Miracle-dz/UniFAR-FTUs huggingface dataset:
Heat shock promotes inclusion body formation of mutant huntingtin (mHtt) and alleviates mHtt-induced transcription factor dysfunction

PolyQ-expanded huntingtin (mHtt) variants form aggregates, termed inclusion bodies (IBs), in individuals with and models of Huntington's disease (HD). The role of IB versus diffusible mHtt in neurotoxicity remains unclear. Using a ponasterone (PA)-inducible cell model of HD, here we evaluated the effects of heat shock on the appearance and functional outcome of Htt103QExon1–EGFP expression. Quantitative image analysis indicated that 80–90% of this mHtt protein initially appears as “diffuse” signals in the cytosol, with IBs forming at high mHtt expression. A 2-h heat shock during the PA induction reduced the diffuse signal, but greatly increased mHtt IB formation in both cytosol and nucleus. Dose- and time-dependent mHtt expression suggested that nucleated polymerization drives IB formation. RNA-mediated knockdown of heat shock protein 70 (HSP70) and heat shock cognate 70 protein (HSC70) provided evidence for their involvement in promoting diffuse mHtt to form IBs. Reporter gene assays assessing the impacts of diffuse versus IB mHtt showed concordance of diffuse mHtt expression with the repression of heat shock factor 1, cAMP-responsive element-binding protein (CREB), and NF-κB activity. CREB repression was reversed by heat shock coinciding with mHtt IB formation. In an embryonic striatal neuron–derived HD model, the chemical chaperone sorbitol similarly promoted the structuring of diffuse mHtt into IBs and supported cell survival under stress. Our results provide evidence that mHtt IB formation is a chaperone-supported cellular coping mechanism that depletes diffusible mHtt conformers, alleviates transcription factor dysfunction, and promotes neuron survival.
Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies

Development of the nervous system is carried out by complex gene expression programs that are regulated at both transcriptional and translational level. In addition, quality control mechanisms such as the TP53‐mediated apoptosis or neuronal activity‐stimulated survival ensure successful neurogenesis and formation of functional circuitries. In the nucleolus, production of ribosomes is essential for protein synthesis. In addition, it participates in chromatin organization and regulates the TP53 pathway via the ribosomal stress response. Its tight regulation is required for maintenance of genomic integrity. Mutations in several ribosomal components and trans‐acting ribosomal biogenesis factors result in neurodevelopmental syndromes that present with microcephaly, autism, intellectual deficits and/or progressive neurodegeneration. Furthermore, ribosomal biogenesis is perturbed by exogenous factors that disrupt neurodevelopment including alcohol or Zika virus. In this review, we present recent literature that argues for a role of dysregulated ribosomal biogenesis in pathogenesis of various neurodevelopmental syndromes. We also discuss potential mechanisms through which such dysregulation may lead to cellular pathologies of the developing nervous system including insufficient proliferation and/or loss of neuroprogenitors cells, apoptosis of immature neurons, altered neuronal morphogenesis, and neurodegeneration.
Establishment of Transgenesis in the Demosponge Suberites domuncula

Sponges (Porifera) represent one of the most basally branching animal clades with key relevance for evolutionary studies, stem cell biology, and development. Despite a long history of sponges as experimental model systems, however, functional molecular studies are still very difficult to perform in these animals. Here, we report the establishment of transgenic technology as a basic and versatile experimental tool for sponge research. We demonstrate that slice explants of the demosponge Suberites domuncula regenerate functional sponge tissue and can be cultured for extended periods of time, providing easy experimental access under controlled conditions. We further show that an engineered expression construct driving the enhanced green fluorescence protein (egfp) gene under control of the Suberites domuncula β-actin locus can be transfected into such tissue cultures, and that faithfully spliced transcripts are produced from such transfected DNA. Finally, by combining fluorescence-activated cell sorting (FACS) with quantitative PCR, we validate that transfected cells can be specifically reisolated from tissue based on their fluorescence. Although the number of detected enhanced green fluorescent protein (EGFP)-expressing cells is still limited, our approach represents the first successful introduction and expression of exogenous DNA in a sponge. These results represent a significant advance for the use of transgenic technology in a cornerstone phylum, for instance for the use in lineage tracing experiments.
Novel cytomorphologic characteristics suggesting human papillomavirus infection in patients diagnosed as negative for intraepithelial lesion or malignancy and a comparison of diagnostic performance of three human papillomavirus tests

Although the Papanicolaou (Pap) test is the first‐line screening method for cervical cancer, it has low sensitivity for detection of human papillomavirus (HPV)‐infected cervical lesion compared to the HPV test. The aims of this study are to determine novel cytomorphologic parameters for HPV infection in patients previously diagnosed as negative for intraepithelial lesion or malignancy (NILM) and to comparatively analyze the detection performance of 3 HPV tests: nested PCR, the DNA Chip test, and the Liquid Beads Microarray (LBMA) assay.
Physical activity and mortality in patients with stable coronary heart disease

Purpose of review To review recent literature on associations between habitual physical activity and mortality in general populations and patients with stable coronary heart disease. Recent findings There are substantial decreases in cardiovascular and all-cause mortality between people who take little or no exercise and those who take regular light or moderate physical activity. The benefits associated with increasing high-intensity exercise are smaller, and an increase in mortality risk is possible. Meta-analyses of trials of exercise-based cardiac rehabilitation suggest a small mortality benefit from supervised exercise training, but because of a high risk of bias, the impact on cardiovascular mortality and hospitalizations is uncertain. Summary Modest habitual physical activity is likely to lower mortality in most patients with stable coronary heart disease.
Receptor CD36 links a risk-associated allele to obesity and metabolic disorders

Mice harboring a particular allele of the human brain-derived neurotropic factor (BDNFM/M mice) develop extreme obesity and insulin resistance when fed a high-fat diet. The underlying mechanisms of this genetic risk factor for obesity are unclear. In the current issue of JBC, Yang et al. report that pharmacological inhibition of integral membrane protein CD36 significantly reduces body weight gain and improves glucose tolerance in BDNFM/M mice. Targeting CD36 may therefore be a promising strategy to improve metabolic dysfunctions and normalize risk factors in obese individuals.
Model-based robocentric planning and navigation for dynamic environments

This work addresses a new technique of motion planning and navigation for differential-drive robots in dynamic environments. Static and dynamic objects are represented directly on the control space of the robot, where decisions on the best motion are made. A new model representing the dynamism and the prediction of the future behavior of the environment is defined, the dynamic object velocity space (DOVS). A formal definition of this model is provided, establishing the properties for its characterization. An analysis of its complexity, compared with other methods, is performed. The model contains information about the future behavior of obstacles, mapped on the robot control space. It allows planning of near-time-optimal safe motions within the visibility space horizon, not only for the current sampling period. Navigation strategies are developed based on the identification of situations in the model. The planned strategy is applied and updated for each sampling time, adapting to changes occurring in the scenario. The technique is evaluated in randomly generated simulated scenarios, based on metrics defined using safety and time-to-goal criteria. An evaluation in real-world experiments is also presented.
The increased release of amino acid neurotransmitters of the primary somatosensory cortical area in rats contributes to remifentanil-induced hyperalgesia and its inhibition by lidocaine

Background Studies have confirmed that activation of the neurons of primary somatosensory cortex (S1) is involved in the process of remifentanil (Remi)-induced hyperalgesia (RIH), which can be suppressed by lidocaine (Lido). A total intravenous anesthesia model of rats mimicking clinical Remi-based anesthesia was set up to explore the release of amino acid neurotransmitters of S1 cortex in RIH and its inhibition by Lido in this study. Materials and methods Sprague Dawley rats were randomly divided into the following four groups: propofol (Pro), Remi, Remi combined Lido, and Lido groups. Mechanical hyperalgesia was evaluated by von Frey test; the amino acid neurotransmitters in the microdialysates of S1 area were detected by high-performance liquid chromatography (HPLC)-fluorescence, and conventional protein kinase C (cPKC)γ levels in the whole-cell lysates and membrane lipid rafts (MLRs) were determined by Western blotting. Results The von Frey test showed that co-administration of Lido significantly inhibited a Remi-induced decrease in the threshold of the paw withdrawal response in Remi group at 2 h postinfusion. Meanwhile, the Remi-induced increases in both the excitatory and inhibitory amino acid releases in S1 were suppressed by co-administrating Lido within 5 h postinfusion. Western blotting showed that the increased cPKCγ level in the membrane lipid rafts (MLR) induced by Remi was also inhibited by Lido. Conclusion The increased release of amino acid neurotransmitters and the translocation of cPKCγ in MLR suggest the activation of S1 neurons, which may be one of the mechanisms underlying RIH. Lido reduces the release of amino acid neurotransmitters in S1 neurons and the translocation of cPKCγ in MLRs after stopping Remi, which may be one of its antihyperalgesic mechanisms.
Nonsteroidal anti-inflammatory drugs, especially aspirin, are linked to lower risk and better survival of hepatocellular carcinoma: a meta-analysis

Objective The roles of nonsteroidal anti-inflammatory drugs (NSAIDs) in the occurrence and prognosis of hepatocellular carcinoma (HCC) remain controversial. This analysis aimed to summarize the relationships between NSAIDs and HCC development. Methods Studies published prior to October 1, 2017, in the PubMed, Embase, Ovid, Web of Science, and Cochrane Library databases were systematically searched and analyzed. Results Eleven studies were included in this analysis. A meta-analysis of five studies revealed that aspirin use could significantly decrease the risk of HCC occurrence (hazards ratio [HR] = 0.64, 95% confidence interval [CI] = 0.45–0.91, P = 0.014). No significant difference was found for the use of NSAIDs (six studies) and non-aspirin NSAIDs (three studies) in HCC occurrence (HR = 0.74, 95%CI = 0.53–1.02, P = 0.064 and HR = 0.98, 95%CI = 0.87–1.12, P = 0.81, respectively). However, subgroup analysis of cohort studies demonstrated that NSAIDs significantly decreased the risk of HCC occurrence (HR = 0.58, 95%CI = 0.43–0.78, P < 0.001). HCC patients who received NSAIDs achieved better disease-free survival and overall survival compared with the non-NSAID users (HR = 0.79, 95%CI = 0.74–0.84, P<0.001 and HR = 0.60, 95%CI = 0.50–0.72, P<0.001, respectively). Additionally, a meta-analysis of two studies showed that aspirin treatment in HCC patients could significantly decrease the 2-year and 4-year mortalities (rate ratio [RR] = 0.50, 95%CI = 0.36–0.69, P < 0.001 and RR = 0.67, 95%CI = 0.45–0.998, P = 0.049, respectively). A meta-analysis of two studies showed that aspirin use was not associated with a higher risk of bleeding in HCC patients (HR = 0.71, 95%CI = 0.41–1.23, P = 0.223). Conclusion The use of NSAIDs, especially aspirin, is linked to a lower risk of HCC development and better survival in HCC populations. High-quality, well-designed trials should be conducted to reevaluate the relationships between NSAIDs and HCC.
P2X4 receptor re‐sensitization depends on a protonation/deprotonation cycle mediated by receptor internalization and recycling

Re‐sensitization of P2X4 receptors depends on a protonation/de‐protonation cycle Protonation and de‐protonation of the receptors is achieved by internalization and recycling of P2X4 receptors via acidic compartments Protonation and de‐protonation occurs at critical histidine residues within the extracellular loop of P2X4 receptors Re‐sensitization is blocked in the presence of the receptor agonist ATP
Social communication disorder: a narrative review on current insights

Social communication disorder (SCD) is a novel diagnosis listed under the rubric of communication disorders within the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) and it is reported to be characterized by impairment in use of verbal and nonverbal communication for social aims. This review attempts to summarize the current understanding of the SCD concept along with its evolution and presents data from previous studies conducted. Suggestions for further research are also delineated. As listed in DSM-5, the criteria for this novel diagnosis are vague, display elevated comorbidity with other neurodevelopmental disorders and other childhood psychopathologies, and show partial overlap with autistic spectrum disorders both in terms of genetics and family histories. Data on cross-cultural presentations and temporal stability are also limited. The social communication model proposed by Catani and Bambini may help integrate the neurobiological findings pertaining to SCD. Valid and reliable assessment methods need to be developed for SCD. This may involve either development of novel instruments capturing the DSM-5 criteria or application of statistical methods such as item response theory to existing instruments. The relationships between broad autism phenotype, pragmatic language impairment, nonverbal learning disorder, learning disorders, autistic spectrum disorders, and SCD should be evaluated with further studies.
Assessing Callous-Unemotional Traits Using the Total Score from the Inventory of Callous-Unemotional Traits: A Meta-Analysis

The Inventory of Callous-Unemotional Traits (ICU) is a widely used rating scale measure of callous-unemotional (CU) traits. Most studies have used a unit-weighted total score that sums all of the items into a composite, despite the consistent finding that items from this measure can be described using a bifactor model (1 general factor and 3 bifactors). We conducted a meta-analysis using the results of past published bifactor tests of the ICU, using indices to estimate the sources of variance in the total and subscale scores. We included studies in our review that tested and found adequate fit for the bifactor model of the ICU resulting in 12 published studies (M age = 9–26 from both community and justice-involved samples) using either the self-report (n = 9) or parent-report (n = 4) versions of the ICU scale (one published study conducted separate factor analyses for each version). We reported model-based reliability estimates that break down unit-weighted ICU scores into the variance due to individual differences in the general factor and the variance due to individual differences in the bifactors. The reliable variance in the unit-weighted total scale score of the ICU is largely determined by the general factor. Findings support the ICU total score as a measure of the general construct of CU traits, despite support for a bifactor model in multiple samples. Concerns about using the unit-weighted subscale scores from the ICU are raised since their reliable variance was strongly influenced by the general factor.
Anlotinib for the Treatment of Patients with Locally Advanced or Metastatic Medullary Thyroid Cancer.

BACKGROUND The prognosis of advanced or metastatic medullary thyroid carcinoma (MTC) is poor, and there are few therapeutic options. Anlotinib has previously shown promising antitumor activity on MTC in preclinical models and a Phase I study. This Phase II clinical trial was devised to confirm the antitumor activity of anlotinib in patients with advanced or metastatic MTC. METHODS Patients with unresectable locally advanced or metastatic MTC received once daily oral anlotinib 12 mg, two weeks on/one week off, until disease progression, death, unacceptable toxicity, or withdrawal of consent for any reason. The dose was adjusted on the basis of observed toxicity. The primary endpoint was progression-free survival (PFS). RESULTS Fifty-eight patients received anlotinib treatment. The primary endpoint PFS has not yet been reached at the time of analysis. On the basis of investigator assessments, 56.9% of patients experienced a partial response. PFS rate at 48 weeks was 85.5%. Forty-five patients had a ≥50% decrease in serum calcitonin concentration from baseline. The most common adverse events were hand-foot syndrome, hypertriglyceridemia, cholesterol elevation, fatigue, and proteinuria. CONCLUSIONS Anlotinib demonstrated a durable antitumor activity with a manageable adverse event profile in locally advanced or metastatic MTC.
Widespread Distribution of Ceratonova shasta (Cnidaria: Myxosporea) Genotypes Indicates Evolutionary Adaptation to its Salmonid Fish Hosts

ABSTRACT The distribution of the freshwater myxozoan parasite Ceratonova shasta in the Pacific Northwest of North America is limited to overlap in the ranges of its 2 hosts: the polychaete Manyunkia sp. , and Pacific salmonids. Studies in the Klamath River (Oregon/California) and Deschutes River (Oregon), showed that the parasite population is comprised of multiple sympatric genotypes, some of which correlate with particular salmonid host species and with differences in clinical disease in those hosts. The 3 primary genotypes O, I, and II are defined by the number of a specific tri-nucleotide repeat in the internal transcribed spacer-1 region. To understand the spatial extent of host–parasite genotype patterns, we sequenced the parasite from 448 salmonid fishes from river basins in California, Oregon, Washington, Idaho, and British Columbia, Canada. We sampled intestinal tissues from 6 species of salmon and trout, both those that exist naturally with the parasite (sympatric) and those that do not naturally co-occur with the parasite and were exposed artificially in cages (allopatric). In most river basins we detected the same primary C. shasta genotypes that were described from the Klamath and Deschutes rivers, and we did not detect any novel primary genotypes. Host–parasite genotype patterns were consistent with previous data: genotype O was found in sympatric trout only; genotype I predominantly in Chinook salmon, and genotype II in all 6 fish species but dominant in coho salmon. Our findings of widespread, consistent host–parasite genotype patterns support the hypothesis that C. shasta has a long evolutionary history with salmonid fishes in the Pacific Northwest, and impels additional studies to determine if these parasite genotypes should be considered different species.
Task-Evoked Functional Connectivity Does Not Explain Functional Connectivity Differences Between Rest and Task Conditions

During complex tasks, patterns of functional connectivity (FC) differ from those in the resting state. What accounts for such differences remains unclear. Brain activity during a task reflects an unknown mixture of spontaneous activity and task-evoked responses. The difference in FC between a task state and resting state may reflect not only task-evoked connectivity, but also changes in spontaneously emerging networks. Here, we characterized the difference in apparent functional connectivity between the resting state and when human subjects were watching a naturalistic movie. Such differences were marginally (3-15%) explained by the task-evoked networks directly involved in processing the movie content, but mostly attributable to changes in spontaneous networks driven by ongoing activity during the task. The execution of the task reduced the correlations in ongoing activity among different cortical networks, especially between the visual and non-visual sensory cortices. Our results suggest that the interaction between spontaneous and task-evoked activities is not mutually independent or linearly additive, and that engaging in a task may suppress ongoing activity.
Interferon-stimulated TRIM69 interrupts dengue virus replication by ubiquitinating viral nonstructural protein 3

In order to eliminate viral infections, hundreds of interferon-stimulated genes (ISGs) are induced via type I interferons (IFNs). However, the functions and mechanisms of most ISGs are largely unclear. A tripartite motif (TRIM) protein encoding gene TRIM69 is induced by dengue virus (DENV) infection as an ISG. TRIM69 restricts DENV replication, and its RING domain, which has the E3 ubiquitin ligase activity, is critical for its antiviral activity. An in vivo study further confirmed that TRIM69 contributes to the control of DENV infection in immunocompetent mice. Unlike many other TRIM family members, TRIM69 is not involved in modulation of IFN signaling. Instead, TRIM69 interacts with DENV Nonstructural Protein 3 (NS3) directly and mediates its polyubiquitination and degradation. Finally, Lys104 of NS3 is identified as the target of TRIM69-mediated ubiquitination. Our study demonstrates that TRIM69 restricts DENV replication by specifically ubiquitinating a viral nonstructural protein.
Reduced Diabetes Mellitus-related Comorbidities by Regular Self-monitoring of Blood Glucose: Economic and Quality of Life Implications

Objectives: The objective of the study was to understand the role of self-monitoring of blood glucose (SMBG) for better management of glycemic fluctuations, reducing the risk of complications, and the associated cost benefits for diabetes patients in India. Materials and Methods: An Excel-based Cost Impact Model was developed to analyze the impact of SMBG by calculating the savings over a 10-year time period. A literature review was undertaken to model the impact of SMBG on the risk of complications and cardiovascular morbidities. The model was developed based on inputs from previous studies. Results: In the base case, SMBG cohort was associated with a 10-year discounted cost of INR 718,340, resulting in an estimated saving of INR 120,173 compared to no SMBG cohort. Implementation of a once-daily SMBG protocol, for a decade, can reduce the complication-related costs. More frequent SMBG and tri-monthly hemoglobin A1c tests along with lifestyle changes can significantly reduce the financial burden on the patient over the lifespan. Conclusion: Our study has shown that proactive management of diabetes with SMBG can improve treatment outcomes and reduce morbidity and mortality associated with this disease. Near-normal blood glucose levels can bring in cost savings in the form of reduced long-term complications and avoidance of repeated hospitalization for the management of such complications, along with an improved quality of life.