity. Results FA in the right limb of the anterior internal capsule was lower in insomnia disorder than in controls (β = −9.76e−3; SE = 4.17e−3, p = .034). In the entire sample, a higher ISI score was associated with a lower FA value of the right internal capsule (β = −8.05e− 4 FA/ISI point, SE = 2.60e− 4, p = .008). Ancillary whole brain voxel-wise analyses showed no significant group difference or association with insomnia severity after correction for multiple comparisons. Conclusions The internal capsule shows small but consistent insomnia-related alterations. The findings support a circuit-based approach to underlying mechanisms since this tract connects many brain areas previously implicated in insomnia.
Tropomyosin: An Excretory/Secretory Protein from Haemonchus contortus Mediates the Immuno-Suppressive Potential of Goat Peripheral Blood Mononuclear Cells In Vitro

During host-parasite interactions, binding of excretory/secretory proteins (ESPs) on the host immune cells is considered the fundamental phase for regulation of immune responses. In this study, gene encoding Haemonchus contortus tropomyosin (Hc-TpMy), was successfully cloned and expressed, and the recombinant protein after host cell surface attachment was evaluated for immune functional analysis with goat peripheral blood mononuclear cells (PBMCs) in vitro. The isopropyl-β-D-thiogalactopyranoside (IPTG)-induced recombinant protein was successfully recognized by the sera of rat experimentally infected with rHc-TpMy. The immunofluorescence assay detected attachment of rHc-TpMy on the surface of host PBMCs. Furthermore, immunoregulatory roles of rHc-TpMy on cytokines expression, PBMC proliferation, migration, nitric oxide (NO) production, apoptosis and monocytes phagocytosis were observed. The results showed that expression of IL-4 and IFN-γ cytokines, cell proliferation, NO production and PBMC migration were significantly suppressed by goat PBMCs after co-incubation with rHc-TpMy protein. However, the productions of IL-10, IL-17 and TGF-β1 cytokines, PBMCs apoptosis and monocytes phagocytosis were elevated at dose dependent manner. Our findings indicated that rHc-TpMy is an important ES binding protein exhibit distinct immuno-suppressive roles on goat PBMCs which might be a potential molecular target to control haemonchosis in future.
Supercoiling, R-Loops, Replication and the Functions of Bacterial Type 1A Topoisomerases

Type 1A topoisomerases (topos) are the only topos that bind single-stranded DNA and the only ones found in all cells of the three domains of life. Two subfamilies, topo I and topo III, are present in bacteria. Topo I, found in all of them, relaxes negative supercoiling, while topo III acts as a decatenase in replication. However, recent results suggest that they can also act as back-up for each other. Because they are ubiquitous, type 1A enzymes are expected to be essential for cell viability. Single topA (topo I) and topB (topo III) null mutants of Escherichia coli are viable, but for topA only with compensatory mutations. Double topA topB null mutants were initially believed to be non-viable. However, in two independent studies, results of next generation sequencing (NGS) have recently shown that double topA topB null mutants of Bacillus subtilis and E. coli are viable when they carry parC parE gene amplifications. These genes encode the two subunits of topo IV, the main cellular decatenase. Here, we discuss the essential functions of bacterial type 1A topos in the context of this observation and new results showing their involvement in preventing unregulated replication from R-loops.