Miracle-dz/UniFAR-FTUs huggingface dataset:
Plasma Biomarkers in Alzheimer’s Disease

Biomarker study on dementia has developed widely. In applying biomarkers, there seems to be several utilizations such as presymptomaticand early-stage detection, differential diagnosis, and evaluation of treatment effect. Currently, most reliable fluid markers are amyloid peptide (Aβ) with microtubule-associated protein tau (TAU) and phosphorylated TAU (P-TAU) detected in cerebrospinal fluid (CSF). Aβ42 correlates with plaque pathology, TAU reflects the intensity of neuroaxonal degeneration, and PTAU may correlate with neurofibrillary tangle (NFT) pathology. An attenuation of the level of Aβ42 and elevation in the ratio of Aβ42 relative to the shorter major species of Aβ42 peptide with 40 amino acid residues (Aβ40) has been identified as significant events in the early stage of Alzheimer’s disease (AD) pathology. In addition, there is great interest in blood-based markers of AD since blood extraction is much less invasive. Moreover, plasma biomarkers can be measured at relatively low expense once a standard system of measurement is established. Although there is not yet an establish‐ ed or validated diagnostic test for plasma biomarkers, there is great interest in bloodbased markers. We will summarize reported biomarkers, describe our novel potential plasma biomarker for AD (annexin A5), offering a strategy for selecting candidates, and show our results and evaluation.
Bath Ankylosing Spondylitis Functional Index Shows Promising Reliability and Validity in the Assessment of Activity Limitations in Axial Spondyloarthritis

Objective. The Bath Ankylosing Spondylitis Functional Index (BASFI) is the most popular method to assess activity capacity in axial spondyloarthritis (axSpA), to our knowledge. It is endorsed by the Assessment of Spondyloarthritis international Society. But it may have recall bias or aberrant self-judgments in individual patients. Therefore, we aimed to (1) develop the instrumented BASFI (iBASFI) by adding a body-worn accelerometer with automated algorithms to performance-based measurements (PBM), (2) study the iBASFI’s core psychometric properties, and (3) reduce the number of iBASFI items. Methods. Twenty-eight patients with axSpA wore a 2-axial accelerometer while completing 12 PBM derived from the BASFI. A chronometer and both manual and “automated algorithm-based” acceleration segmentation identified movement time. Test-retest trials and methods (algorithm vs manual segmentation/chronometer/BASFI) were compared with ICC, standard error of measurement [percentage of movement time (SEM%)], and Spearman ρ correlation coefficients. Linear regression identified the optimal set of reliable iBASFI PBM. Results. Good to excellent test-retest reliability was found for 8/12 iBASFI items (ICC range 0.812–0.997, SEM range 0.4–30.4%), typically with repeated and fast movements. Automated algorithms excellently mimicked manual segmentation (ICC range 0.900–0.998) and the chronometer (ICC range 0.878–0.998) for 10/12 iBASFI items. Construct validity compared with the BASFI was
Distinct Roles of Estrogen Receptor-α and β in the Modulation of Vascular Inducible Nitric-Oxide Synthase in Diabetes

Estrogen is known to affect vascular function and diabetes development, but the relative contribution of estrogen receptor (ER) isoforms is unclear. The aim of this study was to determine how individual ER isoforms modulate inflammatory enzymes in the vascular wall of control and streptozotocin (STZ)-injected rodents. Primary cultures of rat aortic smooth muscle cells (SMCs) were stimulated with inflammatory agents in the presence or absence of increasing concentrations of the ERα and ERβ-selective agonists 4,4′,4′′-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and diarylpropionitrile (DPN), respectively. The production of inducible nitric-oxide synthase (iNOS), a classical indicator of vascular inflammation, was significantly reduced by PPT in control but not diabetic SMCs, whereas it was further enhanced by DPN treatment in both groups. This distinct action profile was not related to changes in ER transcriptional activity. However, extracellular signal-regulated kinase 1/2 signaling was activated by DPN but not by PPT in cytokine-treated SMCs. In cultured aortic rings from both normoglycemic and STZ-diabetic mice, pharmacological activation of ERα attenuated cytokine-driven iNOS induction by 30 to 50%. Vascular iNOS levels were decreased consistently when adding 1 nM 17β-estradiol to aortic tissues from ERβ- but not ERα-knockout mice. These findings suggest a possible role for ERα-selective ligands in reducing vascular inflammatory responses under normo- and hyperglycemic conditions.
Monoclonal gammopathy of renal significance (MGRS) increases the risk for progression to multiple myeloma: an observational study of 2935 MGUS patients

Purpose Monoclonal gammopathy of undetermined significance (MGUS) is a premalignancy preceding multiple myeloma (MM) or related disorders. In MGUS, renal impairment caused by deposition of the monoclonal immunoglobulins or free light-chains monoclonal gammopathy of renal significance (MGRS) is often associated with high morbidity and mortality. We analysed the prevalence of renal impairment, clinical features and the long-term outcome in 2935 patients with MGUS. Methods Between 1/2000 and 8/2016, 2935 adult patients with MGUS were identified in our database. Results In 44/2935 (1.5%) patients MGRS was diagnosed. In MGRS patients, significantly more progressions to MM were observed than in MGUS patients (18% vs. 3%; P<0.001). MGRS patients showed a higher risk for progression (HR 3.3 [1.5-7.4]) in the Cox model. Median time to progression was 23 years for MGUS and 18.8 years for MGRS patients. Corresponding progression rate was 8.8 [7.2-10.7] per 1000 patient-years (py) for MGUS patients and 30.6 [15.3–61] for the MGRS group. Risk for progression within the first year after diagnosis was 1% [0.6-1.4] in the MGUS group and 10% [4-29] among MGRS patients. Conclusion The significantly higher risk for progression to MM means MGRS patients should be monitored carefully and treated in a specialized centre.
Local amplification of highly pathogenic avian influenza H5N8 viruses in wild birds in the Netherlands, 2016 to 2017

Introduction Highly pathogenic avian influenza (HPAI) viruses of subtype H5N8 were re-introduced into the Netherlands by late 2016, after detections in south-east Asia and Russia. This second H5N8 wave resulted in a large number of outbreaks in poultry farms and the deaths of large numbers of wild birds in multiple European countries. Methods: Here we report on the detection of HPAI H5N8 virus in 57 wild birds of 12 species sampled during active (32/5,167) and passive (25/36) surveillance activities, i.e. in healthy and dead animals respectively, in the Netherlands between 8 November 2016 and 31 March 2017. Moreover, we further investigate the experimental approach of wild bird serology as a contributing tool in HPAI outbreak investigations. Results: In contrast to the first H5N8 wave, local virus amplification with associated wild bird mortality has occurred in the Netherlands in 2016/17, with evidence for occasional gene exchange with low pathogenic avian influenza (LPAI) viruses. Discussion: These apparent differences between outbreaks and the continuing detections of HPAI viruses in Europe are a cause of concern. With the current circulation of zoonotic HPAI and LPAI virus strains in Asia, increased understanding of the drivers responsible for the global spread of Asian poultry viruses via wild birds is needed.
Neural connections of the pretectum in zebrafish (Danio rerio)

The pretectum is a complex region of the caudal diencephalon which in adult zebrafish comprises both retinorecipient (parvocellular superficial, central, intercalated, paracommissural, and periventricular) and non‐retinorecipient (magnocellular superficial, posterior, and accessory) pretectal nuclei distributed from periventricular to superficial regions. We conducted a comprehensive study of the connections of pretectal nuclei by using neuronal tracing with fluorescent carbocyanine dyes. This study reveals specialization of efferent connections of the various pretectal nuclei, with nuclei projecting to the optic tectum (paracommissural, central, and periventricular pretectal nuclei), the torus longitudinalis and the cerebellar corpus (paracommissural, central, and intercalated pretectal nuclei), the lateral hypothalamus (magnocellular superficial, posterior, and central pretectal nuclei), and the tegmental regions (accessory and superficial pretectal nuclei). With regard to major central afferents to the pretectum, we observed projections from the telencephalon to the paracommissural and central pretectal nuclei, from the optic tectum to the paracommissural, central, accessory and parvocellular superficial pretectal nuclei, from the cerebellum to the paracommissural and periventricular pretectal nuclei and from the nucleus isthmi to the parvocellular superficial and accessory pretectal nuclei. The parvocellular superficial pretectal nucleus sends conspicuous projections to the contralateral magnocellular superficial pretectal nucleus. The composite figure of results reveals large differences in connections of neighbor pretectal nuclei, indicating high degree of nuclear specialization. Our results will have important bearings in functional studies that analyze the relationship between specific circuits and behaviors in zebrafish. Comparison with results available in other species also reveals differences in the organization and connections of the pretectum in vertebrates.
The T cell receptor‐mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems

The tyrosine kinase Pyk2 is vital for integrating receptor‐mediated signals controlling adhesion and motility in neuronal, epithelial, and hematopoietic cell types. In T cells, the stimulation of the TCR and costimulatory, chemokine, cytokine, and integrin receptors leads to the phosphorylation of Pyk2 and the induction of its catalytic activity. However, our understanding of the mechanism of the TCR‐induced, site‐specific phosphorylation of this kinase is incomplete and contradictory. To address this issue, the role of individual signaling pathways in the phosphorylation of Pyk2 tyrosines 402 and 580 upon TCR activation was assessed in human T cells. In contrast to other receptor systems, the TCR‐induced phosphorylation of Pyk2 tyrosines 402 and 580 was dependent on the Src family kinases, Fyn or Lck. Interestingly, the TCR‐mediated phosphorylation of Pyk2 tyrosines 402 and 580 did not require Ca2+ influx, ZAP‐70 activation, actin cytoskeleton rearrangement, or PI3K function. These observations are different than other receptor systems, which require the induction of one or more of these pathways. Together, these data have defined more fully the mechanism for the TCR‐induced phosphorylation of specific sites on Pyk2, suggesting that the TCR has a distinct pathway for the activation of Pyk2 compared with other receptor systems.
The Renin-Angiotensin System and Progression of Renal Disease: From Hemodynamics to Cell Biology

The renal community is faced with an ever increasing number of patients reaching end-stage renal failure. Clinical studies have provided clear evidence that angiotensin-converting enzyme (ACE) inhibitors, and probably also AT1 receptor antagonists, at least in patients suffering from type 2 diabetes, slow disease progression to end-stage renal failure. This protective effect of drugs interfering with the renin-angiotensin system (RAS) are in part independent of reduction in systemic blood pressure, but involve normalization of glomerular hyperperfusion and hyperfiltration, restoration of altered glomerular barrier function, and reduction of stimulated tubular fluid reabsorption. Angiotensin II (ANG II) has emerged in the last decade as a multifunctional cytokine exhibiting many non-hemodynamic properties such as acting as a growth factor and profibrogenic cytokine, and even having proinflammatory properties. This review tries to bridge the classical hemodynamic actions of ANG II in the kidney with the more recently characterized effects of this vasopeptide. Finally, clinical implications are suggested based on data from clinical studies. A thorough understanding of the RAS is important to recognize the potential of nephroprotective strategies through inhibition of its components.
Right Ventricular Outflow Tract Electroanatomical Abnormalities Predict Ventricular Fibrillation Inducibility in Brugada Syndrome

Electroanatomical mapping has demonstrated abnormal bipolar electrograms at the anterior aspect of the right ventricular outflow tract (RVOT) epicardium along with histopathologic evidence of fibrosis in patients with Brugada syndrome (BrS). 1,2 These epicardial abnormalities are believed to serve as the electric substrate for ventricular fibrillation (VF) initiation and maintenance in BrS.1,2 We have recently demonstrated that patients with BrS display wide areas of endocardial unipolar voltage abnormalities that possibly reflect epicardial structural abnormalities at the free wall of the RVOT.3 We hypothesized that electroanatomical abnormalities detected by high-density endocardial unipolar voltage mapping at the RVOT predict VF inducibility during programmed ventricular stimulation (PVS). The study population consisted of 17 asymptomatic probands (15 males, 37.3±10.8 years) with spontaneous type 1 BrS ECG pattern referred for risk stratification with PVS. A comprehensive evaluation including late gadolinium enhancement cardiac magnetic resonance imaging ruled out structural heart disease in all patients. The study was approved by the Hospital Ethics Committee and written informed consent was obtained from all patients. High-density electroanatomical mapping of the RVOT during sinus rhythm was performed as described previously (Methods in the Data Supplement). 3 In brief, a minimum of 800 points were sampled to …
Interface analysis of small GTP binding protein complexes suggests preferred membrane orientations

Abstract Crystal structures of small GTP binding protein complexes with their effectors and regulators reveal that one particularly flat side of the G domain that contains helix α4 and the C-terminal helix α5 is practically devoid of contacts. Although this observation seems trivial as the main binding targets are the switch I and II regions opposite of this side, the fact that all interacting proteins, even the largest ones, seem to avoid occupying this area (except for Ran, that does not localize to membranes) is very striking. An orientation with this ‘flat’ side parallel to the membrane was proposed before and would allow simultaneous interaction of the lipidated C-terminus and positive charges in the α4 helix with the membrane while being bound to effector or regulator molecules. Furthermore, this ‘flat’ side might be involved in regulatory mechanisms: a Ras dimer that is found in different crystal forms interacts exactly at this side. Additional interface analysis of GTPase complexes nicely confirms the effect of different flexibilities of the GTP and GDP forms. Besides Ran proteins, guanine nucleotide exchange factors (GEFs) bury the largest surface areas to provide the binding energy to open up the switch regions for nucleotide exchange.
Improving stability of PCA-based network anomaly detection by means of kernel-PCA

In the last years, the problem of detecting anomalies and attacks by statistically inspecting the network traffic has been attracting more and more research efforts. As a result, many different solutions have been proposed. Nonetheless, the poor performance offered by the proposed detection methods, as well as the difficulty of properly tuning and training these systems, make the detection of network anomalies still an open issue. In this paper, we face the problem by proposing a way to improve the performance of anomaly detection. In more detail, we propose a novel network anomaly detection method that, by means of kernel-PCA, is able to overcome the limitations of the 'classical' PCA-based methods, while retaining good performance in detecting network attacks and anomalies.
Short-term Repeat Magnetic Resonance Imaging Scans in Suspected Early Axial Spondyloarthritis Are Clinically Relevant Only in HLA-B27–positive Male Subjects

Objective. Our study investigated the natural history of magnetic resonance imaging (MRI)–determined bone marrow edema over a 12-week period in individuals with suspected axial spondyloarthritis. Methods. There were 109 MRI scans performed on 30 patients who fulfilled the Assessment of Spondyloarthritis international Society inflammatory back pain criteria at baseline and at 4, 8, and 12 weeks. Results. There were 29 patients who completed the study. Only 4 (14%) patients changed from MRI-negative to MRI-positive (all HLA-B27–positive, OR 2.74). Three of 7 (43%) male HLA-B27–positive patients, 1 of 8 (12.5%) HLA-B27–positive female patients, and no HLA-B27–negative patients changed from MRI- negative to -positive. Conclusion. Repeat MRI scans within a 12-week period should be considered in HLA-B27–positive males.
High cord signals on magnetic resonance and other factors predict poor outcomes of cervical spine surgery: A review

Background: High cord signals (HCS) on preoperative/postoperative T1, T1 gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), and T2 magnetic resonance (MR) studies, postoperative failure of HCS to regress and/or cord re-expansion, and a triangular cord configuration are poor prognostic factors for surgical patients with cervical spondylotic myelopathy (CSM). Methods: Here, we reviewed the negative prognostic import of high Grades/Types and more extensive locations of preoperative/postoperative HCS on T1, T1 Gd-DTPA, and T2 MR studies in surgical patients with CSM. Additional predictors of poor operative outcomes included postoperative failure of HCS to regress, cord re-expansion at the site of a HCS, and the triangular vs. teardrop or boomerang cord configuration. The Types/Grades of HCS on MR follow:Type/Grade 0 – no/absent signal changes; Type/Grade 1 – mild/light/fuzzy/obscure/low cord signal (LCS) changes; Type/Grade 2 – sharp/intense/well-defined HCS; and Type/Grade 3 – mixed/HCS. The definitions of location/extent of LCS/HCS were: focal (1 level), multifocal (with skip areas), and multisegmental (continuous over >1 segment), while cord configuration was categorized as triangular, teardrop, or boomerang. Results: On MR studies, preoperative/postoperative Types/Grades 0–1 changes correlated with better prognoses (e.g., improved Japanese Orthopedic Association (JOA) scores or Nurick Grades), while Types/Grades 2–3 correlated with poorer outcomes. Multiple poor prognostic indicators also included; failure of postoperative HCS on MR to regress (particularly if multisegmental), postoperative cord re-expansion at the site of a prior HCS, and triangular cord configuration. Conclusions: Grade/Types 2–3 HCS on T1, T1 Gd-DTPA, and T2-weighted MR images on preoperative/postoperative MR studies, failure of HCS to regress (multisegmental), cord re-expansion at the site of a prior HCS, and a triangular cord configuration (atrophy) all contributed to poorer outcomes for CSM surgery.
Textures and Rare Earth Elements Composition of Banded Iron Formations (BIF) at Njweng Prospect, Mbalam Iron Ore District, Southern Cameroon

The REE signature of banded iron formations (BIF) and martite-goethite mineralization of the Njweng ridge (South Cameroon) are used here to decipher the nature of the ocean during the period of BIF precipitation. The textures of typical BIF categories are also presented as the only sedimentary feature. Two types of BIF facies are present at Njweng: the oxide and silicate facies. These facies show two stages of phase transformations. The first is the transformation of the original magnetite mineral into martite by oxidation resulting in trellis texture; the second is a simultaneous transformation by hydration into goethite and dehydration into martite. The samples typically show LREE depleted patterns relative to HREE, a characteristic similar to that of modern seawater. Also the strong positive Eu anomalies from the samples indicate the involvement of hydrothermal plumes of volcanic origin such as at mid ocean ridges (MOR). Yttrium (Y) has a strong positive anomaly pointing to the transportation of REEs as aqueous complexes within these ancient seas. The BIF samples have no positive Ce anomalies, suggesting that the oceans at that time were more reducing with no Ce fractionation than in present day oceans. The martite-goethite mineralization rather shows a positive Ce anomaly that derived from the enrichment in REE during the weathering of REE-bearing minerals. These results are integrated into existing literature on REE in BIFs worldwide and provide new insights into these heretofore unstudied BIFs of the northern edge of the Congo Craton.
Phenotype and Function of Myeloid-Derived Suppressor Cells Induced by Porphyromonas gingivalis Infection

ABSTRACT Porphyromonas gingivalis, a major etiologic agent of periodontitis, has been reported to induce the expansion of myeloid-derived suppressor cells (MDSC); however, little is known regarding the subpopulations of MDSC expanded by P. gingivalis infection. Flow cytometry was used to evaluate bone marrow and spleen cells from mice infected with P. gingivalis and controls for surface expression of CD11b, Ly6G, and Ly6C. To characterize the phenotype of MDSC subpopulations induced by infection, cells were sorted based on the differential expression of Ly6G and Ly6C. Moreover, since MDSC are suppressors of T cell immune activity, we determined the effect of the induced subpopulations of MDSC on the proliferative response of OVA-specific CD4+ T cells. Lastly, the plasticity of MDSC to differentiate into osteoclasts was assessed by staining for tartrate-resistant acid phosphatase activity. P. gingivalis infection induced the expansion of three subpopulations of MDSC (Ly6G++ Ly6C+, Ly6G+ Ly6C++, and Ly6G+ Ly6C+); however, only CD11b+ Ly6G+ Ly6C++-expressing cells exerted a significant suppressive effect on T cell proliferation. Inhibition of proliferative responses required T cell-MDSC contact and was mediated by inducible nitric oxide synthase and cationic amino acid transporter 2 via gamma interferon. Furthermore, only the CD11b+ Ly6G+ Ly6C++ subpopulation of MDSC induced by P. gingivalis infection was able to differentiate into osteoclasts. Thus, the inflammatory response induced by P. gingivalis infection promotes the expansion of immune-suppressive cells and consequently the development of regulatory inhibitors that curtail the host response. Moreover, monocytic MDSC have the plasticity to differentiate into OC, thus perhaps contributing to the OC pool in states of periodontal disease.