Miracle-dz/UniFAR-FTUs huggingface dataset:
Aberrant early endosome biogenesis mediates complement activation in the retinal pigment epithelium in models of macular degeneration

Significance The first lines of communication between cells and the environment are early endosomes, which sort incoming cargo to regulate cell health. Endosomal abnormalities are seen in neurodegenerative diseases, yet the molecular mechanisms remain obscure. Here, using human donor cells and disease models, we demonstrate that excess ceramide promotes expansion of early endosomes in the retinal pigment epithelium (RPE), a primary site of injury in Stargardt and age-related maculopathies. Complement C3 uptake into enlarged endosomes and subsequent cleavage is associated with abnormal mechanistic target of rapamycin activity. Decreasing ceramide using Food and Drug Administration-approved drugs corrects endosomal defects and prevents C3 activation. Our studies establish how organelles modulate RPE complement activity, and identify ceramide as a drug target for macular degenerations. Abnormally enlarged early endosomes (EEs) are pathological features of neurodegenerative diseases, yet insight into the mechanisms and consequences of EE expansion remains elusive. Here, we report swollen apical EEs in the retinal pigment epithelium (RPE) of aged human donors and in the pigmented Abca4−/− mouse model of Stargardt early-onset macular degeneration. Using high-resolution live-cell imaging, we show that age-related and pathological accumulation of lipofuscin bisretinoids increases ceramide at the apical surface of the RPE, which promotes inward budding and homotypic fusion of EEs. These enlarged endosomes internalize the complement protein C3 into the RPE, resulting in the intracellular generation of C3a fragments. Increased C3a in turn activates the mechanistic target of rapamycin (mTOR), a regulator of critical metabolic processes such as autophagy. The antidepressant desipramine, which decreases ceramide levels by inhibiting acid sphingomyelinase, corrects EE defects in the RPE of Abca4−/− mice. This prevents C3 internalization and limits the formation of C3a fragments within the RPE. Although uncontrolled complement activation is associated with macular degenerations, how complement contributes to pathology in a progressive disease is not well understood. Our studies link expansion of the EE compartment with intracellular complement generation and aberrant mTOR activation, which could set the stage for chronic metabolic reprogramming in the RPE as a prelude to disease. The pivotal role of ceramide in driving EE biogenesis and fusion in the Abca4−/− mice RPE suggests that therapeutic targeting of ceramide could be effective in Stargardt disease and other macular degenerations.
Tau protein aggregation is associated with cellular senescence in the brain

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI), and over twenty others. Tau‐containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss (Arriagada, Growdon, Hedley‐Whyte, & Hyman, ), yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis (de Calignon, Spires‐Jones, Pitstick, Carlson, & Hyman, 2009), which suggests that secondary mechanisms are driving toxicity. Transcriptomic analyses of NFT‐containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction. Using four AD transgenic mouse models, we found that NFTs, but not Aβ plaques, display a senescence‐like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late‐stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.
Movement Notation Revisited: Syntax of the Common Morphokinetic Alphabet (CMA) System

Advances in the study of non-verbal behavior and communication have generated a need for movement transcription systems capable of incorporating continuous developments in visual and computer technology. Our research team has been working on the construction of a common morphokinetic alphabet (CMA) for the systematic observation of daily life activities. The project, which was launched several years ago, was designed to create a system for describing and analyzing body motion expression, physical activity, and physical appearance. In this paper, we describe an idiosyncratic application of Noam Chomsky’s phrase marker grammar to the morphokinetic phrase, the objective being to establish the grammatical rules and basic order of the symbol string according to a relational tree formed by the breakdown of the syntactic components identified as structuring the visual description of movement. Criteria for using the CMA as a coding system and a free transcription system are proposed.
A New Microstrip Bandstop Filter for Fully Canonical Cul-de-Sac Coupling Configuration

A new microstrip fully canonical Nth-order Cul-de-Sac coupling bandstop filter (BSF) is proposed in this paper. A Cul-de-Sac coupling matrix based BSF design allows to provide an equiripple stopband response with reflection zeros at passbands, keeping a constant filter length regardless of filter order. However, such a coupling configuration of BSF has not been physically realized yet in a single-layer microstrip structure. The proposed BSF structure is simply formed by the parallel arrangement of even- and odd-mode half-wavelength resonators with respect to a through line connecting input and output ports, which makes it easier to design a higher-order BSF than conventional planar configurations. The effectiveness of the proposed BSF is demonstrated through the design of a 2-GHz, 2%-bandwidth, third-order Cul-de-Sac coupling BSF having three RZs. A sharp cutoff response because of three RZs is numerically and experimentally achieved by the proposed BSF.
Evaluation of wearable IMU performance for orientation estimation and motion tracking

Introducing objective wearable IMU measurements of functional movement quality into clinical assessments may improve accuracy of diagnosis. The goal of the present study was to assess the performance of inexpensive wearable IMUs relative to conventional motion capture equipment during controlled movements that are representative of typical human movement. Thirty-five cycles of spine flexion-extension, lateral bending, and axial twisting were simulated by means of a motorized gimbal at speeds of 20 cycles/min and 40 cycles/min. Differences between cycle-to-cycle maximum angle, minimum angle, and ROM values, as well as correlational analyses within IMUs and between IMUs and motion capture, in all movement directions, were compared. All absolute differences in measurements were < 1.55°. There were very high correlations between repeated IMU measures (R > 0.99) in all movement directions showing reliability between sensors and measurements. Overall, it was revealed that the sensors perform very well in the primary movement direction and one secondary axis; however, correlation in the third axis is suboptimal for orientation estimation and motion tracking.
A Visual Evaluation Study of Graph Sampling Techniques

We evaluate a dozen prevailing graph-sampling techniques with an ultimate goal to better visualize and understand big and complex graphs that exhibit different properties and structures. The evaluation uses eight benchmark datasets with four different graph types collected from Stanford Network Analysis Platform and NetworkX to give a comprehensive comparison of various types of graphs. The study provides a practical guideline for visualizing big graphs of different sizes and structures. The paper discusses results and important observations from the study.
Ectopic Expression of SjCBL1, Calcineurin B-Like 1 Gene From Sedirea japonica, Rescues the Salt and Osmotic Stress Hypersensitivity in Arabidopsis cbl1 Mutant

Extensive studies with Arabidopsis thaliana suggested that calcineurin B-like (CBL) proteins constitute a unique family of calcium sensors in plants, which mediate a variety of abiotic stress responses. However, little is known about their function in most plants that do not have available genome sequences. In this study, we have developed a pair of universal primers that make it possible to isolate CBL1-like genes from various plants without sequence information. Using these primers, we successfully cloned a full-length cDNA of CBL1-like gene in Sedirea japonica (SjCBL1). Bimolecular fluorescence complementation (BiFC) and pull-down assays demonstrated that like Arabidopsis CBL1 (AtCBL1), SjCBL1 can interacts physically with Arabidopsis CBL-interacting protein kinase 1 (AtCIPK1) at the plasma membrane of plant cells in a Ca2+-dependent manner. In addition, overexpression of SjCBL1 in the Arabidopsis cbl1 mutant resulted in not only rescuing the hypersensitive phenotype toward salt and osmotic stresses, but also substantially enhancing the tolerance to them. Taken together, these results strongly suggest that SjCBL1 is a functional ortholog of AtCBL1 in Sedirea japonica, which can play a critical role in response to salt and osmotic stresses. Therefore, it is clear that our findings should significantly contribute to broadening and deepening our understanding of the CBL1-mediated Ca2+ signaling networks in the plant kingdom.
Data Breaches: User Comprehension, Expectations, and Concerns with Handling Exposed Data

Data exposed by breaches persist as a security and privacy threat for Internet users. Despite this, best practices for how companies should respond to breaches, or how to responsibly handle data after it is leaked, have yet to be identified. We bring users into this discussion through two surveys. In the first, we examine the comprehension of 551 participants on the risks of data breaches and their sentiment towards potential remediation steps. In the second survey, we ask 10,212 participants to rate their level of comfort towards eight different scenarios that capture real-world examples of security practitioners, researchers, journalists, and commercial entities investigating leaked data. Our findings indicate that users readily understand the risk of data breaches and have consistent expectations for technical and non-technical remediation steps. We also find that participants are comfortable with applications that examine leaked data—such as threat sharing or a “hacked or not” service—when the application has a direct, tangible security benefit. Our findings help to inform a broader discussion on responsible uses of data exposed by breaches.
Error analysis of applicator position for combined internal/external radiation therapy in cervical cancer

The aim of this study was to analyze the error variation in the applicator placement during the first and second radiotherapy session for cervical cancer. We recruited 22 patients with cervical cancer treated with radiotherapy. According to the image output in the first and second CT-Sim inspection, we conducted comparative analysis of image fusion to accurately measure the errors in applicator position in the horizontal (X-), longitudinal (Y-) and vertical (Z)-axes. The calibration processing was implemented in accordance with the data error measured and the location parameters, such as the angle and depth of the applicator. Electronic portal imaging technology (EPID) was used to calibrate posture change amplitude for the extracorporeal irradiation of patients, and dynamic measurement with applicator position was used to describe the error of the parameters. Finally, the data from two measurements in CT-Sim, digital reconstruction radiography (DRR) and EPID were compared. After calibration, the mean value of error of the applicator were significantly smaller. Image registration planning for error parameter calibration of applicator position can effectively reduce the applied horizontal spatial position error in radiotherapy treatment, and improve the accuracy and effectiveness during treatment.
Multilocus molecular systematics of the circumtropical reef-fish genus Abudefduf (Pomacentridae): history, geography and ecology of speciation

We investigated a pantropical sub-family and genus of damselfishes, the sergeant-majors (Pomacentridae: Abudefdufinae: Abudefduf), to identify the tempo and mechanisms of speciation in the lineage. We examined sequence capture data from 500 loci and 20 species, with multiple individuals sampled from across the geographic ranges of widespread species. Utilizing a maximum likelihood framework, as well as a time-calibrated Bayesian phylogeny, the following key questions are addressed: What is the historical tempo of speciation? What are the relative contributions of vicariant, peripatric and parapatric speciation to sergeant-major diversity? How is speciation related to major variation in trophic ecology? The approximately 20 species of sergeant-majors fall into three main lineages. The ancestral condition appears to be benthivory, which is predominant in two lineages comprising six species. The remaining species of sergeant-majors, of which there are at least 15, fall within a clade composed entirely of planktivores. This clade is sister to a benthivore clade that included one species, Abudefduf notatus, in transition to planktivory. Most speciation of sergeant-majors, which appeared ∼24 million years ago, occurred in the last 10 million years. Present distributional patterns indicate vicariant speciation precipitated by the closure of land barriers between both sides of the Atlantic and the Pacific, and the emergence of land between the Indian and Pacific Oceans. Within this backdrop, frequent oscillations in sea level over the last 10 million years also appear to have generated conditions suitable for both peripatric and vicariant speciation, and most speciation within the genus appears linked to these changes in sea level. Diversification within the genus has been concentrated in planktivorous seargeant-majors rather than benthivores. The root cause is unclear, but does not appear to be related to differences in dispersal potential, which is greater in the planktivorous species, due to the ability of their post-larval juveniles to raft with floating debris. This elevated speciation rate in planktivores and their propensity to form local endemics may reflect relaxation of selective pressures (e.g., on crypticity) that limit speciation in benthivorous sergeant-majors. Finally, our data allow us to clarify relationships of geminate sergeant-major species, indicating that there are subdivisions within the Atlantic for both benthivore and planktivore geminate pairs that may have misled previous studies.
The C-Band HySIC RF Energy Harvester Based on the Space Information, Communication and Energy Harvesting Technology

In this paper, novel ICs made by different types of semi-conductors as the hybrid semiconductor integrated circuit, HySIC, are introduced. A C-band compact full Si rectifier and a HySIC RF rectifier operating at 5.8 GHz were described using 0. 18μm Si CMOS process and chip-to-wafer bonding. From them, RF -DC conversion efficiencies were measured as about 25% and 10%, respectively. Further, a wide power-range HySIC RF energy harvester by combining the rectifiers implemented on the Si substrate was made and the fundamental data were successfully obtained
A randomised placebo-controlled double-blind trial to assess the safety of intramuscular administration of allogeneic mesenchymal stromal cells for digital ulcers in systemic sclerosis: the MANUS Trial protocol

Introduction Systemic sclerosis (SSc) is an autoimmune disease characterised by inflammation, fibrosis and vasculopathy. Digital ulcers (DUs) are a frequent manifestation of vasculopathy in patients with SSc. Despite recent advances in pharmacological treatments, DU still have major health and economic implications. As there is currently no proven therapeutic strategy to promote DU healing, new treatments are urgently needed. Mesenchymal stem or stromal cells (MSCs) may provide a novel therapy for DU in SSc, because of their immunomodulatory and vasculoregenerative properties. Allogeneic MSC therapy involves functionally competent MSCs from healthy donors and may be used as ‘off-the-shelf’ available treatment. This study will evaluate whether allogeneic MSC therapy is a safe and potentially efficacious treatment for DU of SSc. Methods and analysis The MANUS (Mesenchymal stromal cells for Angiogenesis and Neovascularization in digital Ulcers of Systemic Sclerosis) Trial is a double-blind randomised placebo-controlled trial. 20 patients with SSc with refractory DU will be randomised to receive eight intramuscular injections with either placebo or 50*106 MSCs. The primary outcome is the toxicity of the treatment at 12 weeks after administration. Secondary outcomes include (serious) adverse events, number and time to healing of DU, pain, reported hand function, quality of life and SSc disease activity. We will also evaluate changes in nailfold capillaroscopy pattern, as well as biochemical parameters and biomarkers in peripheral blood and skin biopsies. Follow-up visits will be scheduled at 48 hours and 2, 4, 8, 12, 24 and 52 weeks post-treatment. If the results confirm safety, feasibility and potential efficacy, a large multicentre randomised controlled trial with longer follow-up will be initiated focusing on efficacy. Ethics and dissemination The study has been approved by the Dutch Central Committee on Research Concerning Human Subjects (protocol no: NL51705.000.15). The results will be disseminated through patient associations and conventional scientific channels. Trial registration number NCT03211793; Pre-results.
Treatment patterns, health care resource utilization and costs of rheumatoid arthritis patients in Italy: findings from a retrospective administrative database analysis

Objectives This study aimed to: 1) describe treatment patterns and drug utilization profile (in terms of therapeutic strategy used, switch, persistence and drug consumption variation) among adult patients affected by rheumatoid arthritis (RA), and 2) estimate the health care resource utilization and its associated direct cost for the management of RA patients. Methods A retrospective cohort analysis, using administrative databases of six Local Health Units in Italy, was performed. All adult patients with a confirmed diagnosis of RA between January 1, 2010 and December 31, 2014 were enrolled. The date of the first RA diagnosis according to the study criteria during the study period represented the index date (ID) for each patient. Patients enrolled were observed from the ID for at least 12 months (follow-up period), and their clinical characteristics were investigated for 12 months prior to the ID. Results A total of 10,401 patients with a confirmed RA diagnosis were included. Mean age was 63.0 years and 25% were male; 67% of patients were untreated at ID. During the followup period, 67.8% of patients treated with biologic agents were persistent with initial therapy, compared to 45.7% for patients on conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), while 11% of patients treated with biologic agents switched during the follow-up period, compared to 17.6% of csDMARDs-treated ones. At the end of the follow-up period, 14.7% of all patients in the analysis had an increase and 12.6% of them had a decrease in their initial drug consumption. The mean cost per RA patient was €3,743. Conclusion Our study showed that there is still much that needs to be learned about the prescription of csDMARDs and biologics to RA patients in Italy and to identify areas for future research. The knowledge of RA management in a real-life clinical setting could offer an opportunity to improve the management of RA in Italy.
Epidemiology and biology of cutaneous human papillomavirus

Cutaneous human papillomaviruses (HPVs) include β- and γ-HPVs, in addition to a small fraction of α-HPVs. β-HPVs were first isolated from patients with the rare genetic disorder Epidermodysplasia verruciformis, and they are associated with the development of nonmelanoma skin cancer at sun-exposed skin sites in these individuals. Organ transplant recipients also have greater susceptibility to β-HPV infection of the skin and an increased risk of developing nonmelanoma skin cancer. In both immunosuppressed and immunocompromised individuals, cutaneous HPVs are ubiquitously disseminated throughout healthy skin and may be an intrinsic part of the commensal flora. Functional analysis of E6 and E7 proteins of specific cutaneous HPVs has provided a mechanistic comprehension of how these viruses may induce carcinogenesis. Nevertheless, additional research is crucial to better understand the pathological implications of the broad distribution of these HPVs.
Microsatellite marker development for the tetraploid Veronica aragonensis (Plantaginaceae) using next‐generation sequencing and high‐resolution melting analyses

Premise of the Study The tetraploid Veronica aragonensis (Plantaginaceae) is a narrow endemic to the Iberian Peninsula. Specific microsatellite markers were developed to investigate genetic structure and diversity. Methods and Results A total of 15 polymorphic markers were characterized on three populations of V. aragonensis, using a microsatellite‐enriched library on an Ion Torrent sequencer and high‐resolution melting (HRM) analyses to rapidly discard nonreliable, multicopy, and/or monomorphic loci. Allele number per locus ranged from one to five, and levels of observed heterozygosity per population varied from 0.142 ± 0.301 to 0.281 ± 0.369. Most primers also amplified in the closely related species V. rosea and in three subspecies of V. tenuifolia. Conclusions The species‐specific microsatellite markers developed here represent an essential tool to provide genetic information on the population level for V. aragonensis. The low levels of variation detected highlight the importance of continued efforts to improve conservation of the species.