Miracle-dz/UniFAR-FTUs huggingface dataset:
Defects in Axonal Transport in Inherited Neuropathies

Axonal transport is a highly complex process essential for sustaining proper neuronal functioning. Disturbances can result in an altered neuronal homeostasis, aggregation of cargoes, and ultimately a dying-back degeneration of neurons. The impact of dysfunction in axonal transport is shown by genetic defects in key proteins causing a broad spectrum of neurodegenerative diseases, including inherited peripheral neuropathies. In this review, we provide an overview of the cytoskeletal components, molecular motors and adaptor proteins involved in axonal transport mechanisms and their implication in neuronal functioning. In addition, we discuss the involvement of axonal transport dysfunction in neurodegenerative diseases with a particular focus on inherited peripheral neuropathies. Lastly, we address some recent scientific advances most notably in therapeutic strategies employed in the area of axonal transport, patient-derived iPSC models, in vivo animal models, antisense-oligonucleotide treatments, and novel chemical compounds.
Evaluating the preoperative breast cancer characteristics affecting the accuracy of axillary ultrasound staging

We evaluate the preoperative breast cancer (BC) characteristics that affect the diagnostic accuracy of axillary ultrasound (US) and determine the reliability of US in the different subgroups of BC patients. Axillary US assessments in women with invasive BC diagnosed between 2009 and 2016 in a single institution were retrospectively reviewed. The diagnostic accuracy of axillary US was obtained using surgical nodal histology as the gold standard. Preoperative breast tumor sonographic and histological factors affecting axillary US diagnostic accuracy were examined. Of the 605 newly diagnosed invasive BC cases reviewed, 251 (41.5%) had nodal metastases. Axillary US sensitivity was 75.7%, specificity 92.9%, positive predictive value 88.4%, negative predictive value 84.4%, and false‐negative rate 24.3%. Lower US sensitivity was seen with invasive lobular cancer (ILC) (P = .043), grade I/II, (P = .021), unifocal (P = .039), and smaller tumors (P < .001). US specificity was lower in grade III (P < .001), estrogen receptor (ER)‐negative (P < .001), progesterone receptor (PR)‐negative (P = .004), HER2‐positive (P = .015), triple‐negative (P = .001), and larger breast tumors (P < .001). US has moderate sensitivity and good specificity in detecting metastatic axillary lymph nodes. Based on preoperative cancer characteristics, US was less sensitive for nodal metastases from ILC, unifocal, lower grade, and smaller breast tumors. It was also less specific in grade III, ER‐negative, PR‐negative, HER2‐positive, triple‐negative, and larger breast tumors. Caution is suggested in interpreting the US axillary findings of patients with these preoperative tumor features.
Strong Signs for a Weak Wall in Tricuspid Aortic Valve Associated Aneurysms and a Role for Osteopontin in Bicuspid Aortic Valve Associated Aneurysms

Central processes in the pathogenesis of TAV- (tricuspid aortic valve) and BAV- (bicuspid aortic valve) associated ascending thoracic aortic aneurysm (ATAA) development are still unknown. To gain new insights, we have collected aortic tissue and isolated smooth muscle cells of aneurysmal tissue and subjected them to in situ and in vitro analyses. We analyzed aortic tissue from 78 patients (31 controls, 28 TAV-ATAAs, and 19 BAV-ATAAs) and established 30 primary smooth muscle cell cultures. Analyses included histochemistry, immuno-, auto-fluorescence-based image analyses, and cellular analyses including smooth muscle cell contraction studies. With regard to TAV associated aneurysms, we observed a strong impairment of the vascular wall, which appears on different levels—structure and dimension of the layers (reduced media thickness, increased intima thickness, atherosclerotic changes, degeneration of aortic media, decrease of collagen, and increase of elastic fiber free area) as well as on the cellular level (accumulation of fibroblasts/myofibroblasts, and increase in the number of smooth muscle cells with a reduced alpha smooth muscle actin (α-SM actin) content per cell). The pathological changes in the aortic wall of BAV patients were much less pronounced—apart from an increased expression of osteopontin (OPN) in the vascular wall which stem from smooth muscle cells, we observed a trend towards increased calcification of the aortic wall (increase significantly associated with age). These observations provide strong evidence for different pathological processes and different disease mechanisms to occur in BAV- and TAV-associated aneurysms.
NF-κB Dependent Chemokine Signaling in Pancreatic Cancer

Pancreatic cancer is one of the carcinomas with the worst prognoses, as shown by its five-year survival rate of 9%. Although there have been new therapeutic innovations, the effectiveness of these therapies is still limited, resulting in pancreatic ductal adenocarcinoma (PDAC) becoming the second leading cause of cancer-related death in 2020 in the US. In addition to tumor cell intrinsic resistance mechanisms, this disease exhibits a complex stroma consisting of fibroblasts, immune cells, neuronal and vascular cells, along with extracellular matrix, all conferring therapeutic resistance by several mechanisms. The NF-κB pathway is involved in both the tumor cell-intrinsic and microenvironment-mediated therapeutic resistance by regulating the transcription of a plethora of target genes. These genes are involved in nearly all scenarios described as the hallmarks of cancer. In addition to classical regulators of apoptosis, NF-κB regulates the expression of chemokines and their receptors, both in the tumor cells and in cells of the microenvironment. These chemokines mediate autocrine and paracrine loops among tumor cells but also cross-signaling between tumor cells and the stroma. In this review, we will focus on NF-κB-mediated chemokine signaling, with an emphasis on therapy resistance in pancreatic cancer.
Communicating Without Words: School-Based RCT Social Intervention in Minimally Verbal Peer Dyads with ASD

Despite their social withdrawal, school-age children with autism spectrum disorder who are minimally verbal (MVASD; i.e., use a limited repertoire of communicative spoken words) have received few interventions supporting peer engagement. This study examined efficacy of a novel ecological randomized controlled trial—school-based peer social intervention—designed to increase social engagement (via available communication channels) in school-age peer dyads with MVASD. Fifty-four children with MVASD (8–16 years) in 9 Israeli special education schools were randomly assigned to conversation intervention, collaboration intervention, or waitlisted treatment-as-usual (control) group (n = 18 per group). Manualized conversation and collaboration interventions each included 60 lessons (15 weeks × 4), implemented by teachers at school and supervised by researchers. Pretest–posttest improvement in spontaneous peer interaction was measured via 3 data sources/methods: teacher-reported social behavior (Vineland: Socialization domain) and direct observations of children’s spontaneous free play (Modified-Classroom Observation Schedule to Measure Intentional Communication) and free conversation (Social Conversation Scale). Allocation group was masked from reporters/coders. As secondary outcomes, children’s progress was measured in executive functions (BRIEF Inventory), and communication (Vineland). Significant pre–post improvement emerged for both intervention groups’ spontaneous free conversation and for the collaboration group’s spontaneous free play. Teacher reports, although mixed, indicated that the conversation group’s socialization skills improved, but communication did not. Children in the conversation group also improved their metacognitive executive skills (e.g., planning, monitoring, organization). Strengthening this high-risk school-age population’s ability to interact more spontaneously with peers through conversation and collaboration intervention holds promise for reducing social withdrawal in MVASD.
Genome-Wide Identification, Characterization and Expression Patterns of the Pectin Methylesterase Inhibitor Genes in Sorghum bicolor

Cell walls are basically complex with dynamic structures that are being involved in several growth and developmental processes, as well as responses to environmental stresses and the defense mechanism. Pectin is secreted into the cell wall in a highly methylesterified form. It is able to perform function after the de-methylesterification by pectin methylesterase (PME). Whereas, the pectin methylesterase inhibitor (PMEI) plays a key role in plant cell wall modification through inhibiting the PME activity. It provides pectin with different levels of degree of methylesterification to affect the cell wall structures and properties. The PME activity was analyzed in six tissues of Sorghum bicolor, and found a high level in the leaf and leaf sheath. PMEI families have been identified in many plant species. Here, a total of 55 pectin methylesterase inhibitor genes (PMEIs) were identified from S. bicolor whole genome, a more detailed annotation of this crop plant as compared to the previous study. Chromosomal localization, gene structures and sequence characterization of the PMEI family were analyzed. Moreover, cis-acting elements analysis revealed that each PMEI gene was regulated by both internal and environmental factors. The expression patterns of each PMEI gene were also clustered according to expression pattern analyzed in 47 tissues under different developmental stages. Furthermore, some SbPMEIs were induced when treated with hormonal and abiotic stress. Taken together, these results laid a strong foundation for further study of the functions of SbPMEIs and pectin modification during plant growth and stress responses of cereal.
Evidence for Production of Sexual Resting Cysts by the Toxic Dinoflagellate Karenia mikimotoi in Clonal Cultures and Marine Sediments

The toxic dinoflagellate Karenia mikimotoi has been well‐known for causing large‐scale and dense harmful algal blooms (HABs) in coastal waters worldwide and serious economic loss in aquaculture and fisheries and other adverse effects on marine ecosystems. Whether K. mikimotoi forms resting cysts has been a puzzling issue regarding to the mechanisms of bloom initiation and geographic expansion of this species. We provide morphological and molecular confirmation of sexually produced thin‐walled resting cysts by K. mikimotoi based on observations of laboratory cultures and their direct detection in marine sediments. Light and scanning electron microscopy evidences for sexual reproduction include attraction and pairing of gametes, gamete fusion, formation of planozygote and thin‐walled cyst, and the documentation of the thin‐walled cyst germination processes. Evidence for cysts in marine sediments was in three aspects: positive PCR detection of cysts using species‐specific primers in the DNA extracted from whole sediments; fluorescence in situ hybridization detection of cysts using FISH probes; and single‐cell PCR sequencing for cysts positively labeled with FISH probes. The existence of sexually produced, thin‐walled resting cysts by K. mikimotoi provides a possible mechanism accounting for the initiation of annually recurring blooms at certain regions and global expansion of the species during the past decades.
Breast Cancer Resistance Protein (BCRP/ABCG2) Inhibits Extra Villous Trophoblast Migration: The Impact of Bacterial and Viral Infection

Extravillous trophoblasts (EVT) migration into the decidua is critical for establishing placental perfusion and when dysregulated, may lead to pre-eclampsia (PE) and intrauterine growth restriction (IUGR). The breast cancer resistance protein (BCRP; encoded by ABCG2) regulates the fusion of cytotrophoblasts into syncytiotrophoblasts and protects the fetus from maternally derived xenobiotics. Information about BCRP function in EVTs is limited, however placental exposure to bacterial/viral infection leads to BCRP downregulation in syncitiotrophoblasts. We hypothesized that BCRP is involved in the regulation of EVT function and is modulated by infection/inflammation. We report that besides syncitiotrophoblasts and cytotrophoblasts, BCRP is also expressed in EVTs. BCRP inhibits EVT cell migration in HTR8/SVneo (human EVT-like) cells and in human EVT explant cultures, while not affecting cell proliferation. We have also shown that bacterial—lipopolysaccharide (LPS)—and viral antigens—single stranded RNA (ssRNA)—have a profound effect in downregulating ABCG2 and BCRP levels, whilst simultaneously increasing the migration potential of EVT-like cells. Our study reports a novel function of BCRP in early placentation and suggests that exposure of EVTs to maternal infection/inflammation could disrupt their migration potential via the downregulation of BCRP. This could negatively influence placental development/function, contribute to existing obstetric pathologies, and negatively impact pregnancy outcomes and maternal/neonatal health.
Myxozoan Adhesion and Virulence: Ceratonova shasta on the Move

Motility factors are fundamental for parasite invasion, migration, proliferation and immune evasion and thus can influence parasitic disease pathogenesis and virulence. Salmonid enteronecrosis is caused by a myxozoan (Phylum Cnidarian) parasite, Ceratonova shasta. Three parasite genotypes (0, I, II) occur, with varying degrees of virulence in its host, making it a good model for examining the role of motility in virulence. We compare C. shasta cell motility between genotypes and describe how the cellular protrusions interact with the host. We support these observations with motility gene expression analyses. C. shasta stages can move by single or combined used of filopodia, lamellipodia and blebs, with different behaviors such as static adhesion, crawling or blebbing, some previously unobserved in myxozoans. C. shasta stages showed high flexibility of switching between different morphotypes, suggesting a high capacity to adapt to their microenvironment. Exposure to fibronectin showed that C. shasta stages have extraordinary adhesive affinities to glycoprotein components of the extracellular matrix (ECM). When comparing C. shasta genotypes 0 (low virulence, no mortality) and IIR (high virulence, high mortality) infections in rainbow trout, major differences were observed with regard to their migration to the target organ, gene expression patterns and proliferation rate in the host. IIR is characterized by rapid multiplication and fast amoeboid bleb-based migration to the gut, where adhesion (mediated by integrin-β and talin), ECM disruption and virulent systemic dispersion of the parasite causes massive pathology. Genotype 0 is characterized by low proliferation rates, slow directional and early adhesive migration and localized, non-destructive development in the gut. We conclude that parasite adhesion drives virulence in C. shasta and that effectors, such as integrins, reveal themselves as attractive therapeutic targets in a group of parasites for which no effective treatments are known.
β2 Adrenergic Receptor Complexes with the L-Type Ca2+ Channel CaV1.2 and AMPA-Type Glutamate Receptors: Paradigms for Pharmacological Targeting of Protein Interactions.

Formation of signaling complexes is crucial for the orchestration of fast, efficient, and specific signal transduction. Pharmacological disruption of defined signaling complexes has the potential for specific intervention in selected regulatory pathways without affecting organism-wide disruption of parallel pathways. Signaling by epinephrine and norepinephrine through α and β adrenergic receptors acts on many signaling pathways in many cell types. Here, we initially provide an overview of the signaling complexes formed between the paradigmatic β2 adrenergic receptor and two of its most important targets, the L-type Ca2+ channel CaV1.2 and the AMPA-type glutamate receptor. Importantly, both complexes contain the trimeric Gs protein, adenylyl cyclase, and the cAMP-dependent protein kinase, PKA. We then discuss the functional implications of the formation of these complexes, how those complexes can be specifically disrupted, and how such disruption could be utilized in the pharmacological treatment of disease. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 60 is January 6, 2020. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Graphene Oxide and Graphene Reinforced PMMA Bone Cements: Evaluation of Thermal Properties and Biocompatibility

The incorporation of well-dispersed graphene oxide (GO) and graphene (G) has been demonstrated as a promising solution to improve the mechanical performance of polymethyl methacrylate (PMMA) bone cements in an attempt to enhance the long-term survival of the cemented orthopaedic implants. However, to move forward with the clinical application of graphene-based PMMA bone cements, it is necessary to ensure the incorporation of graphene-based powders do not negatively affect other fundamental properties (e.g., thermal properties and biocompatibility), which may compromise the clinical success of the implant. In this study, the effect of incorporating GO and G on thermal properties, biocompatibility, and antimicrobial activity of PMMA bone cement was investigated. Differential scanning calorimetry studies demonstrated that the extent of the polymerisation reaction, heat generation, thermal conductivity, or glass transition temperature were not significantly (p > 0.05) affected by the addition of the GO or G powders. The cell viability showed no significant difference (p > 0.05) in viability when MC3-T3 cells were exposed to the surface of G- or GO-PMMA bone cements in comparison to the control. In conclusion, this study demonstrated the incorporation of GO or G powder did not significantly influence the thermal properties or biocompatibility of PMMA bone cements, potentially allowing its clinical progression.
Travel Time Prediction using Machine Learning and Weather Impact on Traffic Conditions

The growth of Intelligent Traffic System (ITS) have recently been quite fast and impressive. Analysis and prediction of network traffic has become a priority in day to day planning in social, economic and more widespread set of areas. With a vision to further contribute to this vast field of research, we propose an approach to forecast level of traffic congestion on the basis of a time series analysis of collected data using machine learning. Moreover, the proposed approach allows us to find a correlation between varying parameter of weather and level of traffic congestion. Traffic data collected from Uber Movement for the city of Mumbai, India was fed to multiple of pre assessed machine learning algorithm. Comparative analysis of the results of the different machine learning algorithms used have shown us that logistic regression works best with an accuracy of 85% on the collected Uber data. Thus our model can accurately predict the time to travel between different nodes (locations) in Mumbai city based on the data collected from Uber Movement.
Sex differences in escalated methamphetamine self-administration and altered gene expression associated with incubation of methamphetamine seeking.

BACKGROUND Methamphetamine (METH) use disorder (MUD) is prevalent worldwide. There are reports ofsex differences in quantities of drug used and relapses to drug use among individuals with MUD. However, the molecular neurobiology of these potential sex differences remains unknown. METHODS We trained rats to self-administer METH (0. 1 mg/kg/infusion, IV) on a FR-1 schedule for 20 days using two 3-h daily METH sessions separated by 30 min breaks. At the end of self-administration (SA) training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 (WD3) and 30 (WD30). Twenty-four hours later, nucleus accumbens (NAc) was dissected and then used to measure neuropeptide mRNA levels. RESULTS Behavioral results show that male rats increased the number of METH infusions earlier during SA training and took more METH than females. Both male and female rats could be further divided into two phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH SA experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin (Pdyn) and hypocretin/orexin receptors (Hcrtr1/2) than males whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of NAc dynorphin after METH SA. Moreover, there were significant correlations between NAc Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. CONCLUSION Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.
Hearing consequences in Gjb2 knock-in mice: implications for human p.V37I mutation

Human p.V37I mutation of GJB2 gene was strongly correlated with late-onset progressive hearing loss, especially among East Asia populations. We generated a knock-in mouse model based on human p.V37I variant (c.109G>A) that recapitulated the human phenotype. Cochlear pathology revealed no significant hair cell loss, stria vascularis atrophy or spiral ganglion neuron loss, but a significant change in the length of gap junction plaques, which may have contributed to the observed mild endocochlear potential (EP) drop in homozygous mice lasting lifetime. The cochlear amplification in homozygous mice was compromised, but outer hair cells’ function remained unchanged, indicating that the reduced amplification was EP- rather than prestin-generated. In addition to ABR threshold elevation, ABR wave I latencies were also prolonged in aged homozygous animals. We found in homozygous IHCs a significant increase in ICa but no change in Ca2+ efficiency in triggering exocytosis. Environmental insults such as noise exposure, middle ear injection of KCl solution and systemic application of furosemide all exacerbated the pathological phenotype in homozygous mice. We conclude that this Gjb2 mutation-induced hearing loss results from 1) reduced cochlear amplifier caused by lowered EP, 2) IHCs excitotoxicity associated with potassium accumulation around hair cells, and 3) progression induced by environmental insults.